Biophysics and Neurophysiology of the Sixth Sense Biophysics and Neurophysiology of the Sixth Sense Nima Rezaei • Amene Saghazadeh Editors

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Nima Rezaei · Amene Saghazadeh Editors Biophysics and Neurophysiology of the Sixth Sense Biophysics and Neurophysiology of the Sixth Sense Nima Rezaei • Amene Saghazadeh Editors

Biophysics and Neurophysiology of the Sixth Sense Editors Nima Rezaei Amene Saghazadeh Research Center for Molecular Immunology Research Immunodeficiencies, Children’s Medical Center, Children’s Medical Center Center, Tehran University of Medical Sciences Tehran University of Medical Sciences Tehran, Iran Tehran, Iran MetaCognition Interest Group (MCIG) Department of Immunology, School of Universal Scientific Education and Medicine, Research Network (USERN) Tehran University of Medical Sciences Tehran, Iran Tehran, Iran Systematic Review and Meta-analysis Expert Group (SRMEG) Universal Scientific Education and Research Network (USERN) Tehran, Iran

ISBN 978-3-030-10619-5 ISBN 978-3-030-10620-1 (eBook) https://doi.org/10.1007/978-3-030-10620-1

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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface

Let’s start with your eyes and ears. If right now we want to test your sense of vision or hearing, it would be sufficient to ask, “What colors can you see and do you hear my voice? But if we want to test your sixth sense, the simplest solution is to ask yourself: “From 0 to 10 how would you rate your sixth sense?” After seconds of confusion, you may smile and answer me in this way: “What exactly do you mean by that?” Yes; you will put a fake smile on your face, a fake smile which means, “You speaking about that multitasking sense which my mind could never understand—its mechanism of operation, right?” We have always been interested in this all-nothing sense. Such that for marketing purposes, scientists thought to name human-machine interfaces/technologies invented to improve the weak or deficient human senses as the sixth sense. Since Aristotle, more than ten senses have been discovered in humans. The sixth sense and its definition has remained a secret to the human awareness. Which one is running away from the other: the sixth sense from the human awareness or the human awareness from the sixth sense? If you are unable to find the answer until the end of this Preface, then you should promise yourself to read the whole book. The story begins from here; if it remained without definition means that mean it does not exist? Never! The first scene All you have experienced when your head is down and feel someone is looking you, then you lift up your head and you find out who it was! This feeling is not a sense of vision, hearing, or among ten to eleven senses defined for humans. But it is only an effect of our sixth sense. So, hereby, you are informed that the sixth sense does exist. From the Universe! The second scene It brings us into the physics classroom when we were about 13 years old and learned that each process that causes the electrons to revolve is accompanied by induction of an electromagnetic field. For example, sensory information processing. In fact, the vibration of electromagnetic fields in different states of matter (solid, fluid, and gas) is the thing that we can sense. Taking the sense of smell, the matter is air and olfactory nerves transfer vibration of electromagnetic fields to the brain. In the same manner, we can see, hear, taste, and touch. A question

v vi Preface arises: does vibration only occur in matters which we are physically aware of? Definitely not! There are wavelengths below and above those that my eyes can see and there are wave frequencies below and above those that your ears can hear. Finally, there is a dark matter that contains more than fivefold mass-energy compared to the matter you and I live on and vibration occurs in both matters. To sum up, vibrations in the range of known senses makes me aware of Sunday, 20th March 2018, at 3 p.m., the Children’s Medical Center, Tehran. While vibrations beyond the range of known senses, i.e., the sixth sense, makes me aware of other spatiotemporal reality. Future or past does not matter. Far or near does not matter. The third scene At 10:20 a.m., Anissa’s mother suddenly feels worried about Anissa. Anissa comes home at 12 p.m. and her mother notices a new ulcer on Anissa’s knee. The mother calls the school and assistant superintendent of the school says that around the third bell at 10:20 a.m. when Anissa was playing, she fell and her knee was bruised. This indicates the transmission of vibration of electromagnetic fields from Anissa’s school to home. Yes; vibration can travel through a phenomenon named resonance. Again let us provide a simple example of the school physics: resonant pendulums, where applying an external force to a pendulum makes other pendulums to oscillate. One pendulum receives an external signal and other pendulums show the effect of that signal. Anissa is injured and her mother will be worried. The fourth scene How would resonance of vibrating electromagnetic fields influence the brain? There are two main effects that resonating electromagnetic fields might have on the brain. First, it can cause spatiotemporally distant brain networks to be effectively synched together. Synchronization can be easily realized when cars with different speeds and from different origins come up to a traffic jam. Drivers should harmonize the speed of their car with that of others. Second, resonance makes weak electromagnetic fields become stronger so that the brain can evoke responses to related stimuli. This resonance can be touched when a child is swinging; if you exert a force toward the front, the swinging speed is increased and the child will be happy. The fifth scene Ok! Agree! There is a sixth sense and physical matter inside and outside the body are conducting this sense. Tell me how I can manage it? The effect of the sixth sense that someone sends a signal and someone delivers that signal while they are far from each other remembers me of the quantum tunneling, when the quantum state tunnels from a particle into another particle while particles are distant from each other and are not penetrable. According to the principle of quantum tunneling, the less the particle is coupled to the environment, the more likely the quantum state will be transferred. Of course, there should be a minimum coupling to the environment. The sixth scene How can I manage the coupling of the brain to the environment? Should I sleep? Should I be comatose? Or should I die? No; you can reduce the coupling of your brain right now when you are awake and your eyes are open. Listen to me! You think that I’m devoting all my mind and heart to how to end this Preface vii speech. While my mind and heart are mostly involved in thinking of Friday, 27th April 2018, 11 p.m. Yes; I mean that the key of coupling to the environment is your thoughts. In this manner, the sixth sense provides you relative awareness of other spatiotemporal reality instead of leaving the absolute awareness of present spatiotemporal reality. You see in dreams that he has called you. Then, you will awake and check your phone and he has called. This relative awareness may be that what makes the power of the human brain exceeding that of the animal brain and even from that of the robotic brain. Robots which are supposed to be “so intelligent that we will be lucky if they are willing to keep us around the house as household pets”, according to Marvin Minsky at MIT. The above was a string of relations to the reality of sixth sense we had the opportunity to present that in a 6-minute speech on 20th March 2018 in the Children’s Medical Center, Tehran, Iran, as a part of Universal Scientific Education and Research Network (USERN) miniature Talk (mTalk). The topic of the speech was “The Sixth Sense: When the Brain and the Physical Environment Are United”. You can find numerous strings throughout the book! We hope that the book would be welcomed by all scientists who are curious to know more about the sixth sense. We tried to provide an evidence-based text on what has been discussed and challenged in this field.

Tehran, Iran Nima Rezaei Amene Saghazadeh Contents

1 What Would Happen If Humans Live Beyond Time? �� 1 Nima Rezaei and Amene Saghazadeh 2 Neurophysiology of Visual Perception �� 13 Mahsa Mayeli 3 Biophysics of Vision �� 27 Shima Shahjouei and Mahmoodreza Amini 4 Cortex, Insula, and Interoception �� 59 Maryam Rahmani and Farzaneh Rahmani 5 Interoceptive Dysfunction �� 69 Reihaneh Dehghani and Farnaz Delavari 6 The Proprioceptive System �� 85 Pejman Jooya and Farnaz Delavari 7 Extrasensory Perception: Concept and History �� 99 John Nwanegbo-Ben 8 A Psychological Perspective on Extrasensory Perception �� 107 Wenge Huang 9 The Mental Burden of Immunoperception �� 111 Amene Saghazadeh, Sina Hafizi, and Nima Rezaei 10 The Physical Burden of Immunoperception �� 137 Amene Saghazadeh and Nima Rezaei 11 The Immunoemotional Regulatory System �� 155 Amene Saghazadeh and Nima Rezaei 12 Fuzzy Sets: Application to the Sixth Sense �� 179 Amene Saghazadeh and Nima Rezaei

ix x Contents

13 Asymmetry: Extra Sparkle to the Sixth Sense? �� 191 Amene Saghazadeh and Nima Rezaei 14 Synchronization Side of the Sixth Sense Story �� 195 Amene Saghazadeh 15 The Sixth Sense: Let Your Mind Go to Sleep �� 199 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei 16 Dreams Tell the Brain True Stories �� 211 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei 17 Follow Aura and Find the Sixth Sense �� 217 Amene Saghazadeh and Nima Rezaei 18 An Evolutionary Perspective of the Sixth Sense �� 225 Amene Saghazadeh and Nima Rezaei 19 The Sixth Sense: Symphony of Spooky Actions �� 231 Amene Saghazadeh and Nima Rezaei 20 The Sixth Sense Organs: The Immune System �� 235 Amene Saghazadeh and Nima Rezaei 21 The Sixth Sense Organs: The Heart �� 243 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei 22 The Sixth Sense Organs: The Gut �� 251 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, Maryam Mahmoudi, and Nima Rezaei 23 The Sixth Sense Organs: The Eyes �� 257 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei 24 The Sixth Sense Organs: The Ears �� 267 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei 25 The Sixth Sense Organs: The Hands �� 273 Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei 26 Stem Cells Have More Than Five Senses �� 289 Amene Saghazadeh, Reza Khaksar, and Nima Rezaei 27 Intuition and Food Preferences �� 305 Amene Saghazadeh, Reza Khaksar, Maryam Mahmoudi, and Nima Rezaei Contents xi

28 More than a Chance �� 315 Amene Saghazadeh and Nima Rezaei 29 Learning the Sixth Sense �� 319 Amene Saghazadeh, Reza Khaksar, and Nima Rezaei 30 Neurocircuitry of Intuition �� 329 Amene Saghazadeh, Farzaneh Rahmani, and Nima Rezaei 31 Gut Feelings in Practice �� 339 Nima Rezaei and Amene Saghazadeh 32 The Manager’s Sixth Sense: An Art in Organizational, Educational, Moral, and Expert Thinking �� 345 Amene Saghazadeh, Reza Khaksar, and Nima Rezaei

Index �� 351 Chapter 1 What Would Happen If Humans Live Beyond Time?

Nima Rezaei and Amene Saghazadeh

Abstract Thoughts on the future events have enormous potential to affect the way we act now. Therefore, the accuracy of our predictions of the future would be reflected in the adequacy of our current actions in order to achieve our goals. Research led to recognition of some potential factors, in particular, the temporal proximity of the target event, which might influence our estimations of future events. Interestingly, all such factors converge on one point, which is the limitation of information that the conscious brain can process. Given the prominence of unconscious thought to gather and process information than conscious thought, it is proposed that unconscious thinking may promote the quality of prospection by overcoming artifacts from consciousness, thereby providing more accurate estimations of the future. Here, the term conscious/unconscious prospection is defined as the degree of belief in/freedom from the present time. In an attempt to provide a framework for the hypothesis of conscious → unconscious prospection (CUP), the principles of unconscious thought theory and information-integration theory along with the mechanism of action of default-mode network (DMN) are used. The chapter presents evidence of how through which—the mainstream moving from conscious thought towards the unconscious thought—the probability of the secondary information integration and therefore the accuracy of prospective thinking will be increased.

N. Rezaei (*) Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran e-mail: [email protected] A. Saghazadeh Molecular Immunology Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Keywords Information integration · Conscious · Unconscious · Beyond time

Introduction

The real world is much smaller than the imaginary – Friedrich Nietzsche

‘Nima Rezaei’: “Not long ago, I was asked in advance to attend the matter as scheduled for Tuesday, May 19, 2015, at 3 pm. at the Tehran University of Medical Sciences on Avicenna Hall. The subject matter was Medicine, The Infinite Way. Medical students are either consciously or unconsciously absorbed in worries and anxieties about the current and higher education. They are of the best students in their country and have chosen medicine due to their interest in this field. However, actually they are a concrete example of championship swimmers drowned in a beautiful lake. While preparing the speech for such students, I kept in mind two points. First that, the speech should be interesting enough to not only keep these students awake, but also to attract their attention. This was due to that I believed a substantial proportion of medical students would come to the speech after 5 to 7 hours daily work. Second and more important was that the speech should convey my message that these days pass quickly, but your thoughts remain regretting the past. More clearly, I wanted to reach them at the point that they can live better and happier, if they view the world form a different viewpoint. I needed an implicit method to achieve my purpose. Finally, I found it! I decided to take them somewhere so far from the Avicenna hall, such as a star, and then bring them, step by step, closer to the Avicenna hall. In this manner, it was understandable if I told them that prospective thinking is possible and can be potentially fruitful in perceiving the world.”

‘Amene Saghazadeh’: “It was the first month of my externship when I received an email of an event named -Medicine, The Infinite Way-. The lecturer was Dr. Nima Rezaei. Immediately, I saved the event in my calendar. On the scheduled day, I was so tired, but I had prom- ised to attend the meeting. While finding a chair to sit on, I asked myself how I could stay awake during this speech. The speech started while I was sleepy. I saw through my eyelids that the mouse was positioned somewhere around a point on a dark map and Dr. Rezaei asked the audience where this point is. I cannot remember if any responded true at this stage or not because I was still a bit dazed. Then, the target area gradually shifted towards bigger sizes. Finally, I found that the first point was the earth and the last one was where my chair was, i.e. the Avicenna hall. I am sure my eyes were open when my mind was going back and forth speedy. It was the first time I appreciated my mind speed and felt strong such that I could overcome everything and everyone and run from the start point again.” The mind develops prospection as our ability to pre-experience the future. Like the way the concept episodic memory, also known as autobiographical memory, was defined as remembering the past by Tulving in 1972 [1], Atance and O’Neill have established the concept episodic future thinking as a capability to project the self into the future to pre-experience the events [2]. Similarly, as semantic memory has been defined as our knowledge of the world, semantic future thinking is known to be our knowledge of the future [2]. Both episodic future thinking and semantic future thinking must be engaged to relish the future prospects. If I imagine my death, then episodic future thinking would be the dominant component of prospec- 1 What Would Happen If Humans Live Beyond Time? 3 tion. While if I think, like a physician, about the problems of the terminal phase of breast cancer, semantic future thinking would be the dominant component of prospection. Since its establishment in 2001, scientists have conducted research leading to the conclusion that both these cognitive capacities, i.e., prospection and memory, engage the same neural circuitry, mainly involving frontal regions and medial temporal areas. Additionally, it has been shown that the capacity of thinking about the future is disrupted in people, who suffer from impaired memory performance- associated diseases, such as Alzheimer’s disease (AD) [3], schizophrenia [4], and autism [5]. Accordingly, studies suggested that those who intend to think about the future are compelled to remember the past. More clearly remembering the past seems to be a prerequisite for prospective thinking [6], as D. H. Ingvar suggested 30 years ago [7]. It should be noted that the neural network innervating prospection is not only engaged in memory but also is a part of default-mode network (DMN) and contributes to other cognitive activities [8], such as navigation and theory of mind. Apparently, numerous cognitive processes provide the way for prospective thinking.

That Which Is Not Seen

Nowadays, advanced technologies offer different ways to observe events that man cannot easily meet them unless physically moves towards them. For example, ultrasonography is used as a camera to bring us a portrait of human development from conception to birth. In addition, there are some possible ways such as hypnotic regression through which humans can recall events that happened in the past. The main question, that has been heavily worked, but hitherto remained unresolved, is how the man can have a journey through time and see past events that he has not, on his own, experienced or events that will occur in the future and he may or may not experience them, on his own. To state it in an explicit manner, let us categorize events into nine groups relative to (a) the time of occurrence of an event and (b) the amount of awareness that the observer has of that given event (Fig. 1.1). Accordingly, the human is, now, very able to see most of the events assigned to the categories 1, 2, and 4–6, whereas witnessing events assigned to the categories 3 and 7–9 seem like a strong challenge. However, people are more concerned about the future than about the past; this emphasizes the importance of prospection, which can enable us to overcome life’s obstacles.

The Unconscious-Thought Theory

Don’t think. Thinking is the enemy of creativity. It’s self-conscious, and anything self- conscious is lousy. You can’t try to do things. You simply must do things – Ray Bradbury 4 N. Rezaei and A. Saghazadeh

Fig. 1.1 The categorization of events relative to the observer. This categorization has been made according to the time of occurrence of an event and that according to whether that given event was/ is/will becomes a one’s own experience or not. Note that here we use the term “self-experience” for all the events that their occurrences have involved/are involving/will involve the observer directly. The category “A sense of event” contains those events that man has a sense of them, for example, seeing or hearing the death of people. The third series of events, i.e., nonself experience of events without any sense of the event, includes the events, which cannot be assigned to the first and second series of events. The gray circles indicate that the observer can see probably the related events

Unconscious thought is defined as deliberation without attention to a given issue, whereas conscious thought is deliberation with direct attention to that. The theory has its own principles as follows. The capacity principle points to the higher capacity of unconscious thought compared with the conscious thought. The “bottom-up versus top-down” principle indicates that the unconscious thought acts non- schematically in a “bottom-up” manner. On the contrary, the conscious thought acts schematically in a “top-down” manner. The weighting principle embodies the idea that there is a lack of optimal weighting of information in the conscious thought, unlike unconscious thought. The principle reveals the adherence of conscious thought to the strict rules, whereas unconscious thought acts according to rough estimates. The convergence versus divergence principle demonstrates that unconscious thought is more likely to be capable of developing creativity compared to conscious thought [9]. The above principles clearly give unconscious thought more priority than conscious thought. Therefore, it is not surprising that the performance in complex decision-making situations when thinking unconsciously about the problem is enhanced than when consciously thinking about the problem [10]. Meanwhile, Crick and Mitchison proposed a possible mechanism, which paves the way for dream sleep by preventing the parasitic oscillation. The mechanism, called reverse learning, was established based on the automatic activation of the forebrain and the elimination of parasitic modes in the cortex as well [11]. Interestingly, this is consistent with the pattern of brain activity by unconscious thought [12]. 1 What Would Happen If Humans Live Beyond Time? 5

Here, we apply the term conscious/unconscious prospection based on the degree of belief in/freedom from the present time.

The Default-Mode Network

The central-executive network (CEN), the communicating network (CN), and the default-mode network (DMN) have been identified as the three main networks in the human brain. The CEN corresponds with tasks requiring cognitive function, whereas the DMN represents the resting state, but the awake state, in the brain. The CN, also known as the salience network (SN), is known to be responsible for switching from activation of the CEN to deactivation of the DMN [13]. The DMN has been characterized by the intrinsic low-frequency signal fluctuations during the resting state, but the awake state, in the brain. In addition, areas whose activity is decreased during cognitively demanding tasks compared with the resting state are thought to be involved in the DMN. It is, thus, expected that as more a task requires cognitive demand, less the DMN is involved [14]. The DMN comprises brain regions such as the hippocampus, the medial prefrontal cortex (MPFC), the posterior cingulate cortex (PCC), and the ventral anterior cingulate cortex (vACC). The functional connectivity of DMN is diminished after slight sedation induced by Midazolam than normal rest conditions. Also there is a considerable correlation between the functional connectivity of DMN and the level of consciousness [15]. Thus the fact that patients with AD have a limited capacity of thinking about the future compared to control subjects has been, at least in part, explained by diminished DMN activity [16]. However, there appeared almost similar functional connectivity during resting and passive visual processing states [17]. This indicates that the DMN activity would not be significantly altered during unconscious prospection compared with the resting states. Given that its function in the resting state is more prominent than during cognitively demanding tasks, it can be concluded that shifting from conscious to unconscious prospection, as we defined them here, accompanies activation of the DMN.

The Information-Integration Theory

The theory of information integration formulated by Tononi in 2004 suggests that the level of consciousness varies depending on the information integrated [18]. Here we categorize the information intended to be integrated into essential (EII) and secondary (SII). While the EII is considered as a cognitive-demanding task and therefore correlated with a decreased activity of the DMN, the SII is thought to require limited cognitive demand and will be, thus, corresponding with an increased activity of the DMN. 6 N. Rezaei and A. Saghazadeh

The Hypothesis of Conscious → Unconscious Prospection (CUP)

The main principles of the CUP theory are briefly explained below (Fig. 1.2). 1. The degree of consciousness covers a continuous spectrum. As illustrated in Fig. 1.2, the spectrum can be mainly categorized into three, based on the presence/absence of deliberation about and attention to the target event. We propose the CUP theory based on the assumption that conscious prospection and unconscious prospection correspond to the degree of belief in and the degree of freedom from the present time, respectively. 2. The information is integrated at two main levels, essential and secondary. The former one is required for the brain to make predictions about the target event, whereas the latter one improves the accuracy of our prediction of the future by overcoming the constraint of information processed during the previous step. 3. The probability of EII is predominantly correlated with the degree of belief and that the probability of SII is correlated with degree of freedom.

Fig. 1.2 Conscious → unconscious prospection (CUP). Here we categorize the information integration into two: essential (EII) and secondary (SII). The former is required for the brain to make predictions about the target event. The probability of EII is considered to be positively correlated with the degree of belief. While the latter improves the accuracy of our prediction of the future by overcoming the constraint of information processed during the previous step; therefore, the probability of this one (SII) is correlated with the degree of freedom. Moreover, EII will correspond with a decreased activity of DMN, whereas SII will correspond with an increased activity of DMN. Accordingly, considering that the total degree of freedom and degree of belief is constant, it is possible to draw a model of unconscious prospection by remarking three detrimental points. The A point, where the brain has the maximum degree of belief, corresponds to the maximum essential information integration and minimum secondary information integration. Under this condition, the brain is able to predict but has not the opportunity to improve its primary predictions. The C point, where the brain has the maximum degree of freedom, corresponds to the minimum essential information integration and maximum secondary information integration. Under this condition, the brain would not be capable of making predictions at all. At all the points between A and C point, the brain can predict and then has the opportunity to improve its predictions as well. The B point is where the brain makes the prediction of the target event with the maximum accuracy. At this point, the brain has the optimal degree of belief in and freedom from the present time 1 What Would Happen If Humans Live Beyond Time? 7

4. EII will correspond with a decreased activity of DMN, whereas SII will correspond with an increased activity of DMN. 5. The total degree of freedom and degree of belief is constant. Accordingly, it is possible to draw the model of unconscious prospection by remarking three detrimental points (Fig. 1.2). The A point, where the brain has the maximum degree of belief, corresponds to the maximum EII and minimum SII. Under this condition, the brain is able to predict but does not have the opportunity to improve its primary predictions. The C point, where the brain has the maximum degree of freedom, corresponds to the minimum EII and maximum SII. Under this condition, the brain is not capable of making predictions. At all the points between A and C point, the brain can predict and then has the opportunity to improve its predictions as well. The B point is where the brain can make predictions of the target event with the maximum accuracy. At this point, the brain has the optimal degree of belief and freedom.

An Integrated Approach to the Hypothesis of Conscious → Unconscious Prospection (CUP)

Despite recent advances in research, there seem to be some things that their place is still open on the ground of future thinking. Such things are not necessarily new ideas, but they may be just new styles to stare at an old problem. An integrated approach would be more likely to help us act more intelligently in this respect, i.e., envisioning the future, compared with a pure neurocognitive one.

Belief in the Present Time: That Which Generates the Background Noise While Thinking to About the Future

A communicating system basically comprises an information source, a transmitter, a source of noise, a receiver, and eventually a destination. The operation of such system critically depends upon (a) making the message, (b) sending the signal, and (c) receiving the signal. In this manner, the effect of noise can be exerted as the signal travels from the transmitter to the receiver [19–21]. Belief in the present time is actually the source of noise for thinking about the future when a complex communicating system is thought to operate within the brain (Fig. 1.3). Thus, the CUP model can improve the accuracy of our predictions of the future by removing the source of noise, i.e., belief in the present time. 8 N. Rezaei and A. Saghazadeh

Fig. 1.3 Belief in the present time: the noise source of the prospection communication system 1 What Would Happen If Humans Live Beyond Time? 9

Being Out of Time: A Solution to See That Which Is Not Seen at the Present Time

Hawking and some others are of the view that “when one looks at “real” time, there is a very big difference between the forward and backward directions” [22]. It is, thus, reasonable to draw a conclusion that if the human can live beyond time or out of time, there will be no fundamental difference between the forward and backward directions in spatiotemporal scale. More precisely, it does not matter to his/her brain about the past and future events.

Resonance: That Which Occurs If Being Out of Time

Processing information within the brain can be measured by a variety of physical parameters, particularly frequency, wavelet, and entropy [23]. Wavelet-based methods have provided valuable insight into the temporal dynamicity of brain processes by measuring the coherence function which is defined as the estimation of coupling between non-stationary neural signals [24]. Indeed, the coherence concept is only a direct reflection of the resonance phenomenon that is defined as follows: a given system at some frequencies, called preferred frequencies, can oscillate with a relatively more amplitude by another oscillating system or by external forces [25]. Resonance at the neuronal level represents the association between event-related neuronal processes. Each brain can be characterized by a series of temporal relative wavelet energy dependent on its internal information (II). It can be applied to not only the neural coupling between signals in its own brain but also to the neural correlations between isolated brains related to subjects who are physically distant [26–29]. Let us gener- alize this result as follows: each series of wavelet energy signals the start of resonance phenomenon not only to the series related to other brains but also to those related to all the living things and their emergent events. These signals can make effective interactions if wavelets-sending signals have a certain frequency. In conclusion, the resonance phenomenon can occur in the human’s brain as the result of co-frequency of that given brain with another brain/living thing/event. This can be potentially followed by acquiring the ability to get through the aperture of that given event in that given brain. It does not matter whether the event has happened in the past or will happen in the future. According to the CUP theory, the possibility of SII is directly associated with the occurrence of the resonance phenomenon. 10 N. Rezaei and A. Saghazadeh

How Would Entropy Change Relative to Resonance If Being Out of Time?

Looking now and as well as being out of time are complex phenomena so that humans can never claim to perfectly capture the quality of them. Like other complex systems and their emergent behaviors, it is valuable to evaluate changes of entropy – which is defined as a measure of the growing tendency for energy to spread out by time – in the brain during looking now and being out of time. This evaluation is a rather difficult task. This is because the brain is an open system, which would be influenced by environmental factors and their interaction with the renowned five common senses, e.g., sight, hearing, smell, taste, and touch. Here these factors are collectively referred to as external information (EI). As more force that is external is felt, more the brain is involved in EI processing, and therefore, more the brain system would be open to the outside world. Conversely, as less external force is felt, more the brain is involved in internal information processing, and therefore, more the brain system would be open to the inside world. As more a system is closed to the environment, less energy will be dissipated by that system and more energy will be stored in the system. They together lead to an increase in the quality factor – which is directly related to the energy stored and inversely to the energy dissipated per cycle – of that given resonator (i.e., the brain). The increased quality factor corresponds to the increased coupling of neural signals within the brain, while the coupling of the brain itself to the environment has been decreased. Since there seems to be a limit to the energy in the context of information analysis in the brain, it would be understandable if we say that the increased coupling within the brain would impede an effective interaction between that brain and other brains/ events [30]. In this manner, the unconscious prospection may be more likely to be capable of correlating signals between isolated brains. Eventually, it is proved that there is an obvious parallel between the probability of being out of “real” time and the probability of occurrence of the resonance phenomenon and hence the possibility of SII. Accordingly, more the brain’s system is closed to EI, more energy within the brain, like other closed systems, will be stored and therefore entropy will tend to increase with time in order to increase the decreased tendency of the system to spread out its energy. As explained above, this “growing entropy” state accompanies a rise in the quality factor of the resonator. Additionally, we all know that a basal level of energy and hence entropy are required for the system to operate. This statement has a well-known justification that is found when people are categorized according to the number of dreams which they see during a given sleep period and the amount of weakness (energyless) which they feel before sleep. After waking, people who were so tired and energyless prior sleep often say sentences such as “I was passed out” or “I was unconscious.” It emphasizes the necessity of the basal, however low, level of entropy, for the brain to be out of time. 1 What Would Happen If Humans Live Beyond Time? 11

Conclusions

Our chapter corroborated that our prospection would be improved if being out of time. The present chapter provided an integrated approach to the issue and proposed the conscious → unconscious prospection theory. There are potential constraints on the prospective thinking that are mostly imposed by conscious thought and therefore support the view that unconscious prospection can provide more power than conscious thought. The unconscious prospection may improve the accuracy of our predictions by increasing the possibility of forming effective nonclassical neural correlations. Indeed, shifting from the conscious to unconscious prospection can be considered as a simple strategy to overcome the source of noise, i.e., belief in the present time.

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17. Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci. 2003;100(1):253–8. 18. Tononi G. An information integration theory of consciousness. BMC Neurosci. 2004;5(1):42. 19. Shannon CE. A mathematical theory of communication. ACM SIGMOBILE Mob Comput Commun Rev. 2001;5(1):3–55. 20. Shannon CE. Communication in the presence of noise. Proc IRE. 1949;37(1):10–21. 21. Shannon CE. Communication theory of secrecy systems*. Bell Syst Tech J. 1949;28(4):656–715. 22. Hawking SW. The illustrated a brief history of time. Bantam; London, GB:. Bantam Books, 1996. 23. Rosso OA, Blanco S, Yordanova J, Kolev V, Figliola A, Schürmann M, et al. Wavelet entropy: a new tool for analysis of short duration brain electrical signals. J Neurosci Methods. 2001;105(1):65–75. 24. Lachaux J-P, Lutz A, Rudrauf D, Cosmelli D, Le Van Quyen M, Martinerie J, et al. Estimating the time-course of coherence between single-trial brain signals: an introduction to wavelet coherence. Neurophysiol Clin/Clin Neurophysiol. 2002;32(3):157–74. 25. Hutcheon B, Yarom Y. Resonance, oscillation and the intrinsic frequency preferences of neurons. Trends Neurosci. 2000;23(5):216–22. 26. Standish LJ, Johnson LC, Kozak L, Richards T. Evidence of correlated functional magnetic resonance imaging signals between distant human brains. Altern Ther Health Med. 2003;9(1):128. 27. Standish LJ, Kozak L, Johnson LC, Richards T. Electroencephalographic evidence of correlated event-related signals between the brains of spatially and sensory isolated human subjects. J Altern Complement Med. 2004;10(2):307–14. 28. Richards TL, Kozak L, Johnson LC, Standish LJ. Replicable functional magnetic resonance imaging evidence of correlated brain signals between physically and sensory isolated subjects. J Altern Complement Med: Res Paradigm Pract Policy. 2005;11(6):955–63. 29. Lachaux J-P, Rodriguez E, Martinerie J, Varela FJ. Measuring phase synchrony in brain signals. Hum Brain Mapp. 1999;8(4):194–208. 30. Laughlin SB. Energy as a constraint on the coding and processing of sensory information. Curr Opin Neurobiol. 2001;11(4):475–80. Chapter 2 Neurophysiology of Visual Perception

Mahsa Mayeli

Abstract As the richest sensory modality in human beings, vision and visual perception have always been the center of attention for numerous studies. In this chapter, we aim to put together the scattered literature on human visual perception and investigate the magnificent act of transforming a two-dimensional optical input into a three-dimensional reconstruction of the world outside. Herein, the literature is reviewed regarding various aspects of this perceptual phenomenon, starting with a brief introduction toward the neuroanatomical properties of the visual system and proceeding to central regions and pathways in charge of modifying and directing the visual input to pass through the three-dimensional perceptual operations. We move forward by investigating various aspects of object recognition including the perception of form, space, and motion. Moreover, important processes of adaption and gaze control are discussed in the section regarding the role of eye movement in forming perception. Considering the high evolutionary value of face perception, a separate section is dedicated to studying this aspect. After an overall evaluation of neural coding and the constructive nature of visual perception, we conclude with a section on computer vision and future directions.

Keywords Neurophysiology · Space · Vision · Visual perception

M. Mayeli (*) Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Introduction

Vision, so familiar yet so mysterious, is widely considered to be the richest sensory system in human beings. As early as the 1850s, alongside with the invention of the first cameras, a perfect illustration of vertebrates’ eyes seemed to have been developed by pupils and iris forming an aperture ring, and the cornea and lens as refractive optics projecting a small image of the world outside onto the retinal layer (so-called equivalent of a sensor in a camera) at the backside of the eyeball. The retina is the point where the initial combination of visual sensory information takes place. However, from this point on, a three-dimensional representation of the two- dimensional world is being reconstructed in the brain, a capability far beyond any camera being built heretofore. Our impressions of the world are mostly based on sight, empowering us to not only perceive form, movement, and colors, in a highly complex context but also to guide our movements. This leaves no wonder that almost half of the primates’ brains are associated with vision, entitling almost 30 different visual areas to analyze this information. The present chapter begins with a brief review of the neuroanatomical properties of the visual system and proceeds to the underlying mechanisms enabling the high sensitivity and resolution of our vision. We discuss the principles of neural coding leading to the three-dimensional representation of the universe. The fundamental, integrative, and perceptual visual centers in the brain and their so far known interactions through parallel pathways involved in visual perception are presented as well.

Neuroanatomical Properties of Visual System

As in other cognitive operations, visual perception is a unified impression of various features such as motion, depth, form, and color. This unity is a computation of multiple areas of the brain that are fed by at least two major interacting neural pathways. Due to the significance of understanding distributed processing in analyzing the neurophysiology of visual perception, having a grasp of neuroanatomical properties of the involved pathways and areas is critical.

The Eye

Several essential structures are primarily involved in receiving the visual input. The pupil is the aperture that allows light to enter the eye. Its dark appearance is due to absorbing pigments of the retina. The iris is the pigmented circular muscle responsible for our eye color. The iris controls the size of the pupil so that the optimum amount of light can enter the eye in various conditions. The cornea is a transparent 2 Neurophysiology of Visual Perception 15 external surface, covering both the pupil and the iris, comprising the first and most powerful lens of the optical system, regulating the optimum convergence of the light on retinal photoreceptor layer, which is the first-level neural structure in the process of visual perception. Finally, the supporting structure of the eye is the sclera, forming the white of the eye. The sclera is continuous with the cornea. More interestingly, the cornea itself is in continuity with the dura layer of the central nervous system. Another essential element in the eyeball is the lens. Located behind the iris, the lens is suspended by ligaments and is attached to the anterior portion of the ciliary body. The interactions between these ligaments and ciliary body muscles enable the lens to accommodate. The accommodation reflex, in turn, allows the eye to form a sharp image on the retina [1].

The Retina

Described as a thin sheet, the retina is the sensory part of the eye. It appears the most internally located component of the eye and is where visual processing begins. This is why the retina has been broadly described as the brain’s window to the world. Histologically, the retina is a constellation of three cellular layers, which contain five various cell types, separated by two synaptic layers. The outermost layer of the retina contains critical photoreceptor cells, which conduct the essential process of phototransduction, a process in which retina absorbs the light and converts it into a neural signal. These signals pass into bipolar cells, and then follow their path to ganglion cells. The axons of the retinal ganglion cells, that are the projecting neurons of the retina, form the optic nerve. The optical axis that reflects the image on the retina is the smallest, while the optical axis passing through the fovea is the sharpest and is in charge of locating the center of gaze on the objects of our attention. Fovea contains the highest density of photoreceptors, bipolar cells, and ganglion cells [2].

The Optic Pathways

The visual input exits the eyeball posteriorly, forming the optic nerve. The visual pathways from there on comprise chiasm, optic tracts, and optic radiation and terminate in the striate cortex on the medial aspect of the occipital lobes. At the chiasm level, fibers from the temporal aspects of the visual field proceed to the ipsilateral hemisphere, while fibers from the nasal aspect cross to the contralateral hemisphere. Optic tract is formed by the continuation of axons from nasal and temporal hemiret- inas decussating in the optic chiasm toward the lateral geniculate nucleus of the thalamus. Then the visual information relays to the primary visual cortex. Following 16 M. Mayeli the orbitocranial route, the visual pathway reaches to the calcarine fissure of the occipital lobe in a relatively horizontal plane [3]. A second pathway runs from the retina to the superior colliculus, with a dominant role in controlling the eye movements. This pathway continues to the pontine formation in the brain stem and then to the extraocular motor nuclei. A third pathway extends from the pretectal area of the midbrain, where neurons mediate the pupillary reflexes that control the amount of light entering the eye. Optic radiation is a projection of each lateral geniculate nucleus to the primary visual cortex. Two major pathways stem from the primary visual cortex: the ventral path to the temporal lobe carrying information on what the stimulus is and the dorsal pathway into the parietal lobe carrying information about the spatial features of the stimulus, which is critical for guiding the movements. All the sensory information entering the hemispheres connect through corpus callosum, a major fiber bundle located in between the hemispheres. This is where the separate perceptions from each hemifield are united.

Brain Regions and Pathways Involved in Perception

Vision is by far the most richly represented sensory modality in the cortex of primates. In the old world monkey, about one-half of the cortex is dedicated to specialized regions for registration and perception of visual stimuli [4]. In ways that are yet to be fully understood, the visual cortex arrives at a simple and unambiguous interpretation of data from the retinal image, which is useful for the decisions and actions of everyday life [5]. A remarkable body of research indicates that these areas are organized into hierarchical pathways specialized for registering information about particular aspects of the visual scene [6]. The occipital lobe plays an essential role in visual perception. The secondary visual area (V2) is the second major part of visual cortex. Being the first in visual association area, this region receives vast feedforward inputs from V1 and projects strong feedbacks to V3, V4, and V5. The properties related to object surfaces are analyzed in V2. V4 is anatomically located anterior to V2, shifted toward the temporal lobe. As the third cortical area of the ventral stream, this region integrates information about color and object shape. V4 receives feedforward from V2 and relays signals to posterior inferotemporal area. And finally, V5 is located in the middle temporal visual area (MT), playing a significant role in motion perception. Another central region for registering visual information is located in the middle temporal lobe. Studies have demonstrated cortical maps representing the retina on the cerebral cortex, suggesting a number of two to three central areas as mentioned earlier and a number of additional less strategic centers which are mainly located in the occipital lobe [7]. 2 Neurophysiology of Visual Perception 17

A question that remained controversial for long was whether the visual imagery of objects, scenes, and of living beings is associated with the contribution of early visual areas (V1, V2) or is based upon hierarchical higher visual areas [8]. An intriguing experiment investigating the activated regions during the perception of illusory contours has addressed this question by identifying unique regions in the extrastriate cortex to be in charge of perceiving such contours. The authors declared that this type of perception is a good illustration of perceptual grouping processes in the human brain [9]. Inferior temporal cortex is known to encode complex visual stimuli, to the extent in which neurons in this area are insensitive to simple stimulus features such as orientation and color. On the other hand, an individual neuron in this area might strongly fire in response to a complex pattern, such as a crescent.

The Microstructure of the Primary Visual Cortex

A magnificent aspect of the functional organization of the primary visual cortex is its specialized columnar organization. Cells in this area are located close together, extending from the cortical surface to the white matter. This structure develops the orientation specificity and the integration of inputs from the two eyes [10]. Two essential pathways are responsible for conveying visual information. Both originating from the striate cortex, the occipitotemporal pathway, or “ventral stream,” which is vital for conveying the visual information about identification of objects, and the occipitoparietal pathway, or the “dorsal stream,” which is crucial for perceiving the spatial relationships among objects and the visual guidance of movements [4]. The idea of this segregated processing was first raised by the results of lesion studies, especially in old world monkeys. Subsequently, a double dissociation of visual recognition and visuospatial performance was demonstrated in two men with lesions of occipitotemporal and occipitoparietal performance. There is a hierarchical organization along both the occipitotemporal and the occipitoparietal pathways. In a novel study, what and where model acknowledged the importance of parietal cortex for mediating visually guided reaching and grab- bing movements [4]. In a cellular level, a single neuron or column in the visual cortex represents a single object and whenever the object is out there and “seen” by the retina or even imagined, this column changes activity [8]. Alongside with the progress of imaging tools, an increasing interest was developed in investigating the intermediate links between primary visual areas in the occipital lobe and the final stages of visual perception, namely recognizing category- selective regions. Grill and his colleagues have conducted a remarkable experiment to explore these links. Two parameters were simultaneously measured in 12 participants: the spread of activation from the ipsilateral visual field and the preferential activation to images of natural objects compared to highly scrambled versions of the same images. Three distinct foci of activation were revealed in the occipital lobe, which is mediolaterally arranged in both hemispheres. The medial focus is located 18 M. Mayeli over the calcarine sulcus and on the medial surface of the occipital lobe, which is essentially shut off with visual stimuli confined to the ipsilateral visual field, but indicated only minor reduction when objects are highly scrambled. More laterally, a small dorsal focus and a ventral focus are located mainly within the fusiform gyrus, which is preferentially activated with visual stimuli in the contralateral visual field. Lastly, overlapping voxels on the lateral aspect of the fusiform gyrus indicated a clear sensitivity to scrambling stimuli from the ipsilateral visual field. These results are consistent with an underlying hierarchical interpretation of the object. Combined visual-field mapping allowed the researchers to progress the retino- topical investigation of additional visual areas in the brain [11]. In addition, using positron emission tomography (PET), primary visual cortex (V1) was revealed to be activated when subjects visualized objects [12].

Object Recognition

In order to recognize an object in a complex environment, an important step is to separate the object from its background. Setting aside the geometric properties of the object and environment, this process is significantly influenced by cognitive functions such as attention and expectations. The cognitive operation utilized to attain this mean is called visual search, which is an integrative function of simultaneous analysis in parallel visual pathways. Coding dimensionality for objects has been attributed to the ventral visual pathways, although the specific information encoded by these neural responses remains to be addressed [13]. A remarkable aspect of object recognition is the difference between object categories in the way we perceive them. For instance, within-category identification of objects (objects of expertise) is processed in the ventral occipitotemporal cortex [14]. A great body of literature has suggested that the ability to rapidly recognize objects despite substantial appearance variation is enabled with a cascade of reflex- ive, mostly feedforward computations that culminate in a powerful neuronal representation in the inferior temporal cortex. Studies have indicated that for fully understanding the algorithm that culminates and interprets this aspect of visual perception, a multidimensional analysis of neuronal and psychological data sifting through computational models is required [15]. A category-specific and anatomically segregated modular organization has been proposed for object recognition in the ventral pathway. A study utilizing functional MRI (fMRI) has proposed three distinct regions in the ventral temporal cortex (VTC), dedicated to the recognition of faces, buildings, and cars. The study claims the generalization of the results in terms of the existence of separate modules for each category of objects [16]. Following works have provided more support regarding this issue. Emphasizing on eccentricity mapping, various categories of objects have been attributed to different areas in the VTC [17]. Studies have indicated that 2 Neurophysiology of Visual Perception 19 the primate visual system consists of a number of segregated subdivisions, each analyzing a different aspect of the same retinal image [18]. Following is a brief discussion of various aspects of visual primitives essential for perceiving the object as a whole. These primitives include contrast, line orientation, brightness, color, movement, and depth, which are essential milestones for perceiving form, space, and motion in totality [19]. Furthermore, the selective nature of our visual system in identifying the contrast variation in detecting the objects will be explored [20]. As stated earlier, a critical step for object recognition is scene segmentation. Dissecting the scene into different objects involves a constellation of bottom-up processes that obey the Gestalt rule of good continuation and top-down processes that take part in creating object expectation. These top-down influences mainly consist of complex cognitive operations such as spatial attention.

Perception of Form

Extensive psychophysical and computational work proposes that the perception of coherent and meaningful structures in natural images relies on neural processes that convert information about local edges in the primary visual cortex to complex object features represented in the temporal cortex. However, the neural basis of these mid- level vision mechanisms in the human brain remains largely unknown. Functional MRI (fMRI) findings suggest that the human visual system uses a code of increasing efficiency across stages of analysis that is critical for the successful detection and recognition of objects in complex environments [21].

Perception of Space

How space is represented in the visual system, is another fundamental question that appears straightforward at first glance. For long it has been accepted that spatial information is directly encoded, however, recent studies have indicated the insuffi- ciency of this model. The current trend regarding the perception of spatial information is that it is essentially coded spatiotemporally and not merely through the dorsal pathway. The spatial aspect is mainly related to fixational eye movements, which will be further discussed [22].

Motion Perception

Occipitoparietal pathway, or the dorsal pathway, is specialized for registering the information about the locations of objects and their movements within the visual scene, extending into dorsal aspects of extrastriate and posterior parietal cortex [23]. Indeed, the visual system has been hypothesized as being initially evolved not to provide animals to see the world, but to guide their movements [24]. 20 M. Mayeli

Studies have indicated that viewing biological motion selectively activates a region on posterior superior temporal sulcus (STSp). Occipital and fusiform face areas (OFA and FFA) also contain neural signals capable of differentiating biological from nonbiological motion. STS region is also involved in the perception of biological motion, in other words, receiving and interpreting the visual signals of others, which contains an evolutionary survival value [25]. This branch of research on visual perception has been further explored in studies on visual speed perception, which is suggested to be qualitatively consistent with a Bayesian observer that optimally combines noisy measurements with a prior preference for lower speeds. Since human perception of visual motion is greatly biased, considering attributes other than the apparent physical motion is required to properly estimate the speed and direction of the moving visual stimuli [26].

Eye Movements and Perception

Visual perception is an active process that, in part, derives from the shifting of attention across the visual scene. More importantly, small eye movements are critical for maintaining the contrast of objects that we are examining. Without these movements, the perception of an object rapidly fades to a field of gray, which is a result of decreased neuronal firing in V1. Large eye movements maintain the high resolution of fovea through saccadic movements. Saccadic movements also play magnificent roles in the process of shifting attention [27]. Central areas in perceiving the eye shifts in the brain include frontal eye fields, supplementary eye fields, and parietal saccade-related regions. A core network of frontoparietal and temporal brain regions are involved in shifting attention with or without eye movement [28]. Eye movement has been widely attributed to the process of shifting the attention, although more recent studies have indicated the role of the frontal eye field (FEF) in shifting the attention without eye movement [29]. In an evolutionary perspective, stationary objects tend to pose a significantly less value since they are not an indicator of a prey nor predator. It extends to such degree that some nervous systems exclusively detect motion; for instance, a frog is incapable of attending a resting fly, though as soon as the fly initiates a move, the frog rapidly perceives its presence and precise location [30]. In human vision, our eyes are constantly moving to detect more information from the visual scene. It has been argued that even our own visual system detects only moving objects, and the only reason that we perceive stationary objects is that none of the images projected onto our retinas are stationary for long. The importance of studying fixational eye movements is to unravel the type of neuronal response generated by the eye movement during the visual fixation. Neural adaptation governs our visual system, in the sense of being the cornerstone of visual processing. There is an agreement on the existence of three categories of fixational eye movements in today’s scientific society: tremors, drifts, and microsaccades [31]. 2 Neurophysiology of Visual Perception 21

Tremor, or nystagmus in physiologic terms, is an episodic, wavelike motion of the eyes with a relative frequency of 90 Hz. Tremors are as small as a cone in the fovea, therefore difficult to record accurately [31]. Drifts are slow motions of the eye that occur concurrently with tremor. These motions take place during the epochs between microsaccades [31]. Microsaccades, with a frequency of one per second, play the most prominent role in miniature eye movement during fixation [32]. Former studies have linked the microsaccades to perception and suggested critical interactions between their dynamic and cognitive processes such as attention. Using a dual Purkinje image tracker is broadly considered the most accurate optical and feature recognition method. The exact frequency of these movements has been estimated to be around 1° [31].

Adaptation

Our visual system is governed by neural adaptation. Steady illumination produces weak neural responses, while abrupt alterations in illumination lead to strong responses. The cost of such a system is its inability to attend to unchanging features of the scene. Since the uniform stimulation of the retinal receptors tends toward the loss of vision, eye movements during fixation are necessary to overcome this process [31].

Human Gaze Control

As discussed earlier, eye movements are the essential milestones to fixate our eyes and form gaze [33]. The center of perceiving high-quality visual information in human beings is located in the fovea. To reorient the fovea through the scene, a number of rapid eye movements (saccades) are required. Since sensitivity and acuity are optimum at the point of fixation, the visual-cognitive system actively controls the gaze to direct the fixation toward important and informative scene regions in real time [34]. Utilizing fMRI techniques, the perception of eye gaze is mainly attributed to superior temporal sulci [35].

Face Perception

Face perception, perhaps the most highly developed visual skill in humans, is mediated by a distributed neural system in humans that is comprised of multiple bilateral regions. As discussed earlier, there is a significant distinction between the representation of invariant and changeable aspects of faces [36]. Faces are among the most important visual stimuli we perceive, providing us with a vast amount of information in a fraction of a second. Face perception most probably contains a great 22 M. Mayeli survival value for our primate ancestors. Not surprisingly, this has led the human brain to develop specialized cognitive and neural mechanisms dedicated to the perception of faces [37]. Fusiform face area (FFA) is broadly known to be responsible for much of this process. Two essential processes are proposed regarding the interpretation of facial attributes, termed priming or serial dependencies, leading to positive sequential effects, adaptation or habituation and negative sequential effects. In other words, stable attributes, such as the identity and gender of faces require the system to integrate, while for alternating attributes like facial expressions, it ought to engage contrast mechanisms to maximize sensitivity to change [38]. FFA is located in the human extrastriate cortex and has been repeatedly determined for being exclusively involved in both detection and identification of faces [14].

The Constructive Nature of Visual Perception

Many differences raised from comparing the human visual system with a camera eventually led to a Gestalt psychology-based interpretation of the matter. The central idea of this interpretation is that the brain computes what it sees based on its expectations deriving from both previous experiences with the world and its neural predispositions. Moreover, these interpretations depend not merely on the properties of the object itself but also on its context and other features of the visual field. The early twentieth-century theories on visual perception were primarily based on these approaches toward our understanding of similarity, proximity, and good continuation. These notions illustrate the underpinnings of many visual illusions. This is also prominent in the phenomena of contour saliency; whereby smooth contours tend to pop out from complex backgrounds. This is a part of a phenomenon known as contour integration, which is the process of cortical analysis of this information into the shape of the object. The interaction between three factors of visual context, experience-dependent changes in cortical circuitry, and expectation is vital in the visual system’s analysis of complex scenes. This constructive nature has led to the concept of perceptual learning, in which the threshold of discriminating subtle differences in the visual field decreases as the stimulus keeps repeating itself. This process essentially involves the primary visual cortex. The response of neurons in this area changes during the course of perceptual learning, which manifests itself in cognitive analyses like contour saliency. 2 Neurophysiology of Visual Perception 23

Neural Coding and Perception

The brain analyzes a visual scene at three levels: low, intermediate, and high. At the first level, visual attributes such as local contrast, orientation, color, and movement are discriminated. The intermediate level involves analysis of the layout of scenes and of surface properties, parsing the visual image into surfaces and global contours, and distinguishing foreground from background. The highest level involves object recognition. Once a scene has been parsed by the brain and objects have been recognized, the objects could be matched with memories of shapes and their associated meanings. Moreover, three essential cognitive operations can influence the overall visual perception, visual context, experience-dependent changes in cortical circuitry, and expectations. A common illusion in visual perception is that we perceive the objects simultaneously, though, in fact, our overall perception of a scene is a process of serially shifting our attention toward the objects in our visual field [39]. Low-level perception can be identified as the neural-based computations that build unconscious or self-generated inferences during the processing of sensory events. This level of perception does not necessarily require attentional processes, which is why it has been also confounded with non-attentive perception. In fact, low-level visual processing primarily takes place at the cellular level [40]. Experiments investigating the mechanisms involved in visual processing often fail to separate low-level encoding mechanisms from higher-level behaviorally relevant ones. However, a good illustration of the intermediate-level processing is contour integration. In other words, this level of perception is mainly concerned with analyzing various visual primitives. Studies have indicated that various cognitive functions, such as perceiving space, form, and motion, which are the concern of the highest level of visual perception, are encoded separately into anatomically and functionally segregated pathways. The overall visual perception is imbued by these operations.

Computer Vision and Future Directions

Major improvements in the world of technology have evolved into the novel science of computer vision. The new era has equipped scientists with advanced tools, enabling them to explore more complex research questions. The significance of these improvements in the world of medical neuroscience is their impact on better understanding the cortical function. An essential lesson from this branch of studies has indicated that natural images contain properties and structures that vary greatly from the artificial stimuli typically studied by visual scientists. However, our brains are accustomed to understanding the natural images, despite their great complexity, using an alternating dual-task event-related potential (ERP) experimental paradigm, animals or vehicles 24 M. Mayeli categorization, where targets of one task are intermixed among distractors of the other. A study shows visual categorization of a natural scene involves different mechanisms with different time courses: a perceptual, task-independent mechanism, followed by a task-related, category-independent process [41]. Decoding the way these complex patterns might be recognized and lead to actions is one of the fundamental goals of computer-vision researches [5]. In fact, a significant capability differentiating the human visual perception with computer vision is recognizing thousands of object categories in cluttered scenes. Alike in human vision, the essential problem is to distinguish the object from the background [42].

Conclusions

Each brain has its own way of looking at the world. The retina serves as a primary window to create a retinotopic image by transducing the light into a neural signal, which continues its path to form the optic nerve. Anatomically, the optic nerve is a bundle of axons from more than a million retinal ganglion cells. The optic nerve exits the eyeball via the optic canal posteromedially and enters the cranium. Two optic nerves from the eyes decussate at the optic chiasm, located immediately below the hypothalamus. The signals from the nasal sides of each retina cross over to the opposite side of the brain via the continuation of the optic nerve from the optic chiasm. The temporal signals, however, continue on the same side. Beyond the chiasm, optic nerve becomes optic tracts. This process of crossover from the nasal side and direct continuation from the temporal side allows the visual cortex to receive the same hemispheric visual field from both eyes. Visuotopic representation of this information takes place at the cortical level, initiating at V1 with contour integration processes and following its path into the ventral or dorsal stream. Visual perception occurs in three layers. A low-level analysis is mostly mediated by signal-forming retinal cells and is concerned with transducing action of rods, cons, and ganglion cells. The intermediate level is focused on contour integration and takes place at the primary visual cortex. The final stage of visual perception is essentially localized at the medial temporal lobe, and the visual parietal areas, though it receives major inputs from all visual associative areas of the cortex, imbu- ing the overall perception with higher level cognitive functions such as attention and memory-based expectations.

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Shima Shahjouei and Mahmoodreza Amini

Abstract The function of the visual system is far beyond simply focusing the light beams to produce an image. To picture the adaptations to reduce the artifact and enhance the quality of the image, in the first section, we follow the light beams, as they are incident on the surface of the cornea to focus on the retina. We also explained the dynamic mechanisms to produce images of the objects in motion, at different distances, and under various luminances. In the second section, we further explore how the function of the visual system is interwoven with alterations in the magnetic field: visual system provides the components of the magnetic field perception, and the magnetic field affects visual properties. We also introduce the circadian rhythmicity and the modulating role of visual system on it, either directly or indirectly, through conveying the light/dark information and geomagnetic alterations to the brain. To offer a deeper understanding of the physical concepts and their application in biological events, we have provided five boxes. In Box 3.1, optical instruments for focusing a beam of light, fundamentals of refraction, and optical characteristics of the cornea and crystalline lens in normal and pathologic conditions are introduced. Box 3.2 explains diffraction and the role of pupil size in minimizing it. Box 3.3 provides detailed background on the geomagnetic perception and its interaction with visual functions and offers four mechanisms underlying the perception of slight magnetic field alterations. In Box 3.4, the key features of space weather and its manifestation on Earth’s magnetic field and human physiology or pathologies are presented. Finally, Box 3.5 provides more information about circadian rhythms.

Keywords Biophysics · Circadian rhythms · Distance · Electromagnetic field · Geomagnetic field · Light · Magnetic field · Motion · Space · Vision

S. Shahjouei (*) Department of Neurosurgery, Children’s Hospital Medical Centre, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran M. Amini Department of Physics, Shahid Beheshti University, Tehran, Iran

Image Forming Function of Visual System

As the light beam is incident on the surface of the eye, it should pass through a thin layer of the tear, continuing its way through the cornea, anterior and posterior chambers containing aqueous humor, the crystalline lens, and the vitreous chamber filled with the vitreous humor before reaching the retinal layer. With the contribution of the cornea and anterior and posterior surfaces of the crystalline lens, the image is incident on the retina. Each of these media has its own reflective index and optical characteristics. In addition, iris limits the diameter of the beam light entering the eye by providing a dynamic aperture, pupil. As described later, the pupil has unique features in focusing the incoming light beams and reducing the artifacts to the visual system.

Cornea

Cornea, the front transparent window of the eye, is responsible for rigidity and global shape and plays the major role in refracting light in the eye. About 80% of the focusing power of the eye is related to the cornea, and the remaining 20% is provided by the crystalline lens (Box 3.1) [1–3]. Light scattering, diffraction, wavefront aberrations, and attenuated visual quality are consequences of structural

Box 3.1 Although simple lenses are most commonly known as optical instruments for focusing a beam of light on a specific point, there are other methods such as Fresnel technique and gravitational lenses that do the same. The function of classical lenses, which are the first type of optical instruments capable of making a focus point, can be described based on geometrical optics. In this view, the geometry of interference surface plays an essential role on beam behavior. Light rays that are supposed to move in a straight line change their direction according to the interference of a second transmission medium. Change of medium changes the phase velocity, but frequency remains constant. This phenomenon is called refraction, and it is based on the angle of incidence and refractive index of the two transmission media. Refraction follows Snell’s law: sinθ V n 2 ==1 2 , where Ɵ is the angle of incidence, which is defined as the sinθ1 V2 n1 angle between the light ray and the vector perpendicular to the lens surface at the meeting point, V is the velocity of light in each medium, and n is the refractive index.

(continued) 3 Biophysics of Vision 29

Box 3.1 (continued) Refractive index is a measure of light speed in a medium. The higher the refractive index, the slower the light propagates through the medium, and the greater the ray deviates from its original angle. We define vacuum and air refractive index as equal to 1, which is the minimum amount of possible refractive index among different media. To be more precise, the refractive index of an optical medium depends on beam frequency, but it can be neglected in common geometrical optics experiences (Fig. 3.1). In classical lenses, surface curvature is the most important geometrical property that is determined by the radius of the sphere from which the lens is extracted. Clinical Correlates 1 There are a couple of pathologic conditions in which the focal point is shifted from its original point, and therefore, light cannot converge on the retina as a single point (refractive errors). In nearsightedness (myopia), images are focused in front of the retina. This causes blurring of distant objects, while close objects appear normal. In contrast, images are focused behind the retina in farsightedness (hyperopia), and close objects appear blurred, while far objects appear normal. In astigmatism, light beams are scattered, and images are not focused on the retina. This condition results in blurred vision at all distances. Presbyopia is a consequence of normal aging, in which the crystalline lens loses its elasticity and ability during accommodation. The treatments more commonly used for refractive errors are eyeglasses or contact lenses. These lenses place the focusing point accurately on the retina. In myopia, corrective lenses have negative powers, while in hyperopia, convex lenses are used. Surgery is another treatment for refractive errors. In photorefractive keratectomy (PRK), corneal surface tissue is ablated by using an excimer laser.

Fig. 3.1 Different refractive indices of wavelengths with different frequencies

(continued) 30 S. Shahjouei and M. Amini

Box 3.1 (continued) The amount of ablated tissue is determined by the severity of myopia. The principle of laser epithelial keratomileusis (LASEK) is almost the same as that for PRK, except for the use of alcohol to loosen the corneal surface. In laser-assisted in situ keratomileuses (LASIK), the cornea is cut and lifted, and the excimer laser beam ablates the exposed corneal tissue instead of the surface tissue. Similar to PRK and LASEK, this method reshapes the curvature of the cornea and alters its refractive power. Because the corneal flap is replaced and the surface tissue is intact, LASIK is less painful and has a shorter rehabilitation period. In the phakic intraocular lens, an additional lens is implanted inside the eye. In refractive lens exchange (RLE), the crystalline lens is surgically removed and replaced by artificial intraocular lenses. Clinical Correlates 2 Cornea Each compartment of the orbital glob has its own refractive index, which causes the passing light beam to refract accordingly. The cornea is widely known as the most crucial component in focusing the light on the retina, producing about two-thirds to 80% of the focusing power of the eye [1, 2]. This is a direct consequence of the Snell’s law. The greatest difference in refractive indices between each two consecutive transmission media in the eye is those between air and external surface of the cornea. Consequently, the highest refraction fraction is produced as light enters the eye. The anterior surface of the cornea has a power of about 48 D, while the posterior surface produces −8 D, leaving an about 40 D focusing power by the cornea. This is a rough estimate, and each point on the corneal surface has its own refraction power. Lens The crystalline lens inside the eye is another essential component for refracting the light. The lens has an anterior radius of 12 mm and a posterior curvature radius of −6 mm, which can greatly change through accommodation. By contraction of the ciliary muscles, the thin zonular fibers attached to them relax, and this allows the lens to restore its curvature, particularly at the anterior surface. Consequently, the power of the lens is accentuated from 20 D to 33 D. Transparency and GRID As described in the text, the crystalline lens is incapable of protein synthesis in the inner fiber cells and turnover of its intracellular components. As a result, any pathologic insult can affect the integrity and transparency of the lens and pathologies such as cataract. There are numerous etiologies, which lead to alteration of the refractive index and cataract formation. Aging, genetic diseases, viral infections, trauma, radiation, medications, alcohol, and smoking are some of the underlying causes [7, 9]. For example, in uncontrolled diabetes mellitus, glucose leaks to and diffuses through the lens due to its high plasma concentration. The enzyme aldose reductase converts this sugar to its 3 Biophysics of Vision 31

Box 3.1 (continued) corresponding alcohol, sorbitol. The lens is impermeable to sorbitol, and accumulation of this substance causes an imbalance in osmotic equilibrium and absorption of water in the lens. The consequent rise in sodium level and decreased potassium and glutathione levels end up in loss of transparency and cataract formation. This, in turn, will increase light scattering and reduction in vision and glare. Other etiologies may follow the same principles. In galacto- semia, an inherited metabolic disorder, the extra plasma galactose enters the lens and is converted to its corresponding alcohol by aldose reductase. The same as in diabetes mellitus, the resulting metabolite cannot leave the lens, and it demolishes the transparency of the lens. These pathologic events change the transparency of the lens and GRID by inducing aberrations, and light scattering lowers the quality of image formation. Aging and Loss of Ability to Change the Curvature At birth, there is a physiological hyperopia, which is spontaneously corrected by 2+ years as the globe shape changes [77]. Aging can alter the power of the lens by changing its curvature, mass, volume, and thickness. The lens gradually gets stiffer and loses its capability of changing the curvature. Although the anterior surface of the lens gets steeper, it cannot increase the power of the lens as the refractive index of the lens also changes. Alteration of the GRIN is responsible for the underlying refractive index variation [78]. The second type of instruments with focusing ability is the Fresnel method. Fresnel rings are concentric circles that act based on wave characteristics of light. The main idea of this method is the interference and superposition principle of waves based on phase path difference for the specific frequency of light spectrum. As it is known, two waves that travel together can cause interference with different phases at each point of space. If the waves meet each other with the same phase at one point, then the amplitude of the waves will be added to each other and cause strong amplitude at that point. Besides, if waves meet with opposite phase, then the amplitudes will cancel each other and a dark spot will appear (Fig. 3.2). The light ray diffracts after passing through concentric Fresnel rings and creates an interference pattern in space (Box 3.2). Hence, each light color with the specific frequency produces a distinct focal point. In addition, because of the periodic feature of waves, the Fresnel method yields in multiple less bright focal points along the axis of symmetry for each specific wavelength (Fig. 3.3). However, the first bright point of the pattern along the axis of symmetry is considered the focal point for a specific frequency. To take another step forward, it is possible to merge the idea of classical lens and Fresnel rings to create a new type of lenses known as Fresnel lens (Fig. 3.3). These lenses are made by reducing classical lenses into concentric transparent rings. The thinness of the Fresnel lenses is an advantage when compared with classical lenses.

(continued) 32 S. Shahjouei and M. Amini

Box 3.1 (continued)

Fig. 3.2 Superposition theory

Fig. 3.3 Fresnel lens

Focusing methods are not limited to the abovementioned tools. A broad spectrum of different structures, from primitive instruments such as pinhole camera to extremely complicated features such as the gravitational lens, can bend and focus light rays. Gravitational lens, which is the effect of ultra-massive cosmic objects on light geodesies and the idea of four-dimensional space– time structure, was described by the general relativity theory by Einstein. The details of these techniques would be beyond the scope of this chapter. 3 Biophysics of Vision 33 irregularity and changes in curvature and opacity of the cornea [1]. Even slight alteration in the corneal surface, as it may happen when the covering tear film is evaporated, can affect the corneal topographies [4].

Lens

The crystalline lens is located behind the apparatus in the iris and is responsible for accommodation and refraction. The lens consists of a capsule, epithelium layer, and lens fibers. On average, the lens has a diameter of 10 mm with an axial depth of 4 mm (Box 3.1). However, its dimension varies during accommodation. In addition to accommodation, crystalline lens may act in reducing the aberration introduced by the cornea. The diameter, curvature, and structure of the lens vary with aging. Fiber cells are continuously added to the cortex, and the old cells are pushed toward the core of the lens. Besides this, the lens becomes avascular during fetal development and main- tains its metabolism through microcirculation flowing between the fiber cells [5–7]. These events change the refractive profile of the lens. The absence or minimized vasculature and intracellular organelles, highly organized cellular architecture, and equal refractive index of the membranes and cytoplasm of fiber cells in the nucleus help crystalline lens of the eye to keep its unique transparency and mitigate light scattering [5, 7, 8]. In fact, each segment of the lens from the surface to the inner part of the nucleus has its special feature for minimizing light scattering. Differentiating fiber cells present within the remodeling zone of the cortex exhibit extensive cellular disorganization. Through this transformation zone, fiber cells lose their nuclei and undergo cellular rearrangement and membrane and intercellular modifications [5, 7]. After exiting from the remodeling and transformation zones, which are few micrometers wide, fiber cells are arranged in a hexagonal cross-sectional ordered architecture. Fiber cells are arranged side by side from their broad aspect in each column and are connected to the adjacent cell columns by their narrow side [5, 7]. This well-organized geometric order of lens fiber cells minimizes the extracellular space. Thus, despite refractive index mismatch between different compartments, this regular spatial order mitigates light scattering. In the more central parts of the lens, the spatial order and similar spaces between fiber cells are not maintained anymore. Instead, intracellular mechanisms are more prominently responsible for minimizing light scattering. To reduce light scattering due to the difference in refractive index of each organelle and intracellular compartment, these organelles are degraded through the differentiation of lens fiber cells, keeping an almost homogenous cytoplasm. The difference in proteins and intracellular compartments of the fibers in the periphery and the center of the lens makes the gradient of refractive index (GRIN), which, besides anterior and posterior surface curvature, contributes to the optical properties of the lens [7]. GRIN is responsible for the lower refractive index in the lens periphery than in the lens core [7, 9]. GRIN is determined by the water-to-protein ratio, which is higher in the periphery than in the core. The microcirculation of the lens and pattern of ionic homeostasis and water flux actively maintain the GRIN [10]. GRIN makes a negative spherical aberration that, 34 S. Shahjouei and M. Amini together with the positive spherical aberration of the cornea and lens’s geometry, results in the sharpness of the images (Box 3.1) [7, 11]. Although these adaptive mechanisms are essential for removing light scattering, they make the crystalline lens incapable of protein synthesis or turnover of its structural proteins in most sections, leaving the lens susceptible to pathologic conditions (Box 3.1) [5, 7, 8].

Accommodation

Defocus produces blur and reduces the quality of image formation. Accommodation, the ability of the eye to keep the focusing point on retina irrespective of the image distance, is a mystery of the eye. During accommodation, the optical characteristics—more prominently, the spherical refractive power—of the eye change [12]. Integrity and opacity of the cornea and crystalline lens, alteration of corneal and crystalline lens curvature and power, anterior movement of the lens and visual axis elongation are attributed to the accommodation [3, 12–15]. Alteration in crystalline lens’s curvature and dioptric power of the eye is an integral part of the accommodation. The crystalline lens is surrounded by thin suspen- sory zonular fibers, attaching it to the ciliary body. When the object is close to the eye, contraction of these fibers pulls the ciliary body forward. This contraction results in lens relaxation and accentuation of its curvature and, consequently, increasing its focusing power [5, 9]. The proximity of the limbus to the ciliary muscles makes cornea as a counterpart of the crystalline lens in producing accommodation. The ciliary muscle is connected to the scleral spur and ora serrata with the aid of three sets of muscle fibers—cir- cumferential, meridional, and radial—and surrounding connective tissues. The forces produced by contraction of the ciliary muscles pull the limbus of the sclera and cornea centrally. This motion shortens the diameter of the cornea and steepens its curvature. In fact, the contraction of the ciliary and extraocular muscles during accommodation and convergence can be applied to the cornea and change its topography and increase its optical power [3, 4, 14, 15]. Besides steepening of the corneal topography and higher refraction index, decreased anterior chamber depth and volume and decline in higher-order spherical aberration were reported in association with corneal accommodation [16]. Mitigated wavefront higher-order aberration is more prominent in the anterior corneal surface and the entire cornea than in the posterior corneal surface [16]. Despite these findings, other studies revealed that variations in anterior, posterior, and sagittal curva- tures, total corneal power, and corneal pachymetry are insignificant in central, paracentral, and peripheral corneal zones during accommodation [13–15]. The reason for this disparity could be the changes in corneal cylinder axis with accommodation; when this excyclotorsion is accounted, no significant corneal topography alteration can be demonstrated in association with accommodation [12, 15]. In addition to blur, chromatic aberrations, monochromatic aberrations, microfluctuations, and the Stiles–Crawford effect are cues of defocus and accommodation 3 Biophysics of Vision 35

[17, 18]. Microfluctuations, the oscillating alteration of the crystalline lens optical power, occur with high- and low-frequency components. Low-frequency components are more probable in smaller pupil sizes, more prominently in pupils less than 2 mm, while high-frequency components are not a function of the pupil size.

Pupil

Light rays passing through the retina show different visual properties based on the size of the pupil and the direction of the emission. Light rays that enter at the center of the pupil strike the retina straightly, while rays at the edges of a fully dilated pupil strike the retina at an approximate 10° angle [19]. The diameter of the pupil determines the light intensity and degree of retinal stimulation [19]. Stiles and colleagues [20] computed the effect of pupil aperture diameter on the overall luminous efficiencies of light entering the eye and validated their calculations by direct measurements. They proposed that luminous efficiencies of a narrow bundle of rays entering through the pupil depend on the point where the beam passes through the pupil; rays passing through the center of the pupil make the peak luminance, while at the edge of the pupil, the luminance decreases even up to threefold [20]. The reduced visual sensitivity based on the light ray’s entry point to the pupil is called the Stiles–Crawford effect (SCE), also known as the directional sensitivity of retinal cells. Since SCE was introduced, several attempts have been conducted to investigate the extent of its effect. SCE is a crucial feature of the visual system for mitigating the impact of defocus and aberrations on the image, more noticeably when the pupil is dilated. Contrast sensitivity, transverse chromatic aberration, visual acuity, depth of focus, and spatial visual performance are some of the features affected by SCE [21, 22]. SCE is more prominent for myopic than hyper- metropic defocus and has high-contrast rather than low-contrast letters [22]. An extension of the Stiles–Crawford effect, called the optical Stiles–Crawford effect (OSCE), presents the directionality of light reflected from the retina [23]. OSCE follows a similar, and rather, narrower curve, presumably due to energy distribution following reflection [23, 24]. One probable explanation for this finding is the retinal photopigment molecules, shape, alignment, and waveguide characteristic features of retinal cells [19, 23, 25, 26]. The response of rod cells to light is less respective of the angle of the entrance, and these cells express slight directional effect only in the extreme incident angle of the light and high obliquities [26, 27]. In contrast, cones are the integral players of the Stiles–Crawford effect. It is widely demonstrated that cones have a heterogeneous response to directional sensitivity, and parafoveal cones are more sensitive than central foveal cones [26, 28]. This might be explained by the alteration in the shape of the cone cells from the fovea (with the shorter outer segment and morpho- logically much similar to rods) to the peripheral parafovea (resembling the classical cone shape). The other possible mechanism is based on diffraction, the interaction of light beam with the rim of the pupil and photoreceptors’ apertures (Box 3.2) [22, 23]. 36 S. Shahjouei and M. Amini

Box 3.2 We all have seen the waves that are created by throwing a stone in a lake. These circular co-centered waves propagating to the surrounding are called spherical waves. In fact, the spherical waves are created by single spotlike sources in isotropic media—media with similar features in all directions. Now, envisage an extremely large lake with no friction so that the wave can propagate to a far distance without damping. As the waves move away from the wave center (the primary source), the circles will grow bigger and bigger until they can be approximated as flat plates. A more sensible example to assume a curvature as a flat plate is the Earth, as the Earth’s diameter is larger than one can sense its curvature while walking on the street. These spherical waves in the far distance from the source are known as plane waves. When a plane wave goes through a slit, it scatters and the remaining beams that passed through the slit are not able to propagate as a plane wave but rather transform to a spherical wave. This phenomenon, which is the result of wave interaction with the edge of the slit, is known as diffraction. According to Huygens Fresnel principle, each point on the wavefront can be considered as a tiny source emitting spherical waves independent of other sources on the wavefront. The interference pattern of these waves is determined according to the superposition principle. The combination of two waves and creation of a new wave with special features that depend on but different from the initial waves is called superposition principle (Fig. 3.4). The intensity of the light wave energy depends on the wave amplitude. When two waves have constructive interference, their amplitudes are added up, leading to a wave with higher intensity. The opposite is true for destructive interference. If two waves have the same amplitude with destructive interference, then no energy will be transferred. Fig. 3.4 Diffraction pattern of the wavelengths passing through a slit. Superposition of wavelengths creates an interference pattern in which the center point has higher intensity and multiple less bright focal points 3 Biophysics of Vision 37

Box 3.2 (continued) The interaction of the light beam with the aperture through which it is passed, the pupil, produces a special pattern of light spread on the retina. This diffraction pattern of the focus plane has a bright region in the center (Airy disk), surrounded by a series of concentric bright rings (Airy pattern). The diameter of the Airy disk is directly proportional to the wavelength and inversely to the pupil size [19]. In fact, constructive interference of the light rays at the center produces the highest intensity of light. As we move from the center to the surrounding, light waves meet each other with destructive interference, as presented as dimmer concentric rings. The periodic feature of the waves makes the oscillating pattern of the light intensity until the light points become dimmer and dimmer and disappear at the far distance. To be more precise, the location of the second peak of light intensity depends on the light frequency. In fact, all light wavelengths that have incidence on the center and the light waves with higher frequency—short wavelength—peak more closely than waves with long wavelengths. By this means, diffraction can make a scatter pattern similar to the pattern in prism light decomposition. From the center to the surrounding, we can envisage encircling peak intensities with different colors (Fig. 3.5). Interestingly, due to the difference in the size of the pupil and photoreceptor aperture, the incoming light is perceived as a plane wave by the cell and is dif- fracted once more. To reduce the scattering, nonabsorbed light beams are collected by a layer behind the photoreceptors, named retinal pigment epithelium (RPE). The remaining lights can reflect back to the pupil and produce OSCE.

Fig. 3.5 Diffraction pattern of white light passing through a slit. In the center, all light wavelengths are incident and make a white bright focusing point 38 S. Shahjouei and M. Amini

Retina

The retina is a complex multilayer structure composed of more than 100 distinct types of neurons. Light passes through these layers to strike the receptor cells, from which electrical signal is produced. The signal is transmitted through a set of cells, among them are bipolar, amacrine, and horizontal cells, which direct the impulses to the ganglion cells and optic nerve. Photoreceptors and retinal ganglion cells are the main cells capable of absorbing light. Subtypes of the photoreceptors vary greatly on their properties. Cone photoreceptor, responsible for high acuity vision, color vision, and directional sensitivity, has three subtypes with specific spectral sensitivity. Rod photoreceptors exert their function in producing image under dim light. The distribution of the photoreceptors is not even on the retina. The visual center of the retina, fovea, is a slightly depressed surface compared to other parts of the retina. Density of the cells and ratio of the cone to rod cells, cone ellipsoid taper, inner and outer segment length, and taper length are some of the well-described differences of foveal and parafoveal regions [28]. Cones are compact in fovea, while rods are located more prominently at about 20° away from the fovea. The difference in foveal/parafoveal response of retinal cells and SCE also makes it possible to distinguish between photic and scotopic visions [29]. Some of the retinal ganglion cells, which relay the output signal of the retina to CNS, are direction-selective. In fact, direction-selective perception exploits three features: spatial asymmetry of the dendritic tree, nonlinear interaction between responses of different dendritic subregions, and adequate temporality of the response to the stimuli to be summed up for the final response. Dendritic distribution and receptive-field substructures of the direction-selective cells are components of the spatiotemporal perception. Instead of concentric distribution of the dendritic field, dendrites are spread systematically asymmetric in the preferred direction. There is a great diversity of these cells. Some cells only respond to the preferred direction, while other cells might recognize the motion on the opposite direction. In some cells, dendrites are arranged in a bistratified morphology structure—the nonrespon- sive region to the specific direction close to the soma and the responsive dendritic region distributed ventrally and distal to the soma. Postsynaptic mechanisms are also accountable for direction selectivity of the ganglionic cells [30]. Perception of the motion by the visual system not only comprises the movement of the object but also reduces the effect of head and eyes movement of the individual.

Non-image Forming Functions of Visual System

Perception of Magnetic Field

One of the special non-image forming functions of the visual system is the perception of magnetic field (Box 3.3). Geomagnetic field passes freely through moun- tains, oceans, and air, and many taxonomic classes of creatures are capable of 3 Biophysics of Vision 39

Box 3.3 The electromagnetic field frequencies in most of the biological processes are in the extremely low-frequency zone (0–300 Hz) [79, 80]. The magnetic field can be described by (1) its intensity (vector magnitude), (2) inclination angle (the angle between the horizontal plane and the magnetic field vector, and (3) declination angle (magnetic and geographic north angle) [32]. The mystery behind the mechanism of geomagnetic sensation is not fully revealed. Since the geomagnetic field occupies the individuals, unlike other sensory receptors, it is possible that magnetoreceptors are dispersedly located in all tissues [81]. Current knowledge suggests that sensation and interpretation of magnetic field are interwoven with the visual system [82, 83]. Responses to the magnetic field are processed in a similar part of the brain that receives information from the visual system [36, 82, 83]. In some animals, magnetosensation is totally dependent on reception of specific light wavelengths [36, 84, 85]. Many researchers mentioned that magnetoreceptors are located in photoreception areas [86, 87]. Retinal ganglionic cells are more commonly proposed to be the key cells that detect magnetic compass information [87, 88]. However, other cells such as outer segments of double-cone photoreceptor cells are proposed to contain magnetoreceptors [86]. The visual acuity and discrimination threshold are dependent on the geomagnetic field and its direction [41, 84, 89]. The geomagnetic field also alters the level of light adaptation. In addition, Phillips and colleagues proposed that geomagnetic sensation is used as a 3D coordinate system for interpretation of the distance, direction, and spatial position [90]. Different mechanisms have been proposed to explain the magnetoreception in living organisms. Electromagnetic field induction, magnetocaloric properties, photo-induced radical-pair reactions, and the combination of these models were suggested. In the following, we briefly go through four common hypotheses for magnetoreception mechanism. Electromagnetic Induction Hypothesis The induction theories and their extensions were the primary speculations regarding electromagnetic field detection by organisms [91]. Electromagnetic induction is the induction of an electric field by the motion of the organism through a magnetic field. Faraday’s law of induction, a basic law to describe how the interaction of the magnetic field with an electric circuit leads to elec- tromotive force (EMF), is fundamental for the induction theories. EMF is the voltage developed by the source of electrical energy. The induced EMF is proportional to the time rate of magnetic flux changes inside the circuit:

dΦB ε =− , where ε is the EMF and ΦB is the magnetic flux. Flux is defined dt as the amount of vertical component of a field (e.g., magnetic or electric) that passes through a hypothetical surface. Accordingly, flux depends on field

(continued) 40 S. Shahjouei and M. Amini

Box 3.3 (continued) strength, the surface area enclosed by the wire loop that the field vectors pass through, and the angle of incidence between the field vectors and the hypothetical surface. Both electric and magnetic fields apply force on a charged particle. The exerted force on the particle is parallel to the extension of the field, and its direction depends on whether the particle has a negative or a positive charge. The strength of the force is proportional to the charge size and electric field strength:

F = qE⃗, where F⃗ is the force vector, q is the charge of the particle, andE ⃗ is the electric field vector. The interaction of the magnetic field with the charged particle is a bit more complex. The strength of the magnetic force on a particle depends on not only charge size and magnetic field strength but also charge velocity and its angle with the magnetic field:

F = qV × B⃗, where F⃗ is the force vector, q is the charge of the particle,V ⃗ is the velocity vector, and B⃗ is the magnetic field vector. Static particles or those moving parallel to the magnetic field experience no magnetic force. The force-extension is perpendicular to both magnetic field and velocity. The direction of the force would be detectable by the right- hand rule; when putting the right hand in such a way that the fingers are parallel to the velocity direction and the vector of the magnetic field comes out of the palm, the direction of the thumb shows the extension of the force vector. All abovementioned equations are summarized as follows:  Fq=+EqVB→→× ; all notions are the same as above. This equation is known as Lorentz force. Accordingly, when a charged particle passes through a magnetic field, a force perpendicular to its motion and direction of the magnetic field is applied to the particle. As a result of this induction, the charged particles produce a constant voltage by moving through a magnetic field, and this current can flow through the surrounding conductive medium. Passage of ions through transmembrane channels and motion of charged molecules can produce DC electric fields that rapidly detect intracellular and extracellular micro-alterations. The action potential of cardiac, neural, and muscular tissues generates electromagnetic fields in the range of extremely low frequencies. In many physiologic conditions, the strength of the electric field is not sufficient to pass through the cell membrane thickness. However, intracellular compartments sense the induced magnetic field.

(continued) 3 Biophysics of Vision 41

Box 3.3 (continued) Magnetocaloric Hypothesis According to this theory, when intracellular paramagnetic components such as ferritin are located in the magnetic field, the magnetic moments align and reduce the entropy. Increased molecular vibration and heat are the direct consequences of the mitigated entropy [92]. This thermal energy, in turn, can open the temperature-sensitive gated channels. A possible example of this mechanism is the transient receptor potential (TPR) family, which includes ferritin-containing nonselective Ca2+-permeable channels [92, 93]. In TRP vanilloid subfamily member 4 (TRPV4), magnetocaloric effect and increased temperature break a hydrogen bond between the residues L596 and W733 and change the configuration of the channel from close to open [92, 93]. Other members of this family have similar homologies (e.g., F559–W697 bond in TRPV1) and seem to respond alike [94]. Mechanical Hypothesis In this model, the interaction between the cell membrane and intracellular iron-based molecule plays the major role in transducing the magnetic signal to the cell [31, 81, 95]. In fact, the magnetic field induces a torque on the cel-

lular ferromagnetic material and nanoscale crystals such as magnetite (Fe3O4). When the magnetic dipole moments of the magnetite crystal and cell membrane are no longer aligned, the tension and motion produced by the rotation of the crystal are transferred to the cytoskeleton and the membrane. As a result, the mechanically gated ion channels open [31, 81, 95, 96]. There are two possible ways that magnetite can cause magnetosensation. In the first model, the molecule containing iron aligns with the geomagnetic field by its own overall permanent magnetic moment [95]. In the second model, the molecules transitionally encounter magnetic moments under the influence of the surrounding fields [95]. The same as the first model, opening of the mechanoreceptors start a cascade of intracellular signaling pathways. It is postulated that when the external field and magnetic intensity alteration are parallel, the greatest stimulation is applied to the cell. In addition, rotation of the magnetic field direction without any change in its intensity can induce membrane potential variation. This is due to the shift of the magnetic intensity. The intensity of the magnetic field determines the size of the active area of the cell membrane and the state of the channels. Thereby, each cell has a threshold sensitivity for the magnetic intensity oscillations [96].

Single-domain crystals of magnetite (Fe3O4) are the smallest particles containing iron with a permanent magnetic moment at room temperature [97]. In living organisms, magnetotactic bacteria benefit from magnetite mechanism. These bacteria have iron oxide magnetosomes, or iron sulfide magnetosomes, which are arranged in chains. The chains of the magnetite are anchored to the cell membrane. The arranged intracellular ferromagnetic

(continued) 42 S. Shahjouei and M. Amini

Box 3.3 (continued) crystals of magnetite produce a magnetic moment and cause the cell to align itself according to the magnetic field and cause opening of mechanical receptors [32, 98]. In the geomagnetic field, a short iron chain produces 1 pN of force, which is enough for changing the equilibrium and state of the channels that is achieved by thermal agitations [99]. It is possible that cryptochromes, the integral part of the magnetosensory structures, work as a magnetic moment in the absence of light [81]. Cryptochrome signaling reactions are accepted in avian magnetoreception [37]. Qin and colleagues [100] described a nanoscale macromolecule complex contains an iron–sulfur magnetoreceptor (Drosophila CG8198, known as MagR) and interacts with flavoprotein cryptochromes. In this complex, rod-like strings of MagR molecules are linearly polymerized at the core, and the double helix of cryptochrome molecules encompasses them. This light-dependent biocompass aligns in response to the magnetic field and can detect polarity, intensity, and inclination [100]. For this means, light stimulation starts electron transfer from the FAD group of the cryptochromes to the Fe-S cluster. The connection of this alignment to the cellular cytoskeleton and channels would transduce the signal and form the basis of magnetic sensation [100]. Studies on different cell lines and MagR constructs demonstrated that MagR alone cannot produce intracellular current and magnetic reception [101]. In retinal ganglion cells, Cry and MagR are colocalized [88]. In addition, MagR/Cry complex is evolutionarily conserved from insects to mammals [100, 102]. There are other reports in which coupling of ferritin with membrane channels makes magnetoreception possible [103, 104]. These observations make the MagR/Cry complex a putative candidate for magnetoreception. However, there are some comments on the possibility of these assumptions to function in real cellular environments. For example, the number of iron atoms in the MagR/Cry complex is not sufficient to produce the described effect, and the discrepancy is about 5–10 log units [105]. Meister argued the potential of the magnetoreceptors proposed by Qin et al. to be about 5 log units less putative to overcome the thermal force disturbance [105]. Chemical Magnetoreception Hypothesis The basis for this model is the transfer of an electron from the electron donor molecule (D) to the electron acceptor molecule (A) and production of spin- correlated radical pairs [35, 37, 81, 106]. Although the main theory for describing the atomic characteristics is quantum mechanics, we can apply the classical approximations in some special occasions. In the classical view, the electron rotates around the nucleon of an atom in certain orbits. This motion creates an electric current, and as the electron is considered to have an orbit in

(continued) 3 Biophysics of Vision 43

Box 3.3 (continued) a two-dimensional plane, it makes a close flat circuit. Electric circuits have some special electromagnetic features. The first hallmark of electric circuits is based on the electromagnetic theory: an electric current induces a magnetic field in its surrounding, perpendicular to the plate of the current. The knock of creating a microscopic electrical circuit makes atom a potential microscopic magnet. The strength and polarity (N to S direction) of this tiny magnet is determined by a parameter called the magnetic moment of the atom, which depends on the encom- passed area of the circular current and the magnitude of the current itself. The second feature of the electromagnet is based on the nature of the magnetic force: an external magnetic field can induce a magnetic field in the nearby closed electric circuit, with an opposite field direction. Consequently, the external and the induced magnetic fields repel each other. Photo-induced electron transfer reactions are a candidate of the required primary interactions for this hypothesis [37, 84, 88, 106]. For this means, pigment molecules absorb the energy of a photon of light and make A excited. Then an electron is transferred between the two molecules (1A* and 1D), and a pair of doublets (2A− + 2D+) or 1(2A− + 2D+) is formed. These pairs can transform to either the ground state (1A + 1D) or the excited triplet state (3A* + 1D) [106]. The proximity of the electrons causes the transition of the unpaired electron spin state (singlet–triplet intersystem crossing) [107]. The torque exerted by motion and spin of the electrons causes the magnetic moment to process around the direction of the magnetic field (Larmor precession) [79]. Magnetic nuclei, the magnetic field induced by unpaired electrons, and an external field can change (process) the orientation of the electron rotational axis [35]. The precession of electron spin in donor and receptor molecules differs in magnitude and orientation as a result of different magnetic forces that are applied to them [35, 106]. If the transfer of the electron occurs after an adequate interval, the precession of the original spins and the relative amount of singlet or triplet formation can make subsequent reactions possible [35, 81, 107]. Because of the Brownian motion, the ionic pair 2A− and 2D+ spends limited time (in the order of nanoseconds) in close vicinity, and magnetic interactions should play their role in short intervals [106]. Some speculated that lifetime of ∼1 μs can be suitable for the sensation of geomagnetic. Not just doublets, but triplet pairs and triplet–doublet pairs can be influenced by external magnetic fields [106]. Singlet and triplet alignments have energetic degeneracy, and only a perturbation energy of 10−7 eV (e.g., magnetic interactions) is sufficient to produce spin alignment [106]. Radical pair sensors are directionally sensitive, and at least one of the electrons in the radicals should interact anisotropically with the nuclear magnetic spin [84, 87]. In other words, in radical pairs with one dominant hyperfine interaction and adequate lifetime, a magnetic field

(continued) 44 S. Shahjouei and M. Amini

Box 3.3 (continued) with a thousandth of the geomagnetic field strength can produce detectable effects [37, 84, 87, 108]. Many authors have claimed that the magnitude of the energy needed to transfer an electron from one orbital to another and higher kinetic and thermal energy kT of the molecules in physiological temperature make it less possible for biological processes to be affected by magnetic fields in measurable degree [35, 80]. Ions and molecules are bound to water and proteins, and applying solid- state physics is not appropriate for biologic systems [79]. In addition, more than one nuclear spin interacts with the electron spin in the biological system, and presence of other electrostatic couplings has effects on the zero-field degeneracies [84]. Despite these comments being valid, in the presence of a coherent quantum mechanical process perturbation, energies much smaller than kT are sufficient to influence chemical reactions [106]. Magnetic fields of≤ 50 μT can change the lifetime of the photo-induced radical pairs [109]. In fact, the precession of the ionic oscillator in the magnetic field will persist at the Larmor frequency in superposition with thermal forces [79]. Moreover, with the appropriate resonance and coherence, even pT–nT magnetic fields can produce a large effect [79, 110]. The number of radical pairs and direction and intensity of magnetic field determine the signal produced by the magnetoreceptor molecules [111]. In addition, a high concentration of the target molecules (for instance, millimole to micromole in biological reactions) is another factor that makes the magnetic field of picotesla sufficient for producing detectable effects [111, 112]. Zablotskii and colleagues provided the theoretical argument in which a relatively small spatially nonuniform magnetic field (approximately 1 T) with a large gradient (up to 1 GT/m) can alter the membrane potential of the cell [113]. Cryptochromes—Crys, which are important components of the circadian rhythm detection—are the key proteins that respond to the magnetic field [83, 107, 114, 115]. Cryptochrome proteins are organic photoreceptors of vertebrates, which perform their function by radical pairs [37, 84, 87]. One proposed mechanism for magnetoreception of Crys is the radical pair mechanism. The flavin cofactor of the cryptochrome—flavin adenine dinucleotide, FAD— absorbs a photon and becomes excited (FAD*). Absorption of an electron from the adjacent tryptophan forms a radical pair [FADH• + Trp•]. Trp• can absorb another electron from a tyrosine residue and fix the radical pair on FADH• [37]. The responses of Cry extensively depend on the light wavelength [107]. It is stated that cryptochromes need other intracellular molecules for responding to electromagnetic field [115]. 3 Biophysics of Vision 45 detecting it [31–36]. A wide variety of animals including mammals, fish, reptiles, insects, and birds can sense and take advantage of the geomagnetic field as a guide for navigation, orientation, and migration [31, 33, 37]. Earth’s magnetic field extends from the planet’s core up to the atmosphere. Field lines leave the southern pole and curve to enter the northern pole. The geomagnetic field is of the order of a few microteslas and is twice as strong on the magnetic poles as the magnetic equator. The geomagnetic field is a non-time-varying (De) field. This three-dimensional invisible vector protects the Earth from cosmic rays and solar winds. Variations in geomagnetic field occur in the scale of days to centuries. Daily variations are mostly as a consequence of space weather disturbances (Box 3.4).

Box 3.4 Within the solar system, variations in interplanetary space near Earth are referred to as space weather. It affects magnetosphere, ionosphere, thermo- sphere, and exosphere and is different from the terrestrial weather of the Earth’s atmosphere (i.e., troposphere and stratosphere). A ground-level manifestation of space weather event is the induction of electric currents in magnetosphere and ionosphere (geomagnetically induced currents), which exert an effect on Earth’s magnetic field. A couple of events are introduced as key features of space weather. In the following, some of these events are summarized. Coronal Mass Ejection (CME) The corona, which is the outermost layer of the Sun that can be considered as the Sun’s atmosphere, extends beyond the orbit of the Earth. Coronal mass ejections (CMEs) are a large-scale release of high-density and high-velocity plasma from solar corona outward. The plasma is transmitted to the Earth as solar winds’ perturbations. CMEs originate from active solar regions such as sunspots associated with solar flares. During solar maxima—a period of greatest Sun activity in an 11-year solar cycle, with the high number of sunspots—CMEs occur almost three times a day. In solar minima, with diminished sunspot and solar flares, CMEs might appear once in 5 days. CMEs can affect the magnetosphere and cause geomagnetic storms. Solar Energetic Particle Event (SPE) Solar energetic particles (SEPs) consist of protons, electrons, and HZE ions. When these high-energy particles are projected from the Sun, SPE is experienced. Solar energetic particles can originate from the shock waves caused by coronal mass ejections or be associated with solar flare sites. SEPs are accelerated—either through diffusive shock acceleration or by the shock- drift mechanism—to such high energies that they can reach to the Earth in a few hours.

(continued) 46 S. Shahjouei and M. Amini

Box 3.4 (continued) Geomagnetic Storms A geomagnetic storm is a temporary perturbation of the Earth’s magnetosphere due to solar wind, in which magnetic field induced by the intense solar wind compresses the magnetosphere for a prolonged period. Compression and transfer of high energy to the magnetosphere end up to the accelerated electric field inside the magnetosphere, probably because of plasma movement. This electric current induces a magnetic force between solar wind and magnetosphere. During a geomagnetic storm, an abrupt increase in magnetic field intensity for a few hours is followed by a sudden decrease, continued by a recovery phase. Geomagnetic storms are a result of solar coronal mass ejections or solar winds and follow the solar cycle. Storms occur for typically 1–5 days with 100 nT magnitude. During storms, auroras—precipitation of the charged particles in the solar wind and magnetospheric plasma in the upper atmosphere, causing ionization and excitation of the atmosphere and emission of light with different colors—are widely disturb and display in lower latitudes. Van Allen Radiation Belts’ Alterations Energetic, charged particles from the solar wind and cosmic rays are entrapped by the geomagnetic field in two zones called Van Allen radiation belts. Both belts are located in the inner region of the Earth’s magnetosphere. The outer belt is larger than the inner belt, and its components vary greatly. The outer belt is more prevalently disturbed by solar activities than the inner belt. The geomagnetic storms alter the energetic particle fluxes of these belts, which is more pronounced in the outer belt than in the inner belt. Clinical Correlates 1 Chizhevsky, the founder of the heliobiology, proposed the sensitivity of humans to the Earth’s magnetosphere and ionosphere perturbations (for review, see [116]). The nonlinear magnetic sensation is evidenced by means of evoked potentials on electroencephalograms [117]. The magnetic field can alter the concentration of the signaling molecules and substances [118]. Physiological indexes such as heart rate variabilities and metabolite concentrations are geomagnetic latitude dependent [63, 119]. Auroral belt has the highest geomagnetic activity, and habitats in these regions, more probably those who migrated from lower latitudes and are unaccustomed to this geophysio- logical features, are more susceptible to sustain cellular pathologies [116]. The geomagnetic field has oscillations of different timescales, from mil- lennia to decades as a result of its core, to seconds to years in response to solar activities. The Sun’s natural oscillations, pronounced in a wide spectrum of time scales from a few minutes to several years, affect space weather and human life. Cardiovascular parameters and pathologies, heart rate variabilities, blood pressure indices, and MI- and cardiac-related mortality rate correlate with space weather and solar cycles [119–122]. Psychiatric disorders,

(continued) 3 Biophysics of Vision 47

Box 3.4 (continued) more prominently suicidal attempts, mood swings, and psychoses, follow geomagnetic disturbances (for review, see [34]). Variation in Sun’s activities can be sensed on the Earth through the photic mechanism or through solar winds and its interaction with the geomagnetic field. In latter case, the effect would be exerted on the Earth’s surface with a 2–3 days delay. Clinical Correlates 2 While psi awareness and psychiatric disorders follow the melatonin alterations, and melatonin oscillations respond to electromagnetic field variations, does the electromagnetic field changes have an effect on psychiatric parameters? Eyes are not just an organ for image formation, but they perceive EMF changes and determine the psychiatric condition. Geomagnetic field alteration is known to be associated with the potential to remote viewing, dreaming, and psi performance [53, 123–126]. Most of the studies granted successful paranormal experiences such as precognition (experiencing the event before it happens) or telepathic-clairvoyance (experiences of death or illness of a close relative) are more likely to occur in days with quiet geomagnetic activities. The sequence of lower or higher geomagnetic activity on days prior to the event might also be crucial in spontaneous paranormal experiences. In fact, the Earth’s magnetic field can be defined by three components of the magnetic force: horizontal, vertical, and declination. The most commonly used index in describing the applied magnetic field in biological studies is K-index, which is based on the horizontal component. This index is calculated by data gathered from all over the world.

Visual system may convey the cues for the perception of the magnetic field in earth-strength range to the vestibular system (lateral and superior vestibular nuclei, vestibular cerebellum, and nucleus of the basal optic root) [38]. Detection of the magnetic field is direction-selective, and many scientists believe in photoreceptor- dependent mechanisms [38, 39]. Geomagnetic field components, mostly the horizontal component, affect the night vision acuity [40, 41]. A geomagnetic field in the order of less than 50 μT reduces visual discrimination threshold and increases the photopic sensitivity of the visual system by 6–7% [41].

Visual System and Circadian Rhythm

Besides the widely known image forming function, the visual system plays a crucial role in the perception and maintenance of circadian rhythms (Box 3.5). Circadian rhythms are fluctuations of different events based on an approximately 24-h period 48 S. Shahjouei and M. Amini

Box 3.5 The circadian rhythmic pattern of physiological processes is the outcome of an orchestrate function of many organs, the suprachiasmatic nuclei (SCN) of the hypothalamus as the master organizer and pacemaker of this intrinsic complex event [45, 57, 127]. SCN has close connectivity with many other cerebral and peripheral tissues including retina, pineal gland, pituitary gland, pars tuberalis, and Purkinje cells of the cerebellum to regulate and respond to the circadian rhythm. Several molecules are proposed as a candidate of chronobiotics, “a substance that adjusts the timing of the central biological clock” [128], by their ability to follow a 24-h rhythmic expression pattern even in the absence of environmental cues such as light. Any molecule that has a synchronizing effect according to environmental factors, and can be detected in SCN, is a candidate to be chronobiotic [129]. Controlling the circadian rhythm in animals consists of a complex mechanism in which a vast variety of transcriptional, translational, and posttransla- tional feedback loops modulate the clock genes and related proteins [56, 57]. Different genes and proteins are proposed to enroll in circadian rhythmicity. Periods (Per1, Per2, Per3), Clock, Bmal1, and cryptochromes (Cry1, Cry2) are the main clock genes that regulate the circadian rhythm [55, 57]. Per and Cry genes are activated by BMAL1-CLOCK heterodimers, and their products in turn suppress the induced transcription [55]. The oscillations of different tissues are not synchronized and have different durations [56, 129]. Moreover, a free-running circadian rhythm—an intrinsic circadian period without any environmental effect—is suggested to be around 24.2 h [130]. Due to the time lag between the intrinsic circadian period and the 24 h, these two systems became unsynchronized, and people suffer from sleep disorder [128]. This means that the intrinsic oscillating systems should be reset several times to keep pace with the daily 24 h [128]. A vast variety of factors can affect and synchronize circadian oscillations with internal rhythms [45]. Light perception is one of the major time cues [128]. Photoperiodism modulates the seasonal physiology and behavior of the organism according to the day length and direction of annual day length changes [42]. Light–dark cycling properties widely affect the biologic rhythm of the organisms. Due to lightning tools and industrialized technologies, humans are exposed to much brighter night hours than he was exposed to before. Likewise, he spends daytime indoors under artificial lightning. This might cause disorganization of the natural biologic rhythms.

[42]. Retina autonomously functions as an intrinsic timekeeper [43, 44]. The retina is the masterpiece in various circadian cycles such as visual sensitivity, neurotransmitter regulation, melanopsin mRNA and protein expression, oscillations in melatonin and its related enzymes, rate of disc shedding in photoreceptors, photoreceptor outer segment phagocytosis, and CLOCK gene expression [44–46]. Different 3 Biophysics of Vision 49 studies proposed that the entrainment of circadian rhythms, pupillary light reflex, and locomotor activity are not related to cones and rods [43, 47, 48]. It is shown that nonvisual functions of the retina are more probably related to a subset of retinal ganglion cells that express melanopsin [44, 45, 49, 50]. Melanopsin (opsin 4 or Opn4) is a photoreceptor with seven transmembrane domains and peak absorption wavelength of 480 nm [50]. Retinal ganglion cells containing melanopsin relay light–dark information through the retinohypothalamic tract to the suprachiasmatic nuclei (SCN) of the hypothalamus [45, 51]. These cells are very resilient in retinal insults, and their number, level of melanopsin, and projections from the retina to the suprachiasmatic nuclei and the olivary pretectal nucleus remain intact following the ischemic insult [49]. In addition to Opn4, preopsin, retinal G-protein receptor, Opn3, Opn5, and cryptochromes (Crys) are nonvisual photoreceptors located in the inner retina that function in rhythmicity [43, 44]. A part of circadian rhythmicity entrainment in the visual system is performed by oscillations of melatonin and related molecular systems in the retina and pineal gland. Accordingly, in the following section, the rhythmic alterations of retinal melatonin and also some functions of the pineal gland as an end organ of the visual system and its counterpart in electromagnetic field detection and circadian rhythm regulation is described.

Pineal Gland

The pineal gland, also called the epiphysis cerebri, is an isolated gland in the deep brain. It is closely connected to auditory and visual brain centers and was previously considered as the third eye. The gland has close connectivity to the eyes through neurons delivering the information from the retinal neural plexus to suprachiasmatic nuclei, paraventricular nuclei, the intermediolateral cell column, and the superior cervical ganglia. Pineal gland showed direct photoreceptive properties that respond to photic stimuli [52]. Pineal gland participates in the control of circadian rhythms; endocrine, repro- ductive, and sexual functions, sleep cycles, and emotional and psychiatric states. Increase in metabolites of the pineal gland is associated with dreaming, psychoses, and mood disorder [53].

Melatonin: The Main Product of Pineal Gland

Pineal gland shows responses to the electromagnetic field and light–dark diurnal variations in terms of metabolite production [54]. The most known product of the pineal gland is melatonin. Melatonin, also known as N-acetyl-5-methoxy tryptamine, is synthesized from serotonin. SCN modulate melatonin synthesis in the pineal gland through a multisynaptic pathway, containing the hypothalamic paraventricular nucleus and the superior cervical ganglion [55]. In fact, by secreting melatonin, the pineal gland translates the photoperiodic signals to neuroendocrine 50 S. Shahjouei and M. Amini signals. Melatonin secretion follows a diurnal and seasonal variation [56, 57]. Melatonin level increases after the onset of darkness, peaks at mid-dark, and drops on exposure to light with sufficient intensity along with a drop in pineal level. Melatonin is secreted into the blood, and every single cell in the body can sense the state of scotophase (darkness) by its concentration. Pineal melatonin is widely known for its function in the sleep cycle. However, it carries other functions such as seasonal and day–night regulations, DNA repair, epigenetic regulation, antioxidation, and immune responsiveness, and its level is altered in cancer and diabetes [58–62]. Melatonin periodic cycles are presumably correlated with different psychiatric disorders, among them are depression, seasonal affective disorder, premenstrual symptoms, autism, and sleep disorders [63–65]. Melatonin cycles relay dark–light information to the endocrine system and modulate its function. Melatonin concentration modulates the photoperiod-dependent rhythmic variation in clock genes Per1 and Cry mRNA expression in pars tuberalis of the pituitary gland [56, 66, 67]. Melatonin-dependent function of the pars tuberalis is dependent on the presence of pineal gland, and injection of melatonin in the absence of the gland cannot restore this function [67]. Cortisol oscillations coordinated by melatonin, as another example, are more persistent regarding light stimulation than melatonin cycles and can function as a more stable translate of the photoperiodic alterations. Perturbations of cortisol cycles can be associated with depression and seasonal mood disorders [64].

Other Sources of Melatonin

In addition to the pineal gland, melatonin is detected in the hypothalamus, ocular tissues, gastrointestinal tract, and brain stem [68–70]. In the hypothalamus, the circadian rhythm of melatonin has elevated levels at dark onset. The circadian rhythm of retinal melatonin has two peaks—shortly after light and dark onsets, with nadirs at mid-light and mid-dark. Retinal pigment epithelium cells express tryptophan hydroxylases, aralkylamine-N-acetyltransferase (AANAT), N-acetylserotonin-O- methyltransferase (ASMT), HIOMT, melatonin receptors (MT2, RORα1, and RORα4), and quinone oxidoreductase (NQO2) [71]. The properties of alteration in the level of these enzymes or their ligands in ocular tissues are dissociated from their corresponding serum levels. Moreover, the circadian rhythm of retinal melatonin and N-acetyltransferase activity is conserved, even after pinealectomy. These data indicate that although melatonin is synthesized and not just accumulated in the retina, the major portion of serum melatonin is secreted by the pineal gland [68, 72]. Retinal melatonin may affect the photoreceptor outer segment shedding and phagocytosis, cone cell motor movement, or dopaminergic activities [72]. Retinal melatonin regulates the concentration of other neurotransmitters. For example, concentration and activation of retinal melatonin and dopamine are closely related, and melatonin can inhibit dopamine release. In turn, activation of D2 dopamine receptors modulates retinal melatonin synthesis [72]. 3 Biophysics of Vision 51

Dopamine is synthesized in the retina from the amino acid tyrosine and is released in response to photic or electrical stimulation. Dopamine mediates D1 receptor-dependent dissociation of gap junctions between the retinal horizontal cells and regulates the responsiveness of ganglion cells to light stimuli. Likewise, dopamine exerts adaptation functions in long-term exposure to constant light or light deprivation through the D1 receptor. D2 receptor dopamine functions mimic the effect of light on the retina and minimizing photoreceptor degeneration (for review see [72]).

Other Modulators of Melatonin Secretion

A comprehensive study on overnight urine melatonin in subjects from 14 countries in 5 continents showed the correlation of melatonin concentration with latitude [63]. Although overnight melatonin secretion is one of the periodic oscillations with light cue and the light–dark periodic cycling in poles different from lower latitudes, this finding might be due to alteration of other external factors such as an electromagnetic field. It is widely known that not only visible electromagnetic spectrum but also perturbation of other frequencies of the electromagnetic field and magnetic field—static, sinusoid, and geomagnetic field—affect melatonin synthesis [54]. Pineal gland responds to magnetic field perturbations as immediate modulation of the level of melatonin, serotonin, hydroxyl indole acetic acid, and intermediate enzymes and second messengers. The variations in the activity of hydroxy indole-O-methyltransferase (HIOMT) are shown in association with change in magnetic field intensity or horizontal component. Consequently, the concentration of its downstream products such as melatonin or 5-methoxytryptamine is affected by electromagnetic field changes [73]. Serotonin N-acetyltransferase (NAT) is another enzyme involved in the synthesis of melatonin, which is under the influence of alteration of the magnetic field [74]. Artificial electric or magnetic field can inhibit NAT and abolish the downstream metabolite pathways including the melatonin and 5-methoxytryptophol circadian oscillations (reviewed in [75]). Unlike HIOMT that decreases in response to any change in EMF, NAT variations are consistent with the direction of EMF oscillation [40]. In addition to the magnetic field, humans are exposed to anthropogenic extremely low-frequency (50–60 Hz) electromagnetic fields from a wide variety of electrical devices. Melatonin metabolism varies by exposure to extremely low frequencies (50–60 Hz) and rapid static magnetic field changes [76]. An altered circadian rhythm of melatonin synthesis and release from pineal gland and its consequences on endocrine, neuronal, and immune systems is the possible causality under increased risk of cancers, mood disorders, and miscarriage in those exposed to extremely low-frequency electromagnetic field [75]. 52 S. Shahjouei and M. Amini

Conclusions

Visual system orchestrates its complex functions, either as image forming or as non- image forming properties, through physical principles. By perception of magnetic field and regulation of circadian rhythms, the visual system plays a pivotal role in the response of human body not just to its environment on Earth but also to celestial events. A deeper understanding of the biophysics of the visual system would enable us to obtain appropriate measures to prevent or manage a wide variety of pathologic disorders.

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Maryam Rahmani and Farzaneh Rahmani

Abstract Interoception as the ability of human beings to sense their internal body feelings is far beyond visceral sensations and comprises a variety of sensory modalities, including metabolic, immunologic, and autonomic status. The key area onto which interoceptive sensations project is the insular cortex in the brain. Owing to this ability, the posterior portion of the insula makes functional connections to the thalamocortical hubs as well as areas within the limbic system and the amygdala, which is historically known for its role in the perception of anger and fear. The prefrontal gyrus, anterior cingulate cortex, and several other neocortical areas add cognitive input to interoceptive perception. Granular cortices are core modulating units of interoception, while agranular cortices are directly responsible to drive perception and the resulting action that is derived from interoceptive decision making. These cortical outbound communications synchronize the activity of amygdalo- insular region with other cognitive networks and inform the rest of the brain about the interoceptive predictions and sensations, all to produce an integrated representation of internal and external body feelings and a unique form of consciousness. The granular interoceptive cortices are less prone to predictive errors, meaning a more precise interoception and factual interpretation of internal body feelings in relation to sensory input. Affective parts of our consciousness, or what we commonly call an internal sensation, enroot from predictions within the interoceptive system that might or might not be true predictions, but are congruent with overall exteroceptive and interoceptive mood of the body.

Keywords Amygdala · Cortex · Exteroceptive · Insula · Interoception · Neocortex

M. Rahmani Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran F. Rahmani (*) Student’s Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Introduction

Self-feeling, or the feeling of “me,” is tightly linked to a summarized cortical representation of all internal body feelings. These include the visceral feeling of thirst, hunger, etc. as well as somatic sensations such as pain. Our brain forms perceptions, i.e., inferences about the future state of our body, mainly based on limbic sensations within our body. According to Barret and Simmons [1], human brain follows a Bayesian approach to infer future probabilities based on body sensations, which means that the combination of past experience and sensory input forms a priori probability that is then used to infer future conclusions or posterior probabilities based on the current experience. If we look up the word “interoception,” the insula and amygdala come up as central executive nodes of this phenomenon. Insula, the secluded cortex within the Sylvian fissure of the human cortex, is the primary processing center of internal body feeling. Sensory information, from viscera and from skin, converge within layer I and layer II (substantia gelatinosa, SG) of the posterior horn of the spine. The dorsal posterior aspect of the human insula is the primary site for input from visceral and somatic sensations and also autonomic information to enter insula. The thalamocortical projections lend input to the insula, where nearly all body afferents are re-represented in the anterior-most portion of the right insula [2]. Anterior insula (AI) is a central node for subjective awareness of bodily emotions, both positive and negative feeling, including anger, trust, and sexual arousal [3]. AI is active during affective processing, when someone tries to judge and understand others’ emotional feelings (empathy) [4] and feelings of ourselves [5]. Several other roles have been proposed for the insular cortex, such as roles in the active control of attention, awareness of consciousness, and detection of salience [6], along with several other aspects of interoceptive feeling. Amygdala is and has been the focus of attention in finding the neural bases of interoception, as it shares several white matter associational fibers with the insula, so as to form the insular-amygdala network [7]. Stimulation of the interoceptive network, for instance, by listening to a heartbeat, activates a distinct functional hub within the brain, which involves bilateral amygdala, middle frontal gyrus, and supplementary motor area [8]. Activity within the right insular cortex directly predicts the magnitude of autonomic arousal during this experiment. Studies on patients with impaired interoceptive ability, as in patients who fall within autism spectrum disorder, generalized anxiety, and major depressive disorder, have demonstrated impaired functional connectivity of the dorsomedial insular cortex with several limbic hubs, amygdala, prefrontal cortices (PFC), posterior cingulate cortex (PCC), and orbitofrontal cortex (OFC). It is known that amygdala circuitry entails core hubs that are crucial in the perception of fear and anger and that amygdala-insular and amygdala-PFC connectivity are increased in anxiety disorders [9]. The amygdala receives extensive sensory input from central and peripheral autonomic centers, hence regulating the neural bases on which sensory input are interpreted and what would the interoceptive output of bodily feelings be [10]. To conclude, the amygdala is the emotional modulator of the interoceptive system, which works together with insula to form a sentient self. 4 Cortex, Insula, and Interoception 61

Moving on to other less known brain regions, we must introduce the putamen, a caudal part of the striatum with bilateral cortical projections and relations in motor control [11]. The insula has relevant functional connections with caudal ventral striatal regions, which in turn project to the amygdala, as well as direct anatomical connections between putamen and insula, lending support to an overall interconnected network that controls interoception. Interoception has a tremendous effect on the individual’s perception and cognitive interpretation of the events, and this could serve as a clue to the role of interoception in what is called “sixth sense.” Interoceptive focus, which is voluntary attention to bodily feeling, significantly distorts our perception of time passage, memory consolidation, and fear. Interoceptive focus potentially accentuates fear perception in terms of severity and duration [12, 13]. Even direct sympathetic stimulation is unable to accentuate the fear experience if the interoceptive focus is absent or interoception is impaired [13]. Interoceptive awareness, i.e., how strong and precise one can experience bodily feelings, can directly predict the precision and success in decision-making situations that activates the insular hub described above [14], as when someone tries to make the decision to enter a new place, when he/she senses a foul smell or an unknown sense of fear he/she gets from the situation. In the following sections, we continue to discuss the relevance and role of each of the brain regions involved in interoception in more detail, paying attention to neuroanatomical evidence underlying their role in interoception.

Insula

As said, the right AI is the ultimate integrative region for interoceptive sensations, and its activity is tightly correlated with interoceptive accuracy, a function that is disturbed in phobia, anxiety, and major depressive disorders [15, 16]. Insula integrates these interoceptive, exteroceptive, and sensory body feelings, owing to an interconnected hub of afferent corticofugal, thalamofugal, and striatofugal fibers. The posterior short and long insular gyri, located in the dorsal posterior cortex of the insula, receive almost all of the sensory input from neocortical regions [17]. The dorsal insula is functionally connected to the somatosensory cortex and the posterior parietal region [7] as well as precentral gyrus, medial frontal gyrus, and ventromedial PFC [18]. Cortical afferents to the insula are parts of both a top-down cognitive input and a feed-forward of visceral and somatic sensations that ensure maximum accuracy of these representations. Cortical afferents from PFC are the main source of attentional bias in making interoceptive inferences based on interoceptive representations in dorsal insula [19]. These are based on semantic knowledge, unconscious incentives like monetary favors, or emotional incentives like anger or fear. Therefore, not only our interoception forms a priori hypothesis about the emotional or financial value of a situation, but it is also affected by such biases. As an example, drinking a chilly lemonade might not be as pleasurable and satisfy- ing as it used to after you have once been forced to pay extra cash to have one in a luxury restaurant! 62 M. Rahmani and F. Rahmani

Neural representations of past experience lie within the cortex. These are the a priori hypotheses that anticipate imminent insertion of sensory input. These cortical representations fire corticofugal efferents while activating corticocortical connections. Corticofugal afferents to the insula represent previous experience from similar situations as well as a summary of the current semantic knowledge, described above [1]. Cortical connections to motor areas such as precentral gyrus and supplementary motor area, along with putaminal connections, are part of the motor feedback/response loop to interoceptive sensations. They stimulate proper motor response to or produce sensations related to the interoceptive experience.

Amygdala

The amygdala is best known for its role in the emotional control and as a gate for the limbic system. We know that amygdala is necessary to feel fear and anger, both in oneself and in others, but also to modulate these feelings in response to autonomic and visceral body feelings and finally in the consolidation of memories with emotional salience. Indeed, functional connectivity of the amygdala is increased in response to anxiety, as well amygdala’s connectivity with insula. At the same time, the amygdala is functionally disconnected from prefrontal cortices, explaining increased connectivity within visceral control areas [9]. Some of the most exciting insights into the action of the amygdala in the interoceptive regulation of the body are obtained by studying volunteers with uni-/bilateral amygdala lesions. These patients are unable to incept anger or fear but instead respond to an acute increase in autonomic mediators, e.g., isoproterenol, with anxiety and panic sensation while being unaware of the interoceptive feelings corresponding to this sensation, e.g., increased heartbeat and respiratory rate [20]. The visceral motor system in the brainstem that projects into the amygdala is generally involved in arousal and emotional control of arousal and also in fight-or-flight response. Lesions confined to the amygdala impair interoceptive perception of visceral sensory input while at the same time letting the interoceptive sensory regions within the brainstem, including the hypothalamus, convey visceral afferents to visceromotor areas and induce the specific feeling associated with those visceral inputs, e.g., fear, panic, etc. [21]. Amygdala might be considered a subcortical integrative region for exteroceptive and interoceptive stimuli while being in close functional and anatomical connection with insula and visceromotor cortices [22].

Neocortex

Corticocortical connections are crucial for predictive feedback and maturation of the interoceptive hub. According to Simmons, these connections are essential to modulate relevant brain cortices to “be ready” for the incoming sensory input and 4 Cortex, Insula, and Interoception 63 perhaps change their properties for an “active inference.” The model proposed by Barbas and Rempel-Clower for corticocortical connections could help elucidate this model. The granular cortex, containing the granular cell layer, receives most of the thalamocortical sensory input and is the target of modulation by less differentiated cortical columns, dysgranular or agranular cortex. Predictive signals from less differentiated cortical areas commonly originate from deep layers (cortical layers IV and V), which have a tremendous number of projections to other cortical areas, supragranular and granular regions of layer I [23]. These upper layers of the granular cortex are where thalamic and striatal inputs terminate. A reverse projection from upper layers of the granular cortex to deep layers of undifferentiated cortical regions is also possible, which might report back the representational error to cortical connections to modify the input or the priori. So, how are these relevant for interoceptive anticipation and to alter neuronal activity before the sensory input arrives? Predictive signals from less differentiated cortical columns, which perhaps originate from the insula and arrive in deep layers of the cortex, change the firing rate of neurons in layers I–III, in anticipation of the sensory input that lands in layers III and IV of the granular cortex. A difference in the firing rate of upper (I, II, III) and lower layers (IV, V) of a differentiated column is calculated as a “predictive error” and modulates the corticofugal fibers, in terms of firing rate, function, and connectivity [1]. As mentioned above, the predictive error signals are calculated in upper layers of granular cortex and project to deep layers of the agranular cortex. Interestingly, some pyramidal neurons within layers I and II of granular cortical columns act in parallel to neurons that calculate the predictive error. These are called precision units. Precision units effectively decrease the weight of sensory input to reduce prediction error based on the “precision” or confidence in the predictive signals or the sensory input [24]. In other words, the precision units modify the strength and interpretation of sensory input to the brain, providing solid grounds for active inference through interoception. Granular cortices are core modulating units of interoception, while agranular cortices are directly responsible to drive perception and the resulting action. It is useful to look again into the mechanisms through which the prediction system reduces error. This is important to notice, as lower predictive errors mean a more precise interoception and a more factual interpretation of internal body feelings in relation to sensory input. First, the motor components of the interoceptive network actively modulate the incoming sensory input by moving the body, so that the incoming input “feels right” for the predicted internal simulation. Second, the cortical afferents, primarily from PFC, modulate the relative excitability of different sensory modules within adjacent voxels. This computational bias determines the relative salience or precision in a different sensory input, reducing the predictive error while accentuating the role of predictive biases and internal stimuli in the ultimate signal and interpretation of that signal [25]. Eventually, we are able to propose a model for active interoception based on the active inference model within the primary motor cortex. The M1 primary motor cortex is endowed with a fully expressed granular layer IV, unlike agranular cortices 64 M. Rahmani and F. Rahmani in the anterior cingulate cortex (ACC) and insula. The granular cells within layer IV of the M1 cortex are specialized to receive predictive input from the basal ganglia and cerebellum, but not other cortical areas, such as sensory cortex [26]. The M1 cortex provides deterministic commands to the spinal cord; the motor commands to move the body while at the same time sending motor predictions to the somatosensory cortex, in anticipation of the upcoming sensory input from body movements. This is in contrast with the top-down model of interoceptive inference, described above. As the M1 lacks a full-pictured granular cortex, it receives relatively few sensory inputs from the sensorimotor cortex. So how does the motor cortex realize if the motor input to the spinal cord is right and whether it has been executed properly? This answer is that the M1 does not rely on predictive errors issued by sensory input but instead relies on input from the thalamus, relayed from basal ganglia and cerebellum, to refine the deterministic model by which it issues motor commands to the spinal cord. To finalize, the motor cortex changes its “signal-issuing modules” overtime and not as a result of instant refining by predictive errors and sensory input.

Interoceptive Hub and Visceromotor Predictions

Unlike motor and sensory cortices, the visceromotor controlling system is composed only of the agranular neocortex, extending from the middle cingulate cortex and the ACC to posterior vmPFC and OFC and, finally, to the AI. It has been known for a while that these cortical visceromotor control systems exert control over brainstem autonomic control centers via amygdala, hypothalamus, and periaqueductal gray matter [27]. The agranular visceromotor cortices at the same time issue interoceptive predictions to modify the changes in body autonomic, metabolic, and immune status that are about to happen as a result of autonomic commands given through the cortical area mentioned. Unlike the motor anticipatory system described, this information is in turn relayed to the more mid-/posterior insula, where they form an expected pattern of internal sensations that are about to generate within seconds of the visceral command. The interoceptive sensory lines ascend the solitary tract and the parabrachial nuclei, and thalamus, to reach and amplify in the layer IV of the posterior insula. Endowed by extensive neocortical afferents and interoceptive input from the periphery, the posterior insula calculates the predictive error and propagates the error signals to the visceromotor cortices through its supragranular layers, to refine the predictions and also form an interoceptive insight according to our inside feelings. This apparently seamless model goes further to explain how the agranular cortex modulates the whole system in response to prediction errors received. The agranular cortex in the ACC and subgenual cingulum is the only part of the visceral cortex with a semi-developed granular layer IV, as it appears to be the only part of the visceral-motor hub that receives sensory interoceptive signals from the thalamus. The prefrontal and orbitofrontal cortices receive very light projections from the 4 Cortex, Insula, and Interoception 65 thalamus, thereby being unable to receive predictive error signals from the thalamus, as is with the M1 cortex. On the other hand, the visceral sensations are low in resolution and are subject to censorship by precision units in supragranular layers of granular cortex in the posterior cingulum. Overall, these mechanisms make the error signal that reaches the agranular cortex weak and low in quality. Nonetheless, this predictive error is encountered accurately and heavily within the visceromotor cortex. The visceromotor cortex issues new visceral input to the spinal cord to generate the predicted signal, almost similar to the motor cortical feedback hub. Moreover, the agranular-to-granular cortical connections to the posterior insula are modulated to reduce the predictive error by refining the patterns through which the predictive signals are generated there. Most importantly, the AI is functionally connected to thalamic nuclei, through the ACC, as explained above. The thalamic reticular nuclei are very much susceptible to this top-down regulation by the insular pattern that acts as a sampling gate for visceral sensations that are relayed to the agranular cortex. The interoceptive “attentional bias,” rising from the ability of ACC and insula in executive control and attention networks, can reduce sampling and further attenuate interoceptive processing of internal sensations to avoid discrepancy with predictive signals. This potent network enables visceromotor cortices to modulate the gain of thalamocortical afferents, explaining the bases for the involvement of interoceptive awareness/attention in mood and anxiety disorders.

Model for Interoceptive Inference Within Visceral Sensorimotor System

The agranular cortex is where the interoceptive predictions are generated. These are patterns based on the Bayesian model of posterior probability, based on which our brain predicts the internal and external state of our body in the next instance. Interoceptive predictions are the brain’s hypothesis on the autonomic, metabolic, and immunologic state of our body, based on the speculation it makes about the cause of current sensations, according to previous experience. Eventually, the visceromotor issues that are implemented are generated in a way that the predicted sensations are generated. These interoceptive cortices, as mentioned above, are very much less sensitive to sensory errors, compared to exteroceptive cortices. This means that our internal body sensations are very much a prediction of how our brain predicts our body is going to feel, rather than actual feelings received from the periphery. These predictions within the agranular cortices, including AI, are rather stable, considering the ever-changing external context of the body and compared to exteroceptive feelings. On the other hand, the mid-/posterior insula, which is composed of dysgranular/granular cortices, is more sensitive to visceral sensations, as certified by two studies with nociceptive and metabolic stimuli: The evoked potentials within the posterior insula reflect the intensity of pain stimulus, while the evoked potentials in AI respond with a delay, presumably mounting an emotional 66 M. Rahmani and F. Rahmani perception/pattern over the stimulus [28]. Also, acute changes in serum glucose levels change the posterior insula’s response to visualizing food items, while AI’s activation is unchanged [29]. The agranular cortices receive input from vmPFC and nodes within the default mode network (DMN) that are also part of the limbic system. These areas receive light projections from the thalamus and are affected by extended hubs into the limbic regions, making the interoceptive predictions partly susceptible to cognitive biases that rise from these “extended agranular visceromotor cortices.” The granular AI cortex and the agranular cortex of the ACC are key nodes of the small-world network of the visceromotor/interoceptive systems. These two areas enable an effective communication of the interoceptive network with several somatosensory and cognitive hubs outside the network, including the PFC and several cortical areas with high laminar differentiation. This outbound, and less commonly inbound, communications via the “rich-club” nodes within the interoceptive system have two major implications: first, to synchronize the activity of this region with other cognitive networks and, second, to inform the rest of the brain about the interoceptive predictions and sensations, all to produce an integrated representation of internal and external body feelings and a unique form of consciousness. Importantly, the portions of the vmPFC that are part of the visceromotor system are indeed nodes within the DMN that communicate interoceptive predictions to the rest of the network to inform about the upcoming homeostatic changes that engage this network, e.g., self-related processing, mental state inference, and empathy.

Conclusions

The interoceptive system exerts control over all aspects of consciousness, making an experience homeostatically relevant, rather than being accurate and representa- tive. Affective parts of our consciousness, enroot from predictions within the interoceptive system that might or might not be true, but are congruent with overall exteroceptive and interoceptive mood of the body. Does our brain deceive us to perceive what our interior feelings tell us to feel? In this view, the “sixth sense,” or the ability to perceive or predict current or future incidences without having the a priori information about the situation, appears to be a hypocritical statement. An integrated network within our brain is in charge to make what we perceive happen that is most likely the reason for our inner feelings.

References

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Reihaneh Dehghani and Farnaz Delavari

Abstract Information from all over our body is gathered in our insular part of the brain to make an internal body picture known as interoception. Using these data and processing them, our brain makes predictions and sends back signals throughout the body. Any dysfunction along this way can result in an interoceptive-related disorder, for example, mood disturbance, autism, addiction, chronic pain, delusional body border disorders, and eating disorders like anorexia and bulimia nervosa. Signal misinterpretation such as prediction error (the difference between what our brain predicted to happen based on previous data and what actually happened), alliesthesia (the regulation of response to a stimulus according to body status), and aversive conditioning are important pathophysiologies suggested. Other concrete theories are inflammatory processes in the insular area, lesions, brain underconnectivity, and dysfunction of networks which include insula. These theories are mostly supported by neuroimaging data, gray matter volume, and specific experiments such as rubber hand illusion.

Keywords Addiction · Anosognosia · Anxiety · Autism · Autoscopic · Depression · Eating disorders · Fibromyalgia · Functional motor disorders · Heautoscopic · Interoception · Interoceptive dysfunction · Mood disorders · Pain · Phantom limb · Somatoparaphrenia

R. Dehghani (*) Molecular Immunology Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran F. Delavari Media and Life Promotion Group (MLPG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Interoception

Interoception is the understanding of the integrated information received from inside the body, which mainly originates from internal body organs like the cardiorespiratory system. Interoceptive perception helps us define and identify our body [1]. This information together with visual signals, beliefs, and emotions makes up our definition of “bodily self.” Thus, diseases relating to interoceptive dysfunction usually affect a person’s definition of himself or herself. Deficits can be anywhere along the path of the signals that make our interoceptive perception: starting from sensory deficits, identification or discrimination of the signals or transmission, representation, and integration of signals in the cortex. Even deficits in circuits and connections of the insula, the interoceptive center of the brain, and other cortices can cause problems with decision making or cognitive disorders [2]. Many diseases have at least partial interoceptive dysfunction in their etiology. For example, there is a condition that the patient denies the ownership of his or her body; this denial can be limited to a paralyzed organ (anosognosia), or it can be extended to a whole side of the patient’s body (somatoparaphrenia). Another example is anorexia nervosa, an eating disorder, in which patients have illusions regarding their body size. Many mental disorders like depression, chronic anxiety, autism, and some addictions may have interoceptive dysfunction as one of the involved pathologies. In each of these disorders, different parts of the brain may be involved, but the most common and general parts are insula together with the anterior cingulate cortex and somatosensory cortex [3, 4]. Here, we discuss diseases with interoceptive dysfunction, their etiology, and neuroanatomical and some psychological aspects [5–8].

Mood Disturbance

As we discussed earlier, insula is also a center of emotional awareness (EA) [9]. We want to use this contribution to justify the variety of emotional-related disorders caused by insular damage. Although other cortical structures such as the amygdala and anterior cingulate circuit also contribute to EA, studies show that insula is central to EA [10]. A proof for this allegation is that patients with bilateral insular lesions show alexithymia [9, 11]; this means the individual is unable to identify or describe emotions [12]. Insula does so by first integrating bottom-up interoceptive signals that are gathered from the whole body, autonomic nervous system, and somatosensory cortex, and then, it sends top-down predictions to visceral organs and autonomic nervous system [9]. Therefore, any malfunction in this path can cause emotional instability like depression and anxiety. 5 Interoceptive Dysfunction 71

Anxiety Disorders

Anxiety disorders are a group of mental disturbances characterized by excessive fear and behavioral changes, leading to distress in routine life. Also, it is usually accompanied by physiological changes such as tachycardia and dizziness. Some examples of this broad family include panic disorder, specific phobia, and social or separation anxiety disorder [13]. Findings suggest at least a partial role for interoceptive dysfunction in the etiology of anxiety. To exemplify, there is a correlation between higher interoceptive accuracy and anxiety [14]. Supporting this, imaging studies have shown that insula is more activated in patients with anxiety as compared with control groups [15]. More interestingly, patients with social anxiety disorder reveal lower insular volume [16]. There are two main theories that relate anxiety to interoceptive dysfunction. It is known that our insula is constantly receiving signals from the entire body in the shape of interoceptive, proprioceptive, or exteroceptive signals. These signals are integrated into the insula, and based on this information, insula makes predictions that are sent back to the organs. Studies show that the misinterpretation and misat- tribution of these signals may be the reason behind anxiety symptoms. This means that patients with anxiety disorder misunderstand normal stimuli as threatening and hazardous signals [16]. Another explanation is that these top-down signals are too different from the next bottom-up signals, resulting in a high prediction error, a contrast between what our mind thought and what actually happened. This can be another reason for anxiety disorders [17–19]. Paulus and Stein suggest an interoceptive-related model for anxiety based on higher prediction error in anxious people; they say that positive alliesthesia and wrong beliefs can cause prediction error. Alliesthesia means that the body regulates the response toward a stimulus according to internal status. Therefore, positive alliesthesia means that the response gets stronger when a stimulus is repeated, and negative alliesthesia is somewhat habituation toward the stimuli [20]. They also say that the definition of self in anxious individuals is altered by false beliefs. Although the temporoparietal junction (TPJ) and the medial prefrontal cortex (mPFC) are the main areas for the formation of beliefs, the final acceptance would mainly happen within the insula and mPFC [21–23]. These false beliefs cause an unrealistic internal status, and as a result, a greater difference between top-down and bottom-up signals will result in higher prediction error. These wrong assumptions about oneself and nonthreatening stimuli make the anxious patients count nonhazardous stimuli as threatening ones, and positive alliesthesia causes a stronger reaction to these harmful stimuli [23].

Depression

Depressive disorders are usually characterized by dysphoric state and loss of interest in daily activities. It is usually accompanied by sleep disturbance, anhedonia, and social withdrawal along with impaired memory and concentration. Interoceptive 72 R. Dehghani and F. Delavari dysfunction in the form of altered self-image is suggested as one of the main etiologies of depression [2, 23]. Evidence correlates interoception with depression- related somatic, psychological, and social components. Meta-analyses of neuroimaging studies consistently confirm the role of the insula in depression. They show higher insular activity [24, 25], reduced insular gray matter volume [26, 27], and increased sensitivity to pain [28] in depressed patients while encountering negative stimuli. Altered interoceptive sensitivity and awareness is another proof of the role of the insula in depression. Taken together, studies indicate that depressed patients have lower interoceptive sensitivity especially when anxiety is controlled [2, 29, 30]. Evidence supports the idea that interoceptive dysfunction plays a crucial role in depression. Different pathways have been proposed to underpin interoceptive dysfunction in depression. Stein and Paulus suggested that alliesthesia and wrong beliefs make up the high prediction errors. They suggested that bodily signals are noisier in depressed patients and hence harder to distinguish and interpret [23]. Additionally, Kendler proposed negatively altered self-view and low self-esteem in depressed patients [31]. Altogether, these latter two ideas can account for many characteristics of depression like anhedonia, negative biases, dysphoria, and problems with decision making [32]. Harshaw also attempted to explain depression symptoms through interoception- related factors including stress, loss of exteroceptive scaffolding, and shifts in awareness. He put forward that stress and stress hormones can alter the activity of brain areas such as ACC, insula, and OFC, which are involved in interoception. He also said that daily habits, which are the main source of external stimuli, are altered in depressed patients. For example, people who have lost a loved one usually experience social withdrawal in the form of skipping a meal. Following these changes in receiving somatic signals, patients have difficulty in interpreting and disambigu- ating external signals. This can be an initial factor for the third part of his theory. He suggested that rumination and negatively intense self-focus alter the ratio of internal and external signals; therefore, misinterpretation of these signals is not unpredictable [2]. There are other concrete ideas which correlate interoception to depression. An ongoing theory considers depression as a result of inflammation and cytokine induction in the brain [33]. This neuroinflammation causes the sickness behavior comprising malaise, sleep disturbance, and loss of appetite as observed in depression. There is evidence elucidating that this inflammation can modify activity in specific brain regions like insula [34], and this alternation in insular activity results in emotional symptoms of depression [2]. More interestingly, recent studies have found a correlation between gut inflammation and depression. This is consistent with the same pathophysiology of what we just said; increased inflammation in the gut like in Crohn’s disease [35] or altered microbiota [35, 36] stimulates the production of inflammatory mediators in our body. These mediators, in turn, induce depression-like symptoms by vagal nerve [2]. This vagal stimulation can cause heart rate variability, which is a feature of interoceptive dysfunction [2]. 5 Interoceptive Dysfunction 73

Autism

Autism spectrum disorders (ASD) are a group of neurodevelopment disorders where individuals have difficulties with social interactions and display routine and restricted habits and behaviors. Patients with ASD often have language problems as well as motor abnormalities such as motor delay, hypotonia, and difficulty in coordination [37, 38]. The main reason for lack of communication in autistic patients is difficulty with metallization [39]. This means that in addition to their disability to fully process the information from other people, they also have problems in perceiving information from their own body [38]. There have been suggested different mechanisms related to the etiology of ASD, including but not limited to hypersero- tonemia and low GABA levels [40], oxytocin deficiency [41], and genetic and epigenetic factors [42]. Here, we focus on the brain abnormalities and most importantly on the interoceptive aspect of ASD. Altered brain connectivity is another fundamental theory proposed to play a role in the etiology of ASD such that the brain connectivity between different regions is low but increased in local circuits. The evidence conclusively suggests the underconnectivity between the frontoparietal region and the insula in autistic patients [43, 44]. As we mentioned before, the insula contributes to the perception and integration of internal signals that are responsible for the representation of the bodily state. Therefore, this can account for the difficulty with metallization observed in autistic patients [39]. Using functional magnetic resonance imaging (fMRI), studies have shown decreased activity in many parts of the brain, including anterior insula [45]. Patients with ASD have higher interoceptive sensitivity, while their interoceptive accuracy is low. It is, therefore, expected that these patients show a high prediction error, which might trigger anxiety [46]. The impaired signaling of oxytocin has been implicated as a possible mechanism of increased self-focused attention in people with ASD. During infancy, oxytocin is required for the formation of socio-sexual behavior. It does so by improving neural plasticity as well as interoceptive precision through a Bayesian framework (prediction error). Lacking an effective oxytocin system in ASD is, therefore, considered a potential cause of failure to relate interoceptive cues to related causes. It can explain emotional hypersensitivity and low interoceptive accuracy in autistic people [41]. Of note is that impairments in cognitive, emotional, and language domains can arise from insular lesions [47]. This can account for why these impairments co-exist in many autistic patients. Further investigation is, however, warranted to fully understand the basis of communication problems in autistic people.

Addiction

Addiction is defined as the craving for and using a substance habitually, thus causing emotional and physiological attachment to it. Any substance such as cocaine, amphetamine, alcohol, and cigarette can cause addiction which affects the bodily 74 R. Dehghani and F. Delavari sensation in different ways. Interestingly, they are shown to activate the autonomic nervous system, thereby altering heart rate and temperature. These changes would mediate different interoceptive signals which are sent from the organs to the insula. Therefore, insula and altered interoception may contribute to the essential craving that occurs in addiction [48]. Supporting this is that subjects reported that their craving for smoking was diminished after damage to the insula [49]. Below, evidence linking interoception with addiction craving, maintenance, and withdrawal effects is presented. Aversive conditioning is well-appreciated as a major contributor to the initiation and maintenance of addiction. It has been shown to involve the insula. During addiction, the body learns how to manipulate its own signals. At the beginning of withdrawal prior to the physiological aversive states, interoceptive signals exert a negative effect against which the body must be prepared to fight. Drug seeking is a way to fight [50]. Meta-analysis indicates that insula and interoceptive signaling can become conditioned to positive stimuli as well [51]. This has been implicated in cue-reactivity, a situation where the addict sees a substance-related image, followed with the internal bodily signaling and recalling substance-related memories and experiences, and finally resulting in the craving for an urge to use the substance [52]. It is also a common belief that people use drugs until the optimal arousal state is reached. The afferent signals that contribute to arousal appear to overlap with interoceptive processing. This results in the mutual effect of interoception and arousal on each other [53]. Moreover, it has been recently argued but not completely proven that increased activation of the insula is associated with lower reward possibilities [54], aversive prediction error [55], poor insight, and prediction of unexpected rewards [56]. A theory to cover the mentioned effects is alliesthesia and interoception [48]. Alliesthesia describes that the internal body state decides whether a stimulus is pleasurable or not [20]. This may explain why the body’s response to the pleasure of the drug increases while the drug’s effect on body decreases due to homeostatic alterations over time. This causes increased prediction error, which also happens in the insula. This insular dysfunction exacerbates the accuracy of internal signaling, and therefore, the body’s internal awareness is impaired, which leads to denial and low insight in drug addicts [57].

Chronic Pain and Fibromyalgia

Chronic pain is a pain that lasts more than 3 months beyond the healing time. Chronic pain disorders include complex regional pain syndrome (CRPS), chronic low back pain (CLBP), neck and shoulder pain, fibromyalgia, and phantom limb pain [58]. Many theories have been proposed to explain the cause of chronic pain. Some suggest that the chronicity of the pain is due to a disturbance in proprioceptive fibers carrying the pain signals to the brain [59]. It has been recently shown that patients with CRPS have different thermoregulation or even different hair and nail growth in the affected region compared to the healthy ones [60]. This observation 5 Interoceptive Dysfunction 75 led to the conclusion that interoceptive dysfunction is a possible explanation for chronic pain. In a systematic review of interoceptive indices, Di Lernia found that patients with chronic pain have higher interoceptive sensitivity and lower interoceptive accuracy. Some studies have also shown that interoceptive accuracy may be predictive of symptom severity in chronic pain. Patients with higher interoceptive sensitivity are less likely to tolerate pain [61]. Neuroimaging studies of the insula have supported this [62]. One theory is that interoceptive fear conditioning is a reason for pain chronicity. Like what we said earlier for addiction, interoceptive cues could act as a conditioning stimulus and precede and exacerbate the pain. This interoceptive signaling can be palpitation, fatigue, or even the pain itself. For example, mild pain can be a conditioning stimulus for chronic or severe pain [63]. Another theory is based on the dysfunction of brain networks that contain insula as a part of their processing. There are two parts of the insula that contribute to different aspects of pain: the posterior part, which receives signals from somatosensory cortex [64], and the anterior part, which is mostly connected with the areas that process emotional and affective aspects of pain [65]. The connections between the insula and different parts of the brain lead to the formation of networks like the default mode network (DMN), central executive network (CEN), and salient network (SN) that somehow contribute to the modulation of pain [66]. Dysfunction of these networks in either the form of increased connectivity or other abnormalities can cause chronic pain. For example, patients suffering from chronic back pain [67] or diabetic neuropathic pain [68] show increased connectivity in DMN. Other studies suggest that the reason behind chronic pain is NMDA receptor-mediated neural maladaptation in the insular cortex. NMDAR can activate and modulate dopaminergic receptors in the brain. D2 activation and D1 blockade in the insular cortex seem to reduce the pain and delay its onset [64]. Fibromyalgia (FM) is another chronic pain disorder that involves the whole body and is accompanied with chronic fatigue, mood disturbance, and alternation in sleep [69]. Some researchers suggest that patients with FM have abnormal attention and sensitivity to either painful or nonpainful stimuli. This is called hypervigilance [70]. Although FM studies have not been conducted in large groups of patients, an fMRI study of patients with FM showed that they process even nonpainful stimuli mostly in the insula rather than the sensory cortex [71]. Another study using spontaneous sensation that correlates well with interoceptive signaling showed that these patients have increased interoceptive awareness that may be the reason for the hypervigilance and the fact that they feel their body in a different way [70].

Delusional Body Border Disorders

It has been at least a century since the “self-disorders” have been introduced. Patients with disorders of the bodily-self have illusions regarding their body bor- ders. These illusions can be related to limb, a whole side of the body, or even mental thoughts. Brain lesions can account for many symptoms in these patients. More 76 R. Dehghani and F. Delavari interestingly, recent literature has focused on interoceptive ideas in this field [72]. These ideas are based on the fact that our mental image of ourselves results from the integration of information from interoceptive, exteroceptive, and proprioceptive signals gathered from all parts of the body [73]. Therefore, sensory impairment in a body part, spatial disorientation, and visuoperceptual disturbances, which are all disturbances in signals that are a part of the body image, can be the factors contributing in bodily self-disorders [72]. Phantom limb phenomena are conditions in which the person has an illusion of a body part that does not exist usually after amputation. This illusion is usually painful. One theory for the painful phantom limb phenomena is while there is no sensory input, the structure and its functional representation are preserved in the cortical area, thus sending a signal to the insula; this results in delusional body image in these patients [74]. A proof of this theory is that when the somatosensory cortex in patients with phantom pain was stimulated with direct transcranial current, the pain was alleviated [75]. Another theory is that the mirror neurons send signals from the other hemisphere and change the body awareness in the amputated part [76]. Anosognosia refers to a condition in which the patient is unaware of or denies the existence of a disease, which is clinically noticeable. In asomatognosia, the patient fails to recognize a part or a whole side of their body. If patients with asomatognosia develop illusions regarding the affected part, it is called somatoparaphrenia. Their illusion is that the body part belongs to someone else (personification); they may also abuse or physically attack the affected part (misoplegia) [73, 77]. The neuroanatomical explanation for these conditions is the presence of right hemispheric lesions and left hemiplegia. Therefore, in experimental studies, a group of patients who suffered from a right hemispheric stroke was taken as the control group. Both asomatognosia and somatoparaphrenia patients have significant temporoparietal lesions, but somatoparaphrenia patients have larger lesions and they usually have other cortical involvements like insular damage too. Some studies have also shown deep gray matter involvement like thalamus, basal ganglia, and amygdala. Frontotemporal lesion has also been reported in somatoparaphrenia patients [72, 77, 78]. Although lesions are the main etiology of somatoparaphrenia, other theories may better explain the delusions in these patients. For example, loss of multisensory integration and body representation or reduced reaction to stimuli are other theories that are discussed [77, 79, 80]. Lesions can account for the disturbed bottom-up signals and the illusions they result in, but in order to have false beliefs, higher deficits are needed. It suggests that patients with asomatognosia fail to realize the prediction error, the difference between the bottom-up and top-down signals. This is called two-factor theory [81]. However, this cannot completely explain all the symptoms either. Therefore, further studies suggest that awareness dissociation in limbic areas may be another reason [6, 82]. Autoscopic and heautoscopic phenomena are other disorders regarding interoception dysfunction. Autoscopic phenomena mean the person has a hallucination of seeing himself like as a reflection in a mirror. Heautoscopy means seeing a 5 Interoceptive Dysfunction 77 duplicate of oneself that has physical and emotional independence. Patients with autoscopic phenomena usually have lesions on their right extrastriate cortex but those with heautoscopic hallucinations mostly have a deficit in their left posterior insula [73, 83]. Functional motor disorders (FMS) are a subgroup of neurological disorders in which there is no apparent physical deficit, but the patients have abnormal movement and weakness. The symptoms reduce when the patient’s attention is distracted. FMS patients have poorer interoceptive awareness, and they also have a condition named alexithymia; this means they have difficulty in recognizing and sharing their feelings. This supports the fact that the insula plays a role in emotions too [84, 85].

Eating Disorders

Since insula gets direct projections from the gastric part of the dorsal vagal complex, it is not unpredictable for it to play a role in eating disorders [86]. Anorexia nervosa (AN) is an eating disorder that even though patients with this condition are underweight, they avoid eating and have a strong desire to lose weight because they see themselves overweight. Other than delusions of being fat, patients with AN report that they do not feel hungry even in severe food deprivation. These symptoms are because of impairment in multisensory body perception. Factors that may contribute to AN are misinterpretation of visual, tactile, and proprioceptive signals or any way of interoceptive dysfunction [87]. Bulimia nervosa (BN) is another eating disorder in which the patients have episodes of binge eating and purging; this means that they take too much food in a short time, and then, as compensatory actions to lose weight, they use laxative and diuretic or they induce vomiting in themselves. Patients with AN experience only the purging [88]. Obsessive-compulsive disorder, perfectionism, and malfunction of reward circuits are some of the ongoing explanations of the etiology of AN, but here, we focus on interoceptive dysfunction-related theories [89]. As we discussed earlier, our body image is made of integrated signals from our emotions, beliefs, vision, touch, and proprioceptive and interoceptive signals [1]. While literature has focused on the fact that our body image is mostly affected by the visual signals, studies on AN patients suggest that it may not be as influential [87]. AN patients have a normal visual perception of others, but when they look in the mirror or photos of themselves, they have a great distortion of body image [90]. Therefore, visual perception may not play an important role in AN etiology [91]. Either the underlying reason for this illusion is the interoceptive signaling dysfunction or the integration of inner signals is impaired, which both can be explained by damage to the insula. Insular damage can explain many of the symptoms like distorted body image, unawareness of the malnutrition, and illusive beliefs toward food intake [92]. 78 R. Dehghani and F. Delavari

Many studies have tried to relate alteration in interoceptive indices to eating disorders; for example, the measurement of interoceptive accuracy and awareness by Khalsa [93] and Yoshikatsu and Santel [94] showed a reduction in both IAw and IAcc comparing to control. Pollatos have recently suggested a link between reduced IAcc and AN [95]. Some studies have also suggested that AN severity is correlated with lower IAw [96]. However, this result is not consistent with all other studies; this trade is supported by the rubber hand illusion (RHI) that was conducted in patients with eating disorders compared to healthy controls [97]. In RHI, the person’s real hand is hidden while he is seeing a rubber hand in the position of the hidden hand; stimulating the rubber hand simultaneously with the real hand while the person is visually watching the fake hand to be stimulated creates the illusion of the rubber hand’s ownership. This illusion is made by three components of the body image: vision, touch, and exteroceptive signals. One theory to justify this is the low interoceptive signaling in these patients. Visual, touch, and tactile signals (major components of the bodily image) in the RHI experiment supports the illusion, while the interoceptive signals that are coming from the real hand confront it; the brain decides to base its predictions on the more precise signals; therefore, lower interoceptive accuracy is related to greater illusions. AN patients have been showed to have greater RHI that supports the idea of interoceptive malfunctioning in eating disorders [96–98]. In a study of patients with AN, reduced blood flow in the right superior parietal lobe area was detected in the initial stages of AN [99]. This area is responsible for the integration of different signals to form a unique body image [100]. Size- weight illusion (SWI) experiment on AN patients also supported the idea that the integration of signals is impaired in AN patients. SWI is the basic experiment in which we have two objects of the same weight in our hands but their size is different; we predict that the smaller object is heavier even though they have the same weight [101]. Neuroimaging studies have shed light on other aspects of eating disorders. The illusion of being fat in AN patients can be explained with the increased insular volume in these patients. As we discussed earlier, the right insular cortex is associated with interoceptive awareness. The MRI of BN patients showed additional greater volume in the left insular cortex, which is not only associated with self-reported fullness but also with gastric distention. This accounts for the binge episodes in BN patients [3, 102]. Although studies are inconsistent, reduced total gray matter volume in both AN and BN is almost consistent with all the studies [88]. This can be a result of malnutrition, dehydration, and excessive exercising in these patients. Fortunately, the differences between patients with AN and BN can support the theory that their symptoms are due to a neurological deficit, not the other way around. For example, AN patients show an increase in the volume of the left orbitofrontal cortex and right anterior insular cortex. Orbitofrontal cortex is part of the food intake and satiety signaling [103, 104]. Therefore, increased orbitofrontal volume can explain the food avoidance in AN patients, and its reduction is seen in obese people. 5 Interoceptive Dysfunction 79

Conclusions

It can be concluded that many disorders have interoceptive dysfunction as part of their pathophysiology, and many other interoceptive-related disorders are yet to be discovered. Insular damage or its dysfunction somehow seems to be the source of the clinical manifestations of these disorders. There are some theories addressing how interoception is impaired in these conditions, for example, underconnectivity between circuits and chaotic overconnectivity inside interoceptive-related circuits like MPFC and insula, dysfunction of networks including the insula, insular inflammation, and lesions. Alliesthesia and aversive conditioning are examples of theories that include dysfunction of insular networks. The prediction error is one of the most dominant and strongly suggested theories. The footprint of this theory is almost on all of the conducted studies regarding interoceptive dysfunction; for some, it is the main theory like mood disturbance disorders, and for some other, it has a partial role like autism. Although many of these theories need further studies, what we do know for sure is that interoceptive dysfunction should be considered to have at least a partial role in the pathophysiology of many mental disorders.

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Pejman Jooya and Farnaz Delavari

Abstract Proprioception is a sensation that observes the body and gathers data regarding the state of body parts relative to each other and to the external environment. This type of sensation differs from many other sensory systems that are concerned with translating the characteristics of an organism’s external universe and objects which are not owned by the organism itself. When we see a (let’s say) blue object, the data provided by our eyes is attributed to the object as a specific color sensation (in this case) and not to the eyes or any other structure that belongs to our body. Proprioceptive information, however, is translated as states of body parts or alterations of their states relative to each other or to the world outside. This type of sensation is thus fundamentally different from the others, as it enables us to perceive our own existence and to have the knowledge of our bodies’ spatial characteristics and locations. Furthermore, a part of this system, the vestibular system, is specialized for detecting head acceleration and its movement relative to the gravitational field. Combined with information on the state of the neck, which determines the position of the head relative to the trunk, the vestibular system is capable of translating the data regarding the head position to a whole-body perspective. In this chapter, the concept of proprioception and its related structures are briefly introduced. Also, proprioception will be touched as the sixth sense. Further information on the other possible candidates of the sixth sense and its characteristics are to be found in other chapters of the book.

Keywords Proprioception · The sixth sense · The vestibular system

P. Jooya (*) MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran F. Delavari Media and Life Promotion Group (MLPG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Introduction

Proprioception is one of three domains of sensory perception first conceptualized and introduced by Sir Charles Scott Sherrington. He described the body of a mul- ticellular organism as an assemblage of a superficial “sheet” of cells which are in close contact with the external environment and a mass of cells beneath that layer which, he believed, are mainly under the influence of the local changes occurring in that internal environment. In these different populations of cells exist two distinct classes of receptors for providing the organism with information about the external and internal environments. Receptors located in the superficial layers are responsible for converting environmental agencies to nervous signals and are further divided into two subsets, “exteroceptors” and “interoceptors”. Exteroceptors are responsible for detecting a wide range of changes in the vast environment surrounding the organism and are rich in number and diversity. Interoceptors are mainly distributed in internal organs where, according to Sherrington’s description, another cellular sheet is in contact with the nonliving media surrounded by the organ, e.g. gastrointestinal lumen. Finally, the organism obtains information about the state of its deep tissues by means of another class of receptors called “proprioceptors.” They inform the organism of the posture and movements of its own body, the location of its limbs and body parts, the stress and tension imposed upon joints and muscles, and the force produced by contraction of muscular tissues. As a result, proprioceptive information is gathered via mechanoreceptors distributed throughout the deep tissues of the organism as they collectively form the “proprioceptive field” of sensation [1]. Proprioceptive system exchanges information with different parts of the nervous system, spinal gray matter, brainstem, and cerebellar nuclei and a variety of cerebral cortical areas. Its functions range from unconscious reflexes to postural and motor control and involvement in cognitive processes. The system receives afferent signals from both specialized mechanoreceptors in the musculoskeletal system and vestibular apparatus and also from sensory organs and receptors that act mainly as exteroceptors such as eyes and cutaneous receptors. Proprioceptive sensory cortex also receives signals from the motor cortex referred to as corollary discharge [2]. Two systems related to proprioception, the vestibular system and the proprioceptive part of the somatosensory system, are to be covered in this chapter. Meanwhile, the latter will be merely addressed as proprioceptive system throughout the chapter for the purpose of simplicity.

The Proprioceptive System

Afferent signals of the proprioceptive system are provided by receptors located throughout the musculoskeletal system and peripheral tissues transducing mechanical energy into membrane action potential. When a movement occurs in 6 The Proprioceptive System 87 a joint or a collection of joints, the surrounding tissues are affected. This effect is heterogeneous and anisotropic, leading to different patterns of stretching and loosening of tissues in relation to the range and direction of the joint movement. As an instance, during passive flexion of the elbow joint, triceps muscle and its tendon, posterior part of the joint capsule, and the skin covering the tip of the elbow are stretched, while their anterior counterparts are unloaded and relaxed. This difference in the mechanical state is sensed by proprioceptors in each organ leading to a sensation of joint movement and its direction [3]. This type of sensation was of course introduced by Henry Bastian even before Sherrington as kinesthesia, the sense of limb movement and position [2], although that was more indicative of a psychologically defined sense of movement and posture rather than a system of functionally interrelated structures and their physiological characteristics [4]. Two populations of proprioceptors reside within the musculoskeletal system: one in musculotendinous tissues (muscle spindles and Golgi tendon organs) and one in joint capsule and ligaments. There are also signals of remarkable importance for the sense of proprioception coming from specific cutaneous receptors [3]. Here is a brief review of these receptors and their role in proprioception.

Muscle Spindles

Muscle spindles are encapsulated sensory organs residing within the skeletal muscles. They consist of specialized small muscle fibers covered in part by a fusiform capsule. These “intrafusal fibers” are composed of a noncontractile central segment and two contractile poles. Their size and structure are thus different from those of extrafusal fibers, which are responsible for muscle contraction. Muscle spindles receive both afferent and efferent nerve endings. The activity of the afferent endings changes in accordance with the changes in the length of the muscle. These endings are of two distinct types: primary (type Ia afferent) and secondary (type II afferent) endings. Efferent endings are small motor neurons of gamma type that exclusively innervate the spindles, or beta motor neurons that innervate both extrafusal and intrafusal fibers simultaneously. They are part of the fusimotor system that regulates the sensitivity of spindles in accordance with the activity of circumscribing muscle fibers. For instance, when a muscle contracts, its spindles will be unloaded and their firing rate decreases in absence of gamma and beta motor stimulation. This lessens the sensitivity of the muscle spindle to any change in length. Fusimotor signals that result in intrafusal fiber contraction reset the sensitivity for the new state of muscle, enabling the receptor organ to detect changes imposed on the contracted muscle [5]. This altering sensitivity calls for additional information about the level of fusimotor activity for a correct interpretation of incoming signals from the spindles. Primary afferent endings are excited by the muscle length change and are sensitive to the velocity of the change, while the secondary endings are less responsive to the velocity of length change and 88 P. Jooya and F. Delavari continue firing in the absence of movement. Secondary endings provide the CNS with the signals about the static length of muscles and contribute most to the sense of position rather than movement [6]. Although located within the bulk of muscle, signals from these receptors are perceived as a sensation of joint angle and movement instead of a feeling related to their anatomical site [7]. The contribution of muscle spindles in sense of position and movement is prominent. Experiments on the role of muscle spindles in the proprioceptive sense of finger joints showed remarkable loss of proprioception when the muscles, and thus the spindles, were unloaded while the joint was subjected to a passive movement. The more the number of disengaged muscles, the less the sensation of joint movement and the less accurate the prediction of finger position reported by the subjects. On the contrary, local anesthesia of skin and joint receptors was shown to have little effect on the subjective perception of finger position and joint movements when signaling from spindles was intact [3]. Other evidence was provided by the observation that primary spindle afferents could be excited by vibration, while other muscle proprioceptors were rather irresponsive. This enabled the researchers to specifically stimulate this class of proprioceptors and isolate the effects of their activation. By administering vibration to the tendon of the biceps brachii muscle as a flexor, subjects reported a sense of elbow extension while there was no actual movement. Given the fact that vibration does not stimulate other types of proprioceptors to a large extent, the observation shows that primary spindle afferents are almost enough to evoke a sense of joint movement [8]. Direct tendon-pulling experiments also showed the same kind of sensation. Manually pulling the exposed tendon of a specific muscle feels the same as when the joint is moved by the contraction of its antagonistic muscles [8].

Golgi Tendon Organs

Golgi tendon organs (GTOs) are another class of encapsulated receptors associated with skeletal muscles. GTOs are located in the junction between muscle fibers and tendons/aponeurosis associated with them. From one side, 5–25 [9] muscle fibers enter the capsule and immediately converge and attach to the collagen bundles and do not extend further from the entrance to the lumen of the fusiform capsule. Collagen bundles exit the other end to join the tendon/aponeurosis. Inside this capsule, branches of a large-diameter myelinated neuron of type Ib interweave with bundles of collagen fibers in a spirally braided conformation. When stretched, the distances between adjacent collagen fibers decrease, so they squeeze the nerve branches between them [10]. Afferent signals of GTOs contribute to the sense of force imposed on or exerted by the muscles. Though they signal the CNS of the muscle force during a task, the measure of effort made by the subject is shown to depend on afferent signals from the motor system in the form of corollary discharge as well [7]. 6 The Proprioceptive System 89

Joint Receptors

Joint receptors innervate both the capsule and the corresponding ligaments. However, the role of joint receptors in conscious proprioception is negligible, as they are effectively inactive during mid-ranged movements of the joints. They are best excited when joint movement approaches its extremities. Joint receptors are thus mostly considered as “limit detectors” [11].

Free Nerve Endings

Free nerve endings are present in muscular and fibrous parts of the musculoskeletal system. These nerves are of small-diameter myelinated fibers of type III afferents and unmyelinated fibers of type IV afferents. Mechanoreceptor in nature, they are activated only when the stimulus is strong enough to harm the tissues, making them responsive to noxious stimuli rather than physiological movements [5].

Skin Mechanoreceptors

Skin mechanoreceptors conduct signals concerning the stimuli from internal and external body environments and contribute in sense of touch and proprioception. Skin proprioceptors are believed to be slowly adapting type II (SA-II) receptors that are sensitive to lateral skin stretch [12]. Skin stretch patterns change as movement occurs at a joint stretching the skin on one side and unloading it on the opposite side. By sensing these changes in skin tension, stretch receptors can help identify the direction and measure of the joint movement [3]. Slowly adapting receptors also contribute in sense of position [6]. In order to have a conscious perception of the position, movement, force, and effort, the information obtained by these receptors is transmitted to higher CNS centers for further processing. From neck, trunk, and limbs, the afferent axons of 30 spinal nerves ascend in the spine to synapse with neurons of corresponding nuclei in the medulla. From T7 to coccygeal nerve, the axons ascend in a pathway called gracile fascicle and enter gracile nuclei in the medulla. Spinal nerves above T7 form another pathway, the cuneate fascicle, which ends in cuneate and external cuneate nuclei of the medulla. The two fascicles constitute the dorsal column of the spin, and so, the related nuclei are collectively called dorsal column nuclei. Afferent fibers from these centers then form the medial lemniscus of the medulla, cross the midline, and receive fibers from the trigeminal principal nucleus conveying proprioceptive information from the head, face, and oral cavity. The next stop is the ventral superior posterior nucleus of the thalamus, which relays proprioceptive information to the primary somatosensory cortex in the postcentral gyrus of each 90 P. Jooya and F. Delavari parietal lobe. Through intense connections with other parts of the brain cortex, primary somatosensory cortex sends its axons to several other areas of brain cortex such as secondary somatosensory cortex of the parietal lobe, posterior parietal cortex, and primary motor cortex [5].

Distinguishing Self-Stimuli from Non-self, Role of Corollary Discharge

So far, we introduced basic concepts regarding proprioception and its functionally related structures. Proprioception as described deals with mechanical stimuli acting on deep cell layers of an organism’s body. These stimuli can be of two distinct sources, those caused by the action of environmental factors and those that are the consequences of an organism’s own body movements and activities. Sherrington considered the latter to be largely initiated by the signals from exteroceptors. From this point of view, proprioceptive signals are based either on direct mechanical effects of external agents on body parts or on the bodily responses to exteroceptor signals [1]. For addressing purposes, terms “exafference” and “reafference” are used to refer to signals of external and internal origins, respectively [7]. It is a task of the sensory system to distinguish between these two types of signals to attain a realistic model of the surrounding world not confounded by its own actions [7]. For muscle spindles, the situation is even more complicated. They are not only affected by the motor activity of the surrounding extrafusal muscle fibers, but they also have their own contractile activity maintained by the fusimotor system. Gamma motor activation of intrafusal fibers can mimic the state of muscle stretch, while co- activation of alpha and gamma motor terminals prevents spindles from getting relaxed. Their length shortens alongside the contracting muscle, which makes them less sensitive to the ongoing active length change of the muscle. These interactions between motor signals make it impossible to model the state of a muscle based on signals from spindles without taking into account the level of fusimotor activity [7]. Additionally, other aspects of proprioceptive sense such as the sense of effort and sense of the heaviness of an object have also shown to depend on the level of motor activity. The data was provided by muscle curarizing experiments in which subjects with partially curarized muscles tended to overestimate the weight of a given object and the effort needed to hold it. They were able to correctly estimate the force exerted by the muscle during the task without any systematic error though. The overestimation also accorded to the amount of muscle weakness. The same goes for a fatigued muscle. The prominent change in such situations seems to occur in the level of alpha motor activity associated with the weakened or fatigued muscle, while the weight of the object and the actual force remain stationary. A higher level of motor activity ends in a heightened sense of effort and weight [7]. Contribution from motor centers of the nervous system seems to be essential for the sensorium to discriminate between exafferent and reafferent signals. This contribution is in the form of an “efference copy” of ongoing motor activity to 6 The Proprioceptive System 91 sensory areas. This copy or “corollary discharge” is transmitted via corticocortical pathways [2] and is used to estimate the expected afferent input resulting from the concurrent motor action [12]. So the sensorium is aware that a range of possible inputs from the peripheral receptors may be produced which should not be confused with the exafferent signals. Therefore, in the case of fusimotor activation, the joint movement is not misinterpreted or overestimated from a centrally induced loaded spindle [11]. However, despite its contribution to the sense of heaviness and effort and to spindle signal decoding [7], corollary discharge cannot lead to a sensation of movement on its own. In ischemic paralysis of a limb, at a specific phase that sensory nerves are fully paralyzed but the subject is still able to move the limb, movement occurs in the total absence of a subjective sensation. One should expect a report of movement sensation if corollary discharge is to be able to directly evoke a proprioceptive sensation per se, given the fact that it is sent simultaneously as the motor command itself [11]. It is in fact believed that sensory system uses the information from efference copy to evaluate those provided by peripheral proprioceptors. It detects the deviations of incoming data from the expected pattern of sensory input caused by internal factors to extract the pure effects of external stimuli on the receptive field [7]. The relationship between corollary discharge and muscle spindles remains highly problematic though. Variable sensitivity of spindles due to activation of the fusimotor system, on one hand, makes their signals ambiguous without knowing the extent of activation. On the other hand, co-activation of the alpha motor and fusimotor systems makes the latter to act as a corollary discharge to the main command itself. The result of this co-activation is that during an active contraction of a muscle, relaxing effect of extrafusal fiber contraction is compensated by successive spindle sensitivity threshold resetting. So what is reported is the amount of mismatch between the activity of the two systems [7], as well as other extrinsic and non-contraction-related agents.

The Vestibular System

Back to Sherrington’s definitions, other than the classification of cell populations of the body into three groups, he claimed that receptors of different body segments of an organism vary in development and complexity. Motile animals of longitudinally oriented body parts, for example, show privileged areas that are host to highly developed and specialized receptors, specifically from exteroceptor class at one end of their longitudinal body axis. For a motile organism, this end accords with the axis of motion and its direction, say the end is the one closer to the tip of the motion vector. These parts are exposed to environmental stimuli more than the other segments, and they are affected sooner as well. For the exteroceptive system, a class of receptors called “distance receptors” is developed. This class contains receptors that detect environmental alterations caused by sources located not necessarily close to 92 P. Jooya and F. Delavari the body. Photoreceptors of the retina and mechanoreceptors of the auditory system are examples of such specialized exteroceptors. Sherrington argued that such a differentiation also exists in the proprioceptive system in the form of mechanoreceptors of the “labyrinth system” or vestibular system that is located in one of the privileged body parts [1]. In this section, we will mainly stick to the mammalian vestibular system when explaining its structural formation. Variations in the number of canals and receptor cells exist between different classes of animals [13]. The vestibular system is composed of a group of interconnected fluid-filled sacs and canals, which act as the balance organ of the body. Altogether, these structures are called membranous labyrinth of the inner ear located inside the corresponding cavities of the petrous part of the temporal bone, the bony labyrinth [14]. Constituting elements of the membranous labyrinth are three roughly semicircular canals that are two by two oriented at right angles to each other in three- dimensional (3D) space and two otolith organs: utricle and saccule. Semicircular canals detect angular acceleration of the head, while otolith organs sense linear acceleration as well as the gravitational force [14]. Sensory organs inside these structures use different mechanisms to sense angular and linear acceleration, yet the mechanoreceptors responsible for this action are common between them. Mechanoreceptors of the vestibular system are type I and type II hair cells. Situated in the neuroepithelium, a varying number of membrane protrusions exist on their apical pole. Each hair cell has a single true cilium, kinocilium, and 70–100 membrane protrusions, with an axis made up of actin filaments, the stereocilia. Stereocilia of a hair cell are sorted according to their length. The tallest stereocil- ium is the closest to the kinocilium and they become smaller as the distance increases [14]. Kinocilium has a cylindrical form from its base but expands and makes a globular swelling at its tip. Stereocilia are rod-shaped from top to bottom, while before merging with the surface membrane of the cell, they taper and become conical shaped at their base [15]. Movement of stereocilia in regard to the kinocilium affects membrane potential of a hair cell. Bending toward the kinocilium opens more ion channels at the membrane of the stereocilia, therefore depolarizing hair cell. This leads to an increase in the firing rate of its associated afferent neural fibers. Deflection of stereocilia in the opposite direction causes more ion channels to close and the hair cell to hyperpolarize. In this condition, the firing rate of afferent neurons in the synapse with the cells decreases [14]. Type I hair cells have a round basal end encircled by an afferent dendrite forming a calyceal terminal, while the synapse between a type II hair cell and its associated afferent is of typical bouton-like endings [16]. Hair cells and their afferents also receive efferent endings [16]. They synapse with the afferent neurons of type I and type II cells, and the type II cells themselves, and release acetylcholine into the synaptic space [13]. Origin of efferent fibers is in the brainstem where single or multiple clusters of neurons, depending of the organism’s species, form the vestibular efferent nucleus. The function of this organization is yet to be understood particularly in mammalian species. However, possible functional roles are hypothesized for the efferents as sensitivity modulators in response to corollary discharge from spinal centers and in conjunction with 6 The Proprioceptive System 93 the stimulation of other sensory and cognitive systems. Participation in vestibular plasticity and compensation for unilateral sensory loss is also suggested for the efferent system [17]. The key feature of matter that is detected by vestibular organs and acts as an indicator of motion of the head is inertia. Sir Isaac Newton defined the Latin term “vis inertiae” meaning force of inactivity as a feature of the mass resisting any force that tries to change its mechanical condition. In other words, it is a tendency of matter to maintain its resting state or uniform movement along a straight line [18]. Based on this definition, the mechanical status of a massive (m ≠ 0) object remains stationary unless a force is exerted on it, and the amount of force needed for the desired change in state is proportional to its inertia. In linear acceleration, inertia equals the mass of an object [19]. As mentioned earlier, otolith organs are linear accelerometers. Each otolith organ has an area of neuroepithelium called macula. Macula of utricle is located horizontally, while that of saccule is at a vertical plane. Together, they are able to detect linear acceleration in every direction. The macula is covered by a gelatinous membrane that contains otoconia (crystals of calcium carbonate) at its top. Into this membrane protrude the cilia of hair cells. Different cells are oriented in different directions, thereby covering the whole range of possible accelerations in 3D space. Any linear acceleration thus excites a group of hair cells, inhibits another group, and leaves other populations of hair cells unaffected [14]. This directionality accords to a curved line in macula called the “line of polarity reversal” or LPR as the hair cells of two sides are oriented opposite to each other. The surface of the macula is itself divisible into two distinct regions: striolar and extrastriolar zones. Afferent innervation and hair cell typing differ between the regions. Afferent firing shows different patterns of spikes during resting or stimulated states. At extrastriolar zone, the pattern is regular and the frequency of recorded spiking pattern remains constant for a given level of activation. On the contrary, neurons of the striolar zone show irregular activity and the timing between successive spikes varies greatly. Irregular afferents are larger in diameter, respond to dynamic stimuli, and adapt faster than the regular endings. Synaptic terminals are divided into three types. “Calyx-only afferents” are found in the striolar zone and form complex calyces of 2–4 hair cells in nearly 50% of the cases. “Bouton-only afferents” appear only in the extrastriolar zone, and “dimorphic afferents” that synapse with both types of cells exist in both regions. They usually form simple calyces with a single type I cell in contrast with calyx-only types [13]. The exact role of these two systems is not fully understood. However, a higher rate of change per amount of stimuli, higher conduction velocity, and different central connections of irregular afferents may suggest a more prominent role in reflective movements that need a rapid response, while the signals from regular afferents can be used in higher processing levels as they can carry more information about the stimuli than the other system [13]. When the head accelerates in a specific direction, otolithic membrane and otoconia lag behind because of their mass and therefore their inertia. For hair cells, this lag is perceived as a displacement of the otolithic membrane in the opposite 94 P. Jooya and F. Delavari

direction of the original acceleration vector, which deflects their cilia and alters their membrane potential. Cells aligned with the axis of the acceleration vector are maximally influenced. Accelerations of higher magnitude also cause more drastic changes in membrane potential of hair cells and the firing rate of the corresponding nerve fibers [20]. Another agent that influences the otolithic membrane is gravity. Gravitational field exerts an everlasting force on otolithic membranes and, with regard to their spatial orientation, can cause a shear force to be produced between the membrane and neuroepithelium. Otolith organs are thus detectors of the gravitational field as well as linear acceleration [20]. In bipedal animals and humans, saccule is more frequently involved in this task especially in tilting of the head that involves displacement of otolithic organs with respect to the gravitational field [5]. Unlike otolithic organs, semicircular canals detect angular acceleration of the head. Of the three canals at each side, lateral canals are located in the horizontal plane, while anterior and posterior canals are located vertically each with approximate angle of 45° with the sagittal plane. Two by two, canals are placed in the same plane and make pairs for sensation of angular acceleration. When one of the canals in pair gets excited, the other canal gets inhibited and vice versa. It also compensates the loss of one canal in the case it occurs. These pairs are two lateral canals, and each anterior canal is with its contralateral posterior counterpart. Maximal excitation and inhibition for semicircular canals occurs when head rotation is in the same plane as the canal and its pair [14]. A single rotation can affect more than one pair of canals, and coding of the plane of rotation needs data from all of the canals [14]. At one end, canals are open to utricle, while at the other, they expand to form the ampulla. In ampulla exists the sensory neuroepithelium called crista where the hair cells of semicircular canals reside [14]. Mammalian cristae show a similar zonal difference between their central and peripheral regions that correspond to striolar and extrastriolar zones, respectively [13]. This area is covered by the gelatinous cupula that engulfs the cilia of hair cells. Deformation of cupula deflects the cilia and alters the firing rate of nerve fibers associated with them [14]. Sensory function of semicircular canals depends on the inertial effects of the fluid inside. When a rigid body rotates, all parts of it will have the same singular velocity and will not move relative to each other. However, for a liquid inside a fully filled rotating container, the viscosity of the liquid and its interactions with the walls of the container determine the behavior of the fluid, and relative motion of liquid with regard to container occurs [19]. In case of the vestibular system, head rotation in a plane, e.g., horizontal plane, causes the endolymph to lag behind as a result of its inertia and move relative to the canal wall and ampulla. The direction of this motion is also opposite to the direction of angular acceleration. This relative motion toward or away from the ampulla pushes and pulls it, respectively, and the deformation deflects the hair cell cilia accordingly. In the case of lateral canals, pushing the cupula toward the utricle ends in a decrease in the firing rate of the corresponding nerve. For anterior and posterior canals, the response is reversed. However, head rotation with constant angular velocity does not cause the relative 6 The Proprioceptive System 95 fluid motion, and in the case of zero angular acceleration, nerve firing rate equals that of a motionless head, and asymmetry between two paired canals disappears. The symmetric bilateral activity of afferent nerves is thus a signal of zero head acceleration to the CNS [14]. Semicircular canals and otolith organs cooperate with each other in providing a model of head movement and position in 3D space. On their own, semicircular canals can report rotations only from a head-centered frame of reference indipen- dent of the head’s real position in the outside world. Additional data from otolith organs about the direction of gravitational fields is used to determine the direction of motion [21] as they can determine “which way is up” [20]. On the other hand, semicircular canals can provide the vestibular system with the amount and orientation of head tilt or rotation, which is used to differentiate the otolithic activity due to these head movements from the effects of linear acceleration [21]. As the vestibular system is stuck to the skull, it can detect movements of the head, but whether it is accompanied by the same movement in the body or not cannot be decided only using vestibular signals. The frame of reference should also be the head itself when there is no other complementary information and further data processing. However, the position of the head relative to the body is monitored by the neck proprioceptors, and combining with the information from head position and movement, the frame of reference for the vestibular sensation can be transformed to a body-centered one [21] in the corresponding cerebral cortical areas. Vestibular organs contain mechanoreceptors of this system. The data from these organs are processed in associated areas in the brainstem, cerebellum, and cerebral cortex. Axons of afferent neurons from macula and crista ampullaris form vestibular nerve, which subsequently joins the cochlear nerve to form the eight cranial nerve, the vestibulocochlear nerve. The axons then enter into vestibular nuclei of brainstem [14]. Vestibular nuclei also receive signals from the spinal cord, cerebellum, and visual system and send their efferents to various centers in the spinal cord, brainstem, cerebellum, and ventral posterior and ventral lateral nuclei of thalamus [5]. The vestibular system deals with various areas of cerebral cortex, especially those of parietal lobe and insula. In nonhuman primates, the parieto- insular vestibular cortex (PIVC) is the core center for vestibular signals. It contains posterior insula, retroinsular cortex, and perisylvian areas. Other vestibular areas of the cortex associated with the vestibular system are the posterior parietal cortex, motor and premotor cortex, frontal eye field, hippocampus, and cingulate cortex [22]. PIVC and related areas of primary somatosensory cortex (area 2 and 3a) constitute the inner vestibular circle of primate brains [23]. The analogous portion of the human brain cortex is believed to be area OP2 of the posterior parietal operculum with a right hemispheric dominancy. OP2 of the posterior parietal opercular cortex is interconnected to other cortical areas of vestibular association and is pos- sibly solely activated by vestibular inputs from the activity alterations of vestibular hair cells. It might be a center for unimodal data processing of the vestibular system, which does not receive nor integrate data from other sensory modalities, such as visual or somatosensory systems [23]. 96 P. Jooya and F. Delavari

Proprioception as the Sixth Sense

The evidence supporting a sensation of muscular origin was first provided by Charles Bell describing anatomical connections between sensory neurons and eye muscles. In his view, the connections were involved in movement control and their activation would influence the motor actions via CNS signaling [4]. He attributed the name sixth sense to this type of sensation [4]. The importance of a sensory system that monitors the internal conditions is remarkable for providing and maintaining a conceptual framework for the individual to perceive its own body as a distinct entity from the external world and detect the effects of external and internal agents on its body [4]. We perceive the world around us using our brains. For this, information about the objects and events is obtained by means of various sensory modalities and integrated into a conscious experience. Simultaneously, we are aware of our own subjective existence that is experiencing things. One part of this awareness about our own existence concerns our physical body and the body parts. Bodily self- consciousness (BSC) is thus a component of a more general concept, self- consciousness, which also includes higher forms of self as a perceptual entity [24]. In the case of BSC, the signals providing clues on the shape and location of body parts or the whole body play an important role. Even for a reasonable understanding of spatial characteristics of an object in the external world, awareness of the location of the exteroceptor that is sensing it is also necessary [24]. BSC can be further divided into other subdomains. Body ownership, self-location, and first-person perspective are examples of such subsets of BSC [25, 26]. Like other types of conscious perceptions, BSC needs multimodal integration of sensory information. This integration occurs in certain areas of the brain cortex. Areas mostly associated with BSC are ventral premotor cortex, posterior parietal cortex, temporoparietal junction (TPJ) [25], occipitotemporal cortex [26], and posterior insula [24]. Ventral premotor cortex is responsible for the sense of body ownership. Posterior parietal cortex integrates multisensory inputs from various reference frames centered at different body parts and transforms them into a united body-centered frame [25]. A neural network consisting of bilateral TPJs, right supplementary motor area of the frontal lobe, and right insula deals with information regarding self-location and first-person perspective [26].

Conclusions

The sense of muscular origin turned out to be more than a system for movement control that Bell described. Bastian’s kinesthesia, the sense of position and movement, described other aspects of a system that was responsible for sensing one’s body itself, and other aspects of this sense such as the sense of force and effort were added later on. The contribution of proprioception to various aspects of the sensation of the body makes it a good candidate for the sixth sense, as it prominently 6 The Proprioceptive System 97 contributes to the sense of self as an entity distinct from the surrounding universe. A sense inherently different from classical five senses can thus be defined based on this distinction that gives rise to a new possible interpretation of the sixth sense. However, whether we count proprioception as the sixth sense also depends on how we define the word itself. Does it equal someone’s intuition and has a more prominent intellectual aspect or is it based on sensory inputs from any of the three distinct domains? Proprioception itself as the sixth sense was discussed above. However, what if we define the sixth sense as a kind of intuitive feeling that an individual generally experiences. One cannot be traceable to a solitary data input channel. Can proprioception interact with such general feeling and overall mood? Can proprioceptive inputs even affect how we think about the future? Though the role of proprioceptive signals in consciousness and the CNS correlations of this part of proprioception were not meant to be discussed in this chapter, we can still make assumptions regarding such connections. As proprioception monitors the mechanical state of the body, it can detect any kind of excess mechanical tension or stress imposed upon any part of the body. We all might have experienced how a bad sitting position or longstanding muscle twitches make us feel bad. On the other side, massaging or stretching muscles and fasciae makes us feel better. Vestibular inputs also have an important influence on our general feeling. They can also have positive or negative effects on us. Many devices in amusement parks are doing their job by stimulating out the vestibular system, while carsickness is an example of the negative effect. Altogether, we can assume that when the sensory inputs report an abnormal bodily condition and mechanical status, the probability of feeling anxiety, uneasiness, and sickness will be more compared to the normal situations, which ends in different intellectual and emotional functions of the brain in different body conditions. Therefore, we can safely assume that proprioception at least interacts with the sixth sense as the king of intuitive perception. What is the most appropriate definition for the sixth sense? What is the exact relationship between the sixth sense and other sensory systems? Is proprioception really the sixth sense? You will find more clues as you continue reading this book.

References

1. Sherrington CS. The integrative action of the nervous system. New Haven: Yale University Press; 1961. 2. Stillman BC. Making sense of proprioception. Physiotherapy. 2002;88(11):667–76. 3. Grigg P. Peripheral neural mechanisms in proprioception. J Sport Rehabil. 1994;3(1):2–17. 4. Smith R. “The sixth sense”: towards a history of muscular sensation. Gesnerus. 2011;68(2):218–71. 5. Kandel ER. Principles of neural science. 5th ed. New York: McGraw-Hill Education; 2013. 6. Proske U, Gandevia SC. The kinaesthetic senses. J Physiol. 2009;587(Pt 17):4139–46. 98 P. Jooya and F. Delavari

7. Matthews PB. Where does Sherrington’s “muscular sense” originate? Muscles, joints, corollary discharges? Annu Rev Neurosci. 1982;5:189–218. 8. Matthews PB. Where anatomy led, physiology followed: a survey of our developing understanding of the muscle spindle, what it does and how it works. J Anat. 2015;227(2):104–14. 9. Jami L. Functional properties of the Golgi tendon organs. Arch Int Physiol Biochim. 1988; 96(4):A363–78. 10. Schoultz TW, Swett JE. The fine structure of the Golgi tendon organ. J Neurocytol. 1972; 1(1):1–25. 11. Matthews PB. Proprioceptors and their contribution to somatosensory mapping; complex mes- sages require complex processing. Can J Physiol Pharmacol. 1988;66(4):430–8. 12. Johansson RS, Flanagan JR. Coding and use of tactile signals from the fingertips in object manipulation tasks. Nat Rev Neurosci. 2009;10(5):345–59. 13. Eatock RA, Songer JE. Vestibular hair cells and afferents: two channels for head motion signals. Annu Rev Neurosci. 2011;34:501–34. 14. Khan S, Chang R. Anatomy of the vestibular system: a review. NeuroRehabilitation. 2013;32(3):437–43. 15. Hudspeth AJ, Jacobs R. Stereocilia mediate transduction in vertebrate hair cells (auditory system/cilium/vestibular system). Proc Natl Acad Sci U S A. 1979;76(3):1506–9. 16. Mescher A. Junqueira’s basic histology: text and atlas. 12th ed. New York: Mcgraw-Hill; 2009. 17. Mathews MA, Camp AJ, Murray AJ. Reviewing the role of the efferent vestibular system in motor and vestibular circuits. Front Physiol. 2017;8:552. 18. Newton I, Motte A, Chittenden NW. Newton’s principia: the mathematical principles of natural philosophy. New York: Geo. P. Putnam; 1850. 19. Lee GJ. Moment of inertia of liquid in a tank. Int J Naval Archit Ocean Eng. 2014;6(1):132–50. 20. Day BL, Fitzpatrick RC. The vestibular system. Curr Biol. 2005;15(15):R583–6. 21. Angelaki DE, Cullen KE. Vestibular system: the many facets of a multimodal sense. Annu Rev Neurosci. 2008;31:125–50. 22. Lopez C, Blanke O, Mast FW. The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis. Neuroscience. 2012;212:159–79. 23. zu Eulenburg P, Caspers S, Roski C, Eickhoff SB. Meta-analytical definition and functional connectivity of the human vestibular cortex. NeuroImage. 2012;60(1):162–9. 24. Blanke O, Slater M, Serino A. Behavioral, neural, and computational principles of bodily self-consciousness. Neuron. 2015;88(1):145–66. 25. Serino A, Alsmith A, Costantini M, Mandrigin A, Tajadura-Jimenez A, Lopez C. Bodily ownership and self-location: components of bodily self-consciousness. Conscious Cogn. 2013;22(4):1239–52. 26. Ionta S, Martuzzi R, Salomon R, Blanke O. The brain network reflecting bodily self- consciousness: a functional connectivity study. Soc Cogn Affect Neurosci. 2014;9(12): 1904–13. Chapter 7 Extrasensory Perception: Concept and History

John Nwanegbo-Ben

Abstract Extrasensory perception has been a thought-provoking subject among psychologists and philosophers of science. The concept of extrasensory perception (ESP) or what we regard as the sixth sense is that a man can make contact or communicate with distant events and people by unknown procedures that does not engage the application of sensual organs. Natural experimental scientists and critics of this phenomenon posit that claims associated with it are fraudulent, pseudoscien- tific, and nonsensical. The reason for this position is that it does not fit into the whole gamut of information acquired through the natural sciences. This chapter explicates the content of ESP and questions why it has not been acclaimed a monu- mental discovery. It concludes in its analyses that extra-sense makes sense and contributes to the advancement of human knowledge.

Keywords Extra-sense · Extrasensory perception · Sense · Telepathy · The sixth sense

Introduction

Man is naturally an inquisitive being and is a mystery to himself. The mystery surrounding him transcends specific areas of study. The reason for this proposition is that the psychologists have probed deeper into the complexities of mental states but have not been able to explain the nature of memory. Every man alive remembers things all the time, yet nobody knows how he does it. There are various theories to this effect, yet none has been fully accepted. We all sleep and dream, and during the period of dreaming we feel our actions were physically real until we are awake, which also remains as a mystery. Biologists have explained the contents and secrets of inheritance through

J. Nwanegbo-Ben (*) Federal University of Technology Owerri, Owerri, Nigeria MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Owerri, Nigeria

Mendelian gene, delving into the chemical equilibrium of the human anatomy and the intricate electrical structure of the brain. They asked how impulses from the nervous system are translated into consciousness. All these and others remain a philosophical conundrum. The concept, extrasensory perception (ESP) or what we generally refer to as the sixth sense is a research that has been coming up with possible clues to some of these mysteries surrounding the nature of man. Researches appear to confirm clues of an agelong belief which has been labeled pseudoscience, nonsensical dogma, fraud, etc. This position is predicated on the belief that the claimed results of the research in this area do not fit in with the whole body of information acquired through the natural sciences. Despite critics presented by the natural experimental scientists, evidence has shown that man is a being who can make contact or communicate with distant events and people by an unknown procedure which does not engage the application of the sensual organs of taste, smell, touch, or sight, and which to some extent is devoid of time and space. Experiments have proved that at a distance, one human being could become aware of another’s thought or feelings. This curious faculty has become known as telepathy. Others possess the powers to perceive the future and we refer to this ability as precognition. In the same sense, experiments have shown that some individuals can move objects, both tiny and large automobiles. These individuals are said to possess telekinetic abilities. The question is why have these not been acclaimed as a great discovery? This is a question of great psychological and philosophical interest. It is true of course that the faculty of extra-sense has little practical value for the advocates of modern experimental science. However, whatever perception the modern experimental scientists have against this area of study, extra-sense makes sense as a subject of discourse.

Sense and Extra-Sense (the Sixth Sense)

Everything in existence is a combination or unity of opposites. This is the central theme of dialectics [1]. Man is a combination of opposites-sense and extra-sense, a natural being with an element of supernaturalism. The line of thought we wish to discuss here may help us comprehend contending issues embedded in this study. Man naturally has five senses, the sense of touch, taste, smell, sight, and hearing. These are the traditionally recognized empirical tools of man. The natural world revealed to us by our senses is more or less subjective. The way each one of us reacts to stimuli differs. Empirical science is an attempt to produce as far as possible an objective view of the world. To do so, we need to compare our own various perception of the world with those of others; hence, we need instruments that can make measurements of the external world. Some of these instruments we believe can make us increase the range of our senses. Our ears and voices determine how much sense is available to us for communication. This has however been improved in 7 Extrasensory Perception: Concept and History 101 these modern times by technological developments such as radar, radio, television, and the Internet. All of these fall within the confines of sensory realities. We may ask ourselves, what is extra-sense or the sixth sense outside our known traditional five senses? Studies have shown that there are arguments and positions backed by advocates of the existence of sixth sense traced to research centers. These centers provided evidence of the availability of an extra sense. Those within the experimental natural sciences do not appear to recognize these areas of research. The reason is that they see it as having no practical value because they have concluded that it is elusive, unreliable, and sporadic. All these are predicated on two reasons that hinge on scientific dogmatism. On one hand, we have come to accept doubtlessly, a specific hypothesis on which both our practical activities and scientific theories are based on. We take it for granted (as Hume would say [2]) that every event has a cause which precedes it, and that no event can have an effect before it has happened; also for an event to influence another, there must be some transmission of energy between the two. On the other hand, most experimental scientist opposed to the sixth sense take it for granted that consciousness is no more than an aspect of physical processes, that is, it is nonexistent apart from a physical brain. This implies the belief that they do not accept the mind can be separated from the body. Thus, the concept of those who do not accept the existence of that knowledge can only be acquired through the natural sciences. Therefore, for them, extras-sense is nonsense. Despite these positions, experiments have come to confirm that man is a creature who can make contacts with distant events by an unknown procedure which does not involve the use of sight, touch, taste, hearing, and smell and which to some extent is independent of time [3].

Proximate Origin of the Research in Extrasensory Perception

The phenomenon underlining ESP has been a subject of wonder in both primitive and organized society. Attempts at the analysis of this innate force, energy, or powers have been as old as the history of mankind. These latent powers have been a subject of discussion in psychology, philosophy, and the empirical sciences. In modern and contemporary times, approaching this concept from a research perspective is often difficult because of lack of acceptance of the physical reality of most of the purported phenomena. It is worthy of note that, by definition, the ESP does not conform to conventional expectations of the natural sciences. The concept ESP was first coined in 1870 by Richard Burton, a British explorer, used to replace PSI or psychic. PSI, the 23rd letter of the Greek alphabet, is used as a blanket name for psychic in general. However, due to the unfortunate association of psychic phenomena as fraud, especially been seen as superstition, fortune-telling or clairvoyance, researchers took to a neutral expression- extrasensory perception. 102 J. Nwanegbo-Ben

This concept was later adopted by a notable psychologist and researcher J.B Rhine of Duke University. He chose this term to explain psychic phenomena such as intuition, telepathy, clairvoyance, precognition, telekinesis, etc. The fact that natural science does not accept issues that revolve around ESP, J.B Rhine and others delved into experimental procedures in their research in parapsychology to establish evidence. Parapsychology is basically the study of extrasensory perception and paranormal psychic phenomena. Critics believe that research in this area of study has not scientifically proved the existence of extra-sense [4]. It should be noted that criticism of the existence of this innate force in man has not hindered continuous research into the phenomena. Issues bordering on paranormal activities or specifically ESP and the demand for scientific evidence have been of great interest to philosophers and psychologists. This interest in evidence is predicated on the fact that at one time or the other, we have been amazed or heard of those overwhelmed by extramundane powers emanating from some individuals with those abilities. Some people who claim or possess these abilities are sometimes used by investigative teams searching for criminals, things, or missing persons. ESP generally involves awareness of information about acts external to us and not gotten through our normal sense organs or deduced from inductive inference.

Types of Extrasensory Perception

There are various types or aspects of ESP; among these types of which we shall describe two or more are telepathy, precognition, clairvoyance, mediumship, psychometry, retrocognition, and other paranormal activities within this area of research are telekinesis and psychokinesis. Attempts at establishing empirical evidence of ESP have been hampered by negative perceptions and criticisms of the research. Its approach has been labeled pseu- doscientific. This position was observed by Rosaline Haywood, who stressed that this unrecognized faculty in man has been “Cast aside as nonsensical since it would not fit in with the concept of current science [5].” Despite this position by critics, we propose that the simple understanding of such faculty exists and could lead to a revolution in thought about the nature of living creatures and their environment. However, the laws governing these phenomena are unknown. Individuals who have higher extrasensory powers are said to be psychics. There is also this conception that everybody has ESP, however, others think that it is for special individuals with greater abilities [5]. The question of great philosophical or psychological interest is: why is it not acclaimed as a great discovery just like the uncertainty principle? Or like the theory of relativity? Telepathy is an aspect of the sixth sense. It is the ability to receive or perceive another person’s thought, not by means of the ordinary senses. The word telepathy and search about it might be new within the English lexicon and dates as recent as the foundation of the Society for Psychical Research in the late 7 Extrasensory Perception: Concept and History 103 nineteenth century [6]. But the act of telepathy is an ancient psychic phenomenon that has been part of the human race. Some have labeled the phenomenon occult- ism or nonsensical because it has no modern empirical justification. The concept of telepathy has been categorized into two, namely telepathic communication, the ability to transmit information from one mind to another, and telepathic perception, the ability to receive information from another mind, all independent of any known empirical means. We have once argued that the science of telepathy and telekinesis, as a case study, are perceived to be possible due to the activity of what we refer to as “magnetic memory” [8]. We tried to theorize that there is no void in the universe. Percy Seymour recounted in his work The paranormal: Beyond Sensory Science that twins can have some type of pain together, give birth or even die together. He posited that twin sisters Helen and Peg, as published in an Australian Magazine, one night three- quarters of an hour before midnight, Peg was killed in a car crash when the steering wheel penetrated her chest. At the same time, Helen woke up screaming saying she has a severe pain in her chest, on her way to the hospital, she died in the ambulance [7]. This is an example of the possible interconnection between Helen and Peg despite their distance from one another. We all at one time or the other have gotten telepathic experiences that were amazing. It has been argued by advocates of the sixth sense that ESP is a fact. Its recognition will motivate a renewed scrutiny of the axioms on which empirical scientific work is based. An understanding of the workings of ESP would open up the ultimate relationship between mind and matter. Some of us may have been aware of the influence of mind over matter in telekinesis or psychokinesis. Practical examples have been observed; among these individuals with telekinetic powers is Uri Geller [10], the ability to bend metals in a controlled experimental condition. Other individuals on various occasions were able to do the same. Examples also featured on movies of X-men showing the world’s most powerful telepath, who is the founder of Xavier’s school for the gifted youngster. The materialistic theory does not conform to the unknown laws governing the sixth sense. Professor Price in defense of telepathy stated that telepathy is something which ought not to happen if the materialistic theory were true, but it does happen. So there must be something seriously wrong with the materialistic theory, however numerous and imposing the normal facts which support it may be [8]. Another very interesting aspect of the sixth sense after telepathy is recognition. This refers to the ability or powers of the human mind to perceive or see the future or predict an outcome of events. Precognition falls within the confines of intuition or intuitive perceptive, the ability to acquire knowledge without conscious reasoning or comprehending the source of the knowledge acquired. In one form or the other, most of us have unconsciously had precognition or a high intuitive perception that predicted events in the future. Precognition or what we may generally refer to as intuitive perception appears more abstruse to explain as against telepathy. There is really no reliable empirical evidence nor a theoretical framework to explain the workings of this ability. Like other forms of ESP, precognition is considered a pseudoscience. 104 J. Nwanegbo-Ben

We have tried to theorize on the existence of magnetic memory within the universe as an explanatory framework for the possibility of telepathy and telekinesis. But on the issue of precognition which violates the principles that an effect cannot occur before its cause, we tend to be at a loss. The author has on many occasions had accurate precognition of future events that came to fulfillment, but when asked consciously to predict an event in the future, he would be at a loss again. The reason is that the knowledge is received intuitively without reflection, thought, or intention. Despite the lack of scientific evidence, many believe that this phenomenon is real. Daryl Benn, a Professor Emeritus of Psychology at Cornell University, published an article titled “Feeling the Future: Experimental Evidence for Anomalous Radio- active influences on cognition and affect.” In this paper, he provided statistical evidence for the existence of precognition [9]. Despite this publication by such an erudite scholar, there was widespread criticism on the paper. This, however, is expected on a subject that has been labeled pseudoscience.

Conclusions

The conclusion we may draw from this is that there must be a link or interconnection between minds, between the seen and unseen forces, or energy in the universe. The idea of interconnection between all things has for hundreds and even thousands of years been very much part of Eastern religion and mysticism. This interconnection has been fully exposed by modern particle physics a couple of decades ago in the form of relativity and quantum theory. Thus, it should not be surprising that there exists a parallel between mysticism, psychic phenomena, and current foundation of particle physics. Fritjof Capra juxtaposed and corroborated the idea of interconnectedness in nature by stating in his book The Tao of Physics [10], that just as it was in Eastern mysticism, so it is in modern physics that everything in the universe is connected to everything else, no part of it is fundamental. The properties of any part are determined, not by some fundamental law, but by the properties of all the parts. It is true from the foregoing that modern materialistic theory does not accept the claims of the proponents of the sixth sense’s concept. But it cannot deny the fact that a discussion on this area is opening up an unknown sphere of research. It is on this premise that current research in favor of the existence of ESP hypothesizes that every part of the body mental, physical, and emotional forms a continuous interconnected bioenergetic communication network. And the bottom line is in reality, the study of the concept of extra-sense makes sense. 7 Extrasensory Perception: Concept and History 105

References

1. McGill VJ, Parry WT. The unity of opposites: a dialectical principle. Sci Soc. 1948;12(4): 418–444. 2. Norton DF, Norton MJ, editors. A treatise of human nature. Oxford: Claredon Press Publications; 2007. 3. Heywood R. Beyond the reach of sense: an inquiry into extra-sensory perception. New York: Dutton Adult; 1974. 4. Cordón LA. Popular psychology: an encyclopedia. Westport: Greenwood Publishing Group; 2005. 5. Nwanegbo-Ben J. Quantum physics and ESP (an epistemic resolution). Int J Philos. 2016;4(3):11. 6. Luckhurst R. The invention of telepathy. Oxford: Oxford University Press on Demand; 2002. p. 1870–901. 7. Seymour P. The paranormal: beyond sensory science. London: Arkana; 1992. 8. Price HH. Psychical research and human personality. In: Dilley F, editor. Philosophical interactions with parapsychology: the major writings of H.H. Price on Parapsychology and survival. Palgrave Macmillan; 1995. 9. Bem DJ. Feeling the future: experimental evidence for anomalous retroactive influences on cognition and affect. J Pers Soc Psychol. 2011;100(3):407. 10. Capra F. The tao of physics. London: Fontana; 1976. Chapter 8 A Psychological Perspective on Extrasensory Perception

Wenge Huang

Abstract The present opinion proposes a novel hypothesis on extrasensory perception (ESP). The essence of ESP is that false internal stimulations are mistaken as external objective sitmulations which enter through sensory organs, while real external objective stimulations are mistaken as perceptions which do not result from sensory organs when one is in deep hallucinations.

Keywords Extrasensory perception · Complete hallucinations · Deranged hallucinations · Elementary hallucinations · Hallucinations · Paranormal phenomenon

Introduction

Extrasensory perception (ESP) is believed to be a paranormal phenomenon. Similar to other such phenomena, it could happen in various altered states of consciousness (ASC) caused by meditation, mind-altering drugs, hypnosis, and so on. However, the existence of paranormal phenomena—ESP in specific—has been disputed for more than a century; scientific consensus rejects ESP due to the absence of a convincing experimental evidence base and the lack of a theory that could justify ESP. On the other hand, there are so many anecdotal reports backing up the idea that genuine ESP does occur. In order to resolve this dilemma, a novel hypothesis interpreting ESP, based on an original model of hallucinations, needs to be conducted. Hallucinations, based on the definition of modern psychology, are perceptions occurring in the absence of external stimulation. Thus, there are two possible ways for perceptions to occur: first is the effect of external stimulation on perception via sensation and the other one is the effect of internal stimulation on perception directly. In the case of perception, these two ways lead to the same effects.

W. Huang (*) MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Chengdu, China e-mail: [email protected]

Mutually affecting the perception, internal stimulations and external objective stimulations, changes in their relative strength will result in consistence, break- down, and re-consistence of the five senses, which leads to three states of hallucinations: “elementary hallucinations” (one can distinguish reality from fantasy), “deranged hallucinations” (one cannot distinguish reality from fantasy), and “complete hallucinations” (reality and fantasy are totally reversed). These will be discussed in detail.

Elementary Hallucinations

In case the internal stimulation is far weaker than external stimulation, the individual will experience “elementary hallucinations” in which the five senses originating externally are consistent. By the time these hallucinations occur, the individual can detect that the false internal stimulations are not in accordance with the external objective scene and determine that such stimulations are hallucinations.

Deranged Hallucinations

A false internal stimulation, if it is strong enough, can break the consistency of the common five senses and even provide the way for shifting from “elementary hallucinations” to “deranged hallucinations.” Since internal stimulation is equal to the external one, the five senses remain inconsistent. This would eliminate the boundary between internal and external stimulations, making it difficult or impossible to determine which is real. The five senses’ inconsistency helps to explain the generation mechanism of out-of-body experiences and synesthesia. Henrik Ehrsson’s experiment suggested that “being out of body illusion” would be a result of inconsistency in vision and touch which may be regarded as a regular occurrence in “deranged hallucinations”. A mismatch of the two pairs of five senses may lead us toward seeing a sound or hearing a picture. Synesthesia describes an experience in which the external hearing is much stronger while external vision is much weaker, in comparison with their counterparts, leaving the individual to mismatch the objective hearing and the false vision. It is noteworthy that, based on yet undiscovered mechanisms, the five senses’ inconsistency, while eliminating the boundary of internal and external stimulation, integrates internal and external stimulations together as well. The combination of the amplifying function of enhanced awareness (usually occurs simultaneously with hallucinations) and the internal and external stimulations’ integration (not simply superposition), specifically visual and tactile stimulations, have the power to explain various magnificent psychedelic phenomena in ASC. 8 A Psychological Perspective on Extrasensory Perception 109

Complete Hallucinations

Moving forward, shifting from “deranged hallucinations” into “complete hallucinations” occurs simply when false internal stimulation becomes further stronger to form a new consistency in the internally originating five senses. At this point, numerous imaginary scenes are formed causing the external objective world to be ignored and leaving the individual lost in the fantasies. However, some external objective stimulations could become stronger at times. At this moment, since the five senses originating internally are consistent, the individual can detect that such external stimulations are not in accordance with the imaginary scenes. As all false internal stimulations are realized as actual which leaves the preceptor with no clues of what is real or false, it is ideal to naturally treat the inconsistent and “unexplainable” external stimulation as information acquired through psychic abilities, such as clairvoyance, clairaudience, telepathy, or precognition, which is the experience of extrasensory perception. This is in contrary to the previously-explained “elementary hallucinations.” The former is the stronger external against the weaker internal, while the latter is the weaker external against the stronger internal.

Conclusions

Based on the above discussions of the third state of hallucinations, a novel hypothesis thoroughly different from “quantum entanglement” and “multidimensional space-time” to interpret ESP could be conducted: ESP happens in regards of two known pathways through which the perception is affected, and the essence of ESP is that false internal stimulations are mistaken as external objective stimulations which enter through various senses, in contrast, the real external objective stimulations are mistaken as perceptions which do not result from various senses when one is in “complete hallucinations.” The interpretation of external tactile sensation, especially, for one in “complete hallucinations” is considered much more fancy and subtle. When real external stimuli collide with him, since imaginary counterpart is hard for him to conduct, it would lead to the illusion that forces can act on an object without contact. This is the closest rationalization why some people do believe in psychokinesis. Moreover, although there is no scientific evidence to back up this hypothesis yet, Timothy Leary has supported it with his empirical descriptions. In his The Psychedelic Experience: A Manual Based on The Tibetan Book of the Dead, Timothy Leary wrote “On the other hand, the voyager may also feel that he possesses supernormal powers of perception and movement, that he can perform miracles, extraordinary feats of bodily control etc. Hence clairvoyance, telepathy, 110 W. Huang and ESP are said to be possible. Objective evidence does not indicate whether this sense of increased perceptiveness is real or illusory. We, therefore, leave this as an open question to be decided by empirical evidence. This then is the first recognition point of the Third Bardo.” It can be concluded that ESP always occurs in the initial phase of the Third Bardo which immediately follows the “Second Bardo: The Period of Hallucinations” that is clearly identifiable as what is called “deranged hallucinations.” Apparently, the point that ESP occurs accords with the logic of both our hypothesis and our model. As follows, the initial phase of the Third Bardo should be just what we call “complete hallucinations.” Referring to Timothy Leary, an individual at the “Second Bardo: The Period of Hallucinations” feels the hallucinations more intensely in comparison with the initial phrase of Third Bardo. However, our model represents that false internal stimulations are weaker in “deranged hallucinations” than in “complete hallucinations.” The contradiction arises from the consistency with the five senses, no matter originating externally or internally, leaves an individual in a tranquil atmosphere, while the inconsistency with the five senses makes one feel uneasy, even horrified. In conclusion, the previous analysis suggests that no paranormal phenomena exist at all but are rather simple illusions happening along with deep hallucinations which are being composed of “deranged hallucinations” and “complete hallucinations.” However, a remarkable number of the subjects claiming to have them strongly insist that they’re real. This could happen because waking from deep hallucinations is different from waking from dreams. In the dream setting, the five senses’ sensations shut down so the whole stimulations perception receives are both internal and false. Hence, it is easy for the individual to determine whether she was dreaming or not after waking up. Meanwhile, in “deranged hallucinations,” both internal and external stimulations affect perception at the same strength. Accordingly, upon waking up, it is still vague for the individual to differentiate the reality from the hallucinations. Moreover, in “complete hallucinations,” in regard to reversed reality and fantasy, it seems that ESP “truly” occurs. Consequently, by waking up, it would lead an individual to mistakenly believe that he or she really has psychic abilities such as clairvoyance, clairaudience, telepathy, or precognition in that state. Chapter 9 The Mental Burden of Immunoperception

Amene Saghazadeh, Sina Hafizi, and Nima Rezaei

Abstract Emotion regulation (ER) embodies the very essence of the self- regulation setting, albeit along with control of attention and physiological responses to stimulation. Mapping the last two decades clarifies the more than threefold increased number of publications considering the concept of ER during 2004– 2013 compared with 1994–2003. Along with this intense and still increasing concentration on the ER concept, emotion dysregulation (EDR) has been closely correlated with a constellation of mental disorders such as depression, anxiety, and substance abuse. Some of these disorders, especially anxiety and depression, are highly likely to affect medical populations, e.g., patients with HIV, cancer, and diabetes or patients on end-stage diseases. In light of this progress, two reciprocal interactions appear, ER-psychological status/mental diseases and ER-physiological status/physical diseases, and accordingly, EDR can be clearly considered as the common core component between mental and physical conditions. In this chapter, we present evidence that this is owing to the contribution of the immune system, leading to postulate a model consisting of two connecting feedback loops (ER-psychological status and ER-physiological status) with the common background of the immune system, named the Immunoemotional Regulatory System

(IMMERS). Animal studies reveal that immune challenges such as that elicited by endotoxins, enterotoxins, infections, and autoimmune models that induce the secretion of cytokines and their receptors (such as TNF-α, IL-1β, IL-6, IL-10, soluble TNF receptors, and IL-1Ra) confront animals with serious emotionality- related behavioral abnormalities (such as anxiety- and depressive-like behaviors and altered fear responses). Interestingly, these neurobehavioral manifestations can be attenuated by immunomodulatory treatments such as anti-TNF. Human studies demonstrate that challenging of the immune system early in the development can predispose individuals to EDR-related disorders later during the adulthood. In addition, these studies have established close associations between concentrations of inflammation-related markers (especially IL-6) with affective/ emotional states, emotional functioning, and ER-related subscales (such as anxiety, stress, and depressive symptoms) in both clinical settings (anxiety, major depressive disorder, and hemodialysis) and healthy populations dealing with various real-life challenges (e.g., traumatic injuries, perceived discrimination, playing in the orchestra, and delivering preterm). It is followed by an account of numerous psychological states including anxiety, positive and negative affect, aggression, loneliness, stress, worry, well-being, socioeconomic status, shame, and perceived discrimination that already have been associated with changes in ER and immune response. The fact that the etiology of many mental conditions entails two complex processes, i.e., emotion regulation and immune regulation, has an important implication. It is that the value of immunoemotion regulation to humans and its potential clinical benefits should be reasonable to both the human and the medical society. Under these regulations, patients try to regulate their own emotions and physicians help them using both emotion regulation care services and medications used to regulate immune responses.

Keywords Addiction · Alexithymia · Alcohol withdrawal · Anxiety · Aggression · Chronic fatigue syndrome · Depression · Emotion regulation · Emotion dysregulation · Immune system · Immunity · Immunoemotional regulatory system · Loneliness · Mental disorders · Pain · Perceived discrimination · Psychiatric disorders · Psychological status · Shame · Social rejection · Socioeconomic status · Stress · Well-being · Worry

Introduction

Emotion: I’m Just Me!

There have been many quarrels about what is emotion [1, 2], leading to the development of multifarious emotion assessments and therefore resulting in the currently available heterogeneous collection of emotion writings. However, irrespective of how emotions are defined, humans are normally expected to confront with the whole gamut of emotions. Let us exemplify this statement well by putting a simple question to you. My question is have you ever heard of orders such as “calm down,” 9 The Mental Burden of Immunoperception 113

“control yourself,” or even more exactly “control your emotions,” and indubitably, many of you will answer in this way, yes, very often. Such orders obviously overlap in the fulfillment of processes named emotion regulation (ER) which embody the very essence of the self-regulation setting, along with control of attention and physiological responses to stimulation [3]. In the present thesis, emotion is emotion and we have given up trying to select the best definition of emotion. Indeed, we will focus on this major problem that how and why the emotional information and their translation into human lives under the impression of ER processes; either conscious or unconscious [4], impact on our mental and physical health.

The Framework of Emotion Regulation

Let’s follow another example to express our purpose more clearly. Ladies and Gentlemen, I apologize for the delay in my arrival. A little missing-child crying on the road entailed me handing over him to the police department and standing for approximately 1 hour to talk with the police chief. All the time I was waiting for him, I remembered when I had got lost in a large shopping area at around the age of 5. Actually, it is not a customary rule to meet with the police chief, I need to be sure. My heart had its own reasons which reason does not know, as Pascal though. Though the above example simply illustrates an emotion dysregulation (EDR) process, it still seems to be hard to simply define emotion and an ER process. However, this example and similar examples definitely indicate that as a successful ER process leads to the logically desired and positive outcomes, a faulty ER can result in aggression, violence, etc. [5]. More interestingly, EDR has been correlated with a constellation of mental illnesses such as mood, anxiety, and impulse control and addiction disorders. James J. Gross, who is widely respected among psychologists and neuroscien- tists owing to his proposals, practices, and theories on providing a remarkable insight into the nature of emotion and its regulation, has expounded in [6] that the conceptual framework of ER is found on two broad categories, antecedent- and response-focused strategies. This framework speaks about ER with a very straightforward attitude in the way that is triggered by emotional cues, either external or internal, and will be terminated into emotional responses. Antecedent-focused strategies are exerted on emotional cues in order to evaluate them, and a concerted action of behavioral, experiential, and physiological response tendencies ensues as a result of this evaluation. Then, these emotional response tendencies are modulated under the impression of the secondary set of ER strategies, named response-focused ones, and eventually, an emotional response is elicited. At the antecedent-focused level, it has been declared that there are four regulatory points in the way of emotion generation as follows: selection of the situation, modification of the situation, deployment of attention, and change of cognition, while response-focused strategies contribute to modulate other features of an emotional response, such as its amplitude (for review, see [7]). 114 A. Saghazadeh et al.

Accordingly, it is well-expected that the chronological account of the aforementioned emotion regulation strategies would provide us with the great power in practice. To elucidate, cognitive reappraisal and behavioral suppression regulation strategies are suggested to act early and later, respectively, in the emotion-generative process triggered by emotional cues (see review in [8]) in the manner that reappraisers and suppressors have, respectively, greater and lesser well-being, positive emotion expression, and experience [9].

Neuroanatomy of Emotion Regulation

This heading is held under two principal parts: (a) emotional perception and/or production and (b) ER. At the end of this brief part, you are expected to (a) map and (b) juxtapose these two connecting processes at the neurofunctional levels. Neuroimaging techniques including positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) have revealed valuable insight into the functional neuroanatomy of emotion. Systematic reviews and meta-analysis studies support the engagement of two series of emotional circuits, general and specific, in the various emotional tasks [10–12]. Generally, the prefrontal cortex (PFC) contributes to the affective working memory tasks. Particularly, a higher degree of specificity in the work of PFC is detected where its dorsolateral (DLPFC) and ventromedial (VMPFC) components are differently engaged dependent on whether the people are assigned to the goal-directed group or not while expressing their elementary positive and negative emotional aspects [11]. Although the mPFC preserves a general character, brain regions including the amygdala, the anterior cingulate cortex (ACC), the subcallosal cingulate, the occipital cortex, the ventral striatum, and the insula are involved in the perception of specific stimulus or emotions [10, 11]. For example, fear and sadness are, respectively, related to the activity of the amygdala and subcallosal cingulate brain regions [10]. Further, it has been corroborated that the amygdala takes considerable steps toward both the perception of emotional cues and the production of emotional responses [11]. This brain region is, thus, instrumental in the whole of the emotion generation process. About the significance of the stimulus type, for example, the processing of visual emotional stimuli has been associated with activation of the occipital cortex and the amygdala. While emotional recall has been attributed to the activation of ACC and insula [10]. The recruitment of these regions (ACC and insula) is thought to be a reflection of requiring cognitive functions [10]. Furthermore, the observation of higher activity in a set of brain regions, e.g., the mPFC, thalamus, hypothalamus, and midbrain, would allow us to distinguish pleasant and unpleasant emotional conditions from neutral ones [13]. As Davidson and his colleagues have reviewed in [5], ER is innervated by an amazingly intricate neuronal circuit involving several brain regions, particularly the orbitofrontal cortex (OFC), amygdala, hypothalamus, and ACC. Directly focus- 9 The Mental Burden of Immunoperception 115

Fig. 9.1 Emotion regulation processes. Emotion regulation processes are not restricted to our conscious thought, but extended to our unconscious ing, cognitive reappraisal has been correlated positively with early engagement of the prefrontal regions and negatively with activation of the amygdala, the medial OFC, and insula [14, 15]. On the contrary, behavioral suppression led to the activation of amygdala and insula and to the late engagement of PFC [15]. Altogether, it is clearly comprehended that all the factors (either genetic or environmental), which cripple the normal function of this circuit somehow, are capable of contributing to EDR and its correlated conditions, e.g., aggression, depression, bipolar disorder, and substance use [5, 16]. Meanwhile, conscious and unconscious thought employs the same brain regions [17]. It is thus proposed that ER processes are not restricted to our conscious thought but extended to our unconscious thought (Fig. 9.1) [4].

Neuroendocrinology of Emotion Regulation

As its name implies, the neuroendocrine system (NES) is based on interactions between the central nervous system (CNS) and the endocrine system and particularly on the work of the hypothalamus-pituitary-adrenal axis (HPA) (for review, see [18]). The brain regions mostly involved in the NES include the hypothalamus and the limbic center. Also, cortisol is considered as the most important product of the NES. The hypothalamus plays a crucial role in the release of the corticotropin- releasing hormone (CRH) and vasopressin, which exert synergistic effects in 116 A. Saghazadeh et al. releasing adrenocorticotropic hormone (ACTH) from cells in the anterior pituitary. ACTH, in turn, induces cells in the adrenal cortex to produce cortisol. The limbic system collects both perceptual and cognitive inputs received from higher-order brain regions and then conveys the cumulative high-impact message to the hypothalamus aimed at regulating the activity of the HPA axis. In this manner, the limbic system is a crucial contributing factor to the link between ER and HPA functioning so that the HPA axis is also known as limbic-HPA (LHPA). Therefore, this is not surprising that HPA dysregulation is commonly seen in the various EDR-related disorders, such as post-traumatic stress disorder, chronic fatigue syndrome, and depression [19–21].

The Interplay Between Emotion Regulation and the Immune System

As mentioned above, EDR correlates with a myriad of mental illnesses such as mood, anxiety, and impulse control and addiction disorders. Some of these mental illnesses are frequently developed in patients with devastating physical diseases and/or conditions, e.g., traumatic injuries, cancer, diabetes, and end-stage diseases. As well, the early and even prenatal troubles with ER contribute to the development of physical diseases later, thereby leading to increased morbidity and mortality rates [22]. These lines form ER as the common core component between two positive feedback loops: ER-psychological status and ER-physical status. Given the common core, now is the time to seek a common background. A variety of immune challenges including endotoxins (i.e., LPS), enterotoxins (staphylococcal enterotoxins), autoimmune models (e.g., experimental autoimmune encephalitis (EAE)), and infections (e.g., trypanosoma) confront animals/ subjects with serious emotionality-related behavioral deficits (such as anxiety- and depressive-like behaviors and altered fear responses). Such conditions have been shown to stimulate expression of cytokines and their receptors (such as TNF-α, IL-1β, IL-6, and IL-10; soluble TNF receptors; and IL-1Ra) and can be alleviated through immunomodulatory treatments such as anti-TNF-α treatment [23–30]. Further, endotoxins lead to changes in cytokine levels (particularly about IL-1Ra) corresponding with changes in emotional behaviors (such as anxiety and mood) and that both these changes occur in a dose-dependent manner [29]. More interestingly, these changes have been associated with altered activity of the brain regions mainly engaged in regulating the emotional information, such as the insula and cingulate [28]. Note that the inflammatory response should be stimulated enough to be capable of influencing our emotional brain. Supporting this, a low-grade inflammatory model could not be converted into an emotional state, whereas a mild one did it [27, 31]. Early challenges in the immune system predispose individuals to EDR-related disorders in later life. Children with higher IL-6 levels were more likely to suffer 9 The Mental Burden of Immunoperception 117

Fig. 9.2 The immunoemotional regulatory system from depression and psychotic experiences in young adult life [32]. On the correlation analysis lines, the current literature corroborates the presence of close correspondences between concentrations of inflammation-related markers (particularly IL-6) and affective/emotional states, emotional functioning, and ER-related subscales (such as anxiety, stress, and depressive symptoms) in both clinical populations (anxiety, major depressive disorder, and hemodialysis) and healthy populations dealing with various real-life situations (including traumatic injuries, perceived discrimination, playing in the orchestra, and delivering preterm) [33–40]. The role of inflammation, known as a compartment of the innate immune system response, in both psychological and physical diseases, particularly sickness and depression, cancer, atherosclerosis, and metabolic disorders, has been extensively reviewed [41–44]. Taken together, it is a good idea to keep the immune system and its regulation as the background of two connecting feedback loops: ER-psychological status/mental diseases and ER-physiological status/physical diseases (Fig. 9.2). The present chapter deals with the first one.

Aims and Scope of the Present Chapter

Here, the abbreviation “IMMERS” stands for the Immunoemotional Regulatory System. An inordinate number of investigators have well-reviewed the work of this system under the mask of diverse, but overlapping, concepts, such as the mind-body medicine, the bidirectional communication between the immune system and brain, the psychoneuroimmunology framework, the immunoendocrine network or the network of hypothalamic-pituitary-adrenal (HPA) axis and cytokines, and the reciprocal interactions between the nervous and immune system [45–54]. This is the first section of IMMERS’s series which explains how psychological/ mental states are deeply immersed in the IMMERS’s work (Table 9.1). 118 A. Saghazadeh et al.

Table 9.1 Psychological Psychological states/psychiatric diseases states/psychiatric diseases Anxiety associated with the immunoemotional regulatory Negative and positive affects system Aggression Loneliness Stress Worry Well-being Social rejection Socioeconomic status Shame Perceived discrimination Addiction and alcohol withdrawal Generalized anxiety disorder Post-traumatic stress disorder Depression Dysregulation profile Neuropathic pain Pain catastrophizing Alexithymia Intermittent explosive disorder Chronic fatigue syndrome

The Psychological States/Psychiatric Diseases Associated with the IMMERS

Below, evidence linking each subheading to EDR, immune dysregulation, and IMMERS is presented. Note that the data we will present here is a small subset of the current knowledge and we could not cover all of that due to limitations of space.

Anxiety

As Millan has comprehensively reviewed in [55], we get into an anxious state when our fear response to the dangerous stimuli is overwhelmed or is prolonged somehow. Cytokines organize one of several subsystems innervating the anxious state. A study of examination-taking students (ETS) demonstrated that high-anxious individuals had a significantly higher total score of unsatisfactory adjustment (i.e., lower adaptability) than those with low anxiety levels. This was absolutely attributed to the emotional (p = 0.005), but not to other (e.g., health, home, and social), components of anxiety [56]. This anxious phenotype associated with higher emotional instability was reflected in increased levels of TNF-α, which is a 9 The Mental Burden of Immunoperception 119 pro-inflammatory cytokine [56]. Moreover, circulating levels of IL-4, which is an anti-inflammatory cytokine, were higher in freshly admitted students than in two other student groups, ETS and midterm students [56]. Another investigation showed that when compared to the day before taking an examination, students had lower lymphocyte proliferation, IL-2 release, and CD19+ cell count before the academic year begins [57]. Interestingly, higher lymphocyte proliferation corresponded with lower scores on the profile of mood states [57].

Negative and Positive Affects

Circulating levels of IL-18, a pro-inflammatory cytokine, were positively associated with negative emotion during both neutral and sadness states in healthy subjects [58]. Further, both IL-6 and CRP concentrations were also positively associated with the negative affect (NA) trait in the healthy population [59]. However, there was no association between this trait and LPS-stimulated production of cytokines (e.g., IL-6, IL-1β, TNF-α, and IL-10) in the healthy subjects [60]. It has been shown that focus on the negative aspects of the pain condition and the imagined worsening of pain might stimulate the inflammatory response in outpatients with chronic musculoskeletal pain [61]. This study has also demonstrated that the inflammatory response, evaluated by IL-6, is elicited earlier and more transient in men than women, explaining the higher expression of negative emotions in women than men [61]. Exposure to negative mood has led to the increased production of TNF-α and to the decreased release of IL-2 and IL-3, whereas no difference was detected about both IL-1β and IL-6 cytokines [62]. Among healthy individuals, several demographic factors, e.g., female gender, older age, more physical activity, and lower sleep disturbances, were directly related to higher levels of positive affect (PA) [60]. This research has also revealed an inverse correlation between the PA trait and the LPS-stimulated production of IL-6 and IL-10, but not IL-1β and TNF-α, among healthy individuals. Of note, when the study population was stratified, the correlation between IL-10 (an anti-inflammatory cytokine) and PA remained significant for men, but not for women [60].

Aggression

The hostility trait was shown to correlate positively with the levels of IL-6 at 2 hours and to a lesser significance at 75 minutes after the performance of two mental tasks in a population consisting of acute coronary syndrome survivors [63]. This association was also confirmed in healthy individuals, where all the subscales of the hostility trait, e.g., cognitive, affective, and behavioral, were positively correlated with measurements of both IL-6 and CRP [59]. Since the NA trait was correlated considerably with all of the hostility subscales (p < 0.0001), regression analyses were accomplished by controlling NA, and accordingly, only behavioral subscale of hostility was determined to associate independently with inflammatory markers [59]. 120 A. Saghazadeh et al.

Further, in vitro study on healthy participants has revealed a positive correlation between the PHA-stimulated production of T helper 1 (Th1) cytokines (e.g., TNF-α and IFN-γ), but not Th2 cytokines (e.g., IL-4, IL-5, and IL-10), and the hostility trait, principally its cognitive subscale (cynicism) [64]. Hassanain et al. (2003) have depicted a series of experimental studies in the cat and delineated that IL-1β facilitates greatly the midbrain periaqueductal gray’s ability to exhibit the electrical stimulation-induced defensive rage behavior in a dose-dependent manner, albeit conditional on the contribution of 5-HT2 receptor subtypes of the serotonin receptor family [65].

Loneliness

A longitudinal study of older adults has shown that happiness moderates relationships of loneliness with increased mortality or decreased perceived physical activity [66]. On the other side, loneliness could moderate the detrimental positive correlation between EDR and bulimia nervosa (BN)/binge eating disorder (BED). Not only in cancer patients but also in healthy individuals the inflammatory response, evaluated by the amount of change in the cytokine production of peripheral blood mononuclear cells (PBMCs) after stimulation with lipopolysaccharide (LPS), was stimulated more in lonelier individuals compared with less lonely subjects [67]. However, it feels that there is a degree of specificity in this inflammatory response between healthy and cancer subjects. IL-6 and TNF-α were provoked by LPS from PBMCs in healthy individuals, whereas IL-6 and IL-1β in breast cancer patients [67], reflecting their very different physiological states. Further, mental stress tasks led to increasing more substantially the blood levels of IL-6, IL-1Ra, and MCP-1A in lonelier healthy women, but not in men, compared with less lonely controls [68]. Additionally, among patients suffering from breast cancer, the cytomegalovirus (CMV) antibody (Ab) titers were significantly higher in lonelier individuals and both of them, which means that the CMV Ab titers and loneliness, were positively associated with being in the cluster containing three common clinical conditions in cancer patients, e.g., pain, depression, and fatigue [69].

Stress

Definitions of stress have been comprehensively reviewed in [70]. The importance of stressful situations is that we will deal with them not only in the heavy load of stimulation but also in the light load of that. Therefore, a parabola-like curve has been suggested to illustrate the relationship between stress and the stimulation load [70]. This stress response is vital to make adaptations, to keep homeostasis, and to ensure the survival, which was collectively named allostasis. On the other hand, stress can be detrimental due to its potential to fall into a vicious cycle of stressing too much and then impairing the health and then stressing, even more, named allostatic load [71]. EDR, as assessed by two subscales of venting and denial, was found to correlate positively with the stress appraisal scale (p < 0.001) [33]. 9 The Mental Burden of Immunoperception 121

Segerstrom and Miller have done a meta-analysis on more than 300 investigations evaluating our immune response to psychological stress [72]. To this end, they provide evidence under three main headings as follows [72]. Acute stressors are able to upregulate some markers of innate immunity while downregulating some markers of acquired immunity [72]. More exactly, an inflammatory army escorts the experience of acute stress symptoms due to the positive and negative correlations of stress responses with pro- and anti-inflammatory cytokines, respectively [38]. Moreover, both cellular immunity and humoral immunity are suppressed by chronic stressor events, while only cellular immunity-related markers seem to be subjugated by brief realistic stressors (including exams) [72]. Another meta-analysis was accomplished by Steptoe and his colleagues on 30 studies, and finally, they found a change in inflammatory cytokine levels in response to stress is statistically significant for IL-1β (p < 0.001) and IL-6 (p = 0.001) but not for CRP (p = 0.088) [73]. A study on midlife African American individuals has recently demonstrated that stressor appraisals significantly decreased levels of chronic inflammation, which was measured by three related factors, IL-6, C-reactive protein (CRP), and E-selectin [33]. Further, emotional stress could experimentally imitate the immunopathology of colitis via substantial increases in (a) the permeability of epithelium, (b) immune responses to gut-resident commensal microbiota, and (c) the activation of pre- synthesized T cells [74]. However, in vivo models have revealed that the serious repercussion of prior exposure to stress and high-stress levels leave animals more susceptible to develop severe diseases, such as endometriosis and tumor. This impli- cates the positive effect of stress on the immune system activation, which can pro- tect the body against diseases [75, 76]. Neonatal exposure to LPS, as an immune challenge, caused the explosion of arousal in response to stressors in adulthood [77]. In general, maternal emotionality, which leads directly to the disturbed emotionality profile in offspring, has been associated with a significant alteration of the immune system behavior in mothers and their offspring. It seems to shift the immune system of offspring toward a downregulated state, characterized by decreased cytokine concentrations in both periphery and the brain, reduced natural killer cell activity, and low lymphocyte proliferation [78, 79]. In pregnant women, emotional stress has been correlated significantly with the development of an inflammatory state in a trimester-specific manner [80]. So, IL-6 positively corresponded with stress in both the first and third trimesters, whereas a negative relationship was found between IL-10 levels and stress in the first trimester [80]. During the second trimester, stress was significantly and positively associated with CRP levels [80]. On the behavioral side, maternal immune activation impaired prepulse inhibition and latent inhibition in adult offspring. This appeared to be largely contingent on the contribution of IL-6 [81], which is a well-known cytokine for its both pro- and anti-inflammatory properties (for review, see [82]). Even, this challenge was followed at the morphology level of the brain structure. Particularly, the hippocampus region was shown to develop in a schizophrenia-like manner in the adult offspring of rats challenged with the synthetic cytokine releaser polyriboinosinic-polyribocytidylic acid (poly I:C, 4 mg/kg) [83]. According to the investigation on animals exposed to both prenatal stress (PS) and maternal separation (MS), it seems that MS could reduce the effect of prenatal 122 A. Saghazadeh et al. stress on emotionality as assessed by avoidance learning. It led to the suggestion that PS and MS play antagonistic roles in emotion regulation [84]. At the brain levels, the principal effect of MS seems to be impairment in hippocampus-dependent learning and memory, as evaluated by the Morris water maze task and the object recognition task [85]. However, animal studies have well-established a constellation of consequences of MS, including exacerbation of anxiety, emotional and pain responses, and difficulty in coping with novelty. MS is also known as an imitator of irritable bowel syndrome [85–87]. It has been shown that the novelty exposure exerts a more increasing effect on plasma concentrations of corticosterone in MS rats (5 hours per day within days 2–6) compared with controls [86].

Worry

See reference 88 to review various definitions available for worry. So far, the best- cited definition seems to be that stated by Borkovec et al. (2004), who described the trait worry as a cognitive ability employed as the second line of avoidance from future threats in the problem-solving situations, if the attempt of the first line, i.e., behavioral response, rendered the problem solving utterly fruitless [89]. The way in which worry deeply affects ER is the extended “action preparation” state, which is one of the most important results of worrisome thinking and also known as the core of emotion [88]. In addition to various mental disorders, especially generalized anxiety disorder (GAD), the score of trait worry is dysregulated under the influence of stressful situations and medical conditions. It is interesting to point out that mental disorders can be divided into two groups according to the profile of trait worry. For example, the proportion of people with high scores on the trait worry after the earthquake was much the same as that with the low scores [90]. The profiles of trait worry were inversely correlated with the count of natural killer (NK) cells (CD3−CD56+16+) [90]. It seems that low worry persons have a delayed immune response compared with high ones, as the count of NK cells was significantly decreased few days after the earthquake in high worry persons, but the increased number of these cells was not manifested in low worry people even after 2 months [90]. Another observation has shown the increased percentage of NK cells in normal, but not in high, worry people from anticipatory baseline to fear [91]. Altogether, the trait worry needs strong management to avoid its adverse effects on clinical treatments. For example, the response evaluated by the time taken to clear psoriasis to photodynamic therapy was approximately twofold weaker in psoriasis patients with high levels of the trait worry than those with low levels [92].

Well-Being

As mentioned earlier, emotional reappraisals and suppressors have greater and lesser degrees of personal well-being, respectively [9]. In general, positive psychological well-being was found to correlate positively and negatively with restorative and deteriorative health behaviors (for review, see [93]). 9 The Mental Burden of Immunoperception 123

The concept of well-being is defined under two main headings, hedonic and eudaimonic (for review, see [94]). That point is of particular interest that these two distinct views of well-being, which each one impacts significantly each other, means that they are positively correlated, can be distinguished by their patterns of gene expression, especially inflammation-related genes. Regarding this, hedonic scores were found to positively correlate with the expression of proinflammatory genes and negatively with the expression of genes related to antibody synthesis and type I IFN response [95]. By contrast, these correlations were inverted for eudaimonic scores, and some genes involved in immunoregulation, such as nuclear factor-kappa B (NF-κB) and STAT, were associated with eudaimonic scores [95].

Social Rejection

Social rejection stirs up the self-conscious emotions, such as shame and humilia- tion, and switches on the activation of brain regions related to negative emotion processing and rejection-related distress, including anterior insula and dorsal anterior cingulate cortex (for review, see [96]). A follow-up study on women at risk for the major depressive disorder (MDD) illustrated that the mRNA expression levels of both NF-κB and I-κB were significantly higher in meetings that women have witnessed recently to the rejection event than other meetings [97]. In parallel with this line, lower measures of emotional social support, assessed by the Emotional Social Support Index, were found to correlate considerably with higher serum concentrations of three inflammatory markers, CRP, IL-6, and fibrinogen, investigated in a large and relatively healthy sample from the Multi-Ethnic Study of Atherosclerosis [98].

Socioeconomic Status (SES)

A longitudinal study on 618 individuals showed a significant association between low household income and troubles with childhood emotional functioning in children at 7 years old [99]. When children were classified into three groups, low, middle, and high, according to the household income in childhood, there was a close correspondence between troubles with childhood emotional functioning and the CRP levels in adulthood [99]. In an investigation on a US population, there were found inverse correlations between individual SES and IL-6 levels and between community SES with either IL-6 or CRP levels as well [100]. After regression analyses and controlling several factors, mainly lifestyle-related factors, only one of these three correlations remained significant, which was between community SES and IL-6 levels [100]. By contrast, studies on people resident in London revealed that concentrations of all measured inflammatory markers, CRP, IL-1Ra, IL-6, and TNF-α, were significantly higher in the high compared to the low grade of SES [101, 102]. Similar associations were found for total lymphocyte count, T lymphocytes, and NK cells [102]. Thus, this correlation between inflammatory markers and SES varies across geographic 124 A. Saghazadeh et al. regions and to a lesser extent is dependent on definitions considered for SES. No association between SES and cytokine response was observed in this study [101].

Shame

Shame is one of the self-conscious emotions along guilt, embarrassment, and pride evoked in response to social self-threats, e.g., social evaluation or rejection [103]. As reviewed in reference 104, this emotional response (i.e., shame) is accompanied by an increase in proinflammatory cytokine levels. For example, Dickerson and her colleagues asked healthy individuals to write about their self-blamed experiences [105]. As expected, this writing induced shame and guilt significantly [105]. They also measured sTNF-αRII activity before and after writing and concluded that the increased activity of this proinflammatory mediator is largely attributed to shame, not to guilt or negative affect, induced by the writing of self-blamed experiences [105]. A meta-analysis of more than 100 studies has proved conclusively a significantly positive association between shame, especially external shame, and depressive symptoms [106]. Shame status, evaluated by the State Shame and Guilt Scale (SSGS), was positively associated with the LPS-induced production of IL-6 and surprisingly with sensitivity to the anti-inflammatory properties of glucocorticoids in a population made up of young women (mean age, 17.4 ± 1.2 years) [107].

Perceived Discrimination

Perceived discrimination has been frequently associated with several negative mental and physical health indices (for review, see reference [108]). Favorably, a significant positive association was observed between EDR and perceived discrimination, which was, in turn, positively correlated with the level of chronic inflammation (measured by three inflammation-related parameters, IL-6, CRP, and E-selectin) [33].

Burden of Mental Disorders

The prevalence rates of mental disorders differ from region to region. For example, the International Consortium in Psychiatric Epidemiology (ICPE) has reported that mental disorders affect more than 40%, 20%, and 12% of people in the United States, Mexico, and Turkey, respectively [109]. But nevertheless, a recently published meta-analysis on 155 surveys has revealed that nearly one-third of people suffer from one of the most common mental illnesses, i.e., mood, anxiety, and substance use disorders, during their lifetimes [110]. Further, some of the mental disorders are highly likely to affect patients with chronic medical conditions. For example, a meta-analysis of more than 200 studies has recently reported that the 9 The Mental Burden of Immunoperception 125 mean prevalence rate of depression in cancer patients ranges from 8% to 24% [111]. In addition to such high prevalence rates, the long-lasting nature and early onset of these disorders [109] persuade us to explore their exact etiology.

Addiction and Alcohol Withdrawal

At the behavioral level, addiction is associated with the development of depressive- like behaviors and increasing limbic negative emotion [112]. At the pathogenesis level, there are already excellent reviews which have clearly defined the role of the innate immune system in addiction [112]. At the molecular level, the role of CRF is seen in the various stages of substance use disorders from its involvement in drug- induced HPA activation and behavioral effects, drug self-administration, drug withdrawal, and to relapse to drug seeking [113]. Altogether, it is of utmost importance to follow the possible interactions between CRF and the immune system markers. In this regard, it has been shown that like LPS, repeated administration of cytokines including IL-1β, MCP-1/CCL2, and TNF-α into the central amygdala or into the cerebroventricular promoted ethanol withdrawal-induced anxiety behavior, which is significantly palliated by means of prior treatment with CRF-1R antagonist SSR125543 or flumazenil [114, 115]. A dose-dependent manner was observed for both TNF-α and LPS [115]. The effect of TNF-α might be underpinned by the increased presynaptic release of GABA and also by the increased firing rate of neurons in this brain region [114]. Further, pretreatment with MEK inhibitor SL327 could impede the facilitating role of stress on ethanol withdrawal-induced anxiety behavior [114]. In vivo model of chronic exposure to a liquid alcohol diet provided evidence of the increased expression of a series of inflammation-related markers, including TNF-α, Ccl2, NOS-2, Tnfrsf1a, and CD74, and as well the positive staining of another series of them in neighboring neural and endothelial cells, in both the central nucleus of the amygdala (CeA) and the dorsal vagal complex (DVC) at 4 and 48 hours post-withdrawal in the post-acute withdrawal stage [116]. Both CeA and DVC are of brain regions involved in emotional regulation. Sinha and colleagues (2008) have substantiated that both stress and alcohol cue caused the increased intensity of negative emotion and anxiety scale in 28-day abstinent alcohol- dependent individuals compared with social drinkers [117].

Generalized Anxiety Disorder (GAD)

GAD is acknowledged as a basic and chronic anxiety disorder characterized by prolonged worrisome thinking. (Please refer to Chap. 4 of the clinical handbook psychological disorders to have an outlook on definitions and clinical symptoms of GAD [118] and see the review [119] regarding treatments available for GAD.) Current literature indicates clearly the lack of emotion regulatory points and consequently the awkward display of emotional behaviors in individuals with GAD. 126 A. Saghazadeh et al.

Indeed, it seems that the process from emotion perception to generation has been deteriorated due to those people diagnosed with GAD who have reported higher intensity of emotions, lower understanding of emotions, higher negative reactivity to emotional expression, higher difficulties in ER, etc. [120, 121]. The score of ER could also be used as a predictor of GAD, illustrating the clinical importance of EDR in the diagnosis of GAD [121].

Post-traumatic Stress Disorder (PTSD)

Emotion-related problems confronting patients with PTSD are categorized into hyper- and hypo-emotionality (for review see [122]). Measuring the profiles of both pro- and anti-inflammatory cytokines can help us in predicting PTSD in patients faced with traumatic injuries. Higher levels of IL-8 and lower levels of TGF-β at hospitalization in patients encountered with traumatic injuries predicted more PTS symptoms (PTSSs) 1 month later [38]. Further, Katrina survivors relocated to Oklahoma had significantly higher levels of IL-6 compared to controls, and these levels were also more significant in survivors with PTSD than those without PTSD [123]. Both salivary and plasma concentrations of IL-6 were significantly elevated in women with past and current symptoms of PTSD compared to controls. Also, IL-6 levels were shown to associate positively with more negative emotions in these patients [124].

Depression

Studies demonstrate higher levels of cytokines IL-1β, IL-2, IL-18, and IL-10 in patients with MDD than controls. Evidence links cytokine levels to emotionality- related subscales in patients with MDD as well [37, 58]. For instance, IL-6 and IFN-γ levels were associated with anxiety and/or depressive symptoms, and IL-18 concentrations corresponded with sadness-induced μ-opioid system functioning within the various ER-related brain regions, such as subgenual anterior cingulate, ventral basal ganglia, and amygdala [37, 58]. A 6-year prospective cohort study on healthy individuals has revealed that baseline depressive symptoms could predict 6-year changes in IL-6 levels. This was not true about the inverse of this relationship, i.e., the baseline IL-6 levels could not predict changes in depressive symptoms over 6 years, delineating the role of inflammation as an effect, rather than as a cause, of depression [125]. There was no difference in the basal levels of three proinflammatory markers, TNF-α, CRP, and IL-6, between depressed patients and controls. However, following acute negative emotional arousal by mental stress (MS), the production of all the aforementioned inflammatory markers was significantly increased in patients compared to controls [126]. A 2-year follow-up study on depressed patients declared that the manifestation of the manic symptoms was significantly associated with the baseline levels of CRP [127]. 9 The Mental Burden of Immunoperception 127

Dysregulation Profile

Children with dysregulation profile evaluated by the child behavior checklist (CBCL) had significantly higher serum concentrations of CRP when compared to controls [128]. Further, caregivers of children with autism spectrum disorders (ASDs) or attention deficit hyperactivity disorder (ADHD) had significantly higher levels of CRP. Additionally, they reported higher experiences of physical diseases compared with parents of typically developed (TD) children [129].

Neuropathic Pain

The cytokine levels were found to be under the influence of neuropathic pain in a strain and injury model-dependent manner [130]. For example, the mRNA levels of IL-6 in the hippocampus were transiently stimulated by the spared nerve injury (SNI) model in Wistar Kyoto (WK) rats, but not in Sprague-Dawley (SD) rats [130]. However both IL-1β and its receptor, IL-1Ra, exhibited a constant on-and-off expression pattern in the hippocampus in both mentioned strains, e.g., WK and SD, and the increased IL-1β levels were in correlation with neuropathic behavior [130].

Pain Catastrophizing

Pain catastrophizing refers to a negative cognitive-affective response to pain whereby people exaggerate forthcoming or penetrating pain-related situations [131]. Following exposure to psychophysical pain, pain catastrophizing score was shown to correlate positively with the circulating levels of IL-6, and this association was independent of the degree of pain [132].

Alexithymia

Higher CSF concentrations of IL-8 and serum levels of IL-4, but not IL-1 or IL-2, were directly correlated with symptoms of alexithymia, particularly its “difficulty in identifying feelings” subscale, as assessed by the 20-item Toronto Alexithymia Scale (TAS-20) [133, 134].

Intermittent Explosive Disorder (IED)

The most important hallmarks of IED include its high lifetime prevalence rate (7.3%), early onset (mean age, 14 years), high IED-related injuries rate (mean, 43 lifetime attacks) and their associated costs, high rates of concurrent DSM-IV disorders (particularly anxiety, mood, and substance use disorders), and also low treatment rates of anger [135]. It has been recently revealed that (a) IED patients have 128 A. Saghazadeh et al. increased plasma levels of IL-6 and CRP not only compared with control subjects but also compared to nonaggressive individuals with Axis I and/or II disorders and (b) these increased levels are positively associated with the aggression scale [136].

Chronic Fatigue Syndrome (CFS)

This syndrome accompanies abnormalities in various cells of the immune system, including decreased count and activity of NK cells, increased content of suppressor- cytotoxic T cells, and altered concentrations of circulating cytokines, such as IL-6 and IL-2r [137–139]. There was a close correspondence between emotional reactivity, evaluated by Nottingham Health Profile (NHP), and the activity of CD56 NK cells, which was found to decline considerably in CSF patients compared to healthy individuals [140].

Conclusions

Studies have established close associations between concentrations of inflammation- related markers (especially IL-6) with affective/emotional states, emotional functioning, and ER-related subscales (such as anxiety, stress, and depressive symptoms) in both clinical settings (anxiety, major depressive disorder, and hemodialysis) and healthy populations dealing with various real-life challenges (e.g., traumatic injuries, perceived discrimination, playing in the orchestra, and delivering preterm). It is followed by an account of numerous psychological states including anxiety, positive and negative affect, aggression, loneliness, stress, worry, well-being, socioeconomic status, shame, and perceived discrimination that already have been associated with changes in ER and immune response. The fact that the etiology of many mental conditions entails two complex processes, i.e., emotion regulation and immune regulation, has an important implication. It is that the value of immunoemotion regulation to humans and its potential clinical benefits should be reasonable to both the human and medical society. Under these regulations, patients try to regulate their own emotions and physicians help them using both emotion regulation care services and medications used to regulate immune responses.

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Amene Saghazadeh and Nima Rezaei

Abstract The previous chapter introduced the ImmunoEmotional Regulatory System (IMMERS). Also, there was a brief discussion about psychological states/ psychiatric disorders that so far have been linked to the IMMERS. The present chapter considers another aspect of the IMMERS in which physiological states/ physical diseases can be fit to the IMMERS.

Keywords Allergic rhinitis · Asthma · Autoimmune diseases · Cancer · Cardiovascular diseases · Emotion regulation · Emotion dysregulation · Hemodialysis · Human immunodeficiency virus · Immunoemotional regulatory system · Infection · Inflammatory bowel disease · metabolic syndrome · Neurological diseases · Physical diseases · Physiological states · Skin diseases · Sleep disorders · Stroke · Trauma · Vaccination

© Springer Nature Switzerland AG 2019 137 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_10 138 A. Saghazadeh and N. Rezaei

The Physiological States/Physical Diseases Associated with the IMMERS

Allergic Rhinitis and Asthma

Evidence emerged supporting the notion that asthma-related characteristics are linked to various emotions [1]. This link is thought to be mediated by stress- induced corticotropin-releasing hormone (CRH) or related peptides followed by activation of mast cells and an inflammatory process in the airway [2, 3]. Interestingly, forced expiratory volume in 1 s (FEV1), which is an indicator of pulmonary function, was negatively correlated with emotional/mood states induced by videos, particularly negative ones, in asthmatic patients, but not in control subjects without asthma [4, 5]. Moreover, stress-induced situations led to reducing emotional expression in asthmatic children, but not in nonasthmatic ones [4, 5]. The regulation of both emotional and cognitive processing involves anterior cingulate cortex (ACC) (for review, see reference [6]). To investigate the influence of ER on the inflammatory response in asthmatic patients, Rosenkranz and colleagues (2005) enrolled all asthmatic patients into three inhalation challenges (saline, Meth, and Ag) and monitored them for lung function, inflammatory response, and the pattern of brain activity as evaluated using FEV1, the percentage of various immune cells, and functional brain imaging (fMRI), respectively. They demonstrated that throughout the duration of the late-phase response (6–8 hours), there was an increase in the percentage of eosinophils in the sputum sample among asthmatic patients who showed a greater signal change in the ACC and left insula produced by asthma-specific (As)-valence-neutral (Ne) words contrast [7]. Following LPS administration in nonstressed animals, alveolar macrophages produced all the cytokines studied, e.g., TNF-α, IL-1β, and IL-6, in a dose-dependent biphasic manner as well as NO in a monophasic manner [8]. In stressed rats, LPS injection led to induce the levels of TNF-α and IL-1β, but not IL-6, and to reduce NO levels [8]. These lines draw the significance of stress situations to alveolar macrophages (Table 10.1). This influence of emotional problems is not limited to disease exacerbation, but it might become a constraint to routine functioning as well. Allergic rhinitis with or without asthma was demonstrated to associate significantly with “role limitations due to emotional problems,” which was measured using the short-form 36 health survey questionnaire (SF-36) [9].

Autoimmune Diseases (AIDs)

Patients with autoimmune disease (AIDs) commonly confront emotional problems. Moreover, emotional stressors and disorders are capable of causing AIDs. Therefore, emotional stressors have been well established as a potential trigger of some AIDs 10 The Physical Burden of Immunoperception 139

Table 10.1 Physiological states/physical diseases associated with the immunoemotional regulatory system Physiological states/physical diseases Allergic rhinitis and asthma Autoimmune diseases (e.g., systemic lupus erythematosus and multiple sclerosis) Cardiovascular diseases Cancer Hemodialysis Human immunodeficiency virus Inflammatory bowel diseases Infections Neurological diseases Obesity Metabolic syndrome Skin diseases Sleep disturbances Stroke Traumatic injuries Vaccination

such as pemphigus [10, 11]. Further, human studies provided evidence pointing to the increased development of emotional problems and EDR-related disorders in patients with various types of AIDs, such as SLE and multiple sclerosis (MS), in a disease state/severity-dependent manner [12–17]. For example, among patients with childhood-onset SLE, 95% manifest neuropsychiatric SLE (NSLE). Mood and anxiety disorders were the most common psychiatric conditions with the prevalence rate of 60% and 20% [13]. Even about 40% of patients with SLE without CNS manifestations suffer from psychological distress compared with 6% in controls. It is, thus, not surprising that both emotional coping and depressive symptoms were correlated with non-NSLE [14, 15]. Interestingly, there was an increased activation of the brain regions related to emotion regulation/processing (e.g., the amygdala and superior temporal) in SLE patients. However further analyses led to identifying this increased activity of emotional circuit as a consequence of CNS involvement by SLE [18]. Among patients with MS, emotional troubles were more than twofold more likely to occur in patients who had an exacerbation or progressive nonremitting MS compared to stable patients. This was reflected by an increased rate of using emotion-focused coping styles in patients with relapsing- remitting multiple sclerosis (RRMS) compared to stable patients [16, 17]. Mood disturbance was correlated negatively with sIL-2r levels and positively with joint pain in patients with RA [19]. Consistent with data from human studies, animal experiments have also supported the link between emotionality-related behaviors and AIDs. Clearly, AIDs result from IMMDR. Interestingly, the AIDs-related IMMDR has been observed in the specific brain regions associated with emotional 140 A. Saghazadeh and N. Rezaei behaviors, particularly anxiety- and depressive-like behaviors [20]. In this manner, the link between AIDs and IMMERS is strengthened. A high rate of increased emotionality and emotional-like behaviors in AIDs led to propose the term autoimmune-associated behavioral syndrome (AABS). Studies emphasize the pivotal role of cytokines and neuroendocrine factors in the pathogenesis of AABS [21]. B-cell-activating factor (BAFF) transgenic mice model, which is used as an experimental model of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren syndrome, exhibited an anxious phenotype along with the following changes in immune brain signaling, such as increased IgG titers in the hippocampus, hypothalamus, and cortex and increased CD68 (as a maker of activated microglia/macrophages) and GFAP (as a maker of activated astrocytes) immunoreactivity in the hippocampus in mice at 4.5–5 months of age, but not in young (2 months of age) mice [22]. EAE models of MS showed an increase in levels of IL-1β and TNF-α in the hypothalamus. This indicates an inflammatory central basis behind anxiety- and depressive-like behaviors [20]. These emotional deficits were shown to display before the onset of MS [20, 23]. Consistently, behavioral problems usually manifest before symptoms of impaired cognitive and motor performance in dementia. Moreover, this model showed an early (at day 4) and a meaningful increase in circulating cytokine levels and CD3+ T cell counts. Of note, these inflammatory markers began to decrease in the periphery (at day 8) almost when their infiltration in the CNS (at day 10) started [23]. In the MRL-lpr model of AID, which is a well-documented model of emotional deficits [24, 25], a reduced preference to glucose, and as an index of emotionality, was detected in 5- to 6-week-old mice [26]. This deficit could be diminished by immunosuppressive treatment with cyclophosphamide and was pronounced by means of chronic administration of IL-6 [26].

Cardiovascular Diseases

Along with psychosocial stressors, either chronic and acute, and social network- related factors (i.e., social ties, social conflict, and social support), the experience of unpleasant emotions, including anger, depression, sadness, and stress, or, in general, extremely exciting emotions, often promptly, pulls susceptible individuals into a steep road leading to cardiovascular events, particularly ACS (for review see references [27–29]). For example, emotional stress is ranked as the second most common neuropsychological cause of acute myocardial infarction (AMI) owing to its record in approximately 40–50% of these patients [30, 31]. At the molecular levels, these patients have shown increased levels of the proinflammatory cytokines (e.g., TNF-α, IL-1, IL-2, IL-6, and IL-18) and decreased levels of the anti-inflammatory cytokine (IL-10). Thus, it is not surprising that the inflammatory response and respective cytokines are supposed as one of the possible mechanisms linking the experience of negative emotions or ER-related disorders and the progression of cardiovascular diseases, of course along with the neuroendocrine system and apoptosis signaling pathways [27, 30, 32–35]. It is to be noted that when patients with 10 The Physical Burden of Immunoperception 141 cardiovascular diseases are stratified according to their emotional background, some cytokines are more highlighted than others, for example, TNF-α and IL-10, but not IL-6, considering depressive symptoms in CHF patients [35]. Cognitive reappraisal is found to correlate positively with the engagement of the lateral and prefrontal regions and inversely with the engagement of the amygdala and medial orbitofrontal cortex [36]. The role of the inflammatory cytokine IL-6 in the progression of cardiovascular diseases is widely appreciated [37]. Studies show that IL-6 is significantly involved in efforts to arbitrate between the sides of the relationship between the reappraisal-related activation of the dorsal anterior cingulate cortex and preclinical atherosclerosis (evaluated by carotid artery intima-media thickness and inter-adventitial diameter) in healthy individuals [38]. The Normative Aging Study carried out a 3-year follow-up study in older men (mean 60.3 ± 7.9 years). There was a dose-response relationship between negative emotions, evaluated by the Minnesota Multiphasic Personality Inventory (MMPI), and incidence of coronary heart disease (CHD) within the duration of the study (p = 0.005) [39]. Meanwhile, the circulating levels of IL-6 were positively associated with the reappraisal-related activation of the dorsal anterior cingulate cortex in healthy subjects [38]. However, higher reappraisals and suppressions were positively and inversely associated with the serum levels of CRP, respectively [40]. On the other hand, the reflection of watching the ice hockey match, as a real-life emotional excitement, on serum levels of endothelin-1 (ET-1) and IL-6 was more pronounced in spectators with coronary artery disease compared with healthy spectators [41]. Patients with type D personality display concurrently two absolute opposite, positive and negative, tendencies towards the experience and the expression of negative emotions by themselves and in front of other people, correspondingly. Meta-analysis studies and comprehensive literature reviews have revealed that this type of personality is positively associated with contracting cardiovascular conditions and their consequent mortality and morbidity, as well as with a constellation of non-cardiovascular complaints (for details, see [42–44]). Also, individual studies, either cross-sectional or follow-up, have providence evidence of increased levels of proinflammatory cytokine TNF-α and its receptors, sTNFR1 and sTNFR2 [45–48], an enhanced IL-6/IL-10 ratio, and decreased levels of anti-inflammatory cytokine, IL-10, in CHF patients with type D personality compared to those without type D personality [45]. Interestingly, in CHF patients, the inflammatory effect of type D personality appears to resemble closely the effect of aging. There was a similar increased pattern of sTNFR1 and sTNFR2 in younger CHF patients with type D personality and older patients without this personality trait [46].

Immunosenescence

Plasminogen activator inhibitor-1 (PAI-1) is a factor contributing to thrombosis- related cardiovascular diseases in elderly people. Both cytokines and hormones take part in the regulation of the gene expression of PAI-1 (for review, see 142 A. Saghazadeh and N. Rezaei reference [49]). In a model of premature immunosenescence, mice were assigned to either fast or slow group if the amount of time taken to explore the first arm of the maze was ≤20 s or >20 s, correspondingly [50]. When compared to fast mice, slow mice expressed high emotional response to stress and had lower life span [50]. At the immunological levels, slow mice showed a reduction in proliferative response to concanavalin A (Con A) and related release of IL-2 and IL-1β and NK cell activity, while increasing the production of TNF-α [50].

Cancer

An investigation on women who had to undergo breast biopsy indicated that this procedure should be considered as an emotional stressor if the final diagnosis is determined benign. In parallel with this emotional stress, the immune system pre- pares itself before the procedure and seeks for ways to prolong this preparation even 4 months after the procedure. This is a reflection of the joint regulation of our body by both the immune system and the emotional brain [51]. The immune system responds to this challenge by decreasing NK cell activity, decreasing production of IFN-γ, and increasing production of IL-4, IL-6, and IL-10 [51]. Further, there was a significantly positive relationship between mothers with breast cancer and their adult daughters on distress levels. This persuaded scientists to investigate the immune profile and its association with distress in daughters’ group. Daughters’ distress levels were inversely associated with IL-2, IL-12, and IFN-γ production and also with IL-2-induced natural cytotoxic activity (NCA) [52, 53]. Further, NCA activity and the production of Th1 cytokines were both negatively related to the emotional distress degree [53]. Antoni and his colleagues accomplished a genome-wide transcriptional analysis on leukocyte samples taken from women subject to the treatment of stage 0–III breast cancer and demonstrated that the negative affect, evaluated by the affects balance scale (ABS), was significantly associated with greater than 50% increased expression of leukocyte transcripts such as proinflammatory marker-related genes [54]. Another multiplex analysis on circulating concentration of 27 cytokines identified the IL-6 profile as the predictor of physical and cognitive functioning and also the vascular endothelial growth factor (VEGF) profile as the predictor of emotional functioning [55]. Further, the experience of childhood emotional neglect/abuse was associated with lower levels of NCA at the first evaluation after breast cancer surgery [56]. Emotional processing and expression (evaluated by emotional approach coping scale), respectively, tended to be inversely and positively correlated with plasma levels of IL-6, soluble TNF-receptor type 2 (sTNF-RII), and CRP in male patients with prostate cancer [57]. However, among those correlations, two of them, the correlations of emotional expression with IL-6 and CRP, were not found significant (p < 0.10) [57]. In vivo model of ultraviolet-B light-induced squamous cell carcinoma concluded that the high stress and anxiety levels can leave mice prone to the more 10 The Physical Burden of Immunoperception 143 considerably progression of the tumor through increasing the expression of immunosuppressive (CCL2 and T regulatory cells) and angiogenic (VEGF: vascular endothelial growth factor) markers and decreasing the expression of antitu- mor immune markers (CTACK/CCL27, IL-12, and IFN-γ) [58]. On the other side, a peripheral tumor, by itself, could lead to a reduction in the hippocampal function, as reflected in increased depressive-like behaviors and memory impairment. This was, at least in part, underpinned by triggering an inflammatory process both in the hippocampus (↑IL-1β, ↑IL-6, ↑IL-10, and ↑TNF-α) and in the circulation (↑IL-6, ↑IL-1β, and ↑IL-10) [59, 60]. This process was found to be significantly strengthened in infection models compared to peripheral tumor models, explaining the presence and absence of the sickness state in these models, respectively [60].

Hemodialysis

Using Hospital Anxiety and Depression Scale (HADS) test, it was estimated that nearly half of patients with hemodialysis (HD) were in a depressive mood, which was significantly higher than what was reported for control group [61]. Also, there was a higher production of IL-6 in HD patients with anxiety (HADS≥8) than those without anxiety (HADS≤8) [61].

Human Immunodeficiency Virus (HIV)

At least one major psychiatric illness, particularly depression, affects greater than 60% of HIV patients [62]. By virtue of the fact that specific substances of abuse aggregate further the situation of HIV patients at the neuropathological level [62], the inverse correlation between affect regulation and regular substance motivates us to utilize ER as a therapeutic intervention in this population [63]. HIV patients encounter commonly with situations where the social self is threatened. This threat causes shame feelings, which have been associated with increased proinflammatory cytokines [64].

Inflammatory Bowel Diseases

Both emotional and environmental factors affect the gut [65]. Similar to that mentioned for asthma, this affect is mediated by CRF and similar neuropeptides and also by mucosal mast cells [65]. Immunoregulatory factors along with genetic and environmental factors contribute to the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD confront various ER-related problems in their social 144 A. Saghazadeh and N. Rezaei life in a disease severity-dependent manner, such as higher sensitivity to negative emotions, fewer dropping into bar/disco and delayed falling in love, and experiencing more depressive and anxious symptoms, not only compared to controls, but also compared to patients with other chronic conditions [66–70]. Neuroimaging studies have indicated a reduction in both the volume and the activation of brain regions related to emotional processing [71, 72]. The gray matter (GM) volume of both the frontal cortex and the anterior midcingulate cortex was reduced in patients with Crohn’s disease (a type of IBD) compared to controls. More interestingly, disease duration was found to correlate with the GM volumes of some brain regions, importantly, limbic areas [71]. Also, patients with ulcerative colitis (another type of IBD) showed reduced activity, evaluated by BOLD signal, within the amygdala, thalamic regions, and cerebellar areas during the emotional visual task, compared to the control group [72].

Infections

For the first time in 1991, Cohen and his colleagues demonstrated that higher psychological stress is associated with lower resistance to respiratory viruses (rhinovirus type 2, 9, or 14, respiratory syncytial virus, or coronavirus type 229E) in a dose-response manner [73], while positive emotional style (PES), but not negative emotional style (NES), was found to correlate inversely with susceptibility to common cold and upper respiratory infections following exposure to rhinoviruses and influenza A virus in a dose-response manner [74, 75]. Various regression analyses showed that this correlation is independent of prechallenge virus-specific antibody, virus type, age, sex, education, race, body mass, season, and NES, optimism, extraversion, mastery, self-esteem, purpose, and self- reported health [74, 75]. By contrast, childhood socioeconomic status, as assessed by “the number of childhood years during which their parents owned their home,” was found to correspond negatively with both the risk of illness and infection and, in a word, with vulnerability to common colds [76]. This finding along with approximately the similar increased risk of common colds in “those whose parents did not own their home during their early life but did during adolescence” in “those whose parents never owned their home” [76] indicate that (a) the childhood period takes more impression of socioeconomic status of their family than other lifetime periods (e.g., adolescence) such that (b) it would influence the mind-body background of future life. Meanwhile, PES and NES were negatively and positively related to the subjective report of unfounded symptoms of common cold, respectively [74, 75]. However, the basal protein levels of all the investigated proinflammatory cytokines, e.g., IL-1β, IL-6, and IL-8, were associated with illness symptoms/ signs after exposure to rhinoviruses. However, IL-6 was the best cytokine which could predict nasal symptoms/signs [77]. Further, daily evaluation of emotional style and cytokine production in infected individuals on each one of 5 days after 10 The Physical Burden of Immunoperception 145 exposure to rhinoviruses and influenza virus showed that the production of inflammatory cytokines including IL-6, IL-1β, and TNF-α was negatively related to positive affect (PA) on that day or on the next day [78].

Neurological Diseases (NDs)

Neurological diseases including Parkinson’s disease (PD) and Alzheimer’s disease (AD) are accompanied by serious shortfalls in emotional processing in a severity-dependent manner. For example, patients with frontotemporal dementia (FTD) represent a poor recognition of several basic emotions, e.g., anger, sadness, disgust, fear, and contempt. Also, patients with the probable AD are more likely to fail to recognize fear and contempt compared with controls [79]. In patients with mild AD, the recognition of more basic emotions are missed, and they are less able to differentiate between some emotions, e.g., happiness and sadness [80]. Apathy in patients with AD was found to correlate positively with dysfunction in the prefrontal and anterior temporal regions [81]. Regarding memory recall, individuals with AD presented no preference to recall better emotional memories other than nonemotional ones, standing in stark contrast to healthy subjects, either young or older [82]. Experimental models provided evidence that there are deficits in the emotional memory performance in AD, which can be diminished by treatment with cytotoxic necrotizing factor 1 (CNF1) [83]. This pleasant effect of CNF1 was accompanied by a reduced IL-1β expression in the hippocampus, along with other encouraging events, especially enhancing the energy amount evaluated by the ATP (Adenosine triphosphate) levels [83]. There is a spectrum of behavioral problems in patients with AD [84]. Agitation is the second most common behavior in AD, after apathy. It has been associated with cognitive impairment [84]. Inflammatory changes appear to pave the way for agitation. There were higher IL-1β levels and decreased NK cell activity in both the morning and evening periods corresponding with preagitation and agitation phases of AD [85]. Even, Esterling and his colleagues demonstrated changes in the immune profile of AD patients’ spousal caregivers, either former or current. There was a reduced response of enriched NK cells to either rIL-2 or rIFN-γ cytokines in patients’ caregivers than controls [86]. Interestingly, this response was related positively to the emotional and tangible social support levels [86].

Obesity

Women with severe or morbid obesity had significantly increased levels of proinflammatory markers IL-6 and hsCRP in a BMI-dependent manner, which were closely related to anxiety and depression subscales of neuroticism, even after the BMI adjustment [87]. Since these patients had to undergo gastric surgery, these 146 A. Saghazadeh and N. Rezaei markers were measured again after surgery. Interestingly, decreased levels of IL-6 and hsCRP were correlated with lower anxiety and depressive behaviors post- operation [87]. The long-term maternal exposure (4 weeks before mating and during pregnancy and lactation) to a high-fat diet (HFD) led to a decrease in the basal serum levels of CORT in offspring [88]. In addition, the steps toward normalizing the stress-induced CORT levels were made with the lower speed in long-term HFD-exposed offspring than standard chow diet (SD)-exposed offspring at the end of stress challenge [88]. Regarding inflammation-related markers, the increased expression of IL-6 and IL-1Ra in long-term HFD-exposed offspring than chow-exposed ones in the amygdala was found in both females and males [88], while changes in the expression of NF-kB and I-kappa-B-alpha (IkBa) were observed only in female, but not in male, offspring [88]. Mice subjected to short-term (1–3 weeks) HFD also exhibited anxiety-like behaviors in addition to learning and memory impairments and had significantly higher levels of homovanillic acid—a metabolite of dopamine—in their hippocampus and cortex but without any alteration in the gene expression of inflammatory markers [89]. Further, chronic western diet (WD) intake led to the increased responsiveness to LPS, which was represented in higher and more prolonged protein/mRNA measures of IL-6 in both plasma and hypothalamus, while there was no significant difference in the plasma levels of other proinflammatory cytokines such as TNF-α, IL-1β, and IFN-γ between WD and SD groups [90]. In parallel with the increased expression of IL-6, there was significantly increased mRNA expression of SOCS-3, which belonged to the suppressors-of-cytokine- signaling (SOCS) family of proteins, in the hypothalamus in WD than SD mice [90]. However, the LPS-induced mRNA expressions of TNF-α and IFN-γ in the hippocampus were significantly higher in WD than SD mice. Also, LPS augmented the levels of adipokines, e.g., CST, leptin, and resistin, more significantly in WD mice when compared with mice exposed to SD [90]. Altogether, both short-term and long-term obesity in either young adult or maternally can lead to display disturbed anxiety-like behaviors and impaired learning/memory, and brain inflammation might be one of the reasons behind these HFD-related events [88–91]. Chronologically, at first, learning/memory and then anxiety-like behaviors are impaired, and disturbance in depressive-like behaviors is subject to exposure to an immune challenge, such as LPS [90].

Metabolic Syndrome

A high age-adjusted prevalence rate of ~24% is estimated for metabolic syndrome (visceral obesity, dyslipidemia, hyperglycemia, and hypertension) in the United States [92]. Both ER- and EDR-related subscales have been associated with the metabolic syndrome factor [93]. Even, a disease pathway involving EDR can be proposed, which is triggered by low socioeconomic status (SES), followed with low reserve capacity for high negative emotions and eventuated in the metabolic syndrome factor [94]. 10 The Physical Burden of Immunoperception 147

Inflammation plays a major role in metabolic syndrome [95]. It has also been indicated that this role is not performed in the periphery merely, but a mice model of metabolic syndrome proved the presence of central inflammation ↑( TNF-α, ↑IL- 1β, and ↑IL-6) in the hippocampus, explaining the anxiety-like behavior in this model [96]. A possible pathogenic pathway for metabolic syndrome is initiated by emotional stress and ensuing enhancement in the levels of proinflammatory cytokines, e.g., IL-1, IL-6, and TNF-α. Then, these cytokines lead to increased levels of NGF, which in turn stimulates a series of cascades toward insulin resistance and finally resulting in diabetes mellitus (for review, see [97]).

Skin Diseases

Skin diseases are frequently associated with troubled ER, reflecting in problematic emotional expression. For instance, patients with psoriasis, who are more likely to be alexithymic, employ more control over negative emotions and more avoidance of emotional closeness and intimacy compared with controls [98]. It may explain the negative relationship between psoriasis symptoms and affective expression in a severity-dependent manner [99]. When patients with atopic dermatitis were compared to healthy controls, the effect of psychological stress on the various immune parameters, such as ↑ eosinophil count, ↑ CD8+/CD11+ and CLA+T cells, and ↑ cytokines (IL-5 and IFN-γ), was significantly strengthened [100]. The route from EDR to IMMDR in acnegenesis has been explained elsewhere [101]. In summary, emotional distress would make sebocytes prone to the increased expression of receptors for CRH, melanocortins, b-endorphin, vasoactive intestinal polypeptide, neuropeptide Y, and calcitonin gene-related peptide, and then the production of proinflammatory cytokines are stimulated by means of these receptors and binding to their ligands.

Sleep Disturbances

This notion that sleep disturbances are, irrespective of their cause, seen as chronic stressors is supported by evidence at different levels, e.g., immunological, neuropathological, and neuroimaging studies (for review, see [102]). To assess the effects of sleep and its efficiency on susceptibility to respiratory infections, Cohen and his colleagues conducted an investigation on healthy individuals and recorded at first their sleep duration and its efficiency within 14 consecutive days and then made them exposed to rhinoviruses, and after 5 days postchallenge, calculated the rate of clinical cold development [103]. This investigation indicated that those who had average sleep duration (ASD) ≤7 hours were three times more susceptible to clinical cold than those with ASD≥8 hours. 148 A. Saghazadeh and N. Rezaei

Further, there was a 5.5-fold increased risk of clinical cold in individuals with sleep efficiency <92% compared to those with an efficiency of≥ 98%. Therefore, it is well expected that circadian arrhythmia has been associated with EDR-related parameters, e.g., decreased social motivation/functioning, decreased exploratory anxiety, and decreased emotional functioning [104, 105]. In a cancer population, the presence of circadian arrhythmia was associated with decreased levels of all the investigated cytokines, e.g., TNF-α, TGF-α, and IL-6 [105].

Stroke

Alexithymic patients were more likely to suffer from severe forms of stroke when compared with non-alexithymic patients. This alexithymia trait appears to contain an inflammatory component either as a cause or an effect [106]. Study of patients with a first-ever symptomatic ischemic stroke revealed that (a) the circulating levels of IL-18 were correlated positively with the severity of alexithymia, (b) strati- fication of patients made this correlation more statistically significant in those who had right hemisphere lesions, and (c) these increased IL-18 levels were pronounced in alexithymic (TAS-20 score 61) than non-alexithymic patients [106].

Traumatic Injuries

In patients hospitalized for orthopedic injuries, the use of emotion-focused coping was found to correlate positively with the levels of proinflammatory cytokines, IL-6 and IL-8, whereas it was negatively correlated with TGF-β levels [107].

Vaccination

Compared with controls who received placebo, circulating levels of cytokines, in particular, IL-6, were increased at 3 hours after the first-ever typhoid vaccination. It coincided with significant mood impairment [108, 109]. It has been elucidated that when subjects perform psychological tasks (i.e., stress condition) after injection, the IL-6 response is inversely related to optimism in either the Typhim Vi typhoid vaccine or saline placebo group [110]. In response to the implicit emotional face perception task, there was an increased activity in the subgenual anterior cingulate cortex (sACC) along with reduced functional connectivity between sACC and reduced activity within the anterior rostral medial prefrontal cortex (arMPFC), MNI coordinates, nucleus accumbens, right amygdala, STS, and FFAs. These changes were observed in inflammation-associated mood change compared to the placebo group [108]. 10 The Physical Burden of Immunoperception 149

Conclusions

Chapter 10 presented evidence supporting the notion that there are a variety of psychological states/psychiatric diseases where the immune responses, as well as the emotion regulation, are impaired. This chapter provided evidence linking physiological states/physical diseases to the impairment of both the immune system and emotion regulation. Altogether, the immunoemotional regulatory system (IMMERS) covers both psychological states/psychiatric diseases and physiological states/physical diseases. Inevitably, such a system must comprise both the immune mediators and the neuroendocrine messengers, which will be discussed in the next chapter.

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Amene Saghazadeh and Nima Rezaei

Abstract The present chapter provides a digest of data for the compartments of the immunoemotional regulatory system including cytokines, mast cells, lymphocytes, natural killer cells, antibodies and immunoglobulins, toll-like receptors, lipopolysaccharide-binding protein, oxidative stress, microglia cells, NF-κB pathway, hypothalamic-pituitary-adrenal (HPA) axis, neuronal circuits, and blood-brain barrier (BBB). The chapter highlights that the immunoemotional regulatory system (a) fits both of the chronic emotion dysregulation (EDR)-related disorders/conditions and (b) rests on both the immune and non-immune compartments and their functional relationship. Findings highlight the importance of considering psychological status in the immunological studies and warrant further investigations to determine the extent by which manipulating the immune response/emotion regulation (ER) is effective at managing EDR/immune-related disorders.

Keywords Antibodies · Chemokines · Cytokines · Emotion regulation · Emotion dysregulation · HPA axis · Hypothalamic pituitary adrenal axis · Immunity · Immunoemotional regulatory system · Mast cells · Microglia · Natural killer cells · Oxidative stress · T cells · Toll-like receptors

© Springer Nature Switzerland AG 2019 155 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_11 156 A. Saghazadeh and N. Rezaei

Components of the Immune System Contributing to the Emotion Regulation

Cytokines

Clinical studies have demonstrated associations between social/emotional stressors/ negative emotions and elevated levels of proinflammatory cytokines, such as IL-6, IL-1β, and sTNFαRII [1–3]. Supporting this, preclinical studies have indicated that stressors, such as whisker removal, restraint stress, and chronic unpredictable mild stress, result in increased levels of the protein and/or mRNA of proinflammatory cytokines, such as TNF-α, IL-β, and IL-6, in the periphery and also in various brain regions, including the cerebral cortex, frontal cortex, and hippocampus [4–6]. Some of these stressors, such as whisker removal, appeared to simultaneously and significantly suppress the profiles of anti-inflammatory cytokines, such as IL-10, in the same brain regions [4]. Surprisingly, the protein and/or mRNA levels of some proinflammatory cytokines, such as IFN-γ, were also decreased under the influence of some of those stimulators (e.g., whisker removal) [4]. Culture is a factor that is suggested to modify the relation between cytokines and psychological states [7, 8]. As reviewed by Markus and Kitayama [9], the huge power of culture on the widely appreciated aspects of the self-regulation setting has been fully comprehended. One study has shown a significant positive correlation between the experience of negative emotions over the last month and the IL-6 measures in American, but not in Japanese, individuals [2]. This difference in cytokine expression levels has been attributed to the conceptual contrast between the Eastern and Western cultures. The investigators have indicated a significant interaction between culture and negative emotions as well [2]. Despite this clear impression of culture on the levels of IL-6, the current knowledge confirms the viewpoint that the inflammatory profile, which is frequently been indexed by the levels of IL-6 and CRP, is resulted from the complex interaction between a number of factors including, but not limited to, culture, ethnicity, gender, years of education, hours of sleep, smoking, body mass index (BMI), physical activity, past medical history, and personality traits [10, 11]. For example, the proinflammatory markers, such as IL-6 and CRP, were correlated positively with female sex, minor- ity race/ethnicity, BMI, smoking, and hours of sleep, and with personality traits, such as the hostility and negative affect traits. In contrast, they were inversely correlated with personality traits such as the extraversion trait (in particular with the “dispositional activity” subscale), and with demographic characteristics such as years of education, African American race, and level of physical activity [10, 11]. As described earlier, personality traits can be categorized according to their association with inflammatory markers into inflammatory (e.g., depression, hostility, and agreeableness) and contra-inflammatory (e.g., hostility, conscientiousness, neuroticism, and openness) [12]. The interactions between these traits mean that intragroup interactions should be considered in the formulation of the inflammatory profile as well. People with high scores of conscientiousness and neuroticism (i.e., two contra-inflammatory traits) had considerably lower IL-6 levels than other 11 The Immunoemotional Regulatory System 157 groups [13], while high neuroticism and low conscientiousness were separately associated with IL-6 levels [14]. In addition, individuals with higher scores of both depressive symptoms and hostility (i.e., two inflammatory traits) represented the most intensive CRP, but not IL-6, response following an acute emotional stressor (sadness/anger recall) [15]. Contrary to these findings, acute emotional stress (ES) induced by 1 h immobilization with simultaneous electrocutaneous stimulation engendered a homogenous and diminishing effect on the plasma levels of both pro- and anti-inflammatory cytokines (IL-1α, IFN-γ, IL-1β, IL-2, GM-CSF, IL-4, and IL-10) in behaviorally active rats. However, it was only found significant for IL-1α and IFN-γ [16]. Regarding behaviorally passive rats, while IL-1α was significantly decreased, IL-1β was elevated, and the diminishing effect was observed for the levels of all the rest of cytokines except for IL-4 [16]. Pretreatment with melatonin exerted a modulatory effect upon ES-induced altered-cytokine profiles in both behaviorally active and passive rats [17]. Under ES, the level of IFN-γ was significantly lower in active rats as compared with passive rats, and no statistically significant difference was found for other investigated cytokines [16]. These data highlight the importance of the IFN-γ, where both ES and behavioral activity interfere. Cytokines have significantly and frequently been associated with mental illnesses, particularly bipolar disorder, schizophrenia, and major depression [18–20]. Displaying disgust images led to a significant increase in salivary concentrations of TNF-α or IL-6 when compared with displaying negative emotional and neutral images [21, 22]. Further, it has been recently demonstrated that showing disgusting images has a more considerable power to raise the salivary levels of IL-6 in cocaine- dependent individuals than healthy controls. This illuminates more vulnerability of drug-dependent subjects to environmental stimuli and medical conditions associated with inflammation, in particular, IL-6 [22]. In addition to the chronic EDR-related disorders/conditions (e.g., inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), major depressive disorder (MDD), Alzheimer’s disease (AD), aging, and schizophrenia), the acute social/ emotional stressors might lead to an inflammatory state and thereby leaving the brain prone to working harder in the upcoming emotional events. These two clusters, i.e., chronic EDR-related disorders and acute emotional events, differ in their mechanisms of action (for review see [23–25]). Disorders associated with chronic EDR affect both the brain structure and function and inflammatory markers are correlated with both of these alterations. But the acute social/emotional stressors influence the brain function merely, in an emotional load-dependent manner. The social stressor-induced sTNFαRII levels were significantly associated with the activity of the brain regions (dorsal anterior cingulate cortex and anterior insula) associated with social rejection [1]. Of note, the relation between peripheral inflammation and activation of specific brain regions might be established by a single emotional event even for years. O’Connor and colleagues reported that salivary concentrations of two proinflammatory cytokines, IL-1β and sTNFαRII, closely correspond with the activity of brain regions specific to emotional, retrieval, and visual processing (e.g., the subgenual anterior cingulate cortex (sACC), orbitofrontal cortex (OFC), temporal cortex, cuneus, and fusiform gyrus) during a grief-elicitation task in women 158 A. Saghazadeh and N. Rezaei

[26]. Nevertheless, in healthy adults, no association was found between concentrations of proinflammatory cytokines and the number of emotionally traumatic events during childhood [27]. Consistently, the preoperative levels of proinflammatory cytokines were not associated with the post-operative experience of emotional symptoms of depression and emotional aspects of quality of life in peritoneal carci- nomatosis patients [28]. It is, thus, concluded that events accompanied by escorts of positive emotions tend to maintain the well-balanced inflammatory state or even to shift to the anti- inflammatory state. To exemplify, the Proust phenomenon, through which a specific smell summon a specific memory, has strengthened substantially the regional cerebral blood flow (rCBF) in both the medial OFC and the precuneus/posterior cingulate cortex (PCC) and also slackened significantly the circulating levels of proinflammatory cytokines, e.g., TNF-α and IFN-γ in healthy volunteers [29]. Further, the IFN-γ concentrations closely corresponded with the responses of both the mPFC and precuneus/PCC [29]. On the other hand, systemic immune challenges, such as injection of Lipopolysaccharide (LPS), staphylococcal enterotoxins, or infections, can disturb emotionality and emotional-like behaviors, such as anxiety- and depressive-like behaviors, and/or cognitive abilities, such as spatial learning/memory [30–36]. About LPS, these behavioral and cognitive effects were associated with increased levels of protein and mRNA expression of proinflammatory cytokines and adipokines in the blood and several brain regions, including the amygdala, hypothalamus, and hippocampus [34]. However, LPS only altered the mRNA expressions of proinflammatory cytokines, such as TNF-α, IFN-γ , IL-1β, and IL-6, in the brain, and the plasma concentrations of IL-1β and IFN-γ were not altered [34]. At the adrenocortical levels, LPS was shown to significantly upregulate the plasma levels of corticosterone and ACTH along with the turnover of norepinephrine, dopamine, and serotonin in several brain regions, such as paraventricular nucleus (PVN), median eminence, arcuate nucleus, hippocampus, the locus coeruleus, and the nucleus accumbens (see more details in [36]). Staphylococcal enterotoxin A (SEA) or B (SEB), which stimulate the activation of T cells, caused imperfection in emotionality and emotional-like behaviors, such as the exhibition of anxiety-like behaviors, increased reactivity to novelty, decreased consumption of a novel food, and development of appetitive neophobia. These behavioral signatures were underpinned by (a) an increase in the mRNA levels of corticotropin-releasing hormone (CRH) in the PVN and central nucleus of amygdala; (b) increased concentrations of corticosterone and ACTH levels in a dose-dependent manner; (c) increased c-Fos immunoreactivity in several brain regions (e.g., PVN, arcuate nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and lateral septum); and (d) increased levels of various cytokines (particularly IL-2, IFN-γ, TNF-α, and IL-6) [30–32, 35]. As expected, these SEA-induced effects on behavior or adrenocortical levels were significantly suppressed in RAG-1 or TNF-α deficient mouse or after anti-TNF-α treatment [31, 30]. The TNF-α knockdown model revealed that SEA-induced effects are partly determined by CRH [31]. Gene knockout models indicated that depletion of cytokines or their receptors, such as IFN-γ, IL-6, TNF-α receptor (TNFαR) I, and TNFαRII, dramatically 11 The Immunoemotional Regulatory System 159

deteriorates ER, emotionality, and emotional behaviors, including anxiety- or depressive-like behaviors [37–41]. These studies suggest cytokine-specific effects on behaviors. IL-6 deficient animals exhibited higher emotionality and emotional behaviors following exposure to a psychological stressor than wild-type (WT) ones [39, 42]. IFN-γ-deficient mice demonstrated an exaggerated type of basal anxiety- and depressive-like behaviors. However, chronic stress exposure exerted a similar effect in IFN-γ-deficient mice compared to WT mice (except for defeca- tion), and both groups did not differ on the chronic stress-induced emotionality- related behaviors [38]. At the immunological level, chronic stressor did not alter the serum levels of cytokines, such as TNF-α, IL-2, IL-10, and IL-4, in IFN-γ- deficient mice, whereas all of them significantly differed in chronically stressed WT mice [38]. Regarding corticosteroids (CST), it has been shown that lacking IFN-γ significantly increases the basal CST levels compared to WT mice, and chronic stressor has a more significant effect on increasing the CST levels in WT than IFN-γ-deficient mice [38]. A postmortem analysis of the brain samples of TNF-α deficient mice showed a significant increase in the metabolism rate of serotonin [41]. Under the sway of stress challenges, the production of TNF-α from mitogen-induced splenocytes was substantially increased in the uncoupling protein 2 (UCP2) knockout than WT mice [43]. Some cytokines, such as IFN-α, IL-1β, IL-2, and IL-6, are able to cause serious inconveniences in emotionality, as assessed by anxious- and depressive-like behaviors [44–46]. As demonstrated in the model of chronic treatment with IFN- α, this effect is mediated through a series of immunological cascades, including an increase in the production of Th1cytokines (IFN-γ, TNF-α, and IL-2) and in the counts of NK and CD4+CD25+ T regulatory cells and a decrease in the production of Th2 cytokines (IL-4) [44]. Regarding IL-1β, only one intracerebroven- tricular injection (1.0 μg/kg) was able to produce the anxious phenotype [45]. This study indicated that IL-1β plays a detrimental role in synaptic efficacy through desensitizing striatal cannabinoid CB1 receptors (CB1Rs) [45]. Meanwhile, CB1R deficiency is known to induce behavioral symptoms and related biomarkers (for a review see [47]). The effect of IL-1β on emotionality might also be mediated via dopamine and its derivatives (3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) and the arachidonic acid (AA)-eicosanoids-prostaglandin (PG)E2 pathway [48]. A single high dose of IL-1 (5.0 μg/kg) had a long-lasting (3–22 days after injection) effect on the HPA axis leading to increased activation of CRH and its receptor (corticotropin-releasing hormone receptor 1, CRH-R1) in the PVN, together resulting in increased sensitization of the HPA axis to an emotional stressor (novelty) [49]. Chronic treatment with low doses of IL-1β (subpyrogenic) could also augment anxiety behaviors [50]. Accordingly, conditions that increase IL-1β might lead to dysregulation of emotional behaviors, in a dose-dependent manner [51]. Study of intrastriatal treatment with IL-2 pointed to the dose-dependent effect of this cytokine on emotional- and anxiety-like behaviors [46]. Baune and colleagues [52] performed a neurogenetic study and provided valuable evidence linking the IL-1β single nucleotide polymorphism (SNP) with antidepressant treatment and also with the function of specific brain regions 160 A. Saghazadeh and N. Rezaei engaged in emotional tasks. This study has also shown that patients with MDD who carry the GG genotypes of two IL-1β SNPs, rs16944 and rs1143643, were not responsive to 6-week antidepressant treatment and represented a reduction in the activation of the amygdala and ACC brain regions during the emotional visual task.

Chemokines

Chemokines have a critical role in connecting the immune system to emotion regulation centers in the brain [53]. Chronic exposure to hypergravity conditions which serve as a stressor in a gravity-level-dependent manner [54] has been shown to decrease the concentrations of proinflammatory chemokines (MCP-1 and interferon Gamma-Induced Protein 10, IP-10) [54]. Gene knockdown studies revealed that CCR6 deficiency diminishes anxiety-like behaviors while CCR7 deficiency aggregates anxiety-like behaviors, as evaluated by the Zero-Maze test [55]. However, both knockdown models and WT mice did not differ on depressive-like behaviors as assessed by forced swim test [55]. Neither CCR6 deficiency nor CCR7 deficiency altered the levels of proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) in the PFC or hippocampus [55].

Mast Cells

Mast cells are related to emotional states [56] and affective disorders [57]. In preclinical literature, gene knockdown and pharmacological loss of function studies have shown increased anxiety-like behaviors in mice lacking mast cells [58]. Of note, the peripheral blockage of mast cells did not cause this effect. However, the same chemical, i.e., disodium cromoglycate (cromolyn), was used to induce both types of blockage, peripheral and central [58]. These data show that central, but not peripheral, mast cells do a lot to alleviate the anxiety-like behaviors.

T Cells

A significant decrease in anxiety behavior was observed in RAG−/−/OT-II than- RAG−/−/OT-I mice [59]. This highlights the differential importance of OT-I (CD8) or OT-II (CD4) T-cells in ER. This is confirmed by studies demonstrating that social stressor has an incremental and a diminishing effect on the content of CD8 and CD4 T cells, respectively, and this altered percentage of CD8 T cells is positively associated with cortisol changes in neonatal pigs [60]. Moreover, the percentage of T helper cells seemed to decrease immediately after the Trier Social 11 The Immunoemotional Regulatory System 161

Stress Test (TSST) when compared with baseline and rest periods in male individuals [3]. The anti-CD25 Ab treatment which diminishes the CD4+CD25+ population of T regulatory cells has shown to increase the basal levels of proinflammatory (IL-6 and TNF-α), Th1 (IL-2 and IFN-γ), and Th2 cytokines (IL-4 and IL-17A) in mice as well to aggregate anxiety and depressive-like behaviors [61]. Chronic immobilization stress (CIS) appeared to act as a suppressor of CD4+CD25+ of T regulatory population, leaving mice prone to all of the aforementioned effects of anti-CD25 Ab treatment [61].

Natural Killer Cells

Emotional states are shown to affect the number of natural killer cells in humans. For example, examination stress was shown to be associated with alteration of natural killer cell numbers in healthy controls [57].

Antibodies and Immunoglobulins

In breast cancer survivors, the childhood adversity was found to positively correlate with Epstein-Barr virus (EBV) and CMV antibody levels [62]. In a mice multi-antigenic peptide (MAP)-induced lupus model (caused in the substantial rise in serum titers of anti-dsDNA, anti-NR2 Abs), the intraperitoneal administration of epinephrine, as a stress-induced situation-induced hormone disturbing the BBB’s integrity, could inflict serious neuronal damage on the amygdala, but not on the hippocampus, describing the drastic decline in fear response [63]. Emmer et al. (2006) declared that patients with systemic lupus erythematosus (SLE), particularly those with neuropsychiatric manifestations, had significantly lower values of the apparent diffusion coefficient (ADC) in the amygdala, but not in the hippocampus, compared with healthy individuals [64]. Further, when patients were stratified into two main headings according to the existence/lack of anti-NMDAR Abs (ANRAb+,ANRAb−), the ADC values were found to be significantly lower in the ANRAb+ patients than ANRAb− ones [64]. These lines show remarkable consistency in findings of animal and human studies leading to identify epinephrine as a reliable agent to investigate the emotional behavior pattern not only in SLE patients but probably in all autoimmune diseases associated with increased production of autoantibodies, which are able to interfere with NMDA receptors, thus leading to excitotoxicity in a concentration-dependent manner [65]. The increased rates of IgG, IgA, and IgM in mice subject to chronic exposure to twofold increased earth’s gravity conditions (2G) were, respectively, estimated to be ~100%, ~30%, and ~0%, whereas no significant difference in any of these immunoglobulins was observed in mice chronically exposed to 3G conditions [54]. 162 A. Saghazadeh and N. Rezaei

Toll-Like Receptors

The role of toll-like receptors (TLRs) in the context of neuropsychiatric disorders has been frequently investigated. According to a gene-targeted study in mice, it seems that TLR4 exerts a desired effect on the contextual fear-learning, whereas its overall effect on cognitive behaviors, including memory acquisition/retention and motor function, is not pleasant [66]. Further, mice delivering the intracerebroven- tricular infusion of the TLR4 antagonist demonstrated a considerable change in the anxiety levels, while no significant difference was observed for the memory and motor performances [66]. These lines propose a possible role of TLR4 in ER and related parameters.

Lipopolysaccharide Binding Protein (LBP)

The injection of LPS leads to the formation of LPS-LBP complexes, which are, in turn, bound to the CD14 antigen on leukocytes [67]. LPS is, thus, known as an immune challenge for the leukocytes-mediated induction of proinflammatory cytokines. LBP seems to be required for the normal neural development of the hippocampus. LBP gene knockout models exhibited disturbances in the hippocampal function and increased anxiety-like behaviors [68]. Interestingly, maternal separation has been shown to inhibit the expression of LBP [68]. Taken together, the LBP-dependent pathway is a possible mechanism through which those aforementioned detrimental effects of maternal separation (MS) on the hippocampus-related functions and emotionality-related behaviors are exerted.

Oxidative Stress

Oxidative stress is thought to serve as an emotional stressor [69, 70] that links the immune system and the emotional well-being [71]. Sub-chronic treatment with xanthine and xanthine oxidase indicated that this role of oxidative agents is mediated by reduced expression of antioxidant enzymes and transcription, by neurotrophic factors, and as well by increased activation of proinflammatory pathways and respective cytokines in the brain regions mainly involved in regulation and generation of emotionality-related behaviors, e.g., the hippocampus, amygdala, and locus coeruleus (LC) [72].

Microglia Cells

Psychological stress was shown to alter proliferation and morphology of microglia in the brain [73, 74]. Moreover, microglia are suggested to mediate the effects of chronic psychological stress on behavior and the brain function [74]. Supporting 11 The Immunoemotional Regulatory System 163 this, treatment with minocycline was shown to suppress the effect of stress on the brain [75]. The evidence is accumulating to address that cytokines contribute to the activation of microglia cells in specific brain regions, including the hippocampus, medial PFC, and nucleus accumbens, following psychological stress, either acute or chronic [74, 76].

Nuclear Factor Kappa B (NF-κB) Pathway

Emotional stimulators, e.g., whisker removal, have shown to provoke the cytosolic degradation of inhibitor of the ĸB kinase in the cerebral cortex and hippocampus [4]. Further, the elevated expression of inhibitor of the ĸB kinase in the nucleus accumbens led to the significant increase in emotionality-related behaviors, such as social avoidance and anxiety and depressive-like behaviors [77]. In parallel with this line, it has been reported that the activation of NF-κB pathway in the cerebral cortex, hippocampus, amygdala, and LC is a possible mechanism underpinning the role of oxidative stress in generation of anxiety-like behaviors and in general the role of psycho-emotional stressors, such as whisker removal [4, 72].

The Blood-Brain Barrier (BBB)

Acute psychological stress was shown to increase the permeability of the blood- brain barrier (BBB) [78]. Several pathological conditions, which can be categorized into inflammatory and noninflammatory related, were shown to disturb the physical BBB’s integrity [79]. When the BBB’s integrity is disturbed, immune system-related markers such as cytokines and autoantibodies are clearly capable of crossing the BBB and influencing specific brain regions and their respective functions, favorably ER.

The Interplay Between the Immune System-Related Markers and HPA Axis

In neonatal pigs exposed to social isolation stressor, induced changes in stress hormones, ACTH, and cortisol corresponded to the changes in the serum levels of TNF-α and in the LPS-induced production of IL-1β in supernatants of whole blood cell culture [60]. LPS injection could stimulate the expression of pituitary proopiomelanocortin (POMC) in mice lacking both LIF and CRH genetically as much as WT mice [80]. Of note, the POMC expression was significantly increased in mice deficient for both leukemia inhibitory factor (LIF) and CRH compared to mice deficient for one of them only [80]. As expected, this endotoxin led to induce the expression of 164 A. Saghazadeh and N. Rezaei proinflammatory cytokines, TNF-α, IL-1β, and IL-6, in the hypothalamus and pituitary [80]. In response to restraint stress challenge, there is a sharp increase in the serum levels of corticosterone, which is dramatically decreased at the end of a stressful situation [81]. Generally, the basal levels of corticosterone were significantly higher in female than in male rats [81]. However, there was no significant difference in the amount of time to reach the peak and as well to return to the basal levels of corticosterone during and at the end of stress challenge between males and females [81]. It feels that stress challenges systemically increase the expression of CST in order to regulate many factors, such as LBP in the hippocampus and UCP2 in splenocytes [43, 68]. This increased expression of CST necessitates a perfect genetic background, due to its significantly lower profile in UCP2-deficient than wild-type models [43]. Unlike other investigated cytokines, e.g., TNF-α, IL-2, or IFN-γ, the IL-1 has an enhancing effect on the activity of the HPA axis and on plasma concentrations of the respective hormones, e.g., ACTH and glucocorticoids [82]. A significant positive association between serum levels of brain-derived neurotrophic factor (BDNF) and IL-6 (but not TNF-α) in depressed patients, but not in healthy individuals, in addition to this observation that the serum levels of IL-6 can predict the levels of BDNF in melancholic patients, but not in non-melancholic patients [83], suggest that inflammation must be a compensatory mechanism used by our body during a depressive episode. Specific inflammatory markers characterize this inflammatory process depending on the disease severity.

Neuronal Circuits

Brain reward and compulsive circuits comprise pathways originated from prefrontal cortex and terminated into the mediodorsal thalamus. Stress systems consist of the hypothalamic-pituitary-adrenal (HPA) axis and the extrahypothalamic circuit (for a review on HPA circuit please see [84]). Overall, some neurotransmitters and/or neuromodulators such as γ-aminobutyric acid (GABA), dopamine, neuropeptide Y (NPY), glutamate, norepinephrine, orexin, vasopressin, and corticotropin-releasing factor (CRF) are involved in these pathways (see reviews in [85, 86]). All of these interact with cytokines. Kullmann and colleagues examined the impression of exposure to LPS-induced inflammation on the brain activity in response to emotionally aversive visual stimulation task and found a significantly increased activation of the OFC in LPS group as compared with the saline group [87]. Further, the consequences of challenging the peripheral immune system by means of Mycobacterium vaccae (M. vaccae) on serotonergic system, e.g., activation of a distinct series of serotonergic neurons, as assessed by the c-Fos expression, in the interfascicular part of the dorsal raphe nucleus (DRI) and also augmentation of serotonin metabolism in the ventromedial PFC, might largely explain the positive effect of this challenge on emotional behaviors (i.e., decreased immobility in the forced swim test) in preimmunized mice 11 The Immunoemotional Regulatory System 165 after 12 h [88]. Regarding the serotonergic system, the M. vaccae’s effects were observed in M. vaccae, not in ovalbumin-preimmunized mice, which is a reflection of their difference in the immune responses which they induce (M. vaccae and ovalbumin are associated with Th1 and Th2 immune responses, respectively) [88]. At the behavioral level, the M. vaccae’s effect was not exerted in not-preimmunized mice [88]. Altogether, these lines are interestingly interpreting a specific type of peripheral immune challenge as a treatment pleasant to the emotional brain, if immunization against that was provided before. Further, the emotional expression component of emotional approach coping (EAC) scale was found to positively correlate with the relative left-sided frontal EEG asymmetry, which was inversely and respectively associated with baseline IL-6 levels and stress-related sTNFαRII levels in a healthy population [89]. The EAC scale, especially the emotional processing component, was in an inverse correlation with stress-related TNF-α level [89].

Significances

Emotional Disclosure

The expression of emotional experiences in words, defined as “emotional disclosure” (ED), is widely acknowledged for many years [90]. Indeed, ED acts as a medication not only for psychological health but also for physical health. Even, it seems that physiological status is more got into the swing of the ED’s action than psychological status since the findings of a meta-analysis study have led to an interesting conclusion that the writing emotional disclosure intervention have a statistically more impact on physical compared with psychological health variables [91]. Nonetheless, the mechanism of the ED’s action has not been fully disclosed yet. Regarding our topic of interest, e.g., its interference with the immune system, a 4-week oral emotional disclosure intervention in patients with rheumatoid arthritis (RA) has influenced on the serum concentrations of two proinflammatory cytokines, IFN-γ and IL-6 [92]. However, this influence was statistically significant for the cytokine IFN-γ solely [92].

Emotion with Tears

Contrary to the weather information video, viewing the Kramer vs. Kramer movie, as a heart-warming video, led to emotion with tears in greater than 70% of patients with atopic eczema and latex allergy, and this was, interestingly, reflected in the amelioration of allergic response of these patients to latex, i.e., ↓ latex-specific IgE production, ↓ Th1 (IFN-γ and IL-12), and ↑ Th2 (IL-4, IL-10, and IL-13) cytokines [93]. However, there is some research that conflicts with this view. For example, among RA patients, translation of emotions in tears was found to associate 166 A. Saghazadeh and N. Rezaei positively with the serum levels of IL-6 and CD4+/CD8+ratio and negatively with NK cells activity, and that those who translated their emotions in tears were more likely to have an easy control of RA [94].

Stem-Cell Transplantation (SCT)

Human mesenchymal stem cells (hMSCs) convey the widespread impression on the immune system via interacting with chemokine receptors and adhesion molecules and getting various immune cells, e.g., dendritic cells, T-helper cells, and natural killer cells, into an anti-inflammatory state [95, 96]. A 6-month follow-up study has recently elucidated that the combination of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) could significantly modulate emotional responses evaluated by CARS in 9 autistic subjects receiving this therapy in addition to rehabilitation compared with 14 patients who were only on rehabilitation program [97]. This is in parallel with another observation demonstrating the recovery of emotional responses in a 14-year-old boy with severe autism at 6 months after transplantation of autologous bone marrow-derived mononuclear cells [98]. Though these findings are full of optimism (refer to the recently published study reviewing current literature regarding the clinical efficacy MSCs in treatment of ASDs [99]), we cannot abandon the first case report of developing a multifocal brain tumor 4 years after transplantation of human fetal neural stem cells [100]; it is strongly suggested to set long-term follow-up studies concerning the adverse events of stem-cell therapy in autism.

Adequate Sleep

Sleep loss is inversely associated with adult neurogenesis reflecting directly in the hippocampus function, whose abnormality is, in turn, associated with the development of emotional/mood disorders [101].

Mindfulness-Based Stress Reduction (MBSR) Program

Activations of the left and right frontal regions are, respectively, associated with the experimental arousal of positive, approach-related emotions, and negative, withdrawal-related emotions [102]. Regarding ER, the 8-week clinical MBSR program achieved a significant increase in the activation of left-sided anterior regions [103]. Regarding immune system function, healthy subjects who were on the 8-week clinical MBSR program had significantly higher antibody titers following influenza vaccine administration compared with the control group [103]. 11 The Immunoemotional Regulatory System 167

Further, this short clinical-training program led to the significantly increased production of proinflammatory cytokines, particularly IFN-γ and TNF-α, in breast and prostate cancer patients [104, 105]. The desired effect of this short MBSR program on the NIERS is scheduled to begin immediately following intervention and it is possible to prolong, at least for 1 year post-intervention [103–105].

Mindfulness Meditation and Emotion Regulation Therapy

Zautra and his colleagues conducted a placebo-controlled study on 144 patients with RA and thereby explored the effect of cognitive behavioral therapy (P), mindfulness meditation and emotion regulation therapy (M), and education only (i.e., placebo control group) on the self-reported ratings of pain and on the inflammation profile, evaluated by the IL-6 levels, as well [106]. This study provided evidence pointing to the favorable effects of both of eight-week treatments P and M on either pain ratings or IL-6 concentrations, these advantages were, however, more statistically significant for those assigned to the P group [106]. It is not, however, surprising but is an opportunity to note that patients suffering from recurrent episodes of depression benefit more from M compared with P treatment or placebo [106].

Tai Chi Chuan (TCC)

This exercise program exerts powerful effects on the various aspects of both physical and mental health, including psychological symptoms, falls and related risk factors, and quality of life, and more interestingly on the immune function (for review see [107]). It has been indicated that, however, the influences of TCC on the various investigated cytokines are statistically insignificant, but some of these slight influences on cytokines, such as IL-2, IL-6, and IL-8, could be considerably correlated with the conversions of the physical/mental health-related parameters, for example, fat mass, fat-free mass, and emotional role limitation in breast cancer patients [108, 109].

Social Housing

Experimental study on aged hamsters elucidated that the interference effect of social grouping with circadian arrhythmia on emotionality might be, at least in part, attributable to diminished expression of proinflammatory mediators, including IL-1β, and indoleamine 2,3-dioxygenase (Ido) in the hippocampus [110]. The interference effect of social grouping and environment enriching with pre- or postnatal chronic restraint stress on emotionality was along with the increased 168 A. Saghazadeh and N. Rezaei expression of oxytocin (OT) in the paraventricular nucleus (PVN) and secretion of IL-2 by splenocytes and also with decreased serum levels of CORT and the splenocytes-induced IL-1β production [111, 112]. However, the IL-1β levels in the hypothalamus were enhanced [112]. Compared with hamsters grouped in social cages, social separation strengthened the hypothalamic mRNA levels of IL-6 and TLR-4 in female, but not in male, hamsters significantly, which may be an explanation for earlier and more weight loss in these hamsters along with expression of signs of altered emotional behaviors evaluated by anxiety-related feeding/exploration conflict (AFEC) test [113].

Cognitive-Behavioral Therapy

A 10-week cognitive-behavioral stress management (CBSM) intervention inclined to the greater than 50% modification in the expression of leukocyte transcripts (including decreased expression of proinflammatory genes) in women subject to the treatment of stage 0–III breast cancer [114].

Omega-3 Polyunsaturated Fatty Acids (n-3 PUFAs)

Emotionality, measured by time spent on self-grooming in object recognition task, was significantly enhanced in Fmr1-KOs modeling the fragile X syndrome when compared with wild-type littermates [115]. The mechanism underpinning the modulatory effect of n-3 PUFAs supplementation on the emotionality index in Fmr1-KOs can be, at least in part, explained by its widespread impact on the expression of cytokines in the various brain regions, such as significant increase in the expression levels of CD11b and CD45 (both in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) brain regions), TNF-α in the CA1, and IL-1β in the PFC [115]. Additionally, the supplementation exerted a suppressive effect on the levels of IL-1β in the CA1 region [115]. However, in other studies on healthy subjects, either animals or humans, the desired effect of n-3 PUFAs on the depressive-like behaviors and emotional reactivity was not found to mediate via alteration in the cortical levels of cytokines but was largely attributed to the increased levels of docosahexaenoic acid (DHA) in cortex and splenic tissues or in erythrocyte membranes [116, 117]. Omega-3 fatty acid ethyl-eicosapentaenoate (EPA) could also ameliorate the augmenting effects of IL-1β on dopaminergic system in the shell of the nucleus accumbens and on the content corticosterone and PGE2 and activity phospholi- pase A2 (PLA2) [48]. As such, the protective effect of omega-3 fatty acids in AMI patients was observed along an anti-inflammatory influence↓ ( TNF-α and ↓ IL-6). 11 The Immunoemotional Regulatory System 169

Cognitive Communication

Graham and her colleagues have grasped the fact that the greater the number of cognitive words one uses in a marital conflict, as an emotional conflict, the lesser her/his immune system must be tended to shift the balance to the proinflammatory side, evaluated by TNF-α and IL-6, 24 h post-conflict [118]. However, this correlation was not found at conflict baseline. This raises a question whether cognitive processing is beneficial to other emotional situations in order to handle the inflammatory response.

IL-6

To probe the power of IL-6 in learning and memory, Benedict and his colleagues have performed a placebo-controlled study and produced evidence to propose that people who received the intranasal IL-6 treatment had significantly higher circulating concentrations of IL-6, but not CRP and cortisol, along higher slow-wave activity (SWA) during the second, but not, half of sleep and could significantly better retrieve emotional text than neutral text [119]. Since the increased levels of IL-6 in plasma were not associated with memory recall [119], and that there are limited possible targets for the IL-6 transport from the nasal cavity, including blood, brain, and CSF (for review see [120]), it is more probable that the mechanism underpinning this effect of IL-6 treatment involves the CNS in a direct way rather than the periphery in an indirect way.

Herbal Medicine

Treatment with kami-shoyo-san (an herbal medicine) boosted the TNF-α levels significantly compared with antidepressant therapy among postmenopausal women with depression [121].

Cautions

In vivo models provided an invaluable insight into uncovering the conspiracy of dexamethasone (DEX), prescribed as an anti-inflammatory corticosteroid, against specific brain regions underlying emotion processing/regulation/expression, principally the amygdala, reflecting in the abnormal anxiety and fear behaviors [122, 123]. Though both of them were positively proved detrimental to the neuronal 170 A. Saghazadeh and N. Rezaei development of the amygdala, the conspiracy of the prenatal DEX (PreDEX) treatment was more conspicuous than the postnatal one (PostDEX), because of the following: (a) the increased rate of cleaved caspase-3-positive cells in the amygdala was more significant in the PreDEX treatment group than in the PostDEX group, (b) this disadvantage of DEX was evident in the medial and basomedial subregions of the amygdala in the PreDEX group, whereas its evidence merely in the central nucleus region in the PostDEX group, and (c) in the PreDEX group, both male and female animals experienced this disadvantage of DEX, while it was observed only in females in the Post-DEX group [122]. Regarding the PreDEX treatment, a significant increase in the volume of the bed nucleus of the stria terminalis (BNST) provided a contrast to the decreased volume of the amygdala [123]. At molecular levels, the perinatal glucocorticoid treatment with corticosterone resulted in exhibiting disturbed emotional-like behaviors in offspring as evaluated by the open field and forced swim tests. It is possible to be a reflection of the increased leukemia inhibitory factor (LIF) expression in the hypothalamus, and certainly, it is not mediated via CRH, owing to no observation of any difference in its content in the hypothalamus or in the serum concentrations of corticosterone [124]. At genetic levels, deletion of the FK506-binding protein 51 (FKBP5) gene, which regulates glucocorticoid receptor (GR) sensitivity and has been associated with the risk and the prognosis of psychological problems, left mice significantly more vulnerable against acute stressors [125, 126]. However, a double-blind placebo-controlled study has found that peripheral glucocorticoid sensitivity, caused by oral-cortisol treatment, led to a considerable decrease in the stimulated production of IL-6 and that this reduction was considerably correlated with retrieval of emotional words, but not neutral words [127]. However, an interleukin-2 receptor-targeted fusion protein, denileukin diftitox (DAB389IL-2, ONTAK), could exert a pleasant effect on total quality of life and most of its subscales, including emotional functioning [128]. It is of importance that depressive symptoms and quality of life (attributed to its physical, emotional, social, and role functioning subscales, but not to cognitive functioning) are significantly aggravated after 3–4 weeks cytokine (IL-2 and/or IFN-α) therapy in patients with cancer (colorectal, advanced melanoma, and advanced renal cancer) [129, 130]. It is with regret that we had to cite a report of depression development and then suicide in a cancer patient on IL-2 therapy and without a history of any psychiatric diseases [131]. These findings are consistent with the increased level of emotionality in rats following immunosuppressive treatment with cyclosporine A, which is, at least in part, justified by altered immune profile, particularly inhibiting the of IL-2 release and inversely inducing the IL-1β production in the brain [132]. On the contrary, in the MRL-lpr model of AID, the resultant improvement in glucose preference (as an emotionality index) justified the immunosuppressive treatment with cyclosporine [133, 134]. This con- troversy centered on the issue has arisen from their very different genetic background. 11 The Immunoemotional Regulatory System 171

Conclusions

Physiological status/physical diseases have been correlated with a variety of psychological status/mental diseases. The present review was intended to indicate that such correlations exist, at least in part, due to the intertwinement of emotion- regulation processes and immune-system regulation (named immunoemotional regulatory system: IMMERS). The current knowledge corroborates that the IMMERS model fits a huge set of psychological states and/or disorders (anxiety, negative affect, positive affect, aggression, loneliness, stress, worry, well-being, social rejection, socioeconomic status, shame, perceived discrimination, addiction and alcohol withdrawal, generalized anxiety disorder, post-traumatic Stress Disorder, depression, dysregulation profile, neuropathic pain, pain catastrophizing, alexithymia, intermittent explosive disorder, and chronic fatigue syndrome). The fact that the etiology of many mental conditions entails two complex processes, i.e., emotion regulation and immune regulation, has an important implication. It is that the value of immunoemotion regulation to humans and its potential clinical benefits should be reasonable to both the human and medical society. Under these regulations, patients try to regulate their own emotions, and physicians help them using both emotion-regulation care services and medications used to regulate immune responses. However, further investigations are required to the better understanding of IMMERS’ work, which helps us to design strategies as complementary therapies. Chapter 9 discussed how immune regulation and emotion regulation are intriguingly involved in configuring correlation between psychological status/psychiatric disorders and physiological status/physical diseases. This section was intended to unravel the IMMERS’ work and its possible health benefits. We highlighted the role of cytokines as the most important immunological compartment of the IMMERS. However, this system is also composed of many other immune and non- immune compartments, mainly chemokines, mast cells, lymphocytes, natural killer cells, antibodies and immunoglobulins, toll-like receptors, lipopolysaccharide- binding protein, oxidative stress, microglia cells, NF-κB pathway, HPA axis, neuronal circuits, and blood-brain barrier. We concluded this review by compiling a long list of strategies (including emotional disclosure, emotion with tears, stem-cell transplantation, adequate sleep, mindfulness meditation, emotion regulation therapy, exercise programs, social housing, cognitive behavioral therapy, cognitive communication, interleukin-6, and some herbal medicines) that their mechanism of action is, at least in part, innervated by IMMERS’ work.

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Amene Saghazadeh and Nima Rezaei

Abstract Human is full of enthusiasm to heighten his sense of intuition, also known as the sixth sense. He owes his enthusiasm largely to achieving the best possible profit and in other words to winning intense competitions in his life. The per se rule of fuzzy sets and its implications have been the subject of intensive research over the last five decades. Here we will provide a brief account of what an application of fuzzy sets to the sixth sense might bring about. Our primary aim will be on the sixth sense two individuals have of each other. Then the focus will be shifted toward the sixth sense one has of the universe and events.

Keywords Fuzzy · The sixth sense · Decision-making

© Springer Nature Switzerland AG 2019 179 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_12 180 A. Saghazadeh and N. Rezaei

Introduction

Fuzzy Sets

In 1965, the concept of “fuzzy set” was created by L. A. Zadeh as a “class of objects with a continuum of grades of membership” [1]. Membership functions applied to characterize the behavior of fuzzy sets allow us to predict the possible relations between individual fuzzy sets. The properties of fuzzy sets have formed a sound basis for the development of many theories, particularly the theory of possibility [2]. The theory of possibility formulated by L. A. Zadeh (1977) states that possibility methods must be employed to measure the information. In fact, Zadeh proposed to abandon the probabilistic methods for measuring the information because he believed in the possibility as the essence of information rather than in the probability as the essence of information. Mathematicians have made several generalizations of the original theory of fuzzy sets, such as the theory of intuitionistic fuzzy sets [3]. Intuitionistic fuzzy sets are characterized by two functions, a membership function and a nonmembership function, and therefore each object in such a set has two degrees, a degree of membership and a degree of nonmembership. The intuitionistic fuzzy sets have been applied to the different fields of science, such as decision-making models, pattern recognition, and medical diagnosis [4–6]. Altogether the per se rule of fuzzy sets and its generalizations have been the subject of intensive research over the last five decades.

What Is the “Sixth Sense?”

Receiving information from the external environment engages the five traditionally recognized senses including vision, hearing, touch, smell, and taste. There is also the so-called sixth sense that is supposed to be responsible for receiving internal signals [7]. This statement on the sixth sense is tantamount to the definition of “interoception” which was introduced as the feeling one has about the internal physiological conditions of the entire body [8]. This seems, however, to be a somewhat restricted usage of definition. Here we will extend the boundary of the current definition (i.e., his/her own body) and that what we will mean by the sixth sense is the thought and/or feeling one has not only about internal physiological conditions of his own body but also about that of other bodies. Here we will provide a brief account of what an application of fuzzy sets to the sixth sense might bring about. Our primary aim will be on the sixth sense two individuals have of each other. Then the focus will be shifted toward the sixth sense one has of the universe and events. 12 Fuzzy Sets: Application to the Sixth Sense 181

Fuzzy Sets and the Sixth Sense

An Application of Fuzzy Sets to the Sixth Sense Two Individuals Have of Each Other

As mentioned above, each object in a certain fuzzy set has a degree of membership which is determined by the membership function of that set. Below is to prove the point of how the main properties of the original theory of fuzzy sets build a basis for the theory of the sixth sense. Inclusion, consider one’s sixth sense, as defined here, a fuzzy set consisting of both accurate and inaccurate thoughts and/or feelings. If we intended to consider just accurate or inaccurate thoughts and/or feelings, we must apply the theory of intuitionistic fuzzy sets. Here we intend to consider both accurate and inaccurate thoughts and/or feelings and thus must apply the original theory of fuzzy sets. The fuzzy sets “A” and “B” are assigned to Alice’s sixth sense and Bob’s sixth sense and are characterized by functions fA(x) and fB(x), respectively. fA(x) = [0, 1], x ∈ X, X is the set of accurate and inaccurate thoughts and/or feelings. fB(x) = [0, 1], x ∈ X, X is the set of accurate and inaccurate thoughts and/or feelings. Empty, the fuzzy set A is empty if and only if Alice has not any thoughts and feelings. The fuzzy set A is empty if and only if fA = 0 ∀x ∈ X. Equal, two fuzzy sets A and B are equal if and only if Alice and Bob have the same thoughts and feelings with the same grade of membership. Two fuzzy sets A and B are equal if and only if fA(x) = fB(x) ∀x ∈ X. For example, while Alice feels she loves Bob with the membership grade of 0.97, Bob also knows that Alice does love him because he feels she loves him with the membership grade of 0.97. Complement, the complement of the fuzzy set A is A’ assigned to “Andrew.”

A’ is the complement of the fuzzy set A if and only if fA′(x) = 1 − fA(x) ∀x ∈ X. For example, while Alice feels she does like Andrew with the membership grade of 0.03, Andrew thinks that Alice does love him because he feels she does like him with the membership grade of 0.97. Containment, the fuzzy set A is contained in B, if and only if Alice has all the thoughts and feelings Bob has. The fuzzy set A is contained in B if fA(x) ≤ fB(x)∀x ∈ X. For example, while Bob is suffering pain in a car accident, Alice feels Bob in a great deal of pain. Union, the fuzzy set D, assigned to David, is the union of fuzzy sets A and B which contains both thoughts and feelings of Alice and Bob.

The fuzzy set D is the union of two fuzzy sets A and B if and only if fD(x) = Max [fA(x), fB(x)]. 182 A. Saghazadeh and N. Rezaei

Intersection, the fuzzy set S, assigned to Sam, is the intersection of fuzzy sets A and B which contains all common thoughts and feelings between Alice and Bob. The fuzzy set S is the intersection of two fuzzy sets A and B if and only if fS(x) = Min [fA(x), fB(x)], or S = A ∩ B. We interpret the intersection of two fuzzy sets A and B as the aggregate of the sixth sense that Alice has of Bob and the sixth sense that Bob has of Alice. Algebraic product, the AB, assigned to Abbie, is the algebraic product of fuzzy sets A and B which includes all the thoughts and feelings both Alice and Bob have.

fx= fxfx, AB ⊂∩AB AB () AB() () Algebraic sum, the A + B is the algebraic sum of fuzzy sets A and B.

fx= fx+ fx, if fx1 AB++() AB() () AB()

Absolute difference, the A − B is the absolute difference of fuzzy sets A and B.

fx()= fx()− fx() AB− AB Convex combination, the convex combination of two fuzzy sets A and B can be formulated as follows:

CA=∧,B,A=∧ +∧′BA∩⊂BA,B,A∧ ⊂∪B () () fx()= fx()fx()+−1 fx() fx() ()A,B,·∧ ∧∧AB 

As we know A ∩ B ⊂ (A, B, ∧) ⊂ A ∪ B Thus we have Min [fA(x), fB(x)] ≦ f∧(x)fA(x) + [1 − f∧(x)] fB(x) ≦ Max [fA (x), fB(x)] ∀ ∧

fx()− fx() fx()= CB ∧ fx− fx AB() () As the intersection area may be improved through convex combination, it would be possible to propose that both Alice’s sixth sense and Bob’s sixth sense can be strengthened to the extent of the union.

An Application of Fuzzy Sets to the Sixth Sense Each Individual May Have Somewhat of the Universe

The explanation mentioned above was an application of fuzzy sets to the sixth sense two individuals may have of each other. Now, it would be understandable to apply the concept of fuzzy sets to the second point at issue, i.e., the sixth sense each 12 Fuzzy Sets: Application to the Sixth Sense 183 individual may have somewhat of the universe and events. Suppose Alice intends to go to a foreign country to study. She is full of positive and negative feelings on this issue; however, she cannot express them. Below is a prepared list of finite feelings with their grade of membership into Alice’s fuzzy set: x1 = there (i.e., that foreign country) I would be lonely with my books, and fA(x1) = p1 x2 = there I can find friends, and fA(x2) = p2 x3 = there I will face the language problems, and fA(x3) = p3 x4 = there I can speak English, solving language problems, and fA(x4) = p4 x5 = there I will face the monetary problems, and fA(x5) = p5 x6 = there I can work part-time, solving monetary problems, and fA(x6) = p6 x7 = that (the university where Alice intends to go) is one of the best universities in the world, and fA(x7) = p7 Alice must choose between “to go” and “not to go.” As illustrated above, when our sense does not work smoothly, there are often opposite thoughts or feelings. In such situations, if we can accurately estimate the probability of possible events, then our sense would be able to work well. The ideal estimation is that when the aggregate of our estimations of two opposite events or decision is one (i.e., p1 + p2 = 1, p3 + p4 = 1, or p5 + p6 = 1). This reminds us of the Hardy-Weinberg principle. As multifarious diseases can be caused if the Hardy-Weinberg equilibrium is violated, the sixth sense may not work well if the accurate-inaccurate estimates are wrongly predicted. The less these two estimations (about given two opposite events) are nearer, the more we can distinguish them, and our sense can work more smoothly and accurately. On the contrary, the more these two estimations (about given two opposite events) are nearer, the less we can distinguish them, and our sense is expected to work harder and inaccurately. The question is what determines the accuracy of our estimations. We think of entropy as such a factor. In fact, we deal with a system in which the input is the entropy (i.e., the quantity of information demanded), and the output is the accuracy of our estimations. To deal computationally with the issue, the concept of elasticity in economics is explained to provide a vivid illustration of the input/output system. Price elasticity of demand (PED), in economics, is the concept of elasticity that has long been used as a measure for estimating changes in demand and supply in response to price changes. PED emerged to predict consumer behavior to price changes is defined as the proportion of change in quantity demanded to price changes. The effect of price changes would be subtle if PED is less than one, whereas it would be significant if PED is greater than one. There are two main ways of calculating PED as follows:

%/∆QQ PED = %/∆PP P dQ PointPED =× Q dP 184 A. Saghazadeh and N. Rezaei

PP+ ∆Q ArcPED = 12× QQ+ ∆P 12 Considering the formula mentioned above, the inelastic area is where PED is less than one, whereas the elastic area is where PED is greater than one. This note can be applied to our problem. As previously explained, the sixth sense would not continue to work as it should when our estimates about the opposite sides of a given matter are very close to each other. In such situations, the efficiency of the sixth sense is supposed to be minimized. To overcome this state, the brain necessarily demands a greater amount of information. It is reasonable to provide a formula identifying the efficiency of sixth sense based on the relationship between our estimates of and the amount of information related to the matter. The formula would clearly show that the more our estimates are nearer to each other, the greater amount of information the brain demands. To devise this formula, we must first find out how the sixth sense is related to the estimates of that given matter and with the amount of information we have about that. When looking at the example, the possible events can be categorized into two according to that whether or not they are in favor of that Alice’s decision to go to a foreign country to study ([x1, x3, x5] vs. [x2, x4, x6, x7]). The total probability of “to go” is defined as the average of the membership function of related events as follows:

G Σi=1 fx() PPPP24++67+ PTo go = = ,0 ≤≤PGTo go G 4

N Σi=1 fx() PP13++P5 PNottogoN= = , 0 ≤≤PNot to go N 3 ∆∆PP=−PP,0≤≤GN− To go Nottogo

If G > N, then we have (N − G) ≤ ∆P ≤ (G − N) If N > G, then we have (G − N) ≤ ∆P ≤ (N − G) Therefore, the relation between the efficiency of the sixth sense and the ∆P parameter can be depicted as a hyperbola. The concept of entropy can be used to address the latter problem, i.e., the relationship between the sixth sense and the amount of information. Entropy, in order to create the quantity of information which a communication process produces [9], Shannon introduced entropy as follows: N HK=− pplog ∑ i=1 ii, where K is a positive constant and pi is the probability of occurrence of the event i. Power, the power of a fuzzy set A is the quantity of thoughts and feelings Alice has.

N Ff≡ ()x ∑ i=1 A i 12 Fuzzy Sets: Application to the Sixth Sense 185

Considering Shannon entropy which is a probabilistic parameter and the power of a fuzzy set, De Luca and Termini defined nonprobabilistic entropy of generalized fuzzy sets as the degree of fuzziness a system is [10]. N Hf ≡−Kfxfln x ()AA∑ i=1 ()iiA (), where N is the number of elements of A and K is a positive constant. As 0 < fA(xi) ≤ 1, we have ln fA(xi) ≤ 0. Thus H (fA) ≥ 0. For the purpose of decision-making, the entropy of a fuzzy set is considered as the average amount of intrinsic information a system acquires to arrive at a decision. This explains entropy as integral to the sixth sense and thus to the decision- making accuracy. Decreasing entropy and thus the information flow in the brain has been linked to epilepsy, a brain disorder which is characterized by neuronal hyper- synchronous activity [11]. On the other side, it is expected that the efficiency of the system would begin to deteriorate when entropy or disorder exceeds the stability limit. For example, the stability limit in crystal material has been proposed to be a temperature above which the crystal loses its original character and will be transformed into glass [12]. In fact, the ultralimit entropy seems like a threat to structural stability. Regarding the brain, increasing entropy leads to age-related changes which are responsible for the transition from normal aging to abnormal cognitive aging [13]. However, considering entropy as an index of complexity, it is clear that increasing entropy in the brain conveys complexity which underlies the functional connectivity between brain structures [14]. Interestingly the perturbational complexity index (PCI) which measures the complexity over cortical areas has been proposed to predict the level of consciousness [15]. Wakeful individuals showed lower values of the PCI compared to those who had experienced temporary loss of consciousness (i.e., during non-rapid eye movement sleep, after deep sedation, and during general anesthesia). Altogether, the conclusion can be drawn that there should be a peak (a) toward which the efficiency of the sixth sense increases progressively, (b) at which the sixth sense would achieve maximum possible efficiency, and (c) beyond which the efficiency of the sixth sense begins to deteriorate. Accordingly, a hyperbola can be drawn to demonstrate the relationship between the efficiency of the sixth sense and the amount of information (Fig. 12.1). Some special points to be noted are as follows: the first point is that the peak of entropy for a given matter varies among individuals, and this explains why the sixth sense should be considered as an individual difference, and the second one is that individuals can learn to strengthen their sixth sense by altering values of peaks. Let us clarify these points with a simple real-life example. A few years ago I saw my friend’s post on my News Feed. She had posted the message that “do you turn down your music when you are lost?” Simply, individuals who do turn down their music decide to focus solely on where they are and where they should go. However, in fact, they have learned how to reduce the ultralimit entropy and to reach the optimal level of entropy. Now it would be understandable to draw a simple graph illustrating the relationship between the estimates we made and the information we have about a given matter and its impact on the efficiency of the sixth sense (Fig. 12.1). This graph is similar to the graph that represents the relation between price and the quantity 186 A. Saghazadeh and N. Rezaei

Fig. 12.1 The relation between ΔP, Qi, and ESS which stand for the difference in our estimates about the possibilities of two main opposite sides of the target event, quantity of information, and efficiency of sixth sense, respectively demanded and its impact on the price-demand elasticity. To deal more systematically with the issue, we should be familiar with the concept of the transfer functions. The transfer function can be used to demonstrate linear behavior that governs the relationship between input and output in a given system. Composition and combination of transfer functions yield complex linear systems [16]. Such implications of transfer functions can be considered for the systems characterized by dynamic feedforward and/or feedback controllers that impact the initial input at different points in time. In Fig. 12.2, we have drawn a simple block diagrams showing the basic steps of the performance of the sixth sense system. Functions used in the diagram are formulated as follows: Consider F a function that provides us with primary estimates of different aspects of a target event (e).

F (e) = P1 + P2 +…+ Pn where e is the target event, Pi is our estimate about the possibility i for the target event e, and n is the number of possibilities we can consider for the target event e.

Taking a look at our example, we have F (e) = P1 + P2 + P3 + P4 + P5 + P6 + P7. ∑ corresponds to the output of a function F (i.e., ∑ = P1 + P2 + P3 + P4 + P5 + P6 + P7). E corresponds to the point in time when the mind categorizes different possibilities into two main opposite sides (i.e., [x1, x3, x5] vs. [x2, x4, x6, x7]). Consider C a function that calculates the difference between two main opposite sides of that target event (i.e., ∆P).

Ce=∆P ()

[]PPPP24++67+ []PP++P Taking a look at our example, we have C (e) = − 135 . 4 3 U corresponds to the output of a function C (i.e., U = ∆P). D corresponds to the quantity of information the brain demands based on the U. 12 Fuzzy Sets: Application to the Sixth Sense 187

Fig. 12.2 A schematic diagram of the sixth sense system as described in-detail in the text

Take a look at the formula for non-probabilistic entropy of fuzzy sets and suppose that the fuzzy set A includes only one member with the membership grade of 1. The entropy of this fuzzy set would be zero. Considering our example, this would mean that the brain does not demand any excess information for decision- making. But it can certainly make a decision. Consider P a process through which the brain pools the information demanded to revise the estimates primarily made. N fx Accordingly, P (e) = H (fA) ≡ −K ∑ i=1 A ()i ln fA(xi). N corresponds to signals that are not demanded. It would be understandable to propose that there is a linear relationship between the entropy of the system and the quantity of not-demanded signals. More clearly when the system demands more information, it would inevitably receive not-demanded signals. 188 A. Saghazadeh and N. Rezaei

Y corresponds to the output of a function P that might be influenced by the not-demanded signals. This would yield a feedback leading to the “revision” of estimates.

Conclusions

Fuzzy sets have, either implicitly or explicitly, been frequently used in the development of emotion models by which we can treat emotions logically [17–21]. As described in [17], the proposed models can be classified as follows: models of motivational states (e.g., hunger, fatigue, thirst, and pain), event appraisal models of emotion and expectations, and models of emotion in artificial intelligence. However, they have been focused on modeling emotion in individuals or the most was that during interaction with play technologies. Therefore we intended to develop a model based on interrelations that influence individual interoception. We presented a discrete model for the sixth sense by which we could explain how much human can learn and thereby strengthen the sixth sense. Using transfer functions, we described that (a) the properties of fuzzy sets can be applied to the sixth sense individuals have of each other, (b) the sixth sense cannot continue to work smoothly and efficiently when one has conflicting thoughts/feelings about a target event in the universe, and therefore (c) to make attempt to think, the brain demands more information about that event and this corresponds with increased entropy of the system, (d) increasing entropy within the system would raise the possibility of receiving not-demanded signals, and for this reason (e) there must be a feedback loop leading to the “revision” of estimates. The greatest weakness of the present work that should be mentioned is that we have just provided a theoretical framework which must be applied to situations in the real world.

References

1. Zadeh LA. Fuzzy sets. Inf Control. 1965;8(3):338–53. 2. Zadeh LA. Fuzzy sets as a basis for a theory of possibility. Fuzzy Sets Syst. 1978;1(1):3–28. 3. Atanassov KT. Intuitionistic fuzzy sets. Fuzzy Sets Syst. 1986;20(1):87–96. 4. Li D-F. Multiattribute decision making models and methods using intuitionistic fuzzy sets. J Comput Syst Sci. 2005;70(1):73–85. 5. De SK, Biswas R, Roy AR. An application of intuitionistic fuzzy sets in medical diagnosis. Fuzzy Sets Syst. 2001;117(2):209–13. 6. Dengfeng L, Chuntian C. New similarity measures of intuitionistic fuzzy sets and application to pattern recognitions. Pattern Recogn Lett. 2002;23(1):221–5. 7. Zagon A. Does the vagus nerve mediate the sixth sense? Trends Neurosci. 2001;24(11):671–3. 8. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3(8):655–66. 9. Shannon CE. A mathematical theory of communication. ACM SIGMOBILE Mobile Comput Commun Rev. 2001;5(1):3–55. 12 Fuzzy Sets: Application to the Sixth Sense 189

10. De Luca A, Termini S. A definition of a nonprobabilistic entropy in the setting of fuzzy sets theory. Inf Control. 1972;20(4):301–12. 11. Kannathal N, Choo ML, Acharya UR, Sadasivan PK. Entropies for detection of epilepsy in EEG. Comput Methods Prog Biomed. 2005;80(3):187–94. 12. Fecht HJ, Johnson WL. Entropy and enthalpy catastrophe as a stability limit for crystalline material. Nature. 1988;334(6177):50–1. 13. Drachman DA. Aging of the brain, entropy, and Alzheimer disease. Neurology. 2006;67(8):1340–52. 14. Tononi G, Sporns O, Edelman GM. A measure for brain complexity: relating functional segregation and integration in the nervous system. Proc Natl Acad Sci. 1994;91(11):5033–7. 15. Casali AG, Gosseries O, Rosanova M, Boly M, Sarasso S, Casali KR, et al. A theoretically based index of consciousness independent of sensory processing and behavior. Sci Transl Med. 2013;5(198):198ra05–ra05. 16. Erickson RW, Maksimovic D. Fundamentals of power electronics. Dordrecht: Springer; 2007. 17. El-Nasr MS, Yen J, Ioerger TR. Flame—fuzzy logic adaptive model of emotions. Auton Agent Multi-Agent Syst. 2000;3(3):219–57. 18. Mandryk RL, Atkins MS. A fuzzy physiological approach for continuously modeling emotion during interaction with play technologies. Int J Hum Comput Stud. 2007;65(4):329–47. 19. Price DD, Barrell JE, Barrell JJ. A quantitative-experiential analysis of human emotions. Motiv Emot. 1985;9(1):19–38. 20. Salmeron JL. Fuzzy cognitive maps for artificial emotions forecasting. Appl Soft Comput. 2012;12(12):3704–10. 21. Bakhtiyari K, Husain H. Fuzzy model on human emotions recognition. arXiv preprint arXiv:14071474; 2014. Chapter 13 Asymmetry: Extra Sparkle to the Sixth Sense?

Amene Saghazadeh and Nima Rezaei

Abstract It has been more than 40 years since P. W. Anderson published an article entitled “broken symmetry and the nature of the hierarchical structure of science”. There, symmetry was introduced as the unwritten rule to which all that exist in the universe adhere. The present Opinion is to make sense of the symmetry rule by looking at the behavior of the human brain and then of the sixth sense.

Keywords Asymmetry · Microtubules · Neuroplasticity · Protein · Synchronization · Sixth sense

Miscellaneous arrangements of amino acids, which themselves consist of three key functional compartments, e.g., amine, carboxylic acid, and a side chain, have amassed an extensive collection of protein families. In point of fact, it would be possible to predict the function of proteins from their structure, and vice versa. For example, proteins containing the WD-repeat have been associated with several functions in eukaryotes, including signal transduction, vesicle and mitotic-spindle formation, cell division, etc. [1]. Presumably, if we consider that protein function to be isolated from its structure, it would be very difficult or even impossible to make predictions about either function or structure of that protein. In addition to

© Springer Nature Switzerland AG 2019 191 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_13 192 A. Saghazadeh and N. Rezaei the intimate association between the structure and function of proteins, proteins are adjustable in accord with their ligands. They can change their conformational states and the effect of the conformational change would be the change of the biological effect. Assimilating this capacity of proteins for flexibility and adjustability can accelerate the evolving drug development process [2]. Herein, a fundamental question arises: why the proteins change their conformational states. Some possible answers have been suggested. One of the most reasonable answers is that the protein explores the way to interact well-effectively with its ligand. The protein- ligand interaction is associated with an increase in the conformational entropy, which contributes to the more stabilization of that protein, and that the more the protein is stabilized the less the protein will expend energy. So, the core of the issue seems to be the “symmetry”, which has strongly been associated with the state of stability [3]. Protein molecules can make multifarious intrinsic motions. This is recognized as the resultant of the superposition on and/or the transition between multiple minima of substrates [4]. The assemblage of amino acids constructs the structure of proteins and the polymerization of tubulin monomers would produce microtubule polymers. Thus tubulins, like proteins, must be capable of changing their conformational states in order to well-effectively interact with neighbor tubulins and to inaugurate a network through, which the information can circulate. Indeed, the changes that take place in conformational states of tubulins indicate the information processing. In the theory of orchestrated reduction of quantum coherence, established by Hameroff and Penrose about 10 years ago, the brain consciousness with its common meaning; i.e. the awareness of the present time, is considered the consequence that will arise from the coherence phenomena at the quantum level in brain microtubules [5]. Synchronization that can create a coherent combination of gamma oscillations connotes a cognitive process, while desynchronization denotes the switch from one cognitive state to another. Therefore, the pattern of synchronization can be used to predict cognitive function/dysfunction and to portray the neurocognitive part of diseases, favorably autism [6], epilepsy [7], and schizophrenia [8]. Furthermore, it allows us to reckon roughly performance on cognitively demanding tasks. For example, transient synchronization of gamma oscillatory with the high frequency (65–140 Hz) has been related with making the right choice or even with rectifying the wrong choice, but not with making the wrong choice [9]. In addition, attention to the target stimuli, unlike distractors, actuated the activity of neurons with high gamma frequency (35–90 Hz) and abated that of those with low gamma frequency (<17 Hz) [10]. Considering the information that is going to be carried out as the target stimuli and the noise that is potentially attended in the way the information propagates as the distractor, we expect that the sense of intuition, commonly known as the sixth sense, would be preceded by firing or synchronization of oscillations. However, the problem is that how this synchronization or firing can travel through multi-cortical layers. Below is to address the issue using mathematical neuroscience. 13 Asymmetry: Extra Sparkle to the Sixth Sense? 193

The sensory system includes ascending and descending feedback pathways. The inputs are put into the system via ascending pathways and the outputs are produced under the influence of feedbacks descending pathways would receive from higher- order integrative cortical areas [11]. The fact that the firing neurons, even with a low level of firing rate activity, can ultimately pass through cortical areas whereas synchronized spikes would be transmissible if they are adequately strong imply the superiority of firing neurons over synchronized ones. However, recent research has revealed that feedback projections can increase the size of the basin of the propagation attractor and thereby contribute to the stabilization of the propagation of synchronized spikes in cortical networks [12]. Again, the term “stabilization”reminds us strongly of the concept of “symmetry”. It has been more than 40 years since P. W. Anderson published an article entitled “broken symmetry and the nature of the hierarchical structure of science” [3]. It concisely was written; however, he could quite nicely point to seeing symmetry as the unwritten rule to which all that exist in the universe adhere. He illustrated his point with some examples, such as the ammonia molecule. This molecule is a polar molecule and thus has a dipole moment making the molecule unstable and asymmetric. However, the symmetry rule stipulates that this molecule along with its inversion get into a stable state. Indeed, asymmetry renders the molecule to perma- nently revolve. Let to make perfect sense of the symmetry rule by looking at the behavior of the human brain. Neuroplasticity pertains to the property of neurons to permute their function and structure. Apparently, this property that would be especially prominent in conditions where the brain state is considered unhealthy seems to be a double- edged sword. For example, neuroplasticity has been proposed as an underlying mechanism for pain hypersensitivity [13]. While the lesion-induced plasticity in intact areas is supposed to have a great strategic potential of promoting functional recovery [14] and even structural reorganization [15]. This is consistent with per- suasive evidence that synaptic plasticity plays a prominent role in learning [16, 17]. However, taken together, neuroplasticity under all conditions tries to provide the best possible rate of profit for the system, i.e. the central nervous system. Therefore, it can be speculated that there is a relationship between the rule under which the neurons’ plasticity is regulated and the symmetry rule. Below is to explain why. In economic science, there is a direct correlation between the stability of the bank and its participation in the profitable projects; the more the bank participates in the profitable projects the more it will be financially stable. In order to earn the best possible profit, the normal brain is intended to develop its abilities with the mechanism of synaptic plasticity. This accompanies the breaking of one symmetric state and developing another. On the other hand, it would not be an overstate- ment that the brain is rendered unstable by clinical conditions and as a result, undergoes changes in function and/or structure to become stable. In this case, one asymmetric unstable state is reduced to another state with a higher degree of symmetry and stability. 194 A. Saghazadeh and N. Rezaei

Now is to answer the question; how the symmetry rule can influence the sixth sense? Let to overlook defining the sixth sense. Indeed, the source of the issue is why human is full of enthusiasm to heighten his sense of intuition which is also known as the sixth sense and common sense and how it would be possible to him. He owes his enthusiasm largely to achieving the best possible profit and in other words to winning intense competitions in his life. This sometimes corresponds with the breaking of one symmetric state and developing another, whereas sometimes will be corresponded with the reduction of one asymmetric state and developing a relatively more symmetrical state. Altogether, it can be concluded that the symmetry is that old sparkle to the sixth sense and presumably asymmetry adds extra sparkle to the sixth sense.

References

1. Smith TF, Gaitatzes C, Saxena K, Neer EJ. The WD repeat: a common architecture for diverse functions. Trends Biochem Sci. 1999;24(5):181–5. 2. Teague SJ. Implications of protein flexibility for drug discovery. Nat Rev Drug Discov. 2003;2(7):527–41. 3. Anderson PW. More is different. Science. 1972;177(4047):393–6. 4. Elber R, Karplus M. Multiple conformational states of proteins: a molecular dynamics analysis of myoglobin. Science. 1987;235(4786):318–21. 5. Hameroff S, Penrose R. Orchestrated reduction of quantum coherence in brain microtubules: a model for consciousness. Math Comput Simul. 1996;40(3):453–80. 6. Just MA, Cherkassky VL, Keller TA, Minshew NJ. Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain. 2004;127(8):1811–21. 7. Schevon CA, Cappell J, Emerson R, Isler J, Grieve P, Goodman R, et al. Cortical abnormalities in epilepsy revealed by local EEG synchrony. NeuroImage. 2007;35(1):140–8. 8. Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11(2):100–13. 9. Yamamoto J, Suh J, Takeuchi D, Tonegawa S. Successful execution of working memory linked to synchronized high-frequency gamma oscillations. Cell. 2014;157(4):845–57. 10. Fries P, Reynolds JH, Rorie AE, Desimone R. Modulation of oscillatory neuronal synchronization by selective visual attention. Science. 2001;291(5508):1560–3. 11. Sillito AM, Cudeiro J, Jones HE. Always returning: feedback and sensory processing in visual cortex and thalamus. Trends Neurosci. 2006;29(6):307–16. 12. Moldakarimov S, Bazhenov M, Sejnowski TJ. Feedback stabilizes propagation of synchronous spiking in cortical neural networks. Proc Natl Acad Sci. 2015;112(8):2545–50. 13. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–8. 14. Witte OW. Lesion-induced plasticity as a potential mechanism for recovery and rehabilitative training. Curr Opin Neurol. 1998;11(6):655–62. 15. Frost SB, Barbay S, Friel KM, Plautz EJ, Nudo RJ. Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery. J Neurophysiol. 2003;89(6):3205–14. 16. Maren S, Baudry M. Properties and mechanisms of long-term synaptic plasticity in the mammalian brain: relationships to learning and memory. Neurobiol Learn Mem. 1995;63(1):1–18. 17. Ungerleider LG, Doyon J, Karni A. Imaging brain plasticity during motor skill learning. Neurobiol Learn Mem. 2002;78(3):553–64. Chapter 14 Synchronization Side of the Sixth Sense Story

Amene Saghazadeh

Abstract What sixth sense is and how it works are of the vexed questions which scientists from all the fields of science have been gravitated toward them. This grav- itation may be because of the human’s propensity to have the authority on his own brain and on the other brains’ burdens as well. The present opinion is to narrate the synchronization side of the sixth sense story.

Keywords Coupling · Electromagnetic fields · Quantum tunneling · Sixth sense · Synchronization · Traffic jam

One day many years ago, when I was a 13-year old student, I read a funeral bulletin for a father from his daughter who was studying at my school. While returning to the house, I thought about my father and that about he is a perfectly healthy man and then asked myself if it is possible for my father to die. When I arrived at the home, I saw my father while was getting ready for his trip. While eating lunch together, my father’ smile and his talks about souvenir from his trip were alive as much as I suddenly and completely stopped thinking about death. After lunch, he, as usual, went on an excursion into the interior of the country by car. My mother went to bed, but could not sleep. She was anxious and all the time calling my father. Three hours later, we were informed that my father has had a car accident. Two weeks later, my father passed away. The above example is among many real-life situations, which act like a teacher and make their students that would be meant us understand what sixth sense is. However, how it works would presumably be a rather than difficult question. It is postulated that every particle in space possesses a field, where is a region of space containing energy. Whenever electrons revolve, an electric filed is engendered through which electric current passes and this generates a magnetic field too. So, it would be evident that revolving electrons produce both electric and magnetic

A. Saghazadeh (*) Molecular Immunology Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

© Springer Nature Switzerland AG 2019 195 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_14 196 A. Saghazadeh fields, so-called electromagnetic field, whereby electricity and magnetism, so-called electromagnetic waves, are conducted. According to these well-acknowledged theories, it is an indisputable inference that all the events that urge electrons to revolve would emit electromagnetic waves and information processing as such event do it so. Processing information within the brain can be measured by a variety of physical parameters particularly frequency, wavelet, and entropy [1]. Wavelet-based methods have provided valuable insight into the temporal dynamicity of brain processes by computing the coherence function which is defined as the estimation of coupling between non-stationary neural signals [2]. Indeed, the coherence concept is only a direct reflection of the resonance phenomenon that is defined as follows; a given system at some frequencies, called preferred frequencies, can oscillate with relative more amplitude by another oscillating system or by external forces [3]. The resonance at the neuronal level represents the association between event-related neuronal processes and the interaction between brain’s regions engaged. The fact that each brain can be characterized by a series of temporal relative wavelet energy dependent on its internal information explains not only the neural coupling between signals in its own brain but also the neural correlations between isolated brains related to subjects who are physically distant [4–7]. This fact can be easily extended as follows; each series of wavelet energy signals the start of resonance phenomenon not only to the series related to other brains but also to those related to all the living things and their emergent events and that signals will make effective interactions if wavelets-sending signals will be synchronized. In conclusion, the resonance phenomenon can occur in the human’s brain as the result of co-frequency of that given brain with another brain/living thing/event. This occurrence can potentially develop the ability to get through the aperture of that given event in that given brain, whether the event has happened in the past or would be happened in the future. Now, knowing when this crosstalk happens would be challenging. To address the issue, it is imperative to have an adequate understanding of quantum tunneling that is a well-known concept not only in physics but also in chemistry. Initially, let us clearly illuminate the issue. Car crashes caused by traffic jams are a tangible example of the brain crosstalks that are arisen from synchronized electromagnetic fields. Reducing vehicle velocity will redound to traffic jamming, upon which cars come very near each other in order to avoid collisions as much as possible. In general, jamming makes drivers to harmonize their cars’ velocity. The harmonization of the car velocity in traffic jamming where the density of cars is increased is equivalent to the synchronization of the wave frequency in situations under which the intensity of electromagnetic fields is increased. In addition, the intensity of the electromagnetic field the brain forms and its interaction with other fields is determined by the amount of processing information. 14 Synchronization Side of the Sixth Sense Story 197

The quantum tunneling takes place during or post-synchronization. In general, this phenomenon occurs where a particle transcends a barrier not by climbing the barrier, but by crossing it using a tunnel. Let it not remain unsaid that the Schrodinger’s cat clearly exemplifies quantum tunneling by considering that a cat is both alive and dead in a closed box where there is a radioactive source so that its emission ensues a flask containing poison is uncorked. It seems that the possibility of quantum tunneling a particle can produce is contingent upon the strength of the coupling of that particle to the environment in the way that the more the particle is coupled to the environment the less the particle can produce quantum tunneling. Accordingly, it has been proposed that there are three principal profiles of the quantum tunneling for a given particle as follow. First, the particle would not be capable of tunneling if it is strongly coupled to the environment. Second, the particle would be capable of incoherently jumping if it is intermediately coupled to the environment. Third, the particle would be capable of coherently oscillating if it is weakly coupled to the environment. In addition, a particle without adherence to the environment is able to tunnel at the quantum level in an energy- independent manner [8]. It is not surprising, then, when two fields are synchronized, the quantum tunneling into one field will take place if that field is weakly coupled to the environment, or at least is not strongly coupled to the environment, and this is the event that all people know it as the sixth sense. Now we know how and when it happens; it is time to tackle the key question: which physical factor(s) can enormously influence the contingency of crosstalks and the strength of synchronization between every two distinct electromagnetic fields? As mentioned above, the contingency of quantum tunneling is extremely circum- scribed by the extent of coupling of the particle to the environment. One possible explanation is that the coupling of the particle to the environment would presumably impede that particle to interact with the two wavefunctions in an effective way. In addition, the extent to which the particle is coupled to the environment would presumably be associated with the amount of energy the particle requires to begin the process of quantum tunneling. Techniques of meditation are a concrete example to support this statement. Meditation, through which individuals try to be detached from the world, increases gamma-band activity [9] and that increased gamma-band activity has also been found following top-down processing [10]. Therefore, it can be inferred that the detachment from the environment may enhance synchronization of the wavefunctions in favor of quantum tunneling and thereby strengthen the “sixth sense.” As it can serve as the mechanism of enhancement of sixth sense in those whose sensory system is intact, it can also serve as the mechanism of compensation in those who have sensory deficiencies. In the latter case, it, in fact, encour- ages creativity in the use of relatively strong senses. This story clearly illuminates Beethoven’s deafness and his great musical creativity or Bramblitt’s blindness and his enormous capability to paint and many other similar examples. 198 A. Saghazadeh

References

1. Rosso OA, Blanco S, Yordanova J, Kolev V, Figliola A, Schürmann M, et al. Wavelet entropy: a new tool for analysis of short duration brain electrical signals. J Neurosci Methods. 2001;105(1):65–75. 2. Lachaux J-P, Lutz A, Rudrauf D, Cosmelli D, Le Van Quyen M, Martinerie J, et al. Estimating the time-course of coherence between single-trial brain signals: an introduction to wavelet coherence. Neurophysiol Clin/Clin Neurophysiol. 2002;32(3):157–74. 3. Hutcheon B, Yarom Y. Resonance, oscillation and the intrinsic frequency preferences of neurons. Trends Neurosci. 2000;23(5):216–22. 4. Standish LJ, Johnson LC, Kozak L, Richards T. Evidence of correlated functional magnetic resonance imaging signals between distant human brains. Altern Ther Health Med. 2003;9(1):128. 5. Standish LJ, Kozak L, Johnson LC, Richards T. Electroencephalographic evidence of correlated event-related signals between the brains of spatially and sensory isolated human subjects. J Altern Complement Med. 2004;10(2):307–14. 6. Richards TL, Kozak L, Johnson LC, Standish LJ. Replicable functional magnetic resonance imaging evidence of correlated brain signals between physically and sensory isolated subjects. J Altern Complement Med. 2005;11(6):955–63. 7. Lachaux J-P, Rodriguez E, Martinerie J, Varela FJ. Measuring phase synchrony in brain signals. Hum Brain Mapp. 1999;8(4):194–208. 8. Gatteschi D, Sessoli R. Quantum tunneling of magnetization and related phenomena in molecular materials. Angew Chem Int Ed. 2003;42(3):268–97. 9. Lutz A, Greischar LL, Rawlings NB, Ricard M, Davidson RJ. Long-term meditators self- induce high-amplitude gamma synchrony during mental practice. Proc Natl Acad Sci U S A. 2004;101(46):16369–73. 10. Kaiser J, Lutzenberger W. Human gamma-band activity: a window to cognitive processing. Neuroreport. 2005;16(3):207–11. Chapter 15 The Sixth Sense: Let Your Mind Go to Sleep

Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei

Abstract Sleep-wake cycles revolve around the regulation of chemo-electrical signaling, especially in thalamocortical regions. The present chapter provides an overview of the transition from wakefulness to sleep and vice versa. Thereby, readers can find periods where the function of the brain allows the mind to draw true dreams of the real world.

Keywords Dream · Memory · Oscillations · Sleep · Sixth sense · Thalamocortical

A. Saghazadeh Molecular Immunology Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran H. Mojtabavi MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran Student’s Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran R. Khaksar MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran N. Rezaei (*) Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran e-mail: [email protected]

Brain Oscillatory Activities During Sleep and Wake

Memory is commonly used as an outcome measure of sleep. It is a phenomenon that takes place in different forms: declarative (explicit) and non-declarative (implicit) [1]. Declarative memory is vital to consciously recall facts and events and is of two types: episodic (events) and semantic (facts). While non-declarative memory allows us to unconsciously recall events and consists of four types: procedural skill, conditioning, non-associative, and priming. Sleep-wake cycles revolve around the regulation of chemo-electrical signaling, especially in thalamocortical regions. Generally, the brain oscillatory activities turn from high-frequency, low amplitude rhythms in the awakening hours to low- frequency, large amplitude rhythms in the sleeping hours (for review see [2]). Like memory, sleep is comprised of two broad phases: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep [3].

The Wake-Sleep Transition

The main electrical activities that occur during the transition from wakefulness to NREM sleep include the prolongation of the hyperpolarization periods and increases of the membrane conductance in thalamocortical areas. In this manner, the cortex will be ignorant of the external world and instead will be immersed into the inside world [4]. More precisely, the wake-sleep transition process induces an increase in theta (4–8 Hz) power and a decrease in upper alpha (10–12 Hz) power [5]. Synchronization of theta rhythms is elicited by encoding new information [6] and memory retrieval [7, 8], while desynchronization of upper alpha is driven by semantic memory [9]. It is proposed that the co-occurrence of theta synchronization and upper alpha desynchronization is an indicator of intentional encoding [10].

Non-rapid Eye Movement Sleep

In turn, the NREM sleep happens in stages 1 to 4, which corresponds to progressively increasing depth of sleep [3].

Spindle Oscillations

The early stage of quiescent sleep, also known as NREM sleep, is represented by spindle oscillations. These oscillations which are in the range of 7–14 Hz occur in the thalamus at the rate of one per 3–10 s and last for 1–3 s. At the molecular level, spindle rhythms are initially produced by low-threshold Ca2+ spikes in the thalamic 15 The Sixth Sense: Let Your Mind Go to Sleep 201 reticular nucleus. Then, inhibitory postsynaptic potentials (IPSPs) are elicited by the neuromodulator gamma-aminobutyric acid (GABA) in thalamocortical neurons. If an IPSP can reduce the inactivation of low-threshold Ca2+ currents so that create a rebound Ca2+ spike, then spindle rhythms will appear in thalamocortical neurons. Therefore, ionic currents of the reticular nucleus are critical for the synaptic production of spindle rhythms in the thalamocortical regions. Of note, absence seizures are a disease of the spindle rhythms where the inhibitory authority of reticular neurons over thalamocortical neurons is decreased and so rebound Ca2+ spikes are triggered more often than expected.

Delta Oscillations

The late stages of quiescent sleep are characterized by delta and slow oscillations. Delta oscillations fall in the range of 1–4 Hz and are of two types according to the site of origin (for review see [4]). Clock-like thalamic delta oscillations are obtained in thalamocortical neurons as the result of the interaction of the hyperpolarization- activated cation (Na+ and K+) current and the transient low-threshold Ca2+ current. Therefore, synaptic network activity is not required for the formation of these waves. However, synchronization is required to coordinate their transmission from single neurons to neural networks. Cortical delta oscillations arise from the cortex and so remain available after thalamectomy.

Slow Oscillations

Slow oscillations occur at frequencies of less than 1 Hz. Both synaptic N-Methyl-D- aspartate (NMDA) receptors and sodium current contribute to the generation of these oscillations. The primary site slow oscillations originate from the neocortex. Synchronization helps these oscillations to propagate over reticular and thalamocortical regions. The slow oscillations are present in a bimodal form in EEG and can be categorized according to intracellular activities: depth-negative EEG waves and depth-positive EEG waves [11]. The former corresponds to the depolarization state of neurons whereas the latter happens in the hyperpolarization state of neurons. Therefore, the depth-positive slow waves turn the EEG state into a more synchronized pattern. Overall, the slow-wave sleep is accompanied by the absence of REMs. While the muscle tone is present.

Ripple Oscillations

The transition from early to late stages of sleep is accompanied by a progressive increase in the synchronization of ripple oscillations [12]. These high-frequency oscillations happen in the human rhinal cortex and hippocampus at the frequency of 80–140 Hz and contribute to memory consolidation [13]. The rate of ripple oscillations is related to the neural state such that increased and decreased ripple 202 A. Saghazadeh et al. bursts correlate with the up-state and down-state. More interesting is the temporal coupling between parahippocampal ripples, sleep spindles, and slow-wave oscillations [14]. Such temporal coupling requires an intact mesiotemporal structure. As a result, this coupling is interrupted in patients with mesiotemporal lobe epilepsy.

The Sleep-Wake Transition

In contrast, the rapid eye movement (REM) sleep is associated with the presence of REMs and the absence of muscle tone [11]. While the waking state is related to episodic contractions and sporadic eye movements. Both REM sleep and the waking state are accompanied by suppression of spindle oscillations, delta rhythms, and slow waves as well as by promotion of high-frequency oscillations [2]. They are characterized by a unimodal membrane potential distribution. Numerous neuromodulators including norepinephrine, serotonin, histamine, and glutamate are involved in the transition from slow-wave sleep to the activated state of sleep and waking [2]. In particular, the neurotransmitter acetylcholine engages nicotinic and muscarinic receptors in order to depolarize thalamocortical neurons. This depolarizing effect has been proposed to result from inhibition of resting potassium current [11].

You Are Awake Because Your Brain’ Synapses Are Online

The study in Drosophila denoted that sleep deprivation dictates the continuous expression of proteins involved in the active synaptic machinery including Bruchpilot (BRP), Discs-large (DLG), and cysteine string protein (CSP) [15]. During sleep, the expression of these proteins is progressively decreased, turning the synaptic machine off-line. Of note is that such synaptic calibration covers the large-scale neural assemblies within the antennal lobes, β lobes of the mushroom bodies, the ellipsoid body of the central complex, and the entire central brain [15]. This indicates that wakefulness requires the engagement of brain regions related to the multisensory (vision, touch, olfaction, and audition) integration, memory, and learning.

Your Eyes Move During Deep Sleep Because You Are Seeing Something

The REMs during REM sleep (mean of 3.7 REMs per minutes) and during wakefulness (mean of 2.6 REMs per minutes) are comparable in terms of number and morphology [16]. While the mean number of REMs is almost zero 15 The Sixth Sense: Let Your Mind Go to Sleep 203 during NREM sleep. Event-related potential (ERP) study revealed that for both REM sleep and wakefulness conditions, each REM is characterized by two positive components: the first one before the onset of a saccade −( 25 to 0 ms) and the second one after the saccade (50–200 ms). Visual stimulation postponed the emergence of the second component (200–600 ms). Evoked potentials in the medial temporal lobe (MTL) regions, e.g., the amygdala, hippocampus, entorhinal cortex, and parahippocampal gyrus, were observed around 150 ms after a REM. Interestingly, these early evoked potentials were not elicited in response to fixation without eye movement. In contrast, relatively late evoked potentials (300–400 ms) were present both in association with REMs (during both REM sleep and wakefulness condition) and with fixation without eye movement. Similarly, both REMs and visual stimulation resulted in a reset of theta oscillations. Of note, REM periods show a steady frequency pattern but changing from individual to individual. However, they appear to occur at the average rate of one every 92 minutes. EEG records reveal REM periods as relatively low-voltage fast activities in the brain [17]. While between REM periods that occur in deeper sleep stages either are present by high-voltage slow activities or by low-voltage sleep spindles. Awakening following cessation of REM periods reinforces the most dream recall compared to awakening following NREM periods [17]. Therefore, REMs have been recognized as an objective indicator of dream activity [17, 18].

The Role of Slow-Wave Oscillations in Cognitive Functions

As above explained, synchronization provides the way for propagation of slow- wave oscillations over large-scale neural networks within the neocortex, thalamus, and hippocampus. Neural activity states can be realized from the current of slow- wave oscillations: a. global neuronal depolarization with excitation represents the “up” state and b. neuronal hyperpolarization with neuronal silence represents the “down” state. In this manner, hippocampal slow-wave oscillations are able to exert a temporal grouping effect over neocortical slow waves, thalamic spindles, and hippocampal ripples [19]. With such broad distribution of neural activities, it is not surprising that sleep, in particular, slow-wave sleep, acts an offline system to capture information and consolidate them into learning and memory.

Slow-Wave Oscillations and Memory

NREM sleep helps improve performance in declarative memory tasks by amplifying the slow-wave oscillations [20]. Supporting this even a short day-time nap (1 hour) including NREM sleep, but not REM sleep or wakefulness, can enhance 204 A. Saghazadeh et al. performance on declarative memory tasks [21]. Of note is the association of slow- wave sleep stages 3 and 4 with this enhancement of memory performance. In turn, slow waves lead to the reactivation of hippocampal place cells. The place cells are a part of the vestibular system processing information about the position and distance. It is however also suggested that these cells play role in memory consolidation [22]. There is a heavy filtering applied to new information to enter into the long-term memory. It is interesting to note that the offline system, i.e., slow-wave sleep, more works than the online system (wakefulness) to add information to the long-term memory. In particular, it is proposed that slow-wave sleep helps the consolidation of declarative memories to aid prospective memory retrieval [23]. The prospective thinking is discussed in Chap. 1.

Slow-Wave Oscillations and Learning

Although no effect of learning was observed on the number and length of slow- wave oscillations, learning led to a dramatic change in wave morphology as follows; an increase in the amplitude of slow-wave oscillations during the depolarizing up- state after (500–800 ms) the negative peak, an increase in the amplitude of slow- wave oscillations during the depolarizing up-state before (450–200 ms) the negative peak, an increase in the frequency of up-state positive peaks in early range, and a decrease in the frequency of positive peaks in delayed range [24]. Additionally, learning led to facilitating the transition from early to late NREM sleep stages, as reflected in an increased spindle activity [24].

Neural Correlates of Slow-Wave Oscillations

In the study [25], the authors mapped neural correlates of the NREM sleep which (on average) takes about 47 minutes. Brain regions whose activation was differentially associated with slow-wave oscillations included the pons, cerebellum, and parahippocampal gyrus. The corresponding regions selectively related to delta rhythms were the medial prefrontal cortex and inferior frontal gyrus. In addition, there were numerous regions, e.g., the pontine tegmentum, midbrain, cerebellum, parahippocampal gyrus, inferior frontal gyrus, middle frontal gyrus, precuneus, and posterior cingulate cortex, wherein activity increased with both delta and slow-wave oscillations. 15 The Sixth Sense: Let Your Mind Go to Sleep 205

Sleep as a Bimodal Phenomenon: The Dreaming Brain and the External Stimuli-Responsive Brain

The Dreaming Brain

You are located in coordinates 31.3183° N, 48.6706° E and read about a painting gallery in coordinates 40.4637° N, 3.7492° W. When sleeping that night, you dream that you are walking in the street nearby that gallery.

Consciousness and Dreaming

As reviewed in [26], the primary consciousness is mediated by effects of perception, emotion, and sensation on the mind, while secondary consciousness is a construct of the self-reflective awareness and is comprised of different domains including language, abstract thinking, volition, and meta-cognition. Dreams demonstrate features more typical for primary consciousness rather than for secondary consciousness. It is, therefore, expected that dreams can happen during the REM sleep, which is thought to be the prototype of primary consciousness, rather than during the awake state, which is considered as the prototype of secondary consciousness, and the NREM sleep, where both primary and secondary types of consciousness begin to wane. The cognitive processes that take part in the dreaming mainly include memory activation, organization, and conscious interpretations. Lucid dreaming is defined as “the experience of achieving conscious awareness of dreaming while still asleep” [27]. Lucid dreams appear to rather stem from the conscious mind whereas non-lucid dreams from the subconscious mind. Therefore, lucid dreaming, like the mind consciousness, is predominantly produced by the neocortical network comprising bilateral precuneus, bilateral inferior and superior parietal lobules, bilateral basal occipitotemporal cortex, left frontopolar cortex and right frontopolar/ dorsolateral prefrontal cortex, right cuneus, left frontal eye field, and bilateral lin- gual gyrus [28].

REM Sleep

The REM sleep consists of tonic and phasic components. The tonic component is represented by muscle atonia, hippocampus-generating theta oscillations, high arousal threshold, and cortical desynchronization [29]. The phasic component is characterized by REMs, involuntary muscle twitches, cardiorespiratory variability, and cortical synchronization of ponto-geniculo-occipital spikes [29]. Dreams are more likely to occur during the phasic than during tonic REM sleep. This might reflect the higher immersion of the brain during the phasic REM sleep into the 206 A. Saghazadeh et al. internal world. Whereas, the brain during the tonic REM sleep is more likely to be influenced by the external stimuli, for example, auditory stimuli [30].

Sleep Oscillations and Sensory Stimuli

I Sleep But I Fear If You Speak

This heading attempts to address how the brain innervates the following experience: if one calls you in this way “Wolf! Wolf! Wake up!” when you are asleep, then you will be wake up and say with horror “where is the wolf?”. EEG allowed scientists to record auditory-evoked responses (AERs) in the wakeful state and in both REM and NREM sleep [31]. Accordingly, an AER is comprised of three positive waves (recording at 50, 175, and 800 ms) and two negative waves (recording at 100 and 325 ms).

REM Sleep

High-Frequency Oscillations and Auditory Stimuli

Magnetoencephalography (MEG) records indicated the emergence of thalamocortical 40-Hz oscillations during REM sleep and wakefulness, but not during delta sleep [32]. The importance of these oscillations is that they are responsive to the sensory stimuli. More precisely, the study [32] found that a reset of 40-Hz oscillations occurs in response to the auditory stimuli. This reset was observed only under awake state, but not under REM sleep and delta sleep conditions [32]. However, according to the data from event-related brain potentials (ERPs), the tonic REM sleep seems more vulnerable to capture auditory stimuli compared with the phasic REM sleep, as reflected in increased amplitude of P3 and P210 waves [30]. fMRI records revealed that the bilateral activation of auditory cortices by acoustic stimulation was more pronounced for the wakeful state than for the tonic REM sleep and for the tonic REM sleep rather than for the phasic REM sleep [33]. In fact, the auditory cortex was nearly not responsive to auditory stimuli in the phasic REM sleep. Even, signal amplitude in thalamus declined with increasing number of REMs during the phasic REM sleep. At the functional analysis level, there were different synchronization patterns related to the wakefulness (between thalamic and auditory cortical areas), tonic REM sleep (between visual cortex and cuneus), and phasic REM sleep (between cortical and thalamic areas). Finally, the phasic versus tonic REM sleep was associated with increased inter- regional activity within thalamocortical areas including the putamen, brainstem, 15 The Sixth Sense: Let Your Mind Go to Sleep 207 occipital lobe, superior and middle temporal gyrus, amygdala, insula, anterior and posterior cingulate gyrus, parahippocampal gyrus, and the middle and inferior frontal gyrus.

NREM Sleep

Slow-Wave Oscillations Hear the Surrounding Sound

Studies show that the brain during NREM sleep is able to not only can detect auditory stimuli but also can discriminate meaningful versus meaningless stimuli [34]. Overall, auditory stimulation either meaningful (the subject’s name) or meaningless (beep) during both wakefulness and NREM sleep evoked the same pattern of bilateral activation of the auditory cortices including superior temporal gyrus (STG) and thalamus [34]. However, it is well expected that this evoked activation appeared to be modified by the type of auditory stimuli and sleep-wake states [34]. The meaningful stimulus (the subject’s name) was correlated with more activation of the auditory regions including the middle temporal gyrus and bilateral orbitofrontal cortex [34]. In addition, the activation of the auditory cortex lying in the left parietal cortex, bilateral prefrontal cortices, thalamus, cingulate gyrus, and in the periamygdalar regions in response to auditory stimulation was more pronounced in the wakeful state than in the NREM sleep [34]. Finally, when both parameters, i.e., the type of auditory stimulation and the brain state, were considered in the interaction analysis, brain regions that were more activated by the subject’s name during sleep than by beep during the wakeful state included the left amygdala and left prefrontal cortex [34]. The study by Ngo et al. 2013 [35] demonstrated that the introduction of auditory stimuli in phase with the slow-wave oscillations during NREM sleep results in the amplification of slow-wave trains and in the improvement of memory consolidation. Whereas, out-of-phase auditory stimulation had an interrupting impact on the ongoing slow-wave oscillations. This interruption not only directly disturbs the sleep cycle but might influence the autonomic nervous system and the immune system in unwanted ways. Such widespread effects of noise on circadian rhythms are frequently seen among critically ill patients [36].

Slow-Wave Oscillations Smell the Surrounding Odors

Odors are important signaling molecules known to play role in memory abilities especially autobiographical and spatiotemporal memory. Of particular importance is that study [37] shows that re-exposure to learned odor during slow-wave sleep can improve hippocampus-dependent memory. Such improvement was not found when re-exposure was introduced during REM sleep or wakefulness state. 208 A. Saghazadeh et al.

Conclusions

The Chapter first provided a rapid overview of different oscillatory activities present in the brain according to the sleep stage. In the meantime, it addressed how the brain makes necessary changes in the chemo-electrical activity in order to facilitate the wake-sleep transition and the sleep-wake transition. Finally, sleep is discussed as a bimodal phenomenon through which the brain can turn into dreaming (as being immersed in the internal world) as well as the brain can detect sensory stimuli (as being responsive to the external world). In this manner, the sleepy brain is not an offline machine but actually, it is able to appear on multiple parallel lines.

References

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Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei

Abstract True dreams are a vivid reflection of pseudo-telepathy. The discussion around pseudo-telepathy goes back to more than 60 years ago when the question whether “persons acting as ‘agents’ could transfer their thoughts to the minds of sleeping ‘subjects’ and influence their dreams” was posted. The previous chapter provided evidence supporting the neuroscientific aspect of such a phenomenon. In the present opinion, entanglement is explained as its physical basis.

Keywords Dream · Entanglement · Nonlocal · Pseudo-telepathy · Quantum · Radio-telepathy · Sixth sense · Telepathy

Telepathy

The term telepathy or thought transference that was first put forward by Frederic W. H. Myers in 1882 refers to information transfer between people who are not involved in any physical interaction with each other. Of course, there should be a form of communication that allows the transmission of information from one to another.

Radio-Telepathy

Computations of Alice-Bob-Eve wireless channel corroborate that the current map of communication is location-specific and reciprocal [1]. It means that the map of communication does not depend upon which one of Alice or Bob is transmitter or receiver. This map is also time-varying. It implies that the adversary, Eve, cannot eavesdrop on what is communicated between Alice and Bob from more than half a wavelength (λ).

Pseudo-Telepathy

It is a relatively fresh term proposed by Brassard in 2005 [2]. Pseudo-telepathy is applicable to conditions where the product of telepathy is observed between people without any communication with each other and therefore without transmission of information. Let’s refer to the original example provided by Brassard [2]. Consider the animal-guessing game, two players Alice and Bob, and two investigators Xavier and Yolande. The game is played as follows; “first, Xavier and Yolande secretly decide on two lists of animals, such as (Xavier: 1. Lion, 2. Tiger, 3. Hyena, 4. Crocodile, 5. Platypus and Yolande: 1. Giraffe, 2. Tiger, 3. Elephant, 4. Alligator, 5. Platypus). Then, Xavier takes Alice far away from Bob and Yolande. At predetermined times, Xavier and Yolande name animals from their lists to Alice and Bob. For example, Xavier and Yolande simultaneously say “lion” and “giraffe,” respectively. Without consulting each other, Alice and Bob must immediately decide whether or not they were presented with the same animal; in this case, they should both answer “no!”. If Alice and Bob succeed systematically in a sufficiently long sequence of trials, Xavier and Yolande will conclude that Alice and Bob are able to communicate somehow. But if communication is clas- sically impossible because Alice and Bob are sufficiently far apart that a signal from Alice going at the speed of light would not reach Bob in time to influence his answer (and vice versa from Bob to Alice), then Xavier and Yolande would be forced into believing that Alice and Bob are able to communicate in a way unknown to (classical) “physics.” 16 Dreams Tell the Brain True Stories 213

Dreams and Telepathy

It is a vivid application of pseudo-telepathy. The discussion around the issue goes back to more than 60 years ago [3, 4]. As declared in the book entitled Dream Telepathy [5], it is centered on whether “persons acting as ‘agents’ could transfer their thoughts to the minds of sleeping ‘subjects’ and influence their dreams.” In the previous Chapter, we provided evidence supporting the neuroscientific aspect of such a phenomenon. Here, entanglement is explained as its physical basis.

Entanglement: From Microscopic to Macroscopic Behavior

Two loved ones are far from each other. Two days after leaving the home, the man who is far from home has been sick. Simultaneously, the woman who is in the home begins to worry about his husband. The principle of uncertainty was first proposed by Werner Heisenberg in 1927 [6]. In quantum mechanics, it is applicable to complementary variables (also known as conjugate quantities), for example, position and momentum. According to the principle of uncertainty, the more precision with which the position of a particle is specified, the less precision with which the momentum of that particle can be estimated. Other pairs of complementary variables include time and energy, angular position and angular momentum, and entanglement and coherence. Presumably, the story of entanglement started in 1935 when Einstein, Podolsky, and Rosen proposed the Einstein, Podolsky, and Rosen (EPR) paradox [7]. In the ERP paper, the authors first defined some concepts as follows: complete, “every element of the physical reality must have a counterpart in the physical theory”; reality, “if without in any way disturbing a system, we can predict with certainty (i.e. with probability equal to unity) the value of a physical quantity, then there exists an element of physical reality corresponding to this physical quantity”; and state, “which is supposed to be completely characterized by the wave function, which is a function of the variables chosen to describe the particle’s behavior.” Accordingly, the authors reached this conclusion that “when the momentum of a particle is known, its coordinate has no physical reality.” To deal with this, they had to put two possible hypotheses: 1. the quantum-mechanical description of reality given by the wave function is not complete or 2. when the operators corresponding to two physical quantities do not commute, the two quantities cannot have simultaneous reality. Through calculations on “two systems, I and II, which we permit to interact from the time t = 0 to t = T, after which time we suppose that there is no longer any interaction between the two parts,” the first one was proved. The “spooky” feature was suggested to account for the “existence of global states of the composite system which cannot be written as a product of the states of individual subsystems.” Schrödinger wrote such global states as the product of “entanglement” between the individual states [8]. 214 A. Saghazadeh et al.

In the following, Bell’s inequalities including “(i) measurement results are determined by properties the particles carry prior to, and independent of, the measurement (‘realism’), (ii) results obtained at one location are independent of any actions performed at space-like separation (‘locality’) (iii) the setting of local apparatus are independent of the hidden variables which determine the local results (‘free will’)” emerged in 1964 [9]. Any violation of Bell’s inequalities (realism, locality, or free will) can lead to quantum entanglement. Quantum entanglement is applicable to quantum systems where “the simultaneous emission of two particles with opposite spin from an atom produces a condition such that altering the spin of one instantaneously reverses the spin of the other no matter what the distance” [10]. While macro-entanglement is applicable to “larger aggregates of space sufficient to contain living systems,” for example, the human brain [11]. Taken together, entanglement is now regarded as a means of “nonlocal correlations” between spatially distant events and individuals [12]. At the neuronal level, large-scale networks are essential to the functioning brain [13]. Such networks are built on the basis of reduced coherent states and therefore of entangled spiking neurons [14]. The human brain is, however, believed to be comprised of a quantum system as well. One of the first experiments which asserted the existence of entanglement between spatially distant subjects was performed by Grinberg-Zylberbaum in 1994 [15]. In this experiment, seven pairs of participants meditated together for 20 minutes. After meditation, participants were assigned to one of two chambers: the simulation chamber and the transference chamber, which were distant 14.5 m each other. The 100 flashes were delivered to the participant in the simulation chamber, while, no flashes were applied to the other participant in the transference chamber. EEG records were gathered under two conditions: without prior knowing each other and with prior knowing each other. The authors found that if the participants knew each other, then the participant in the transference chamber (without stimulus) generated evoked potentials similar to those observed in the participant in the simulation chamber (flash stimulation), the so-called transfer potential. Other EEG studies providing evidence of entanglement between two spatially distant subjects can be found here [16]. In this manner, entanglement is central to dreams which denote nonlocal correlations of neuronal fields to reveal a hidden meaning.

How Entanglement Helps the Brain to Reinforce Dreaming?

From the above it is understood that entanglement leads to the exchange of quantum information between distant particles or fields. While the principle of superposition points to the existence of a particle in more than one state and so causes the exchange of information between different locations of a given particle. For example, if a particle simultaneously exists in two states, then the superposition between these two states causes a two-state system, which is also known as a quantum bit or qubit [17]. If such two-state systems are entangled, then the quantum gates will be made. 16 Dreams Tell the Brain True Stories 215

These gates can fulfill nonclassical logical operations. Interestingly, they are able to process in parallel that would facilitate the addressing of large-scale qubit arrays in a relatively faster speed [17]. Let us suppose two interacting qubits control and target, where the control qubit does not undergo any changes but its state will cause the state of the target qubit to become determined as follows: 1. “If the control is 0, nothing happens to the target, 2. if the control is 1, the target undergoes a well-defined transformation, and 3. if the control is in some coherent superposition of 0 and 1, the output of the gate is entangled.” If 0 is considered as consciousness (wakefulness/external reality), then 1 will become determined as nonconsciousness (sleep/internal reality) and their coherent superposition as a state between consciousness (wakefulness/external reality) and nonconsciousness (sleep/internal reality). The target is active cognitive functioning which turns into passive cognitive functioning. The entangled state benefits from both active and passive cognitive functioning (internal and external reality) and is accompanied by nonclassical logics, for example, dreams. Additionally, if 0 is considered as conscious thought, then 1 will become determined as unconscious thought and their coherent superposition as a state between conscious and unconscious thought. In Chap. 1, it has been explained how consciousness can be engaged in task different from the target. This state can be considered as superposition between conscious and unconscious thought. Under above-entangled mind states, the brain can achieve more information and build excess nonlocal correlations, whereby more true stories will be engendered.

References

1. Mathur S, Trappe W, Mandayam N, Ye C, Reznik A, editors. Radio-telepathy: extracting a secret key from an unauthenticated wireless channel. In: Proceedings of the 14th ACM international conference on mobile computing and networking. ACM; 2008. 2. Brassard G, Broadbent A, Tapp A. Quantum pseudo-telepathy. Found Phys. 2005;35(11): 1877–907. 3. Soal SG, Bateman F. Modern experiments in telepathy. New Haven, CT, US: Yale University Press; 1954. 4. Freud S. The standard edition of the complete psychological works of Sigmund Freud (J. Strachey, Ed.). Oxford, England: Macmillan; 1964. 5. Ullman M, Krippner S, Vaughan A. Dream telepathy: experiments in nocturnal ESP. Jefferson: McFarland & Co; 1989. 6. Heisenberg W. Über den anschaulichen Inhalt der quantentheoretischen Kinematik und Mechanik. Original Scientific Papers Wissenschaftliche Originalarbeiten. Berlin/Heidelberg: Springer; 1985. p. 478–504. 7. Einstein A, Podolsky B, Rosen N. Can quantum-mechanical description of physical reality be considered complete? Phys Rev. 1935;47(10):777. 8. Schrödinger E, editor. Discussion of probability relations between separated systems. Cambridge: Cambridge University Press; 1935. 216 A. Saghazadeh et al.

9. Bell JS. Einstein-Podolsky-Rosen experiments. In: Quantum mechanics, high energy physics and accelerators: selected papers of John S Bell (With Commentary); 1995. p. 768–77. 10. Bohr N. Quantum physics and philosophy: causality and complementarity. Firenze: La Nuova Italia Editrice; 1958. 11. Persinger MA, Lavallee CF. Theoretical and experimental evidence of macroscopic entanglement between human brain activity and photon emissions: implications for quantum consciousness and future applications. J Conscious Explor Res. 2010;1(7):785. 12. Horodecki R, Horodecki P, Horodecki M, Horodecki K. Quantum entanglement. Rev Mod Phys. 2009;81(2):865. 13. Eliasmith C, Stewart TC, Choo X, Bekolay T, DeWolf T, Tang Y, et al. A large-scale model of the functioning brain. Science. 2012;338(6111):1202–5. 14. Hameroff S, Penrose R. Orchestrated objective reduction of quantum coherence in brain microtubules: the “Orch OR” model for consciousness. Math Comput Simul. 1996;40: 453–80. 15. Grinberg-Zylberbaum J, Delaflor M, Attie L, Goswami A. The Einstein-Podolsky-Rosen paradox in the brain: the transferred potential. Phys Essays. 1994;7(4):422–8. 16. Wackermann J, Seiter C, Keibel H, Walach H. Correlations between brain electrical activities of two spatially separated human subjects. Neurosci Lett. 2003;336(1):60–4. 17. Haroche S, Raimond J-M. Quantum computing: dream or nightmare? Phys Today. 1996; 49(8):51–4. Chapter 17 Follow Aura and Find the Sixth Sense

Amene Saghazadeh and Nima Rezaei

Abstract How to sense aura is an interesting question science needs to answer. There is limited scientific knowledge about variables formulating this question; aura and the sixth sense. Auras precede different clinical states such as migraines, seizures, and the sixth sense, also known as interoception, which is defined as the subjective sense of internal physiological states of the entire body. At this moment, the best possible way that seems to satisfy this old insatiable curiosity is to ponder over the neuroanatomy of aura and the sixth sense. The visual aura has been associated with cortical spreading depression within the visual cortex. Migraines with aura cause a decrease in the functional connectivity between the salience network (SN) and central executive network (CEN). Almost half of the patients with temporal lobe epilepsy experience aura prior to the development of seizure. This type of epilepsy has been demonstrated to decrease the functional connectivity between the default mode network (DMN) and SN. Altogether, aura might influence the whole

© Springer Nature Switzerland AG 2019 217 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_17 218 A. Saghazadeh and N. Rezaei way of functional connectivity within the brain. On the other side, interoceptive tasks have been shown to involve the somatomotor, cingulate cortices, and particularly insula. The sixth sense seems to require the intact functional connectivity within and between all three major brain networks (DMN, SN, and CEN). Because that hyperconnectivity of the SN has been observed among low-resilience individuals and its hypoconnectivity has been observed among patients with depressive disorder and schizophrenia. All of these disorders have been associated with lower performance in interoceptive tasks. In summary, aura and the sixth sense face each other within the brain. However, none of them can be seen when the brain is in the stable state. They seem to be contralateral asymmetric states of the brain so that they reach each other while attempting to get the brain into the stable state.

Keywords Aura · Default mode network · Epilepsy · Migraine · Schizophrenia · Sixth sense

Introduction

Migraines and probable migraines collectively afflict approximately 16% of the US population. The manifestation of aura in migraines is important to the extent that migraine headaches are broadly categorized into two, migraine with aura and migraine without aura. Auras, either visual or sensory, are commonly reported by migraine patients [1]. Visual auras which are the most common migraine-associated auras with the prevalence of more than 30% among migraine subjects are explained as a “serrated arc of scintillating, shining, crenulated shapes, beginning adjacent to central vision and expanding peripherally over 5–20 min, within one visual field, usually followed by headache” [2]. Epilepsy is a disease of the brain which can be characterized by at least one of the following conditions: “(1) at least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome” [3]. Migraines with aura have been associated with an eight-fold increased risk of epilepsy whereas the study showed no correlation between migraines without aura and the risk of subsequent epilepsy [4]. This proposes a hypothesis that aura, but not the migraine, is part of the whole mechanism of epileptogenesis. The hypothesis is supported by the fact that auras form a distinct class in semilogical seizure classification [5]. We have a limited scientific knowledge of auras and that is that they may precede different clinical states such as migraines [1] and seizures [6, 7] and therefore are of clinical importance by helping patients and their physicians to predict, being prepared for, or probably to prevent disease attacks. How auras alter brain activity is of fundamental questions about the nature of aura. To this end, we should know the state of the brain before, during, and after aura. 17 Follow Aura and Find the Sixth Sense 219

Brain at Different States

Brain During Aura

Functional magnetic resonance imaging (fMRI) studies proposed cortical spreading depression (CSD) as a possible mechanism by which visual auras are developed. Visual aura-associated CSD could be characterized by an initial increase in the blood oxygenation level-dependent (BOLD) signal within the extrastriate cortex, its progression within the occipital cortex, followed by its decrease. These electrical events correspond to physiological events vasodilation and vasoconstriction, respectively, which occur in the human visual cortex during visual aura prior to the development of a migraine headache [8].

Brain Before Aura (Here We Would Mean the Brain State at Rest)

Positron-emission tomography (PET) and fMRI studies recognized a network of brain regions whose activity decreased during goal-directed behaviors and suggested that as a baseline state of the brain [9]. This network, the so-called default mode network (DMN), is a part of resting state networks (RSNs) and includes mainly the ventromedial prefrontal cortex (VMPFC) and the posterior cingulate cortex (PCC). RSNs refer to brain regions which are spontaneously activated by the brain in the absence of any task or stimulus or under anesthesia. This spontaneous, ongoing activity of the brain seems to significantly affect the evoked brain activity and its large temporal variability [10], reflecting that the present resting-state activity is essential for future evoked brain responses. Resting-state activity is mathemat- ically characterized by two parameters: temporal variability and signal synchronization. The strong coupling between these parameters was observed while the human brain was in the conscious state in subjects without any disorders of consciousness, but not under anesthesia conditions or in patients with disorders of consciousness [11]. Research recently revealed that the interaction between spontaneous and evoked activity is not linearly additive, but is non-additive and is under the sway of long-range temporal variability [12].

Brain at Work

Attention is presumably the most interesting as well as the most intricate brain function. Attention is not just directing attention to a target event, but it is a series of mental processes that need to be well-connected such that the attention system will work as effective as possible. As reviewed in [13], the main mental processes of attention are (a) orienting to sensory inputs, (b) detecting signals for focal (conscious) processing, and (c) maintenance of a vigilant or alert state. 220 A. Saghazadeh and N. Rezaei

Fig. 17.1 How the brain networks would be influenced by different conditions so that patients may develop aura. Red lines convey inhibitory functions, and green lines convey stimulatory functions. CEN central executive network, SN salience network, RSN resting-state network, DMN default mode network

There are two main attention systems, the bilateral dorsal system and the right- lateralized ventral system (Fig. 17.1). Voluntary or top-down orienting of attention is innervated by the former one which includes the intraparietal sulcus (IPS) and the junction of the precentral and superior frontal sulcus. Whereas orienting of attention to salient stimuli is underpinned by the latter one which includes the right temporal- parietal junction (TPJ) and the right ventral frontal cortex. It is very interesting that the activity of these systems is not conditional upon the presence of external stimuli, but they are spontaneously active even in the absence of external stimuli [14]. As the DMN is deactivated during cognitively demanding tasks, the central executive network (CEN) will be activated. The CEN mainly engages the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC). The salience network (SN) which includes the dorsal anterior cingulate and orbital frontoinsular cortices is thought to be responsible for switching the activity status between the DMN and CEN networks [15]. Nicotine is apparently able to mimic the working of the salience network, as it could deactivate the DMN and thereby improving visuospatial attention [16]. There seems to be no link between Nicotine and aura. Studies found no association between migraines with aura and smoking status [17].

Brain After Aura

Brain During a Migraine

Above it was explained that how CSD underlies a migraine visual aura. The question is that how CSD and thus aura may contribute to the development of migraine headaches. Migraine model has shown that CSD could trigger the activity of 17 Follow Aura and Find the Sixth Sense 221 trigeminovascular afferents. Since trigeminal nerves take part in migrainogenesis, the aura can provide the way for migraine headaches through CSD [18]. Imaging studies provided evidence of increased intrinsic DMN and right central executive network connectivity to the insular cortex in patients with migraines without aura [19]. To the best of our knowledge, DMN activity has not been well-investigated in patients with migraines with aura. However, there is a report revealing the decreased connectivity between the insular cortex and occipital areas in patients with migraines with aura [20], standing in marked contrast to that observed in patients with migraines without aura [19].

Brain During Epilepsy

Epileptic seizures, apart from their type, are associated with high-frequency discharges from neurons. Study of 290 cases with partial and complex seizures reported the occurrence of aura before epilepsy in more than half of patients (185/290) [21]. Psychic and autonomic auras were the most common type of auras among epilepsy patients who experience an aura before the seizure. As recorded by the electroencephalogram (EEG), these types of auras (i.e., auras with psychic and autonomic symptoms) were commonly correlated with right-sided temporal lobe lesions. EEG- correlated fMRI study [22] revealed that resting state activity is decreased in the considerable proportion of patients with temporal lobe epilepsy (TLE), but not in patients with extra TLE. The authors of the study also found increased activity in the ipsilateral hippocampus in TLE patients. These findings indicate that TLE and related interictal discharges are very likely to interfere with the working of the DMN.

Brain and Hallucinations

Patients with schizophrenia have been shown to suffer from both spatial and temporal disturbance of the DMN [23]. When compared to neurotypical controls, schizophrenia patients have been shown to have lower gray matter volume and surface area in the total insular region and particularly in the left anterior subregion [24]. More interestingly there were significant associations between the insular gray matter volume/surface area and the psychotic symptoms, e.g., hallucinations, such that the less the insular volume and cortical surface is, the more the psychotic symptoms appear [25]. All these clearly explain why schizophrenia patients have an alteration in the SN function connectivity during information processing [26].

Brain and Autoscopic Phenomena

It is a type of hallucination in which one “sees an image of him/herself in external space, viewed from within his/her own physical body.” Autoscopic phenomena including out-of-body experience, autoscopic hallucination, and heautoscopy can be caused by various factors, such as neurological problems (epilepsy), 222 A. Saghazadeh and N. Rezaei psychiatry (schizophrenia) and personality disorders [27]. There seems to be a divergence between autoscopic phenomena from the neurofunctional view. However, in general, studies have indicated that the temporal-parietal junction might play an integral part in innervating the autoscopic phenomena [28]. As mentioned above the temporal-parietal junction is engaged while orienting attention to salient stimuli. Thus, it is well-expected that damage to this region would pose problems in attentional processing [29].

Brain, the Sixth Sense, and Aura

The five traditionally recognized senses including vision, hearing, touch, smell, and taste collectively receive information from outside the body. The “sixth sense,” also known as “interoception” or as the “common sensation,” is speculated to be the subjective sense of internal physiological states of the entire body [30]. Neuroimaging studies have indicated that interoceptive tasks mainly involve the insula, somatomotor, and cingulate cortices. As well the study corroborated a considerable correlation between the amount of activity within the right anterior insular/opercular cortex and the accuracy of performance. The more the right anterior insular/opercular cortex is active, the more one will display the true sense of his body [31]. As mentioned above, the insular cortex is part of the salience network. A recent study reported that compared to groups of high and normal resilience, individuals with low resilience had decreased interoceptive awareness [32]. However, they showed greater activity in insular and thalamic regions. This might be due to increased attention to aversive stimuli. In fact, low-resilience individuals are less able to direct their attention to stimuli that what should be paid and they are easily distracted by the stressors. While in these individuals the interoception- related brain regions are intact and can be activated even more than high- and normal-resilience groups, the way of activity seems to be wrong. Taken together it would be possible to propose that the crux of the problem in low-resilience individuals may be arisen from the aberrant activity during resting states or more exactly from the impaired DMN functional connectivity. A meta-analysis study has recently revealed that the functional connectivity in all three main brain networks, i.e., the DMN, SN, and CEN, is altered in patients with the major depressive disorder (MDD) [33]. The study showed that MDD patients had reduced functional connectivity (a) over the frontoparietal network, (b) between frontoparietal systems and parietal regions, and (c) between the salience network and midline cortical regions. However, they demonstrated an increase in the DMN functional connectivity. Altogether these strong lines of evidence hold the notion that patients with depression also suffer from impairments in interoceptive awareness and attentional processing. 17 Follow Aura and Find the Sixth Sense 223

Conclusions

Evidence suggests that individuals whose brain can switch more between the DMN and CEN can better perceive their own body. This has been observed in patients with migraines without aura, whereas patients with migraines with aura showed decreased connectivity between the SN and CEN (Fig. 17.1). This may arise from the reduced connectivity between the DMN and the SN that needs to be investigated. Also, patients with TLE who often develop aura showed decreased DMN activity. Altogether these lines of evidence propose that the connectivity properties of the DMN may be the main determinant of people’s sense of their internal body. The more these properties evolve, the more the brain would be able to delineate true pictures of both the internal and external environments, helping to strengthen the sixth sense, whereas the less they do function properly, the more the brain would be able to draw false pictures of both the internal and external environments, i.e., auras. However, it should be mentioned that the increased connectivity just within the DMN does not achieve the purpose, but it requires the connectivity with salience and central networks. Without this requirement satisfied, the brain will develop much negativity such as aura, hallucination, and depression. As abnormality is used to define normality, here we followed aura to find the sixth sense.

References

1. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American migraine prevalence and prevention (AMPP) study. Headache: J Head Face Pain. 2013;53(8):1278–99. 2. Buzzi MG, Moskowitz MA. The pathophysiology of migraine: year 2005. J Headache Pain. 2005;6(3):105–11. 3. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475–82. 4. Ludvigsson P, Hesdorffer D, Olafsson E, Kjartansson O, Hauser WA. Migraine with aura is a risk factor for unprovoked seizures in children. Ann Neurol. 2006;59(1):210–3. 5. Lüders H, Acharya J, Baumgartner C, Benbadis S, Bleasel A, Burgess R, et al. Semiological seizure classification*. Epilepsia. 1998;39(9):1006–13. 6. Acharya V, Acharya J, Lüders H. Olfactory epileptic auras. Neurology. 1998;51(1):56–61. 7. Chen C, Shih YH, Yen DJ, Lirng JF, Guo YC, Yu HY, et al. Olfactory auras in patients with temporal lobe epilepsy. Epilepsia. 2003;44(2):257–60. 8. Hadjikhani N, del Rio MS, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci. 2001;98(8):4687–92. 9. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A. 2001;98(2):676–82. 10. Arieli A, Sterkin A, Grinvald A, Aertsen AD. Dynamics of ongoing activity: explanation of the large variability in evoked cortical responses. Science. 1996;273(5283):1868–71. 11. Huang Z, Zhang J, Wu J, Qin P, Wu X, Wang Z, et al. Decoupled temporal variability and signal synchronization of spontaneous brain activity in loss of consciousness: an fMRI study in anesthesia. NeuroImage. 2016;124:693–703. 224 A. Saghazadeh and N. Rezaei

12. Huang Z, Zhang J, Longtin A, Dumont G, Duncan NW, Pokorny J, Qin P, Dai R, Ferri F, Weng X, Northoff G. Is there a nonadditive interaction between spontaneous and evoked activity? Phase-dependence and its relation to the temporal structure of scale-free brain activity. Cereb Cortex. 2017 Feb 1; 27(2):1037–59. 13. Posner MI, Petersen SE. The attention system of the human brain: DTIC Document. 1989. 14. Fox MD, Corbetta M, Snyder AZ, Vincent JL, Raichle ME. Spontaneous neuronal activity distinguishes human dorsal and ventral attention systems. Proc Natl Acad Sci. 2006;103(26):10046–51. 15. Sridharan D, Levitin DJ, Menon V. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci U S A. 2008;105(34):12569–74. 16. Hahn B, Ross TJ, Yang Y, Kim I, Huestis MA, Stein EA. Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network. J Neurosci. 2007;27(13):3477–89. 17. Ulrich V, Olesen J, Gervil M, Russell MB. Possible risk factors and precipitants for migraine with aura in discordant twin-pairs: a population-based study. Cephalalgia. 2000;20(9):821–5. 18. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. 2002;8(2):136–42. 19. Xue T, Yuan K, Zhao L, Yu D, Zhao L, Dong T, et al. Intrinsic brain network abnormalities in migraines without aura revealed in resting-state fMRI. PLoS One. 2012;7(12):e52927. 20. Niddam DM, Lai K-L, Fuh J-L, Chuang C-YN, Chen W-T, Wang S-J. Reduced functional connectivity between salience and visual networks in migraine with aura. Cephalalgia. 2015;36:53–66. 21. Gupta AK, Jeavons PM, Hughes RC, Covanis A. Aura in temporal lobe epilepsy: clinical and electroencephalographic correlation. J Neurol Neurosurg Psychiatry. 1983;46(12):1079–83. 22. Laufs H, Hamandi K, Salek-Haddadi A, Kleinschmidt AK, Duncan JS, Lemieux L. Temporal lobe interictal epileptic discharges affect cerebral activity in “default mode” brain regions. Hum Brain Mapp. 2007;28(10):1023–32. 23. Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD. Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatr. 2007;164:450. 24. Makris N, Goldstein JM, Kennedy D, Hodge SM, Caviness VS, Faraone SV, et al. Decreased volume of left and total anterior insular lobule in schizophrenia. Schizophr Res. 2006;83(2):155–71. 25. Crespo-Facorro B, Kim J-J, Andreasen NC, O’Leary DS, Bockholt HJ, Magnotta V. Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first- episode patients. Schizophr Res. 2000;46(1):35–43. 26. White TP, Joseph V, Francis ST, Liddle PF. Aberrant salience network (bilateral insula and anterior cingulate cortex) connectivity during information processing in schizophrenia. Schizophr Res. 2010;123(2):105–15. 27. Dening TR, Berrios GE. Autoscopic phenomena. Br J Psychiatry. 1994;165(6):808–17. 28. Blanke O, Mohr C. Out-of-body experience, heautoscopy, and autoscopic hallucination of neurological origin: implications for neurocognitive mechanisms of corporeal awareness and self-consciousness. Brain Res Rev. 2005;50(1):184–99. 29. Robertson LC, Lamb MR, Knight RT. Effects of lesions of temporal-parietal junction on perceptual and attentional processing in humans. J Neurosci. 1988;8(10):3757–69. 30. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3(8):655–66. 31. Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ. Neural systems supporting interoceptive awareness. Nat Neurosci. 2004;7(2):189–95. 32. Haase L, Stewart JL, Youssef B, May AC, Isakovic S, Simmons AN, et al. When the brain does not adequately feel the body: links between low resilience and interoception. Biol Psychol. 2016;113:37–45. 33. Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiat. 2015;72(6):603–11. Chapter 18 An Evolutionary Perspective of the Sixth Sense

Amene Saghazadeh and Nima Rezaei

Abstract Innovative research has recently suggested if our sixth sense does not work well, it does not matter. Sensory substitution technology provides us with a lot of useful information from the real world; thus the sixth sense would be able to work more smoothly and efficiently. Here this matter has been argued.

Keywords Creativity · Evolution · Innovation · Intelligence · Interoception · Sensory Substitution · Sixth sense

Creativity and Innovation

Creativity calls for all our skills as social animals, comprising cognitive capabilities, personality characteristics, and social factors [1]. However, originality and appropri- ateness have been proposed as the two main preconditions of the creative capability in the standard definition as suggested by Runco [2]. The concept of creativity, unlike innovation, is more applicable to individuals rather than organizations or firms. Creativity is, however, defined by both words and concept which somewhat resemble those of innovation. In fact, creativity is just the personalized concept of innovation.

© Springer Nature Switzerland AG 2019 225 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_18 226 A. Saghazadeh and N. Rezaei

Cohen and Levinthal described absorption as “the ability of a firm to recognize the value of new, external information, assimilate it, and apply it to commercial ends” [3]. Absorption and its current meaning seem to be more, if not absolutely, applicable to firms or organizations rather than individuals. The existence of absorption capability was considered to be necessary to have innovative capabilities and to be dependent on prior knowledge. In light of the fact that many individuals are involved in the establishment of firms, it is well expected that the innovation capabilities of the organization will be influenced by the individual’s expertise and capabilities, e.g., knowledge and multiple intelligences.

Intelligence, Creativity, and Innovation

Howard Gardner recognizes intelligence as “the ability to solve problems or to create products that are valued within one or more cultural settings.” While adhering firmly to this principle, he formulated the theory of multiple intelligences [4] reflecting the notion that there are multiple intelligences by which all individuals can learn [5]. Intelligence and its definition imply the importance of intelligence to creativity. The theory of multiple intelligences then poses the question, does each domain of multiple intelligences originate and/or encourage creativity just in that domain-related certain performances, for example, does verbal-linguistic intelligence originate and/or encourage creativity just in writing, reading, and speaking? The answer is no with certainty because authors have found no difference in the IQ scores between creative and control individuals [6]. Additionally, if the answer was yes, how could we justify Beethoven’s deafness and his great musical creativity or Bramblitt’s blindness and his enormous capability to paint and many other similar examples? Let us provide a simple example that can illustrate the importance of intelligence in innovation and/or creativity. Art in health is an innovation in health-care services. It can result in a better quality of life of many people worldwide and this is very noticeable to the people. On the contrary, there are foods enriched with vitamins or any other nutrients. Some enriched foods are not really delicious and thus some people are not keen enough to consume them. The main difference between these two innovations is that the first one, i.e., art in health, has been developed with the active engagement of the most domains of multiple intelligences, whereas the second one, i.e., food enrichment, has been formulated with the primary focus on certain domains of multiple intelligences. Thus it is well-expected that more people will be satisfied with art rather than food enrichment.

The Sixth Sense and Interoception

Receiving information from the external environment engages the five traditionally recognized senses including vision, hearing, touch, smell, and taste. There is also the so-called “sixth sense” that is supposed to be responsible for receiving internal 18 An Evolutionary Perspective of the Sixth Sense 227 signals [7]. This statement on the sixth sense is tantamount to the definition of “interoception” which was introduced as the feeling one has about the internal physiological conditions of the entire body [8]. The sixth sense can be defined as not only the sense one has of her or his own body but also the sense one has of about the entire universe, all the people/events, everywhere, and all the time. Adhering to this definition, interoception can be interpreted as the personalized concept of the sixth sense, or vice versa the sixth sense can be speculated as the generalized concept of interoception.

What Causes and/or Supports Creativity and Interoception?

Studies have demonstrated a higher prevalence of mental illnesses, particularly affective disorders, in creative subjects and their first-degree relatives compared with control counterparts, despite no difference in the average IQ scores [6]. Therefore, it was possible to propose plausible hypotheses about the development of creativity as follows. In view of Amabile’s opinions that creativity is constructed of the three key elements, expertise, motivation, creative-thinking skills [9], a hypothesis is that mental illnesses may generate the necessary motivation for creativity. Another hypothesis attributes creativity to the increased detachment from work in formal environments and to the increased loneliness that both may inspire individuals to imagine more, and imagination is considered a thinking skill that may improve creativity. The question what causes interoception is straightforward, and emotions are seriously considered the chief cause of interoceptive signals [10].

Variability and Creativity: Where Innovation, the Sixth Sense, and Interoception Meet

In summary, the sixth sense requires interoception and both (i.e., the sixth sense and interoception) and innovation call for creativity. More clearly, the human sixth sense of the unseen world, either the unseen arrow of time or the unseen events and persons, requires creativity. Then a question arises; how does natural selection affect these intriguing capabilities over time? In a sentence, all these metacognitive abilities accumulate to create the variability within the human brain. The variability is vital to evolution. It is well-appreciated that the brain, the most variable and fastest-evolving human organ, and its mains features (e.g., intelligence and creativity) play the leading role in this variability. There, however, exist reciprocal effects between the variability and the main brain features and/or functions. Favorably, creativity increases the degree of variability and the variability, in turn improving creative thinking skills, such as artistic creativity [11]. Interestingly satisfactory performance on cognitive flexibility demanding tasks (task switching) has been directly associated with neural variability within task- engaged brain regions. On the contrary, there appeared an inverse correlation 228 A. Saghazadeh and N. Rezaei between neural variability within task-engaged brain regions and performance on cognitive stability demanding tasks (distractor inhibition) [12]. This explains why attention lapses have been associated with high levels of variability [13]. Moreover, aging may lead to a decrease in distributed neural/information processing and to an increase in local neural/information processing [14]. Altogether a reduction in the degree of variability within the brain may accompany aging, and not surprisingly natural selection prefers young brains in favor of old brains. Like aging, anesthesia and loss of consciousness disorders affect the temporal variability. They have shown decoupling between the main two features of wakefulness, i.e., temporal variability and signal synchronization [15]. Altogether these lines of evidence indicate that the types of cognitive tasks and the level of consciousness can be interpreted as the main determinant of the optimal neural variability and its coupling to the signal synchronization, respectively. Consistent with the sixth sense, interoception, and innovation as cognitive flexibility demanding tasks, the degree of variability can be used as an index of creativity.

An Evolutionary Perspective: Sensory Substitution for Having Some Sixth Sense

A kind of mechanical systems was developed to provide sensory services for people whose sense does not work efficiently. Actually, they serve as an unsevered sensory organ and include visual, auditory, and tactile systems. It has been proposed that brain plasticity intriguingly innervates the adaption capacity of the brain to sensory substitution systems [16]. Also, scientists have recently suggested sensory substitutions for having or heightening the sixth sense. The MIT Media Lab’s Fluid Interfaces Group developed a simple sixth sense technology which begins working with the hand gesture [17]. Such artificial systems are wearable computers that act as a brain-machine interface and make it convenient for the brain to be informed on the scope and superiority of environmental information [18]. The sixth sense technology seems to abolish creativity and using creative- thinking skills. We should just point at something we would like to more know about that in every situation. Thus this innovative machine would probably lower the neural variability within the brain, and this is out of favor of natural selection from an evolutionary perspective. There is a small debate about situations where humans have not any sense of the problem at the issue. In such situations, the sixth sense technology offers him some information, and thus it would be possible for the brain to acquire the creative-thinking skills. This is just a remote, however reasonable, possibility. On the contrary, there is a great probability of creativity and using creative skills while humans intend to think and make a decision using their own sixth sense. Therefore, it would be no exaggeration to say the sixth sense is a source of creativity, variability, and thus evolution. What would happen if the humans are addicted to employ the sixth sense technology? Inevitably, a fertile source of evolution, i.e., the human sixth sense, may be annihilated. 18 An Evolutionary Perspective of the Sixth Sense 229

References

1. Amabile TM. The social psychology of creativity: a componential conceptualization. J Pers Soc Psychol. 1983;45(2):357. 2. Runco MA. Creativity research: originality, utility, and integration. Creat Res J. 1988;1:1. 3. Cohen WM, Levinthal DA. Absorptive capacity: a new perspective on learning and innovation. Adm Sci Q. 1990 Mar 1; 35(1):128–52. 4. Gardner H. Frames of mind: the theory of multiple intelligences. New York: Basic books; 2011. 5. Silver HF, Strong RW, Perini MJ. So each may learn: integrating learning styles and multiple intelligences (No. 370.1523 S585s). Virginia, US: Association for Supervision and Curriculum Development. 2000. 6. Andreasen NC. Creativity and mental illness. Am J Psychiatry. 1987;144(10):1288–92. 7. Zagon A. Does the vagus nerve mediate the sixth sense? Trends Neurosci. 2001;24(11):671–3. 8. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3(8):655–66. 9. Amabile TM. How to kill creativity. Boston: Harvard Business School Publishing; 1998. 10. Seth AK. Interoceptive inference, emotion, and the embodied self. Trends Cogn Sci. 2013;17(11):565–73. 11. Zeki S. Artistic creativity and the brain. Science. 2001;293(5527):51–2. 12. Armbruster-Genç DJN, Ueltzhöffer K, Fiebach CJ. Brain signal variability differentially affects cognitive flexibility and cognitive stability. J Neurosci. 2016;36(14):3978–87. 13. Weissman DH, et al. The neural bases of momentary lapses in attention. Nat Neurosci. 2006;9(7):971–8. 14. Wang H, et al. Age-related multiscale changes in brain signal variability in Pretask versus Posttask resting-state EEG. J Cogn Neurosci. 2016;28:971. 15. Huang Z, et al. Decoupled temporal variability and signal synchronization of spontaneous brain activity in loss of consciousness: an fMRI study in anesthesia. NeuroImage. 2016;124:693–703. 16. Bach-y-Rita P, Kercel SW. Sensory substitution and the human–machine interface. Trends Cogn Sci. 2003;7(12):541–6. 17. Mistry P, Maes P. Unveiling the “Sixth Sense”, game-changing wearable tech: TED; 2009. 18. Rao S. Sixth sense technology. IEEE. Chapter 19 The Sixth Sense: Symphony of Spooky Actions

Amene Saghazadeh and Nima Rezaei

Abstract Albert Einstein described spooky actions at a distance as “the acquisition of a definite value of a property by the system in region B by virtue of the measurement carried out in region A.” Thus it would not be astonishing that the spooky feature facilitates spanning space via founding connections between physically distant locations. Such a scenario is similar to the way in which our common sense, also known as the sixth sense, works. The present Opinion comes to state how switching from the conscious thought to the unconscious thought lead to a symphony of spooky actions which allow us to see the real world with different values and views. This symphony is that what signifies the sixth sense, that sense which makes humans unique creatures.

Keywords Electroencephalogram · Entropy · Quantum entanglement · Sixth sense · Spooky actions · Squeezed states · Superposition

Like a rainbow which is a multicolored arch formed by the sunlight, when it is raining, a three-colored arch (orange-red, purple, and blue) appears, but with much more frequency in the sky at the sunset. Since I could see this beautiful

© Springer Nature Switzerland AG 2019 231 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_19 232 A. Saghazadeh and N. Rezaei three-colored arch through the window of my room the first time, I searched much but did not find it astonishing as seen for the first time. The above example clearly implies how the act of observer makes the physical property a reality. To write more explicitly, it is our task to make physical properties a reality [1]. This idea led to emerging the theory of quantum entanglement which is based on the existence of spooky feature of quantum machinery: “this feature implies the existence of global states of the composite system which cannot be written as a product of the states of individual subsystems” [2]. Albert Einstein described spooky actions at a distance as “the acquisition of a definite value of a property by the system in region B by virtue of the measurement carried out in region A” [1]. Thus it would not be astonishing that the spooky feature facilitates spanning space via founding connections between physically distant locations. Let us provide an example of what we mean by the “sixth sense.” We are all well aware of the power of a mother’s love. It is presumably a common situation where a housekeeper mother suddenly feels a nagging anxiety about the health of her child who has to get out of the house and when the child returns to the house mother sees her injured child as a result of the football match. This genuine feeling which can be found any time anywhere is what we simply mean when we talk about the “sixth sense.” But its mechanism of action is still open to question. It is, however, indubi- ous that the work of sixth sense, like other mental states, must pursue quantum mechanics and the rules which are fitted to govern it [3]. Quantum entanglement is an essential prerequisite for transfer of quantum information that takes place via the process of quantum teleportation. This process through which quantum state will be transferred from a particle into another particle [4] takes place over particles which are physically distant to each other at a quantum system. No one can obtain the information content associated with the quantum state to be transferred. Such a scenario is similar to the way in which our common sense, also known as the sixth sense, works. Entanglement is assumed to occur finitely in the real world. Enhancing the amount of entanglement definitely engen- ders increased quantum teleportation and information transfer. This will reasonably result in heightening the sixth sense eventually. Speculating that quantum teleportation is a mechanism accounting for the work of sixth sense, it would be possible to predict how the sixth sense may be heightened by addressing the question that how the quantum entanglement and thereby teleportation are enhanced. Below is to support this statement with respect to evidence in physics and biology. Entropy is regarded as an indicator of the amount of molecular disorder within the system. Von Neumann suggested the von Neumann’ entropy to formulate the entropy within a quantum system. It has been proposed that the probability of quantum teleportation may be improved when there is an interaction with the local environment [5]. A dissipative interaction with the environment may enhance entanglement which in turn improves quantum teleportation. However, it is not difficult to understand that the interaction between the brain’ state and the environment would be often beyond our control and this results in that the information transfer between the individuals’ mental states is often canceled. It would be simply meant that the overwhelmed amount of “metal state-environment” interaction 19 The Sixth Sense: Symphony of Spooky Actions 233 results in the ever-distorted transfer of the initial quantum state. If the amount of this interaction is optimal, entanglement, quantum teleportation, and information transfer may be improved accompanied by the increase of von Neumann entropy [6]. Thus, physics provide evidence that it is exigent for quantum entanglement to have a basal, however low, level of entropy. It can be postulated that there is a border up to which entanglement and information transfer increase, whereas beyond which they decrease. At the neuronal level, irregularities of electroencephalogram (EEG) signals represent the entropy changes within the brain which indicate the alteration in the level of consciousness. The more\less the amount of irregularity of EEG signals increases, the more\less the level of entropy and consciousness the brain has. This approach was developed to monitor the depth of anesthesia in patients [7]. However, it could also help to illuminate that the level of entropy is decreased while decreasing the level of consciousness. In addition, as mentioned above, information transfer requires a basal, however low, level of entropy. Therefore it can be deduced that there must be an optimal level of unconsciousness, corresponding with that entropy border, toward which information processing increases, whereas beyond which information processing begins to decrease. The “squeezed states” are what those continuous variables require to be entangled. To become acquainted with the concept of “squeezed states,” consider the two quadrature components of an electric field created by a monochromatic plane. When fluctuations within the two quadratures are equal, the term “coherent state” is applied to the product quantum state. Under this condition, the quantum noise is distributed randomly. Whereas the term “squeezed state” is applied to any quantum states in which inequality of fluctuations would lead to the deliberately increase distribution of quantum noise in one quadrature than the other [8]. The squeezed coherent states are produced when two operators work in order to reach a minimum of the Heisenberg’ uncertainty. For example, in quantum optics, possible operations include photon subtraction, photon addition, or combinations of addition and subtraction. The coherent superposition of photon subtraction and addition has been suggested as a possible strategy to enhance quantum entanglement within small squeezing regime [6]. However, the sole photon subtraction seems an optimal operation within a large squeezing regime [6]. Meanwhile, if the concept squeezed states is applied to the brain’ field, the conscious and unconscious thought would be in consequence craved to simulate the photon addition and subtraction, correspondingly. Now, it is the time to conceive of a possible strategy aimed at strengthening the capacity of our sixth sense. The coherent superposition of conscious and unconscious thought may improve information transfer between the individual’ brain and any fields created by somebody or events which are near to that given individual in the space-time. Whereas the unconscious thought may be more impressive than the conscious thought in providing the way for information to be transferred between the individual’ brain and the fields created by somebody or any event which are far from that given individual in the space-time. However, as mentioned above, it should be noted that the level of unconsciousness should not be less than the optimal 234 A. Saghazadeh and N. Rezaei level. This strategy seems to provide the way spooky actions at a distance and time work. Switching from the conscious thought to the unconscious thought leads to conduct a symphony of spooky actions which are able to make us see the real world with different values and views. This symphony signifies how the sixth sense makes humans unique creatures.

References

1. Mermin ND. Is the moon there when nobody looks? Reality and the quantum theory. Phys Today. 1985;38(4):38–47. 2. Horodecki R, et al. Quantum entanglement. Rev Mod Phys. 2009;81(2):865. 3. Conte E, et al. Mental states follow quantum mechanics during perception and cognition of ambiguous figures. Open Syst Inf Dyn. 2009;16(01):85–100. 4. Bouwmeester D, et al. Experimental quantum teleportation. Nature. 1997;390(6660):575–9. 5. Badziag P, et al. Local environment can enhance fidelity of quantum teleportation. Phys Rev A. 2000;62(1):012311. 6. Lee S-Y, et al. Enhancing quantum entanglement for continuous variables by a coherent superposition of photon subtraction and addition. Phys Rev A. 2011;84(1):012302. 7. Vakkuri A, et al. Time-frequency balanced spectral entropy as a measure of anesthetic drug effect in central nervous system during sevoflurane, propofol, and thiopental anesthesia. Acta Anaesthesiol Scand. 2004;48(2):145–53. 8. Walls DF. Squeezed states of light. Nature. 1983;306(5939):141–6. Chapter 20 The Sixth Sense Organs: The Immune System

Amene Saghazadeh and Nima Rezaei

Abstract Non-nervous systems particularly endocrine and immune systems interact with the nervous system. As a result, nervous system-related features favorably sensory perception can be found in as well as out of the nervous tissues.

Keywords Cytokines · Hypothalamic–pituitary–adrenal axis · Immune system · Immunity · Inflammation · Sixth sense · Vagus nerve

Introduction

The origin of neuroimmunoendocrinology goes back to the late 1900s when evidence began to accumulate that the immune function would be influenced by the neuroendocrine system. An initial explanation for neuro-immune correlates was that there are nerve endings that reside within the immune system-related tissues. Stimulation of these endings by peripheral sensory stimuli and central neural challenges relates to alteration of immune responses. In line with endocrine-immune correlates is the association of growth hormone deficiency with impaired cellular immunity. On the other side, there are the effects that the immune system may have

© Springer Nature Switzerland AG 2019 235 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_20 236 A. Saghazadeh and N. Rezaei on the neuroendocrine system. Now, the neuro-immune-endocrine circuits are well understood so that we can refer to their certain processes and properties in the present book. Interestingly, other organs, for example, the heart and gut, like the immune system, possess nociceptors through which sensory inputs transmit from peripheral to central nervous system to serve in part as a sensory organ, while the nervous system with its multiple arms is specifically responsible for sensory functions throughout the body.

The Neuroendocrine System: The Garden of the Sensory Organs

The nervous system is discussed from different main aspects: 1. The nervous system includes central and peripheral organizations. 2. The nervous system includes sensory and motor organizations. 3. The nervous system includes somatic and autonomic organizations. The central nervous system (CNS) is composed of the brain and spinal cord. The peripheral nervous system (PNS) consists of ganglia and nerves that exist outside the brain and spinal cord. The sensory nervous system attaches to both the CNS and to the PNS. The sensory nervous system includes organs such as the eyes, ears, tongue, nose, and skin that receive information from the surrounding world. Also, this system consists of internal sensory organs that provide sensations of pain, pressure, and fullness. The somatic nervous system, also known as the voluntary nervous system, is an adjunct to the PNS that directs voluntary movements. The motor nervous system that merely belongs to the central nervous system is responsible for monitoring body movements in response to sensory stimuli. Finally, an important adherent of the PNS is the autonomic nervous system which, in turn, consists of sympathetic, parasympathetic, and enteric organizations. Generally, vital functions from blood pressure, gastrointestinal motility, and body temperature to respiratory rate and heart rate are regulated by the autonomic nervous system. The neuroendocrine system is based on the interactions between the nervous system and the endocrine system, particularly on the function of the hypothalamic–pituitary–adrenal axis (HPA) (for a review see [1]). The brain regions involved in the NES mainly include the hypothalamus and limbic region. The limbic system collects perceptual and cognitive inputs that are received from higher- order brain regions and then conveys a cumulative high-impact message to the hypothalamus aimed at regulating the activity of the HPA axis. Cortisol is considered the most important transmitter of the neuroendocrine system. The hypothalamus plays a crucial role in the release of corticotropin-releasing hormone (CRH) and vasopressin, which exert synergistic effects on releasing adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH stimulates cells in the adrenal cortex whereby cortisol is eventually produced. 20 The Sixth Sense Organs: The Immune System 237

The Immune System as a Sensory Organ

As widely known, the immune system is precisely designed to operate as the unit for holding sense of self – resulting in discrimination to non-self – throughout the body. In 1984, Blalock came with the idea that the immune system serves as a sensory organ with a chemical language similar to that of the endocrine and nervous systems [2]. Indeed, the idea was originated from the complex interplay between chemicals from the immune system mainly cytokines and messengers of the neuroendocrine system, i.e., neurotransmitters and hormones. After a two-decade period, this ability of the immune system to speak with a language that is familiar for both the nervous and endocrine systems was introduced as the sixth sense of the immune system [3]. As well-described in [4], it is important to note that this common language encompasses several elements, including cytokines (IFN, IL-1, IL-6) that exert hormonal- like effects, leukocytes that produce the precursor of neuropeptides (POMC, proopiomelanocortin), and immune cells that express receptors for a variety of neuropeptides and neurotransmitters (ACTH, arginine vasopressin, atrial natriuretic peptide, chorionic gonadotropin, CRH, endorphins, FSH, LH, GH, ILGF1, LHRH, met-enkephalin, oxytocin, prolactin, parathyroid hormone-related protein, substance P, thyroid-stimulating hormone, and vasoactive intestinal peptide). Altogether, sharing such common biochemical language would provide the way for the development of bidirectional interactions between the involved systems [5].

The Brain Hears the News of the Immune System Immediately from Cytokines

Immune challenges with bacterial endotoxins and exogenous cytokines have been shown to act as a stimulus to the HPA [6]. Besedovsky et al. [7] showed that exogenous administration of IL-1 results in a dose-dependent increase in ACTH. Administration of IL-1 antibodies could completely abolish the increase of ACTH elicited by inoculation of Newcastle disease virus (NDV) into mice. These findings indicate the effect of IL-1 on the HPA. More interestingly, it seems there is synchronization between immune and neuroendocrine processes. Besedovsky et al. [8] observed that the immune responses of rats to immunization with sheep red blood cells and trinitrophenylated hemocyanin were concurrent with an enhanced firing rate of hypothalamic neurons. Research suggests cytokines particularly interleukin (IL)-1 and tumor necrosis factor (TNF)-α as potential neuromodulators.

Blood-Born Cytokines

Inflammatory processes are accompanied by elevation of concentrations of positive acute-phase reactants circulating in the blood. Cytokines, e.g., IL-1β and TNF-α, are recognized as such reactants. There are specific transport systems through which 238 A. Saghazadeh and N. Rezaei cytokines can breach the blood–brain barrier (BBB) to reach the CNS (for review see [9]). However there are brain regions, known as “windows of the brain” [10], which lack vascular BBB and so are capable of directly transferring blood-born cytokines to the brain. These regions include the OVLT, the subfornical organ, the median eminence, and the area postrema in the brainstem which are collectively referred to as the sensory circumventricular organs.

Brain-Born Cytokines

The study of human brain tissues indicated the distribution of nerve fibers immunoreactive to IL-1β in the hypothalamus [11]. IL-1β-immunoreactive nerve fibers traced throughout the hypothalamus include the regions that contribute to (a) the anterior pituitary control (periventricular and arcuate nuclei, the parvocellular and magnocellular parts of the paraventricular nucleus, the infundibulum, and the supra- optic nucleus) and (b) central autonomic control (the autonomic parts of the paraventricular nucleus, the dorsomedial nucleus of the hypothalamus, the lateral hypothalamic area, the subfornical organ, the bed nucleus of the stria terminalis, the substantia innominata, the ventromedial nucleus of the hypothalamus, the posterior hypothalamic area, and the paraventricular nucleus of the thalamus). However, the periventricular regions revealed the most accumulation of IL-1β-immunoreactive nerve fibers. These regions are central to the hypothalamic control of the anterior pituitary, which signals to different body organs by means of different hormones: GH, growth hormone (liver); ACTH, adrenocorticotropic hormone (adrenal cortex); TSH, thyroid-stimulating hormone (thyroid); FSH, follicle-stimulating hormone (ovary); LH, luteinizing hormone (ovary and testis); and prolactin (breast). In addition, Breder et al. [12] recorded the pattern of TNF-α expression in the brain of the mouse before and after exposure to Salmonella typhimurium LPS. The authors revealed the spontaneous expression of TNF-α in the periventricular preoptic and suprachiasmatic nuclei in the hypothalamus, in the preoptic portion of the bed nucleus of the stria terminalis, and in the ventrolateral medulla. Administration of LPS significantly increased the expression of TNF-α in the organum vasculosum of the lamina terminalis (OVLT), the anteroventral periventricular nucleus, the median eminence, and the area postrema [12].

The Brain Transmits Received News from Cytokines to the Output Services

Both blood-born and brain-born cytokines tend to bind to their receptors in the brain regions that then interact with the hypothalamus. These special regions mainly include the circumventricular organs and the medial preoptic area. Upon activation, the paraventricular nucleus of the hypothalamus produces corticotropin-releasing factor (CRF), a factor that permits the transmission of inflammatory input under 20 The Sixth Sense Organs: The Immune System 239 different output processes which include the HPA axis, the sympathetic nervous system (SNS), and the efferent vagal nerves (for review see [13]).

The Brain Engages Different Output Processes to Generate an Anti-inflammatory Response

In 2002, Tracey proposed “the inflammatory reflex” as a mechanism through which the nervous system holds sway over the immune system [14]. Based on this theory, the nervous system tries to trigger an anti-inflammatory response when encountering an inflammatory stimulus. To this end, the nervous system will introduce inflammatory information into different output processes.

The Sympathetic Anti-inflammatory Pathway

The SNS which constitutes the dominant part of the autonomic system is also known as the emergency system which is responsible for eliciting the fight-or-flight response during stress. This response is accompanied by an increase in heart rate, basal metabolic rate, blood pressure, blood sugar, and muscle strength. In contrast, digestion, urination, and ejaculation are downregulated. Neurons that are involved in providing the fight-or-flight response must have a dual function, affecting both the stellate ganglion and adrenal gland. The sympathetic stellate ganglion regulates cardiovascular responses to stress (heart rate and blood pressure), while activation of the adrenal gland results in the release of adrenal medullary catecholamines (CAs) such as cortisol, adrenalin, and noradrenaline. Jansen et al. [15] identified several CNS regions (rostral ventromedial medulla, rostral ventrolateral medulla, and caudal raphe nuclei) that contained neurons with such dual function. The interaction between the SNS and the immune system lies in (a) the sympathetic innervation of immune or lymphatic organs (the thymus, bone marrow, spleen, lymph nodes, and mucosa-associated lymphoid tissues) as well as in (b) the expression of adrenergic receptors on immune cells. Besides structural overlapping, medullary CAs have the capacity to exert anti-inflammatory effects. Studies show that CAs lead to a reduction in the production of pro-inflammatory cytokinesparticularly interferon (IFN)-γ, TNF-α, IL-1β, IL-2, and IL-12 while inducing the production of IL-10, which is a regulatory cytokine, by monocytes [16]. This response is mediated by the beta-adrenergic component of the sympathetic nervous system through a cAMP/protein kinase A-dependent pathway. Sympathetic storms are seen in CNS injury. Infections are highly common following a CNS injury so that CNS injury is considered a cause of immunodeficiency [13]. Therefore, CAs-mediated anti-inflammatory effects are suggested as a possible mechanism through which CNS injury causes immunodeficiency. Similarly, CAs are involved in mediating the anti-inflammatory effects of exercise [17]. 240 A. Saghazadeh and N. Rezaei

The Hypothalamic–Pituitary–Adrenal Axis

The HPA axis is another component of the stress system. As well-explained in [18], both cholinergic and serotonergic neurotransmitters mediate stimulation of the stress system, whereas GABA-benzodiazepines and POMC peptides are related to its inhibition. Inflammatory mediators including cytokines (IFN, IL-1, IL-2, IL-6, and TNF-α), lipid mediators (prostanoids and platelet-activating factor), and growth factors (EGF and TGF-β) constitute a stress. The stress system improves motor reflexes, attention, cognitive performance, and pain tolerance while leading to decrease the appetite and sexual arousal. Activated hypothalamic CRH neurons stimulate the induction of ACTH by the anterior lobe of the pituitary gland. ACTH leads to the production of glucocorticoids by the adrenal gland. The anti- inflammatory effects of glucocorticoids have been well-documented (for review see [19]). Of note, other products of the HPA axis including pituitary hormones and hypothalamic hormones have pro-inflammatory effects rather than anti- inflammatory effects.

The Vagal Anti-inflammatory Pathway

The vagus nerve is the longest cranial nerve consisted of parasympathetic afferent and efferent fibers. The broad distribution of the vagus nerve allows it to establish several branches throughout the body, which can be divided into sensory and motor branches. Sensory branches go to the heart, lungs, bronchi, trachea, larynx, phar- ynx, gastrointestinal tract, and external ear. Motor branches go to the heart, lungs, bronchi, and gastrointestinal tract. Overall, the vagus nerve plays a leading role in regulating different autonomic sensory and motor functions related to its anatomical branches. Gaykema et al. (1995) demonstrated that afferent fibers of the vagus nerve are at least in part responsible for mediating the effect of endotoxin on the HPA [20]. Activation of the HPA axis results in the release of ACTH by the pituitary gland. ACTH, in turn, provokes the release of the neurotransmitter acetylcholine (ACh) from efferent fibers of the vagus nerve [21]. ACh activates α7-nicotinic acetylcholine receptor (α7nAChR) in macrophages to induce the second messenger cyclic adenosine monophosphate (cAMP). This messenger inhibits translocation of nuclear factor-κB (NF-κB) and therefore mitigating the expression of inflammatory mediators notably the high mobility group box 1 protein (HMGB1) [22] and cytokines TNF-α, IL-1β, IL-6, and IL-18. In this manner, efferent fibers convey the anti- inflammatory response of the HPA to immune challenges. This signaling pathway is also known as the “nicotinic anti-inflammatory pathway” [23]. Based on the above-described pathway, selective agonists for nicotinic receptors [24], for example, nicotine [25] and choline [26], which engage nicotinic ACh receptors and thereby imitate the action of ACh have emerged as a pharmacological strategies for treatment of inflammatory diseases (ulcerative colitis) [27] as well as for treatment of inflammation-related psychiatric (schizophrenia) [28] and 20 The Sixth Sense Organs: The Immune System 241 neurodegenerative (Alzheimer’s disease) [29] diseases. It is also expected that vagus nerve stimulation (VNS) could effectively inhibit systemic inflammatory responses [30, 31] and therefore be useful for treatment of autoimmune (Crohn’s disease [32] and rheumatoid arthritis [33]), neurological (migraine [34]), psychiatric (depression and eating disorders [35, 36]), and endocrine disorders [37].

Conclusions

The key point of this chapter is that the sixth sense has sensory organs as other senses have. However, contrary to the five senses that the five common sensory organs are specified by sensory stimuli, for example, eye for the sense of vision, the sixth sense appears as the key to awareness of sensory stimuli not otherwise specified. In fact, several sensory organs capture the sixth sense. The present chapter which was aimed to give readers a nudge into the world of the sixth sense organs provided evidence supporting the sixth sense of the immune system. In the next five chapters, the spread of the sixth sense will occur in the heart, gut, eyes, ears, and hands.

References

1. Stansbury K, Gunnar MR. Adrenocortical activity and emotion regulation. Monogr Soc Res Child Dev. 1994;59(2–3):108–34. 2. Blalock JE. The immune system as a sensory organ. J Immunol. 1984;132(3):1067–70. 3. Blalock JE. The immune system as the sixth sense. J Intern Med. 2005;257(2):126–38. 4. Blalock JE, Smith EM. Conceptual development of the immune system as a sixth sense. Brain Behav Immun. 2007;21(1):23–33. 5. Blalock JE. A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol Rev. 1989;69(1):1–32. 6. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res. 2003;9(1):3–24. 7. Besedovsky H, et al. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986;233(4764):652–4. 8. Besedovsky H, et al. Short papers. Eur J Immunol. 1977;7(5):323–5. 9. Banks WA. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des. 2005;11(8):973–84. 10. Johnson AK, Gross PM. Sensory circumventricular organs and brain homeostatic pathways. FASEB J. 1993;7(8):678–86. 11. Breder CD, Dinarello CA, Saper CB. Interleukin-1 immunoreactive innervation of the human hypothalamus. Science. 1988;240(4850):321–4. 12. Breder CD, et al. Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc Natl Acad Sci. 1994;91(24):11393. 13. Meisel C, et al. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005;6(10):775. 14. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853. 242 A. Saghazadeh and N. Rezaei

15. Jansen ASP, et al. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science. 1995;270(5236):644–6. 16. Woiciechowsky C, et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med. 1998;4(7):808. 17. Gleeson M, et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011;11(9):607. 18. Chrousos GP. The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351–63. 19. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci. 1998;94(6):557–72. 20. Gaykema RP, Dijkstra I, Tilders FJ. Subdiaphragmatic vagotomy suppresses endotoxin- induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology. 1995;136(10):4717–20. 21. Arnason BG, et al. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler (Houndmills, Basingstoke, England). 2013;19(2):130–6. 22. Wang H, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10(11):1216. 23. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov. 2005;4(8):673. 24. Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol. 2009;151(7):915–29. 25. Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002;2(5):372. 26. Alkondon M, et al. Choline is a selective agonist of α7 nicotinic acetylcholine receptors in the rat brain neurons. Eur J Neurosci. 1997;9(12):2734–42. 27. Bencherif M, et al. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation- based diseases. Cell Mol Life Sci. 2011;68(6):931–49. 28. Martin LF, Kem WR, Freedman R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology. 2004;174(1):54–64. 29. Kem WR. The brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: studies with DMXBA (GTS-21). Behav Brain Res. 2000;113(1–2):169–81. 30. Borovikova LV, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458. 31. Zhang Y, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing modelclinical perspective. Circ Heart Fail. 2009;2(6):692–9. 32. Bonaz B, et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28(6):948–53. 33. Koopman FA, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci. 2016;113(29):8284–9. 34. Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia. 2005;25(2):82–6. 35. Rush AJ, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multi- center study∗. Biol Psychiatry. 2000;47(4):276–86. 36. Wernicke JF, Terry Jr RS, Baker Jr RG. Treatment of eating disorders by nerve stimulation. 1993, Google Patents. 37. Wernicke JF, Terry Jr RS. Treatment of endocrine disorders by nerve stimulation. 1993, Google Patents. Chapter 21 The Sixth Sense Organs: The Heart

Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei

Abstract At the cardiovascular clinics, we are accustomed to saying and patients are accustomed to hearing “stress is forbidden.” Actually, the question is why the heart must understand our surrounding environment and fear of loud sounds.

Keywords Autonomic nervous system · Fetal heart rate · Coherence · Heart · Heart rate variability · Music therapy · Sixth sense

The Heart Rate Variability

The Role of the Autonomic Nervous System

The heart is equipped with an intrinsic nervous system consisting of sensory, inter- connecting, and motor neurons [1]. The autonomic nervous system (ANS) of the heart allows it to dynamically change in response to any pressure either from the external environment or from the internal voices [2]. It is thought that the degree of change is substantially determined by the pre-pressure or background activity of the ANS [3]. Then, according to the type of pressure, either the sympathetic or parasympathetic nervous system would also play a leading role in the degree of change in heart rate. For example, the sympathetic nervous system (SNS), rather than the parasympathetic nervous system, is responsible for the reduction of the heart rate during exercise. Overall, beat-to-beat heart rate variability (HRV) is required for the ventricular function. Frequent reductions and loss of HRV may be reflections of an overactivated sympathetic system or underactivated parasympathetic system [4]. They have the potential to render patients at risk for arrhythmia (especially ventricular fibrillation) and sudden cardiac death [5]. Therefore, HRV is commonly used as a noninvasive method to evaluate the function of the cardiac autonomic neurons. More importantly, reduction of HRV is validated as an independent marker of increased risk of new cardiac events [6] and of total cardiac mortality after myocardial infarction [7]. The sympathetic nerve endings in the heart contribute to the release of bradykinin (BK) [8]. BK engages beta-2 adrenergic receptors (β2 adrenoreceptors) to stimulate the cardiac C nerve fibers that carry sensory information. Then, the adrenergic nerve endings will release norepinephrine (NE) in response to the stimulation of sensory C fibers. The stimulatory role of BK on C nerve fibers is strengthened by cyclooxy- genase products and a lower pH level, whereas it is inhibited by histamine H3 receptors. Neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P may play a role in signaling from the stimulated sensory C fibers to the adrenergic nerves and therefore in the release of NE.

The Cardiovascular Control System

In the study [9], the authors suggested that the renin-angiotensin system (RAS) serves a role in the short-term cardiovascular control similar to that of sympathetic and parasympathetic systems. More precisely, Saykrs described three peaks occurring at low (0.04), middle (0.12 Hz), and high (0.35 Hz) frequency in the heart rate power spectrum in human [10]. Generally, the parasympathetic nervous system is engaged in the generation of HRV at all the three peak frequencies. The peaks at low and middle frequency involve the SNS as well. The RAS particularly contributes to the heart rate peak at low frequency. 21 The Sixth Sense Organs: The Heart 245

The Role of Respiration on Heart Rate Variability

It should be noted that respiration has the potential to influence the heart rate peak at high frequency [10]. R-R interval which normally takes 0.12–0.20 seconds is a measure used to calculate heart rate beats per minute. Inhalation is accompanied by a shortening of R-R interval, corresponding to increased heart rate, while exhalation induces the prolongation of R-R interval, corresponding to decreased heart rate. Less than 10% difference in the heart rate between inhalation and exhalation (E:I ratio) may be a reflection of ANS dysfunction. To test this hypothesis, the authors in [11] evaluated the E:I ratio in patients with diabetic neuropathy. More than 50% of patients showed E:I ratios.

The Heart Response to the Internal World

The Heart Is Diseased Because the Mind Is Sick

No effort is necessary to make the heading clear when even a facial expression that lasts only a few seconds can alter autonomic system responses including HRV and temperature changes [12]. Additionally, autonomic responses, including HRV, not only reflect but also alter the difference between positive (happiness and surprise) and negative emotions (anger, fear, sadness, and disgust) depending on the type of negative emotion. Interestingly, the observation of heart rate deceleration before the demonstration of emotional pictures indicates that the heart receives intuitive information about forthcoming challenges [13]. Of note, such HRV deceleration is more pronounced for females than males. The link between mental disorders and heart diseases is another evidence that there exists at least an overlapping mechanism that innervates both the mind and the heart. The ANS is such a mechanism [14]. Major mental disorders including particularly depression are associated with changes in levels and responses of catecholamines and their transporters [15, 16], which indicate the aberration of the ANS. Additionally, the relative decrease of HRV in patients with depression, anxiety, and hostility is an alert to indicate that the cardiovascular health may be disturbed [17].

The Irritable Heart of Soldiers

During the American Civil War, Jacob Mendes Da Costa defined the irritable heart of soldiers— which is also known as the Da Costa’s syndrome—as a condition where a weak emotional or exciting stimulus can cause shortness of breath, palpitation, sweating, chest pain, and dizziness, while physical examination reveals no evidence of abnormal physical diseases. Therefore, anxiety is considered the main cause of the irritable heart of soldiers. Studies suggest that the threshold of SNS is 246 A. Saghazadeh et al. abnormally low in this condition, making patients prone to over-respond to stimulatory factors (adrenaline) as well as to under-respond to suppressor factors (apoco- deine) [18].

The Abnormal Sense of Coherence

In 1979, Antonovsky [19] proposed the sense of coherence to describe that there is a continuum of the mental health. The theory is mainly centered on the role of coping strategies for managing stressful challenges to improve subjective psychological well-being. Failure to employ good coping skills results in aggravation of stress, which can be an actual threat to the mind and body’s health. From the mind’s perspective, the world is not “comprehensible, manageable, and meaningful” [20]. It is very likely to become ill with mind and heart diseases under such condition. Supporting this is the significant, positive association between the sense of coherence and the self-related health score [21]. For example, the HeartMath emotional management techniques are used to achieve or sustain physiological coherence. McCraty et al. [13] compared changes in the heart rate between participants with and without prior training in the HeartMath emotional management techniques. The heart rate was monitored prior to, during, and after the presentation of pictures (calm versus emotional). In subjects without prior training, heart rate deceleration for emotional pictures was significantly increased than for calm pictures, and this difference was evident in both pre-stimulus and post-stimulus periods and for both males and females. In subjects with prior training, this difference was true only in post-stimulus period for females and not for males. This reveals the effect of coherence on the management of emotional stimuli.

The Heart Is Healthy Because the Mind Is Happy

Participation in the community is considered a strategy to prevent heart diseases. The study by [22] showed the role of psychosocial factors including perceived incentive value, self-efficacy, outcome expectancies, sense of community, and perceived policy control in community participation.

The Mind Is Altered Because the Heart Is Replaced

Inspector et al. [23] investigated adaptation to another person’s heart in 35 heart recipients at the mean of 2 years after transplantation. Using different self-report measures, patients were asked to share their attitudes and fantasies regarding the 21 The Sixth Sense Organs: The Heart 247 received heart. Besides high levels of stress, more than 70% of patients thought that the new heart brought them a new attitude toward life. Also, some believed that the new heart has harbored the donor’s characteristics. This might indicate the deterministic role that the heart plays in the brain’s perception of personality and in the mind’s balance of magical thoughts and logical rules, so that the new heart may revolutionize the way the person thinks about.

The Mind Is Happy Because the Heart Is Active

The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is used as a self- administered measure of quality of life in patients with cardiovascular diseases [24]. The lower the score in MLHFQ, the better the quality of life is. An 8-week program of aerobic exercise led to the significant reduction in patients’ scores on the MLHFQ and to the improvement of sense of coherence [25].

The Heart Response to the External World

Fetal Heart Rate

Fetal heart rate changes in response to auditory and vibratory stimuli [26, 27]. The heart acceleration response is thought to represent fetal well-being [28]. The study of 36-week pregnant women demonstrated that the baseline heart rate in fetuses of mothers with depression is increased than that in fetuses of mothers without depression [29]. Moreover, the fetal heart acceleration in response to vibroacoustic stimuli was significantly prolonged in fetuses of mothers with depression compared with fetuses of mothers without depression. Interestingly, mothers with depression reported elevated anxiety levels. It is consistent with the findings of another study that fetuses of mothers with above average anxiety scores displayed a significant increase in heart rate [30], whereas fetuses of mothers with below average anxiety scores revealed a reduction in heart rate which was non-significant. Shreds of evidence like this are what inspired scientists to suggest the term the “infant’s sixth sense” [31]. And the human sixth sense development begins before birth.

Effect of Music Therapy

Root Mean Square of the Successive Differences (RMSSD) is defined by Stein et al. (1994) as the root-mean-square differences of successive R-R intervals [32]. This measure of HRV indicates “the integrity of the vagus nerve-mediated autonomic 248 A. Saghazadeh et al. control of the heart.” Lower scores in RMSSD predict a higher risk of sudden unexplained death in epilepsy (SUDEP) [33]. The measure of pNN50 developed by Ewing et al. [34] is “the mean number of times per hour in which the change in successive R-R interval was greater than 50 ms.” The normal count of pNN50 is 150–250 during waking and 350–450 during sleeping. Reduction of the pNN50 in diabetic patients with medically denervated hearts, cardiac transplant patients with surgically denervated hearts, and even in diabetic patients with normal cardiovascular reflexes would propose this measure as a reliable marker of parasympathetic activity. As previously explained in the present chapter, power spectrum analysis by Akselrod et al. [9] revealed that the parasympathetic activity is required for HRV within the high-frequency (HF) band (0.15–0.40 Hz). Okada et al. [35] investigated the effect of music therapy (ten 45-minute sessions) on the measures of parasympathetic activity in elderly patients with cardiovascular diseases. Music therapy could effectively increase all the investigated measures, e.g., RMSSD, pNN50, and HF, while decreasing the occurrence of congestive heart failure events. It is of importance that MT also reduced the plasma level of catecholamines, e.g., noradrenaline and adrenaline and proinflammatory cytokine IL-6. More interestingly, a relaxing music for only 20 minutes was able to reduce heart rate and respiratory rate in patients with acute myocardial infarction and that this significant effect lasted for more than 1 hour [36].

Conclusion

This chapter provided evidence supporting the fact that the heart is perfectly aware of stimuli of both the external and internal worlds.

References

1. Armour JA. Potential clinical relevance of the ‘little brain’ on the mammalian heart. Exp Physiol. 2008;93(2):165–76. 2. Slonim T. The polyvagal theory: neuropsychological foundations of emotions, attachment, communication, & self-regulation. Int J Group Psychother. 2014;64(4):593–600. 3. Robinson BF, et al. Control of heart rate by the autonomic nervous system: studies in man on the interrelation between baroreceptor mechanisms and exercise. Circ Res. 1966;19(2):400–11. 4. Kleiger RE, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59(4):256–62. 5. Sztajzel J. Heart rate variability: a noninvasive electrocardiographic method to measure the autonomic nervous system. Swiss Med Wkly. 2004;134(35–36):514–22. 6. Tsuji H, et al. Impact of reduced heart rate variability on risk for cardiac events: the Framingham Heart Study. Circulation. 1996;94(11):2850–5. 7. Rovere MTL, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet. 1998;351(9101):478–84. 21 The Sixth Sense Organs: The Heart 249

8. Seyedi N, Maruyama R, Levi R. Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release? J Pharmacol Exp Ther. 1999;290(2):656–63. 9. Akselrod S, et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981;213(4504):220–2. 10. Saykrs BM. Analysis of heart rate variability. Ergonomics. 1973;16(1):17–32. 11. Sundkvist G, Almer LO, Lilja B. Respiratory influence on heart rate in diabetes mellitus. Br Med J. 1979;1(6168):924–5. 12. Ekman P, Levenson RW, Friesen WV. Autonomic nervous system activity distinguishes among emotions. Science. 1983;221(4616):1208–10. 13. McCraty R, Atkinson M, Bradley RT. Electrophysiological evidence of intuition: Part 1. The surprising role of the heart. J Altern Complement Med. 2004;10(1):133–43. 14. Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med. 2005;67:S29–33. 15. Light KC, Kothandapani RV, Allen MT. Enhanced cardiovascular and catecholamine responses in women with depressive symptoms. Int J Psychophysiol. 1998;28(2):157–66. 16. Klimek V, et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci. 1997;17(21):8451. 17. Gorman JM, Sloan RP. Heart rate variability in depressive and anxiety disorders. Am Heart J. 2000;140(4):S77–83. 18. Fraser F, Wilson RM. The sympathetic nervous system and the “irritable heart of soldiers”. Br Med J. 1918;2(3002):27. 19. Antonovsky A. Health, stress, and coping. San Francisco: Jossey-Bass Publishers; 1979. 20. Antonovsky A. The life cycle, mental health and the sense of coherence. Isr J Psychiatry Relat Sci. 1985;22:273–80. 21. Eriksson M, Lindström B, Lilja J. A sense of coherence and health. Salutogenesis in a societal context: Åland, a special case? J Epidemiol Community Health. 2007;61(8):684–8. 22. Altman DG, et al. Psychosocial factors associated with youth involvement in community activities promoting heart health. Health Educ Behav. 1998;25(4):489–500. 23. Inspector Y, Kutz I, Daniel D. Another person’s heart: magical and rational thinking in the psychological adaptation to heart transplantation. Isr J Psychiatry Relat Sci. 2004;41(3):161. 24. Rector TS. Patients’ self-assessment of their congestive heart failure: content, reliability, and validity of a new measure, the Minnesota Living with Heart Failure questionnaire. Heart Fail. 1997;3:198–209. 25. Gustavsson A, Bränholm I-B. Experienced health, life satisfaction, sense of coherence, and coping resources in individuals living with heart failure. Scand J Occup Ther. 2003;10(3):138–43. 26. Grimwade JC, et al. Human fetal heart rate change and movement in response to sound and vibration. Am J Obstet Gynecol. 1971;109(1):86–90. 27. Sontag LW, Wallace RF. Changes in the rate of the human fetal heart in response to vibratory stimuli. Am J Dis Child. 1936;51(3):583–9. 28. Read JA, Miller FC. Fetal heart rate acceleration in response to acoustic stimulation as a measure of fetal well-being. Am J Obstet Gynecol. 1977;129(5):512–7. 29. Allister L, et al. The effects of maternal depression on fetal heart rate response to vibroacoustic stimulation. Dev Neuropsychol. 2001;20(3):639–51. 30. Monk C, et al. Maternal stress responses and anxiety during pregnancy: effects on fetal heart rate. Dev Psychobiol: J Int Soc Dev Psychobiol. 2000;36(1):67–77. 31. Porges S. The infant’s sixth sense: awareness and regulation of bodily processes. Zero Three. 1993;14(2):12–6. 32. Stein PK, et al. Heart rate variability: a measure of cardiac autonomic tone. Am Heart J. 1994;127(5):1376–81. 33. DeGiorgio CM, et al. RMSSD, a measure of heart rate variability, is associated with risk factors for SUDEP: the SUDEP-7 inventory. Epilepsy Behav: E&B. 2010;19(1):78–81. 250 A. Saghazadeh et al.

34. Ewing DJ, Neilson JM, Travis P. New method for assessing cardiac parasympathetic activity using 24 hour electrocardiograms. Heart. 1984;52(4):396–402. 35. Okada K, et al. Effects of music therapy on autonomic nervous system activity, incidence of heart failure events, and plasma cytokine and catecholamine levels in elderly patients with cerebrovascular disease and dementia. Int Heart J. 2009;50(1):95–110. 36. White JM. Effects of relaxing music on cardiac autonomic balance and anxiety after acute myocardial infarction. Am J Crit Care. 1999;8(4):220. Chapter 22 The Sixth Sense Organs: The Gut

Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, Maryam Mahmoudi, and Nima Rezaei

Abstract After the skin, the gastrointestinal (GI) tract provides one of the largest interfaces in humans. This interface can interact with the external world and with the internal world as well. Therefore, the gut is seen as a sensory organ where chemicals and microorganisms receive sensory information and then, the effector systems including the endocrine, immune, neural, and organ defense systems are triggered in response to this information.

A. Saghazadeh Molecular Immunology Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran H. Mojtabavi MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran Student’s Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran R. Khaksar MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran M. Mahmoudi Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran Dietitians and Nutrition Experts Team (DiNET), Universal Scientific Education and Research Network (USERN), Tehran, Iran N. Rezaei (*) Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran e-mail: [email protected]

Keywords Brain–gut axis · Enteroendocrine system · Feeding behavior · Gut · Immune system · Nutrients · Sixth sense

Introduction

The view of the gut as a sensory organ is in a substantial part indebted to the community of commensal bacteria resident in the intestine, which are collectively referred to as the gut flora. As we go lower and lower into the GI tract, the bacterial density increases from 101–103 CFU/ml (colony-forming units per milliliter) at the stomach and duodenum and 104–107 CFU/ml at the jejunum/ileum to 1011– 1012 CFU/ml at the colon. Altogether, this host bacterial population fulfills a variety of functions including protective, structural, and metabolic functions (for review see [1]).

The Gut Detectors

As reviewed by Furness et al. [2], the intestinal mucosa has a range of detectors: 1. The enteric nervous system which is made up of 108 neurons 2. The gastroenteropancreatic endocrine system wherein more than 20 hormones take part and therefore it is thought to have the largest contribution to the formation of the body’s endocrine system [3] 3. The gut immune system which encompasses a large part of what we recognize as the human immune system In this manner, the gut detectors are optimized for all types of sensory information.

The Multifaceted Role of γ-Aminobutyric Acid (GABA)

GABA is an inhibitory neurotransmitter. Because of the expression of its receptors in both the CNS and GI tract, GABA is able to modulate a variety of neural functions inside the CNS as well as GI functions outside the CNS. In the GI tract, GABA and its receptors are synthesized in both the enteric nerves and endocrine- like cells [4]. Additionally, studies point to the anti-inflammatory activities of the GABAergic system in the GI tract [5]. Overall, the GABA system has the potential to contribute to the processing of different types of sensory stimuli that the GI tract might receive. 22 The Sixth Sense Organs: The Gut 253

The Brain–Gut Axis

The evidence for the concept brain–gut axis was first provided with experiments that showed the effect of emotional states or reactions on the GI function [6]. The brain–gut axis is innervated by the intrinsic and extrinsic neural pathway. The former is the enteric nervous system that is comprised of sensory neurons, motor neurons, and interneurons. It is chiefly responsible for GI functions, including motility, secretion, and mucosal blood flow. The latter engages different innervation pathways such as vagal pathways, sacral pathways, spinal pathways, and also neural pathways underlying the innervation of the striated muscle regions.

The Gut Is Irritable Because the Brain Is in Stress

The irritable bowel syndrome (IBS) is a good example of brain–gut axis dysfunction. IBS is a functional GI disorder, which means that there are neither definite pathological findings nor diagnostic methods for it. However, fortunately, the causes of this disorder are in-hand. They are nothing more than stressors including physical (infection and inflammatory conditions) and psychological (anxiety, depression, and negative life events especially in early life, for example, maternal separation [7]) stressors [8].

Feeding Behavior

The process of fat digestion is accompanied by the release of an endogenous high-affinity agonist of peroxisome proliferator-activated receptor-a (PPAR-α), named oleoylethanolamide (OEA) [9]. The interaction of OEA with its receptor PPAR-α results in fatty acid catabolism, reduction of blood lipid levels, and reduction of weight gain. The sympathetic nerve fibers underlie the actions of OEA in the GI, while the parasympathetic fibers transduce the fat-induced OEA signaling from the GI to the brain. In the following, the brain is directly involved in the control of feeding behavior [10]. The lateral hypothalamic area is known as feeding or appetite center, whereas the ventromedial hypothalamic area is the satiety center. 254 A. Saghazadeh et al.

The Gut Is Hungry Because the Brain Is in Stress

Along with energy deficiency and taste, stress plays a key role in the stimulation of feeding behavior [10]. It is proposed that chronic stress causes induction of glucocorticoids, which, in turn, inhibit the activity of the HPA axis and its related products, e.g., ACTH and corticosterone B [11]. This might lead to the increased ingestion of comfort foods.

The Fetal Gut Is Malfunctioning Because the Maternal Brain Is in Distress

Maternal stress would profoundly influence the endocrine profile of placenta and fetuses. It has been shown to cause a smaller pancreatic β-cell mass and to lower plasma levels of glucose, growth hormone, and ACTH [12]. Therefore, it is understandable that mothers with psychological distress are more likely to have a child with decreased fetal weight [13]. Consistently, increases in maternal concentrations of cortisol, which is a major stress hormone, predicted decreased fetal weight.

The Enteroendocrine System Senses Nutrients

The enteroendocrine system (EES) is specialized for the first-line detection of ingested nutrients [14], an action which is also known as chemosensing or taste- signaling. Enteroendocrine cells which serve as a receptor for nutrients [15] engage different molecular chemosensing mechanisms according to the type of nutrients. However, G protein-coupled receptors and effectors are generally involved in chemosensing [15]. Primary afferent fibers that transmit nutritional information from the upper GI to the CNS consist of intrinsic, spinal, and vagal neural pathways [16]. After taste perception, the EES also plays a key role in the regulation of physiological response including motility, secretion, glucose homeostasis, and appetite.

The Gut Immune System

From the Joint to the Gut and Vice Versa

The observation of rheumatic symptoms in patients with celiac disease (CD) and conversely GI symptoms in patients with rheumatoid arthritis (RA) illuminates that the immune system of the gut is interdigitated with that of the joint [17]. CD and RA 22 The Sixth Sense Organs: The Gut 255 are linked with common characteristics that are reviewed in [18] in detail. Although considered as a gut feeling, it is still promising that perhaps there exists a common approach to both diseases.

The Gut Dysfunction: The Mother of Diseases

Concomitant Disorders of the Brain, Gut, and Immune System

It is, however, thought to be more than a gut feeling that brain disorders, autoimmune disorders, and GI disorders are closely linked with each other [19, 20]. With its connection with the brain and immune system, the gut is a potential candidate that might bring together these specific disorders in one individual. For example, both autism spectrum disorder (ASD) and schizophrenia have been associated with autoimmune conditions [20] and gastrointestinal symptoms [19]. Of note, the microbiota profile is altered in both of these brain disorders [19, 21]. Therefore, the gut is seen as the natural route to treat these disorders thought to be originated from the brain [22, 23].

From Gut Dysfunction to Multiorgan Failure

Critical conditions such as trauma, surgery, and starvation cause the gut to undergo a variety of changes including stress ulceration, bacterial overgrowth, mucosal atrophy, loss of intestinal barrier integrity, and increased permeability [24]. It is of importance that these changes might lead to gastrointestinal failure, which may subsequently progress to multiorgan failure (MOF). Therefore, maintenance of gastrointestinal function is mandatory for prevention of MOF in the mentioned conditions.

Conclusion

The gut is placed at a distinct location in the body. In spite of its local location, the gut does exert a widespread effect to the body such that the gut dysfunction can lead to concomitant disorders of the brain and immune system and even to multiorgan failure. 256 A. Saghazadeh et al.

References

1. O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7(7):688–93. 2. Furness JB, Kunze WAA, Clerc N. II. The intestine as a sensory organ: neural, endocrine, and immune responses. Am J Physiol Gastrointest Liver Physiol. 1999;277(5):G922–G8. 3. Ahlman H, Nilsson O. The gut as the largest endocrine organ in the body. Ann Oncol. 2001;12(suppl_2):S63–S8. 4. Hyland NP, Cryan JF. A gut feeling about GABA: focus on GABAB receptors. Front Pharmacol. 2010;1:124. 5. Auteri M, Zizzo MG, Serio R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res. 2015;93:11–21. 6. Aziz Q, Thompson DG. Brain-gut axis in health and disease. Gastroenterology. 1998;114(3):559–78. 7. O’Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation as a model of brain–gut axis dysfunction. Psychopharmacology. 2011;214(1):71–88. 8. Fichna J, Storr M. Brain-gut interactions in IBS. Front Pharmacol. 2012;3:127. 9. Piomelli D. A fatty gut feeling. Trends Endocrinol Metab. 2013;24(7):332–41. 10. Konturek SJ, Konturek PC, Pawlik T, Brzozowski T. Brain-gut axis and its role in the control of food intake. J Physiol Pharmacol. 2004;55(2):137–54. 11. Pecoraro N, Reyes F, Gomez F, Bhargava A, Dallman MF. Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress. Endocrinology. 2004;145(8):3754–62. 12. Mairesse J, Lesage J, Breton C, Bréant B, Hahn T, Darnaudéry M, et al. Maternal stress alters endocrine function of the feto-placental unit in rats. Am J Physiol Endocrinol Metab. 2007;292(6):E1526–E33. 13. Diego MA, Jones NA, Field T, Hernandez-Reif M, Schanberg S, Kuhn C, et al. Maternal psychological distress, prenatal cortisol, and fetal weight. Psychosom Med. 2006;68(5):747. 14. Psichas A, Reimann F, Gribble FM. Gut chemosensing mechanisms. J Clin Invest. 2015;125(3):908–17. 15. Sternini C, Anselmi L, Rozengurt E. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):73. 16. Grundy D. Neuroanatomy of visceral nociception: vagal and splanchnic afferent. Gut. 2002;51(suppl 1):i2–5. 17. Lerner A, Matthias T. Rheumatoid arthritis–celiac disease relationship: joints get that gut feeling. Autoimmun Rev. 2015;14(11):1038–47. 18. Molberg Ø, Sollid LM. A gut feeling for joint inflammation–using coeliac disease to understand rheumatoid arthritis. Trends Immunol. 2006;27(4):188–94. 19. Severance EG, Yolken RH, Eaton WW. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. 2016;176(1):23–35. 20. Brown AC, Mehl-Madrona L. Autoimmune and gastrointestinal dysfunctions: does a subset of children with autism reveal a broader connection? Expert Rev Gastroenterol Hepatol. 2011;5(4):465–77. 21. Rosenfeld CS. Microbiome disturbances and autism spectrum disorders. Drug Metab Dispos. 2015 Oct 1; 43(10):1557–71. 22. Campbell-McBride N. Gut and psychology syndrome: natural treatment for autism, dys- praxia, ADD, dyslexia, ADHD, depression, schizophrenia. 2nd ed., Medinform Pub. Soham, Cambridgeshire, 2010. p.392. 23. Dinan TG, Borre YE, Cryan JF. Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry. 2014;19(12):1252. 24. Baue AE. The role of the gut in the development of multiple organ dysfunction in cardiotho- racic patients. Ann Thorac Surg. 1993;55(4):822–9. Chapter 23 The Sixth Sense Organs: The Eyes

Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei

Abstract The authors have well-discussed the neurophysiological and biophysical aspects of vision in Chaps. 2 and 3. The present Chapter is a special look at the eyes as the providers of the spatial presence.

Keywords Circadian clock · Eye · Gaze · Melatonin · Pineal gland · Presence · Sixth sense · Third eye · Vision · Visual illusions

The World Scanner: Where Am I?

Presence

The eye serves as the natural scanner of the real-world scenes. The eye-provided scans play a critical role in the perception of the external world and in the formation of a gestalt of the environment, the environment in which at present we are residing. Presence is a multidimensional construct associated with different definitions. It is commonly defined as “the sense of being there in the virtual environment.” To discuss a more practical definition, Slater [1] proposed to consider presence “as a perceptual mechanism for selection between alternative hypotheses: ‘I am in this place’ and ‘I am in that place’ (‘I am confused’).” The motive behind this proposal comes from the thought of Richard Gregory that “perception is a continual series of simple hypotheses about the external world which are built up and selected by sensory experiences.” [2] As defined by Slater 2002, the concept presence is the case when one receives sensory signals from two or more environments. Otherwise, there would be no alternative hypotheses than that “I am in this place.” But if it is the case that one receives competing signals from multiple environments, then the mind begins to build alternative gestalts, each one of which is associated with a set of actions. Actions can occur involuntarily (heart rate change) or voluntarily (decision to walk) and consciously (walking) or unconsciously (postural sway change).

A Break in Presence: The Aha Moment

A break in the presence or that the aha moment occurs when, either consciously or unconsciously, the mind shifts from processing the gestalt of a given environment to processing the gestalt of another environment [1]. Thereby, the subject would experience an “aha” moment. Generally, at this moment, he/she will see what he/she has never seen before, for example, one might be able to solve a creative problem [3]. Chapter 1 discussed a break in both spatiotemporal dimensions of presence.

Strategies to Manipulate Presence

Mind Wandering

In fact, mind wandering is a manifestation of the constraints imposed by consciousness on the mind [4]. It comes when the mind no longer attends the present and his/her attention wanders toward the non-present moments, particularly to the future moments. It is thus expected that mind wandering increases with target 23 The Sixth Sense Organs: The Eyes 259 probability [5], time on task, and low-level cognitive demand tasks [6]. Whereby the mind will turn into a rhythmic movement from the outside world to the inside world and vice versa [7]. If the mind would not be aware of its intermittent wandering (lack of meta-awareness), then the mind wandering may cause performance errors in a task which the participant is otherwise proficient on [5]. Otherwise, the mind is suited to supervise the task performance [5]. Almost 50% of people are engaged in thinking about other than what they are currently doing [8]. This engagement can be carried out either in an intentional way or unintentional way which correspondingly have shown direct and inverse correlations with non-reactivity to inner experience (a facet of mindfulness) [9]. What activity that allows the highest mind wandering is that working [8]. Other activities associated with high level of mind wandering include talking, home computer, watching television, listening to the radio, news and other, commuting, traveling, and relaxing [8]. Though the topics of mind wandering are pleasant rather than unpleasant, regardless the type of concurrent activity that is undertaking [8], the more the mind is unhappy the more the mind will wander [10]. Further, the contents of mind wandering indicate the prevailing trend toward the future which is particularly focused on autobiographical planning [11]. Thinking to future (prospective thinking) requires working memory capacity, so does mind wandering. Mind wandering can be read from eye movements, with increased fixation [12] and decreased complexity [13]. Interestingly, the amount of fidgeting corresponds with deep, but not mild, mind wandering [14, 15]. The matter that wandering is not confined to the mind but extends to the body plainly confirms the quick integration between the mind and body. The brain disorders such as schizophrenia boost the mind wandering. Spontaneous neural activity model of auditory verbal hallucinations (AVH) proposes that an increased mind wandering reflects in higher levels of random noise and therefore stochastic resonance, whereby weak signals are amplified and then abnormally modulated to develop hallucinations [16]. Mind wandering is full of numerous pit- falls and profits depending on the contents of the concurrent task and of mind wandering [17]. Costs associated with mind wandering include decreased alertness and sensory processing [18], hallucinations [16], goal-neglect [19], and performance errors in the various cognitive tasks [20]. While its benefits to creative [21] and prospective thinking [11] have long been appreciated.

Mindfulness

Mindfulness that can be achieved through meditation demands sustained attention to the present and so minimizes thinking about other than present [22]. Thereby, it is possible to heighten the ability of the mind to control mind wandering [23] and automatic thoughts [24], avoid the biases and fallacies in making intuitive judgments [22], and enhance mood, cognitive and executive functioning [25]. 260 A. Saghazadeh et al.

From Visual Perception to Motor Actions

Two Vision Systems

In 1982, Mishkin and Ungerleider [26] proposed the theory that the visual system is comprised of two distinct subsystems. The pattern recognition is underpinned within the inferior temporal cortex that receives projections from the lateral striate cortex. Whereas the visuospatial ability is embodied within the parieto-preoccipital cortex that received projections from both lateral and medial striate cortices. Also, the first subsystem or dorsal stream was known as “what pathway,” and the second subsystem or ventral stream was known as “where pathway.” Then, a sequential series of studies of patients with neurological disorders [27–30] emerged confirming the theory of two vision systems in a different manner. More precisely, the observation of an apparently intact perception of the target in patients with parietal damage who could not grasp that object and the observation of an accurate grasp of the target in patients with primary visual cortex damage who could not perceive that object led to the suggestion that there are two vision systems: one for the conscious visual perception of an object and one for the grasp of an object. Though grasping an object is relatively simple for healthy subjects, it often requires conscious calibration. When deciding to grasp an object, the subject moves his/her hand to the target and opens between the index finger and the thumb to pick up the object. Before picking up the object, the aperture between the index finger and the thumb reaches its maximum, which is known as the preshape aperture. The preshape aperture has a linear association with the target object size.

Visual Illusions

Visual illusions where the contextual information interferes with the perception of actual contrast, size, or continuity can occur in patients with neuropsychiatric disorders (schizophrenia, epilepsy, and stroke) as well as in healthy subjects [31–33]. They are explained as “things seen seemed clearer or blurred; nearer or farther; larger or smaller; fatter or thinner.” If there are two vision systems, the next question is that which one is impaired in visual illusions. The work by Aglioti and colleagues [34] demonstrated that despite illusory perceptions of the size, the preshape aperture size was correctly determined in accordance with an actual size of the objects. This indicated that visual illusions might affect perceptual judgments rather than motor actions. But this hypothesis was rejected by Franz et al. [35] who provided evidence of the effect of visual illusions on both visual perceptions and motor actions. Note that visual illusions may also occur in response to tactile and auditory stimuli [36, 37], which are discussed in the next two chapters. 23 The Sixth Sense Organs: The Eyes 261

Presence as Place Illusion

Immersion into virtual reality can be as intense as perceptual illusions of reality. Simply speaking, the mechanism of action of immersive virtual reality (IVR) is that sensory augmentation [38]. It means that the more the sensorimotor contingencies an IVR can support, the stronger the illusions are [39]. And in turn, the stronger the illusions are, the more they can affect the subject’s behavior [40]. Keeping in mind its definition as “the sense of being there in the virtual environment,” presence is, in fact, an illusion of place (PI). On the other hand, plausibility illusion (Psi) is defined as “the illusion that the scenario being depicted is actually occurring.” It is suggested that the both of these variables play role in determining the extent of responsiveness of subjects to the IVR [39]. Such an IVR is similar to cinema, which brings us pleasure [41]. Therefore, it is possible to suppose that these types of illusions are often optimistic. This cannot be serious in today’s world where humans are always either consciously or unconsciously exposed to hear about negative forthcoming events, for example, age-related diseases [42]. Maybe these optimistic illusions provide a means to overcome today’s difficulties.

The Gaze Detection System: I Feel Someone Is Watching Me

The human can simply send his message to another person through eye-gaze. Studies show that another person’s direct eye-gaze conveys the tendency to approach whereas another person’s averted eye-gaze conveys the tendency to avoid [43]. The former causes a relatively left-sided EEG asymmetry, whereas the latter presents with a right-sided EEG asymmetry in the intended recipient of eye- gaze [43]. Perception of an eye-gaze, especially a direct eye-gaze, is accompanied by autonomic responses as well [43]. Brain regions that are active during perception of eye-gaze include superior temporal sulcus (STS), lateral fusiform gyrus (LFG), inferior occipital gyrus (IOG), and intraparietal sulcus (IPS) [44]. During perception of averted gaze, subjects exhibited higher activation within bilateral IPS and left STS than during perception of the direct gaze. As expected, patients with schizophrenia are good in detecting eye-gaze direction but are prone to misinterpret averted eye-gaze. This can be a result of self- referential processes in these patients [45]. More than interesting is the ability of children with autism spectrum disorder in detecting eye-gaze [46]. Autistic children not only spend less time to detect direct eye-gaze than typically developed children but also are significantly better at detecting averted eye-gaze. 262 A. Saghazadeh et al.

The Master Oscillator

The Circadian Clock and Presence

The circadian clock is well-conserved from bacteria to humans and therefore can be seen as an “origin of life” event. This clock enables the organism to predict the behavior of the surrounding environment and accordingly prepare the timing program of physiological functions [47]. Therefore, the circadian clock serves to maintain and manipulate physiological functions over presence. Supporting this is the dependence of the entrainment of the offspring circadian clock on maternal presence [48].

The Role of the Eyes in the Circadian Clock

In humans, the functional timing of the body’s peripheral organs, e.g. heart, lung, kidney, liver, spleen, stomach, and thyroid gland, is handled by a central circadian system that is the suprachiasmatic nuclei (SCN) (for review see [47]). Precisely, the light information will be transmitted from the retina to the SCN through the retinohypothalamic tract. Whereby, the electrical information carried by light will be converted into the chemical information. This chemical information is able to adjust the phase of clock genes in some neurons in the SCN. These neurons will, in turn, influence the other neurons through the interneuronal coupling. In this manner, all the SCN neurons represent the adjusted phase. The new phase is transmitted to the other brain areas and even to the peripheral organs and tissues. This is how the retina and SCN contribute to the road of transition to phase synchronization.

The Role of the Pineal Gland: From the Third Eye to the Circadian Clock

The Pineal Gland as the Third Eye

The pineal gland or epiphysis has provided a powerful extraocular photoreceptive structure to contribute to the evolution of nonmammalian vertebrates including reptiles, fish, and birds. As a result, the pineal gland is known as the third eye, the inner eye, the mind’s eye, or the pineal eye in the mentioned species. At the molecular levels, the photoreceptor function in both the pineal gland and retina involves the same mediators, e.g., opsins, transducin, cGMP-phosphodiesterase, cGMP- gated cation channel, and interphotoreceptor retinoid-binding protein (for review, see [49]). However, there are genes contributing to photoreceptor function that are 23 The Sixth Sense Organs: The Eyes 263 differentially expressed in the retina and in the pineal gland. Altogether, these findings support a partial overlap in the evolution of photoreceptor function between the pineal gland and retina.

The Pineal Gland as a Collection of Oscillators

The pineal gland exists in mammals and that the mammalian pineal cells have also retained the expression of some genes related to the photoreceptor function. So, it is obscure why the photoreceptor function of the pineal gland has not remained in mammals. A reasonable answer is that the photoreceptor function has been evolved to increase the function of the pineal gland in the circadian clock of mammals. Studies of the avian pineal gland reveal that this gland contains a collection of oscillators and that even less than 1% of the pinealocytes present rhythmicity in the synthesis of melatonin [50].

The Pineal Gland, Melatonin, and the Circadian Clock

In contrast to its photoreceptor function, the role of the pineal gland in the synthesis of melatonin (N-acetyl-5-methoxytryptamine) has been well conserved during evolution. The master oscillator, the SCN, chiefly regulates the synthesis of melatonin by the pineal gland. This regulation depends on the light/dark cycle and on the seasonal cycle. The pineal gland receives neural inputs of central, sympathetic, and parasympathetic origins. In particular, the retino-hypothalamo-pineal pathway conveys innervation from sympathetic nerves. The noradrenergic enzymes arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase are critical for daily and seasonal regulation of melatonin synthesis in mammals. In addition, various peptidergic and non-peptidergic transmitters play a role in the regulation of melatonin synthesis (for review, see [51]). Studies stress the effects of the hormone melatonin on the circadian clock, seasonal rhythms, immune system, neurotransmission, and the retina in mammals.

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Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei

Abstract In the previous chapter, we talked about how both visual perceptions and motor actions are impaired in visual illusions. We also discussed the role of eyes as provider of spatial presence. In this chapter, we will see that verbal hallucinations do not necessarily indicate the presence of psychopathologies. We also hear the orchestra of ears as the providers of both temporal and spatial dimensions of presence.

Keywords Auditory illusions · Auditory stimuli · Ear · Low-frequency oscillations · Presence · Sixth sense · Space · Time · Verbal hallucinations · Voice

The Vestibular System

The inner ear is equipped with vestibular structures evolved to achieve widespread success with sensorimotor functions. This success is indebted in a substantial manner to the integration of information from the vestibular system with that of other sensory sources (vision and proprioception). In this manner, the vestibular system primarily serves to detect the orientation and motion of the head relative to space, thereby maintaining posture and balance. This system also helps the body to initiate movements ranging from involuntary reflexes (of the head, gaze, and body) to voluntary movements in response to environmental cues. Higher cognitive functions which are fulfilled by the vestibular system include spatial memory and navigation. The central vestibular system receives in parallel regular and irregular afferents from peripheral sensory structures [1]. Regular afferents transmit information in accordance with their spike time patterns. Such precise spike timing windows are essential for information coding in sensory modalities, e.g., vision, audition, touch, and olfaction. Irregular afferents carry information about high-frequency stimuli associated with increasing the gain. Altogether, it is possible to be on the view that the vestibular system is an inher- ent multisensory and multimodal system [2] suggested to play a role in the sixth sense [3].

The Vestibular System as the Sixth Sense

The vestibular system is comprised of complementary organs including three orthogonal semicircular canals and two otolith organs that sense physical motions and gravity. Rotational movements are sensed by the semicircular canals whereas linear accelerations by the otolith organs. The vestibular system contains four cross- ings: three in the brain and one in the cortex. Involuntary reflexes occur at the brain stem/cerebellar level whereas voluntary motions at the cortical/subcortical level. However, the integration of vestibular and extra-vestibular (visual and proprioceptive) information can be observed in every level of the vestibular organization. The vestibular system owns an amazing ability to elicit sensorimotor responses of very short latency. This ability lies in the fact that there are neurons in the brain stem that can function as both second-order sensory neurons and premotor neurons for the vestibular system. As a result, these neurons can receive afferent sensory inputs and shortly after this, activate projections to motor neurons.

The Place Cells: The Real World Versus Virtual Reality

Although the place cells within the hippocampus are active during both real world and virtual reality, they are engaged twice in the real world compared with the virtual reality [4]. Additionally, the place cells are completely involved in encoding 24 The Sixth Sense Organs: The Ears 269 information about position in the real world. While, these cells particularly contribute to encoding information about distance in virtual reality. More interestingly, virtual reality appears to reduce the frequency of theta oscillations, the oscillations which are critical for the “on-line” state of the hippocampus [5].

The Voice Is the Only Thing that Remains

Humans rely on their visual rather than on their aural comprehension. Although vision is critical for scanning the spatial dimension of presence, the audition is that which well-represents the acceleration of time. In contrast to the resistance of spatial properties against changes, momentariness is the nature of time. Audition at each point of time and its characteristics remain constant over time so that the stream of auditory information serves as an indicator of temporal segmentation. Therefore, articulation is suggested as the way through which archaeological knowledge can be transmitted [6]. But this approach is constrained with the neglect of sound. This approach primarily requires the skill of hearing.

Do You Hear Voices I Hear?

Although auditory verbal hallucinations often occur in the context of psychopathologies particularly schizophrenia, the general population is influenced by these hallucinations as well. On average, 10–15% of the general population have the experience of auditory verbal hallucinations. Of these, almost 1% report the frequent occurrence of such hallucinations. The most common hallucinations in the general population were “hearing a voice call one’s name aloud when alone” and “hearing one’s thoughts as if spoken aloud” [7]. The coping strategies used to deal with these hallucinations were mainly “distraction, ignoring the voices, selective listening to them, and setting limits on their influence” [8]. It remains controversial whether these hallucinations in patients with schizophrenia and schizotypal personality disorder and those in otherwise healthy people can be linked to the same entity [9, 10].

Auditory Illusions: A Means of Filling in Gaps in Speech

Despite the noises in the context, humans are able to hear the speech because of (1) sensory repair mechanisms and (2) the auditory continuity illusion [11]. Brain regions innervating repair mechanisms include the Broca’s area, bilateral anterior insula, and pre-supplementary motor area. Explained as follows are neural correlates of auditory illusions. These two processes jointly constitute a coherent perception of interrupted speech. 270 A. Saghazadeh et al.

Neural Basis of the Perception of Auditory Illusions

The Heschl’s Gyrus and the Superior Temporal Gyrus

A sound is categorized as (1) discontinuous if it is interrupted by silence and (2) continuous if it is interrupted by noise. In the study [12, 13], the authors used broadband Gaussian noise bursts as maskers. This study included two conditions: (1) interrupted target stimuli, where “onsets and offsets of gaps and maskers were synchronized,” and (2) uninterrupted target stimuli, where “no gaps were inserted in the target.” As compared with baseline, there was a relative increase in the activity of auditory cortex during perception of both interrupted and uninterrupted target sounds. The higher the levels of masking, the stronger the continuity of illusion for interrupted targets is. The lower the levels of masking, the stronger the true continuity for the uninterrupted targets is. Brain regions which are activity decreased with the level of masking for interrupted targets included the lateral transverse gyrus (Heschl’s gyrus, HG) and the superior temporal gyrus (STG). Of note was the direct association between the listeners’ perceptions of the continuity for interrupted targets and activity within a lateral part of the right HG and the left hemisphere. Best- frequency mapping underlined a low-frequency cluster within the HG and a cluster within lateral portion of the STG capable of innervating perceptions of continuity.

Low-Frequency Oscillations

In electroencephalogram (EEG), the noise intervals corresponded to an increase in the power of low-frequency theta oscillations (3–7 Hz) [13]. This noise-induced theta synchronization was more pronounced after a gap interval and for interrupted targets. In addition, a gap interval after interruption resulted in desynchronization of high-frequency beta oscillations (13–27 Hz).

Auditory Stimuli Induce Visual Illusions

This point was first established by Shams et al. 2000 [14, 15] who observed “when a single visual flash is accompanied by multiple auditory beeps, the single flash is incorrectly perceived as multiple flashes.” The effect of auditory stimulation is more evident when a single flash was presented in periphery compared with when a single flash was presented in fovea [16]. More interesting is the activation of the primary visual cortex (V1) by auditory stimuli. This activation is even more pronounced after the development of visual illusions [17]. In addition, Shams and colleagues [16] showed the modulating effect of illusory flashes on visual evoked potentials. They found that the temporal intervals of peak activities (the intervals 170–200 ms and 250–350 ms) during physical flashes overlap with those during illusory flashes in the timing, duration, and wave morphology. Altogether, such observations support the cross-modal interactions. 24 The Sixth Sense Organs: The Ears 271

References

1. Cullen KE. The vestibular system: multimodal integration and encoding of self-motion for motor control. Trends Neurosci. 2012;35(3):185–96. 2. Angelaki DE, Cullen KE. Vestibular system: the many facets of a multimodal sense. Annu Rev Neurosci. 2008;31:125–50. 3. Goldberg JM, Wilson VJ, Angelaki DE, Cullen KE. The vestibular system: a sixth sense. New York: Oxford University Press; 2012. 4. Ravassard P, Kees A, Willers B, Ho D, Aharoni D, Cushman J, et al. Multisensory control of hippocampal spatiotemporal selectivity. Science (New York, NY). 2013;340(6138):1342–6. 5. Buzsáki G. Theta oscillations in the hippocampus. Neuron. 2002;33(3):325–40. 6. Witmore CL. Vision, media, noise and the percolation of time: symmetrical approaches to the mediation of the material world. J Mater Cult. 2006;11(3):267–92. 7. Posey TB, Losch ME. Auditory hallucinations of hearing voices in 375 normal subjects. Imagin Cogn Pers. 1983;3(2):99–113. 8. Romme MAJ, Honig A, Noorthoorn EO, Escher A. Coping with hearing voices: an emancipa- tory approach. Br J Psychiatry. 1992;161(1):99–103. 9. Sommer IEC, Daalman K, Rietkerk T, Diederen KM, Bakker S, Wijkstra J, et al. Healthy individuals with auditory verbal hallucinations; who are they? Psychiatric assessments of a selected sample of 103 subjects. Schizophr Bull. 2008;36(3):633–41. 10. Daalman K, Boks MP, Diederen KM, de Weijer AD, Blom JD, Kahn RS, et al. The same or different? A phenomenological comparison of auditory verbal hallucinations in healthy and psychotic individuals. J Clin Psychiatry. 2011;72(3):320–5. 11. Shahin AJ, Bishop CW, Miller LM. Neural mechanisms for illusory filling-in of degraded speech. NeuroImage. 2009;44(3):1133–43. 12. Riecke L, van Opstal AJ, Goebel R, Formisano E. Hearing illusory sounds in noise: sensory- perceptual transformations in primary auditory cortex. J Neurosci. 2007;27(46):12684–9. 13. Riecke L, Esposito F, Bonte M, Formisano E. Hearing illusory sounds in noise: the timing of sensory-perceptual transformations in auditory cortex. Neuron. 2009;64(4):550–61. 14. Shams L, Kamitani Y, Shimojo S. Illusions: what you see is what you hear. Nature. 2000;408(6814):788. 15. Shams L, Kamitani Y, Shimojo S. Visual illusion induced by sound. Cogn Brain Res. 2002;14(1):147–52. 16. Shams L, Kamitani Y, Thompson S, Shimojo S. Sound alters visual evoked potentials in humans. Neuroreport. 2001;12(17):3849–52. 17. Watkins S, Shams L, Tanaka S, Haynes JD, Rees G. Sound alters activity in human V1 in association with illusory visual perception. NeuroImage. 2006;31(3):1247–56. Chapter 25 The Sixth Sense Organs: The Hands

Amene Saghazadeh, Helia Mojtabavi, Reza Khaksar, and Nima Rezaei

Abstract The representation of peripersonal space is a parallel processing that simultaneously calls for visual and somatosensory information. Having both tactile and visual receptive fields (RF), bimodal neurons mediate this parallel processing, and their damage, for example, due to stroke, can lead to disturbances in the perception of peripersonal space and therefore in being made aware of the self in the body. Of particular interest to this chapter is the role that the multisensory representations of the peripersonal space play in the unconscious form of the bodily self-consciousness.

Keywords Autism spectrum disorder · Bimodal neurons · Hands · Interoception · Mirror therapy · Peripersonal space · Proprioception · Rubber hand illusion · Schizophrenia · Sensory extinction · Sixth sense · Touch

Bimodal Neurons Encode the Peripersonal Space: Converging Evidence from Monkeys

From the 1980s to 1996, studies [1–5] performed in monkeys, whose brain resembles the human brain in structural and functional aspects, pointed to the existence of visual receptive fields (RFs) that were responsive to visual stimuli independent of eye position. These receptive fields were found in the periarcuate cortex [4], in the inferior area in the premotor cortex (area F4) [5], in the inferior area in the frontal lobe (area 6), in the parietal lobe (area 7b), and in the putamen [3]. In the periarcuate cortex, visually responsive neurons include pericutaneous (54%) and distant peripersonal (46%) neurons [4]. Pericutaneous neurons are mostly located caudal to the arcuate sulcus and effectively respond to the stimuli presented in “the space immediately surrounding our bodies,” the so-called peripersonal space. Distant peripersonal neurons reside in the rostral arcuate sulcus and are responsive to the stimuli presented within the animal’s reaching distance, referring to distant peripersonal space. In the putamen, responsive neurons consist of somatosensory (52.6%), visual (15.8%), and bimodal (visual and somatosensory) (31.6%) neurons. Somatosensory neurons are sensitive to manual palpation, joint manipulation, and gentle pressure and to skin stroking with a cotton swab. Their RFs are found on the tail, legs, trunk, shoulders, arms, face, and mouth. Visual neurons were only responsive to visual stimuli moving towards the face as far away as 50 cm. Having RFs on the face and arms, bimodal neurons are able to detect the light touch of the skin and the ray of light moving towards the face and arms. Bimodal cells can also be divided into three sets: A, B, and C. Both A and B cell types were responsive to tactile stimuli at the contralateral arm and visual stimuli in the contralateral periphery. Bimodal cells of C type have bilateral RFs for both tactile and visual stimuli. All the three types were able to detect stimuli as far away as 1.5 m. In area 7b of the parietal lobe, responsive neurons included somatosensory (31%), visual (22%), and bimodal (47%) neurons. Somatosensory neurons appear to be accumulated in the face. The area 7b contains a rich source of bimodal neurons with tactile receptive fields located on the face, arms, chest, and the whole upper body. According to the RF size, visual RFs of bimodal cells are categorized into three: (1) RFs responsive to stimuli as far away as 20 cm, (2) RFs responsive to stimuli as far away as 1 m, and (3) a minor proportion of RFs responsive to the stimuli as far away as 2 cm. Bimodal cells type A possess tactile RFs at the contralateral arm and visual RFs in the contralateral side of the lower visual field. This type of cells effectively responds to touching the jaw. Bimodal cells of both types 25 The Sixth Sense Organs: The Hands 275

B and C have tactile RFs at the contralateral arm and face and visual RFs in the contralateral periphery. In addition to the mentioned difference in RF size between these types of cells, type A and B cells are only sensitive to visual stimuli approaching the face, whereas type C cells can respond to visual stimuli presented within their RFs regardless of movement direction. Of F4 neurons, 87% are responsive to sensory stimuli. They can be categorized into somatosensory (30%), visual (14%), and bimodal neurons (56%). The response of somatosensory and bimodal neurons can be elicited by light touch, whereas the response of visual neurons is mainly induced by an approaching object. RFs of somatosensory and bimodal neurons are often placed in the face, neck, trunk, and arms. While visual RFs are often present in peripersonal space. Most of the neurons residing in visual RFs are insensible to eye position, the so-called somatocentered neurons, but are more sensitive to stimuli moving at a faster speed. The above are among the earliest studies of the specification of region-specific bimodal neurons in monkeys. Thereafter, many studies describing structural and functional properties of bimodal neurons in other brain regions, for example, the ventral intraparietal (VIP) area, have been published [6]. Studies converge on the following items as the functional properties of the bimodal neurons: 1. “visual and tactile RFs are in spatial register, that is, visual RFs match the location of tactile RFs on body surface 2. visual RFs have limited extension in depth, being restricted to space immediately surrounding the monkey’s hand, face or body 3. visually related activity shows a response gradient, that is, the discharge decreases as the distance between visual stimulus and cutaneous RF increases 4. visual RFs operate in coordinate systems centered on body parts; they remain anchored to the tactile RFs of a given body part when this is moved, and their spatial locations do not change when the eyes move” (for a review, see [7].) It should be noted that hand mirror neurons responding to the observation and performance of motor actions have also been implicated in the processing of the monkey’s peripersonal and extrapersonal space [8]. Taken together, these monkey studies well-served to move the field “peripersonal space” forward.

Sensory Extinction

To realize the functional properties of bimodal neurons in humans, it is sufficient to recognize the effects of their dysfunction. In general, the term sensory extinction refers to conditions where the ability to simultaneously detect more than one sensory stimuli is deteriorated. This condition is frequently seen in patients with stroke, with this common pattern that patients are unable to perceive a contralesional (on the opposite side to the lesion) sensory stimulus if it is co-present with an ipsile- sional (on the lesion side) sensory stimulus [9]. Sensory extinction can occur as unimodal (tactile, visual, or auditory), multimodal, and cross-modal [10, 11]. 276 A. Saghazadeh et al.

Extinction to tactile stimuli is more common in patients with stroke and can be used to predict the functional status of these patients [12]. In [13], di Pellegrino reported a case presented with cross-modal extinction to tactile stimuli, when “an ipsile- sional visual stimulus could induce extinction of a contralesional tactile stimulus.” The patient was able to detect unilateral tactile and visual stimuli. However, tactile extinction was evident when bilateral stimuli were presented. The above case and many similar cases [14] support the view that the representation of peripersonal space is a parallel processing that simultaneously calls for visual and somatosensory information. Having both tactile and visual RFs, bimodal neurons mediate this parallel processing [15], and their damage, for example, due to stroke, can lead to disturbances in the perception of peripersonal space and therefore in being made aware of the self in the body.

The Peripersonal Space: The Unconscious Regulator of Bodily Self-Consciousness

The bodily self-consciousness which can be defined as “the nonconceptual and pre- reflective representation of body-related information” is comprised of different components including self-location, self-identification, and the first-person perspective [16]. Studies demonstrate that disturbances in the multisensory integration would predispose individuals to out-of-body experiences (OBEs). OBEs occur in conjunction with three possible impressions: 1. “the self is localized outside one’s body (disembodiment or extracorporeal self-location) 2. seeing the world from an extracorporeal and elevated first-person perspective 3. seeing one’s own body from this perspective” [16] Of particular interest to this chapter is the role that the multisensory representations of the peripersonal space play in the unconscious form of the bodily self- consciousness. This was suggested by the work of Salomon et al. [17] who investigated whether the multisensory inputs below the threshold of consciousness can influence the multisensory integrations required for the bodily self-consciousness in humans. Multiple experiments led to the conclusion that if subthreshold visual stimuli are presented within the peripersonal space, then they can effectively promote processing of tactile stimuli such that the body will be able to detect near- threshold tactile stimuli.

On the Specific Role of Touch

Sensory inputs that are required for the processing of peripersonal space come from different modalities including vision, audition, and touch. Parietal–frontal bimodal neurons are responsible for the processing of peripersonal space, which contributes 25 The Sixth Sense Organs: The Hands 277 to defensive movements and voluntary actions. The peripersonal space was defined above as “the space immediately surrounding our bodies.” It is deemed to be different from the concept “body schema” which is defined as “a representation of body- parts’ dimensions and positions in the external space” (for a review, see [18]). The processing of body schema calls for sensory inputs from modalities proprioception, kinesthesis, and touch and occurs in the pre-frontal and parietal cortex. In this manner, multisensory representations of the peripersonal space are not simply and absolutely distinguishable from the representations of body schema, and they play a coordinated role in preparing the body for actions [19]. The motive behind placing this paragraph here is to point to the role that tactile inputs have in representations of both the peripersonal space and the body schema.

Peripersonal Space and Body Schema Are in Hand

Iriki et al. [20] investigated whether the neural processing of body schemata is influenced by using a hand-held tool (rake). The authors mapped neural activity within the caudal postcentral gyrus when macaque monkeys were trying “to retrieve distant objects using a rake.” The region of interest was found to have bimodal neurons and that monkeys exhibited an enlarged visual RF during tool use. The study [21] was also aimed to assess the effect of a hand-held rake on the severity of cross-modal tactile extinction in patients with unilateral stroke (n = 7) and left tactile extinction under different conditions: pre-tool, post-tool immediate, post-tool delayed, and post-pointing immediate. Patients were asked “to use a tool to retrieve objects located out of the hand-reaching space.” Overall there was a significant difference in the detection of left tactile stimuli between experimental conditions. In particular, the worst performance was on the post-tool immediate condition, compared with the pre-tool condition and with the post-tool delayed condition. In fact, the performance of patients returned to baseline after “a short period of time during which patients were required to hold the rake.” By a method similar to the above, there have been reported many studies confirming that hands and their held tools bring a remarkable dynamical plasticity to the peripersonal space and body schemata [22]. Below we will see that even a dummy hand can bring such an effect.

Neural Coding of Peripersonal Space in Humans

Multiple lines of evidence indicate the collective contribution of premotor-parietal areas to the sensorimotor integration in achieving the representation of hand peripersonal space [23, 24]. Experimental conditions that are used in humans for the study of neural correlates of peripersonal space and body schema are interesting to be mentioned at least once in the Book. Below we will describe one of these studies. 278 A. Saghazadeh et al.

Makin et al. [25] collected fMRI data in healthy subjects (n = 11) and “con- trasted the BOLD response to the ball approaching and receding from the left hand with the response to a ball approaching and receding from a distant target far from the hand” under four experimental conditions: (1) real-hand experiment, “where the subject’s left hand was placed (palm up) on a table above the subject’s left thigh and”; (2) retracted-hand experiment, where “the subject’s left hand was retracted toward their left shoulder and covered from sight”; (3) occluded-hand experiment, where “the subject’s hand was placed close to the near target, no visual feedback of hand position was available, so that any specificity for the near ball was likely to be based on proprioceptive information”; and (4) dummy-hand experiment, where “a realistic dummy hand was placed by the near target, while the subject’s own hand was retracted away. This created the illusory visual input of a hand positioned close to the near target, thus conflicting with veridical information from proprioception regarding the subject’s actual hand position.” During the experiment A, the right hemisphere activity dominated the left hemisphere activity. Right hemisphere regions that were more active included the occipital cortex, extending from the calcarine sulcus (CalS) and the posterior collateral sulcus (pColS) reaching into the caudal part of the intraparietal sulcus (IPS), the parietal cortex along the IPS and the intraparietal transverse occipital cortex (IPTO), the frontal cortex around the middle frontal sulcus, the ventral premotor cortex (PMv), and the right lateral occipital complex (LOC). Right hemisphere regions including the occipital cortex (CalS, pColS, and IPTO) were recruited during experiment B. During experiment C, these regions along with a small cluster in PMv within the inferior frontal gyrus were active. Finally, the right hemisphere regions required for the experiment D were located within the occipital cortex (CalS, pColS, and IPTO), LOC, and within the posterior parietal cortex along the IPS. The authors also investigated the BOLD response to tactile stimuli and found brain regions that were activated by both visual and tactile stimuli. These regions included the postcentral sulcus and the anterior section of the IPS for experiment A and the right superior parietal gyrus and left inferior postcentral sulcus for experiment D. The above example study suggests the IPS as a brain region that mediates innervation of visuotactile representations of the hand peripersonal space. Also, it provides a clear demonstration of the potential effect of a dummy hand on the representation of peripersonal space, an effect that is as much analogous to that of the real hand such that it is not a dummy hand.

Rubber Hand Illusion

We have a feeling of ownership of our body and limbs, that is, “when we look at our hands, we immediately know that they are part of our own body” [26]. Studies suggest there are individual differences [27] involved in the biological development of 25 The Sixth Sense Organs: The Hands 279 this feeling of ownership [28]. The illusion regarding this ownership is referred to as the rubber hand illusion, that is “watching a rubber hand being stroked, while one’s own unseen hand is synchronously stroked, may cause the rubber hand to be attributed to one’s own body, to feel like it’s my hand” [29]. Simply speaking, this illusion induces the mind to enter the rubber hand into the mental representations of one’s own body parts. Despite sporadic reports, it was not until the late 1990s and early 2000s that repeated studies about the mechanism of action of this common out-of-body illusion began to emerge (for review see [30]). One of such earliest studies is the work by Botvinick and Cohen [31]. This work examined the self-reported experiences of healthy subjects when their hidden hand and the rubber hand were stroked (with brushing) in a synchronous manner. The most common experiences were: (1) “it seemed as if I were feeling the touch of the paintbrush in the location where I saw the rubber hand touched, (2) it seemed as though the touch I felt was caused by the paintbrush touching the rubber hand, and (3) I felt as if the rubber hand were my hand.” Thereafter, many studies with interesting experimental conditions were depicted [32].

Rubber Hand Illusion: A Constraint Satisfaction Problem of Exteroception, Interoception, and Proprioception

Botvinick and Cohen [31] observed proprioceptive drift (displacement of reaches toward the rubber hand) in subjects after illusion and that the more time the subject experienced the illusion, the more his proprioceptive acuity was worsened. So it was understandable to propose a constraint satisfaction problem where vision, touch, and proprioception are coupled to each other as well as to the rubber hand illusion. As a result, proprioceptive drift has been and is an objective behavioral measure of the rubber hand illusion. However, Rohde et al. [33] reported the demonstration of proprioceptive drift in the asynchronous condition when the subjective rating of the rubber hand illusion is low. Also, they could not confirm the finding of Botvinick and Cohen 1998 that proprioceptive drift is significantly increased by synchronous versus asynchronous visuotactile stimulation. More clearly, in the study by Rohde et al., there was no significant difference in proprioceptive drift between synchronous and asynchronous visuotactile stroking. Moreover, this study found proprioceptive drift when only visual stimuli were applied. Interestingly, proprioceptive drift was nearly abol- ished with continuous asynchronous stimulation. These lines of findings posed the question of whether proprioceptive drift can still serve to dissociate the feeling of ownership from the feeling of no-ownership. Besides the role of proprioception and exteroception (vision and tough), recent studies ascribe a role to interoception in the multisensory integration and therefore in the experience of body ownership. 280 A. Saghazadeh et al.

For example, the study by Suzuki et al. [34] included three blocks, each one having four trials. Before the trial began, individual interoceptive sensitivity was assessed using a feedback test “in which participants were asked to judge whether auditory cardiac feedback was synchronous or asynchronous with their heartbeat.” Each trial was divided into the following components: resting period, first proprioceptive drift test, induction period, second proprioceptive drift test, and self-report questionnaire. Proprioceptive drift difference (PDD) was defined as the change in the proprioceptive drift from before to after the induction period. There were three induction conditions, each one having “synchronous and asynchronous feedback subconditions.” Induction conditions included (1) cardiac still, where “participants were instructed to keep their left hand still and to focus their gaze and attention on the visual pulsing of the virtual hand”; (2) cardiac move, where “participants were instructed to move their fingers without any constraints other than to keep their hand in the same place, while still focusing on the virtual hand”; and (3) tactile, where “the real hand was stroked with a paintbrush while tactile-visual feedback was presented via the head-mounted-display; again participants were asked to focus on the virtual hand.” In conditions 1 and 2, “the virtual hand was modulated by cardio-visual feedback for the full 120s”. The study revealed that PPD is significantly influenced by condition and feedback such that higher PDD values are observed with synchronous feedback compared with asynchronous feedback in conditions 1 and 3. While in condition 2, high PPD values were comparable at synchronous and asynchronous feedbacks. Altogether, these lines of evidence support the view that both bottom-up and top- down processes play a role in the regulation of the rubber hand illusion [29].

Rubber Hand Illusion: An Intersensory Bias

Rubber hand illusion is seen as a consequence of intersensory bias which can be treated by introducing an asynchrony. Studies [31, 35] show that asynchronous stimulation of the hidden hand and the rubber hand would dramatically reduce the prevalence of illusion and the magnitude of post-stimulus proprioceptive drift compared with when synchronous stimulation is applied. Temporal discrepancies between visual stimulation of the rubber hand and tactile stimulation of the subject’s hand also appear to affect the subjective vividness of rubber hand illusion [36]. The rated illusion strength was high when there were temporal discrepancies of less than 300 ms. The postural mismatch between the rubber hand and the subject hand due to the postural change of the rubber hand could obliterate illusion from the subject’s mind [37]. Such an effect was not observed with the postural mismatch between the rubber hand and the subject hand due to the postural change of the subject’s hand [37]. More interesting is the combined effect of the mode of stimulation and postural mismatch on the rubber hand illusion. In the study by Tsakiris and Haggard [29], the congruent posture condition, where subjects viewed “the rubber hand in a congruent 25 The Sixth Sense Organs: The Hands 281 position with their own unseen hand”, resulted in the greater proprioceptive drift in synchronous versus asynchronous visuotactile stroking, whereas under the incongruent condition, where the rubber hand was rotated by −90° with respect to the subject’s hand, the proprioceptive drift in synchronous visuotactile stroking was lower than that of asynchronous stroking. Additionally, rubber hand illusion was developed under congruent condition but not under incongruent condition. Another potential factor that has been shown to affect the rubber hand illusion is the subject’s hand movement in terms of stronger illusion with active movement of the hand and weaker illusion with passive movement of the hand [38]. In the active movement condition, subjects were trained “to move their arm continuously in a horizontal plane while being exposed to the similarly moving rubber hand”. In the passive movement condition, subjects were trained to “relax their right arm and to not resist the ensuing movement.”

Rubber Hand Illusion and Reality

The study [39] examined the rubber hand illusion in three experimental conditions: (1) reality, “when one’s own hand is placed out of view and a visible fake hand is repeatedly stroked and tapped in synchrony with the unseen hand”; (2) virtual reality, “where both the fake hand and its stimulation were projected on the table in front of the participant”; and (3) mixed reality, “where the fake hand was projected, but its stimulation was unmediated.” The highest illusion strength was observed in the real condition, while the illusion strength in the virtual reality was comparable to that of the mixed reality condition.

Rubber Hand Illusion and Peripersonal Space

As mentioned above, rubber hand illusion is associated with the proprioceptive drift toward the rubber hand. In addition, recent research demonstrates the extension and switching of real peripersonal space boundaries into the realm of the virtual body [40]. Again this effect was observed only with synchronous visuotactile stroking, not with asynchronous visuotactile stroking.

Neural Correlates of Rubber Hand Illusion

As reviewed in [30], neuroimaging studies demonstrate that the initiation of rubber hand illusion requires both the premotor cortex and the parietal cortex, while its propagation engages the right insula, in particular, the frontal operculum. The first of these studies, by Ehrsson and colleagues [26], looked at the brain regions 282 A. Saghazadeh et al. related to the development, severity, and temporal progression of rubber hand illusion. First, brain regions critical for the development of the illusion condition were located within the posterior bank of the precentral sulcus (ventral premotor area 6), the anterior bank of the precentral sulcus (posterior part of area 44, and the bilateral frontal operculum. Second, activity within the regions including left precentral sulcus, right precentral sulcus, and right lateral cerebellum was directly associated with severity of illusion. Third, an increase in the activity of bilateral precentral sulcus and right cerebellum occurred at the time when subjects reported the initiation of illusion (usually 11 seconds after synchronous stimulation). In another interesting study, Ehrsson et al. [41] tracked the effect of threatening a rubber hand on neuronal activity during the illusion. After confirming higher illusion strength with synchronous stimulation than with asynchronous stimulation, the synchronous stimulation and asynchronous stimulation conditions were called as “ownership” and “no-ownership” conditions, correspondingly. Threatening a rubber hand caused anxiety levels to rise. Of note, this raise was comparable to that when the subject’s hand was threatened but was more pronounced in the “ownership” condition than in the “no-ownership” condition. Then, the fMRI data collected during “threat-ownership” condition were con- trasted with those recorded during “threat-no-ownership” condition. Analysis indicated two regions substantially critical for the feeling of “ownership” as well as for the response to the threat. These were the border zone between presupple- mentary motor area (pre-SMA) and supplementary motor area (SMA) proper. Additionally, regression analyses related the illusion’s vividness to the increased activity within the left anterior insular cortex, right anterior insula, and within the bilateral ACC. Finally, the authors found correlations between activity within the ownership-associated regions (the bilateral ventral premotor cortex and the left intraparietal cortex) and activity within the threat-related regions (the left anterior insular cortex and insula). To describe the role of the inferior parietal lobule (IPL) in the rubber hand illusion, Kammers and collaborators applied repetitive transcranial magnetic stimulation (rTMS) over the IPL. In immediate perceptual judgments (“immediately after the induction of illusion”), rTMS over the IPL led to the reduction of illusion strength [42], while in the delayed perceptual judgments (“after making two reach- to-point movements”), rTMS over the IPL exerted no influence on the illusion strength. In addition, rTMS affected neither proprioceptive drift (assessed by reach- to-point movements) nor the feeling of ownership of the rubber hand. Based on these findings, the authors proposed that the role of IPL might be critical for perceptual body judgments, but not for perceptual body actions (proprioceptive drift) and affective body judgments (the feeling of ownership). In addition, EEG studies reveal that rubber hand illusion is accompanied by an increase of interelectrode oscillatory synchronization in the high-frequency (gamma-band) range [43, 44]. 25 The Sixth Sense Organs: The Hands 283

Schizotypal Symptoms Strengthen Rubber Hand Illusion

The study [35] demonstrates that during synchronous stimulation, patients with schizophrenia are more likely to develop rubber hand illusion and present greater and larger proprioceptive drift, compared with controls. More interesting was the positive association of self-reported illusion with both positive and negative schizotypal symptoms in healthy controls. This indicates that the more the schizotypal symptoms, the higher the probability of rubber hand illusion. Another study by Germine et al. [45] correlated the rubber hand illusion with positive, but not with negative, psychosis-like symptoms in healthy subjects. As well, this study confirmed that introducing an asynchronous visuotactile stimulation would abrogate the illusion-psychosis correlation. Peled et al. [46] compared EEG data before and during the illusion period in patients with schizophrenia compared with controls. At the longest somatosensory evoked potentials (SEP) latency, the pre-illusion values in two electrodes C4 and P4 were higher compared with illusion period in patients with schizophrenia. In contrast, pre-illusion values in these electrodes were lower than illusion values in control subjects.

Empathy Increases Rubber Hand Illusion: Evidence from Patients with Autism Spectrum Disorder

Studies show that children aged 4–9 years are sensitive to visuotactile synchrony similar to adults [28]. In the study [47], before brushing begins, children with autism spectrum disorder (ASD) were as good in proprioceptive judgment as typically developed (TD) children. During both blocks of asynchronous stroking (each block lasted for 3 minutes), neither ASD nor TD children reported the illusion. In contrast, during both blocks of synchronous stocking, TD children experienced the illusion, while children with ASD exhibited illusion only after the second block of synchronous stocking (from minute 6). Consistently, during asynchronous stroking, the proprioceptive drift declines for both groups. During synchronous stroking, control children showed a reduction in the proprioceptive drift from block 1 to block 2, whereas autistic children showed a remarkable increase in the proprioceptive drift from block 1 to block 2. Among children with ASD, there was a negative correlation between empathy scores and illusion. Paton et al. [48] confirmed that self-reported feeling of illusion in patients with autism was comparable to that in controls following asynchronous stroking. But, patients rated higher feeling of illusion during synchronous stroking. Interestingly, patients with autism were better in proprioceptive performance than controls, and this better performance was present in both asynchronous and synchronous conditions. 284 A. Saghazadeh et al.

These findings indicate that patients with ASD display a delay in initiating the illusion, which might be a reflection of (a) abnormal multisensory integration or (b) better proprioceptive acuity in these patients.

Rubber Hand Illusion and Physiological Responses

Temperature

The skin temperature reduces in the stimulated hand and rises in the unstimulated hand [35]. This thermal alteration is more pronounced during the stimulation of the right hand rather than during the stimulation of the left hand [35]. This might be due to the higher baseline temperature of the left hand. In addition, the experimental condition might affect skin temperature so that lower temperatures are observed with synchronous stimulation compared with asynchronous stimulation [49]. In contrast, Rohde et al. [50] evaluated alteration of skin temperature during rubber hand illusion induced by a manual arm versus an automated arm. Despite the development of illusion by synchronous stocking in both conditions, hand cooling was only present in the manual stimulation condition, not in the automated stimulation condition.

Skin Conductance Response (SCR)

In the work by Armel and Ramachandran [51], participants looked at “the fingers of the fake hand and hidden real hand which were simultaneously stroked, tapped, and lifted in synchrony” under three experimental conditions: (1) “after 2.5 min of the touching procedure, both the real and fake fingers were lifted, but only the fake finger was bent into a ‘painful’ position”, (2) “a barren table was stroked and tapped in the same manner and in the same relative locations as the real hand”, and (3) “each subject viewed touch to a fake hand in a ‘realistic’ location in one condition and then to a distant fake hand in another”. All the three experiments showed that the illusion strength and SCR for the fake hand or for the table were significantly increased compared with their control conditions. In contrast, both illusion and SCR were attenuated “if the real hand was simultaneously visible during stroking, or if the real hand was hidden but touched asynchronously.” In the study of Petkova and Ehrsson [32], participants viewed “a body other than oneself from the first person perspective whilst being subjected to synchronized visual and tactile stimulation.” A life-sized mannequin was used as the other’s body. In the threatening condition where subjects viewed “a knife ‘cutting’ the mannequin’s abdomen”, subjects showed an increase in the SCR. The magnitude of this increase was higher with (1) knife usage compared with spoon usage, 25 The Sixth Sense Organs: The Hands 285

(2) “synchronous visuotactile stimulation of either the hands or the abdomen” compared with asynchronous stimulation, and (3) mannequin compared with a rectangular object.

Histamine Reactivity

In a single-blind randomized experiment, Barnsley et al. [52] established a role for histamine in the induction of rubber hand illusion. Healthy subjects were assigned to control and experimental arms. Subjects in the experimental arm received an intradermal injection of histamine. The authors observed an interesting linear relationship between the size of wheal (raised edematous region around the site of injection) and the vividness of rubber hand illusion in participants who received histamine and developed illusion. The size of wheal is a plain reflection of individual sensitivity to the applied allergen, that is, the greater the size of the wheal, the more active is the histamine. This hyperactivity following antigen challenge seems to be mediated via the vagus nerve such that it can be abrogated in pigs by vagotomy [53]. In the previous chapters, the vagus nerve has been recurrently mentioned.

Mirror Therapy

Ramachandran et al. [54] demonstrated that seeing the movement of a real hand, either his own hand or the experimenter’s hand, while it is superimposed on the phantom hand, in the mirror induces the feeling of movement of the phantom hand. Also, mirror therapy could resolve clenching spasms in the phantom hand immediately and revive the phantom hand in long term. In a randomized, sham-controlled trial [55], patients who suffered from phantom limb pain after amputation of a leg or foot were allocated to three groups: (1) mirror group (n = 6), where subjects “attempted to perform movements with the amputated limb while viewing the reflected image of the movement of their intact limb”; (2) covered mirror group (n = 6), where subjects “attempted to perform movements with both their intact and amputated limbs when the mirror was covered by an opaque sheet”; and (3) mental visualization (n = 6), where subjects were trained to “close their eyes and imagine performing movements with their amputated limb.” After 4 weeks of treatment, effective alleviation of pain was observed for all patients in the mirror group, whereas overall only three patients from other two groups reported pain reduction. There have been reported many studies examining the effectiveness of mirror therapy for the recovery of motor function [56–61] and alleviation of pain [62, 63] after stroke (for a review, see [64]). Even more interesting is the effect that mirror therapy can produce on the cortical organization. More precisely, fMRI studies suggest that mirror therapy helps to reduce inter-hemispheric neural activity imbalance 286 A. Saghazadeh et al. by shifting to the affected primary motor cortex [65]. However, some argue that mirror therapy engages the precuneus and the posterior cingulate cortex, and this engagement is in fact responsible for the effectiveness of mirror therapy [66].

References

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Amene Saghazadeh, Reza Khaksar, and Nima Rezaei

Abstract The application of both embryonic stem cells and adult stem cells has been subject to certain restrictions that could be removed with the development of induced pluripotent stem (iPS) cells. The induction of pluripotency is a complex process through which the effects of (a) exogenous and endogenous transcription factors and their interaction with each other and with molecular components of chromosome, (b) matrix elasticity and nuclear plasticity, and (c) intrinsic and extrinsic mechanisms of the asymmetric cell divisions are pooled and will be pronounced as the stem cell fate. Also, stem cells strongly feel about the effects of both ionizing and nonionizing radiation. The effects are dose-dependent and include cell death, mutagenesis, and tumorigenesis. Nevertheless, stem cells have been proven to play a role in the repair of radiation-induced multiorgan damage. Understanding the biology of stem cells, particularly iPS cells, and their biophysical behavior, especially upon exposure to radiation, helps to make further advances in both the field of regenerative medicine and disease treatment and prevention.

Keywords Induced pluripotent stem cells · iPSC · Regenerative medicine · Radiation · Sixth sense

Introduction

The essential features that distinguish stem cells from other cell types include the ability to self-renew and the ability to differentiate into more specialized cells. Stem cells demonstrate these abilities in physiological conditions and under pathological conditions as well. According to their abilities, they can help regenerate the damaged tissue, and this has revolutionized the field of regenerative medicine, which refers to “an emerging interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any cause” [1]. Intriguingly, they proved their abilities in the process of carcinogenesis as well; here on, the term “cancer stem cell” is used to refer to cancerous cells that have the ability of self-renewal like stem cells [2]. However, on the whole, we cannot forbear to use stem cells, as they have generated substantial profits for the treatment of different diseases. The three main types of stem cells are embryonic stem cells, adult stem cells, and induced pluripotent stem cells (iPSC). Embryonic stem cells and adult stem cells differ in almost all respects, including artificial system, pluripotency, efficient differentiation, the expression in culture, rare cell types, and the risk of teratoma [3]. There are few respects, however, in which they agree, such as “stemness.” Stemness is defined as that which supports the common abilities of stem cells to self-renew and to produce differentiated cells. Stemness is supposed to be consti- tuted of more than 200 genes that are involved in many cellular processes, mainly signaling, transcriptional regulation, DNA repair, cell cycle regulation, cell death, RNA processing, translation, protein folding, ubiquitin pathways, vesicle traffic, and toxic stress response [4]. Embryonic stem cells, which are isolated from the inner cell masses of blastocysts, are able to differentiate into cells of three germ layers. It is not surprising, therefore, that they can cause teratoma. Adult stem cells, also known as somatic cells, reside in different mammal tissues such as bone marrow, brain, spinal cord, blood vessels, peripheral blood, fat, skin, dental pulp, umbilical cord, digestive system, pancreas, and retina. They can be differentiated into neurons, glia, smooth muscle cells, and adipocytes based on their location of residence. Therefore, they are considered multipotent stem cells without increasing risk of teratoma. The application of both embryonic stem cells and adult stem cells has long been subject to certain restrictions. The major restriction of embryonic stem cells is that they are derived from embryos. Another serious restriction on the use of fetal cells is that they can be cancerous and form a tumor. For example, a case who suffered from ataxia telangiectasia developed glioneuronal tumor around 4 years 26 Stem Cells Have More Than Five Senses 291 after cell therapy with human fetal neural stem cells [5]. The major restriction of adult stem cells is that they are not pluripotent and therefore can be differentiated into certain specialized cells. The development of iPSCs could remove these restrictions. The iPSCs are developed through the induction of somatic cells by given transcriptional factors (e.g., the combination of Oct3/4, Sox2, c-Myc, and Klf4 or the combination of OCT4, SOX2, NANOG, and LIN28) in ES cell culture conditions [6, 7]. The iPSCs, which are the product of reprogramming of somatic cells to pluripotent cells, exhibit the properties (e.g., morphology, proliferation, cell surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity) that resemble those of embryonic stem cells [8]. Notably all cell types, i.e., mesodermal, endodermal and ectodermal cells, can be induced into iPSCs. Many factors, including growth factors, matrices, and forces, have been found to influence the generation and differentiation of iPSCs [9]. The biophysical behavior of stem cells forms the basis of future research in the field of regenerative medicine. However, first, understanding the biology of stem cell is needed. What stem cells are is a fundamental question that remains to be answered yet. For this reason, there is no way we can realize them unless being acquainted with their properties [10].

Endogenous vs Exogenous

Transcription factors are a fundamental requirement for induction of pluripotency. They have been proven to interact with cohesion components that contribute to the organization of chromosomes, another fundamental requirement for induction of pluripotency. The medium culture is the place where the effects of transcription factors (both exogenous and endogenous factors) and their interaction with each other and with molecular components of the chromosome are pooled and will be pronounced as the stem cell fate. Studies have established that transcription factors which are mainly involved in induction of pluripotent stem cells from multipotent cells include Oct4/Sox2/Klf4/c-Myc and Oct4/Sox2/Nanog/LIN28. Some somatic cells produce these factors endogenously. For example, neural progenitor cells (NPCs) produce Sox2 endogenously. This fact explains why NPCs can be reprogrammed into pluripotency state independent of the exogenous administration of Sox2 [11]. In addition to transcription factors, it has been revealed that certain small molecule compounds can result in reprogramming of somatic cells that endogenously do not express factors required for induction of pluripotency. For example, the combination of BIX-01294 (a diazepin-quinazolin-amine derivative that operates to hinder the function of G9a histone lysine methyltransferase [12]) and BayK8644 (a dihydropyridine that acts as an agonist of calcium channel [13]) could promote reprogramming of mouse embryonic fibroblasts [14]. 292 A. Saghazadeh et al.

Inside vs Outside

Outside the Cell: Matrix Elasticity

The integration of cells and organization of body is beholden to cell-cell junctions and the extracellular matrix (ECM) [15]. The ECM is constructed by proteins which are the most copious constituents of cells. It creates a non-cellular environment which is used by cells to communicate with each other and to be assembled into tissues. Cells secrete components of the ECM and it too, in turn, serves as a mediator of cell-cell interactions. As the ECM transfer extracellular forces to cells, cells transfer intracellular signals to the ECM [16]. Altogether there is a bilateral relationship between the ECM and cells which is reasonably regarded as an amazingly intricate structure. The ECM has been implicated in the whole stem cell behavior through its physical interactions with the cell, thereby influencing intracellular processes [17]. The physical properties of ECM known to influence the stem cell fate include rigidity, flexibility, and nanotopography. Stiff substrates made freshly isolated muscle stem cells lose the property of “stemness,” whilst soft substrates have been proven to provide the place ideal for freshly isolated muscle stem cells in culture [18]. Also, it was observed that softer gels compared with harder gels created a more suitable place where adult neural stem cells demonstrated increased differentiation capacity as measured by beta III Tubulin levels [19]. The iPSCs exhibit a very elastic behavior upon altering the properties of their microenvironment. It has been revealed that naïve mesenchymal stem cells cultured on soft, relatively stiffer, and rigid matrices were respectively committed to the neurogenic, myogenic, and osteogenic cell progeny after several weeks in culture. However, they were all reprogrammed into iPSCs during the first week of culture. Notably, the matrix elasticity was found to determine the lineage choice dependent on non-muscle myosin II [20].

Inside the Cell: Nuclear Plasticity

The nuclei of stem cells are more plastic than those of other cell types and therefore they are more prone to deformation. The nucleus plasticity is decreased as the level of differentiation increases. There was a sixfold increase in nucleus plasticity (as measured by the amount of deformation) among embryonic stem cells compared to adult stem cells. The Lamin A/C seems to largely determine the amount of deformation. This notion is upheld by observing that (1) the Lamin A/C is expressed in specialized cells, but not in stem cells, and (2) the removal of Lamin A/C led epithelial cells to be deformed like adult hematopoietic stem cells (HSCs) [21]. Like ECM, the cell material has been shown to influence the spreading and differentiation of embryonic stem cells. As mentioned above, the nuclei of 26 Stem Cells Have More Than Five Senses 293 undifferentiated cells are more plastic than that of differentiated cells. Murine embryonic stem cells (mES) were shown to be 10 times softer than mES-differentiated cells. The relative softness of mES, compared with mES-differentiated cells, would result in increased sensitivity and spreading in response to stress. In fact, the lower the degree of stiffness, the lower the threshold of spreading response is. However, it should be noted that the spreading response requires soluble factors as well, including myosin II contractility, F-actin, Src, or Cdc42 [22].

Intrinsic vs Extrinsic

As explained above, two features that distinguish stem cells from other cell types include the ability to “self-renew” and the ability to “differentiate” into specified progeny. To renew, they should produce cells with the stem cell identity, i.e., “stemness.” To differentiate, they should produce cells with the identity of certain progeny, referred to as the “differentiatedness.” Therefore, the maintenance of stem cells requires the asymmetric cell division(s), which may be acquired individually or collectively [23]. The former strategy, often adopted by a unicellular organism, means that a stem cell is constantly divided into a progenitor cell and a stem cell and thus each cell division is asymmetric. This strategy provides stem cell with a relatively “static” role. The latter strategy, often adopted by mammalian tissues, means that a stem cell based on the “balance of probabilities” can be divided sym- metrically or asymmetrically in three possible ways: two stem cells, a progenitor cell and a stem cell, or two progenitor cells. In this way, the asymmetry may be achieved at the end of a collection of cell divisions, and thus this strategy provides stem cells with a relatively “dynamic” role. The former one is intrinsically held constant over time and is not expected to be influenced by any external signal, reflecting the notion that elementary systems may use such strategy of maintenance, while using the latter strategy which is influenced by external signal reflects the complexity of that system, i.e., the stem cells, their niche, and interactions between them. Stem cells are keen to regulate and sustain the balance between asymmetric and symmetric cell divisions by means of the second strategy [24]. The symmetric division can be used to increase the number of stem cells, whereas the asymmetric division can be used to create progeny cells. This balance is very delicate. Individuals may be more susceptible to developing diseases, particularly tumors if such a delicate balance is disturbed. In addition, some clinical conditions may alter this balance. For example, the injury makes stem cells using symmetric division preferably because that regeneration requires a large number of stem cells. Mechanisms which operate to regulate the asymmetric cell divisions are broadly categorized into intrinsic and extrinsic. The “intrinsic” mechanism refers to the asymmetric segregation of cell fate determinants and the asymmetric localization of cell polarity factors operates independently of extrinsic signals.While the “extrinsic” mechanism refers to the asymmetric orientation of the mitotic spindle 294 A. Saghazadeh et al. retains operates under the influence of extrinsic signals [24]. Few factors known to control the stem cell division include developmental and environmental cues. Much research has been devoted to finding more such factors. Above we briefly discussed how inside and outside, intrinsic and extrinsic, and endogenous and exogenous factors influence the behavior of stem cells. To continue this discussion, we intend to illustrate our point of view with an obvious example. Suppose ground beef, its substance, and the stewpan to be stem cells, their microenvironment and the macroenvironment (i.e., the body). As we, based on the substance, can cook many delicious dinners with ground beef, from cheeseburgers with sautéed mushrooms, arugula, and Dijon to slow cooker bean and beef hot pot, stem cells, based on their microenvironment, can be differentiated into various types of progeny cells. Both of these events, i.e., cooking and differentiation, take place within a larger environment, i.e., the stewpan and the body. So far we know many aspects of the story but not all of them. Another important aspect of the story is the heat source, which may be a gas stove, induction cooktop, halogen cook top, etc. We regard the radiation effect for differentiation processes as tantamount to the heating effect for cooking purposes.

Radiation: Ionizing and Non-ionizing

Radiation is broadly categorized into two: nonionizing and ionizing. Nonionizing radiation refers to the types of radiation that have as much energy to pass through matters and excite cells but are not capable of ionizing atoms. Nonionizing radiation covers a broad spectrum of wavelengths and frequencies and is made up of two portions: electromagnetic fields and optical radiations. The former one includes microwaves, radio frequency, and extremely low-frequency (ELF) electric and magnetic fields. The latter one includes ultraviolet (UV), visible, and infrared (IR) radiation [25]. Ionizing radiation refers to radiation types with high amounts of energy so that they can ionize atoms while passing through matters. Ionizing radiation includes X-rays and gamma rays. The different types of nonionizing radiation have been associated with a variety of biological effects such as skin erythema, skin malignancies, photosensitivity, thermal injuries involving the retina, and heating effects [25]. Also, they have shown opposite effects on cell proliferation and growth [26, 27]. ELF magnetic fields, but not microwaves, appeared to augment cell proliferation in the human cells. More interestingly microwaves led to decreased cell growth, whereas ELF magnetic fields increased cell growth. Microarray study proved that the ionizing radiation elevated the expression of more than 30 genes which are known to take part in cell cycle regulation, apoptotic, and DNA damage repair processes [28]. Altogether current evidence indicates that ionizing radiation compared with nonionizing radiation seems to have more serious effects on intracellular pathways and processes even though both have been shown to exert significant biological effects. 26 Stem Cells Have More Than Five Senses 295

Are Stem Cells Sensitive to X-rays?

The notion that the occurrence of regeneration in animals is restricted to certain animals posed the question of what is required of regeneration that some animals have and others do not. The planarian, a platyhelminth, seems to be equipped with a high capacity for regeneration, and for this reason, planarian regeneration can be employed as a simple but very useful model in the study of regeneration in animals [29]. Cell proliferation and morphallaxis are regarded as the fundamentals of planarian regeneration, and neoblasts are thought to be totipotent stem cells that play a pivotal role in cell proliferation [30]. Neoblasts are X-ray sensitive cells. Notably, both X-ray-irradiated and non-irradiated planarians have shown the same morphology that resembles closely that of stem cells [31]. This suggests that X-ray irradiation is not likely to endanger the regeneration capability of neoblasts. The chromosomal aberration rate is used for measuring mutagenesis [32]. Study of mouse embryonic stem cells showed no significant difference in the aberration rate between sparsely ionizing X-rays-exposed and non-exposed cells. However, exposure to densely ionizing carbon ions significantly raised the aberration rate. Interestingly cells that survived at day 8 after exposure to either ionizing X-rays or carbon ions remained pluripotent [33]. X-ray exposures have long been employed in the study of mutagenesis in the experimental studies [34]. These studies led to the conclusion that the human genome is more prone to translocations than murine genome, while susceptibility to deletions and mutations did not differ between human and murine genome [35].

Are Stem Cells Sensitive to Gamma Rays?

Generally, radiation therapy (using X-rays, gamma rays, or high-energy particles) could provide cure rate of 40% for cancer patients [36], and for this reason, it is increasingly used for cancer treatment, and radiation oncologists have been specialized for this purpose. Inevitably, it may produce undesirable side effects, both acute and chronic. Acute side effects which often settle quickly once the course of treatment is finished include radiation sickness, hair loss, and dermato- logical side effects. Chronic side effects which are more serious than acute side effects include tissue injury (e.g., fibrosis and necrosis), memory deficits, and infertility problems. Particularly, gamma radiation has been considered to be one of the therapeutic options for the management of patients after state placement, due to its efficiency in reducing restenosis rates [37]. However, it has some unfortunate side effects, such as late thrombosis and myocardial infarction. Overall, the core goal of radiation therapy has always been to prevent specific unwanted accumulations, such as accumulations of cancerous cells or accumulations of calcium. 296 A. Saghazadeh et al.

Radioactive decay processes include alpha decay, beta decay, and gamma decay. Gamma decay processes that take place in the radionuclides such as cobalt-60, radium, and cesium emit a type of electromagnetic radiation, the so-called gamma radiation. Study of human mesenchymal stem cells demonstrated that gamma radiation emitted by a cobalt-60 source could lead to the induction of cell cycle arrest in G2 phase and thereby a decrease in proliferation rate, despite no significant effect on both viability and apoptosis of cells. Also, it increased activity, expression, or phosphorylation of proteins (e.g., cyclin-dependent kinases inhibitor 2A, senescence-associated β-galactosidase, and tumor suppressor protein 53 (p53)) that have been associated with cellular senescence and with suppression of tumor growth [38]. Even high dose of ionizing radiation did not alter the expression of stem cell markers, and reasonably mesenchymal stem cells could preserve the pluripotency capability [39]. Gamma radiation elicits the oxidative stress response in both human and rodent neural stem cells. Compared to rodent neural stem cells, the survival benefit of low dose and/or low dose rate priming was more pronounced in human neural stem cells. This might be due to increased production of oxidative stress products such as reactive oxygen and nitrogen species in human neural stem cells compared to rodent neural stem cells. In fact, it seems that the priming radiation-induced oxidative stress response which is remarkably enhanced in human neural stem cells protects cells against radiation challenges [40]. Notably, the study has indicated that antiradiation resistance is more prominent in quiescent neural stem cells than proliferating (i.e., active) neural stem cells. They employ cell cycle entry as an adaptive strategy to cope with radiation challenges. Reasonably this strategy is not applicable to proliferating and progenitor stem cells because the cell cycle is currently active in them [41]. As above mentioned, radiation therapy might cause tissue injury. Stem cells have been proven to play a role in the repair of radiation-induced multiorgan damage. A study has revealed that upon co-administration with hematopoietic stem cells, mesenchymal stem cells are found in injured organs such as the muscle, skin, bone marrow, and gut. More clearly, it seems that hematopoietic stem cells help mesenchymal stem cells choose injured tissues as their nests [42].

Are Stem Cells Sensitive to Radio Waves?

Radiation therapy holds great promise in treating brain tumors. However, it does not make a substantial profit for patients with glioblastoma as compared with patients who have other types of brain tumors [43]. This could be explained, at least in part, by radioresistance of cancer stem cells [44]. It has been shown that the relative amount of CD133-expressing glioma stem cells increased after radiation therapy. A proposed mechanism through which CD133-positive glioma cells might contribute to recurrent or refractory disease is promoting the activity of DNA damage checkpoints, i.e., Chk1 and Chk2, and reinforcing the DNA repair 26 Stem Cells Have More Than Five Senses 297 capability after radiation. In addition, radiotherapy has led to lower the risk of recurrence. However, it cannot completely remove the risk of recurrence [45]. Therefore radiation therapy is at the present unable to satisfy all the patient demands. As stem cells (e.g., central nervous system stem cells, HSCs, and epithelial stem cells) compared to their progeny cells had lower levels of reactive oxygen species (ROSs), their cancer stem cells compared with non-cancerous cells had lower levels of ROSs [46]. This observation in addition to the notion that ROSs contribute to the high-energy radiation-induced DNA damage [47, 48] propose ROS depletion as a mechanism by means cancer stem cells reduce their sensitivity and will develop resistance to radiation. Therapeutic targeting of ROS scavengers that has shown to sensitize cancer stem cells to radiation is an important aspect that should be considered in the radiation therapy. Studies of mice have indicated that hematopoietic stem cells (HSCs) are made up of two main subpopulations: pluripotent and multipotent. They can be distinguished based on the presence or absence of stem cell antigen-1 (Sca-1).The Sca-1-positive population that is known for their pluripotent capability comprises only 0.05% of the murine bone marrow cells. Despite the relatively small quantity, they are considered to be highly potent. They cannot only produce progeny of all hematopoietic and lymphoid lineages but also powerful protective effect against the lethal dose of radio frequency (RF) radiation. The transfer of only 30 Sca-1-positive cells has led to the survival of 50% of mice exposed to lethal radiation, while at least 13,000– 33,000 Sca-1-negative cells must be transferred to obtain comparable yields [49]. As a result, Sca-1-positive cells have represented a ~400- to 1100-fold increase in radioprotection activity compared with Sca-1-negative cells. Side population consists of bone marrow cells which are phenotypically similar to multipotent HSCs and thus can produce progeny of lymphoid and myeloid lineages. Also side population cells, compared with whole bone marrow cells, have led to a ~300-fold increase in radioprotection activity [50]. Mesenchymal stem cells derived from the adult bone marrow, the so-called multipotent adult progenitor cells (MAPCs), demonstrated ability to differentiate into multiple cell lineages, including the hematopoietic and digestive lineages. Consistent with their radiosensitivity, low-dose irradiation has been indicated to enhance the engraftment of MAPCs into the haematopoietic and digestive system [51]. Some organs and cells that are known to be highly radiosensitive include the lymphoid organs, bone marrow, white blood cells, testes, ovaries, and intestines.

Stem Cells and Sensitivity to High-Energy Alpha Particle Radiation

Studies have shown that people who reside in Radon zones or people who work in Uranium mines are more prone to develop lung cancer than the general population [52–55]. Radon which is one of the decay by-products of Uranium-238 emits alpha particles. The tumorigenic effect of Radon exposure is thought to be at least in part owing to high-energy alpha particles. These particles are heavy such that 298 A. Saghazadeh et al. they cannot pass through the epidermis. Therefore the only way they can get into the body would be through swallowing and inhalation, and this can result in mutagenic and carcinogenic events in lung tissues. Because the observed mutagenic effect of alpha particles was greater than the expected effect [56], it has been suggested that the mutagenic effect of alpha particles is the sum of the radiation- induced direct effect and the radiation-induced bystander effect. Given the fact that the radiation-induced bystander effect is innervated by the cell-cell communication [57], it would not be astonishing that the mutagenic effect is reduced using lindane, which acts as an inhibitor of cell-cell communication. Altogether alpha particles can either directly or indirectly cause genomic instability, which may be persistent or may be provoked by just one particle [58–60]. Unlike that seen in human somatic cells, no radiation-induced bystander effect has been shown in human stem cells, e.g., bone marrow mesenchymal stem cells and embryonic stem cells [61]. On the other side, alpha particles can also exert an apoptotic effect; thus they have long been employed in the design of radioimmunotherapies targeting cancer cells [62, 63]. Alpha particle emitters are known as bone-seeking agents, and for this reason, they are particularly applied to the treatment of bone metastases. In one study [64], the authors evaluated the percentage of cells that absorbed the reference doses of alpha particle radiation emitted by Ra-223. They used the trabecular models of marrow cavities in which the hematologic stem and progenitor cells were placed in the endosteal and shallow marrow layers. Study elucidated that radiation doses received by almost half of the hematologic stem and progenitor cells were less than reference levels. This specific model implies that Ra-223 used as an alpha emitter in the trabecular model is not likely to be toxic to HSCs. However, when cells were directly exposed to radiation, there was a higher incidence of chromosomal aberrations in the HSCs exposed to a large amount of alpha particle radiation compared with those exposed to X-ray irradiation. They were constant and transmittable changes, usually for the worse, because chromosomal aberrations were transmitted from the HSCs exposed to alpha particle radiation to their progeny cells. Consistent with this, the alpha emitters also engendered lesions in the HSCs and their progeny [65]. This notion that alpha particle radiation-induced chromosomal aberrations are transmittable and thereby may be additive, and it can be concluded that both single and multiple chromosomal aberrations may occur upon long-term radiation exposure to alpha particle radiation. Single and simple chromosomal aberrations would most likely represent the damage to the somatic cells rather than to the stem cells, whereas multiple and complex ones would certainly represent the damage to the stem cells. Consistently, a case report study of a man who received internal alpha particle radiation for 40 years showed both multiple and single chromosomal aberrations within the genome [66]. Of note, a study investigating biomarkers for the exposure to high-linear energy transfer (LET) alpha particles has shown that complex chromosomal aberrations can serve as an indicator of high-LET alpha particles when compared with low-LET X-rays [67]. 26 Stem Cells Have More Than Five Senses 299

Stem Cells Are Sensitive to Ultraviolet (UV) Light

UV radiations (UVR) are categorized according to their wavelength into three: UVA (315–400 nm), UVB (280–315 nm), and UVC (100–280 nm). As we are not threatened by short-wavelength UVR (i.e., UVC) due to its filtration by the atmosphere, the main attention should be given to long- and to a lesser extent to medium-wavelength UVR (i.e., UVA and UVB). In fact, solar radiation that the earth’s surface receives is composed of 90–99% UVA and 1–10% UVB [68]. Experimental studies have revealed the ability of UV radiation to cause clinical signs and/or symptoms and histological features that resemble Xeroderma pigmentosum group A disease [69], a hereditary DNA repair syndrome associated with immunodeficiency [70]. Accordingly, the UVR-induced immunosuppression is supposed to be an underlying mechanism of skin tumorigenesis. The UV radiation-induced adverse effects are dose-dependent. Exposure to high-dose UV radiation has been often associated with cell death, and thus the high-dose UV-irradiated stem cells are not expected to transmit the mutagenic effects of radiation to their progeny. On the contrary, cells often survive upon exposure to low-dose UV radiation; thus the low-dose UV-irradiated stem cells are seen as a potential source of mutagenic effects transmitted to the progeny cells [71]. Studies have proposed two possible pathways through which UV radiation induces apoptosis in human keratinocyte stem cells: the p53-dependent and p53-independent pathways [72]. The p53 response is a result of UV radiation which leads to cell cycle arrest or apoptosis. The β1-integrin which plays a crucial role in keratinocyte adhering has been indicated to mediate the p53-independent pathway leading to UV-induced apoptosis.

Stem Cells and Mobile Phones

As explained above, the P53 protein which acts as a tumor suppressor is involved in cell cycle arrest or cell death upon exposure to stress stimuli, e.g., radiation-induced DNA damage. Not only the P53 protein but also its binding protein tumor suppressor P53(TP53) binding protein 1 (53BP1), which boosts p53-mediated transcriptional activation, has been proven to play a key role in DNA damage. UV radiation results in increase of both P53 and TP54 [73]. New evidence supports greater sensitivity of stem cells to mobile phone microwaves than differentiated cells [74]. Mobile phone microwaves have been shown to affect the DNA damage repair and stress responses. One study has reported more observations of TP53 foci in mesenchymal stem cells than differentiated cells upon exposure to the same frequency (905 MHz) of microwaves. Considering TP53 as an indicator of sensitivity/cellular response to DNA damage, stem cells 300 A. Saghazadeh et al. seem to be more sensitive or responsive to microwave frequencies. A study of embryonic stem cells has suggested that cellular response to electromagnetic fields depends on the genetic background. P53-deficient embryonic stem cells represented increases in the expression of markers that have been associated with cellular stress (i.e., Hsp70: the 70 kilodalton heat shock proteins), cell cycle progression (p21), and cellular proliferation and death (c-Myc and c-Jun) upon exposure to the global system for mobile communications (GSM) signals at the frequency of 1.71 GHz, whereas P53-wild-type embryonic stem cells did not represent any alteration in the expression of cellular response-associated markers [75].

Conclusions

The application of both embryonic stem cells and adult stem cells has been subject to certain restrictions that could be removed with the development of induced pluripotent stem cells (iPSCs). The induction of pluripotency is a complex process through which the effects of (1) exogenous and endogenous transcription factors and their interaction with each other and with molecular components of chromosome, (2) matrix elasticity and nuclear plasticity, and (3) intrinsic and extrinsic mechanisms of the asymmetric cell divisions are pooled and will be pronounced as stem cell fate. Also, stem cells strongly feel about the effects of both ionizing and nonionizing radiation. It can be concluded that there is a single mechanism of action through which all factors that may affect the proliferation and differentiation of iPSCs operate. That is an imbalance between intracellular and extracellular forces, getting stem cells into a hyper-instability state. Also, stem cells strongly feel about the effects of both ionizing and nonionizing radiation. The effects are dose-dependent and include cell death, mutagenesis, and tumorigenesis. Cells that survive after exposure to X-rays remain pluripotent, while gamma radiation leads to the induction of cell cycle arrest. High-dose UV radiation can induce apoptosis in human keratinocyte stem cells, while low-dose UV-irradiated stem cells are seen as a potential source of mutagenic effects transmitted to the progeny cells. It has been revealed that cancer stem cells can develop radioresistance to radiation explaining the fact that radiotherapy does not make a substantial profit for a substantial proportion of patients with cancer. Alpha particles can either directly or indirectly cause genomic instability. They are known as bone-seeking agents, and for this reason, they are particularly applied to the treatment of bone metastases. New evidence supports greater sensitivity of undifferentiated stem cells to mobile phone microwaves than differentiated cells. Thereby phone microwaves can contribute to tumorigenesis via activating cancer stem cells. In this manner, this chapter supports the view that stem cells have sixth sense [76]. 26 Stem Cells Have More Than Five Senses 301

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Amene Saghazadeh, Reza Khaksar, Maryam Mahmoudi, and Nima Rezaei

Abstract The role of nutrients in brainwave balance has been reviewed elsewhere. In particular, research recently remarked that retinoic acid plays role in the generation of delta oscillations, which, in turn, are required for the cortical synchrony during slow-wave sleep. The last decade has witnessed numerous attempts, leading to the view of vitamin A as a vitamin for the brain. The present chapter first provides evidence pointing to different mechanisms underlying food preferences. It is also followed with a brief opinion entitled “From Nutrients to Brainwaves” addressing two related issues: a. why if an individual has deficiency in a certain nutrient (nutrients), then he/she will feel more hunger for foods that are high in that given deficient nutrient (e.g., people with iron deficiency feel a desire to eat soil. Additionally,

A. Saghazadeh Molecular Immunology Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran R. Khaksar MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran M. Mahmoudi Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran Dietitians and Nutrition Experts Team (DiNET), Universal Scientific Education and Research Network (USERN), Tehran, Iran N. Rezaei (*) Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran e-mail: [email protected]

© Springer Nature Switzerland AG 2019 305 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_27 306 A. Saghazadeh et al. people who are in the early stages of dehydration feel extremely thirsty) and b. why some humans have the desire for eating blood (bloodthirsty)/humans (cannibal).

Keywords Alliesthesia · Bloodthirsty · Brainwave · Buffering agent · Cannibals · Coherence · Electroencephalogram · Environment · Exteroception · Flavor · Food preference · Interoception · Intuition · Meat · Nutrient · Pleasure · Retinoic acid · Sixth sense · Toxin · Vitamin A · Vitamin B12

Food Preference

Food preference is a multi-dimensional construct, where genetic, evolutionary, cultural, and transcultural factors are in coevolutionary competition [1, 2]. For example, today’s tolerance to lactose in Europeans appears to lie in the high incidence of cattle milk protein genes in the European Neolithic cattle farming sites [3]. Insensitivity to the bitter taste is associated with genetic variants as well as is frequent among Africans [1]. Interestingly, that what causes Asian people to change their intuitive eating style following economic development is western influence [2]. Additionally, in the American population, less healthy foods are being implicitly considered tastier than more healthy foods, the so-called unhealthy-tasty intuition [4], whereas, in the French population, if food is healthy, then it is tasty, the so-called healthy-tasty intuition [5]. Other factors that influence the determinants of food preferences include age, gender, lifestyle, social context, learned preferences, familiarity and food acceptance, and nutritional knowledge [6–10]. The effects of all such factors in the human food preference are understandable. But if two or more foods are equally delicious and the subject nutritional knowledge about these foods is poor, then which factors control the food preference. To address this, below is to present evidence of the way animals behave to determine the food preferences.

Flavor

The flavors are used to enhance the consumption of target nutritious food. In a conditional model, first a flavor agent is used to induce a significant preference for nutritious foods (with flavor) versus nonnutritious foods (without flavor), and then even without the addition of flavor agent, animals prefer that target nutritious food [11].

Buffering Agent

Consumption of a large amount of grain correlates with acidosis. As for the human, both acute and chronic acidosis conditions cause life-threatening reactions in sheep and cattle [12]. Studies demonstrate the preference of sheep fed grain for foods that include NaHCO3, which is known as an antacid [13]. 27 Intuition and Food Preferences 307

Familiar Environment

It has been shown that sheep in an unfamiliar location is less likely to prefer novel foods than in a familiar location. Even, they are more willing to eat familiar, however aversive, food rather than to eat novel food [14].

Nutrient

Protein infusion during deprivation changed the preference of adult rats, decreasing their appetite for flavored non-nutritive fluid whereas increasing for protein [15].

Toxin

The study [16] showed that how much rapidly do the sheep learn to adjust consumption of a nutritious food (barley) that contains a toxin (lithium chloride, LiCl). Only 15 minutes per day was sufficient for sheep to adjust the intake of a food that contained constant amounts of LiCl. More interestingly, though with lower speed, sheep were able to dynamically adjust food intake in response to repeated changes in the amounts of LiCl. Evidence presented above proves that animals tend to consume the best available foods to maintain their body’s needs under different environmental conditions. The next question is how this tendency is encoded within the brain.

Acquired Food Preferences: The Role of Exteroception and Interoception

From a developmental perspective, there are three categories of predisposing factors for food preferences: (1) innate unlearned responses to basic tastes, (2) neophobic reactions to new foods, and (3) acquired learned preferences based on postingestive consequences [17, 18]. Learned preferences play role in today’s food preferences. Each food or drink item is a multimodal stimulus that requires both exteroceptive (visual, gustative, and olfactory) and interoceptive information for its coding [19, 20]. The caudal part of the orbitofrontal cortex (OFC) in macaque includes unimodal neurons as well as bimodal neurons [21]. Unimodal neurons were responsive to visual, taste, and olfactory stimuli. Bimodal neurons were responsive to both taste and olfactory stimuli or to both taste and visual stimuli. Even more interesting is that the OFC is among regions located in the network hub of interoception [22]. Additionally, the OFC is as an essential element of the reward system that innervates learning and decision making about reward [23]. 308 A. Saghazadeh et al.

Consistently, the OFC is activated by both food liking and wanting food [24]. In this manner, the OFC is suggested as the region where exteroceptive information from food-related stimuli converge with interoceptive information. With such extensive coding configuration, it is not surprising that each food or drink item is associated with a certain mental representation that regulates habituation to that particular food or drinks [25].

The Sense of Pleasure: From External Stimuli to Internal Signals

All the above was passed to reach this point that the sense of pleasures is not a direct reflection of external motivations but rather depends on the internal signals. In 1971, Cabanac called the mentioned internally driven sense of pleasure/unpleasure as alliesthesia, and described how thermal, gustative, and olfactory sensations enable internal signals to label related external stimuli as pleasant or unpleasant [26]. At the beginning of the present chapter, we discussed how different detectors, including the enteric nervous system, the endocrine system, and the immune system, make the gut sensitive to external sensory stimuli. When encountering a stimulus, this sensitivity enables the gut to make nervous impulses. Via the aforementioned afferent pathways, impulses can reach the brain, where a conscious sensation occurs. This sensation leads the appraisal process of the external stimuli based on its usefulness; an external stimulus is (1) pleasant if it can resolve an internal error and (2) unpleasant if it can potentially threaten or even simply does not make any sense to the internal environment and internal homeostasis. For example, cold is pleasant to a hyperthermic patient, and in contrast, it is unpleasant to a hypothermic patient, or sweet solution is pleasant to a fasting individual, whereas it turned unpleasant after repeated exposure. The result of this appraisal is the judgment about whether or not that certain stimulus is pleasant. Finally, this judgment would impact the behavior, favorably food preference behavior.

Postingestive Alliesthesia and Food Preferences

The mechanism of action of alliesthesia that is initiated by external stimuli and sensation, followed by an appraisal of usefulness and judgment of pleasure, and eventually results in behavior changes appears to be relevant to the way animals learn new food preferences. Animals learn to prefer nutritious foods that cause satiety (the feeling of comfort), and they are able to acquire aversions to foods, for example, foods lacking sufficient amounts of nutrients or foods containing toxins, that cause malaise (the feeling of discomfort) [27]. In this manner, positive alliesthesia would increase the appetite for foods, whereas negative postingestive 27 Intuition and Food Preferences 309 alliesthesia would decrease the appetite for foods [28]. Study on healthy subjects with postingestive negative alliesthesia to olfactory and gustative stimuli suggested duodenal nervous chemoreceptors that are involved in nutrient sensing as the main mediators of carbohydrate load of the duodenum and therefore negative alliesthesia [29].

A Greater Sense of Coherence and Increased Preference for Healthy Foods

The sense of coherence, also known as a “sense of the world” [30], is considered as a determinant of health [31]. It is generally suggested as a predictor of life satisfaction. In particular, one of the items on the sense of coherence scale explicitly asks: “Is doing the things you do every day a source of great pleasure and satisfaction or a source of pain and boredom?” A cohort study demonstrated that subjects in the highest quartile of the score for the sense of coherence (as rated using the sense of coherence scale [32]) reported a lower intake of energy, total and satu- rated fat, sucrose, and sweets and instead were more likely to consume fruits and vegetables [33].

Negative Olfactory Alliesthesia and Increased Preference for Sweet

Depression is an interoceptive disorder [34] associated with anhedonia and negative olfactory alliesthesia [35, 36]. Research demonstrates that depressed moods increase the preference for sweets (foods rich in fat or carbohydrate) [37].

Alliesthesia and Autonomic Responses

In the study [38], neonates were assigned to receive five olfactory stimuli: familiar regular formula, unfamiliar regular formula, protein hydrolysate formula, vanillin, and control. Regardless of the prandial condition, all olfactory stimuli resulted in the respiratory rate increase. Such an effect was not observed for heart rate change. However, analysis of the interaction of the prandial condition and olfactory stimuli indicated higher heart rate change from preprandial to postprandial condition in neonates who smelled familiar regular formula compared with neonates exposed to other odors. When compared with the preprandial condition, all olfactory stimuli increased the percentage of neonates who displayed aversive facial expression during the postprandial condition. 310 A. Saghazadeh et al.

From Nutrients to Brainwaves

Brainwave Abnormalities in Subjects with Nutrient Deficiency

As compared to control children, children with iron deficiency revealed more theta energy in all leads and also more delta energy in the frontal area [39]. Sleep spindles in NREM sleep were also different in infants with iron deficiency in terms of lower density and frequency and longer inter-spindle intervals [40]. A study of 19 adults with iron deficiency anemia indicated abnormal EEG findings mainly generalized paroxysmal high voltage delta activity, diffuse slowing of background activity, and paroxysmal sharp activity in more than half of patients. Also, adults with iron deficiency showed an increase in the latency of event-related potentials (N200 and P300) and a decrease in the amplitude of P200 and P300 [41]. A study of older subjects showed correlations between plasma carotene levels and increased EEG power in the left frontal and right lower frontal regions [42]. Also plasma vitamin A levels demonstrated a negative association with EEG power in the left temporal region and positive association with EEG power in the left frontal region. Plasma vitamin C levels in addition to riboflavin content were also correlated with altered EEG variables. There were also significant associations between plasma albumin levels and increased power in the left parietal lobe as well as between blood urea nitrogen (BUN) levels and increased power in right and left occipital regions. Plasma zinc levels were related to increased EEG power in the right temporal lobe. Iron levels were associated with increased power in the right temporal region and with decreased power in the left frontal region. A double-blind study of healthy postmenopausal women indicated that compared to high magnesium consumption, low magnesium intake causes an increase in EEG power in the right temporal, frontal, and parietal regions [43]. Also, low magnesium intake led to frequency-specific increases in the following regions: delta power in the left occipital region, theta power in most regions, alpha power in the right frontal and right temporal regions, and beta power in the frontal regions. This study highlighted that the effects of low magnesium intake are predominantly related to eyes-closed conditions, whereas those of boron to eyes-open conditions [43]. In mice, a vitamin A-deficient diet demonstrated to decrease delta power during NREM sleep [44].

Effects of Nutrition Therapy on Brainwave Abnormalities

Vitamin B12 treatment has been shown to effectively restore normal EEG activity in most of the patients with pernicious anemia [45, 46]. Folic acid appears to have anticonvulsant effects. However, its administration in high doses should be treated with caution. EEG monitoring revealed that it can cause spike discharges that contribute to the generation of epileptic discharges [47]. Generally, EEG abnormalities were resolved with iron therapy in almost one-third of patients. 27 Intuition and Food Preferences 311

In particular, iron therapy could not rescue prolonged latencies of N200 and P300 but was able to improve the amplitudes of P200 and P300 in adults with iron deficiency anemia [41]. With above evidence linking brainwave changes to nutrient deficiencies/consumption, it is possible to propose that the desire to eat/drink foods rich in nutrient(s) which the body is deficient in might be adopted as a strategy of the brain to regain wave balance.

Meat Supplementation Increases Vitamin B12 Levels

Vitamin B12 is essential to brain development and functioning. Vitamin B12 deficiency is particularly seen in vegetarians and might disturb normal brain development in early life and cause brain atrophy in later life [48, 49]. A study of undernourished children underlined vitamin B12 as the only micronutrient which increased in response to meat supplementation [50]. Therefore, it can be supposed that bloodthirsty or cannibal in actual fact suffer from the deficiency in a nutrient (nutrients) in which blood and human meat are rich, where the precise sense of deficiency and then the desire to foods rich in deficient component come from. Such sense is mediated at the neuronal levels but does not belong to known senses. As if the brain is equipped with an amazing abacus and nutrients in the need of brain are counted using this abacus.

Conclusions

This chapter first provided evidence that both exteroceptive and interoceptive signals play role in acquiring food preferences. In the following, it contained evidence that nutrient deficiency is not merely disease of the body but affects the brainwaves as profound as the individual feels his/her body needs to eat the blood or the humans. In fact, such feeling is the strategy adopted to regain the brainwave balance.

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Amene Saghazadeh and Nima Rezaei

Abstract This opinion piece illustrates the close correspondence between the sixth sense, chance, and prospective thinking. Then, the placebo effect – when a fake treatment produces clinical effects similar to those of active treatment – is explained as a by-product of the sixth sense which is more than a chance.

Keywords Chance · Placebo · Sixth sense

The Sixth Sense: Is It a Chance?

A while ago, in an introductory seminar on Universal Scientific Education and Research Network (USERN), the audiences were invited to ask event organizers any questions. An interesting however unrelated question was how you rate the role of chance in success. Three event organizers, who all were of the top young talents, responded to this question; two seriously believed that hard work is the key to success and one could not directly address the question, i.e., so-so. Then a guest lecturer, who was nominated for his contribution to astrophysics, was called to the scene. At the opening of his speech, he firmly said that he had many chances,

© Springer Nature Switzerland AG 2019 315 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_28 316 A. Saghazadeh and N. Rezaei the chance of studying in the top universities in London, the chance of being healthy, and the chance of attending this event. The Dempster-Shafer theory suggests that the probability of one question can be calculated according to the probability of another however related question [1, 2]. This allows us to arrive at important decisions when there is missing information. What was mentioned above is a concrete example of this theory; event organizers responded to the question about the role of chance in success according to a different related question that was about the role of hard work in success. As the Dempster- Shafer theory is discussed dependent on the correlation between those two questions, this discussion on the example can continue in two main different ways based on the hypothesis that chance coexists with or contradicts hard work in the way of success. Man’s selection is a key element to go through this step. Let us overlook the fact that human often underestimates the power of uncertainty due to a high degree of reliance on certainty and its outcomes. Instead, let us address a series of similar, but more intriguing, questions using the Dempster-Shafer theory. The first one is how to rate the role of sixth sense in prospective thinking. Then it should be clarified whether there is any correlation between the sixth sense and chance. Eventually, it would be relatively easy to face with the question of how to rate the role of chance in the accuracy of prospective thinking. While intentionally thinking of any events, we can make some possible hypotheses about the target event. The number of possible hypotheses we can make and the probability of each one in part rely on the amount of experience of that particular event we have, i.e., inexperienced or experienced. In the real world, the more experience people have, the less uncertainty they feel, and the more tendency they would have to make predictions, using their memory. On the contrary, the less experience people have, the more uncertainty they feel, and the more tendency they would have to make predictions using their common sense, i.e., the sixth sense. However, this is only that what is usually seen in the general population. Here we answered the question about the role of sixth sense in prospective thinking based on the other question about the role of experience and certainty in prospective thinking. First, it should be noted that we used the term “chance” owing to that people have a closer acquaintance with this term than the term “subjective probability” [3]. However, the concept of subjective probability is what we mean by the term “chance.” Sudano and Martin recently proposed a probability information content (PIC) variable, which is applied to “assign an information content value to any set of probability” [4]. The PIC = 1 points to that a hypothesis has the probability of one, and as a result, the rest of the hypotheses have the probability of zero. The value of PIC is expected to be 1 only, when the information and knowledge about the target event are virtually complete. The value of PIC varies between 0 and 1 when the information and knowledge about the target event are incomplete. Probabilities of predictions we make would fluctuate according to our sense of that given event. The fluctuation would be prominent particularly when we are inexperienced with that given event. Fifty years ago, Tversky and Kahneman [5] proposed that people stick to a number of definite heuristic principles while predicting probabilities of uncertain events. 28 More than a Chance 317

Though they seem prosperous, it should not be disregarded that certain rules would not be quite sufficient for making predictions about uncertain events. The sixth sense is what perhaps allows us to think relatively indefinitely and thereby revising our current projections of future uncertain events. This feature of common sense is very similar to that of is known about the chance from the people’s view. Chance is commonly seen as an opportune moment that allows us to correct deviations by establishing another deviation [5]. However, that what distinguishes the sixth sense from the chance is that the sixth sense is not very out of the way, but it is somewhere around the man’s brain. Up to here, this opinion piece illustrated the close correspondence between the sixth sense, chance, and prospective thinking using the formula of statistics. From here, evidence supporting the placebo effect in different settings are presented.

The Placebo Effect

A placebo (fake treatment) may produce clinical effects similar to those of active treatment, the so-called placebo effect. For example, the striatal dopaminergic system is impaired in Parkinson’s disease. It has been shown that the placebo can induce dopamine release in the striatum [6], and thereby cause a significant improvement in clinical signs and symptoms. The placebo effect has been observed in a variety of clinical settings including, but not limited to, depression [7], Ménière’s disease [8], angina pectoris [9], osteoarthritis [10], and irritable bowel syndrome [11]. These observations led to suggest different neuropsychobiological mechanisms underlying the existence of the placebo effect [12]. They also brought scientists to the conclusion that the placebo effect is largely responsible for the effect that active treatments will have on patients [6]. The placebo effect is proposed as the powerful product of self-control or subjective control of thought [12]. But indeed how the placebo can influence the brain and body in a spatiotemporal scale compat- ible with that of the active drug. Presumably, such condition-specific placebo effect is a by-product of the sixth sense which is more than a chance.

References

1. Shafer G. A mathematical theory of evidence. Princeton: Princeton University Press; 1976. 2. Dempster AP. A generalization of Bayesian inference. J R Stat Soci Series B (Methodol). 1968:205–47. 3. Anscombe FJ, Aumann RJ. A definition of subjective probability. Ann Math Stat. 1963;34(1):199–205. 4. Sudano JJ. Pignistic probability transforms for mixes of low-and high-probability events. arXiv preprint arXiv:150507751. 2015. 5. Tversky A, Kahneman D. Judgment under uncertainty: heuristics and biases. Science. 1974;185(4157):1124–31. 318 A. Saghazadeh and N. Rezaei

6. De la Fuente-Fernández R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science. 2001;293(5532):1164–6. 7. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, et al. The functional neuroanatomy of the placebo effect. Am J Psychiatr. 2002;159(5):728–37. 8. Thomsen J, Bretlau P, Tos M, Johnsen NJ. Placebo effect in surgery for Meniere’s disease: a double-blind, placebo-controlled study on endolymphatic sac shunt surgery. Arch Otolaryngol. 1981;107(5):271–7. 9. Benson H, McCallie DP Jr. Angina pectoris and the placebo effect. N Engl J Med. 1979; 300(25):1424–9. 10. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67(12):1716–23. 11. Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336(7651):999–1003. 12. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta J-K. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25(45):10390–402. Chapter 29 Learning the Sixth Sense

Amene Saghazadeh, Reza Khaksar, and Nima Rezaei

Abstract Cross-modal plasticity causes an ordinary sense to become a supernormal wisdom as a result of deprivation in one sensory modality. This ability of the brain has created a potentially fertile framework for the development of sensory substitution systems and brain-machine interfaces.

Keywords Auditory · Bimodal neurons · Brain-machine interfaces · fMRI · Cross-modal plasticity · Multisensory neurons · Navigation · Proprioception · Prosthetics · Sensory substitution · Sixth sense · Tactile · Vision

Introduction

From Multisensory Neurons to Cross-Modal Plasticity

Multisensory neurons are aggregating nodes, as the name implies, that integrate sensory information from more than one sensory modality, a process that is called “multisensory integration.” Multisensory integration is the ability of the brain to maintain the body at balance when encountering intrinsic and extrinsic problems [1]. It is a developmental ability that improves as we grow. The representations of the body parts as they are by default are an early mechanism of multisensory integration, while to dynamically update the spatial positions of the body parts in response to the surrounding environment is a mechanism of multisensory integration which is developed later in life [2]. Such a well-developed mechanism receives postural information from different sensors, in particular, proprioception and vision. In cats, there is a high density of multisensory neurons in the superior colliculus (SC) where is assumed to receive ascending sensory pathways that convey auditory and somatosensory inputs and descending projections from the cortex. In particular, descending cortical neurons receive excitatory visual and auditory inputs from the anterior ectosylvian visual area (AEV) and from the auditory fields of the anterior ectosylvian region (FAES) [3]. FAES reveal great responsiveness to auditory stimuli. Unilateral deactivation of FAES causes a specific condition: auditory deficits and visual facilitation. Congenital deaf cats present such condition as well. Recordings from the FAES neurons in early-deafened cats demonstrated a dramatic increase in the number and diameter of visual receptive fields compared with that in hearing cats [4]. Of note, visually responsive FAES neurons behaved like cortical neurons in early-deafened cats. It means that they were able to detect direction and speed. In the search for neural correlates of the above condition, Lomber et al. [5] showed that the posterior auditory field (PAF) contributes to the enhancement of visual peripheral localization as so does the dorsal zone of auditory cortex (DZ) for the movement detection. In this manner, the auditory cortices undergo an effective reorganization to compensate for the loss of auditory function through the enhancement of visual functions. The above condition is a common example of cross-modal plasticity, an ability of the brain by which “sensory deprivation in one modality can have striking effects on the development of the remaining modalities” [6]. These effects are striking because they can turn an ordinary sense into a supernormal wisdom. For example, early-blind subjects show enhanced auditory localization compared with sighted controls [7, 8]. A number of studies that have provided clinical evidence for compensatory visual function in deaf individuals as well as for compensatory auditory function in blind individuals can be found here [9]. For the additional review of neural reorganization as a consequence of sensory deprivation see [10]. Cross-modal plasticity created a potentially fertile framework for the development of sensory substitution systems. 29 Learning the Sixth Sense 321

Sensory Substitution

The term sensory substitution can be defined as “the translation of sensory information that is normally available via one sense to another” [11]. A sensory substitution system consists of: 1. Sensors that receive information about the surrounding context. 2. Coupling device that transduces that sensed data to actuators. 3. Actuators that ultimately convey information to the body [11].

Brain-Machine Interfaces

Chapin et al. [12] implanted arrays of microwire electrodes across layer V of the primary motor cortex (MI) forelimb area and VL thalamus of six rats as well as bundles of microwire electrodes into the ventral lateral nucleus (VL) of the thalamus. To evaluate muscle activity, the investigators also placed four bipolar electro- myography (EMG) electrodes in the forelimb muscles of two rats. Before electrode implantation, rats were trained to move a lever so that to control the robot arm and obtain water. A week after electrode implantation, electrodes were linked to a 64-channel Many-Neuron-Acquisition-Processor (MNAP). This brain-machine linking induced to a sequential cascade of events at the neuronal level, leading to the effective forelimb movements: 1. Discharge of pre-flexion neurons: before brachial flexion to initiate lever reach. 2. Discharge of flexion neurons: after the onset of antebrachial flexion. 3. Discharge of pre-extension neurons: pre-onset and onset of carpal flexion to initiate antebrachial extension before forepaw placement on the lever. 4. Discharge of extension neurons: onset of antebrachial extension and placement of forepaw on the lever [12]. Of note, analysis of artificial neural networks (ANNs) determined the pre-lever- movement peak as the best predictor of lever movement. The above as the earliest experiment of the field elucidates how brain-machine interfaces (BMIs) effectively influence neuronal populations to guide goal-directed motor functions. Enthusiasm for the development of new BMIs with greater utility in paralyzed people (neuroprosthetics) has grown at an exponential rate thereafter (for review see [13]).

Proprioception

Thanking his sense of proprioception which is also known as “sense of self and others” [14], “sense of self-ownership” [15], “aesthetic sense” [16], “sense of one’s body” [17], “sense of effort” [18], or “sense of agency” [19], human is able to 322 A. Saghazadeh et al. estimate about the motion and position of different parts of the body. Also, recent studies extend the role of proprioception beyond processing the body’s position to visual associations [20]. We previously discussed proprioception in Chap. 6. Now is to understand how sensory substitution and neuroprosthetics can help restore as well as enhance proprioceptive function. In a correspondence entitled “In Search of the Sixth Sense” [21], Alison Abbott wrote the story of Ian Waterman (IW), who is popular as the man who lost his body due to an acute sensory neuropathy. Only some months were enough for him to force his body to sit up. After the first time he succeeded, he practiced more and learned to do limb movements as well. The most interesting point is that he was able to control his body until his eyes were open, while a healthy human is expected to do so even if his eyes are closed. Therefore, it poses that sensory feedback, which in this case means visual feedback, can contribute to the compensation of proprioceptive function.

Tactile Vestibular Sensory Substitution

The brain has a lot to do to keep the body at balance. Various resources including cognitive processing, control of dynamics, orientation in space, sensory strategies, movement strategies, and biochemical constraints are needed to coordinate stability and orientation of human posture (for review see [22]). Therefore, control of posture is handled based on the integration of information from different sensory modalities including proprioceptive, vestibular, tactile, and visual systems. In the study [23], Tyler et al. 2003 investigated effects of a tongue-placed vestibular substitution (VS) system on performance on the modified Romberg test under two conditions: eyes closed (EC) and eyes closed with vestibular substitution (EC-VS). The study included four subjects with bilateral vestibular dysfunction (BVD) and eight control subjects. During VS period, patients with BVD were generally comfortable and happy with VS and clearly expressed their position as “stable” and “normal.” After VS period, the amplitude of anterior-posterior (A/P) oscillations began to emerge, and congruently, the upper body began to become unstable. Happily, more recent studies which can be found here [24, 25] consistently confirm the effect of tongue-placed vestibular substitution (VS) on postural stability (as assessed by the Sensory Organization Test (SOT), Dynamic Gait Index (DGI), Activities-specific Balance Confidence Scale (ABC), and Dizziness Handicap Inventory (DHI)) in patients with peripheral or central vestibular loss. Additionally, the light touch is deemed to help postural compensation for vestibular loss [26]. 29 Learning the Sixth Sense 323

Auditory Vestibular Sensory Substitution

A 1-minute audio-biofeedback (AFB) training was able to effectively reduce postural sway in both control subjects without BVL (n = 9) and in patients with severe BVL (n = 9) [27]. Before ABF, patients had greater postural sway compared with controls. The study [28] confirmed the effectiveness of AFB on postural sway and also clarified that ABF might exert its effect by enhancing brain activity to promote postural stability, not through regulating muscle activity.

Tactile Navigation Sensory Substitution

Using a visual-to-tactile sensory substitution on the tongue, both congenitally blind (n = 16) and sighted controls (n = 11) could qualify the properties of the obstacle including size (“How big is the obstacle?”), distance (“How far away do you think it is?”), and type (“What does it look like?”) [29]. At the next step, congenitally blind subjects displayed a greater capacity to detect and avoid the obstacles compared with control subjects. In particular, blinds’ performance was superior to that of controls for detecting small obstacles. In fact, blinds’ performance was comparable to their counterparts for detecting large, step-around (SA), and step-over (SO) obstacles. Nagel et al. [30] assessed effects of 6-week training with a wearable belt that gives the user orientation information as vibrotactile stimulation on the subject performance on the navigation tasks under two experimental conditions: correct belt information (CI) and no belt information (NI). In the beginning, control and experimental subjects showed a comparable performance on both CI and NI conditions. At the end of 6-week training, this remained the case for control subjects. However, subjects trained with the belt had better performance in the CI than in the NI condition, while their performance in the NI condition was not significantly influenced by training. Therefore, it can be concluded that this better performance could be definitely attributed to an enhanced performance in the CI condition, but not to a worsened performance in the NI condition. The authors also evaluated the effect of training on vestibular nystagmus. In the experimental group, the difference in the frequent fast eye movements between CI and NI conditions was increased from 1% before training to 34% after training. This indicates that sensory (vibrotactile) feedback can pave the way for enhancement of proprioceptive function. Additional studies that show the effect of tactile sensory substitutions on performance in navigation tasks are [31] as follows. 324 A. Saghazadeh et al.

Vision

The present chapter was intended to primarily focus on devices and interfaces that aid to promote proprioceptive function. However, below is to hold a brief introduction to the context of visual sensory substitution, owing to the demonstration of the role of both visual and proprioceptive cues in making an exact representation of the body and its limbs [32]. Visual sensory substitutions assist the blind in perceiving the space around him by transforming “visual information into auditory or tactile representations” [33].

Tactile Vision Sensory Substitution

In 1969, the Tactile Vision Sensory Substitution (TVSS) system was introduced [34]. After training, blind individuals could be as good and as rapid as sighted individuals in detecting line orientation. In 2001, a tongue-placed tactile sensory substitution was tested in six sixth sighted blindfolded individuals and six congenitally and totally blind [35]. Before training, both sighted and blind individuals showed comparable visual acuity as reflected in performance on the Snellen test. Nine-hour training with the device could improve subject performances by 100%.

Auditory Vision Sensory Substitution

In the study [36], Ward et al. 2010 described the visual experience of two blind subjects (PF and CC) who used this type of sensory substitution that translates visual images to auditory signals for years. The sensory substitution allowed them to gradually perceive edges, contrast, depth, movement, and even color only for PF. Meantime, the sensory substitution caused both subjected to have developmental synesthesia. Their experiences are interesting to read (see [36]). For a review of studies investigating the effects of different sensory substitution devices on visual rehabilitation see [33].

Neural Correlates of Sensory Substitution Devices

In the study [37], the authors collected fMRI data for blind subjects (n = 2), sighted experts who were trained to use the auditory vision sensory substitution device (n = 5), and sighted controls (n = 5). The study included multiple conditions where participants should recognize novel objects with or without using a 29 Learning the Sixth Sense 325 sensory substitution device. Compared with sighted controls, sighted experts were noticeably better in novel object recognition using the device. During object recognition, brain regions within three clusters: the occipitotemporal cortex (lateral- occipital tactile-visual area), parietal cortex (intraparietal sulcus, IPS), and prefrontal cortex (mainly in the pre-central sulcus) were active merely in blind and sighted experts, but not in sighted controls.

Sensory Substitution in Prosthetics

Amputation of a limb means to lose all its related motor and sensory functions at once. In these cases, prostheses can help compensate for motor functions. Nevertheless, a lot of challenges remained for the restoration of sensory functions in the prosthetic limb (for review see [38]). It is promising that sensory substitution devices and brain-machine interfaces useful to this aim are proposed. Overall, these instruments provide efficient sensory feedback that enables the brain to reform representations of the amputated limb and to optimize peripersonal space boundaries around the artificial limb [39, 40].

Conclusions

Evidence-based information during the last 40 years supports that sensory substitution devices and BMIs have produced desirable results in experiments. It is, however, less than expected that such results still remain at the experimental level and could not be translated into practice as it should be [41, 33].

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Amene Saghazadeh, Farzaneh Rahmani, and Nima Rezaei

Abstract The popular definitions of intuition converge on four aspects: nonconscious information processing, holistic associations, affectively charged, and speed (Dane E, Pratt MG. Conceptualizing and measuring intuition: a review of recent trends. In: International review of industrial and organizational psychology, vol. 24; 2009. p. 1–40). With this and similar definitions, it is not surprising that the term intuition conceptually overlaps with other related cognitive constructs such as creativity (Finke RA, Ward TB, Smith SM. Creative cognition: theory, research, and applications. 1992), tacit knowledge (Reber AS. Implicit learning and tacit knowledge: an essay on the cognitive unconscious (Oxford Psychology Series, No 19). Oxford: Oxford University Press; 1993), implicit learning and knowledge (Dienes Z, Berry D, Psychon Bull Rev, 4(1):68–72, 1997; Reber AS, J Exp Psychol Gen, 118(3):219, 1989), instinct, and insight (Mayer RE. The search for insight: Grappling with Gestalt psychology’s unanswered questions. 1995; Nisbett RE,

Ross L. Human inference: strategies and shortcomings of social judgment. p. 1980). The present chapter discusses neural correlates of intuition in the different contexts.

Keywords Analytic mind · Auditory intuition · Expert · fMRI · Interoception · Intuition · Intuitive mind · Learning · Mathematics · Neurocircuitry · Novice · Semantic intuition · Social intuition · Visual intuition

Introduction

Borrowed from Late Latin, the term intuition comes from the root words in, meaning “at, on” and tueri, meaning “to look at, watch over.” In the Oxford dictionary, intuition is defined as “the ability to understand something instinctively, without the need for conscious reasoning.” Intuition has been defined frequently because of its broad application in different academic areas. However, the popular definitions converge on four aspects: nonconscious information processing, holistic associations, affectively charged, and speed [1]. With this and similar definitions, it is not surprising that the term intuition conceptually overlaps with other related cognitive constructs such as creativity [2], tacit knowledge [3], implicit learning and knowledge [4, 5], instinct, and insight [6, 7]. Hodgkinson et al. have provided an overview of the definitions of intuition in cognitive and behavioral sciences in [8]. Also, they presented neuroimaging evidence in [9] to justify dissociating intuitive judgment from instinctive or insightful judgment. In the book [1], Dane and Pratt have discussed intuition under three headings: 1. Problem-solving intuitions are referred to as “automatic acts of recognition due to pattern matching.” 2. Creative intuitions are defined as “feelings that arise when knowledge is combined in novel ways.” 3. Moral intuitions are “affective, automatic reactions to issues that are viewed as having moral/ethical content.” Domain-relevant knowledge and expertise are known to potentially influence the ability of pattern recognition, which is the main process responsible for problem- solving intuition. Therefore, the terms “problem-solving intuitions” and “expertise- based intuition” might be interchangeably used. Both problem-solving and moral intuitions often depict convergent/tight associations based on the domain-relevant knowledge and moral prototypes, whereas creative intuitions are built based on the integration of knowledge from various domains and so are often related to divergent/broad associations. The role of emotion in problem-solving intuitions is less pronounced than that in moral and creative intuitions. Below we will discuss neural correlates of intuition in the different contexts. 30 Neurocircuitry of Intuition 331

Intuition in the Context of Learning

Both implicit and explicit processes play role in learning. Arthur Reber defined implicit learning as “a primitive process of apprehending structure by attending to frequency cues.” While explicit learning is “a more explicit process whereby various mnemonics, heuristics, and strategies are engaged to induce a representational system” [5, 10]. Robert Dekeyser subsequently proposed a simpler definition of these learning processes [11]: 1. Implicit learning as learning without awareness of what is being learned. 2. Explicit learning as learning with awareness of what is being learned. In A Social Cognitive Neuroscience Approach to Intuition, Lieberman [12] put forward a hypothesis that perhaps there exists a close bidirectional relationship between implicit learning and social intuition. Additionally, at the neural level both engage the basal ganglia including the caudate and putamen.

Intuition in the Context of Mathematics

Arithmetic thinking takes place under exact and approximate processes, which are thought to differentially engage verbal and non-verbal visuospatial networks [13]. More precisely, greater activation of the bilateral inferior parietal lobules was observed with approximate arithmetic processes rather than with exact arithmetic processes, whereas innervation of exact arithmetic processes mainly involved the left inferior prefrontal cortex. Kuo et al. 2009 [14] collected fMRI data for 21 subjects playing number games and box games. Both number and box games included two conditions: dominance- solvable games, “where finding an optimal strategy is purely a mathematical problem,” and pure coordination games, “where successful play requires the players to go beyond the mathematics of the game.” Dominance-solvable games activated bilateral frontal and parietal regions, including the middle and superior frontal gyri, precuneus, and inferior parietal lobule, more than pure coordination games. Compared with dominance-solvable games, pure coordination games engaged bilateral insulae and anterior cingulate cortex (ACC), mainly involving the middle and posterior insulae, the caudal ACC, the cingulate motor area (CMA), and the supplementary motor area (SMA), to a greater degree.

Intuition in the Context of Discovery

Intuition in this context has been defined by Bowers et al. 1990 [15] as the “preliminary perception of coherence (pattern, meaning, structure) that is at first not consciously represented.” 332 A. Saghazadeh et al.

Auditory Intuition

In the study by Volz et al. 2008 [16], 14 healthy subjects performed a difficult recognition task across 150 auditory stimuli consisted of “68 forward-played sound stimuli, 71 backward-played sound stimuli, and 11 null events.” Each trial took 8 seconds and a trial was considered as coherent if “the featuring sound stimuli that represented meaningful auditory event.” Overall, more than 50% of stimuli could be approximated as coherent. Subjected tended to correctly judge more forward-played sound stimuli than backward-played sound stimuli as coherent (74% versus 59%). In addition, they responded to forward-played sound stimuli in a less time- consuming manner. Then, the investigators compared fMRI activation pattern during trials of the sound stimuli that were incorrectly categorized as coherent (false alarms) with that during trials of the sound stimuli that were correctly categorized as coherent (hints). The analysis revealed that incorrect judgment of the auditory stimuli as coherent is accompanied by activation within the left rostral medial OFC, lateral OFC, right frontal operculum (FOP), inferior frontal gyrus, left anterior medial temporal pole, and middle temporal gyrus (MTG) and within the bilateral superior temporal gyrus.

Visual Intuition

The authors of the above study also conducted a similar study using pictorial stimuli under two conditions: the object condition (coherent trial) and the non-object condition (incoherent trial) [17]. In the former, subjects were asked whether or not the meaningful fragmented line drawings of common objects (e.g., violin) are meaningful (coherent gestalt) for them. According to the level of fragmentation, this condition included three series of objects. In the latter, subjects were asked whether or not the meaningless fragmented line drawings are meaningful for them. Generally, it was more time-consuming to judge stimuli as meaningful than to judge stimuli as meaningless. Moreover, it was more likely to correctly judge stimuli as meaningless than to judge stimuli as meaningful (83.5% versus 33.3%). The authors compared fMRI activity patterns during trials which subjects judged to be coherent with that during trials which subjects judged to be incoherent. The intuitive judgment of drawings (coherent) was associated with functional connectivity within the anterior and posterior medial OFC, right anterior insula, the right lateral portion of the amygdala complex, midbrain area, right thalamus, bilateral ventral occipitotemporal (VOT), and within the right cerebellum. Horr et al. 2014 [18] also included 24 healthy subjects whose task was to express their judgment on the coherence/incoherence fragmented line drawings and scrambled line drawings. Demonstration of each line drawing lasted for 500 ms. The rate of coherence judgment was higher for fragmented than for scrambled line drawings (81.4 versus 51.2%). This rate was noticeably decreased with increasing the 30 Neurocircuitry of Intuition 333 difficulty of stimuli. Magnetoencephalography (MEG) data analysis demonstrated that a coherence judgment employs the neural function within the following clusters and related time spans: (1) the left OFC (174–249 and 270–500 ms), (2) the left inferior frontal gyrus (183–232 and 307–500), (3) the left inferior temporal/ fusiform gyrus (217–260 and 382–454 ms), (4) the left middle temporal gyrus (343–500 ms), (5) the right middle/superior frontal gyrus (125–183 and 304– 357 ms), and (6) the right occipital cortex (193–302 and 384–500 ms). The activity of cluster 5 started earlier than that of cluster 1, but the cluster 5 it remained active less time that the cluster 1 (58 versus 75 ms). Additionally, the activity of cluster 5 disappeared at 357 ms after stimuli presentation, while cluster 1 remained active until the end of stimuli presentation. Altogether, these observations highlight the prominent role of OFC in the intuitive encoding of the coherent gestalt. Using a method similar to the above study, Luu et al. 2010 [19] evaluated elec- troencephalography (EEG) data in 22 subjects during task performance. Consistently, subjects could make a coherence judgment on fragmented line drawings in a less time- consuming fashion than on scrambled line drawings. Additionally, it took less time to reach an incoherence judgment on scrambled line drawings than on fragmented line drawings. The true alarm rate was 0.65 for the fragmented stimuli, whereas the false alarm rate was 0.14 for the scrambled stimuli. Analysis of EEG recordings revealed the divergent point of 150 ms as when the ERP effect associated with a coherence judgment for the fragmented stimuli begin to diverge from that with an incoherence judgment for the scrambled stimuli. For the coherent condition, the regions of interest (ROI) analysis indicated significant associations between right temporal-parietal-occipital (TPO) activity at T2 and T3 and ongoing medial OFC activity at T5 and then between medial OFC activity at T5 and TPO activity at T6–T8, while there was no such spatiotemporal association for the incoherent condition.

Semantic Intuition

Bolte et al. [20] investigated the effect of emotion on intuitive coherence judgment of semantic gestalt. First, the authors asked participants (n = 24) to decide whether the three clue words were semantically coherent, and then to suggest a solution word (using the keyboard). This experiment showed that neutral people could make an intuitive judgment of semantic coherence. The second experiment was performed on 48 participants who primarily underwent negative and positive mood induction. Overall, the rate of coherence judgment was 23% for the solved trials. The hit rate was defined as “the proportion of unsolved coherent triads that were correctly classified as coherent.” The false alarm rate was defined as “the proportion of unsolved incoherent triads that were incorrectly classified as coherent.” The intuition index was defined as “the difference between hit and false alarm rates.” Subgroup analysis identified a significant intuition index only for the positive- mood group, but not for the negative-mood group. 334 A. Saghazadeh et al.

Novice Versus Expert Learner and Intuition

Lieberman et al. [21] suggested the X-system to serve as an automatic pattern matching system that consists of vmPFC, basal ganglia, amygdala, and lateral temporal cortex, whereas the C-system is likely to be responsible for three inter-related operations: 1. “identifying when problems arise in the X-system 2. taking control away from the X-system. 3. remembering situations in which such control was previously required” [21] This system is comprised of lateral PFC, posterior parietal cortex, hippocampus, and medial temporal lobe structures. Collectively, the C-system structures contribute to cognitive functions including working memory, episodic memory, controlled processing of social cognition, explicit pattern matching, deductive reasoning, self-regulation of pain and prejudice, and intentional reappraisal of affective stimuli [22]. Lieberman et al. [22] obtained fMRI data from 21 participants when made self- descriptiveness of words related to soccer and acting in high-experience and low- experience domains. The study included 10 higher soccer players and 11 improvisational actors. Both actors and athletes responded earlier to the words related to their high-experience domain. Brain regions that were more active during making self-judgments of words in the high-experience domain than low-experience domain included left ventromedial prefrontal cortex (vmPFC), left nucleus accumbens in the basal ganglia, left amygdala, right lateral temporal cortex, and right posterior parietal cortex. These regions, except the posterior parietal cortex, are related to the X-system, while there was only one brain region that was more active during making self-judgments of words in the low-experience domain than in high- experience domain. It was the right lateral PFC, where its activation is linked to the C-system. These findings indicate the role of brain X-system in intuitive self-judgments. Limb and Braun [23] evaluated musical improvisation in six full-time professional pianists under two paradigms: scale, where “a relatively low musical complexity” was administered, and jazz, where “a musically rich context was provided for improvisation.” Spontaneous improvisation engaged brain regions including the frontal polar portion of the MPFC, neocortical sensory areas (anterior portions of the superior temporal sulcus (STS), inferior temporal, fusiform and lateral occipital gyri, inferior and superior parietal lobules, and the intervening intraparietal sulci), neocortical premotor and motor areas (ventral and dorsal lateral premotor areas, supplementary motor area, and portions of the primary motor cortex), the anterior cingulate cortex, cingulate motor area, and the right lateral cerebellar hemisphere. In contrast, it disengaged brain regions within the PFC (all of the lateral prefrontal cortices, extending from lateral LOFC to the superior portions of the dorsolateral PFC, and dorsal portions of the medial PFC) and within the limbic and paralimbic (the amygdala, entorhinal cortex, temporal pole, posterior cingulate cortex, parahippocampal gyri, hippocampus and hypothalamus) regions. 30 Neurocircuitry of Intuition 335

The Transition from Novice to Expert Intuition

The study [24] answers how the brain underlies the gradual development of cognitive intuition. Nineteen subjects with little knowledge of the games of shogi and mini-shogi underwent daily training of these games for 15 weeks. The authors collected fMRI scans during the next-move generation task at two points of time: week 2–3 and week 14–15. Training significantly improved the subject’s performance as revealed by increased difference from the chance level (15% at fMRI2 vs 6% at fMRI1). Analysis of fMRI data demonstrated that cortical areas, such as the dorsolateral prefrontal cortex, dorsal premotor cortex, pre-supplementary motor area, and posterior precuneus, were active at both times and their activity was not affected by training and performance. However, activation within the caudate was found to be significantly improved by training.

The Transition from Analytic Mind to Intuitive Mind

Frank et al. [25] investigated whether drug-induced impairment of explicit memory enforces building intuitive judgments. The study included 23 healthy subjects who performed a cognitive learning task and a name recall test at 20 and 45 minutes after injection of midazolam. Additionally, the study included two sessions of learning tasks: implicit transitive inference (TI) in one session and probabilistic selection (PS) in another session. The PS task activates striatum while midazolam interferes with the activation of the hippocampus, which is involved in explicit memory and logical inference. As expected, the study showed that midazolam improved performance on the TI test while impairing the recall. Moreover, midazolam did not influence the subject’s performance on the PS task.

The Transition from an Intuitive Mind to Analytic Mind

The Cognitive Reflection Test (CRT) was designed by Frederick [26] to evaluate the ability of individuals to overcome incorrect “intuitive” answer and instead give more reflection to the subject to reach toward the correct “analytic” answer. Subjects who had higher scores on this test were more tolerant (time preference) and were more keen to gamble (risk preference). The CRT has shown great potential to predict performance on heuristics and biases (HB) tasks [27]. The original version of CRT consisted of three items. It was recently rearranged by Toplak [28] to make seven items. Alter et al. [29] randomly assigned participants (n = 40) to one of the two conditions: fluent, where “a three-item version of the CRT written in easy-to-read black Myriad Web 12-point font” was administered, and dysfluent, where “a three-item version of the CRT printed in difficult-to-read 10% gray italicized Myriad Web 336 A. Saghazadeh et al.

10-point font” was administered. The rate of the correct answer in the dysfluent condition was significantly greater than that in the fluent condition (mean: 2.45 versus 1.90). Also, the probability of an incorrect answer was significantly decreased in the dysfluent condition compared with that in the fluent condition (90% versus 35%). Consistently, the rate for incorrect “intuitive” answers was 10% in the dysfluent condition versus 23% in the fluent condition. This study included three other experiments (for more information see [29]). Altogether, the findings suggest task difficulty as a stimulus for the transition from intuitive to analytic thinking.

Conclusions

This chapter attempted to trace the neurocircuitry of intuition in the different contexts such as learning, mathematics, and discovery. Additionally, we presented evidence that intuitive processing is an ability that can be developed and its development is accompanied by changes in the brain function.

References

1. Dane E, Pratt MG. Conceptualizing and measuring intuition: a review of recent trends. In: International review of industrial and organizational psychology, vol. 24; 2009. p. 1–40. 2. Finke RA, Ward TB, Smith SM. Creative cognition: theory, research, and applications. Cambridge: MIT Press; 1992. 3. Reber AS. Implicit learning and tacit knowledge: an essay on the cognitive unconscious (Oxford Psychology Series, No 19). Oxford: Oxford University Press; 1993. 4. Dienes Z, Berry D. Implicit synthesis. Psychon Bull Rev. 1997;4(1):68–72. 5. Reber AS. Implicit learning and tacit knowledge. J Exp Psychol Gen. 1989;118(3):219. 6. Mayer RE. The search for insight: Grappling with Gestalt psychology’s unanswered questions. 1995. 7. Nisbett RE, Ross L. Human inference: strategies and shortcomings of social judgment. Englewood Cliffs: Prentice-Hall; 1980. 8. Hodgkinson GP, Langan-Fox J, Sadler-Smith E. Intuition: a fundamental bridging construct in the behavioural sciences. Br J Psychol. 2008;99(1):1–27. 9. Hodgkinson GP, Sadler-Smith E, Burke LA, Claxton G, Sparrow PR. Intuition in organizations: implications for strategic management. Long Range Plan. 2009;42(3):277–97. 10. Reber AS. Implicit learning of artificial grammars. J Verbal Learn Verbal Behav. 1967;6(6):855–63. 11. DeKeyser R. Implicit and explicit learning. In: Doughty CJ, Long MH, editors. The handbook of second language acquisition, vol. 27; 2008. p. 313. https://doi.org/10.1002/9780470756492. ch11. 12. Lieberman MD. Intuition: a social cognitive neuroscience approach. Psychol Bull. 2000;126(1):109. 13. Dehaene S, Spelke E, Pinel P, Stanescu R, Tsivkin S. Sources of mathematical thinking: behavioral and brain-imaging evidence. Science. 1999;284(5416):970–4. 14. Kuo W-J, Sjöström T, Chen Y-P, Wang Y-H, Huang C-Y. Intuition and deliberation: two systems for strategizing in the brain. Science. 2009;324(5926):519–22. 30 Neurocircuitry of Intuition 337

15. Bowers KS, Regehr G, Balthazard C, Parker K. Intuition in the context of discovery. Cogn Psychol. 1990;22(1):72–110. 16. Volz KG, Rübsamen R, von Cramon DY. Cortical regions activated by the subjective sense of perceptual coherence of environmental sounds: a proposal for a neuroscience of intuition. Cogn Affect Behav Neurosci. 2008;8(3):318–28. 17. Volz KG, von Cramon DY. What neuroscience can tell about intuitive processes in the context of perceptual discovery. J Cogn Neurosci. 2006;18(12):2077–87. 18. Horr NK, Braun C, Volz KG. Feeling before knowing why: the role of the orbitofrontal cortex in intuitive judgments—an MEG study. Cogn Affect Behav Neurosci. 2014;14(4):1271–85. 19. Luu P, Geyer A, Fidopiastis C, Campbell G, Wheeler T, Cohn J, et al. Reentrant processing in intuitive perception. PLoS One. 2010;5(3):e9523. 20. Bolte A, Goschke T, Kuhl J. Emotion and intuition: effects of positive and negative mood on implicit judgments of semantic coherence. Psychol Sci. 2003;14(5):416–21. 21. Lieberman MD, Gaunt R, Gilbert DT, Trope Y. Reflexion and reflection: a social cognitive neuroscience approach to attributional inference. Adv Exp Soc Psychol Elsevier; 2002. p. 199–249. 22. Lieberman MD, Jarcho JM, Satpute AB. Evidence-based and intuition-based self-knowledge: an FMRI study. J Pers Soc Psychol. 2004;87(4):421–35. 23. Limb CJ, Braun AR. Neural substrates of spontaneous musical performance: an FMRI study of jazz improvisation. PLoS One. 2008;3(2):e1679. 24. Wan X, Takano D, Asamizuya T, Suzuki C, Ueno K, Cheng K, et al. Developing intuition: neural correlates of cognitive-skill learning in caudate nucleus. J Neurosci. 2012;32(48):17492–501. 25. Frank MJ, O’Reilly RC, Curran T. When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychol Sci. 2006;17(8):700–7. 26. Frederick S. Cognitive reflection and decision making. J Econ Perspect. 2005;19(4):25–42. 27. Toplak ME, West RF, Stanovich KE. The cognitive reflection test as a predictor of performance on heuristics-and-biases tasks. Mem Cogn. 2011;39(7):1275. 28. Toplak ME, West RF, Stanovich KE. Assessing miserly information processing: an expansion of the cognitive reflection test. Think Reason. 2014;20(2):147–68. 29. Alter AL, Oppenheimer DM, Epley N, Eyre RN. Overcoming intuition: metacognitive difficulty activates analytic reasoning. J Exp Psychol Gen. 2007;136(4):569. Chapter 31 Gut Feelings in Practice

Nima Rezaei and Amene Saghazadeh

Abstract This opinion first gives an overview of the different types of gut feelings in practice: clinicians’ gut feeling, surgeons’ gut feeling, and patients’ gut feeling. It is then followed with the discussion on major obstacles to clinical intuition.

Keywords Anti-gut feeling · Expert · Gut feeling · Intuition · novice · Practice · Psychotherapy · Sense of alarm · Sense of reassurance

Gut Feelings in Practice: A “Sense of Alarm” Versus a “Sense of Reassurance”

It is possible to experience two types of gut feelings in practice: a “sense of alarm” and a “sense of reassurance.” The authors in [1] carried out a Delphi consensus study (n = 27) to reach a consensus on the definition of these gut feelings. Accordingly, a “sense of alarm” can be defined as “an uneasy feeling perceived by a GP as he/she is concerned about a possible adverse outcome, even though specific indications are lacking: There’s something wrong her.” While a “sense of reassurance” can be defined as “a secure feeling perceived by a GP about the further

© Springer Nature Switzerland AG 2019 339 N. Rezaei, A. Saghazadeh (eds.), Biophysics and Neurophysiology of the Sixth Sense, https://doi.org/10.1007/978-3-030-10620-1_31 340 N. Rezaei and A. Saghazadeh management and course of a patient’s problem, even though the doctor may not be certain about the diagnosis: Everything fits in.” Also, focused group discussions among GPs (n = 28) identified the deterministic role of fitting or alerting factors, contextual knowledge or interfering factors, medical education and practice, and personality for the formation of clinician’ gut feelings [2].

Clinicians’ Gut Feeling

In a prospective observational study, Van den Bruel et al. [3] evaluated 3890 children (0–16 years) consecutively referred to primary care for an acute illness. In this study, clinical impression was defined “as a subjective observation that the illness was serious on the basis of the history, observation, and clinical examination.” Clinician’s gut feeling was defined as “an intuitive feeling that something was wrong even if the clinician was unsure why.” There were 3369 children for whom clinical assessment suggested that the illness is not serious. Of these, six were admitted to hospital for 24 or more hours due to serious infections. Clinician’s gut feeling was present for two of the six missed cases. The study led to the conclusion that the clinician’s gut feeling has the capacity to avoid these cases being missed. However, it should be noted that the gut feeling might not always operate correctly. Stolper et al. [4] asked 128 general practitioners (GPs) in the European General Practitioners Research Network (EGPRN) whether they recognized the “sense of alarm” and if so how their recognition was expressed/described. Of those, 30 GPs (a response rate of 23.4%) answered the question, and all affirmed that they have recognized such a sense of alarm.

Surgeon’s Gut Feeling

Hartley and Sagar [5] addressed whether the surgeon’s gut feeling can predict the postoperative outcome of patients (n = 120) who underwent GI surgeries. The findings suggested the surgeon’s gut feeling as a significant predictor of patient outcome.

Gut Feeling in Practice: From Novice to Expert

According to the Benner’s Stages of Clinical Competence, five stages through which the novice passes to become an expert nurse are the novice, advanced begin- ner, competent, proficient, and the expert. An interesting point that distinguishes the expert stage from others is a fluent ability that an expert has for analytic as well as intuitive decision-making in emergency situations [6, 7]. 31 Gut Feelings in Practice 341

Interview with expert emergency nurses (n = 14) in Australia revisited the Benner’s expert stage and developed a more-detailed construct that is comprised of three phases [8]: 1. Cognitive intuition, where assessment is processed subconsciously and can be rationalized in hindsight. 2. Transitional intuition, where a physical sensation and other behaviors enter the nurse’s awareness. 3. Embodied intuition, when the nurse trusts the intuitive thoughts. These lines totally support the role of intuition in transitioning novice nurses to expert nurses.

Gut Feeling in Psychotherapy

In her book [9], Terry Marks-Tarlow refers clinical intuition as a process that: 1. Fills the gap between theory and practice. 2. Involves the perception of relational patterns, both in self and other. 3. Is a necessary ingredient for deep change during psychotherapy.

Patients’ Gut Feeling

The tendency to neglect the patient’s intuitions is a warning, because from the patient view these intuitions are extremely valuable, even if from the clinical view they are not useful for predicting patient outcomes. So the patient’s intuitions should at least be heard. Moreover, in Buetow’s opinion, the patient intuitions must be considered as particularly credible sources if the intuitions of patients: 1. Reflect their individualized knowledge. 2. Can complement the common absence of scientific evidence in managing health problems. 3. Can quickly and effectively process key information in complex cognitive tasks [10].

Obstacles to Clinical Intuition

Despite the above evidence, some believe that there is nothing such as “intuition” in practice, unless in the magic or mystical sense [9]. So they are not happy with using intuition in practice and continue to ignore the importance of clinical intuition. These all hinder the firm investing in clinical intuition. 342 N. Rezaei and A. Saghazadeh

An Anti-gut feeling Account in Practice

The same conclusion driven from intuition research in different fields is that what intuition says to us may be true or false. Factors that determined the accuracy of intuition remained secret to scientists [11]. Because of this uncertainty in the accuracy of intuition, some argue that intuition contributes to overoptimism or over- pessimism, and therefore professional decision-making should not be held with intuition because of its imposed costs on patients. For example, in a prospective cohort study[12], Christakis et al. (2000) assessed the accuracy of doctors’ estimates on the survival of terminally ill patients (n = 468). Collectively, 80% of estimates were categorized into overoptimism and over-pessimism groups, while the remaining 20% of estimates were accurate and occurred in the real. It is interesting that predictions that were proven to be wrong were more likely to be over-optimistic (n = 295) rather than over-pessimistic (n = 81).

Research on “Gut Feeling” in Practice Should Be Inclusive

At present, the gut feeling questionnaire is available in English, French, German, Polish, and Dutch [13]. It is, therefore, expected that the associated documents are mainly produced by European countries. Moreover, Stolper et al. [14] set a European research agenda on gut feeling in practice, and GPs from the Netherlands and Belgium participated in that. Therefore, international cooperation should be launched to promote the global exchange of knowledge on “gut feeling” in practice.

Lesson from a True Story: When We Have No Adequate Authority to Manage the Patient, Then What Does Our Sense of Alarm Make Sense for?

When writing the chapter “The Sixth Sense Organs: The Eyes,” I just entered into the second month of my internship. It was the first day that I began my surgical internship and was on call intern of surgery line X. The first patient resident and I visited was a 67-year-old male diagnosed with colon cancer 1 month before that day and referred to our hospital due to partial obstruction. The resident explained this patient to me in this manner; Mr. MAH reported his first defeca- tion and gas passage yesterday, and he is now a candidate for elective surgery. When the resident was introducing the patient to me, I noticed that the patient had respiratory distress and tachycardia. The resident also noticed that the 31 Gut Feelings in Practice 343 patient’s SpO2 was fluctuating between 87% and 92%. Because the patient’s hands were cold, the resident placed the pulse oximeter on the patient’s ear. But the SpO2 remained fluctuating and the resident said that this is because the patient is cold. Then, the resident requested a routine lab test and consultation with the nephrologist and cardiovascular specialists. During visiting hours, my sense was always alarming, but the resident told me that you can go and the nurse’s station would call you if any lab test or consultation were responded and then please you call me. After the resident left the ward, I read patients’ history and began to write progress notes at 12 pm. The first patient was Mr. MAH. His oral temperature was 35.2 °C. When I was making the progress note for Mr. MAH, the ICU resident who came to visit another patient looked at me and Mr. MAH. He also noticed that the patient was in distress and told me if you want I can visit him and sign his admission order. I turned happy and told him, “thank you very much.” But the patient still remained in the surgery ward, because there was no empty bed in the surgical ICU. However, there were two empty beds in the general ICU and if the surgery resident ordered this, then the patient could be admitted to that. At 1 pm, I again took an oral temperature of Mr. MAH. It was 35.9 °C. I controlled the oral temperature of another patient; his temperature increased from 36.5 to 37.1 °C. So I found out that the increase in temperature of Mr. MAH is due to the sunlight shining on the patients’ room. At 1:30 pm, responses on routine lab test were online and I saw dramatic rises in INR and creatinine and a decrease in blood sugar. The cardiologist also had reported that heart ejection fraction is 40% and the nephrologist requested sonography. I immediately called the resident and explained the responses of consultation with specialists and told him that SpO2 is still fluctuating and he might have hypo- thermia. He could hear the stress in my voice. He told me please: “reorder all orders requested by the nephrologist and request urgent routine lab tests.” All his orders were done and again I controlled the patient condition. When talking with the patient, I noticed that his left eye was closed and opened and his son told me that he wants to sleep. I put an oxygen mask on his face and told him several times that do not remove the mask. He told me: “go and do not worry for me.” At 3:15 pm, when it was the time of meeting patients with their family, I controlled the patient’s mask and asked the nurse’s station to call me when the lab tests were reported. In the pavilion, I saw another intern who was on call intern of surgery line Y. I strongly asked her to please call me if any events happened. At 3:30 pm, she called me and told me that a cardiac arrest just occurred for one of your patients. From 3:45 pm to 6:45 pm, the doctor announced the time of death after three rounds of cardiopulmonary resuscitation (CPR). Since that morning, the patient should be intubated and ventilated under intensive care and undergo CT angiography for pulmonary thromboembolism. But no one tried to understand what my sense and eyes could see. 344 N. Rezaei and A. Saghazadeh

References

1. Stolper E, Van Royen P, Van de Wiel M, Van Bokhoven M, Houben P, Van der Weijden T, et al. Consensus on gut feelings in general practice. BMC Fam Pract. 2009;10(1):66. 2. Stolper E, van Bokhoven M, Houben P, Van Royen P, van de Wiel M, van der Weijden T, et al. The diagnostic role of gut feelings in general practice. A focus group study of the concept and its determinants. BMC Fam Pract. 2009;10(1):17. 3. Van den Bruel A, Thompson M, Buntinx F, Mant D. Clinicians’ gut feeling about serious infections in children: observational study. BMJ. 2012;345:e6144. 4. Stolper E, Van Royen P, Dinant GJ. The ‘sense of alarm’ (‘gut feeling’) in clinical practice. A survey among European general practitioners on recognition and expression. Eur J Gen Pract. 2010;16(2):72–4. 5. Hartley MN, Sagar PM. The surgeon’s ‘gut feeling’ as a predictor of post-operative outcome. Ann R Coll Surg Engl. 1994;76(6 Suppl):277–8. 6. Lyneham J, Parkinson C, Denholm C. Expert nursing practice: a mathematical explanation of Benner’s 5th stage of practice development. J Adv Nurs. 2009;65(11):2477–84. 7. King L, Clark JM. Intuition and the development of expertise in surgical ward and intensive care nurses. J Adv Nurs. 2002;37(4):322–9. 8. Lyneham J, Parkinson C, Denholm C. Explicating Benner’s concept of expert practice: intuition in emergency nursing. J Adv Nurs. 2008;64(4):380–7. 9. Marks-Tarlow T. Clinical intuition in psychotherapy: the neurobiology of embodied response (Norton series on interpersonal neurobiology). New York, NY, US: WW Norton & Co; 2012. 10. Buetow SA, Mintoft B. When should patient intuition be taken seriously? J Gen Intern Med. 2011;26(4):433–6. 11. Gigerenzer G. Gut feelings: the intelligence of the unconscious: (audio book: Tantor Media, 2007) 2007: http://hdl.handle.net/11858/00-001M-0000-0025-7C13-5 12. Christakis NA, Smith JL, Parkes CM, Lamont EB. Extent and determinants of error in doctors' prognoses in terminally ill patients: prospective cohort study Commentary: why do doctors overestimate? Commentary: prognoses should be based on proved indices not intuition. BMJ. 2000;320(7233):469–73. 13. Barais M, Hauswaldt J, Hausmann D, Czachowski S, Sowinska A, Van Royen P, et al. The linguistic validation of the gut feelings questionnaire in three European languages. BMC Fam Pract. 2017;18(1):54. 14. Stolper E, van Leeuwen Y, Van Royen P, van de Wiel M, van Bokhoven M, Houben P, et al. Establishing a European research agenda on ‘gut feelings’ in general practice. A qualitative study using the nominal group technique. Eur J Gen Pract. 2010;16(2):75–9. Chapter 32 The Manager’s Sixth Sense: An Art in Organizational, Educational, Moral, and Expert Thinking

Amene Saghazadeh, Reza Khaksar, and Nima Rezaei

Abstract As for the other cognitive constructs, intuition is not a constant, but its development continues throughout life. The manager’s intuition guides his/her thought in the right direction so that opportunities at the group level can be realized. The managerial role of the teacher is central to the creation of a dynamic environment for emotional and cognitive learning. Similarly, intuitions also play role in the formation of moral emotions. The present opinion ends with the point that not only expertise and intuition do not conflict with each other but also expertise-based intuition would direct the rapid generation of single decision options rooted in extensive domain-specific language, pattern recognition, and automaticity.

Keywords Education · Emotion · Expert · Intuition · Manager · Moral decision- making · Novice · Organization · Sixth sense · Teacher

Introduction

Recent research witnessed the return of interest in dealing with the dilemma of whether or not to do decision-making with intuition. This rebound might be driven by that rational rules could not satisfy all requirements humans need for decision- making. In addition, this rebound is accompanied by some comments that have revolutionized the concept of intuition, among which is the proposal that intuition is not merely sensing a feeling but it is comprised of knowing and sensing which are respectively considered as intuition as expertise and intuition as feeling [1]. Managerialism is proposed as the prototype of the reign of analytic mind across the intuitive mind [2]. Managerialism which is expected to be applied to all from different domains including practitioners, managers, and policy makers operates in an “over-standardized framework.” Subsequently, it seems that managerialism is a reflection of restraint of emotion, while studies prove that either conscious or unconscious, human emotions and feelings depict a significant effect on his/her decision- making process at multiple levels of operations [3]. Therefore, management needs to meet the emotional demands of humans, maybe just with an add-on item, intuition, “as a non-sequential information processing mode, which comprises both cognitive and affective elements and results in direct knowing without any use of conscious reasoning” [4]. The manager plays a central role from the beginning of making decisions and communicating them to others through the supervision of implementing final decisions. To accomplish this, the manager must have good knowledge of the target working environment [5]. Such knowledge allows the manager to smooth the way so that employees and the manager himself/herself will be able to experience emotional intuitions. Thinking processes take place in individual and group mode. The manager’s sixth sense guides his/her thought in the right direction so that opportunities at the group level can be realized. Intuition and its role in management research can be formulated in the following way: 1. Intuition is a capacity for attaining direct knowledge or understanding without the apparent intrusion of rational thought or logical inference. 2. Executives do make significant use of intuition and the proportion of executives with an intuitive preference is likely to increase with seniority. 3. The quality and utility of the knowledge gained from incidental and unplanned learning opportunities depend upon the extent to which feedback is used positively to nurture intuitive skills and develop good intuitions. 4. Gut feelings are inevitable, but effective learning from them is not. 5. Intuitive knowledge, understanding, and skill can be learned through experience and practice [1]. The result of adhering to such proposal is that an intuitive decision-making can overcome the limitations of a completely rational analysis as reviewed in [6]. 32 The Manager’s Sixth Sense: An Art in Organizational, Educational, Moral… 347

The Two Minds Model: Analysis Versus Intuition

There have been proposed dual processing theories [7], among which is the analytic and intuitive mind model [6]. From the evolutionary perspective, the intuitive mind is much more ancient than the analytic mind. Rational analysis is a rule- based process that takes place in our conscious thought. However, gut feeling or intuition comes from our unconscious into conscious thought. The analytic mind is a serial controlled processor whereas the intuitive mind is a parallel automatic processor [6]. The analytic mind operates in a systematic step-by-step manner, whereas the intuitive mind is a heuristic that uses the whole platform to recognize patterns. So it is expected that the analytic mind has a slower operation than the intuitive mind. In the book [8], Gigerenzer (2007) has defined intuition as a judgment with three assumed characteristics: 1. “that appears quickly in consciousness, 2. whose underlying reasons we are not fully aware of, and, 3. is strong enough to act upon”. In addition, Gigerenzer believed that intuition has its own rationale: “1. simple rules of thumb, which take advantage of. 2. evolved capacities of the brain” Akinci and Sadler-Smith [9] have reviewed the timeline of the evolutionary road of intuition research in management and in base/related disciplines. Barnard was one of the first who proposed the executive role of intuition. In 1938 [10], he defined logical and non-logical mental processes as follows: “by ‘logical processes’ I mean conscious thinking which could be expressed in words, or other symbols, that is, reasoning. By ‘non-logical processes’ I mean those not capable of being expressed in words or as reasoning, which are only made known by a judgment, decision or action.” More interestingly, Barnard believed that the non-logical mental processes have two origins with the same objective: 1. Non-logical mental processes that lie in physiological conditions or factors, or in the physical and social environment, mostly impressed upon us unconsciously or without conscious effort on our part. 2. Non-logical mental processes that consist of the mass of facts, patterns, concepts, techniques, abstractions, and generally what we call formal knowledge or beliefs, which are impressed upon our minds more or less by conscious effort and study. This second source of non-logical mental processes greatly increases with directed experience, study, and education. Thereafter, several have described the role of intuition in management. After defining the concept of executive intuition, it is now more important to apply intuition thereby increasing the productivity of thinking. 348 A. Saghazadeh et al.

Organizational Thinking

Crossan et al. [11] suggested the cascade of intuiting, interpreting, integrating, and institutionalizing processes as a framework for organizational learning. Also, in the book [12] by Van der Heijden, the manager’s sixth sense is seen as the solution to what can limit or prevent organizational thinking about the future of an organization. Such limitations include “inertia, biases, stress avoidance, group-think, fragmentation and tacit cultural assumptions.” Under these limitations, the manager’s sixth sense would allow him/her to develop thinking scenarios which are more comprehensive than their traditional counterparts. It is the inclusiveness of thought that ultimately brings disparate perspectives under an umbrella organization that can compete against any other organizations without using such a tool. In this manner, the sixth sense makes the manager’s organizational eyes open to new opportunities.

Educational Thinking

The managerial role of the teacher is central to the creation of a dynamic environment for emotional and cognitive learning. Skilled intuitions contribute to the construct of emotional thoughts which in turn will provide a “platform for learning, memory, decision-making, and creativity both in social and non-social contexts.” This suggests learners use relevant intuitions in order to integrate emotional and cognitive processes, making learning more efficient. The key element to stimulate relevant emotional intuitions in a classroom is teaching knowledge in an emotionally meaningful way [13]. The success of traditional tactics of teaching, e.g., assigning homework and taking quizzes, depends upon individual student characteristics and so do not work for all students in the same effective way [14]. Even such tactics tend to exacerbate the achievement levels in students who, on their own, are not efficient learners. In today’s modern world, playing is an invitation to fun and pleasure and so can motivate the emotional intuitions [13] and the sixth sense of students [14].

Moral Thinking

Similarly, intuitions also play role in the formation of moral emotions [15]. In an interesting study by Cushman et al. [16], volunteer subjects were presented with moral scenarios and asked to judge their responses according to the three principles: 1. The action principle: Harm caused by action is morally worse than equivalent harm caused by omission. 32 The Manager’s Sixth Sense: An Art in Organizational, Educational, Moral… 349

2. The intention principle: Harm intended as the means to a goal is morally worse than equivalent harm foreseen as the side effect of a goal. 3. The contact principle: Using physical contact to cause harm to a victim is morally worse than causing equivalent harm to a victim without using physical contact. In general, participants revealed a higher tendency to justify their responses using the action and contact principles but not with the intention principle. This indicates that moral judgments are less likely to rely on intentions than post hoc realizations referring to intuitive judgments [17]. Altogether, it is concluded that although the role of conscious reasoning cannot be definitely neglected, intuition seems to be more responsible for moral decision-making.

Expert Thinking

Some assume expertise and intuition as conflict with each other with the reason that intuition uses a heuristic approach associated with biases versus expertise that involves a naturalistic approach for decision-making. However, this point no longer can be accepted. Because, as for the other cognitive constructs, intuition is not a constant, but its development continues throughout life. So, intuitive skills can range from immature (novice) to mature (expert). In the study [18], Baylor (2001) for the first time drew a U-shaped curve to demonstrate the effect of expertise on intuition, where the Y-axis represents the availability of intuition and the X-axis represents the level of expertise. The curve reflects that the development of intuition is a gradual process from immature intuitive thinking to analytic thinking, and finally to mature intuitive thinking. Also, Kahneman and Klein in [19] put forward an advanced understanding of professional intuition. So, it was possible to reach the conclusion that intuition and expertise can complement each other and propose the concept “intuitive expertise.” A variety of factors, including practice, both implicit and explicit learning, focused attention, “kind” learning structures, environmental uncertainty, complex domain-relevant schemas, and judgmental tasks, are involved in the effectiveness of intuitive decision-making (for review see [20]). It is clear that the more the environment is predictable, the more perfect our intuitive judgments are [20]. However, it should be borne in mind constantly that the environment uncertainty is what enforces the mind to build intuitive judgments and so helps the evolution of intuitive thinking. More clearly, if the environment is definitely predictable, then the mind doesn’t really need to charge any from intuition. The study [7] is an example attempt to develop the construct comprised of intuition and expertise. Expertise can be defined as “high levels of skill or knowledge within a given domain.” It helps the organizational team to adapt performance processes, for example, sense making, mental stimulation, situation assessment, and problem representation that fit the demands of a domain, while intuition is an 350 A. Saghazadeh et al.

“affectively charged judgment that arises through rapid, nonconscious, and holistic associations” [20]. Taken together, expertise-based intuition directs the rapid generation of single decision options rooted in extensive domain-specific language, pattern recognition, and automaticity [7].

References

1. Sadler-Smith E, Shefy E. The intuitive executive: Understanding and applying ‘gut feel’in decision-making. Acad Manag Exec. 2004;18(4):76–91. 2. Trevithick P. Humanising managerialism: reclaiming emotional reasoning, intuition, the relationship, and knowledge and skills in social work. J Soc Work Pract. 2014;28(3):287–311. 3. Bechara A, Damasio H, Damasio AR. Emotion, decision making and the orbitofrontal cortex. Cereb Cortex. 2000;10(3):295–307. 4. Sinclair M, Ashkanasy NM. Intuition: myth or a decision-making tool? Manag Learn. 2005;36(3):353–70. 5. Simon HA. Making management decisions: The role of intuition and emotion. Acad Manag Perspect. 1987 Feb;1(1):57–64. 6. Sadler-Smith E. The intuitive mind: profiting from the power of your sixth sense. Hoboken: Wiley; 2010. 7. Salas E, Rosen MA, DiazGranados D. Expertise-based intuition and decision making in organizations. J Manag. 2010;36(4):941–73. 8. Gigerenzer G. Gut feelings: the intelligence of the unconscious. New York: Penguin; 2007. 9. Akinci C, Sadler-Smith E. Intuition in management research: a historical review. Int J Manag Rev. 2012;14(1):104–22. 10. Barnard C. The functions of the executive. Cambridge, MA; 1938. 11. Crossan MM, Lane HW, White RE. An organizational learning framework: from intuition to institution. Acad Manag Rev. 1999;24(3):522–37. 12. Van der Heijden K, Bradfield R, Burt G, Cairns G, Wright G. The sixth sense: accelerating organizational learning with scenarios. Hoboken: Wiley; 2002. 13. Immordino-Yang MH, Faeth M. The role of emotion and skilled intuition in learning. In: Mind, brain, and education: Neuroscience implications for the classroom, vol. 69; 2010 Nov 1. p. 83. 14. Baines LA, Slutsky R. Developing the sixth sense: play. educational HORIZONS. 2009;87(2):97–101. 15. Adolphs R. Cognitive neuroscience: cognitive neuroscience of human social behaviour. Nat Rev Neurosci. 2003;4(3):165. 16. Cushman F, Young L, Hauser M. The role of conscious reasoning and intuition in moral judgment: testing three principles of harm. Psychol Sci. 2006;17(12):1082–9. 17. Patterson R, Rothstein J, Barbey AK. Reasoning, cognitive control, and moral intuition. Front Integr Neurosci. 2012;6:114. 18. Baylor AL. A U-shaped model for the development of intuition by level of expertise. New Ideas Psychol. 2001;19(3):237–44. 19. Kahneman D, Klein G. Conditions for intuitive expertise: a failure to disagree. Am Psychol. 2009;64(6):515. 20. Dane E, Pratt MG. Exploring intuition and its role in managerial decision making. Acad Manag Rev. 2007;32(1):33–54. Index

A Artificial neural networks (ANNs), 321 Absorption, 226 Asomatognosia, 76 Accommodation, 34, 35 Asthma, 138 Acetylcholine (ACh), 240 Asynchronous visuotactile stroking, 281 Active cognitive functioning, 215 Attention deficit hyperactivity disorder Acute myocardial infarction (AMI), 140 (ADHD), 127 Acute side effects, 295 Audition, 269 Addiction disorder, 73, 74, 113, 116, 125 Auditory continuity illusion, 269 Adequate sleep, 166 Auditory-evoked responses (AERs), 206 Adrenocorticotrophic hormone (ACTH), 116 Auditory intuition, 332 Adult stem cells, 290 Auditory stimulation, 270, 320 Affects balance scale (ABS), 142 Auditory verbal hallucinations Agranular cortex, 65 (AVH), 259, 269 Agranular visceromotor cortices, 64 Auditory vestibular sensory substitution, 323 Aha moment, 258 Auditory vision sensory substitution Alcohol withdrawal, 125 device, 324 Alexithymia, 127 Auras Allergic rhinitis, 138 CEN, 223 Alliesthesia, 71, 79, 308 DMN, 223 Alzheimer’s disease (AD), 3, 145 SN, 223 Amygdala, 60, 62, 114 See also Brain Analytic mind, 335 Autism spectrum disorders (ASDs), 73, 127, Anorexia nervosa (AN), 77, 78 255, 283 Anterior cingulate cortex (ACC), 64, 114, 138, Autoimmune-associated behavioral syndrome 331 (AABS), 140 Anterior insula (AI), 60 Autoimmune disease (AIDs), 138–140, 255 Anterior rostral medial prefrontal cortex Automatic pattern matching system, 334 (arMPFC), 148 Autonomic nervous system (ANS), 244 Antibodies and immunoglobulins, 161 Autoscopic phenomena, 77 Anti-gut feeling, 342 Average sleep duration (ASD), 147 Anxiety disorders, 71, 118, 119 Anxiety-related feeding/exploration conflict (AFEC) test, 168 B Apparent diffusion coefficient (ADC), 161 B-cell-activating factor (BAFF), 140 Arithmetic thinking, 331 Bed nucleus of the stria terminalis Articulation, 269 (BNST), 170

Bell’s inequalities, 214 Bulimia nervosa (BN), 77, 78, 120 Beyond time, 9 Bimodal cells, 274 Bimodal neurons, 274, 275 C Binge eating disorder (BED), 120 Calcarine sulcus (CalS), 278 Biophysics, 52 Calcitonin gene-related peptide (CGRP), 244 See also Visual system Cancer, 142 Blood–brain barrier (BBB), 163, 238 Cancer stem cell, 290 Blood oxygenation level-dependent (BOLD), Cancer treatment, 295 219 Cardiopulmonary resuscitation (CPR), 343 Bloodthirsty/cannibal, 311 Cardiovascular control system, 244 Blood urea nitrogen (BUN), 310 Cardiovascular diseases, 140, 141 Bodily self-consciousness (BSC), 96 Catecholamines (CAs), 239 Bone marrow cells, 297 Cautions, 169, 170 Bone metastases, 298 CB1 receptors (CB1Rs), 159 Bradykinin (BK), 244 CD133-expressing glioma stem cells, 296 Brain Cell-cell communication, 298 after aura Central executive network (CEN), 5, 75, 220 and autoscopic phenomena, 221 Central nervous system (CNS), 115, 193, 236 during epilepsy, 221 Central nucleus of the amygdala (CeA), 125 during, migraine, 220 Central vestibular system, 268 and hallucinations, 221 Chemical magnetoreception hypothesis, 42, 44 sixth sense, 222 Chemokines, 160 before aura, 219 Child behavior checklist (CBCL), 127 during aura, 219 Chromosomal aberration rate, 295, 298 at work Chronic fatigue syndrome (CFS), 128 bilateral dorsal system, 220 Chronic immobilization stress (CIS), 161 CEN, 220 Chronic low back pain (CLBP), 74 DLPFC, 220 Chronic pain, 74, 75 DMN and CEN networks, 220 Chronic side effects, 295 IPS, 220 Circadian clock, 262 mental processes, 219 Circadian rhythms PPC, 220 in animals, 48 right-lateralized ventral system, 220 cryptochromes, 44 TPJ, 220 melatonin synthesis, 50, 51 Brain disorders, 259 orchestrate function, 48 Brain oscillatory pineal gland, 49 chemo-electrical signaling, 200, 208 retinal melatonin and N-acetyltransferase delta oscillations, 201 activity, 50 NREM sleep (see NREM sleep) visual system, 47, 49 ripple oscillations, 201 Cognitive-behavioral stress management sleep-wake transition, 202 (CBSM) intervention, 168 slow oscillations, 201 Cognitive communication, 169 wake-sleep transition Cognitive function/dysfunction, 192 NREM sleep, 200 Cognitive functions semantic memory, 200 slow wave oscillations (see Slow wave synchronization, 200 oscillations) Brain-born cytokines, 238 Cognitive Reflection Test (CRT), 335 Brain-derived neurotrophic factor (BDNF), Coherence, 9, 246 164 Color vision, 38 Brain–gut axis, 253 Common sensation, 222 Brain-machine interfaces (BMIs), 321 Communicating network (CN), 5 Brownian motion, 43 Communicating system, 7 Bruchpilot (BRP), 202 Complete hallucinations, 109 Index 353

Complex regional pain syndrome (CRPS), 74 D Computer vision, 24 Da Costa’s syndrome, 245 Concanavalin A (Con A), 142 Decision-making, 187 Concept of entropy, 184 Declarative memory, 200, 203, 204 Conscious, 2, 5 Default mode network (DMN), 3, 5, 66, 75, Conscious/unconscious prospection (CUP) 219 integrated approach, 7 Delphi consensus study, 339 principles, 6, 7 Delta oscillations, 201 SII, 9 Delusional body border disorders Cord blood mononuclear cells (CBMNCs), anosognosia, 76 166 autoscopic, 77 Cornea, 28 FMS, 77 Coronal mass ejections (CMEs), 45 heautoscopic, 77 Coronary heart disease (CHD), 141 phantom limb, 76 Cortex signals, 76 agranular, 63–66 Dempster-Shafer theory, 316 dorsal posterior, 61 Depressive disorders, 71, 72, 126, 309 granular, 63, 64 Deranged hallucinations, 108, 110 insular, 60 Dexamethasone (DEX), 169 secluded, 60 3,4-Dihydroxyphenylacetic acid (DOPAC), sensory, 64 159 somatosensory, 61 Differentiatedness, 293 visceral, 64 Discs-large (DLG), 202 Cortical spreading depression (CSD), 219 Distance, 29, 36, 37, 39 Corticotropin-releasing factor (CRF), 238 Distant peripersonal neurons, 274 Corticotropin-releasing hormone (CRH), 115, Domain-relevant knowledge, 330 138 Dominance-solvable games, 331 Crohn’s disease, 144 Dorsal raphe nucleus (DRI), 164 Cross-modal plasticity, 320 Dorsal vagal complex (DVC), 125 Crystalline lens, 30 Dorsolateral (DLPFC), 114 Cyclic adenosine monophosphate (cAMP), Dorsolateral prefrontal cortex (DLPFC), 220 240 Dream telepathy, 213 Cysteine string protein (CSP), 202 Drug development process, 192 Cytokines, 117 and adipokines, 158 anti-inflammatory cytokines, 156 E anti-TNF-α treatment, 158 Eating disorders anxious- and depressive-like behaviors, AN, 77, 78 159 BN, 77, 78 culture and negative emotions, 156 Educational thinking, 348 cytokine expression, 156 Einstein, Podolsky, and Rosen (EPR) depressive symptoms and hostility, 157 paradox, 213 emotional stress (ES), 157 Einstein’s general relativity theory, 32 gene knockout models, 158 Electrode implantation, 321 IFN-γ-deficient mice, 159 Electroencephalogram (EEG), 221, 233, mental illnesses, 157 270, 333 personality traits, 156 Electromagnetic field, 196 proinflammatory cytokines, 156, 157 biological processes, 39 proinflammatory markers, 156 cardiac, neural and muscular tissues, 40 social/emotional stressors, 156 cryptochromes, 44 spatial learning/memory, 158 detection, 39, 49 systemic immune challenges, 158 induction, 39 Cytomegalovirus (CMV), 120 melatonin secretion, 51 Cytotoxic necrotizing factor 1 (CNF1), 145 5-methoxy-tryptamine, 51 354 Index

Electromagnetic field (cont.) European General Practitioners Research mood disorders and miscarriage, 51 Network (EGPRN), 340 pineal gland, 49 European Neolithic cattle farming sites, 306 psychiatric parameters, 47 Event-related brain potentials (ERPs), 206 Electromagnetic induction, 39, 40 Event-related potential (ERP), 203 Electromagnetic theory, 43 Evolutionary perspective Electromagnetic waves, 196 absorption, 226 Elementary hallucinations, 108 creativity, 225–227 Embryonic stem cells, 290 innovation, 225, 226 Emotion dysregulation (EDR), 113 intelligence, 226 Emotion regulation (ER) interoception, 227 aggression, 119 IQ scores, 226 anxiety, 118, 119 sensory substitution, 228 attention and physiological responses, 113 sixth sense, 226 framework, 113, 114 theory of multiple intelligences, 226 immune system, 116, 117 variability and creativity, 227 loneliness, 120 Examination-taking students (ETS), 118, 119 mental and physical health, 113 Experimental autoimmune encephalitis multifarious emotion assessments, 112 (EAE), 116 negative and positive effects, 119 External information (EI), 10 neuroanatomy, 114 Exteroception, 307 neuroendocrinology, 115 Exteroceptive cortices, 65 perceived discrimination, 124 Extracellular matrix (ECM), 292 SES, 123 Extra-sense, 100, 101 shame, 124 Extrasensory perception (ESP) social rejection, 123 awareness, 102 stress, 120, 121 clairvoyance, 102, 109 therapy, 167 complete hallucinations, 109, 110 well-being, 122 concept, 101 worry, 122 deranged hallucinations, 108 Emotion regulation therapy, 167 elementary hallucinations, 108 Emotion with tears, 165 empirical evidence, 102 Emotional and cognitive learning, 348 environment, 102 Emotional approach coping (EAC), 165 innate force, energy/powers, 101 Emotional disclosure (ED), 165 interconnection, minds, 104 Endothelin-1 (ET-1), 141 magnetic memory, 103, 104 Entanglement mediumship, 102 brain, reinforce dreaming, 214, 215 paranormal phenomena, 107 microscopic to macroscopic behavior parapsychology, 102 Bell’s inequalities, 214 precognition, 103, 104 EEG, 214 psychokinesis, 109 EPR paradox, 213 psychometry, 102 neuronal level, 214 relationship, 103 nonlocal correlations, 214 sense and extra-sense, 100, 101 principle of uncertainty, 213 stimulations perception, 110 quantum mechanics, 213 telepathy, 102, 103, 109 quantum systems, 214 Eye, 14 Enteric nervous system, 308 definition, 258 Enteroendocrine system (EES), 254 eye-gaze, 261 Entropy, 10, 232, 233 neurological disorders, 260 Epilepsy, 218, 221 rhythmic movement, 259 Epiphysis cerebri, 49 role, 258 Epstein-Barr virus (EBV), 161 schizophrenia, 261 Ethyl-eicosapentaenoate (EPA), 168 SCN, 262 Index 355

temporal cortex, 260 General practitioners (GPs), 340 Eye movements and perception, 20, 21 Generalized anxiety disorder (GAD), 122, 125 Geomagnetic field components, 47 F iron chain, 42 Face perception, 21 microteslas, 45 Feeding behavior, 254 navigation, orientation and migration, 45 Feeding/appetite center, 253 oscillations, timescales, 46 Fetal heart rate, 247 remote viewing, dreaming and psi Fibromyalgia (FM), 75 performance, 47 Fields of the anterior ectosylvian region sensory receptors, 39 (FAES), 320 sun’s activities, variation, 47 Fixational eye movements, 20 Van Allen radiation belts, 46 FK506 binding protein 51 (FKBP5) gene, 170 variations, 45 Food preference visual acuity and discrimination threshold, acidosis, 306 39 alliesthesia, 308 Geomagnetic storm, 46 antacid, 306 Glioneuronal tumor, 290 depression, 309 Global System for Mobile communications flovors, 306 (GSM), 300 French population, 306 Glucocorticoid receptor (GR), 170 internal signals, 308 Golgi tendon organs (GTOs), 88 nutritious foods, 308 Granular cortex, 64, 66 OFC, 307, 308 Gravitational lens, 28, 32 protein infusion, 307 Gray matter (GM), 144 sensation, 308 Gut toxin, 307 brain–gut axis, 253 unfamiliar location, 307 detectors, 252 Forelimb movements, 321 EES, 254 Fresnel lens, 32 fat digestion, 253 Fresnel method, 31 GABA, 252 Fresnel rings, 31 IBS, 253 Fresnel technique, 28 OEA, 253 Frontal eye field (FEF), 20 sensory information, 252 Frontotemporal dementia (FTD), 145 stress, 254 Functional brain imaging, 138 Gut feeling Functional magnetic resonance imaging ICU, 343 (fMRI), 19, 114, 219 magic/mystical sense, 341 Functional motor disorders (FMS), 77 patient, 341 Fusiform face areas (FFA), 20, 22 phases, 341 Fuzzy sets psychotherapy, 341 artificial intelligence, 188 questionnaire, 342 emotion and expectations, 188 routine lab test, 343 interoception, 180, 188 surgeon, 340 membership function, 180 motivational states, 188 non-membership function, 180 H properties of, 180 Hallucinations complete, 109 deranged, 108 G elementary, 108 Gamma-aminobutyric acid (GABA), 201, 252 Heart Gamma radiation, 295, 296 fetal heart acceleration, 247 Gaussian noise, 270 HRV, 244 356 Index

Heart (cont.) Information integration theory, 5 mental disorders, 245 Inhibitory postsynaptic potentials (IPSPs), 201 MHLF, 247 Insula, 61, 62, 64 physical examination, 245 Intention principle, 349 psychosocial factors, 246 Intermittent explosive disorder (IED), 127, respiration, 245 128 stress, 246 International Consortium in Psychiatric Heart rate variability (HRV), 244 Epidemiology (ICPE), 124 HeartMath emotional management techniques, Interoception, 60, 61, 63, 70, 180, 188, 222, 246 227 Heautoscopic, 77 causes and supports Hematopoietic stem cells (HSCs), 297 straightforward and emotions, 227 Hemodialysis (HD), 143 creativity, 227 Herbal medicine, 169 Interoceptive dysfunction High-fat diet (HFD), 146 addiction, 73, 74 Homovanillic acid (HVA), 159 anxiety, 71 Hospital Anxiety and Depression Scale ASD, 73 (HADS), 143 delusional body border (see Delusional Human immunodeficiency virus (HIV), 143 body border disorders) Human mesenchymal stem cells (hMSCs), depression, 71, 72 166, 296 eating disorders, 77, 78 Huygens Fresnel principle, 36 fibromyalgia (FM), 75 Hydroxy-indole-O-Methyltransferase mood disturbance, 70 (HIOMT), 51 pain, 74, 75 Hyperbola, 185 Interoceptive hub, 62, 64, 65 Hypothalamic-pituitary-adrenal (HPA), 115, Interoceptive inference, 65, 66 117, 163, 164, 236, 240 Interoceptive predictions, 64, 65 Hypothalamus, 114, 140 Intraparietal sulcus (IPS), 220, 278 Intrinsic information, 185 Intuition, 346 I auditory, 332 IL-6, 169 bilateral inferior parietal lobules, 331 Image distance, 34 cognitive intuition, 335 Immersive virtual reality (IVR), 261 context, 331 Immune system CRT, 335 ACTH, 237 fMRI data, 331 bacterial endotoxins and exogenous PFC, 334 cytokines, 237 PS, 335 CNS and PNS, 236 semantic, 333 cytokines, 237 visual, 332–333 endocrine systems, 237 Intuitive mind model, 347 HPA, 236 Irritable bowel syndrome (IBS), 253, 317 nervous system, 236, 237 peripheral sensory stimuli, 235 PNS, 236 L Immune system-related markers, 163, 164 Laser assisted in situ keratomileuses (LASIK), Immunoemotional Regulatory System 30 (IMMERS), 117 Laser epithelial keratomileusis (LASEK), 30 Immunosenescence, 141 Learned preferences, 307 Infections, 144 Learning processes, 331 Inferior parietal lobule (IPL), 282 Lenses, 33, 34 Inferior temporal cortex, 17 ability, 31 Inflammatory bowel disease (IBD), 143, 144 aging, 31 Inflammatory reflex, 239 cornea, 30 Index 357

focusing methods, 32 unpaired electrons, 43 geometrical optics, 28 visual system, 39 transparency and GRID, 30, 31 Magnetocaloric hypothesis, 41 Lesion-induced plasticity, 193 Magnetoencephalography (MEG), 206, 333 Leukemia inhibitory factor (LIF), 163, 170 Magnetoreception mechanism, hypothesis Light chemical magnetoreception, 42, 44 atmosphere and emission of, 46 electromagnetic induction, 39, 40 beam, 28, 37 magnetocaloric, 41 constructive interference, 37 mechanical, 41, 42 dependent biocompass, 42 Major depressive disorder (MDD), 123, 222 gravitational lens, 32 Managerialism, 346 intensity, 35, 36 Many-Neuron-Acquisition-Processor melatonin, 50 (MNAP), 321 perception, 48 Mast cells, 160 photon, 43 Maternal separation (MS), 121 pineal gland, 49 Maternal stress, 254 pupillary light reflex, 49 Mathematical neuroscience, 192 receptor cells, 38 Mechanical hypothesis, 41, 42 refraction fraction, 30 Mechanism of epileptogenesis, 218 retina, 29, 30, 35 Medial prefrontal cortex (MPFC), 5 rod cells, 35 Medial temporal lobe (MTL), 203 scattering, 28, 31, 33 Melatonin, 49, 50, 263 spectrum, 31 Memory, 200–202, 205, 207 stimulation, 42 Ménière’s disease, 317 velocity, 28 Mental disorders wave characteristics, 31 addiction and alcohol withdrawal, 125 wavelengths, 39, 44 alexithymia, 127 Limbic-HPA (LHPA), 116 CFS, 128 Lipopolysaccharide (LPS), 120 depression, 126 Lipopolysaccharide binding protein (LBP), dysregulation profile, 127 162 GAD, 125 Low-frequency oscillations, 270 IED, 127, 128 neuropathic pain, 127 pain catastrophizing, 127 M PTSD, 126 Magnetic field Mental stress (MS), 126 charged particle, 40 Metabolic syndrome, 146, 147 earth’s magnetosphere, 46 Microglia cells, 162 electromagnetic induction, 39 Microtubules, 192 electromagnetic theory, 43 Migraine-associated auras, 218 HIOMT, 51 Mind wandering, 258, 259 intracellular compartments, 40 Mindfulness, 259 light-dependent biocompass, 42 Mindfulness-based stress reduction (MBSR) magnetic force, 47 program, 166 melatonin and 5-methoxytryptophol Mindfulness meditation, 167 circadian oscillations, 51 Minnesota Living with Heart Failure membrane potential variation, 41 Questionnaire (MHLF), 247 perception, 38, 47, 52 Minnesota Multiphasic Personality Inventory photo-induced radical pairs, 44 (MMPI), 141 picotesla, 44 Mirror therapy, 285 pineal gland, 51 Mood disturbance, 70 serotonin N-acetyl-transferase (NAT), 51 Moral decision-making, 349 signaling molecules and substances, 46 Moral emotions, 348 torque, 41 Motion, 34, 38–43 358 Index

Motor and sensory functions, 325 O Multi-Ethnic Study of Atherosclerosis, 123 Obesity, 145, 146 Multiorgan failure (MOF), 255 Object recognition Multiple sclerosis (MS), 139 coding dimensionality, 18 Multipotent adult progenitor cells (MAPCs), complex cognitive operations, 19 297 computational models, 18 Multisensory neurons, 320 motion perception, 19 Murine embryonic stem cells (mES), 293 perception of form, 19 Music therapy, 247, 248 perception of space, 19 scene segmentation, 19 ventral occipitotemporal cortex, 18 N ventral pathway, 18 Natural cytotoxic activity (NCA), 142 Obsessive-compulsive disorder, 77 Natural killer (NK) cells, 122, 161 Occipital face areas (OFA), 20 Neck and shoulder pain, 74 Occipitoparietal pathways, 17, 19 Negative emotional style (NES), 144 Occipitotemporal pathway, 17 Neocortex, 62–64 Oleoylethanolamide (OEA), 253 Neural adaptation, 20 Olfactory stimuli, 309 Neural coding, 23 Omega-3 polyunsaturated fatty acids (n-3 Neural progenitor cells (NPCs), 291 PUFAs), 168 Neuroanatomical properties of visual system Optic pathways, 15, 16 eye, 14 Optical axis, 15 optic pathways, 15, 16 Optical Stiles–Crawford effect (OSCE), 35 retina, 15 Orbitofrontal cortex (OFC), 60, 114, 307 Neuroanatomy, 114 Organizational learning, 348 Neuroendocrine system (NES), 115 Organum vasculosum of the lamina terminalis Neuroimaging studies, 281 (OVLT), 238 Neuroimmunoendocrinology, 235 Oscillating system, 196 Neurological diseases (NDs), 145 Out-of-body experiences (OBEs), 276 Neurological problems, 221 Oxford dictionary, 330 Neuromodulators, 164 Oxidative stress, 162 Neuronal circuits, 164, 165 Oxytocin (OT), 168 Neuroplasticity, 193 Neuropsychiatric SLE (NSLE), 139 Neurotransmitters, 164 P N-Methyl-D-aspartate (NMDA), 201 Pain, 74, 75 Noise-induced theta synchronization, 270 Paraventricular nucleus (PVN), 168 Non-declarative memory, 200 Parieto-insular vestibular cortex (PIVC), 95 Nonionizing radiation, 294 Parkinson’s disease (PD), 145 Non-logical mental processes, 347 Passive cognitive functioning, 215 Non-probabilistic entropy, 185, 187 Perceived discrimination, 117, 124 Non-rapid eye movement (NREM), 200 Periarcuate cortex, 274 Norepinephrine (NE), 244 Peripersonal space, 276 Nottingham Health Profile Peripheral blood mononuclear cells (PBMCs), (NHP), 128 120 Novice, 340 Personality disorders, 222 NREM sleep Perturbational complexity index (PCI), 185 spindle oscillations Phantom limb, 76 GABA, 201 Photo-induced electron, 43 IPSPs, 201 Photoperiodism, 48 thalamocortical regions, 201 Photoreceptor function, 262 surrounding odors, 207 Photoreceptors, 38 surrounding sound, 207 Photorefractive keratectomy (PRK), 29 Nuclear factor-kappa B (NF-κB), 123, 163 Physical and cognitive functioning, 142 Index 359

Pineal gland, 262, 263 musculoskeletal, 86 circadian rhythms, 49 receptors, 86 dreaming, psychoses and mood disorder, skin mechanoreceptors, 89 49 stimuli, 90 melatonin, 49, 50 Prospective cohort study, 342 modulators of melatonin secretion, 51 Prospective observational study, 340 Pituitary proopiomelanocortin (POMC), 163 Prosthetics, 325 Placebo effect, 317 Protein Plasminogen activator inhibitor-1 (PAI-1), 141 families, 191 Platyhelminth, 295 function, 191 Plausibility illusion (Psi), 261 molecules, 192 Positive emotional style (PES), 144 structure and function, 192 Positron-emission tomography (PET), 114, Protein-ligand interaction, 192 219 Pseudo-telepathy, 212, 213 Posterior auditory field (PAF), 320 Psychiatry (schizophrenia), 222 Posterior cingulate cortex (PCC), 5, 60, 219 Psychokinesis, 103 Posterior parietal cortex (PPC), 220 PTS symptoms (PTSSs), 126 Postnatal one (PostDEX), 170 Pupil, 35 Post-traumatic stress disorder (PTSD), 126 Pupillary light reflex, 49 Precuneus/posterior cingulate cortex (PCC), 158 Preferred frequencies, 9, 196 Q Prefrontal cortex (PFC), 60, 114 Quantum bit/qubit, 214 Premotor cortex, 274 Quantum entanglement, 214, 232, 233 Prenatal DEX (PreDEX) treatment, 170 Quantum tunneling, 196, 197 Prenatal stress (PS), 121 Preshape aperture, 260 Price elasticity of demand (PED), 183, 184 R Price-demand elasticity, 186 Radiation therapy, 294, 296 Primary motor cortex, 286 Radio frequency (RF), 294, 297 Primary visual cortex, 17, 18 Radioactive decay processes, 296 Principle of uncertainty, 213 Radio-telepathy, 212 Probabilistic selection (PS), 335 Radon zones, 297 Probability information content (PIC), 316 Rapid eye movement (REM), 200, 202 Processing information, 196 Rational analysis, 347 Proprioception, 321 Reactive oxygen species (ROSs), 297 bodily conditions, 97 Receptive fields (RFs), 274 body sensation, 96 Refractive errors, 29 exteroceptors, 86 Refractive index, 29 receptors, 86 Refractive lens exchange (RLE), 30 sensory, 86 Regenerative medicine, 290 sixth sense, 96 Regional cerebral blood flow (rCBF), 158 vestibular system (see Vestibular system) Regions of interest (ROI) analysis, 333 Proprioceptive drift difference (PDD), 279, Relapsing-remitting multiple sclerosis 280 (RRMS), 139 Proprioceptive system Renin-angiotensin system (RAS), 244 corollary discharge, 91 Repetitive transcranial magnetic stimulation exchanges information, 86 (rTMS), 282 free nerve endings, 89 Resonance, 9 gamma motor activation, 90 Resonance phenomenon, 9 GTOs, 88 Resting state networks (RSNs), 219 joint receptors, 89 Retina, 15, 38 motor activity, 90 Retinal melatonin, 50 muscle spindles, 87, 88 Retinal pigment epithelium (RPE), 37 360 Index

Rheumatic symptoms, 254 Sleep spindles, 310 Rheumatoid arthritis (RA), 140, 165, 254 Sleep-wake cycles, 200 Ripple oscillations, 201 Sleep-wake transition, 202 Romberg Test, 322 Slow oscillations, 201 Rotational movements, 268 Slow-wave activity (SWA), 169 Rubber hand illusion, 280, 281 Slow wave oscillations and learning, 204 and memory, 203, 204 S neural correlates, 204 Saccadic movements, 20 synchronization, 203 Salient network (SN), 5, 75, 220 Social housing, 167, 168 Schizophrenia, 221, 222, 283 Social rejection, 123 Self-feeling, 60 Socioeconomic status (SES), 123, 146 Semantic intuition, 333 Solar energetic particles (SEPs), 45 Sense, 100, 101 Somatic cells, 290 Sense of alarm, 339 Somatoparaphrenia, 76 Sense of intuition, 192 Somatosensory evoked potentials (SEP), 283 Sense of reassurance, 339 Somatosensory neurons, 274 Sense of self and others, 321 Space, 19 Sense of the world, 309 cognitive functions, 23 Sensorimotor cortex, 64 interference pattern, 31 Sensory branches, 240 perception, 19 Sensory cortex, 64 phases, 31 Sensory feedback, 322 weather (see Space weather) Sensory inputs, 276 weather disturbances, 45 Sensory substitution, 321, 324 Space weather Sensory system, 193 CMEs, 45 Sham-controlled trial, 285 geomagnetic storm, 46 Single-blind randomized experiment, 285 SEPs, 45 Single nucleotide polymorphism (SNP), 159 Van Allen radiation belts, 46 Sixth sense Spared nerve injury (SNI) model, 127 and common sense, 194 Spatial attention, 19 description, 180 Spherical waves, 36 evolutionary perspective (see Evolutionary Spindle oscillations, 200 perspective) Spooky actions fuzzy sets (see Fuzzy sets) coherent superposition, 233 synchronization (see Synchronization) description, 232 Sjögren syndrome, 140 entropy, 232, 233 Skilled intuitions, 348 metal state-environment, 232 Skin conductance response (SCR), 284 quantum entanglement, 232, 233 Skin diseases, 147 sixth sense, 232, 233 Skin erythema, 294 squeezed states, 233 Skin temperature, 284 symphony of, 234 Sleep Sporadic reports, 279 bimodal phenomenon Sprague-Dawley (SD), 127 consciousness and dreaming, 205 Squeezed states, 233 REM sleep, 205 Stability, 193 brain oscillatory activities (see Brain Stabilization, 193 oscillatory) Staphylococcal enterotoxin A (SEA), 158 brain’ synapses, 202 Staphylococcal enterotoxin B (SEB), 158 and sensory stimuli State Shame and Guilt Scale (SSGS), 124 NREM sleep (see NREM sleep) Stem cell transplantation (SCT), 166 REM sleep, 206 Stem cells Sleep disturbances, 147 clinical applications, 290 Index 361

ECM, 292 Tactile Vision Sensory Substitution (TVSS) features, 293 system, 322, 324 heat source, 294 Tai Chi Chuan (TCC), 167 human and murine genome, 295 T cells, 160 intrinsic mechanism, 293 Telekinesis, 103 iPSCs, 291 Telepathy, 100, 102, 103, 212 matrix elasticity, 292 Temporal discrepancies, 280 mesenchymal, 296 Temporal lobe epilepsy (TLE), 221 microenvironment and Temporal-parietal junction (TPJ), 220 macroenvironment, 294 Thalamocortical regions, 200, 201 mobile phone microwaves, 299 The Sixth sense nuclei, 292 ESP, 100, 101 pluripotency, 291 proprioception, 96 progenitor cells, 293 Theory of multiple intelligences, 226 static role, 293 Theory of quantum entanglement, 232 stem cell division, 294 Thinking processes, 346 symmetric division, 293 Toll-like receptors (TLRs), 162 transcription factors, 291 Transfer function, 186 types, 290 Traumatic injuries, 148 Stemness, 290 Trier Social Stress Test (TSST), 160–161 Stiles-Crawford effect (SCE), 35 Trypanosoma, 116 Stress system, 240 Typically developed (TD), 127, 283 Striatal dopaminergic system, 317 Stroke, 148 Subgenual anterior cingulate cortex U (sACC), 148 Ultrasonography, 3 Sudden unexplained death in epilepsy Umbilical cord-derived mesenchymal stem (SUDEP), 248 cells (UCMSCs), 166 Superior colliculus (SC), 320 Unconscious, 2, 10 Superior temporal gyrus (STG), 207, 270 Unconscious prospection, 5, 7, 10 Superior temporal sulcus (STS), 20 Unconscious thought theory, 4 Superposition principle, 36 Uncoupling protein 2 (UCP2) knockout, 159 Superposition theory, 32 Universal Scientific Education and Research Supplementary motor area (SMA), 282 Network (USERN), 315 Suppressors-of-cytokine-signaling (SOCS), UV-irradiated stem cells, 299 146 UV radiations (UVR), 299 Suprachiasmatic nuclei (SCN), 48, 49, 262 Symmetry, 193 Sympathetic anti-inflammatory pathway, 239 V Sympathetic nervous system (SNS), 239, 244 Vaccination, 148 Synaptic plasticity, 193 Vagus nerve, 240 Synchronization, 192 Van Allen radiation belts, 46 coupling, 196, 197 Vascular endothelial growth factor (VEGF), 142 electric filed, 195 Ventral intraparietal (VIP), 275 electromagnetic field, 196, 197 Ventral occipitotemporal (VOT), 332 quantum tunneling, 196, 197 Ventral premotor cortex (PMv), 278 sensory deficiencies, 197 Ventral temporal cortex (VTC), 18 wavelet energy signals, 196 Ventromedial (VMPFC), 114 Synchronous stimulation, 283 Ventromedial prefrontal cortex (VMPFC), Systemic lupus erythematosus (SLE), 140, 161 219, 334 Vestibular structures, 268 Vestibular system, 268 T crista, 94 Tactile navigation sensory substitution, 323 definition, 93 362 Index

Vestibular system (cont.) fixational, 20 deflection, stereocilia, 92 human gaze control, 21 differentiation, 92 microsaccades, 21 distance-receptors, 91 neural adaptation, 20 hair cells, 92, 93 saccadic movements, 20 head movements, 94, 95 tremor, 21 macula, 93 face perception, 21 mechanoreceptors, 92, 95 highest level, 23 membranous labyrinth, 92 inferior temporal cortex, 17 motile organism, 91 intermediate level processing, 23 otolithic membrane, 94 low-level perception, 23 semicircular canals and otolith organs, 95 middle temporal lobe, 16 synaptic terminals, 93 neural coding, 23 Visceral sensorimotor system, 65 occipital lobe, 16 Visceromotor control systems, 64 Visual search, 18 Visceromotor cortices, 65 Visual system Vision, 14, 21 image forming function acuity, 47 accommodation, 34, 35 cortex of primates, 16 cornea, 28 human, 20 lens, 33, 34 photic and scotopic, 38 pupil, 35 Visual and somatosensory information, 276 retina, 38 Visual illusions, 260 non-image forming functions Visual intuition, 332–333 circadian rhythm, 47, 49 Visual perception magnetic field, perception of, 38, 47 brain regions and pathways pineal gland (see Pineal gland) neural coding, 23 Vitamin B12 treatment, 310 object recognition (see Object recognition) primary visual cortex, 17, 18 W constructive nature, 22 Wavefunctions, 197 eye movements Wavelet-based methods, 9, 196 adaptation, 21 Wavelet energy, 9 drifts, 21 Windows of the brain, 238 FEF, 20 Wistar Kyoto (WK), 127