Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 306

Pharma Science Monitor 8(2), Apr-Jun 2017

PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES Journal home page: http://www.pharmasm.com

BRAINWAVES AS NEUROPHYSIOLOGICAL OUTCOMES IN NEUROSEDATION Nikhil C. Shah1, Srabona Lahiri1 and Dhrubo Jyoti Sen2* 1Bethany Mission School, Near Ashirwad Flat, Behind Hingraj Society, Mehsana-384002, Gujarat, India 2Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India

ABSTRACT is rhythmic or repetitive neural activity in the central nervous system. Neural tissue can generate oscillatory activity in many ways, driven either by mechanisms within individual neurons or by interactions between neurons. In individual neurons, oscillations can appear either as oscillations in membrane potential or as rhythmic patterns of action potentials, which then produce oscillatory activation of post-synaptic neurons. At the level of neural ensembles, synchronized activity of large numbers of neurons can give rise to macroscopic oscillations, which can be observed in an electroencephalogram. Oscillatory activity in groups of neurons generally arises from feedback connections between the neurons that result in the synchronization of their firing patterns. The interaction between neurons can give rise to oscillations at a different frequency than the firing frequency of individual neurons. A well- known example of macroscopic neural oscillations is alpha activity. Neural oscillations were observed by researchers as early as 1924 (by Hans Berger). More than 50 years later, intrinsic oscillatory behavior was encountered in vertebrate neurons, but its functional role is still not fully understood. The possible roles of neural oscillations include feature binding, information transfer mechanisms and the generation of rhythmic motor output. Over the last decades more insight has been gained, especially with advances in imaging. A major area of research in neuroscience involves determining how oscillations are generated and what their roles are. Oscillatory activity in the brain is widely observed at different levels of observation and is thought to play a key role in processing neural information. Numerous experimental studies support a functional role of neural oscillations; a unified interpretation, however, is still lacking. KEYWORDS: EEG, qEEG, MEG, fMRI, Brain waves, Infra low brain waves, Delta waves, Theta waves, Alpha waves, Beta waves, Gamma waves, Mu waves, REM & NREM , K- complex.

INTRODUCTION At the root of all our thoughts, emotions and behaviours is the communication between neurons within our . Brainwaves are produced by synchronized electrical pulses from masses of neurons communicating with each other. Brainwaves are detected using sensors placed on the scalp. They are divided into bandwidths to describe their functions but are best thought of as a continuous spectrum of ; from slow, loud and functional - to fast, subtle, and complex. It is a handy analogy to think of Brainwaves as musical notes - the low frequency

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 307 waves are like a deeply penetrating drum beat, while the higher frequency brainwaves are more like a subtle high pitched flute. Like a symphony, the higher and lower frequencies link and cohere with each other through harmonics. Our brainwaves change according to what we’re doing and feeling. When slower brainwaves are dominant we can feel tired, slow, sluggish, or dreamy. The higher frequencies are dominant when we feel wired, or hyper-alert. The descriptions that follow are only broadly descriptions - in practice things are far more complex and brainwaves reflect different aspects when they occur in different locations in the brain. Brainwave speed is measured in Hertz (cycles per second) and they are divided into bands delineating slow, moderate and fast waves.[1] Infra-low (<0.5Hz): Infra-Low brainwaves (also known as Slow Cortical Potentials), are thought to be the basic cortical rhythms that underlie our higher brain functions. Very little is known about infra-low brainwaves. Their slow nature makes them difficult to detect and accurately measure, so few studies have been done. They appear to take a major role in brain timing and network function. Delta waves (0.5 to 3 Hz): Delta brainwaves are slow, loud brainwaves (low frequency and deeply penetrating, like a drum beat). They are generated in deepest and dreamless sleep. Delta waves suspend external and are the source of empathy. Healing and regeneration are stimulated in this state, and that is why deep restorative sleep is so essential to the healing process. Theta waves (3 to 8 Hz): Theta brainwaves occur most often in sleep but are also dominant in deep meditation. It acts as our gateway to learning and memory. In theta, our senses are withdrawn from the external world and focused on signals originating from within. It is that twilight state which we normally only experience fleetingly as we wake or drift off to sleep. In theta we are in a ; vivid imagery, intuition and information beyond our normal conscious awareness. It’s where we hold our ‘stuff’, our fears, troubled history, and . Alpha waves (8 to 12 Hz): Alpha brainwaves are dominant during quietly flowing thoughts, and in some meditative states. Alpha is ‘the power of now’, being here, in the present. Alpha is the resting state for the brain. Alpha waves aid overall mental coordination, calmness, alertness, mind/body integration and learning. Beta waves (12 to 38 Hz): Beta brainwaves dominate our normal waking state of consciousness when is directed towards cognitive tasks and the outside world. Beta is a ‘fast’ activity, present when we are alert, attentive, engaged in problem solving, judgment, decision making, and engaged in focused mental activity.

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 308

Beta brainwaves are further divided into three bands; Lo-Beta (Beta1, 12-15Hz) can be thought of as a 'fast idle, or musing. Beta (Beta2, 15-22Hz) is high engagement or actively figuring something out. Hi-Beta (Beta3, 22-38Hz) is highly complex thought, integrating new experiences, high anxiety, or excitement. Continual high frequency processing is not a very efficient way to run the brain, as it takes a tremendous amount of energy. Gamma waves (38 to 42 Hz): Gamma brainwaves are the fastest of brain waves (high frequency, like a flute), and relate to simultaneous processing of information from different brain areas. It passes information rapidly, and as the most subtle of the brainwave frequencies, the mind has to be quiet to access it. Gamma was dismissed as 'spare brain noise' until researchers discovered it was highly active when in states of universal love, altruism, and the ‘higher virtues’. Gamma is also above the frequency of neuronal firing, so how it is generated remains a mystery. It is speculated that Gamma rhythms modulate and consciousness, and that a greater presence of Gamma relates to expanded consciousness and spiritual emergence. What brainwaves mean to you: Our brainwave profile and our daily experience of the world are inseparable. When our brainwaves are out of balance, there will be corresponding problems in our emotional or neuro-physical health. Research has identified brainwave patterns associated with all sorts of emotional and neurological conditions. Over-arousal in certain brain areas is linked with anxiety disorders, sleep problems, nightmares, hyper-vigilance, impulsive behaviour, anger/aggression, agitated depression, chronic nerve pain and spasticity. Under- arousal in certain brain areas leads to some types of depression, attention deficit, chronic pain and . A combination of under-arousal and over-arousal is seen in cases of anxiety, depression and ADHD. Instabilities in brain rhythms correlate with tics, obsessive-compulsive disorder, aggressive behaviour, rage, , panic attacks, , migraines, , , , vertigo, tinnitus, anorexia/bulimia, PMT, diabetes, hypoglycaemia and explosive behaviour.

Figure-1: EEG waves

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 309

Altering your brainwaves: By rule of thumb, any process that changes your perception changes your brainwaves. Chemical interventions such as medications or recreational drugs are the most common methods to alter brain function; however brainwave training is our method of choice. Over the long term, traditional eastern methods (such as meditation and yoga) train your brainwaves into balance. Of the newer methods, brainwave entrainmentis an easy, low-cost method to temporarily alter your brainwave state. If you are trying to solve a particular difficulty or fine-tune your brainwave function, state-of-the-art brain training methods like neurofeedback and pEMF deliver targeted, quick, and lasting results.[2] Alpha waves are neural oscillations in the frequency range of 7.5–12.5 Hz arising from synchronous and coherent (in phase or constructive) electrical activity of thalamic pacemaker cells in humans. They are also called Berger’s wave in memory of the founder of EEG. Alpha waves are one type of brain waves detected either by (EEG) or magneto encephalography (MEG) and predominantly originate from the occipital lobe during wakeful relaxation with closed eyes. Alpha waves are reduced with open eyes, drowsiness and sleep. Historically, they were thought to represent the activity of the in an idle state. More recent papers have argued that they inhibit areas of the cortex not in use, or alternatively that they play an active role in network coordination and communication. Occipital alpha waves during periods of eyes closed are the strongest EEG brain signals. Alpha waves can be quantified using Quantitative electroencephalography (qEEG) using freely available toolboxes, such as, EEGLAB or the Neurophysiological Biomarker Toolbox. An alpha- like variant called mu (µ) can be found over the motor cortex (central scalp) that is reduced with movement, or the intention to move. Alpha waves seem not to appear until three years of age. Types: Some researchers posit that there are at least two forms of alpha waves, which may have different functions in the wake-. Alpha waves are present at different stages of the wake-sleep cycle. The most widely researched is during the relaxed mental state, where the subject is at rest with eyes closed, but is not tired or asleep. This alpha activity is centered in the occipital lobe and is presumed to originate there, although there has been recent speculation that it instead has a thalamic origin. This wave begins appearing at around four months and is initially a frequency of 4 waves per second. The mature , at 10 waves per second, is firmly established by age 3. The second occurrence of alpha wave activity is during REM sleep (). As opposed to the awake form of alpha activity, this form is located in a frontal-central

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 310 location in the brain. The purpose of alpha activity during REM sleep has yet to be fully understood. Currently, there are arguments that alpha patterns are a normal part of REM sleep and for the notion that it indicates a semi-arousal period. It has been suggested that this alpha activity is inversely related to REM sleep pressure.[3]

Figure-2: Brain waves It has long been believed that alpha waves indicate a wakeful period during sleep. This has been attributed to studies where subjects report non-refreshing sleep and have EEG records reporting high levels of alpha intrusion into sleep. This occurrence is known as alpha wave intrusion. However, it is possible that these explanations may be misleading, as they only focus on alpha waves being generated from the occipital lobe. Alpha wave intrusion occurs when alpha waves appear with non-REM sleep when delta activity is expected. It is hypothesized to be associated with fibromyalgia although the study may be inadequate due to a small sampling size. Despite this, alpha wave intrusion has not been significantly linked to any major , including fibromyalgia, chronic fatigue syndrome and major depression. However, it is common in chronic fatigued patients and may amplify the effects of other sleep disorders. Because of alpha waves' connection with relaxed mental states, increase in alpha wave activity is a desirable outcome for some types of biofeedback training. EEG can be used to provide the subject with feedback when alpha waves increase, enabling some individuals to consciously increase alpha wave activity. There are several different prospects of this training that are currently being explored. Arguably, the most popular one is the use of this training in meditation. Zen-trained meditation masters produce noticeably more alpha waves during meditation. This fact has led to a popular trend of biofeedback training programs for everyday stress relief. Psychologists are hoping to use this technique to help people overcome phobias, calm down hyperactive children and help children with stuttering problems to relax enough to practice regular speech. There are other uses of biofeedback training beyond therapy. Defense

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 311

Department researchers are exploring biofeedback as a way of getting captured soldiers to create alpha waves, potentially foiling enemy lie detectors. Biofeedback training has also been receiving attention as a possible way of monitoring attention. It has been theorized that teaching machines could use biofeedback as a way of monitoring children's attention, with the appearance of alpha waves signaling a lapse of attention.[4]

Figure-3: Sleep cycle Following this lapse-of-attention line of thought, a recent study indicates that alpha waves may be used to predict mistakes. In it, MEGs measured increases of up to 25% in alpha brain wave activity before mistakes occurred. This study used common sense: alpha waves indicate idleness and mistakes are often made when a person is doing something automatically, or "on auto-pilot" and not paying attention to the task they are performing. After the mistake was noticed by the subject, there was a decrease in alpha waves as the subject began paying more attention. This study hopes to promote the use of wireless EEG technology on employees in high-risk fields, such as air traffic controlling, to monitor alpha wave activity and gauge the attention level of the employee.[5]

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 312

Figure-4: K-complex graph As demonstrated by Adrian Upton, it is possible for extraneous sources (ambient fluctuations detected with a mound of Jell-O in Upton's experiments) to cause signals to appear on an EEG readout, causing false signals to be interpreted as healthy alpha waves. This finding suggests that it is possible that a non-flat EEG could lead to the interpretation that a patient is still living when in fact he or she is long dead. Cecil Adams from The Straight Dope discusses this scenario: Sometimes it's claimed Jell-O brainwaves are identical to a healthy adult's. That's clearly a stretch, but the Jell-O EEG readings do look pretty similar to a normal human alpha rhythm. Alpha waves are observed when a patient is awake and resting with eyes closed and in some kinds of sleep and reversible coma. True, the Jell-O waves are a little slower and of much lower amplitude, barely within normal human limits, but that doesn't tell you much by itself. Hypoxia, encephalitis and other medical conditions can cause reduced frequency and amplitude, as can drug use.[6] , or beta rhythm, is the term used to designate the frequency range of human brain activity between 12.5 and 30 Hz (12.5 to 30 transitions or cycles per second). Beta waves can be split into three sections: Low Beta Waves (12.5–16 Hz, "Beta 1 power"); Beta Waves (16.5–20 Hz, "Beta 2 power"); and High Beta Waves (20.5–28 Hz, "Beta 3 power"). Beta states are the states associated with normal waking consciousness. Beta waves were discovered and named by the German psychiatrist Hans Berger, who invented electroencephalography (EEG) in 1924 as a method of recording electrical brain activity from the human scalp. Berger termed the larger amplitude, slower frequency waves that appeared over the posterior scalp when the subject's eyes were closed alpha waves. The smaller amplitude, faster frequency waves that replaced alpha waves when the subject opened his or her

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 313 eyes were then termed beta waves. Low amplitude beta waves with multiple and varying frequencies are often associated with active, busy or anxious thinking and active concentration. Over the motor cortex beta waves are associated with the muscle contractions that happen in isotonic movements and are suppressed prior to and during movement changes. Bursts of beta activity are associated with a strengthening of sensory feedback in static motor control and reduced when there is movement change. Beta activity is increased when movement has to be resisted or voluntarily suppressed. The artificial induction of increased beta waves over the motor cortex by a form of electrical stimulation called Transcranial alternating-current stimulation consistent with its link to isotonic contraction produces a slowing of motor movements. Beta waves are often considered indicative of inhibitory cortical transmission mediated by gamma aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian nervous system. Benzodiazepines, drugs that modulate GABAA receptors, induce beta waves in EEG recordings from humans and rats. Spontaneous beta waves are also observed diffusely in scalp EEG recordings from children with duplication 15q11.2-q13.1 syndrome

(Dup15q) who have duplications of GABAA receptor subunit genes GABRA5, GABRB3 and GABRG3. For this reason, it is possible that, in certain clinical contexts, beta waves could be a general biomarker of GABAA receptor gene over expression or otherwise aberrant GABAergic transmission.[7] Theta waves generate the theta rhythm, a neural oscillatory pattern in electroencephalography (EEG) signals, recorded either from inside the brain or from electrodes glued to the scalp. Two types of theta rhythm have been described. The "hippocampal theta rhythm" is a strong oscillation that can be observed in the and other brain structures in numerous species of mammals including rodents, rabbits, dogs, cats, bats and marsupials. "Cortical theta rhythms" are low-frequency components of scalp EEG, usually recorded from humans. Theta rhythms can be quantified using Quantitative encephalography (qEEG) using freely available toolboxes, such as, EEGLAB or the Neurophysiological Biomarker Toolbox (NBT). In rats, the most frequently studied species, rhythmicity is easily observed in the hippocampus, but can also be detected in numerous other cortical and sub cortical brain structures. Hippocampal theta waves, with a frequency range of 6–10 Hz, appear when a rat is engaged in active motor behavior such as walking or exploratory sniffing and also during REM sleep. Theta waves with a lower frequency range, usually around 6–7 Hz, are sometimes observed when a rat is motionless but alert. When a rat is eating, grooming, or sleeping, the

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 314 hippocampal EEG usually shows a non-rhythmic pattern known as Large irregular activity or LIA. The hippocampal theta rhythm depends critically on projections from the medial septal area, which in turn receives input from the hypothalamus and several brainstem areas. Hippocampal theta rhythms in other species differ in some respects from those in rats. In cats and rabbits, the frequency range is lower (around 4–6 Hz) and theta is less strongly associated with movement than in rats. In bats, theta appears in short bursts associated with echolocation. In humans, hippocampal theta rhythm has been observed and linked to memory formation and navigation. The function of the hippocampal theta rhythm is not clearly understood. Green and Arduini, in the first major study of this phenomenon, noted that hippocampal theta usually occurs together with desynchronized EEG in the neocortex and proposed that it is related to arousal. Vander wolf and his colleagues, noting the strong relationship between theta and motor behavior, have argued that it is related to sensori motor processing. Another school, led by John O'Keefe, have suggested that theta is part of the mechanism animals use to keep track of their location within the environment. Another theory links the theta rhythm to mechanisms of learning and memory. These different theories have since been combined, as it has been shown that the firing patterns can support both navigation and memory.[8] Cortical theta rhythms observed in human scalp EEG are a different phenomenon, with no clear relationship to the hippocampus. In human EEG studies, the term theta refers to frequency components in the 4–7 Hz range, regardless of their source. Cortical theta is observed frequently in young children. In older children and adults, it tends to appear during meditative, drowsy, hypnotic or sleeping states, but not during the deepest stages of sleep. Several types of brain pathology can give rise to abnormally strong or persistent cortical theta waves. Although there were a few earlier hints, the first clear description of regular slow oscillations in the hippocampal EEG came from a paper written in German by Jung and Kornmüller. They were not able to follow up on these initial observations and it was not until 1954 that further information became available, in a very thorough study by John D. Green and Arnaldo Arduini that mapped out the basic properties of hippocampal oscillations in cats, rabbits and monkeys. Their findings provoked widespread interest, in part because they related hippocampal activity to arousal, which was at that time the hottest topic in neuroscience. Green and Arduini described an inverse relationship between hippocampal and cortical activity patterns, with hippocampal rhythmicity occurring alongside desynchronized activity in the cortex, whereas an irregular hippocampal activity pattern was correlated with the appearance of large slow waves in the cortical EEG.

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Over the following decade came an outpouring of experiments examining the pharmacology and physiology of theta. By 1965, Charles Stumpf was able to write a lengthy review of "Drug action on the electrical activity of the hippocampus" citing hundreds of publications and in 1964 John Green, who served as the leader of the field during this period, was able to write an extensive and detailed review of hippocampal electrophysiology. A major contribution came from a group of investigators working in Vienna, including Stumpf and Wolfgang Petsche, who established the critical role of the medial septum in controlling hippocampal electrical activity and worked out some of the pathways by which it exerts its influence. Because of a historical accident, the term "theta rhythm" is used to refer to two different phenomena, "hippocampal theta" and "human cortical theta". Both of these are oscillatory EEG patterns, but they may have little in common beyond the name "theta".[9] In the oldest EEG literature dating back to the 1920s, Greek letters such as alpha, beta, theta and gamma were used to classify EEG waves falling into specific frequency ranges, with "theta" generally meaning a range of about 4–7 cycles per second (Hz). In the 1930s–1950s, a very strong rhythmic oscillation pattern was discovered in the hippocampus of cats and rabbits (Green & Arduini, 1954). In these species, the hippocampal oscillations fell mostly into the 4–6 Hz frequency range, so they were referred to as "theta" oscillations. Later, hippocampal oscillations of the same type were observed in rats; however, the frequency of rat hippocampal EEG oscillations averaged about 8 Hz and rarely fell below 6 Hz. Thus the rat hippocampal EEG oscillation should not, strictly speaking, have been called a "theta rhythm". However the term "theta" had already become so strongly associated with hippocampal oscillations that it continued to be used even for rats. Over the years this association has come to be stronger than the original association with a specific frequency range, but the original meaning also persists. Thus, "theta" can mean either of two things: 1. A specific type of regular oscillation seen in the hippocampus and several other brain regions connected to it. 2. EEG oscillations in the 4–7 Hz frequency range, regardless of where in the brain they occur or what their functional significance is. The first meaning is usually intended in literature that deals with rats or mice, while the second meaning is usually intended in studies of human EEG recorded using electrodes glued to the scalp. In general, it is not safe to assume that observations of "theta" in the human EEG have any relationship to the "hippocampal theta rhythm". Scalp EEG is generated almost entirely by the cerebral cortex and even if it falls into a certain frequency range, this cannot be taken to indicate that it has any functional dependence on the hippocampus.

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Due to the density of its neural layers, the hippocampus generates some of the largest EEG signals of any brain structure. In some situations the EEG is dominated by regular waves at 4– 10 Hz, often continuing for many seconds. Type 1 and type 2: In 1975 Kramis, Bland, and Vanderwolf proposed that in rats there are two distinct types of hippocampal theta rhythm, with different behavioral and pharmacological properties. Type 1 ("atropine resistant") theta, according to them, appears during locomotion and other types of "voluntary" behavior and during REM sleep, has a frequency usually around 8 Hz, and is unaffected by the anticholinergic drug atropine. Type 2 ("atropine sensitive") theta appears during immobility and during anesthesia induced by urethane, has a frequency in the 4–7 Hz range and is eliminated by administration of atropine. Many later investigations have supported the general concept that hippocampal theta can be divided into two types, although there has been dispute about the precise properties of each type. Type 2 theta is comparatively rare in unanesthetized rats: it may be seen briefly when an animal is preparing to make a movement but hasn't yet executed it, but has only been reported for extended periods in animals that are in a state of frozen immobility because of the nearby presence of a predator such as a cat or ferret. Relationship with behavior: Vanderwolf made a strong argument that the presence of theta in the hippocampal EEG can be predicted on the basis of what an animal is doing, rather than why the animal is doing it. Active movements such as running, jumping, bar-pressing, or exploratory sniffing are reliably associated with theta; inactive states such as eating or grooming are associated with LIA. Later studies showed that theta frequently begins several hundred milliseconds before the onset of movement and that it is associated with the intention to move rather than with feedback produced by movement. The faster an animal runs, the higher the theta frequency. In rats, the slowest movements give rise to frequencies around 6.5 Hz, the fastest to frequencies around 9 Hz, although faster oscillations can be observed briefly during very vigorous movements such as large jumps. There is also a distinction between sleep states: REM (dreaming) sleep is associated with theta; slow-wave sleep is associated with LIA.[10] Mechanisms: Numerous studies have shown that the medial septal area plays a central role in generating hippocampal theta. Lesioning the medial septal area, or inactivating it with drugs, eliminates both type 1 and type 2 theta. Under certain conditions, theta-like oscillations can be induced in hippocampal or entorhinal cells in the absence of septal input, but this does not occur in intact, undrugged adult rats. The critical septal region includes the medial septal nucleus and the vertical limb of the diagonal band of Broca. The lateral septal nucleus, a major recipient of

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 317 hippocampal output, probably does not play an essential role in generating theta. The medial septal area projects to a large number of brain regions that show theta modulation, including all parts of the hippocampus as well as the , perirhinal cortex, retrosplenial cortex, medial mamillary and supramamillary nuclei of the hypothalamus, anterior nuclei of the thalamus, amygdala, inferior colliculus and several brainstem nuclei. Some of the projections from the medial septal area are cholinergic; the rest are GABAergic or glutamatergic. It is commonly argued that cholinergic receptors do not respond rapidly enough to be involved in generating theta waves and therefore that GABAergic and/or glutamatergic signals must play the central role. A major research problem has been to discover the "pacemaker" for the theta rhythm, that is, the mechanism that determines the oscillation frequency. The answer is not yet entirely clear, but there is some evidence that type 1 and type 2 theta depend on different pacemakers. For type 2 theta, the supramamillary nucleus of the hypothalamus appears to exert control. For type 1 theta, the picture is still unclear, but the most widely accepted hypothesis proposes that the frequency is determined by a feedback loop involving the medial septal area and hippocampus.. Several types of hippocampal and entorhinal neurons are capable of generating theta-frequency membrane potential oscillations when stimulated. Typically these are sodium-dependent voltage- sensitive oscillations in membrane potential at near-action potential voltages. Specifically, it appears that in neurons of the CA1 and dentate gyrus, these oscillations result from an interplay of dendrite excitation via a persistent sodium current (INaP) with perisomatic inhibition. Generators: As a rule, EEG signals are generated by synchronized synaptic input to the dendrites of neurons arranged in a layer. The hippocampus contains multiple layers of very densely packed neurons—the dentate gyrus and the CA3/CA1/subicular layer—and therefore have the potential to generate strong EEG signals. Basic EEG theory says that when a layer of neurons generates an EEG signal, the signal always phase-reverses at some level. Thus, theta waves recorded from sites above and below a generating layer have opposite signs. There are other complications as well: the hippocampal layers are strongly curved and theta-modulated inputs impinge on them from multiple pathways, with varying phase relationships. The outcome of all these factors is that the phase and amplitude of theta oscillations change in a very complex way as a function of position within the hippocampus. The largest theta waves, however, are generally recorded from the vicinity of the fissure that separates the CA1 molecular layer from the dentate gyrus molecular layer. In rats, these signals frequently exceed 1millivolt in amplitude. Theta waves recorded from above the hippocampus are smaller and polarity-reversed

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 318 with respect to the fissure signals. The strongest theta waves are generated by the CA1 layer, and the most significant input driving them comes from the entorhinal cortex, via the direct EC→CA1 pathway. Another important driving force comes from the CA3→CA1 projection, which is out of phase with the entorhinal input, leading to a gradual phase shift as a function of depth within CA1. The dentate gyrus also generates theta waves, which are difficult to separate from the CA1 waves because they are considerably smaller in amplitude, but there is some evidence that dentate gyrus theta is usually about 90 degrees out of phase from CA1 theta. Direct projections from the septal area to hippocampal also play a role in generating theta waves, but their influence is much smaller than that of the entorhinal inputs (which are, however, themselves controlled by the septum). Research findings: Theta-frequency activity arising from the hippocampus is manifested during some short-term memory tasks. Studies suggest that these rhythms reflect the "on-line" state of the hippocampus; one of readiness to process incoming signals. Conversely, theta oscillations have been correlated to various voluntary behaviors (exploration, spatial navigation, etc.) and alert states in rats. Suggesting that it may reflect the integration of sensory information with motor output. A large body of evidence indicates that theta rhythm is likely involved in spatial learning and navigation. Theta rhythms are very strong in rodent hippocampi and entorhinal cortex during learning and memory retrieval and are believed to be vital to the induction of long-term potentiation, a potential cellular mechanism of learning and memory. Based on evidence from electrophysiological studies showing that both synaptic plasticity and strength of inputs to hippocampal region CA1 vary systematically with ongoing theta oscillations. It has been suggested that the theta rhythm functions to separate periods of encoding of current sensory stimuli and retrieval of episodic memory cued by current stimuli so as to avoid interference that would occur if encoding and retrieval were simultaneous. In animals, EEG signals are usually recorded using electrodes implanted in the brain; the majority of theta studies have involved electrodes implanted in the hippocampus. In humans, because invasive studies are not ethically permissible except in some neurological patients, by far the largest number of EEG studies have been conducted using electrodes glued to the scalp. The signals picked up by scalp electrodes are comparatively small and diffuse and arise almost entirely from the cerebral cortex—the hippocampus is too small and too deeply buried to generate recognizable scalp EEG signals. Human EEG recordings show clear theta rhythmicity in some situations, but because of the technical difficulties, it has been difficult to tell whether

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 319 these signals have any relationship with the hippocampal theta signals recorded from other species. In contrast to the situation in rats, where long periods of theta oscillations are easily observed using electrodes implanted at many sites, theta has been difficult to pin down in primates, even when intracortical electrodes have been available. Green and Arduini in their pioneering study of theta rhythms, reported only brief bursts of irregular theta in monkeys. Other investigators have reported similar results, although Stewart and Fox described a clear 7–9 Hz theta rhythm in the hippocampus of urethane-anesthetized macaques and squirrel monkeys, resembling the type 2 theta observed in urethane-anesthetized rats. Most of the available information on human hippocampal theta comes from a few small studies of epileptic patients with intracranially implanted electrodes used as part of a treatment plan. In the largest and most systematic of these studies, Cantero et al. found that oscillations in the 4– 7 Hz frequency range could be recorded from both the hippocampus and neocortex. The hippocampal oscillations were associated with REM sleep and the transition from sleep to waking and came in brief bursts, usually less than a second long. Cortical theta oscillations were observed during the transition from sleep and during quiet wakefulness; however, the authors were unable to find any correlation between hippocampal and cortical theta waves and concluded that the two processes are probably controlled by independent mechanisms.[11] Studies have shown an association of with stronger theta-frequency activity as well as with changes to the gamma-frequency activity. A is a high amplitude brain wave with a frequency of oscillation between 0.5–4Hz. Delta waves, like other brain waves, is recorded with an electroencephalogram (EEG) and is usually associated with the deep stage 3 of NREM sleep (Non Rapid Eye Movement sleep), also known as slow wave sleep (SWS) and aid in characterizing the depth of sleep. "Delta waves" were first described in the 1930s by W. Grey Walter, who improved upon Dr. Hans Berger’s electroencephalograph machine (EEG) to detect alpha and delta waves. Delta waves can be quantified using quantitative electroencephalography (qEEG) using freely available toolboxes, such as, EEGLAB or the Neurophysiological Biomarker Toolbox (NBT). Delta waves, like all brain waves, can be detected by EEG. Delta waves were originally defined as having a frequency between 1-4 Hz, although more recent classifications put the boundaries at between 0.5 and 2 Hz. They are the slowest and highest amplitude classically described brainwaves, although recent studies have described slower (<0.1 Hz) oscillations Delta waves begin to appear in stage 3 sleep, but by stage 4 nearly all spectral activity is dominated by delta waves. Stage 3 sleep is

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 320 defined as having less than 50% delta wave activity, while stage 4 sleep has more than 50% delta wave activity. These stages have recently been combined and are now collectively referred to as stage N3 slow-wave sleep. During N3 SWS, delta waves account for 20% or more of the EEG record during this stage. Delta waves occur in all mammals and potentially all animals as well. Delta waves are often associated with another EEG phenomenon, the K-complex. K-Complexes have been shown to immediately precede delta waves in slow wave sleep. Delta waves have also been classified according to the location of the activity into frontal (FIRDA), temporal (TIRDA) and occipital (OIRDA) intermittent delta activity. A K-complex is an electroencephalography (EEG) waveform that occurs during stage 2 of NREM sleep. It is the "largest event in healthy human EEG". They are more frequent in the first sleep cycles. K-complexes have two proposed functions: first, suppressing cortical arousal in response to stimuli that the sleeping brain evaluates not to signal danger, and second, aiding sleep-based memory consolidation. The K-complex was discovered in 1937 in the private laboratories of Alfred Lee Loomis.[12] Neurophysiology: K-complex consists of a brief negative high-voltage peak, usually greater than 100 µV, followed by a slower positive complex around 350 and 550 ms and at 900 ms a final negative peak. K-complexes occur roughly every 1.0–1.7 minutes and are often followed by bursts of sleep spindles. They occur spontaneously but also occur in response to external stimuli such as sounds, touches on the skin and internal ones such as inspiratory interruptions. They are generated in widespread cortical locations though they tend to predominate over the frontal parts of the brain. Both K-complex and delta wave activity in stage 2 sleep create slow-wave (0.8 Hz) and delta (1.6–4.0 Hz) oscillations. However, their topographical distribution is different, and the delta power of K-complexes is higher. They are created by the occurrence in widespread cortical areas of outward dendritic currents from the middle (III) to the upper (I) layers of the cerebral cortex. This is accompanied by a decrease in broadband EEG power including gamma wave activity. This produces "down-states" of neuronal silence in which neural network activity is reduced. The activity of K-complexes is transferred to the thalamus where it synchronizes the thalamocortical network during sleep, producing sleep oscillations such as spindles and delta waves. It has been observed that they are indeed identical in the "laminar distributions of transmembrane currents" to the slow waves of slow-wave sleep. K-complexes have been suggested both to protect sleep and also to engage in information processing, as they are both an essential part of the synchronization of NREM sleep,

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 321 while they also respond to both internal and external stimuli in a reactive manner. This would be consistent with a function in suppressing cortical arousal in response to stimuli that the brain needs to initially process in regard to whether it is dangerous or not. Another suggested function is aiding the activation homeostasis of synapses and memory consolidation. The activation thresholds of cortical synapses become lowered during wakefulness as they process information, making them more responsive, and so need to be adjusted back to preserve their signal-to-noise ratio. The down-state provided by K-complexes does this by reducing the strengths of synaptic connections that occur while an individual is awake. Further, the recovery from the down-state they induce allows that "cortical firing 'reboots' in a systematic order" so that memory engrams encoded during neuronal firing can be "repeatedly practiced and thus consolidated". They are present in the sleep of 5-month-old infants, and develop with age. Between 3 and 5 years of age a faster negative component appears and continues to increase until adolescence. Another change occurs in adults: before 30 years of age their frequency and amplitude is higher than in older people particularly those over 50 years of age. This parallels the decrease in other components of sleep such as density and delta power.[13] Physiology Sex differences: Women have been shown to have more delta wave activity and this is true across most mammal species. This discrepancy does not become apparent until early adulthood (in the 30's or 40's, in humans), with men showing greater age-related reductions in delta wave activity than women. Brain localization and biochemistry: Delta waves can arise either in the thalamus or in the cortex. When associated with the thalamus, they are thought to arise in coordination with the . In the cortex, the suprachiasmatic nuclei have been shown to regulate delta waves, as lesions to this area have been shown to cause disruptions in delta wave activity. In addition, delta waves show a lateralization, with right hemisphere dominance during sleep. Delta waves have been shown to be mediated in part by T-type calcium channels. During delta wave sleep, neurons are globally inhibited by gamma-aminobutyric acid (GABA). Delta activity stimulates the release of several hormones, including growth hormone releasing hormone GHRH and prolactin (PRL). GHRH is released from the hypothalamus, which in turn stimulates release of growth hormone (GH) from the pituitary. The secretion of (PRL), which is closely related to (GH), is also regulated by the pituitary. The release of thyroid stimulating hormone (TSH), is decreased in response to delta-wave signaling. Infants have been shown to spend a great deal of time in slow-wave sleep and thus have more delta wave activity. In fact,

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 322 delta-waves are the predominant wave forms of infants. Analysis of the wakefulness EEG of a newborn infant indicates that delta wave activity is predominant in that age and still appears in a waking EEG of five-year-olds. Delta wave activity during slow-wave sleep declines during adolescence, with a drop of around 25% reported between the ages of 11 and 14 years. Delta waves have been shown to decrease across the lifespan, with most of the decline seen in the mid- forties. By the age of about 75, stage four sleep and delta waves may be entirely absent. In addition to a decrease in the incidence of delta waves during slow-wave sleep in the elderly, the incidence of temporal delta wave activity is commonly seen in older adults and incidences also increase with age. Regional delta wave activity not associated with NREM sleep was first described by W. Grey Walter, who studied cerebral hemisphere tumors. Disruptions in delta wave activity and slow wave sleep are seen in a wide array of disorders. In some cases there may be increases or decreases in delta wave activity, while others may manifest as disruptions in delta wave activity, such as alpha waves presenting in the EEG spectrum. Delta wave disruptions may present as a result of physiological damage, changes in nutrient metabolism, chemical alteration, or may also be idiopathic. Disruptions in delta activity is seen in adults during states of intoxication or delirium and in those diagnosed with various neurological disorders such as dementia or .[14] Temporal Low-voltage Irregular Delta Wave: Temporal low-voltage irregular delta wave activity has been commonly detected in patients with ischemic brain diseases, particularly in association with small ischemic lesions and is seen to be indicative of early- stage cerebrovascular damage. : It is a category of sleep disorders, are often associated with disruptions in slow wave sleep. Sleep walking and sleep talking most often occur during periods of high delta wave activity. Sleep walkers have also been shown to have more hypersynchronous delta activity (HSD) compared to total time spent in stages 2, 3 and 4 sleep relative to healthy controls. HSD refers to the presence of continuous, high-voltage (>150µV) delta waves seen in sleep EEGs. Parasomnias which occur deep in NREM sleep also include sleep terrors and confusional arousals. : Total sleep deprivation has been shown to increase delta wave activity during sleep recovery and has also been shown to increase hypersynchronous delta activity.[15] Parkinson's disease: Sleep disturbances, as well as dementia, are common features of Parkinson’s disease and patients with this disease show disrupted brain wave activity. The

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 323 drug Rotigotine, developed for the treatment of Parkinson's disease, has been shown to increase delta power and slow-wave sleep. Delta-wave inducing peptide injected into the substantia nigra of the rat model has been shown to increase Parkinsonian symptoms. Schizophrenia: People suffering schizophrenia have shown disrupted EEG patterns, and there is a close association of reduced delta waves during deep sleep and negative symptoms associated with schizophrenia. During slow wave sleep (stages 3 and 4), schizophrenics have been shown to have reduced delta wave activity, although delta waves have also been shown to be increased during waking hours in more severe forms of schizophrenia. A recent study has shown that the right frontal and central delta wave dominance, seen in healthy individuals, is absent in patients with schizophrenia. In addition, the negative correlation between delta wave activity and age is also not observed in those with schizophrenia. Diabetes and insulin resistance: Disruptions in slow wave (delta) sleep have been shown to increase risk for development of Type II diabetes, potentially due to disruptions in the growth hormone secreted by the pituitary. In addition, hypoglycemia occurring during sleep may also disrupt delta-wave activity. Low-voltage irregular delta waves, have also been found in the left of diabetic patients, at a rate of 56% (compared to 14% in healthy controls). Fibromyalgia: Patients suffering from fibromyalgia often report unrefreshing sleep. A study conducted in 1975 by Moldovsky et al. showed that the delta wave activity of these patients in stages 3 and 4 sleep were often interrupted by alpha waves. They later showed that depriving the body of delta wave sleep activity also induced musculoskeletal pain and fatigue.[16] Alcoholism: Alcohol has been shown to decrease slow wave sleep and delta power, while increasing stage 1 and REM incidence in both men and women. In long-term alcohol abuse, the influences of alcohol on sleep architecture and reductions in delta activity have been shown to persist even after long periods of abstinence. Temporal lobe epilepsy: Slow waves, including delta waves, are associated with -like activity within the brain. W. Grey Walter was the first person to use delta waves from an EEG to locate brain tumors and lesions causing temporal lobe epilepsy. Neurofeedback has been suggested as a treatment for temporal lobe epilepsy and theoretically acts to reduce inappropriate delta wave intrusion, although there has been limited clinical research in this area. Other disorders: Other disorders frequently associated with disrupted delta-wave activity include: Narcolepsy, Depression, Anxiety, Obsessive-compulsive disorder, Attention deficit hyperactivity disorder (ADHD) and its three subtypes.

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 324

Juvenile chronic arthritis: Initially, dreaming was thought to only occur in rapid eye movement sleep, though it is now known that dreaming may also occur during slow-wave sleep. Delta waves and delta wave activity are marked, in most people, by an apparently unconscious state and the loss of physical awareness as well as the "iteration of information". Nevertheless, some people who practice a type of deep meditation called Yoga Nidra (Sleep yoga) can remain conscious while in delta-sleep. Delta wave activity has also been purported to aid in the formation of declarative and explicit memory formation. In Advaita Vedanta, deep dreamless sleep is considered the highest state of consciousness. If one can stay aware or conscious while in deepest dreamless sleep, a deep meditative state (known as "jagrat sushupti") is said to be achievable. This notion of paradoxical consciousness may be linked to high cortical activity which happens during the delta-sleep. While most drugs that affect sleep do so by stimulating , or disrupting REM sleep, a number of chemicals and drugs have been shown to alter delta wave activity. Delta sleep inducing peptide, as the name suggests, induces delta wave EEG activity. Alcohol reduces SWS delta wave activity, thereby restricting the release of growth hormone (GH) by the pituitary. The muramyl peptide, muramyl dipeptide (MDP, N- acetylmuramyl-L-alanyl-D-isoglutamine) has been shown to increase delta wave activity during slow wave sleep. The drug gabapentin, a drug used to control epileptic , increases delta- wave activity and slow wave sleep in adults. While hypnotic drugs increase slow wave sleep, they do not increase delta wave activity and instead increase spindle activity during slow wave sleep. Gamma-hydroxy butyrate (GHB) increases delta slow-wave sleep as well as sleep-related growth hormone (GH). Diets very low in carbohydrates, such as a ketogenic diet, have been shown to increase the amount of delta activity and slow wave sleep in healthy individuals.[17] Mu waves, also known as mu rhythms, comb or wicket rhythms, arciform rhythms, or sensorimotor rhythms, are synchronized patterns of electrical activity involving large numbers of neurons, probably of the pyramidal type, in the part of the brain that controls voluntary movement. These patterns as measured by EEG, MEG, or (ECoG), repeat at a frequency of 7.5–12.5 (and primarily 9–11) Hz and are most prominent when the body is physically at rest. Unlike the alpha wave, which occurs at a similar frequency over the resting visual cortex at the back of the scalp, the is found over the motor cortex, in a band approximately from ear to ear. A person suppresses mu wave patterns when he or she performs a motor action or, with practice, when he or she visualizes performing a motor action. This suppression is called desynchronization of the wave because EEG wave forms are caused

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 325 by large numbers of neurons firing in synchrony. The mu wave is even suppressed when one observes another person performing a motor action or an abstract motion with biological characteristics. Researchers such as V. S. Ramachandran and colleagues have suggested that this is a sign that the mirror neuron system is involved in mu wave suppression, although others disagree. The mu wave is of interest to a variety of scholars. Scientists who study neural development are interested in the details of the development of the mu wave in infancy and childhood and its role in learning. Since a group of researchers believe that autism spectrum disorder (ASD) is strongly influenced by an altered mirror neuron system and that mu wave suppression is a downstream indication of mirror neuron activity, many of these scientists have kindled a more popular interest in investigating the mu wave in people with ASD. Assorted investigators are also in the process of using mu waves to develop a new technology: the brain-computer-interface (BCI). With the emergence of BCI systems, clinicians hope to give the severely physically disabled population new methods of communication and a means to manipulate and navigate their environments. The mirror neuron system consists of a class of neurons that was first studied in the 1990s in macaque monkeys. Studies have found sets of neurons that fire when these monkeys perform simple tasks and also when the monkeys view others performing the same simple tasks. This suggests they play a role in mapping others' movements into the brain without actually physically performing the movements. These sets of neurons are called mirror neurons and together make up the mirror neuron system. Mu waves are suppressed when these neurons fire, a phenomenon which allows researchers to study mirror neuron activity in humans. There is evidence that mirror neurons exist in humans as well as in non-human animals. The right fusiform gyrus, left inferior parietal lobule, right anterior parietal cortex and left inferior frontal gyrus are of particular interest. Some researchers believe that mu wave suppression can be a consequence of mirror neuron activity throughout the brain and represents a higher-level integrative processing of mirror neuron activity. Tests in both monkeys (using invasive measuring techniques) and humans (using EEG and fMRI) have found that these mirror neurons not only fire during basic motor tasks, but also have components that deal with intention. There is evidence of an important role for mirror neurons in humans, and mu waves may represent a high level coordination of those mirror neurons.[18] A fruitful conceptualization of mu waves in pediatric use that is independent of their frequency is that mu wave suppression is a representation of activity going on in the world, and is detectable in the frontal and parietal networks. A resting oscillation becomes suppressed during the

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 326 observation of sensory information such as sounds or sights, usually within the frontoparietal (motor) cortical region. Measured in this way, the mu wave is detectable during infancy as early as four to six months, when the peak frequency the wave reaches can be as low as 5.4 Hz. There is a rapid increase in peak frequency in the first year of life and by age two frequencies typically reaches 7.5 Hz. The peak frequency of the mu wave increases with age until maturation into adulthood, when it reaches its final and stable frequency of 8–13 Hz. These varying frequencies are measured as activity around the central sulcus, within the Rolandic cortex. Mu waves are thought to be indicative of an infant’s developing ability to imitate. This is important because the ability to imitate plays a vital role in the development of motor skills, tool use and understanding causal information through social interaction. Mimicking is integral in the development of social skills and understanding nonverbal cues. Causal relationships can be made through social learning without requiring experience firsthand. In action execution, mu waves are present in both infants and adults before and after the execution of a motor task and its accompanying desynchronization. While executing a goal-oriented action, however, infants exhibit a higher degree of desynchronization than do adults. Just as with an action execution, during action observation infants’ mu waves not only show a desynchronization, but show a desynchronization greater in degree than the one evidenced in adults. This tendency for changes in degree of desynchronization, rather than actual changes in frequency, becomes the measure for mu wave development throughout adulthood, although the most changes take place during the first year of life. Understanding the mechanisms that are shared between action perception and execution in the earliest years of life has implications for language development. Learning and understanding through social interaction comes from imitating movements as well as vowel sounds. Sharing the experience of attending to an object or event with another person can be a powerful force in the development of language. Autism: It is a disorder that is associated with social and communicative deficits. A single cause of autism has yet to be identified, but the mu wave and mirror neuron system have been studied specifically for their role in the disorder. In a typically developing individual, the mirror neuron system responds when he or she either watches someone perform a task or performs the task him- or herself. In individuals with autism, mirror neurons become active (and consequently mu waves are suppressed) only when the individual performs the task him- or herself. This finding has led some scientists, notably V. S. Ramachandran and colleagues, to view autism as disordered understanding of other individuals' intentions and goals due to problems with the mirror neuron system. This deficiency would explain the difficulty people with autism have in

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 327 communicating with and understanding others. While most studies of the mirror neuron system and mu waves in people with autism have focused on simple motor tasks, some scientists speculate that these tests can be expanded to show that problems with the mirror neuron system underlie overarching cognitive and social deficits. Based on findings correlating mirror neuron activity and mu wave suppression in individuals with autism as in typically developing individuals, studies have examined both the development of mirror neurons and therapeutic means for stimulating the system. A recent study has found that fMRI activation magnitudes in the inferior frontal gyrus increase with age in people with autism. This finding was not apparent in typically developing individuals. Furthermore, greater activation was associated with greater amounts of eye contact and better social functioning. Scientists believe the inferior frontal gyrus is one of the main neural correlates with the mirror neuron system in humans and is often related to deficits associated with autism. These findings suggest that the mirror neuron system may not be non-functional in individuals with autism, but simply abnormal in its development. This information is significant to the present discussion because mu waves may be integrating different areas of mirror neuron activity in the brain. Other studies have assessed attempts to consciously stimulate the mirror neuron system and suppress mu waves using neurofeedback (a type of biofeedback given through computers that analyze real time recordings of brain activity, in this case EEGs of mu waves). This type of therapy is still in its early phases of implementation for individuals with autism, and has conflicting forecasts for success.[19] Brain-computer interfaces (BCIs) are a developing technology that clinicians hope will one day bring more independence and agency to the severely physically disabled. Those the technology has the potential to help include people with near-total or total paralysis, such as those with tetraplegia (quadriplegia) or advanced amyotrophic lateral sclerosis (ALS); BCIs are intended to help them to communicate or even move objects such as motorized wheelchairs, neuroprostheses, or robotic grasping tools. Few of these technologies are currently in regular use by people with disabilities, but diverse arrays are in development at an experimental level. One type of BCI uses event-related desynchronization (ERD) of the mu wave in order to control the computer. This method of monitoring brain activity takes advantage of the fact that when a group of neurons is at rest they tend to fire in synchrony with each other. When a participant is cued to imagine movement (an "event"), the resulting desynchronization (the group of neurons that was firing in synchronous waves now firing in complex and individualized patterns) can be reliably detected and analyzed by a computer. Users of such an interface are trained in visualizing movements, typically of the foot, hand, and/or tongue, which are each in

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 328 different locations on the cortical homunculus and thus distinguishable by an EEG or electrocorticograph (ECoG) recording of electrical activity over the motor cortex. In this method, computers monitor for a typical pattern of mu wave ERD contralateral to the visualized movement combined with event-related synchronization (ERS) in the surrounding tissue. This paired pattern intensifies with training and the training increasingly takes the form of games, some of which utilize virtual reality. Some researchers have found that the feedback from virtual reality games is particularly effective in giving the user tools to improve control of his or her mu wave patterns. The ERD method can be combined with one or more other methods of monitoring the brain's electrical activity to create hybrid BCIs, which often offer more flexibility than a BCI that uses any single monitoring method. Mu waves have been studied since the 1930s, and are referred to as the wicket rhythm because the rounded EEG waves resemble croquet wickets. In 1950, Henri Gastaut and his coworkers reported desynchronization of these waves not only during active movements of their subjects, but also while the subjects observed actions executed by someone else. These results were later confirmed by additional research groups, including a study using subdural electrode grids in epileptic patients. The latter study showed mu suppression while the patients observed moving body parts in somatic areas of the cortex that corresponded to the body part moved by the actor. Further studies have shown that the mu waves can also be desynchronized by imagining actions and by passively viewing point-light biological motion.[20] The (SMR) is a brain wave. It is an oscillatory idle rhythm of synchronized electric brain activity. It appears in spindles in recordings of EEG, MEG and ECoG over the sensori motor cortex. For most individuals, the frequency of the SMR is in the range of 13 to 15 Hz. The meaning of SMR is not fully understood. Phenomenologically, a person is producing a stronger SMR amplitude when the corresponding sensorimotor areas are idle, e.g. during states of immobility. SMR typically decrease in amplitude when the corresponding sensory or motor areas are activated, e.g. during motor tasks and even during motor imagery. Conceptually, SMR is sometimes mixed up with alpha waves of occipital origin, the strongest source of neural signals in the EEG. One reason might be, that without appropriate spatial filtering the SMR is very difficult to detect because it is usually flooded by the stronger occipital alpha waves. The feline SMR has been noted as being analogous to the human mu rhythm.[21] Neurofeedback: Neurofeedback training can be used to gain control over the SMR activity. Neurofeedback practitioners believe that this feedback enables the subject to learn the regulation

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 329 of their own SMR. People with learning difficulties, ADHD, epilepsy and autism may benefit from an increase in SMR activity via neurofeedback. In the field of Brain-Computer Interfaces (BCI), the deliberate modification of the SMR amplitude during motor imagery can be used to control external applications.[22] A gamma wave is a pattern of neural oscillation in humans with a frequency between 25 and 100 Hz, though 40 Hz is typical. According to a popular theory, gamma waves may be implicated in creating the unity of conscious perception (the ). However, there is no agreement on the theory; as a researcher suggests: Whether or not gamma wave activity is related to subjective awareness is a very difficult question which cannot be answered with certainty at the present time. Gamma waves were initially ignored before the development of digital EEG as analog electroencephalography is restricted to recording and measuring rhythms that are usually less than 25 Hz. One of the earliest reports on them was in 1964 using recordings of the electrical activity of electrodes implanted in the visual cortex of awake monkeys.[23] History of idea: The idea that distinct regions in the brain were being stimulated simultaneously was suggested by the finding in 1988 that two neurons oscillate synchronously (though they are not directly connected) when a single external object stimulates their respective receptive fields. Subsequent experiments by many others demonstrated this phenomenon in a wide range of visual . In particular, Francis Crick and Christ of Koch in 1990 argued that there is a significant relation between the binding problem and the problem of visual consciousness and, as a result, that synchronous 40 Hz oscillations may be causally implicated in visual awareness as well as in visual binding. Later the same authors expressed skepticism over the idea that 40 Hz oscillations are a sufficient condition for visual awareness. A number of experiments conducted by Dr. Rodolfo Llinás, MD, PhD, supports a hypothesis that the basis for consciousness in awake states and dreaming is 40-Hz oscillations throughout the cortical mantle in the form of thalamocortical iterative recurrent activity. In two papers entitled "Coherent 40-Hz oscillation characterizes dream state in humans” (Rodolfo Llinás and Urs Ribary, Proc Natl Acad Sci USA 90:2078-2081, 1993) and "Of dreaming and wakefulness” (Llinas & Pare, 1991), Llinás proposes that the conjunction into a single cognitive event could come about by the concurrent summation of specific and nonspecific 40-Hz activity along the radial dendritic axis of given cortical elements, and that the resonance is modulated by the brainstem and is given content by sensory input in the awake state and intrinsic activity during dreaming. According to Llinás’ hypothesis, known as the thalamocortical dialogue hypothesis

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 330 for consciousness, the 40-Hz oscillation seen in wakefulness and in dreaming is proposed to be a correlate of cognition, resultant from coherent 40-Hz resonance between thalamocortical-specific and nonspecific loops. In Llinás & Ribary (1993), the authors propose that the specific loops give the content of cognition, and that a nonspecific loop gives the temporal binding required for the unity of cognitive experience. A lead article by Andreas K. Engel et al. in the journal Consciousness and Cognition (1999) that argues for temporal synchrony as the basis for consciousness, defines the gamma wave hypothesis thus: The hypothesis is that synchronization of neuronal discharges can serve for the integration of distributed neurons into cell assemblies and that this process may underlie the selection of perceptually and behaviorally relevant information.[24] Role in attentive focus: The suggested mechanism is that gamma waves relate to neural consciousness via the mechanism for conscious attention: The proposed answer lies in a wave that, originating in the thalamus, sweeps the brain from front to back, 40 times per second, drawing different neuronal circuits into synch with the precept [sic], and thereby bringing the precept [sic] into the attentional foreground. If the thalamus is damaged even a little bit, this wave stops, conscious awarenesses do not form, and the patient slips into profound coma. Thus the claim is that when all these neuronal clusters oscillate together during these transient periods of synchronized firing, they help bring up memories and associations from the visual percept to other notions. This brings a distributed matrix of cognitive processes together to generate a coherent, concerted cognitive act, such as perception. This has led to theories that gamma waves are associated with solving the binding problem. Gamma waves are observed as neural synchrony from visual cues in both conscious and subliminal stimuli. This research also sheds light on how neural synchrony may explain stochastic resonance in the nervous system. Gamma Waves are also implicated during Rapid eye movement sleep and anesthesia, which involves visualizations.[25] Contemporary research: A 2009 study published in Nature successfully induced gamma waves in mouse brains. Researchers performed this study using (the method of combining genetic engineering with light to manipulate the activity of individual nerve cells). The protein channelrhodopsin-2 (ChR2), which sensitizes cells to light, was genetically engineered into these mice, specifically to be expressed in a target-group of . These fast-spiking (FS) interneurons, known for high electrical activity, were then activated with an optical fiber and laser—the second step in optogenetics. In this way, the cell activity of these interneurons was manipulated in the frequency range of 8–200 Hz. The study produced empirical evidence of

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 331 gamma wave induction in the approximate interval of 25–100 Hz. The gamma waves were most apparent at a frequency of 40 Hz; this indicates that the gamma waves evoked by FS manipulation are a resonating brain circuit property. This is the first study in which it has been shown that a brain state can be induced through the activation of a specific group of cells.[16]Pushed by the need of understanding how gamma might affect disease pathogenesis, a recent study published in Nature demonstrates that entraining oscillations and spiking at 40 Hz in the hippocampus of a well-established model of Alzheimer's disease (5XFAD mice) reduces Aβ peptides and at the same time activates a response. Relation to meditation: Experiments on Tibetan Buddhist monks have shown a correlation between transcendental mental states and gamma waves. A suggested explanation is based on the fact that the gamma is intrinsically localized. Neuroscientist Sean O'Nuallain suggests that this very existence of synchronized gamma indicates that something akin to a singularity - or, to be more prosaic, a conscious experience - is occurring.[18] This work adduces experimental and simulated data to show that what meditation masters have in common is the ability to put the brain into a state in which it is maximally sensitive. As mentioned above, gamma waves have been observed in Tibetan Buddhist monks. A 2004 study took eight long-term Tibetan Buddhist practitioners of meditation and, using electrodes, monitored the patterns of electrical activity produced by their brains as they meditated. The researchers compared the brain activity of the monks to a group of novice meditators (the study had these subjects meditate an hour a day for one week prior to empirical observation). In a normal meditative state, both groups were shown to have similar brain activity. However, when the monks were told to generate an objective feeling of compassion during meditation, their brain activity began to fire in a rhythmic, coherent manner, suggesting neuronal structures were firing in harmony. This was observed at a frequency of 25–40 Hz, the rhythm of gamma waves. These gamma-band oscillations in the monk’s brain signals were the largest seen in humans (apart from those in states such as seizures). Conversely, these gamma-band oscillations were scant in novice meditators. Though, a number of rhythmic signals did appear to strengthen in beginner meditators with further experience in the exercise, implying that the aptitude for one to produce gamma-band rhythm is trainable. Such evidence and research in gamma-band oscillations may explain the heightened sense of consciousness, bliss, and intellectual acuity subsequent to meditation. Notably, meditation is known to have a number of health benefits: stress reduction, mood elevation, and increased life expectancy of the mind and its cognitive functions. The current Dalai Lamameditates for four hours each morning, and he says that it is hard work. He elaborates that

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 332 if neuroscience can construct a way in which he can reap the psychological and biological rewards of meditation without going through the practice each morning, he would be apt to adopt the innovation. Opposing evidence: Many neuroscientists are not convinced of the gamma wave argument. Arguments against it range from the possibility of mismeasurement – it has been suggested that EEG-measured gamma waves could be in many cases an artifact of electromyographic activity – to relations to other neural function, such as minute eye movements. However, proponents like O'Nuallain and Andreas Engel argue that gamma evidence persists even with careful signal separation. Moreover, recent studies using (MEG), which does not suffer the potential artifacts associated with EEG, have identified gamma activity associated with sensory processing, mainly in the visual cortex. A recent study with micro-electrodes in monkey and human showed that gamma oscillations are present and are clearly correlated with the firing of single neurons, mostly inhibitory neurons. The gamma oscillations were found in humans during all states of the wake-sleep cycle, and were maximally coherent during slow-wave sleep. Bearing this theory in mind, a number of questions remain unexplained regarding details of exactly how the temporal synchrony results in a conscious awareness or how a new percept "calls for" the synchrony, etc.[26] The after image will appear for a while before it disappears. With practice, the after image will appear for longer and longer periods. Eventually, you will be able to see it in its primary colours – that is, it will be as if you are staring at the picture as it is. You can practice in natural light or artificial light and you can either turn off the lights or close your eyes to see the after image. The Wink program contains both Photo Eyeplay cards and a DVD. I have tried both and I find it easier to see the after image using the Photo Eyeplay DVD. You can make your own Photo Eyeplay cards by using vivid pictures like the one shown above. Use pictures from magazines, cut them out and mount it on cardboard and mark a dot in the center as a focal point. This is what they do in Heguru. This is my own extrapolation, but I believe that if you can see the actual image in primary colours after you have closed your eyes, you have very likely also developed your photographic memory so there are additional benefits for doing this exercise. 3D Stereogram When I was in high school, there was a period when Magic Eye Books became really popular. If you aren’t familiar, they are books with pages of patterns which you are supposed to stare at for a while until a 3D image floats out towards you. Below is an example of a Magic Eye Image

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 333 from Photostuff. If you stare at it for a while, you should be able to see the word “SCOLA” on top of some block pattern.

Figure-5: Magic eye If you are having trouble adjusting your eyes to see the image, the Magic Book suggests putting your nose up against the picture and relaxing your eyes. Slowly draw the picture away from you and maintain your eye focus and the image should start to appear. I don’t know if you want to try this method with an image on the computer screen though. The other alternative is to look at the image as if you are staring at an object behind it and wait for the image to appear. That’s the method I use. There are many books available using the Magic Eye concept these days so it is easy to get practice material. Alternatively, you can use Google images to find you some free ones. However, if you are worried about staring too intently at a computer for too long, I recommend buying a book to practice on – just look for books on 3D stereograms. Eye Training This activity is done in Shichida and the Wink program (Eye Exercises). I’m not sure if Heguru does this with the older children, but I would presume so because they display it on their demo video. The practice cards look like the one shown below: The idea is to trace your eyes along the lines as quickly as you can. According to Tobitani’s book, if you can “get it right”, you should be able to see colours emerging from the image. You are encouraged to paint the patterns you see. This training is also done to improve speed reading, so there are dual benefits for practicing this exercise. CONCLUSION It is well known that the brain is an electrochemical organ; researchers have speculated that a fully functioning brain can generate as much as 10 watts of electrical power. Other more conservative investigators calculate that if all 10 billion interconnected nerve cells discharged at

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 334 one time that a single electrode placed on the human scalp would record something like five millionths to 50 millionths of a volt. If you had enough scalps hooked up you might be able to light a flashlight bulb. Even though this electrical power is very limited, it does occur in very specific ways that are characteristic of the human brain. Electrical activity emanating from the brain is displayed in the form of brainwaves. There are four categories of these brainwaves, ranging from the most activity to the least activity. When the brain is aroused and actively engaged in mental activities, it generates beta waves. These beta waves are of relatively low amplitude, and are the fastest of the four different brainwaves. The frequency of beta waves ranges from 15 to 40 cycles a second. Beta waves are characteristics of a strongly engaged mind. A person in active conversation would be in beta. A debater would be in high beta. A person making a speech, or a teacher, or a talk show host would all be in beta when they are engaged in their work. The next brainwave category in order of frequency is alpha. Where beta represented arousal, alpha represents non-arousal. Alpha brainwaves are slower, and higher in amplitude. Their frequency ranges from 9 to 14 cycles per second. A person who has completed a task and sits down to rest is often in an alpha state. A person who takes time out to reflect or meditate is usually in an alpha state. A person who takes a break from a conference and walks in the garden is often in an alpha state. The next state, theta brainwaves, are typically of even greater amplitude and slower frequency. This frequency range is normally between 5 and 8 cycles a second. A person who has taken time off from a task and begins to daydream is often in a theta brainwave state. A person who is driving on a freeway, and discovers that they can't recall the last five miles, is often in a theta state--induced by the process of freeway driving. The repetitious nature of that form of driving compared to a country road would differentiate a theta state and a beta state in order to perform the driving task safely. Individuals who do a lot of freeway driving often get good ideas during those periods when they are in theta. Individuals who run outdoors often are in the state of mental relaxation that is slower than alpha and when in theta, they are prone to a flow of ideas. This can also occur in the shower or tub or even while shaving or brushing your hair. It is a state where tasks become so automatic that you can mentally disengage from them. The ideation that can take place during the theta state is often free flow and occurs without censorship or guilt. It is typically a very positive mental state. The final brainwave state is delta. Here the brainwaves are of the greatest amplitude and slowest frequency. They typically center around a range of 1.5 to 4 cycles per second. They never go down to zero because that would mean that you were brain dead. But, deep dreamless sleep would take you down to the lowest frequency. Typically, 2 to 3

Sen et al. / Pharma Science Monitor 8(2), Apr-Jun 2017, 306-337 Impact factor: 3.958/ICV: 4.10 ISSN: 0976-7908 335 cycles a second. When we go to and read for a few minutes before attempting sleep, we are likely to be in low beta. When we put the book down, turn off the lights and close our eyes, our brainwaves will descend from beta, to alpha, to theta and finally, when we fall asleep, to delta. It is a well known fact that humans dream in 90 minute cycles. When the delta brainwave frequencies increase into the frequency of theta brainwaves, active dreaming takes place and often becomes more experiential to the person. Typically, when this occurs there is rapid eye movement, which is characteristic of active dreaming. This is called REM, and is a well known phenomenon. When an individual awakes from a deep sleep in preparation for getting up, their brainwave frequencies will increase through the different specific stages of brainwave activity. That is, they will increase from delta to theta and then to alpha and finally, when the alarm goes off, into beta. If that individual hits the snooze alarm button they will drop in frequency to a non- aroused state, or even into theta, or sometimes fall back to sleep in delta. During this awakening cycle it is possible for individuals to stay in the theta state for an extended period of say, five to 15 minutes--which would allow them to have a free flow of ideas about yesterday's events or to contemplate the activities of the forthcoming day. This time can be an extremely productive and can be a period of very meaningful and creative mental activity. In summary, there are four brainwave states that range from the high amplitude, low frequency delta to the low amplitude, high frequency beta. These brainwave states range from deep dreamless sleep to high arousal. The same four brainwave states are common to the human species. Men, women and children of all ages experience the same characteristic brainwaves. They are consistent across cultures and country boundaries. Research has shown that although one brainwave state may predominate at any given time, depending on the activity level of the individual, the remaining three brain states are present in the mix of brainwaves at all times. In other words, while somebody is an aroused state and exhibiting a beta brainwave pattern, there also exists in that person's brain a component of alpha, theta and delta, even though these may be present only at the trace level. It has been my personal experience that knowledge of brainwave states enhances a person's ability to make use of the specialized characteristics of those states: these include being mentally productive across a wide range of activities, such as being intensely focused, relaxed, creative and in restful sleep. REFERENCES 1. http://www.brainworksneurotherapy.com/what-are-brainwaves 2. Llinas R. R. Intrinsic electrical properties of mammalian neurons and CNS function: a historical perspective. Front Cell Neurosci. 8: 320, 2014.

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