Fall 2010 Vol 2 Issue 1 Thenerve

Fall 2010 Vol 2 Issue 1 thenerve

Spatial Navigation and the Memory Network

The Religious Brain The Drugs and Mechanisms of General Anesthesia

Neuroscience and the Military

TheResolving Rise of the the Cyborgs Line Between Genius and Insanity Mind and Brain Society

The Mind and Brain Society (MBS) was founded in the fall of 2008 in concert with BU’s new Undergraduate Program in Neuroscience. The group aims to create a network for undergraduate students who wish to take an active role in current issues and research. MBS serves as a hub for not only Neuroscience majors, but all students interested in Psychology, Biology, Philosophy, Computer Science, etc. Our goal is to support an eager multidisciplinary undergraduate community with the conversations and resources fundamental to Neuroscience today. Throughout the academic year, MBS hosts events spotlighting many different facets of Neuroscience. We hold discussion sessions during which we informally discuss a topic of interest over coffee; previous topics include “The Neuroscience of Religion” and “NeuroEthics.” The group also hosts research presentations by BU professors and screenings of thought-provoking films containing neuroscience motifs. CONTENTS Spring 2010 Vol. 1 Issue 2

RESEARCH IN BRIEF 5

ARTICLES Sports-related Concussions and the NFL by John Batoha & Evan Stein 11

Resolving the Line Between Genius and Insanity by Frank DeVita 17

Ten Minutes to a Trance by Anuhya Caipa 22

Trick or Treatment? The Placebo Effectby Natalie Banacos 24

Brain Research and National Defense by Aisha Sohail 27

REVIEWS General Anesthesia: Drugs and Mechanisms by Grigori Guitchounts 32

Spatial Navigation: Decoding the Human Memory Network by Evan Stein 41

OPINION Evolutionary Psychology on the Couch by Devyn Buckley 49

Do brains run algorithms? by Kayla Ritchie 57

SPRING 2010 | 3 “When we speak of nature it is wrong to forget that we are ourselves a part of nature.” -Henri Editors-In-Chief Grigori Guitchounts Matisse Kimberly LeVine tudents of neuroscience decide to join the field for a myriad of reasons- not the least of which includes a Editors Ssentiment of vanity. “My brain is amazing and I want Frank DeVita to know how it works.” At the beginning, many walk around Lauren Joseph fascinated, suddenly more in tune with how we know and experience what we do- spouting off “Did you know’s…” to Associate Editors unsuspecting friends and family. As study continues, we Natalie Banacos learn of tinier molecules, more complex proteins, and the John Batoha most finely tuned processes. The scale becomes smaller Devyn Buckley and several steps removed from our consciousness. It is easy to consider these inner-workings as only controlled Monika Chitre experiments under careful watch in a lab, but if we can keep Jennifer Richardson in mind that such precise orchestrations occur naturally Kayla Ritchie within us, the whole thing becomes even more astounding. Evan Stein Welcome to the second year of The Nerve’s infancy. Once again, we are thrilled to present an issue with breadth Artistic Director across the field of neuroscience while spotlighting a few of Kayla Ritchie our favorite topics from the last six months. We’d like to extend our deepest thanks to The Nerve staff and writers and Boston University faculty for pushing us into our sec- Artwork ond volume. Mursal Atif As you read each article, be a little self-centered. Con- Devyn Buckley sider the way your wiring affects your daily life. Consider Mariya Marioutina the amount of electricity running through you. Consider Margaret Mcguinness each molecule taking its course through your brain, moving Aubrey Reuben in such synchrony to make your very reading this possible! It’s a lot to think about, but the exquisitely intricate nature of the system is what makes it so extraordinary. MBS Staff This and other issues of The Nerve would not have been Megan Mataga possible without the generous help ofPaul Lipton, Howard Macayla Donegan Eichenbaum, Lindsey Clarkson, Denise Parisi, Zachary Bos, Shea Gillet and Jarret Frank. Advisors - Grigori Guitchounts and Kimberly LeVine Paul Lipton Editors-In-Chief Zachary Bos RESEARCH IN BRIEF Elucidating a New Pathway for Pain Management

Pain management is an important branch of med- peripheral nervous system and suppress FAAH activ- icine, especially in fields that consider long-term pain- ity, thus increasing anandamide levels in the periph- related diseases such as cancer or arthritis. People ex- ery. As a result, behavioral responses to peripheral perience pain as a result of nerve impulses traveling nerve pain and inflammation were reduced and neu- through the spinal cord to the central nervous system ronal activation in pain processing was suppressed in in response to noxious stimuli. As the pain signal trav- rodent models in response to increased anandamide els to the brain, it can be modulated in a number of binding at CB1 receptors. different ways by intervening nerve fibers that cause Experiments subjected rodent models to neuro- an inhibitory effect, thus reducing pain. This interfer- pathic and inflammatory pain to test the efficacy of ence can be experienced in the common instinct rub URB937 as an analgesic. For neuropathic pain, sciatic a wound: our body’s touch receptors connect to pain nerve injury was induced and the compound was im- signal fibers in the upward pain pathway to the brain mediately administered. Results showed decreased and slow the noxious signal’s travel by inducing vari- sensitivity to pain and daily administration of the ous neuronal interactions. Other ways to modulate drug showed consistent results. Chemically induced pain incorporate the use of analgesic drugs, most inflammatory swelling in the rodents was combated commonly opiates, such as morphine for acute pain, with URB937 with equally effective results. Spinal or lighter analgesics such as acetaminophen (Tylenol) pain perception was also investigated by measuring and salicylic acid (Aspi- levels of the protein Fos, rin). Both act within the whose levels are elevated in brain itself through mo- response to neuronal activi- lecular interactions to ty in the spinal cord and thus modulate pain in a top in response to pain. URB937 down fashion through was able to attenuate Fos neurotransmitter sys- levels in regions of the neck tems. and dorsal horn of the spinal Neurotransmitters cord, implying that the trav- are a crucial piece of the eling pain signal was sup- puzzle in the neurosci- pressed before it was able to ence underlying pain. reach the brain itself. Current research is elu- The suggestion of this cidating the mechanisms research is that increased of anandamide, a myste- anandamide levels in the rious neurotransmitter periphery and CB1 recep- that acts on the much-re- tors can effectively attenuate searched cannabinoid CB1 and CB2 receptor as well pain signals to the CNS. Since URB937 was designed as the vaniloid receptors. We do not know much about to remain exclusively outside the CNS, this research anandamide, but its levels spike in response to pain establishes the existence of a previously unexplored or inflammation and these receptors bind the neu- connection between the peripheral endocannabinoid rotransmitter, creating an analgesic affect. In a recent system and pain perception. Given their results, the Nature Neuroscience study, researchers elucidated a researchers hypothesize that peripheral anandamide mechanism of anandamide in the peripheral nervous acts as a diffuse paracrine signal to modulate pain system (PNS) and its action on cannabinoid recep- stimuli as they arrive in damaged tissues. This implies tors. The team created an inhibitor of fatty acid amide that pain stimulates anandamide production and CB1 hydrolase (FAAH), a compound that degrades anan- receptors are present in abundance in peripheral damide under normal circumstances. The inhibitor, nerve endings and throughout tissues and organs. dubbed URB937, was designed to remain only in the These results open new doors to pain therapy that can FALL 2010 | 5 RESEARCH IN BRIEF

exploit the cannabinoid system to effectively attenu- matic learning difficulties. The causes of ADHD are ate pain without the highly undesirable side effects largely unknown. The general population, as well as a produced by classical opioid pain therapy. portion of the scientific community, has believed that it is likely attributed to poor parenting and a sugar — Frank DeVita rich diet, but this study presents the first evidence that ADHD is instead a genetic neurodevelopmental original paper: ClapperNature JR et Neuroscience al. Anandamide disorder. suppresses pain initiation through a peripheral en- The study conducted at Cardiff University ana- docannabinoid mechanism. 13, lyzed the genomes of 366 children with ADHD and 1265–1270. 2010. 1047 controls. These children with ADHD were aged Rare CNVs in the ADHD 5-17 years who were diagnosed with ADHD or hy- perkinetic disorder, but not schizophrenia or autism. Genome The researchers genotyped single nucleotide poly- morphisms (SNP:DNA sequence variation in which a single nucleotide differs from the appropriate base pairing) for both groups, looking for and comparing ADHD is a disorder known to almost everyone; copy number variants (CNVs) in their genomes. it has established a prevalence in our school systems CNVs occur when one of the two copies of a gene and the media. The Center for Disease Control high- is missing or when there are too many copies. Their lights that 3-7 percent of school-aged children suf- findings showed that 57 large, rare CNVs were iden- fer from ADHD. In the United Kingdom, where this tified in the ADHD population, in contrast to the 78 particular study was done, it is reported that around CNVs that were found in the much larger control pop- one in 50 children is affected by the disorder. But ulation. This data shows that these rare CNVs were even with such high prevalence and awareness about almost twice as likely to occur in children with ADHD ADHD, the causes of the disease have escaped the sci- (14%) compared to controls (7%), including a rate entific and medical community. Recentresearch from of CNVs that was particularly high in ADHD subjects Cardiff University offers potential ground and stigma with intellectual disability. breaking information, shedding some light on this elu- This data is the first of its kind to suggest a genetic sive disorder. basis to this disorder. The researchers also highlight Children diagnosed with ADHD are restless, im- that the rare CNVs identified occur in genomes in the pulsive and distractible, and often experience dra- brain that are known to correlate with susceptibility

6 | THE NERVE RESEARCH IN BRIEF

to autism and schizophrenia. One of these particular to theobromine (3,7-dimethylxanthine) and theophyl- regions was identified on chromosome 16, which has line (1,3-dimethylxanthine). been found crucial in the development of the brain In the first segment of the experiment mice were and is affected in various major psychiatric and devel- given doses of saline or caffeine 10 minutes, 30 min- opmental disorders. utes, 1 hour, 2 hours, or 6 hours before doses MPTP The suggestion supported by this research is that or saline was administered. The saline administration ADHD is not based on social elements or poor parent- provided a control to compare the effects of the actual ing, but instead a direct genetic fault. This CNV data chemical. Then the same dose of caffeine or saline paired with the fact that ADHD is known to be highly was administered10 minutes, 30 minutes, 1 hour, 2 heritable, points the scientific and therapeutic ap- hours, or 6 hours after the first. The second segment proach to this condition in a whole new direction. of the experiment involved testing the action of the metabolites. Caffeine, Theophylline, Paraxanthine, or — Jennifer Richardson saline was administered 10 minutes before MPTP or saline was administered. original paper: Williams NM et al. Rare Chromo- Dopamine levels were measured by extracting the somal deletions and duplications in attention-deficit striatum from the right cerebral hemisphere. Caffeine hyperactivity disorder: a genome-wide analysis. The was measured from the trunk blood of mice. Serum Lancet 376: 9750. 1401 - 1408. 2010. and supernatant of brain homogenates were mea- Neuroprotection by Caffeine sured for caffeine and its three metabolites. The results showed that caffeine was not only effective in at- tenuating dopamine depletion when co-administered with the toxin (10 minutes before MPTP), but also 30 For any student of Neuroscience, the neurotrans- minutes before administration. However, when caf- mitter dopamine immediately brings to mind the feine was administered earlier than 6 hours before pathways of“reward signaling.” However, this neu- MPTP it no longer had a significant effect. When caf- rotransmitter also plays a critical role in regulating feine was administered 10 minutes, 30 minutes, or an movement. Parkinson’s disease (PD), which injures hour after, but not 4, 8, or 24 hours after MPTP, striatal dopaminergic neurons, unleashes a devastating effect dopamine depletion was reduced significantly. on body control. In PD, the damaged nerve cells fire Similarly, in the second segment of the experi- rapidly, losing all control over dopamine and causing ment, Caffeine metabolites theophylline and parax- involuntary muscle movements or tremors. Other ef- anthine pre-treatments attenuated MPTP-induced fects of the disease include rigidity, slowness, or loss dopamine depletion in mice. Caffeine not only has a of coordination. A study conducted this year by Mas- neuroprotective effect against this model for PD, but sachusetts General Hospital and Harvard Medical acts in this role in a range of 2 hours before and after School revealed that caffeine and its metabolites, the MPTP administration. However, there are differences parts left when it’s broken down, may provide some in how caffeine is metabolized in humans versus ro- neuroprotective properties that resist the damaging dents. The half life of caffeine is around 2.5 to 4.5 effects of Parkinson’s disease. hours in humans, but about an hour in rodents. The Epidemiological studies have demonstrated a longer half-life of caffeine in humans suggests its neu- link between caffeine consumption and PD. In this roprotective effects may be greater than those in rats. particular study, the MPTP model of PD focuses on Caffeine seems to hold great promise in preventing the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydro- the damaging effects of Parkinson’s disease—news pyridine (MPTP) in causing the devastating the dis- that should make any coffee or soda addicted readers ease. The effects of caffeine on countering the actions happy. of MPTP revealed insight into its effect against PD as a whole. Metabolites of caffeine as they appear in — Devyn Buckley the human body when it is being broken down were administered to rodents so that the effects could be original paper: Xu K et al. Neuroprotection by as similar to humans as possible.Over 80% of orally Caffeine: time course and role of its metabolites on administered caffeine metabolizes to paraxanthine in the MPTP model of Parkinson’s Disease. Neurosci- (1,7-dimethylxanthine), and about 16% is converted ence. 167:2, 475-481. 2010 FALL 2010 | 7 RESEARCH IN BRIEF

The Introspective Brain: Accuracy and Structure

Every day, we find ourselves “metacognitive” sensitivity refers choice task. The first part of the making countless decisions, some to “the ability to discriminate cor- task, a series of visual judgments, of which are nearly reflexive, and rect from incorrect perceptual was meant to provide a measure others that require further rea- decisions.” Its accuracy, or lack of objective performance, and the soning and perceptive abilities. thereof, will later direct an indi- difficulty of said task was varied on This decision-making process also vidual’s behavior and action. It was a per-participant basis to keep per- includes our introspective abil- hypothesized that individual dif- formance at a constant level (71%) ity—the capability to reflect on a ferences in these abilities would near sensory threshold. The sec- particular decision and determine be reflected in anatomy of brain re- ond part of the task required that whether or not it was a correct one, gions responsible for this function. the participants provide ratings of a capacity that varies across indi- In order to test this hypothesis, the confidence in their decisions after viduals. In a recent study published variability in metacognitive sensi- each trial, rated on a one-to-six in Science Fleming, et al. display tivity between individuals was ob- scale, with participants encour- evidence of a possible neuroana- jectively quantified and related to aged to use the whole scale where tomical basis of this introspective interindividual differences in brain one = low relative self confidence ability. Their findings show a corre- structure, which were measured and six = high relative self confi- lation between gray-matter volume with magnetic resonance imaging dence. These ratings were used to as well as white matter microstruc- (MRI). determine metacognitive ability at ture in the anterior prefrontal cor- The study consisted of 32 an individual level through the contex (PFC) and introspective ability. healthy human subjects, who par- struction of a type II receiver oper- In the study, introspective or ticipated in a two-part, forced- ating characteristic (ROC) curve. 8 | THE NERVE RESEARCH IN BRIEF

The area between the major diago- with gray-matter volume in the the anterior PFS show deficits in nal and an individual’s ROC curve is right anterior PFC. Furthermore, subjective reports as compared to a measure of the ability to link con- gray-matter volume in this region controls, which is consistent with fidence to perceptual performance did not correlate with task perfor- the theory. These findings, though (Aroc). mance. It was also found that FA (a they provide no direct causal rela- Two distinct measures were measure of white-matter integrity) tion between these neuroanatomi- then used to find whether the in the genu of the corpus callosum cal areas and metacognitive sensi- variability shown in introspective was posttively dependent on Aroc. tivity, do however provide an initial judgments could be predicted by These regions might contrib- window to the biological basis of variability in brain structure. First, ute to metacognition in that ante- the ability to link objective perfor- gray-matter volume was measured rior subdivisions of the PFC have mance and subjective confidence. from T1-weighted anatomical im- been implicated on high-level ages, and second, the fractional an- control of cognition and are well —Lauren Joseph isotropy (FA) of white matter was placed to integrate supramodal measured from diffusion tensor perceptual information with deci- original paper: Fleming SM et images (DTI). It was found that an sion output, a process thought to al. Relating Introspective Accuracy individual’s metacognitive ability be key for introspective ability. Ad- to Individual Differences in Brain (Aroc) was significantly correlated ditionally, patients with lesions to Structure. Science 329, 1541. 2010. Astrocytes Regulate Breathing

Astrocytes are best known for their role in keeping the brain’s neurons structurally and metaboli- cally sound. However, new evidence from a study published in Science this July demonstrates that in fact, there is more to astrocytes than just support for our brain cells. In the study, Alexander V. Gourine et al. probed the chemosensitivity of astrocytes, testing whether or not astrocytes in the respiratory che- moreceptor regions of the brainstem help regulate breathing by acting as pH sensors. To observe the astrocytes in question, the scientists engineered rats to express the Case 12 gene, a Ca²⁺ indicator. The gene was expressed in the chemoreceptive region of the ventral surface of the medulla (VS) in the rats tested. When the pH was decreased by 0.2 units in the VS, Ca²⁺ concentration increased instantly in the rats. Astrocytes adjacent to the VS FALL 2010 | 9 RESEARCH IN BRIEF

in the chemoreceptive retrotrapezoid nucleus (RTN) This study also employed optogenetics to inves- showed long, continuous Ca²⁺ responses. These acid- tigate the chemoreceptive VS astrocytes. A mutant ification-induced Ca²⁺ excitatory responses were also version of light-sensitive channelrhodopsin-2 was demonstrated in in vitro preparations of brainstem combined with a far red-shifted fluorescent protein slices which showed several pH-sensitive astrocytes (AVV-sGFAP-ChR2(H134R)-Katushka1.3) and ex- near the blood vessels in the VS. pressed in rats. Cultures and brainstem slices with the By inhibiting RTN neurons with tetrodotoxin (to incorporated AVV-sGFAP-ChR2(H134R)-Katushka1.3 block sodium channels) and muscimol (to block GAB- showed increases in astrocyte Ca²⁺ concentration AA receptors) the researchers showed that the Ca²⁺ when exposed to 470 nm light. Astrocytes with the op- excitation of the astrocytes was not merely a response togenetic construct incorporated showed immediate to excitation of nearby neurons in the RTN. While the ATP release and prolonged depolarization of labeled RTN neurons were being treated with tetrodotoxin RTN neurons was observed upon activation. and muscimol, Ca²⁺responses in reaction to acidifi- Anesthetized, artificially ventilated rats with their cation still occurred in RTN astrocytes. Additionally, vagus nerve fibers surgically divided and transduced activation of the RTN neurons beside them did not in- with AVV-sGFAP-ChR2(H134R)-Katushka1.3 on one duce Ca²⁺ elevation in RTN astrocytes. side of the ventral brainstems were tested to observe As it turns out, this Ca²⁺ excitation in the VS is the respiratory effects of pH-induced Ca²⁺ excita- modulated by adenosine triphosphate (ATP). A 0.2 tion. When the VS was exposed to light of the proper unit decrease in pH causes a continuous release of wavelength, respiratory activity was generated from ATP from the VS. Testing with ATP-hydrolyzing en- apnea in the rats. Recordings from the phrenic nerve zyme apyrase eliminated pH-evoked Ca²⁺ excitation, demonstrated increased amplitude when rats breath- and the addition ATP receptor antagonists markedly ing normally were optogenetically stimulated. An ATP decreased such excitation. Three different antagonists receptor antagonist inhibited the response of the re- were tested, that reduced the Ca²⁺ signals by 80%, spiratory system to optogentic stimulation of the as- 82% and 83%. These findings suggest that ion-gated trocytes. The side of the VS that was not transduced ATP receptors might play a role in this mechanism. did not respond to illumination. The excitation is spread among the chemorecep- This study serves to highlight the role of astro- tive astrocytes via gap junctions, but predominantly cytes in chemoreception that was once thought to be through release of ATP by exocytosis. Blocking as- reserved for particular neurons in the medulla and trocyte gap junctions with concentrated carbenoxo- pons. Their anatomical location - in close proximity lone reduced acidification-induced Ca²⁺ excitation to arteries going into the brain - allows them to keep by about 43%, but inhibiting ATP production and track of what enters the brain. Clearly, they are vital release essentially eliminates excitation. In addition, components in maintaining homeostasis RTS neurons’ resting potentials were not affected by decreased pH, but their pH-induced depolarizations — Natalie Banacos decreased markedly when treated with a apyrase, and also when treated with an ATP receptor antagonist. original Paper: Gourine, Alexander V. Astrocytes The neurons’ pH sensitivity appears to be the result of Control Breathing Through pH-Dependent Release of prior ATP release. ATP. Science. 329, 571-575. 2010.

10 | THE NERVE ARTICLES Sports-related Concussions and the NFL

by John Batoha and Evan Stein

FALL 2010 | 11 ARTICLES

Sports-related concussions and the NFL

by John Batoha and Evan Stein

y November of 2009, the National Football ciated with SRC include deficits in memory, attention, League season was winding down, and with a and concentration, as well as a decrease3, 6, 7 in reaction playoff berth and a shot at the Super Bowl on time and cognitive processing speed . Even repeti- the line, each new contest meant more than the last. tive subconcussive hits, or minor trauma-induced in- “These are the games you don’t get back,” observed juries, that accumulate over time5 may eventually lead Pittsburgh Steelers wide receiver Hines Ward. to similar cognitive impairments . With only four weeks left in the season, teams A particularly concerning aspect of SRC is that like the Arizona Cardinals and Ward’s own Pittsburgh athletes who sustain one concussion are four to six Steelers were prepared to put anything on the line for times more likely to suffer a second4, 10 one than athletes Ba victory – except their starting quarterbacks. without a history of concussions . Guskiewics et al Ben Roethlisberger of the Steelers and Kurt War- also found that subsequent concussions have relative- ner of the Cardinals stayed on the bench that Sunday, ly lower injury thresholds, thus making4 the athlete both looking on as their teams lost heartbreaking more susceptible to a second injury . This disparity games. Each looked completely healthy; Roethlis- seems to disqualify the notion that the increased like- berger had even practiced the Thursday before. But lihood of a second concussion is due entirely to a ge- both had sustained in-game concussions a week earli- netic predisposition to the injury. er, and in the wake of recent reports about the dangers Long-term cumulative effects of SRC have also of repetitive head trauma, elected not to play. been identified in De Beaumont et al.’s transcranial Unlike more apparent injuries like a torn ligament magnetic stimulation (TMS) study investigating mo2- or broken bone, concussions can be hard to define, let tor cortex inhibition in concussed football players . alone diagnose. But as more information about the Their study provides significant evidence that previ- dangers of concussions – and their long-term implica- ously concussed athletes who sustain additional con- tions – emerges, more people are paying attention to cussions2 exhibit long term motor system abnormali- this particularly insidious injury. ties . Their conclusion – that subsequent concussions Sports-related concussion (SRC) is a common in- exacerbate this dysfunction – provides further evi- jury in a wide variety of contact sports. It has been dence that the adverse effects of SRC are cumulative. commonly defined as any alteration in mental status But while repetitive concussions can cause cogni- experienced as a result of head-jarring trauma that9 tive function to slowly wither, the injury can be deadly may or may not include a loss of consciousness (LOC) . in the short term too. Consider a situation common in A concussion, also known as a mild traumatic high school football games. Time is expiring in the first brain injury (MTBI), can result from either a direct half and a teenage standout is tackled hard. The hit blow to the face or head, or as the indirect result6 of sends him to the ground and though his head bounces an impulsive force transmitted to the head , where off the turf, he shakes it off and gets up. At halftime, he abrupt acceleration7 or deceleration impacts the brain mentions to a teammate that he feels lightheaded and against the skull . dizzy, but does not tell his coach. Long-term neuropsychological impairments asso- In the second half he seems fine, but after receiv- 12 | THE NERVE ARTICLES

6 ing several routine blows to the head, he collapses tion system . on the field. Four days later, he is pronounced brain This new system classifies MTBI as simple or dead at a local hospital. The autopsy shows subcor- complex, based on how long the athlete’s symptoms tical ischemia, diffuse brain swelling, and a subdural persist. A simple concussion is diagnosed when an hematoma. athlete recovers within 7 to 10 days. A complex con- This young athlete fell victim to a deadly3, 6 condition cussion occurs when the athlete has prolonged and called second-impact syndrome (SIS) , a rare but se- persistent cognitive deficits, sustained multiple con- rious condition that occurs when an athlete does not cussions, or suffers from sequelae such6 as convulsions fully recover from a previously sustained concussion or an LOC lasting more than 1 minute . One inherent before receiving a second blow to the head. Real cases shortcoming of this classification system is that con- mirroring this vignette occur each year and until ath- cussions cannot be properly diagnosed until the athletes and trainers alike gain a better understanding lete fully recovers from all signs and symptoms. De- of the dangers and symptoms of SRC, these tragedies layed onset symptoms also render this6 classification will continue. system impractical in the acute setting. The Center for Disease Control and Preven- But while the cognitive deficits following SRC tion (CDCP) has estimated that between 50,000 and have been discussed at length in recent years, the 300,000 athletes in the United States1 sustain concus- pathology that underlies these phenomena has re- sions within one athletic season . Even this striking mained an enigma. It seems intuitive, for scientists number may grossly underestimate the true incidence and athletes alike, that repetitive head trauma could of concussive events; the CDCP study only included damage the brain, but until recently, no one was quite athletes who experienced a loss of consciousness. sure how to prove it. A slew of recent studies, many Moreover, various studies concerning SRC reveal an focused on retired NFL players, have raised some dis- alarmingly high rate of under-reporting of concus- turbing questions about why these deficits arise, and sions by the athlete, attributable to a lack of educa- just how drastic their implications can be. Though still tion, awareness, and appreciation of a concussion as a incomplete, the studies are beginning to indicate that serious medical condition. what arises from repetitive concussions is not merely Other reasons for the underreporting of concus- a collection of cognitive deficits, but a unique, perva- sions by the athlete include the feeling that the injury sive, and ultimately fatal pathology. is too insignificant to report, external and internal John Grimsley, a former linebacker for the Hous- pressure to continue playing, and simply the failure ton Oilers, shot himself in the chest while cleaning his of the3, 6 athlete or trainer to recognize the symptoms of gun in February of 2008. While authorities initially SRC . ruled the death an accident, Grimsley’s family and Easily overlooked, subtle symptoms such as friends were shocked that he could be so careless. headache, dizziness and lightheadedness can all in- They emphasized his skill with guns, and insisted that dicate SRC; other symptoms include poor judgement, he had used them countless times without incident. photophobia, and difficulty concentrating. Further They recounted observing changes in Grimsley, most complicating the diagnostic process, these common notably a decline in his mental health, for some time. indicators often seem insignificant to the athlete, and They also reported that the standout linebacker’s per- overlap with unrelated etiologies like dehydration, sonality had shifted drastically in his last years. Long lack of sleep, overtraining and hypoglycemia. More- known as a passive, even-keeled man, he had become over, the symptoms – already ambiguous enough – of- emotionally unstable, and sometimes even violent. ten have a delayed6 onset up to several days after the Disturbingly, several parallel cases have emerged time of injury . in recent years which, taken together, begin to build In the past, concussions were diagnosed only a coherent set of symptoms in retired NFL players. when an athlete experienced LOC or amnesia; how- Justin Strzelczyk, a former Pittsburgh Steeler, led po- ever, studies have now provided significant evidence lice on a high-speed chase for over 40 miles in 2004 that LOC and amnesia alone are insufficient for assess- before eventually crashing his car into a tanker truck. ing the severity of, and recovery from, a concussion. He had reported repeated hallucinations prior to the To address these concerns, experts have abandoned incident. the concussion-grading system and return-to-play Fellow Steeler Mike Webster died in 2002 at age guidelines, leading to the rise of a two-fold classifica- 50 after bouts with depression, drug addiction, and FALL 2010 | 13 ARTICLES

homelessness. Like Grimsely and Strzelczyk, he had athletes constitute perhaps the toughest hurdle in ad- sustained countless blows to the head over the course dressing CTE, it was largely the efforts of a former foot- of his career. These representative tragedies are only ball player that helped bring the dangers of repetitive a handful of the incidents that together reveal an ex- concussions to light. In the late 1990’s, Chris Nowin- tensive pattern of symptoms and deficits in retired ski was a sociology concentrator at Harvard College, NFL players. Their collective symptoms: dementia, and an exceptional defensive lineman on the football memory loss, and emotional instability, had been re- team. He recalls sustaining several concussions dur- ported before. Dementia Pugilistica, or “punch drunk” ing his career there. After graduation, Nowinski be- syndrome, and had already been observed in boxers. gan a stint with the World Wrestling Entertainment As pathologists began examining the brains of (WWE) circuit under the pseudonym Chris Harvard, a the NFL players, they noticed clear abnormalities in pretentious anti-hero who would often enter the ring their brain tissue similar to those observed in “punch reading a book. drunk” fighters. Most notable were massive aggre- He sustained several more concussions during his gations of tau protein, a common marker in several time with the WWE, finally suffering one from which major neurological disorders, including Alzheimer’s he felt he never quite recovered. Experiencing head- disease (AD). Now, physicians refer to this premature aches, memory problems, and bouts of emotional in- buildup of tau, and the substantial behavioral abnor- stability, he moved back to Boston, taking a desk job malities that accompany it, as Chronic Traumatic En- until his symptoms subsided and he could re-enter the cephalopathy, or CTE. ring. But thedementia symptoms pugilistica persisted and the concerned Both the symptoms and the histology of CTE wrestler began doing some research. He discovered manifest like a premature form of Alzheimer’s. Dis- reports of , and wondered if the tinguishing between the two can be difficult; a formal mental deterioration described in boxers could occur diagnosis of either can be made only upon postmor- in other athletes. He enlisted the help of Robert Can- tem examination. But where Alzheimer’s involves a tu, a neurosurgeon at the Boston University School of buildup of both tau protein and accompanying beta- Medicine, and the two co-founded the Sports Legacy amyloid plaques, the brains of CTE patients only con- Institute to determine if other athletes were suscepti- tain tau. ble to the disease. With both their publicity and their Although the neurobiological markers of CTE funding building, the Boston group began to study the have become clearer, physicians are still struggling to pathology and long-term neuropsychological effects describe the exact mechanism of the neurodegenera- of repetitive concussions. tion. Some have suggested that inflammation and oxi- What they have already found has been striking. dative stress brought on by the force of the impact may Ann McKee, a Boston University neuropathologist, cause tau to aggregate. Others have pointed to studies has discovered CTE in each brain of the four retired suggesting that genetics may play a role in an athlete’s pros she’s examined. And these results, however re- susceptibility to concussions, and consequently, in markable, are no anomaly. A pathologist at the Uni- CTE. Apolipoprotein E (ApoE) may make people more versity of Pittsburgh, Bennett Omalu – the first to susceptible to the ill effects of concussions, exacerbat- document neurodegeneration in an NFL player –has ing the effect of each blow. But even with the precise found evidence of CTE in eight of the nine NFL play- biochemical processes unknown, the psychological ef- ers he’s examined. As case studies continue to mount, fects of CTE, and its characteristic physical markers, the researchers began to find support even in the ma- are impossible to ignore. cho world of the NFL, where the striking data had be- Despite the high profile cases that have emerged, gun to raise concerns among players. To date, over and the neurological evidence to corroborate it, not all 150 athletes, including at least 40 NFL players, have athletes are buying it. “I could see some players or agreed to donate their brains to Boston University for teammates questioning, like, “It’s just a concussion,’” a postmortem examination to search for pathology. wide receiver Hines Ward told the Boston Globe. “I’ve As the body of evidence that repetitive concussions been out there dinged up; the following week, got can lead to CTE grows, the dangers of playing football right back out there. I’ve lied to a couple of doctors at the professional level have become harder to refute, saying I’m straight, I feel good, when I know that I’m even for players. not really straight.” But that doesn’t mean the NFL isn’t trying. Even Though the toughness and machismo of many as the heartbreaking stories of former athletes were 14 | THE NERVE ARTICLES

beginning to garner national attention, the NFL ad- References ministration was doing everything in its power to 1. CDCP. (1997). Sports-related recurrent brain injuries – United downplay the dangers of concussions. When Omalu States. Morbidity & Mortality Weekly Report 46, 224-227. published his paper on CTE in 2005, the NFL demand- 2. De Beaumont, L., Lassonde, M. Leclerc, S., Theoret, H. (2007). ed an immediate retraction, claiming that the study Long-term and cumulative effects of sports concussion on mo- was inconclusive and misleading. They hired their tor cortex inhibition. Neurosurgery 61, 329-337. own team of independent experts to evaluate the ef- 3. Delaney, J.S., Abuzeyad, F., Correa, J.A., Foxford, R. (2005). Rec- fects of repetitive concussions – a move described by ognition and characteristics of concussions in the emergency some as reminiscent of the tobacco industry’s early department population. J. Emergency Medicine 29, 189-197. attempts to downplay the role of cigarettes in lung 4. Guskiewicz, K.M., McCrea, M., Marshall, S.W., Cantu, R.C., Ran- cancer. dolph, C., Barr, W., et al. (2003). Cumulative effects associated But amidst the building evidence, their conten- with recurrent concussion in collegiate football players: The tious response found fewer sympathetic ears, and the NCAA concussion study. Journal of the American Medical As- NFL finally began to address the concerns about con- sociation, 290(19), 2549-2555. cussions. It disbanded its team of hired experts, agree- 5. McKee, A.C., Cantu, R.C., Nowinski, C.J., Hedley-Whyte, E.T., Gavett, ing instead to work with the Boston researchers to B.E., Budson, A.E. Santini, V.E., Lee, H., Kubilus, C.A., & Stern, investigate CTE. Even more recently, league officials R.A. (2009). Chronic traumatic encephalopathy in athletes: have begun to work to keep players better informed progressive tauopathy after repetitive head injury. Journal of about the symptoms and effects of concussions. The Neuropathology and Experimental Neurology 68:7, 709-735. New York Times reported in 2010 that teams would 6. Meehan, P.W., Bachur, R.G. (2009). Sport-related concussion. Pe- be required to hang an informational poster about diatrics 123, 114-123. concussions in their locker rooms. Baltimore Ravens 7. Moser, R.S., Iverson, G.L., Echemendia, R.J., Lovell, M.R., Schatz, P., lineman Matt Birk discussed the development with a Webbe, F.M., Ruff, R.M., Barth, J.T. (2007). Neuropsychological Times reporter, “To put it out there in writing in the evaluation in the diagnosis and management of sports-related locker rooms, at least it’s publically acknowledging concussion. Archives of Clinical Neuropsychology 22, 909-916. that ‘hey this is real’. There’s risks in everything you 8. Omalu, B.I., Hamilton, R.L., Kamboh, M.I., DeKosky, S.T., Bailes, J. do and this one is real. You can’t sweep it under the (2010). Chronic traumatic encephalopathy (CTE) in a National rug anymore.” But even as the NFL began to address Football League Player: Case report and emerging medicolegal concerns, the most disturbing piece of information to practice questions. J. Forensic Nursing 6, 40-46. date about CTE emerged: 9. Shuttleworth-Edwards, A.B., Radloff, S.E. (2008). Compromised Owen Thomas, the captain of the football team at visuomotor processing speed in players of Rugby Union from the University of Pennsylvania, hanged himself in his school through to the national adult level. Archives of Clinical apartment in April 2010. A postmortem examination Psychology, 23(5), 511-520. revealed characteristic Tau aggregations in his brain, 10. Zemper, E.D. (2003). Two-year prospective study of relative risk of a second cerebral concussion. American Journal of Physical leading to the diagnosis of CTE – the first for a college11 player. Owen had never sustained a concussion . Medicine & Rehabilitation, 82(9), 653-659. 11. Penn’s Owen Thomas had CTE. http://sports.espn.go.com/ncf/ news/story?id=5569329. Accessed 10/2010.

FALL 2010 | 15 ARTICLES Genius or Insanity? An Investigation of Creativity and Mental Illness

By Frank P. DeVita

16 | THE NERVE An Investigation of the Link Between Creativity and Mental Illness

by Frank P. DeVita

Introduction

ften times, creative individuals are plagued ability is investigated through various psychological with various psychological afflictions ranging tests. Batteries such as the Torrence Tests of Creative from depression and autism spectrum disor- Thinking (TTCT) present a series of tasks in picture der to conditions such as schizophrenia or bipolar dis- generation to a subject who must then generate pic- order. In fact, these afflictions have beset people such tures from partial drawings and4 generate original as Salvador Dalí, Pablo Picasso, Sylvia Plath, Earnest works with a given set of shapes. A selection of the Hemmingway, Pyotr Tchaikovsky and many others. Berlin Intelligence Structure Test (BIS) also contains A combination of mental illness and creativity spans a figural battery with line drawing in addition to a across many different media and its bearers personify verbal battery that asks for novel uses of various ob- Othe struggle that arises from straddling the line be- jects and a numeric battery that2 requires generation tween genius and insanity. Yet it is this paradox that of unique number sequences. In both series of tests, has produced some of history’s greatest innovations. higher scores reflect an ability to create unique solu- Only now are we beginning to understand the under- tions to single problems and, in theory, are results of lying mechanisms behind what many may be defined heightened creativity. as both a gift and a curse. In fact, there is a neurobio- Over time, these tests have gauged human cogni- logical and psychological link between creativity and tion, and led to conclusions about intelligence and the mental illness that may begin to resolve the line be- creative thought process. Raymond Cattell and John tween genius and insanity. Horn stated that human intelligence is compartmen- Creativity is defined by the Oxford English Dic- talized into fluid and crystallized ability. The fluid tionary as, “the use of the imagination or original component grounds critical thinking, problem solv- ideas, 1 especially in the production of an artistic ing, pattern recognition and learning, while the crys- work.” Through humanity’s existence, creativity has tallized grounds retention5,6 of facts, formulae and other been an important factor in the evolution of global malleable information. Additionally, John Carroll culture through its manifestations in science, visual thought that the mind functions within a general intel- art, music, design, architecture, politics and war. It can ligence, combining the fluid/crystallized dynamic with be argued that these human innovations start with a perception,7 processing and specific specialized abili- latent spark of creativity that evolves into a brilliant ties. Researchers administering divergent thinking flame - but where does this spark come from? Creative tasks have found that there are significant correlates potential seems uniquely human as no other species among a defined set of these specialized abilities and Definingcan match and the Investigatinghuman imagination. Creativity divergent thinking, specifically fluency (the number of valid responses), originality (the frequency of valid responses), flexibility (number of unique categories produced), switching (ability to shift between catego- Creativity was defined very recently as, “the abil- ries) and elaboration (extensive nature of responses). ity to produce work that is at the same time novel2 These factors are dynamically interacting in each in- and meaningful, as opposed to trivial and bizarre.” dividual, and certain combinations theoretically serve In many circles, creativity is deemed concordant with as the foundation for divergent and creative thinking. divergent thinking, the thought process used when3 a For instance, subjects who exhibit high fluency scores problem is solved by multiple unique solutions. It is often demonstrate increased flexibility of thought and thought that an increased ability to think divergent- the ability to create an increased2 number of uncom- ly, may imply enhanced creative potential, and this mon solutions on the tests. Creative individuals have SPRING 2010 | 17 ARTICLES

an uncanny ability to perceive related stimuli, under- nonpre-exposed group learns faster than the pre- stand them with great variation, and generate unique exposed group, demonstrating higher levels of latent outputs through words, music, paint, prose or other inhibition. This shows that pre-exposure to a stimulus media. This ability to make novel associations about lessens the ability to form concrete associations with incoming stimuli is the purest essence of human cre- that stimulus. In relation to creativity, this deficit in Extremesativity on the in Creativitymacroscopic level. associational ability may enable increased free association. Creativity has been evaluated with respect to latent inhibition through LI and divergent thinking tasks plus an arts and sciences creative achievement Associational ability also is affected by a widely evaluation,. It was shown that pre-exposed modest investigated phenomenon called latent inhibition creative achievers have higher levels of latent inhi- (LI). It is the varying capacity of the brain to focus on bition than their nonpre-exposed counterparts, and stimuli previously experienced as irrelevant or insig- that pre-exposed highly creative achievers score11 com- nificant.9 LI can be quantified as the ability to learn parably to their nonpre-exposed counterparts. This to ignore irrelevant stimuli and focus10 on important demonstrates reduced latent inhibition among pre- parts of the incoming sensory stream. For example, exposed highly creative groups and contributes to an in an environment with noise and other distractions, overall trend of incrreased creativity correlated with latent inhibition allows us to focus on and perform a attenuated latent inhibition. specific task efficiently while ignoring the distractins Interestingly, reduced latent inhibition is also – akin to reading with the television or radio on, but linked10,11 to the psychopathology of schizophrenia still understanding the reading. Thus, more attenu- (SZ) , creating a curious psychological link be- ated/decreased latent inhibition can lead to a reduced tween creativity and mental illness. There are many ability to focus properly and/or learn by associaton environmental, genetic, neurobiological, psychologi- efficiently. Essentially, LI is a filter that keeps the brain cal and familial factors that lead to the development from being distracted. Decreased LI can then cause and expression of schizophrenia. However, it has increased sensitivity to one’s environment. In the been observed that latent inhibition is improved in context of creativity, decreased latent inhibition can medicated schizophrenic compared to unmedicated allows an individual to perceive their environment as schizophrenic patients, and more so impaired in those markedly more novel. The brain is not ignoring irrele- who had12 recently experienced their first psychotic vant stimuli, but rather interpreting it repeatedly and episode. This sheds light on the psychotic processes uniquely multiple times over. This is a crucial compo- associated with schizophrenia, by which patients ex- nent of divergent thinking and forms the groundwork press irrational paranoia, delusions of grandeur, and for making grandiose free associations about one’s en- disconnected thought patterns. As a result of their de- vironment and possibly the basis for creative thought. creased filtering and attenuated latent inhibition, SZ Latent inhibition is reduced to different extents in patients perceive the world as markedly more novel, different creative individuals,11 which may enable their strange or even malicious as a result of their hyper- unique cognitive abilities. LI is measured and related sensitivity to the environment. However, there is more to creativity through a combination of auditory and vi- to be learned here. While a individual with SZ may be- sual discrimination tasks. Subjects are first separated lieve their peers are going to kill or hurt them, may into “pre-exposed” (PE) and “nonpre-exposed” (NPE) assume the consciousness of a celebrity, or perceive groups, and are presented with audiovisual tasks. The human emotion from static objects, they are demon- NPE group is presented with an audio sample of sylla- strating divergent thinking on overdrive. Since their bles and a video clip that flashes a yellow circle before latent inhibition is critically lowered and the incoming a target syllable, and the subject must learn to asso- information stream remains relatively unfiltered, rad- ciate the appropriate sound with the visual stimulus. ical thoughts and associations become second nature. The PE group is first presented the same audio sample Although these thoughts are peculiar, their foundation combined with white noise, then separately presented still lies in divergent thinking. Although schizophrenic with the same audiovisual task as the NPE group. LI is thought demonstrates the problems in extreme diver- measured as the speed of learning the syllable stream gent thinking, these thoughts are arguably creative at (the conditioned stimulus) is paired with the yellow their very core. circle (the unconditioned stimulus). Classically, the 18 | THE NERVE ARTICLES

Real World Evidence

somewhat warped perception of the real world that allows them to turn the average and real into the sur- Many may think that there is greater madness in real, embodying a more feral psyche. The emotive the arts as compared to the sciences, and in fact, art- painters exhibit overtly original technique in their ab- ists may express a greater lifetime prevalence of men- stract expressions that is very difficult to define and tal illness 14as compared to natural scientists and social create a sense of confusion and awe in their paintings. scientists. This greater instance of mental illness in These artists show the highest rates of mental illness, artists through their lifetimes may be accounted for reflected by their eclectic techniques. Other painters by an environment that values decreased objectivity, not included in the study also embody this phenom- rationality and precision as compared to fields in the enon. Salvador Dali, arguably the most prominent natural and social sciences, where there are more stan- surrealist painter in history, was a victim of paranoid dards, laws and constraints. Interestingly, the mental personality disorder and erratic personality disorder condition of an artist often manifests itself in the tech- based on his unusual behavior and personal accounts. nical aspects of their artwork, and this is most eas- This phenomenon is not unique to visual art. A ily seen in the visual creativity and men- arts. Mandlebrot’s15 Innovations start tal illness trend fractal theory ad- is also present in dresses this idea of music and writing. “self similarity,” stat- Classical composers ing that irregulari- with a latent spark such as Tchaikovsky ties in small parts of and Shumann have an object reflect the been linked to af16- overall composition of creativity - but fective disorder , of the whole. This and instances of also applies to the compulsive disor- creativity and men- where does this der and depression tal illness argument were present in the in that the part is the lives of jazz musi- technical attributes cians Miles Davis17 of an artistic work spark come from? and John Coltrane. and the whole is its Renown novelist creator. and pioneer of con- This notion of fessional poetry Syl- self-similarity by via Plath and was af- fractal theory was investigated in three forms of art: flicted with psychosis that drove her to commit suicide formal (exhibiting compositional emphasis), symbolic at home in the presence of her children at the tender (exhibiting social realism or narration) and emotive age of 30, while fellow writer Earnest Hemmingway (exhibiting abstract expressionism). Formalists such also succumbed to suicidal depression. This evidence as Picasso and Matisse, exhibited the lowest instance suggests a real-world presence of a link between men- of lifetime mental illness, while symbolic/surreal Biologicaltal illness and Creativity creativity. and the Link to Mental Illness painters such as Hopper and Cezanne fell at the median, and emotive modern artists such as DeKooning and Rouault demonstrated14 the highest instance of lifetime mental illness. Formalists show a more rigid While psychology has provided much to under- and defined technical style despite abstract subject standing divergent thinking and creativity, there have matter, which reflects their more stable mental state. been advances in neurobiology that strive to bolster Their art is a result of careful, methodic manipulation theory with functional evidence. In investigating the of conventions to create unique works that although biological basis of creativity, studies have been con- strange at times, are certainly technically well defined. verging on the thalamus, the brain’s relay station and The symbolic/narrative painters exhibit comparable sensory gating system before the prefrontal cortex. technical efficiency, but their output is a result of a The thalamus contains a plethora of chemical recep- FALL 2010 | 19 ARTICLES

tors for the neurotransmitter dopamine, and spe- ternal environment. Also, given that the thalamus has cifically, the dopamine D2 receptor has been studied an elevated level of D2 receptors, it has been suggest- with regard to neurobiological creativity. Imaging ed that decreased D2BP decreases thalamic ability to studies (MRI/PET) have revealed significantly higher strictly filter the incoming stream of information8 flow- densities of D2 receptors in the thalamus relative to ing rapidly to the prefrontal cortex. Thus, the pre- other parts of the brain (the only place with a higher frontal gating system goes awry, allowing for input of density is the striatum), and they enable the filtering an unfiltered stream into the frontal lobe, which could function of the thalamus8 to prevent information over- be the neurological basis for creativity. This makes load in the cortex. These dopamine pathways play a sense with respect to neurobiology, as decreased fil- critical role in creativity in that D2 receptor density tering by the thalamus facilitates information flow to and thalamic D2 dopamine binding potential (D2BP) the prefrontal cortex and the frontal lobe, where in- decrease as divergent thinking test scores increase.8 put is available for free association. Since the creative This suggests that subjects who score high on diver- mind has taken in more information, it can create gent thinking tasks also may exhibit decreased D2BP more original associations as a function of mathemat- in the thalamus and a smaller amount of D2 receptors. ics – if there is more information to be strewn togeth- D2 dopamine binding in the thalamus may then have er, there will be more output. The incoming informa- an important role in thalamic filtering and divergent tion stream coupled with an open sensory gate in the sensory processing. thalamus may create the conditions for the infamous The dopamine system is dysfunctional in schizo- and elusive creative spark, but for some, the spark can phrenia. It becomes hypersensitive, over active and Propositionlead to psychosis. of a ContinuumWhat then chooses the path? particularly, dopamine binding in the striatum increases with intensity of positive psychotic symptoms. These include2 hallucinations, delusions and dis- ordered thought. Interestingly enough, the dopamine In a Harvard study, intelligence was investigated pathways rendered dysfunctional in schizophrenia, with respect to latent inhibition in a group of pre-ex- bipolar disorder and (albeit to a lesser extent) de- posed individuals from a latent inhibition11 diagnostic pression show significant overlap with the thalamus to investigate IQ’s role in creativity. After re-adminis- and straitum – brain areas seemingly2 important for tration of latent inhibition tasks and creative achieve- creativity and divergent thinking. Additionally, de- ment evaluations, individuals were given an IQ test, creased D2BP and reduced D2 receptor density in and it was found that those who demonstrated higher the thalamus are 2,8included in the molecular pathology levels of creative achievement also demonstrated re- of schizophrenia Studies show that as cortical and duced latent inhibition. Trends in IQ accounted for limbic D2BP decreases, intensity of positive schizo- 20% of the variance of the results, and IQ was a signifi- phrenic symptoms increases,8 thus establishing the cant variable. In further investigation, the group’s em- role of the D2 receptor in this mental illness. Although inent creative achievement (ECA) was analyzed. The very controversial, this emergent piece of evidence researchers defined this as publishing/sale of a novel, links psychological and biological creativity through book or poetry, sale of recorded music, patented con- the dopamine brain pathways and D2 receptors. An struction of a prototype invention, private exhibition analogous negative correlation also exists between of original artwork or scholarship/prize for a scientif- divergent thinking test scores and D2 receptor den- ic discovery. The group analyzed consisted of 4 artists, sity in the thalamus. D2 density is lower in 8subjects 5 composers, 2 writers, 2 inventors, 3 dramatists, 7 who score high on divergent thinking tests. Thus, a scientists and 2 choreographers, whose IQ and latent biological link between creativity and mental illness is inhibition scores were compared to a control group. brought to light. Since both schizophrenic pathology These eminent creative achievers showed markedly and divergent thinking exhibit decreased D2 receptor lower levels of latent inhibition than the controls and density and DA binding potential, this suggests that were seven times more likely to demonstrate attenu- there are associations between some of the underly- ated latent inhibition. Pertaining to IQ, it is suggested11 ing mechanisms of creativity and mental illness. that a score of 120 is the threshold for creativity , and Given the above testament, it can be argued that in comparing the IQs of the subjects, 84% of the cre- the ability to think creatively arises from an increased ative achievers had an IQ score greater than 120 while capacity to make free associations of stimuli in the ex- only such was the case for 44% of the control group. 20 | THE NERVE ARTICLES

Further statistical analysis demonstrated a higher in- realm of psychosis and neural function. Through the stance of reduced latent inhibition in eminent creative psychopathology of mental illness, we are better able achievers with an IQ greater than 120. to understand what is happening in the brain at the This data and the previously presented neuro- level of neurophysiology, which will prove important biological and psychological ideas suggest that at- in understanding the brain as a system. While we can tenuated latent inhibition is associated with both high diagnose and treat all mental illnesses , we do not creativity and mental illness, with IQ serving as a pos- understand the complete brain mechanisms of all of sible modulating factor. These extrema of creativity these disorders. Breakthrough molecular neurobiol- and mental illness may exist in a continuum linked by ogy has and will continue to help us further under- latent inhibition and modulated by IQ. Reduced latent stand these conditions and open up possibilities for inhibition is associated with schizophrenia in multiple treatment at more localized levels. If we are able to cases, but may also be related to an increased likeli- understand specific receptor-ligand mechanics, neu- hood of creativity. Furthermore, there are other corre- rochemistry, neuroanatomy, and neurophysiology lations between creative individuals and schizophren- of various mental illnesses, we will be better able to ic patients11 in latent inhibition and divergent thinking better treat them. In the context of creativity, this tasks. Without the modulating function of IQ, all cre- evidence further allows us to understand and inves- ativity could be explicitly synonymous with psychosis, tigate our established metaphysical and psychological but this clearly is not the case. Intelligence may serve ideas under a microscope. Modern understanding of as the mediator between an individual’s susceptibility the mechanisms of mental illnesses allows us to de- to psychosis and ability to be creative. This also sug- velop new treatments and prophylactic interventions gests that intelligence may influence how each indi- to prevent disorders before they even start. More in- vidual’s mind responds to and functions under atten- terestingly however, is the idea of manipulating these uated levels of latent inhibition, which relates back to mechanisms for our benefit once we fully understand the defined set of abilities associated with creativity them. Theoretically, it may be possible one day to Finalmentioned Thoughts earlier. modulate brain function from the level of genes and molecules, opening the door to a new realm of self-enhancement by molecular intervention. Just think, one day you may be able to take a pill to access the cogni- What does all this mean in a larger context? Prin- tive plane of Pablo Picasso or Ludwig van Beethoven cipally, it expands our knowledge of the mysterious for just a few hours.

1. “Creativity” Oxford English Dictionary. Online Edition. Accessed July 2010. bridge University Press, Cambridge. 2. de Manzano Ö , et al. (2010). Thinking Outside a Less Intact Box: Thalamic 10. Gray NS, et al. (1995) “Latent Inhibition in Drug Naïve Schizophrenics: Rela- Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Cre- tionship to Duration of Illness and Dopamine D2 Binding using SPET.” Schizo- ativity in Healthy Individuals.” PLoS ONE 5(5): e10670. doi:10.1371/journal. phrenia Research Vol. 17 pp. 95-107. pone.0010670 11. Decreased Latent Inhibition Is Associated with Increased Creative Achieve- 3. Guilford JP (1957). “Creative Abilities in The Arts.” Psychological Review Vol. ment in High-Functioning Individuals (2003).J Personality and Social Psy- 64, No. 2, pp. 110-118. chology Vol. 85, No. 3, pp. 499-506. 4. Kim KH (2006). “Can We Trust Creativity Tests? A Review of the Torrence 12. Vatil D, et al (2002). “Latent Inhibition and Schizophrenia: Pavlovian Condi- Tests of Creative Thinking.” Creativity Research Journal Vol. 18, No. 1, pp. 3-14. tioning of Autonomic Responses. Schizophrenia Research Vol. 55 pp. 147-158. 5. Cattell RB (1963). “Theory of Fluid and Crystallized Intelligence: A Critical 13. Swerdlow NR, et al. (1996). “Latent Inhibition in Schizophrenia.” Schizo- Experiment.” Journal of Educational Psychology Vol. 54, No. 1 pp. 1-22. phrenia Research Vol. 20 pp. 91-103. 6. Horn, J. L., & Cattell, R. B. (1966a) “Refinement and test of the theory of fluid 14. Ludwig AM (1998). “Method and Madness in the Arts and Sciences” Creativ- and crystallized general intelligences.” Journal of Educational Psychology Vol. ity Research Journal Vol. 11, No, 2, pp. 93-101. 57, pp. 253-270. 15. Mandelbrot BB (1983) The Fractal Geometry of Nature. Various selections. 7. Carroll JB (1993). “Human Cognitive Abilities: A Survey of Factor Analytic W.H. Freeman, 1st Edition, 1983. Studies” Cambridge University Press. 16. Jamison, K. R. (1993) Touched With Fire: Manic Depressive Illness and the 8. Takahashi H, Makoto H & Suhara T (2006) “The Role of Extra-Striatal Dopa- Artistic Temperament. Various selections. New York: The Free Press. mine D2 Receptors in Schizophrenia.” Biological Psychiatry Vol. 59 pp. 919- 17. Wills, GI (2003) Forty Lives in the Bebop Business: Mental Health In a Group 928 of Eminent Jazz Musicians. British Journal of Psychiatry Vol. 183, pp. 255-259. 9. Lubow R. E. (1989) Latent Inhibition and Conditioned Attention Theory, Cam-

FALL 2010 | 21 ARTICLES Ten Minutes to a Trance: Exploring I-Dosing and the Binaural Beat Phenomenon

by Anuhya Caipa

n 0.19 seconds, the Google manipulated by German physicist will be of 105 Hz while 5the binau- search engine retrieves over Heinrich Wilhelm Dove, the father ral beat will be of 10 Hz . Once the 9,600,000 results concerning of the2,3 binaural beat phenome- binaural auditory beat travels to I-Dosing, the newest Internet fad non . Since their discovery, binau- the brainstem’s superior olivary that is taking the world’s youth ral beats have been implemented nucleus, where specialized nuclei by storm. The next time you hear both clinically and experimentally that encode binaural stimulation someone talking about drugs, you to assess the audio-perceptive abil- are located, a4,7 beat of neural activity might get confused when you hear ities and integrity of corticosenso- Welcomeis generated to . the Digital High- them talking about crazy beats and ry tracts. Way: Advocates Isoundproof headphones. However, In general auditory situations, an increasing number of people when a sound of a particular fre- are listening to sound files that are quency hits one ear earlier than specifically designed to alter an in- the other, the brainstem auditory As a ‘cognitive arousal’ tech- dividual’s state of consciousness processing areas, the superior ol- nique, the administration of bin- and induce a ‘high’ that is claimed ive, inferior colliculus, and lateral aural beats demands a general to mimic the psycho-physiological lemniscus, detect the difference knowledge of the electrical behav- effects felt after the administration in auditory stimulation time and ior of the brain. Typically, electri- of an actual psychoactive drug; this estimate the direction a4 particular cal brain activity can be sorted into “drug trip” is called I-dosing. To feel sound is coming from . However, five frequency-based categories. optimal effects, the user is advised when the two ears are simultane- Gamma waves (30-100Hz; usually to wear stereo headphones, lie ously presented with a sinusoidal 40Hz) are the brain’s highest fre- down in a comfortable position in sound of a slightly different frequency electrical waves and are a dark room, close his or her eyes, quency, as in binaural beat stimu- present during multimodal pro- and drift 1off into the world of digi- lation, the slight frequency dif- cessing of sensory information. tal-drugs . As ludicrous as I-Dosing ference is not what is perceived. Beta waves (14-30Hz) and alpha may seem, the scientific foundation Instead, the result is a sinusoid waves (8-13Hz) typify wakefulness for digital-drugs dates back to as whose interaural time difference and conscious cognitive function early as the mid nineteenth cen- changes slowly. Consequently, this (pad). Alpha frequency waves oc- Thetury. Biological Basis Behind Bin- frequency difference between the cur at more relaxed cognitive states aural Beats two tones creates a binaural beat, a while beta waves are produced at sound that seems to move in space. higher arousal states. Delta and If this resulting movement is rapid, theta waves characterize an uncon- the beat will “fill the head” rather scious state. Delta waves (1-4Hz), The human brain, being a dy- than being perceived as5 coming the lowest-frequency brainwaves, namic and adapting organ, has the from a particular location . promote dreamless sleep, and capacity to rapidly alter its electri- For example, if the left ear is theta waves (4-8Hz) are associated cal activity in response to incoming presented with a sound of 110 with REM8 sleep, meditation, and information. In 1839, the percep- Hz while the right ear receives a creativity . tive ability of the brain to encode frequency of 100 Hz, the sound When a binaural beat is of the and react to exogenous stimuli was perceived by the auditory system same frequency range as any one 22 | THE NERVE ARTICLES

of the five brainwaves, it is claimed present their audio stimuli. The beats may be significant statistical- to be capable of altering an indi- user interface of the I-Doser pro- ly, Dr. Shinn-Cunningham says the vidual’s state of consciousness by gram is organized into folders, with effects of binaural stimulation on stimulating the reticular-thalamic the parent folder labeled “Dose brain activity are smaller than the activating system, a neural system6,8 Files.” These dose files, lasting from effects of more overt cues in music, responsible for cognitive arousal . ten to forty minutes, range from such as the rhythmic beats that we Studies conducted with EEGs have hallucinogens to club drugs and all dance to and hear consciously. shown that binaural beats of a opioids. When asked about how Additionally, many experiences theta wave frequency will induce a the program works, I-Doser ex- of a psycho-physiological ‘high’ be- feeling of drowsiness in a listener. plains, “each audio track contains ing felt by I-Dosers could be due to Conversely, binaural beats in the [our] advanced binaural beats that a placebo effect and may not even beta wave range will cause the lis- will synchronize [your] brainwaves simulate the high resulting from tener to become more aroused and to the same state as the recreation- a recreational psychoactive drug. alert, with enhanced7,9 memory and al dose. Mixed with [our] advanced Although it has been shown that task performance . auditory pulses are soothing back- drugs do have13 an effect on brain- Advocates of the use of binau- tracks of ambient soundscapes wave activity , it is not known if ral beats for cognitive manipula- to help the brain induce a state of these effects can be replicated by tion are convinced of its potential mood lift, euphoria,1 sedation, and binaural beats alone. Furthermore, therapeutic effects. Robert Monroe, hallucination” However, I-Doser drug activity on the brain is largely founder of the Monroe Institute, Labs does not have everyone con- dose dependent, making the ap- developed multi-layered sound Youvinced. Are Only as High as You Want proximation of the effects of binau- files that manipulate brain waves to Be: Skeptics ral beats on the brain hard to mea- and transform the brain into a state sure in comparison to a real high. of “hemispheric synchronization,” Regardless of the disagree- an occurrence in which both hemi- ments concerning the impact spheres of the brain are in unison Although there are studies binaural beats have on cognitive with each other. Research director publicizing the application of bin- arousal, the major ethical issue is of the Monroe Institute, F. Holmes aural beats to cognitive arousal the message I-Dosing is sending Atwater, markets the Institute’s purposes, many are skeptical of to unsuspecting individuals perus- product by describing HemiSync these claims and point out how few ing the Internet. Although I-Dosing as an “audio guidance program… legitimate, peer-reviewed scientific and other methods of brain wave for obtaining10 altered states of con- papers document affects on brain manipulation may not be danger- sciousness” . There are also a few state. Boston University professor ous or even effective, there is a published articles concerning the Dr. Barbara Shinn-Cunningham de- concern that these methods of digi- investigation3,8,11 of HemiSync in clini- scribes the true application of bin- tal stimulation will act as gateway cal settings . In preoperative aural beats as a prognostic tool to drugs. It is up to the user to decide settings, it was shown that patients identify the brain’s ability of spatial12 whether to go digital or not. undergoing surgery required sig- hearing and auditory encoding . References nificantly less anesthetic if they3 Dr. Shinn-Cunningham relates listened to a HemiSync sound file . methods of ‘cognitive arousal’ to Further, in preoperative-associated other common methods to alter anxiety, nearly half of patients ben- consciousness, such as meditat- 1. I-Doser: Binaural Brainwave Doses. efited8 from listening to binaural ing or simply listening to relaxing [accessed 2010 July 20]; Available beats . music. She asserts that in most from: http://www.i-doser.com/. HemiSync, having been devel- situations, binaural beats do not 2. Dabu-Bondoc S. Hemispheric Synchro- oped before I-Dosing, set the stage induce any considerable12 difference nized Sounds and Intraoperative for the future of digital brainwave in brain wave behavior . The brain Anesthetic Requirements. Anesth manipulation. I-Doser Labs, one of is an easily manipulated organ, and Analg. 2003;97:3. the many designers of marketed differences in electro-cognitive 3. Kliempt P, Ruta D, Ogston S, Landeck binaural beat audio, has even de- activity can be a result of simply A, Martay K. Hemispheric-syn- veloped a proprietary program to “thinking.” While effects of binaural chronisation during anaesthesia: a FALL 2010 | 23 ARTICLES

double-blind randomised trial using Trick or Treatment? audiotapes for intra-operative noci- ception control. Anaesthesia. 1999 Neuroscientific and medical applications Aug;54(8):769-73. 4. Barr DF, Mullin TA, Herbert PS. Appli- of the placebo effect cation of binaural beat phenomenon by Natalie Banacos with aphasic patients. Arch Otolar- yngol1977 Apr;103(4):192-4. Introduction 5. Pratt H, Starr A, Michalewski HJ, Dimitrijevic A, Bleich N, Mittel- How To Trick Your Brain man N. Cortical evoked potentials to an auditory illusion: binau- ooling our own brains is an ral beats. Clin Neurophysiol2009 appealing concept: everyone Aug;120(8):1514-24. enjoys optical illusions, mag- By definition, the placebo ef- 6. Lane JD, Kasian SJ, Owens JE, Marsh GR. ic tricks and riddles. But can fooling fect is a physiological state brought Binaural auditory beats affect vigi- our brains help heal our bodies? on when one anticipates a health- lance performance and mood. Physi- When it comes to taking medicine, related result from biologically ir- ol Behav. 1998 Jan;63(2):249-52. people have consistently proven relevant treatments or procedures. 7. Wernick JS, Starr A. Binaural interac- themselves to be highly suggest- The placebo effect can target sev- tion in the superior olivary com- ible. The color of pills, the number eral different neurological systems, plex of the cat: an analysis of field Fof pills and the brand of pills can in- thus the wide range of possible potentials evoked by binaural- fluence our assumptions about the effects: analgesia, mood improve- beat stimuli. J Neurophysiol. 1968 medications we are taking. We tend ment, and even immunosuppres- May;31(3):428-41. to think that capsules are stronger sion¹. 8. Padmanabhan R, Hildreth AJ, Laws D. A than pills, and that injections are Brain pathways involving do- prospective, randomised, controlled more powerful than medicine tak- pamine are important in under- study examining binaural beat au- en orally¹. Even surgery has been standing the placebo effect. Dopa- dio and pre-operative anxiety in evaluated for its potential placebo mine is a neurotransmitter that lets patients undergoing general anaes- effect: in one experiment on ar- us associate a stimulus in our envi- thesia for day case surgery. Anaes- throscopic knee surgery, both the ronment with a reward, and it is thesia2005 Sep;60(9):874-7. osteoarthritis patients receiving released when we are engaging in 9. Kennerly RC. An empirical investiga- the operation and those who just behavior that will bring about that tion into the effect of beta frequency got an incision and stitches showed reward. Dopamine activity in the binaural audio signals on four mea- significant, decreases in knee pain nucleus accumbens (NAC) is evi- sures of human memory. 1994. ¹². dent when pain relief is expected, 10. Holmes M. Hemi-Sync and Remote The preferred test to prove and people who show more activity Viewing. Monroe Institute 2008. the effectiveness of an experimen- in the NAC when expecting a mon- 11. Lewis AK, Osborn IP, Roth R. The ef- tal drug evaluates whether or not etary reward are more noticeably fect of hemispheric synchronization its effects can beat those of a pla- affected by placebos³. on intraoperative analgesia. Anesth cebo in a double-blind, placebo- A second contributing neural Analg2004 Feb;98(2):533-6, table of controlled, randomized trial. Many system is known as the endogenous contents. experimental drugs fail this test, or opioid system. Our brains release 12. Shinn-Cunningham B. Personal Inter- often the placebo trial may give the their own opioid substances in review with Dr. Barbara Shinn-Cun- drug a run for its money. So, if the sponse to pain (endogenous opi- ningham. Interviewed Boston 2010. placebo is so difficult to beat and is oids) and when that is not enough, 13. Banoczi W. How some drugs affect devoid of side-effects, then why not doctors prescribe painkillers with the electroencephalogram (EEG). use it as the treatment itself? This similar chemical structures. So how Am J Electroneurodiagnostic Tech- question is being raised by physi- do we know that natural opioids nol2005 Jun;45(2):118-29. cians, researchers and bioethicists: are involved in the placebo effect? can safe, affordable treatment be Naloxone, a substance that blocks found in fake medicine? opioid receptors, has been shown 24 | THE NERVE ARTICLES

to prevent placebo analgesia, dem- and opioid systems, the serotonin Even surgical placebos - sham onstrating the placebo’s reliance system has also been proven to play surgeries - have proven effective, on our brain’s natural painkillers⁴. a role in the placebo effect. The in- perhaps most notably in Parkin- Knowing this, conditioning studies volvement of this system in the pla- son’s patients. One study looked at have been able to demonstrate that cebo effect is often observed in ex- patients who had had electrodes expectation of pain relief is asso- periments concerning depression, for deep-brain stimulation treat- ciated with the release of opioids although it is difficult to have a true ment implanted in their brains. One in the brain. One such study used control for the placebo groups of group of patients was told that the morphine, an opioid painkiller, and these studies because the subjects treatment was functioning, and an- ketorolac, a non-steroidal anti-in- have often had outside interven- other group was told that the stim- flammatory drug (NSAID). Subjects tion like counseling. Nonetheless, ulator had been dialed down. The were conditioned to expect either changes in brain glucose metabo- patients who believed that their morphine or ketorolac injections. lism have been observed in similar electrodes were working expected After getting two real injections, regions of the brain in subjects tak- improved motor performance to they received saline placebos that ing fluoxetine, an antidepressant, result from deep-brain stimula- triggered analgesic responses Tricksand subjects for Treatment taking a placebo⁷. tion. Although they were never similar to the drug they had been given the treatment, these patients administered previously, whether associated the fake subthalamic they expected pain relief or not. In- stimulation with better motor per- jections of naloxone, independent The broad range of effects that formance and were able to move of the subjects’ expectations of re- have been produced by placebos their hands faster. The necessary ceiving a painkiller, decreased pain are evident in their wide experi- brain changes occurred within tolerance significantly⁵. mental use. Although they tend to minutes⁹. In another study, after Both opioid and dopamine treat the symptoms rather than injecting Parkinson’s patients with systems rely on cognitive and con- the cause, the inherent lack of side medication that would help relieve ditioning factors. For instance, effects makes placebos prime can- muscle stiffness, the subjects were when taking a biologically active didates for treating a variety of ail- given a placebo and their subtha- substance, the effectiveness of a ments. Research is being directed lamic brain activity was monitored. placebo that physically resembles toward finding a useful place for Individual neurons in this brain re- an active drug will be increased placebos in medicine. gion became less active so that the in both humans and animals⁶. We Effective methods to use place- patients’ muscles could relax and are conditioned to respond to the bos as painkillers are being investi- function more easily¹⁰. physical act of taking medicine, gated. A 2001 study demonstrated Though it is an unpredictable but we hold an expectation in our that subjects tolerate pain better disease, and thus difficult to con- minds of what the active drug is when they can actually see that trol for in placebo studies, multiple supposed to look like. Conditioning they are being given an analgesic. sclerosis (MS) has been another factors refer to drug conditioning - When test subjects received the potential candidate for placebo giving a subject a certain number of opioid receptor-blocker naloxone remedies. Multiple sclerosis is an doses of a drug before replacing it after the seeing themselves inject- autoimmune disease in which the with a placebo. The cognitive part ed with the NSAID ketorolac, their body attacks the myelin insulation of the effect is introduced when pain tolerance was the same as it covering its own nerves. In a trial the subjects are given expectation was after only receiving a hidden of interferon-β-la treatment for MS, cues, being led to think that they injection of ketorolac⁸. In May, the the group given a placebo showed are or are not taking a particular Boston Globe reported on a study a twenty percent decrease in areas substance. In terms of anatomy, the published in Science last year in of inflammation due to the body anterior cingulate cortex seems to which patients given cream to put attacking its myelin, expressed play a role in both systems, and is on their arms showed much less as MRI lesions, compared to their activated in the placebo groups of pain-related activity in their spinal baseline MRIs¹¹. Epilepsy, a simi- analgesia, anxiety relief and mood cords when told that the treatment larly unpredictable condition, has improvement studies¹. they had been given was in fact a been shown to respond to place- In addition to the dopamine powerful painkiller². bos. The placebo groups of anticon- FALL 2010 | 25 ARTICLES

vulsant trials regularly show sig- experimental design became popu- in psoriasis patients showed that nificant (more than fifty percent) lar after World War II, it became corticosteroids administered in reductions in seizure frequency ¹². apparent that people responded smaller-than-standard doses inter- Placebos may also be used to positively to placebos. In fact, Hen- spersed with placebo doses could address cognitive issues associated ry Beecher declared that thirty-five prove a better, safer treatment plan with aging. In a study of healthy percent of patients responded well than regular, standard doses of the adults aged 65-85, subjects taking to placebos. This is no doubt an ex- same medication¹⁷. “You’re talking what they were told was a cognitive aggeration, as confounders were about many, many, many millions enhancement pill performed better not fully taken into consideration, of dollars a year in drug treatment on cognitive tests than the group but nonetheless placebos have be- costs. If [doctors] can produce ap- of subjects that had not taken any come a big research topic in recent proximately the same therapeutic pills. In one Alzheimer’s study, fifty years ¹⁵. effect with less drug, then it’s ob- percent of the placebo group had A principal ethical issue sur- viously safer for the patient, and I shown either improvement or sta- rounding placebo medicine is in- can’t believe they wouldn’t want to bility in their condition six months formed consent - the patient’s right look into doing this,” Robert Ader, into the trial¹³. It is interesting, to understand their treatment. The the leader of the study at the Uni- then, that Alzheimer’s has been fact remains that placebos involve versity of Rochester remarked in demonstrated to deter the placebo deception by definition. It can be the Boston Globe². In that respect, effect, perhaps because of frontal argued, however, that this decep- placebo treatments irrefutably ad- Trickylobe impairment Business ¹⁴. tion is merely putting the effects dress two major problems facing of mental and emotional states on Conclusionthe health care field today. the body’s well-being to use. Inter- estingly, the deception can actually The placebo effect is a neuro- be lessened by letting the patient in biological phenomenon that has on the fact that he or she is taking a The placebo effect is an in- the potential to aid in the treat- placebo without ruining the effect. triguing neurological process in- ment of a number of disorders. The The treatment can still work be- volving many facets of the brain: wide range of neural systems it af- cause there is a healing element of chemically, cognitively, and ana- fects gives it the potential to serve the treatment routine itself: simply tomically. The diverse range of as treatment for a great variety of being seen by a doctor and taking systems that appear to be involved conditions. Research directed to- medicine promote recovery. Unfor- in placebo phenomena account for ward finding medical uses for the tunately, over an extended period the usefulness of placebos in many placebo effect will undoubtedly be of time, extinction of the body’s different kinds of clinical trials. As put under great ethical scrutiny be- conditioned recovery response to the highest standard for pharma- fore being used clinically. this routine can occur. To maintain ceutical testing, the effective use of Placebos are not a new concept. the placebo’s efficacy in the face of randomized, double-blind, place- They were used as early as the 16th extinction, a physician could ex- bo-controlled trials has prompted century in the form of fake holy ob- plain that he or she does not fully those in the biomedical field to ask jects given to people believed to understand the mechanisms of the why placebos are not used as med- be possessed. If the victims were prescribed drug (a placebo) but is ications themselves². While treat- upset by these false relics, priests recommending it on the grounds ing symptoms more than causes, would know that the possession that it will not cause the serious the relief achieved with a placebo was imaginary - only a real relic side effects associated with the might contribute to the body’s abil- was thought to bother a possession better-understood treatment op- ity to heal itself. If this becomes a victim. By the late 1700’s, placebos tion¹⁶. real movement in medicine, in- were used medically, but merely to Another potential benefit in formed consent may not end up placate patients. This “undoubt- introducing placebos into clini- being a problem: perhaps patients edly led to the tainted reputation of cal use would be a reduction in will come to accept the possibil- placebos and placebo effects that health care costs. As well as being ity that they could be issued “fake” persisted until very recently” ¹⁵. free of side effects, placebos are medication for their own benefit. When the randomized control trial very inexpensive. A recent study Studies have shown placebo effec- 26 | THE NERVE ARTICLES

tiveness in disorders ranging from science 1999; 19: 484-94. 53: 679-86. depression to multiple sclerosis 6. Benedetti, F. The opposite effects of the 12. Cereghino JJ, Biton V, Abou-Khalil B, Drei- to Parkinson’s disease. On their opiate antagonist naloxone and the fuss F, Gauer LJ, Leppik I.Levetiracetam own or alongside the medications cholecystokinin antagonist proglu- for partial seizures. Neurology 2000; they are imitating, placebos seem mide on placebo analgesia. Pain 1996; 55: 236–42. to have great potential in helping 64: 535-43. 13. Wilcock, G. et al. Efficacy and safety of patients get safer, more affordable 7. Mayberg et al. The functional neuroanat- galantamine in patients with mild to omy of the placebo effect. American moderate Alzheimer’s disease: mul- References:health care. Journal of Psychiatry 2002; 159: 728- ticentre randomised controlled trial. 37. Galantamine International-1 Study 1. Oken, Barry. Placebo effects: clinical as- 8. Amanzio M. Response variability to anal- Group. British Medical Journal 2000; pects and neurobiology. Brain 2008; gesics: a role for non-specific activa- 321: 1445-9. 131: 2812-2823 tion of endogenous opioids. Pain 2001; 14. Benedetti, F. et al. Loss of expectation- 2. Tuhus-Dubrow, Rebecca. The magic cure. 90: 205-15. related mechanisms in Alzheimer’s The Boston Globe 2010. 9. Pollo et al. Expectation modulates the re- disease makes analgesic therapies less 3. Scott, D.J. et al. Individual differences in sponse to subthalamic nucleus stimu- effective. Pain 2006; 121: 133-44. reward responding explain placebo- lation in Parkinsonian patients. Neuro- 15. Finniss et al. Biological, clinical, and ethi- induced expectations and effects. Neu- report 2002; 13:1383-6. cal advances of placebo effects. Lancet ron 2007; 55: 325-36. 10. Benedetti, F. et al. Placebo-responsive 2010; 375: 686-95. 4. Levine, J.D. et al. The mechanism of pla- Parkinson patients show decreased ac- 16. Lichtenberg, P. The ethics of the placebo cebo analgesia. Lancet 1978; 2: 654-7. tivity in single neurons of subthalamic in clinical practice. Journal of Medical 5. Amanzio, M. and F. Benedetti. Neurophar- nucleus. Nature Neuroscience 2004; 7: Ethics 2004; 30: 551-554. macalogical dissection of placebo an- 587-8. 17. Ader et al. Conditioned Pharmacothera- algesia: expectation-activated opioid 11. OWIMS. Evidence of interferon beta-1a peutic Effects: A Preliminary Study. systems versus conditioning-activated dose response in relapsing-remitting Psychosomatic Medicine 2009. specfic subsstems. Journal of Neuro- MS: The OWIMS study. Neurology 199; 18. London, Jack. The Cruise of the Snark. Brain Research and National Defense

How Neuroscience Funding by the Department of Defense is Going to Revolutionize Science, Technology and Computation by Aisha Sohail

ormed in 1958 in response to tion implemented ARPA with three launched Explorer I on January 31, the successful Soviet launch concrete goals: to get us into space, 1958. Despite breakthroughs in of the Sputnik satellite into protect us from Soviet missile at- military technology such as the un- space, national defense depart- tacks, and develop technology to manned combat air vehicle Boeing ment agency DARPA (Defense Ad- detect Soviet nuclear tests. As a na- X-45, the M16 Assault Rifle, useful vanced Research Projects Agency) tional security agency, DARPA has radars and lasers, DARPA’s discov- has been responsible for research been funded1. . entirely by taxpayer ery of ARPAnet in 1973 is probably into breakthrough, though often money . the agency’s most far-reaching highly speculative military technol- As a result of DARPA-concen- and revolutionary invention as Fogy. The Eisenhower administra- trated efforts, the United States it eventually lead to the develop- FALL 2010 | 27 ARTICLES

ment of the Internet and what we funded by a defense agency should inhibiting pharmaceuticals such as now know as the World Wide Web. stop skirting the ethical issues in- Modafinil that can enhance cogni- Although DARPA’s mission state- volved”. This editorial urges neuro- tion while replacing sleep in order ment has remained the same, the engineers to evaluate synergies be- to build better soldiers. DARPA also agency has undergone a series of tween the goals of military research funds the development of brain name switches between DARPA and neuroscience. The editorial prostheses that allow for more ef- and ARPA as dependent upon ad- also recommends DARPA-funded ficient information 6.processing and ditional responsibilities 2. assumed neuroscientists be more open to storage in subjects . This research during wartime industry . answering questions from oppo- has ignited a new generation of Since then, DARPA has evolved nents of the development of such bioethical and philosophical de- into an agency that supports re- technologies in order to “achieve a bates between the humanists ap- search bordering on the realm of better quality and balance5. with re- prehending a robot apocalypse science fiction. Recent project so- searchers’ engagement” . and the transhumanists hoping to licitations include BaTMAN (Bio- Dr. Jonathan D. Moreno, an eth- achieve a positive Singularity. chronicity and Temporal Mecha- ics professor at University of Penn- A potentially intrusive DARPA nisms Arising in Nature) – which sylvania and editor of Science Prog- patent is one in which a wireless aims to better understand the spa- ress magazine, is another relevant neuroimaging module with por- tio-temporal universe, and, from source on the subject. Dr. Moreno table monitors that offer both neu- there, “transform biology from a published a book titled Mind Wars ronal and vascular signals, which descriptive to a predictive field of in 2006 to review DARPA’s recent would ultimately be capable of science”; and RoBIN (Robustness accomplishments in neuroscience reading the private brain states of of Biologically-Inspired Networks), and offer his expertise on the ethi- its potentially unwilling subjects which aims to, “create a dynamic cal questions posited by defense6 (See DARPA patent # SB031-010 biologically-inspired network of funded neuroscience research . for “Wireless Near-Infrared Devic- scientists and other experts for cri- Along with the Nature edito- es for Neural Monitoring in Opera- sis response3,4. and complex decision rial, Moreno also notes that most tional Environments”). The patent support” . These two projects DARPA-funded neuroscientists are reads: highlight a unique trend in military reluctant to debate the potential “The market for non-intrusive research: the desire to develop a military uses of now extant tech- portable monitoring by means of greater understanding of biology nologies called brain machine in- non-invasive brain monitoring of- to gain advances in national se- terfaces. Dr. Moreno empathizes by fers a most exciting and significant curity. This editorial will examine saying that defense-funded neuro- break-through, impacting many in- how advances in defense-funded scientists have an “understandable dustries. Early adapters are expect- research of brain biology, or neuro- reluctance to jeopardize relation- ed from the military for training science, will revolutionize military ships with research funding sourc- under stress; medical-head trauma technology and all sciences that re- es”, especially with the added sen- evaluations; educational-diagnosis Historyquire intensive of DARPA computation. and neurosci - sitivity to defense disclosures in of learning disabilities; and law ence the post 9/11 and WikiLeaks era. enforcement-for interrogation.“ Given the nature of this research, Moreno concludes his book DARPA-funded neuroscience ap- by encouraging the ethical regula- pears secretive and obscure to the tion of neurodefense technology Many of DARPA’s projects in- public. that could be misused to threaten volve the funding of neuroscience Despite the secretive nature of public health and privacy. The research. A google search of the DARPA researchers, Moreno’s per- American government has already subject reveals several papers ex- sistent exploration into the subject faced significant criticism due to amining the ethical, social, and reveals a history of DARPA-funded reports of torture and other inhu- legal issues posed by the burgeon- neuroscience research that raises mane interrogation tactics at Abu ing field. One such Nature edito- novel ethical, legal, and philosophi- Ghraib and Guantanamo Bay. In a rial titled “Silence of the neuro- cal issues. Past defense projects response to public disapproval, the engineers” spawned in 2003 with demonstrate military interests in Obama administration took efforts the intrepid byline: “Researchers the workings of sleep and sleep- to shut down Guantanamo as one 28 | THE NERVE ARTICLES

of its first acts, and would likewise SyNAPSEpublishable. Project memory resistor, and it works by benefit from conducting open-end- registering how much current8 has ed discussions about neurodefense passed through a circuit . A mem- technologies to prohibit the imple- ristive circuit effectively stores in- mentation of publicly unpopular One of BU CNS department’s formation by measuring the change DARPAdefense andpolicies. Universities more lucrative projects is called the in electrical resistance when cur- Systems of Neuromorphic Adaptive rent is applied. This effect can be Plastic Scalable Electronics, or the compared to a neural synapse, DARPA SyNAPSE project. Featuring which uses electrical gradients In my significant coursework articles in Wired, NewScientist, en- formed by the influx and efflux of at Boston University’s (BU) Cog- gadget, and Singularity magazine sodium and potassium ions across nitive and Neural Systems (CNS) hplus, the program promises to the cellular membrane to transmit department, I have come to no- develop “a brain inspired electron signals. The success of memristor tice that most of the technology ‘chip’ that mimics that function, computation depends significantly research at the department is fi- size, and power consumption14,15,16 of a on the sensitivity of the resistor: a nanced by DARPA. Pooling most of biological cortex” . This chip memristor with a high resistance its money from DARPA, NIH, and will use neuroscience inspired ar- can be interpreted by the computer CELEST (Center for Excellence in chitecture to simulate cognitive as a “1” in processing terms, and a Education, Science, and Technol- abilities such as perception, plan- low resistance can be interpreted ogy funded by the National Sci- ning, decision-making, and motor as a “0”. It would be a bit silly if neu- ence Foundation) the department control. Funds allocated by DARPA rons only had binary outputs to re- accrues roughly $6-7 million dol- to prime contractors HP, HRL, and lay since the number of neurons re- lars a year in funding. This funding IBM have been granted only to BU, quired to compute a simple motor exclusively directs the research of Stanford, and7. a handful of other task would take an infinite amount roughly 25 post-doctoral students laboratories . of time. Needless to say, biological and approximately 40 other grad- One way to develop such a and memristive processing is more uate students. A reliable source chip is through the discovery of efficient than8 traditional binary within the department confirms a memristor, a type of computer processing . that DARPA funding amounts to that uses neuron inspired archi- In the past two years, HP has roughly $2-3 million of the de- tecture to compute. The discovery successfully demonstrated the use partment’s fiscal budget. This fig- of memristors has the potential to of memristors using two layers ure means that a national defense revolutionize the electronics mar- of titanium oxide to create heat- agency directs roughly 50% of the ketplace by allowing for highly ef- induced differences in 9 resistance systems-level neuroscience de- ficient and relatively inexpensive between the two layers . Control- partments’ research, and 25% of computation. Any technology that ling this heat-current allows the the department’s post-doctoral can benefit from faster process- computer to record data. Earlier research. These funds cover the ing that requires less power– cell this year, the work of Dr. Wei Lu at direct and indirect costs of 4 to 6 phones, personal computers, game University of Michigan confirmed post-doctoral researchers involved consoles, supercomputers, robot- that memristors indeed simulate in defense research through CNS. ics, etc. – would ultimately benefit synapses as electrical synaptic According to this source, computa- from the discovery of this missing connections either strengthen or tional neuroscience laboratories at circuit element. Neuroscientists weaken depending on the timing other top-level schools such as MIT will be especially thrilled with the of firing of two memristive circuits. receive even more of their funding ability of such technology to pro- This appears to occur in a Hebbian from military agencies. MIT allows Howcess large does data the sets. memristor hard- fashion – just as two neurons that its defense research to be classi- ware work? fire action potentials concurrently fied, and laboratories such as the are more likely to pass future mes- Draper and Lincoln laboratories sages, a memristive synapse also in Cambridge take full advantage becomes more likely to pass later of that privilege; BU on the other First theorized by Leon Chua messages between two elements hand requires all research to be in 1971, ‘memristor’ is short for that are often simultaneously ac- FALL 2010 | 29 ARTICLES

10 Whytive do. we need memristors? vances in all scientific7 fields, espe- rely on computational devices. As cially neuroscience . Just imagine such, neuromimeticists will prob- that: a brain-inspired device being ably make more money, have more used to discover deeper complexi- media exposure, and accordingly, The current generation of com- Otherties of its implications very inspiration! of faster- acquire even more funding. In fact, putational devices suffers from an than-brain computation this has prediction has already upper threshold for computational proven valid if we perform some efficiency because processors can- simple calculations on the finan- not execute a program faster than cial statistics mentioned earlier: they can fetch instructions for its As a technological retailer, HP’s if 50% of CNS’s funding, or about execution via RAM (Random-ac- primary interest is in the market- $3 million dollars, is distributed in cess memory). Although increasing ing of memristors for cell phones, direct/indirect costs to 5 post-doc- clock speed and transistor density, videogames, computers, etc. For toral defense researchers, each de- and adding processors and fea- the rest of us, however, the creation fense researcher has a crude aver- tures such as cache memory has al- of a mere chip that can compute age of $600,000 in funding (which lowed for an exponential increase better than any human could bear may not seem like a lot, but is en- in computing capacity until now, immense philosophical weight. For tirely sufficient for computational processing beyond the clock speed example, a memristive computer modelers who often do not require of a few gigahertz is still too power- with more synapses than a hu- expensive hardware). On the other expensive. Hence the justification man brain could technically hold hand, CELEST funding amounting for development of memristors: enough associative memories11 to be to a roundabout of $4 million is if we want continued exponential able to pass a Turing test . A Tur- distributed between the other 20 growth of computational processing test employs an interrogator post-doctoral biological research- ing, next-generation devices will who asks written questions to de- ers, which allows for an average need to integrate memory and cide whether its subject is a human of only $200,000 per postdoctoral computation into one step,7 much or machine. Surprisingly, there has researcher. Although these calcula- like a biological SyNAPSE . been no machine to date that can tions are approximate, the glaring The human brain contains convincingly pass the test and suc- contrast between the amount of about 10 billion neurons, and each cessfully mimic a human enough to funding awarded to both parties is neuron is connected to other neu- actually fool one, though the dis- too asymmetrical to be ignored. rons through an average of about covery of the memristor will prob- Despite this pronounced im- 10,000 synapses – a big number, ably change that. balance in funding, I recognize that but a finite number, nonetheless. In addition to this philosophi- my loyalty is to discovering how DARPA’s SyNAPSE project is com- cal weight, neural modelers will brain processes give rise to emer- mitted to scaling memristor tech- also have to bear the financial gent properties such as dreams, nology to biological levels and once implications of such a discovery; emotions, desires, beliefs, and ulti- accomplished, surpassing biologi- many computational neuroscien- mately, consciousness - seemingly cal computation is the next logical tists will be forced to decide wheth- infinite complexities that machines step in the technological revolution7 er they choose to work at designing may never even be capable of re- wrought by memristive devices . neuromimetics (i.e. brain-inspired producing. Neuroscience research- Memristor chips function like technology) or strictly modeling ers may be apprehensive about the flash memory and retain data even neurobiological circuit processes. increasing difficulties for computa- after a computer is turned off while As a young neuroscientist (and tional neurobiologists to compete consuming less energy, requiring self-proclaimed gadget junkie), I with the amount of funding that less silicon and fewer transistors. have to admit myself feeling con- defense agencies can offer to bio- Since individual memristive cir- flicted at times between the two mimetic projects such as remote cuits hold their own memory and fields: I would consider neuromi- sensing software designed for processor, memristors hold the metics a more lucrative field in the PackBot robots deployed in Iraq (as ability to tremendously expedite sense that technologies created engineered by the brilliant minds12 data processing and consequently through it will revolutionize the at BU’s very own CNS Tech Lab) . hold the key to accelerating ad- everyday lives of most people who As we all know, acquiring sufficient 30 | THE NERVE ARTICLES

4. “Robustness of Biologically-Inspired Net- funding for research is the bane of funding could be easily redirected works (RoBIN).” DARPA, Web. 4 October most scientist’s careers. It seems toward developing applications 2010. http://www.darpa.mil/dso/solici- only inevitable that systems level inspired by neural design. Under- tations/sn10-56.htm neuroscience departments will standing complex brain mecha- 5. “Silence of the neuroengineers: Researchers start producing more and more nisms such as consciousness and funded by a defense agency should stop bionic research with little compa- advancing research in organic neu- skirting the ethical issues involved.” Edi- rable growth in biological model- ral circuits will certainly prove use- torial 423.6942 (2003): 787. Web. 24 Aug ing research if developing neuro- ful not only in solving the myster- 2010. morphic technology is considered ies of complex brain diseases such 6. Moreno, Jonathan D. Mind Wars: Brain Re- so much more profitable. as schizophrenia, depression, and search and National Defense. New York, NY So what can we do to change epilepsy, but it will also contribute 10151: The Dana Foundation, 2006. Print. this disparity? The root of the to the human understanding of bio- 7. “The SyNAPSE Project.” 4 October 2010. ce- problem is buried deep within logical networks and how they can lest.bu.edu/outreach-and-impacts/the- the workings of our governmen- be integrated into a “Theory of Ev- synapse-project tal system and the priorities our erything”. Brain mechanisms have 8. Chua, Leon. “Memristor - The missing Circuit government chooses to assign to already proven to be infinitely more Element.” Circuit Theory, IEEE Transac- developing cutting-edge military complex than any artificial intelli- tions on. 18.5 (1971): 507-519. Print. technology as compared to funding gence design we could even dream 9. Dmitri B. Strukov, Gregory S. Snider, Duncan R. biological research. In 2010, DAR- of programming, and it would be a Stewart & R. Stanley Williams. “The Miss- PA’s proposed budget is 3.25 bil- shame to waste any more time in ing Memristor Found.” Nature 453: 80-83. lion dollars, whereas the National determining them. As such, neuro- March 2008. Institute of Mental Health (NIMH) scientists should reserve the right 10. Sung Hyun Jo, Ting Chang, Idongesit Ebong, is appropriated less than half that to question whether their research Bhavitavya B. Bhadviya, Pinaki Mazumder, amount by the NIH. Continuing the is directly relevant to discovering and Wei Lu. “Nanoscale Memristor Device wars in Iraq and Afghanistan is of the processes of the brain and will as Synapse in Neuromorphic Systems.” little everyday concern to most it help people in need? Nano Letters. December 2009. Americans; the research of neural This editorial is not against 11. Turing, Alan. “Computing Machinery and In- dynamics that eventually leads to artificial intelligence inspired by telligence”. 1950. Mind LIX (1950): 236 pp the eradication of schizophrenia neural mechanisms; it is merely 433–460. and depression, however, could po- a suggestion for a separation be- 12. Neurala LLC. Neurala, n.d. Web. 24 Aug 2010. tentially help over 25 million peo- tween biological neuroscience and http://www.neurala.com/ Conclusionple in the United States alone. neuromimetics in order to ensure 13. National Institute of Health: History of Ap- that discovering the laws of neu- propriations.” National Institute of Health, robiology is at the forefront, espe- n.d. Web. 24 Aug 2010. http://www.nih. cially as it becomes more and more gov/about/almanac/appropriations/in- I surmise that the impact that profitable to create technologies dex.htm memristors have on neuroscience References:inspired by neural models. 14. “Are memristors the future of Artifical In- research should generally be a pos- telligence? DARPA thinks so.” Engad- itive one. Allowing for the study of 1. “DARPA’s First 50 years”. DARPA, Web. 4 Oc- get, Web. 4 October 2010. engadget. brain computation at a speed that tober 2010. 4 October 2010. HYPERLINK com/2009/07/14/are-memristors-the- is faster than the speed of brain “http://www.darpa.mil/about.html” future-of-artifical-intelligence-darpa- computation will enable faster data http://www.darpa.mil/about.html think/ processing, and thus, faster output 2 “50 Years of Innovation and Discovery.” DAR- 15. “Synapse on a chip.” Hplus magazine, Web. of research. PA, Web. 4 October 2010. HYPERLINK 4 October 2010. hplusmagazine.com/ar- Nevertheless, the impact DAR- “http://www.darpa.mil/history.html” ticles/ai/synapse-chip PA funding has on neuroscience http://www.darpa.mil/history.html. 16. “Memristor minds: The future of artificial still deserves monitoring as it could 3. “Biochronicity and Temporal Mechanisms intelligence.” NewScientist, Web. 4 Oc- direct resources away from brain Arising in Nature (BaTMAN).” DARPA, tober 2010. newscientist.com/article/ research. As artificial computation Web. 4 October 2010. http://www.darpa. mg20327151.600-memristor-minds-the- becomes faster than the speed of mil/dso/solicitations/sn10-55.htm future-of-artificial-intelligence.html brain computation, neuroscience FALL 2010 | 31 REVIEWS

General Anesthesia:

Molecules to Pink Elephants

by Grigori Guitchounts

32 | THE NERVE REVIEWS

The Drugs and Mechanisms of General Anesthesia by Grigori Guitchounts

Introduction

“ entlemen, this is no humbug,” the surgeon John thetics etomidate and propofol are widely appreciat- Warren is said to have declared to the audience ed for their anesthetizing properties, but are also as- at Massachusetts General Hospital after Wil- sociated with unfavorable toxicities. Patients develop liam Morton’s first successful demonstration1 of gen- “propofol infusion syndrome” after prolonged expo- eral anesthesia on October 16th, 1846. Before then, sure to the drug; this is associated with dysrhythmias, surgery was a miserable experience for both patient lipemia,8 fatty liver, metabolic acidosis, and rhabdomy- and surgeon. The term anesthesia – literally meaning olysis . Etomidate causes adrenal suppression,9 put- “without sensation” – was first used by the ancient ting patients at high risk of mortality . More common Greek surgeon Dioscorides and resurrected by Dr. Oli- side effects include respiratory depression, hypoten- Gver Wendell Holmes after the demonstration at MGH. sion, and postoperative nausea and vomiting. Anesthesia has indeed transformed medicine It is therefore critical for safety and the progress of and while great improvements have been made in medicine that better drugs and methods be developed the clinical aspect of anesthesia since the 1840’s, the for use in general anesthesia. This review focuses on mechanism by which anesthesia produces reversible the goals of general anesthesia, the theories behind its changes in central nervous system function have re- mechanism of action, and studies of the structure and mained a mystery until recently. function of the GABAA receptors that mediate anes- In the past decade, anesthesia has grown to be Goalsthetic action.of General Anesthesia used in various medical settings outside the operat- ing room. Children undergoing Magnetic Resonance Imaging (MRI), Computed Tomography (CT) scans, or endoscopy are often sedated or anesthetized2,3 to assure The basic idea of general anesthesia (GA) is to cooperation and the required immobility . Likewise, make the patient unaware of the surgical trauma and electroconvulsive therapy, long considered more tor- unmoving, and to allow the surgeon to perform his ture than treatment, is now being used with the aid job with precision. More specifically, the goals of GAs of general anesthesia as an effective treatment for are to reversibly induce immobility, amnesia, and hyp- medication-resistant4 depression and schizophrenic nosis (unconsciousness) in the patient; a fourth and affective disorders. often debated goal is analgesia, which some argue is However, despite the multitude of benefits to an irrelevant measure since the patient is unconscious medical procedures that anesthesia has provided, it during anesthesia. remains a somewhat dangerous and toxic5 procedure, The three goals have dissociable correlates in the usually involving postoperative6 delirium and some- brain; amnesia, consciousness, and immobility are times cognitive dysfunction ; even more frightening is mediated by different neural systems and therefore the fact that one in 7750 patients remain aware during respond differentially to drugs. Potency of inhaled general anesthesia . The intravenous general anes- anesthetics is assessed using a scale of concentra- SPRING 2010 | 33 REVIEWS

tions required to suppress patient response to certain ing (fMRI) studies show that the brain regions13 affected stimuli. Potency is inversely related to the amount of by sleep or anesthesia overlap significantly . Studies anesthetic required – as measured by alveolar concen- of the brain during sleep may therefore inform what tration – to reach certain behavioral goals like immo- we know of GA-induced unconsciousness. bility after a noxious stimulus or no response to spo- The thalamus acts as a major relay center in the ken commands. The most commonly used scale is the brain, passing sensory20 information from the outside Median Alveolar Concentration (MAC or MAC-immo- world up to cortex . In the awake brain, thalamocor- bility), which measures end-respiratory concentra- tical neurons receive depolarizing input from arousal tion of anesthetic for which half of the patients10 do not nuclei in the ventrolateral preoptic area, VLPO, which withdraw in response to a surgical incision . Other allows them to faithfully pass along information to21 common scales include MAC-awake, a concentration cortical neurons in a single-spike tonic firing fashion . that prevents physical response to spoken comments, In contrast, during sleep the ascending arousal input such as to squeeze the doctor’s finger; and MAC-BAR, to thalamocortical cells is inhibited. Thalamocortical a concentration of anesthetic that blocks autonomic cells lacking this depolarization enter20 an oscillatory responses like blood pressure or heart rate changes to firing mode, generated by Ih and ICa , which subse- a surgical incision. quently prevents the transmission of signals to cortex. That the behavioral end-goals of amnesia, uncon- The most obvious similarities between sleep and sciousness, and immobility require different concen- loss of consciousness under anesthesia aside, the trations of anesthetics (i.e. they have different MAC two states share nearly identical EEG signatures (i.e. values) and that the ratios of MAC-awake to MAC-im- spindles and delta waves), suggesting that the thala- mobility vary among different volatile anesthetics10, mus is involved in sleep13 as well as anesthetic-induced suggest that the three behavioral end-goals are medi- loss of consciousness . However, general anesthetics Immobilityated by different neural mechanisms. do have widespread molecular targets, such as GAB- AA receptors, which are found in a large number of inhibitory cortical interneurons. It remains unclear whether their effects in the thalamus (specifically on A common assumption has been that all anes- the reticular system) are necessary and/or sufficient thetic effects are mediated by the central nervous Amnesiafor loss of consciousness. system (CNS) above the brainstem. However some studies have implicated the spinal cord as key to producing immobility. Experiments in goats, whose unique circulatory system makes it possible to isolate The hippocampus and surrounding medial tem- the forebrain’s circulation from that of the brainstem poral lobe (MTL) structures are responsible for the22 and spinal cord, have shown that immobility11 is in fact formation and consolidation of episodic memories . produced primarily by the spinal cord. Selective The hippocampus is therefore a likely target of gener- administration of isoflurane to the brain raises the al anesthetics. The formation of memory depends on concentration required to suppress 12movements in re- the integrity of Long Term Potentiation (LTP), which sponse to noxious stimuli threefold . In contrast, ad- requires functioning NMDA receptors. It follows that ministration of isoflurane to only the body (brainstem inhibition of NMDA receptors by general anesthetics, and below) induces immobility at the concentrations such as cyclopropane and ketamine, would impair required for whole animals. So while the brain is able memory. Some studies also implicate the amygdala, to induce immobility, it is not required, nor is it the which processes affective information23 and is strongly Hypnosisprimary actor. THEORIESconnected to OF the ACTION hippocampus .

Lipid vs. Protein

Hypnosis is defined as the impairment of perception and awareness, or loss of consciousness10 – a critical component of general anesthesia . Loss of At the beginning of the 20th century, Hans Meyer consciousness in anesthesia is remarkably similar to and Charles Overton observed a correlation between stages of sleep. Functional magnetic resonance imag- the potency of anesthetic agents and their solubility 34 | THE NERVE REVIEWS

THREE GROUPS OF ANESTHETICS in olive oil. The Meyer-Overton rule predicts that the more hydrophobic the anesthetic, the higher its potency. From the Meyer-Overton rule, it followed that General anesthetics have been classified into all anesthetics must act through a common mecha- three groups based on their relative potencies for be- nism, probably in the cell membrane, which is a hy- Grouphavioral 1: endpoints Etomidate, and propofol, effects on and the barbiturate EEG. drophobic lipid bilayer, and that anesthetics somehow disrupt that bilayer. And while most people agreed s that the final result of the perturbation of the cell membrane was a conformational change in the struc- Etomidate, propofol, and barbiturates produce ture of membrane proteins, none13 of the lipid theories amnesia and hypnosis at doses far lower than those explained how this could happen . for immobility (reviewed in ref 17). These drugs act It was not until the latter half of the 20th century via GABAA receptors, the most abundant inhibitory that research emphasis turned to the interactions be- ligand-gated ion channels in the brain. Convincing tween anesthetics and proteins themselves.14 In an im- evidence for their action via GABAA receptors comes portant set of experiments, Franks andAs Lieb many showed asfrom one mutation in and transgenic animal studies. that the lipid-free enzyme lu- Etomidate’s action via GAB- ciferase could be inhibited by 750 patients remain AA receptors has been confirmed18 anesthetics following the Mey- in studies utilizing its chirality . er-Overton rule: the higher the aware during general R(+)-etomidate is 20 times more hydrophobicity of the anesthet- potent at inducing Loss of Right- ic, the more potently it inhibit- anesthesia ing Reflex (LORR) in animals, a ed luciferase. While anesthetics surrogate test of consciousness, target diverse10 molecules, such than S(-)-etomidate. Likewise, as PKC , transmembrane ion the R(+) enantiomer modulates channels have received the most attention. Research GABAARs 20 times more potently than does the S(-) since then has focused mostly on the hypothesis that enantiomer. anesthetics enhance the action of inhibitory ion chan- Moreover, mutations on the GABAAR subunits af- nels (GABA and glycine receptors) and inhibit excit- fect GABAAR electrophysiology and in vivo respons- atory ion channels (Serotonin type 3; nicotinic ace- es to anesthetics similarly. For example, mice with a tylcholine; and glutamate receptors). For example, methionine residue in place of asparagine at the 265 electrophysiological studies have shown that the GAB- position on the β3 subunit exhibited a four-fold reduc- AA receptor is a major target of intravenous15 general tion in sensitivity to propofol and etomidate anesthe- anesthetics, such as propofol and etomidate . sia, specifically immobility. The same point mutation Current work is focused on the structure-function reduces anesthetic modulation of the receptors in relationships of the target ligand-gated ion channels electrophysiology studies. The same mutation on the (i.e. how the molecular structure of a receptor me- β2 subunit did not affect17 immobility or hypnosis, but diates its ion-conducting function) in order to eluci- reduced sedation in mice . Furthermore, mice lacking date the molecular mechanism by which such chan- α5 GABAAR subunits19 were insensitive to emotidate’s nels open and close; and the sites at which anesthetic amnesic effects . And while the β3(N265M) mutation agents bind and affect those channels. While the reduces hypnosis and immobility response, it pre- former has been of interest to the entire neurobiol- serves the undesirable effect of respiratory depres- ogy community since the 1950’s, when Hodgkin and sion, showing that GABAARs are not etomidate’s only Huxley proposed a model of the action potential that Grouptarget in 2: the Nitrous body. oxide, cyclopropane, and ket- depended on a 16mystical conduction of ions across the amine cell membrane , the latter promises the more practical improvement of clinical outcomes for patients undergoing general anesthesia. With the elucidation of the pharmacologic interactions between proteins and Drugs in Group 2 act mostly via glutamatergic anesthetics, researcher-physicians may soon have at NMDA receptors, as opposed to GABA receptors. Glu- their disposal better drugs that produce minimal side tamate is the most abundant excitatory neurotrans- effects and toxicity. mitter in the brain, so it’s no surprise that inhibition FALL 2010 | 35 REVIEWS

of glutamate receptors would produce anesthetic ef- function of the nAChR began27,28,29,30 with the studies of the fects, which among the Group 2 drugs 17are mostly an- Torpedo electric ray nAChR . Electron micros- algesia, weak hypnosis and immobility . copy revealed that the receptor is composed of five As with etomidate, ketamine chirality has been subunits organized around a central pore. Molecular used to correlate its anesthetic effects with NMDA cloning showed that each subunit consists of four receptor modulation. S-ketamine was 1.9 times more α-helical transmembrane domains (TM1-4). TM2 potent in inhibiting NMDA receptors in hippocampal lines the pore, TM1 and 3 are next to it, and TM4 faces slice preparations than was17 R-ketamine; the same ef- the membrane. Importantly, TM2 is able to interact fect was observed in vivo . with hydrophilic molecules since it faces the water- Horace Wells noted nitrous oxide’s (NO2, “laugh- permeable pore, while the other transmembrane do31- ing gas”) analgesic properties while attending a mains interact with the hydrophobic cell membrane . demonstration in 1845; Wells’ own demonstration Advances in genomics have produced large li- of nitrous oxide’s anesthetic properties at MGH was braries of eukaryotic and prokaryotic genes that are deemed a failure. Transgenic animal studies have available for analysis. Interestingly, these libraries shown that NO2 also acts via NMDA receptors. Trans- have brought to light a large number of cys loop 32 / genic mice lacking the ε1 subunit (homolog of the pentameric LGIC genes conserved in prokaryotes . human NR2A) of the NMDA receptor do not exhibit One such advance was the discovery of the Acetyl- immobility or24 loss of righting reflex under NO2 ad- choline Binding Protein (AChBP) found in the snail ministration . Lymnaea stagnalis, where it mediates neurotransmis- However, using an NMDA antagonist MK-801, sion. Even though AChBP is water-soluble and lacks Stabernack et al. showed that inhibition of NMDA the transmembrane domain of mammalian nAChRs, receptors is not sufficient to produce anesthesia. Ad- it nonetheless forms a homopentamer33 with distinct ministration of MK-80125 alone reduced MAC but did acetylcholine and nicotine binding sites . As expected Groupnot produce 3: Halogenated immobility volatile. anesthetics from prior experiments, ligand binding occurs at the interface between subunits, with different affinities for acetylcholine, nicotine, and the agonist carbamylcholine. While ligand binding induces local confor- The halogenated volatile anesthetics, usually iso- mational changes, studies of signal transduction in a flurane, sevoflurane, desflurane, and halothane, are system that lacks the transmembrane domain that is the least selective of the general anesthetics. These integral for the study of channel gating have to be in- anesthetics affect the GABAARs, two-pore K+ chan- terpreted with caution. nels, NMDA and26 5HT3 receptors, Na+ channels, and In contrast with AChBP, which is a good model for STRUCTUREother targets . AND FUNCTION OF CYS-LOOP LI- the extracellular domain of the nAChR, the Erwinia GAND-GATED ION CHANNELS chrysanthemi (ELIC) and Gloebacter violaceus (GLIC) channels reveal the minimal structural requirements for a functional LGIC in the Cys-loop family. Even though ELIC and GLIC share only 16% and Studies show that the GABAA receptor is a major 20%, respectively, of the sequence with 34,35 the nAChR, target of halogenated volatile anesthetics and intrave- their structures are remarkably similar . GLIC is nous anesthetics such as etomidate and propofol. The activated by protons, while ELIC’s activating ligand GABAAR is a member of a large family of ligand-gated has not been discovered yet. The X-ray crystallogra- ion channels known as the cys-loop family for the cys- phy structures of ELIC and GLIC are valuable because teine loop that all family members share; other mem- they are thought to show the closed and open confor- bers include the 5HT3, glycine, and nACh receptors. mations of the protein, respectively. Hilf and Dutzler Most of what is known about the structure of the GAB- suggest that the difference in the two conformations AAR comes from studies of the nicotinic acetylcholine can explain the mechanism of gating (channel open- Nicotinicreceptor. Acetylcholine Receptor ing). Specifically, it is the difference in orientation of TM2 and TM3 α helices and the extracellular β sheet between the GLIC and ELIC structures that Hilf and Dutzler base their hypothesis on. Serious investigation into the structure and Similar to the pores of other cation channels, the 36 | THE NERVE REVIEWS

GLIC pore-lining TM2 domain is composed of hydro- Ligand binding is described in terms of an alloste- phobic bulky residues; the intracellular half is filled ric model in which ligands bind and affect the protein with polar residues such as serine and threonine, at sites distinct (and sometimes far) from the GABA making this part of the pore hydrophilic. Cation selec- site. These allosteric sites may be found in the extra- tivity arises most likely from a conserved ring of glu- Extracellularcellular and transmembrane Domain domains of the GABAAR. tamate residues on the intracellular end of the pore; this “intermediate ring of charges”36 is also found in the Torpedo and muscle nAChR . GABAARs have two binding sites for GABA, each in GABAA Receptors the extracellular domain at the interface between the α and β subunits47; GABA binding at these sites opens the Cl- pore. Baumann et al used point mutations on The GABAA receptor is the major inhibitory li- linked subunits to differentiate the contributions of gand-gated ion channel in CNS neurons, found in all each site to channel gating (using free subunits does layers of the cerebral cortex, the hippocampus and the not indicate which of the two α/β interfaces has the rest of the limbic37 system, the cerebellum, thalamus, desired mutation), showing that the α/β site where α and brainstem . The receptor is composed of five sub- is adjacent to γ is more sensitive to GABA; and con- units arranged pseudosymmetrically around a central versely that the α/β site where β is adjacent to γ is ion-conducting pore. Nineteen subunit varieties have more sensitive to the48 competitive antagonists bicucul- been cloned to date, which theoretically allows for a line and muscimol . tremendous38 amount of diversity of expressed recep- Classic benzodiazepines enhance37 inward cur- tors . However, not all possible combinations have rents produced by GABA binding . Benzodiazepines been found assembled, and indeed the majority of bind with high affinity at the interface between α and the neuronal37 receptors are composed of α, β, and γ γ subunits, sites homologous to GABA’s at the two subunits . Nevertheless, the abundance of subunit αβ interfaces. Rusch and Forman showed that ben- varieties, as well as subunit-dependent localization of zodiazepines enhance GABA currents by enhancing the receptors in the brain39 make GABAARs a promising GABA gating as opposed to binding. Using the Monod- target for drug discovery . Wyman-Changeux allosteric model, they were able to Upon activation by GABA, the receptor pore con- conclude that benzodiazepines are high-affinity but ducts Cl- and bicarbonate ions, hyperpolarizing the low-efficacy co-agonists, in stark contrast to general neuron and thereby reducing the action potential fir- anesthetics such as etomidate,43 which are low-affinity ing rate. GABAARs are thought to be the major target high-efficacy agonists . The differences between ben- of several general40,41 anesthetics, including etomidate, zodiazepine and etomidate agonism are further high- propofol,42 alcohols , halogenated43 volatile anesthet- lighted by single-channel studies. These studies show ics , and barbiturates . The understanding of how that etomidate lengthens the mean single-channel these and other drugs affect the GABA receptor is open time, whereas benzodiazepines do not; although essential for improvements in anesthetic drugs and single channels did open more frequently49,50 in the pres- Structuretreatments of CNS diseases. Transmembraneence of benzodiazepines Domain or etomidate .

Using a forced subunit assembly method, Sigel A diverse set of organic compounds has been and colleagues determined that receptors composed shown to act by binding to sites in the GABAAR40 trans- of α1β2γ2 subunits (the major isoform) are arranged membrane51 domain. These52 include alcohols 42, neuros- γ2β2α1β2α1 counterclockwise44 when viewed from the teroids , barbiturates53,54 , volatile anesthetics , etomi- synaptic cleft . Each of the five subunits making up Alcoholsdate, and propofol . a GABAAR contains a large N-terminal domain, four transmembrane domains (TM1-4) and45 an intracellular domain between TM3 and TM4 . The receptor conducts ions in an all-or-none fashion, transitioning Alcohols40 enhance GABA-induced currents in αβγ among the open, closed, and desensitized states46. GABAARs , and reduce currents in receptors with FALL 2010 | 37 REVIEWS

41 ρ1 subunits . Mihic et al (1997) constructed chime- is bulky and hydrophobic like etomidate), α1M236W ric receptors containing sequences from the GABA ρ and β2M286W, mimic etomidate presence. Stewart subunit and the glycine receptor α1 subunit (a close et al used these mutations to show that one class58 of homolog of αβγ GABAAR). They were able to identify sites is sufficient to explain etomidate’s effects. The a region of 45 amino acids between TM2 and TM3 β2M286W mutant was insensitive to etomidate direct that are necessary and sufficient for enhancement of activation and had zero GABA enhancement by etomi- currents by ethanol and enflurane. Specifically, the date, consistent with one type of modulatory site. α1S270 and β1S265 in the TM2, as well as α2A291, In contrast, the α1M236W mutant showed reduced β1M286, and β3N265 in the TM3, were critical to eth- GABA potentiation by etomidate compared to wild- Barbituratesanol’s enhancement of GABA currents. type but increased direct activation. These opposite effects seem to suggest two classes of etomidate sites, but are nevertheless consistent with the interpretation of one class of sites: etomidate’s efficacy is re- Barbiturates are CNS depressants, and have been duced in the α1M236W mutant, but direct activation used through the 20th century to treat conditions appears to be enhanced because the mutant has high such as insomnia, anxiety and epilepsy; and in the OR spontaneous activity, which lowers the energy barrier as inducers of anesthesia (their history is reviewed in required for channel opening. ref 55). Like etomidate, pentobarbital enhances GABA Propofol has been thought to act near the TM2 currents at low concentrations and52 activates GAB- domain at α1Ser270/β2Asn265 and TM3 domain at AARs directly at high concentrations ; at even high- α1A291/β2M286. Cysteine protection experiments er concentrations (millimolar) pentobarbital blocks showed that propofol protects all four of these resi- EtomidateGABA currents. and Propofol dues, but only β2M286 in a dose-dependent manner,59 implicating this residue as the propofol binding site. However, Siegwart et al showed that the mutants β3M286W as well as β3N265M significantly reduce At clinically relevant concentrations, the potent propofol enhancement53 of GABA currents and direct intravenous anesthetic etomidate enhances activation activation by propofol. Propofol’s varying effects on of GABAARs by GABA (lowers EC50) . This interaction receptors composed of different forms of the β sub- directly activates GABAARs56 at higher concentrations, Newunit may or Improved be useful inDrugs drug discovery or modification. in the absence of GABA . These two types of activation suggest that GABAARs have two types of etomidate sites – high-affinity sites that enhance GABA sensitivity and low-affinity sites that directly activate the Going forward, two major branches of research receptor. These observations suggest an orthosteric must be pursued to ensure success in the develop- model where etomidate binds to the same site as GABA ment of new anesthetic drugs. These are the study of to directly activate the receptor (and an allosteric site the structure and function of LGICs, as well as their to enhance GABA activation). However, using electro- subunit compositions and localization in the human physiological methods and the Monod-Wyman-Chan- brain; and drug discovery, including high-throughput geux allosteric model, Rusch et al. (2004) showed that assays of novel agents and chemical modification of a single class of sites can explain both enhancement existing drugs such as etomidate. and direct activation, concluding that etomidate’s af- Efforts to improve etomidate include methoxy finity for the receptor changes depending on the re- carbonyl- (MOC-)etomidate, which is designed60 to ceptor’s state (open or closed); the open receptor has be metabolized quicker than etomidate and car- a high affinity for etomidate,56 whereas the closed re- boetomidate, which is a significantly61 weaker inhibi- ceptor has a low affinity). tor of adrenal cortisol synthesis . The goal of these Evidence that etomidate acts at the interface of chemical modifications is to remove etomidate’s toxic the α and β subunits comes from experiments using properties while preserving the anesthetizing ones. a photoactivatable etomidate analog, [3H]azi-etomi- Another approach is drug discovery. Recently, Lea date, which labels57 the amino acids αM236 (TM1) and et al (2010) reported a high-throughput screening of βM286 (TM3). compounds that interact with apoferritin, a soluble Mutations of these residues to tryptophan (which protein that mimics the GABAAR’s interaction with an- 38 | THE NERVE REVIEWS

62 7. Forman SA. Awareness during general anesthesia: concepts and contro- esthetics. Of 1280 compounds, about 1% were hits. versies. Semin Anesth Perioperat Med Pain. 2006;25:211–218. Obviously further electrophysiological, metabolic, and 8. Corbett SM, Montoya ID, Moore FA: Propofol-related infusion syndrome clinical characterizations are necessary before any of in intensive care patients. Pharmacotherapy 28:250, 2008 Conclusionthose compounds can be used as general anesthetics. 9. Wagner RL, White PF, Kan PB, et al: Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med 310:1415, 1984 10. Campagna, J. A., Miller, K. W. & Forman, S. A. Mechanisms of actions of inhaled anesthetics. N. Engl. J. Med. 348, 2110–2124 (2003). While surgeons and patients have enjoyed the 11. Antognini JF and Schwartz K. Exaggerated anesthetic requirements availability of general anesthesia for over 150 years, in the preferentially anesthetized brain. Anesthesiology 79: 1244- scientists have not made progress in elucidating its 1249. 1993. mechanism of action until quite recently. That para- 12. Collins et al Anesthetic actions within the spinal cord: contributions digm shift came in the 1980s, when Franks and Lieb to the state of general anesthesia. Trends Neurosci. 1995. 18:549-53 showed that anesthetics act via proteins, not the lipid 13. Franks NP. General anaesthesia: from molecular targets to neuronal membrane; research since then has focused primarily pathways of sleep and arousal. Nature Reviews Neuroscience. 2008 on ligand-gated ion channels that mediate fast synap- volume 9 370-384 tic transmission in the CNS. 14. Franks NP and Lieb WR. Do general anaesthetics act by competitive Numerous techniques are available for the study binding to specific receptors? Nature 310, 599 – 601. 1984. of the structure and function of LGICs, including elec- 15. Franks NP. Molecular targets underlying general anaesthesia. British tron microscopy, cysteine substitution, point muta- Journal of Pharmacology. 147, S72-S81. 2006. genesis, and x-ray crystallography. Our current con- 16. Hodgkin AL, Huxley AF. A quantitative description of membrane cur- ception of the 3D structure of the GABAAR is largely rent and its application to conduction and excitation in nerve. J based on x-rays of the nicotinic acetylcholine recep- Physiol. 1952 Aug;117(4):500-44. tor and its homologs. While the overall structure ap- 17. Solt K and Forman SA. Correlating the clinical actions and molecular pears to be conserved among the Cys-loop receptors, mechanisms of general anesthetics. Curr Opin Anaesthesiol. 2007. the fine details (including single amino acids) are dif- 18. Belelli D et al. The in vitro and in vivo enantioselectivity of etomidate ferent. 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Plos One. 2009; 4(9): e7150.

40 | THE NERVE Decoding the human memory network: A brain mapping approach to spatial navigation by Evan Marc Stein

he resection of Patient H.M.’s bilateral medial els, but a confounding problem with animal studies temporal lobe (MTL) structures in 1957 pro- on episodic memory is that animals cannot explicitly duced a deficit in encoding new episodic mem- describe their declarative experience after perform- ories, leaving short-term memory, non-declarative15 ing their task, which is a critical aspect when studying memory, and other cognitive functions intact . The declarative memory. discovery of the relationship between MTL damage In a study 40to provide a solution to this problem, and the development of anterograde amnesia has pro- Schenden et al. used fMRI and a serial reaction time vided evidence that these areas are responsible for task (SRTT) to actively test both hypotheses in hu- memory processes. Animal models have also support- mans by seeing if the activation of the MTL is depen- Ted the hypothesis that these areas play a major role dent on the subject’s conscious awareness of learning in memory function, using lesion methods that have sequences. As predicted by the declarative memory replicated H.M.’s bilateral damage to20 the hippocampus hypothesis, the MTL structures should not be activat- and the surrounding MTL cortices . Although animal ed when a subject is unconsciously aware of learning a models of memory research have provided ample evi- sequence of events. In favor of the relational memory dence in support of this hypothesis, the development hypothesis, this study provided significant fMRI evi- of human brain mapping techniques, such as func- dence that the hippocampus is activated regardless of tional magnetic resonance imaging (fMRI), positron the subject’s conscious awareness when learning high- emission tomography (PET), diffusion tensor imaging er order sequences during the SRTT. Since the SRTT (DTI), magnetoencephalography (MEG) and transcra- has both spatial and temporal memory components, nial magnetic stimulation (TMS), allow researchers the activation of the hippocampus during sequence to apply the findings from animal studies and Patient learning, regardless of the subject’s conscious aware- H.M.’s case to investigate both spatial and temporal ness, supports the hypothesis that the hippocampus is aspects of the neural network underlying the human involved in binding sequential information and events memory system, and more specifically, the role of this into a distinct episodic experience. These studies thus memory network in spatial navigation. provide evidence that hippocampus, along with the Due to the evidence provided by animal studies, surrounding MTL structures, are involved and criti- clinical cases and H.M.’s case, two hypotheses regard- cal for learning associations of both spatial and non- ing the role of MTL structures in declarative mem- spatial stimuli across time and for learning sequences ory have been suggested. The declarative memory44, of events. Though these findings suggest a role of hypothesis, proposed by Squire and Zola-Morgan the MTL in association and sequence learning, these posits that the MTL is critical for declarative memo- studies have yet to find the role of the MTL in disam- ry processes only, whereas non-declarative memory biguating between overlapping sequences of episodic components engage areas outside14 of the MTL. Two events. years later, Cohen and Eichenbaum proposed a com- The role of the MTL in encoding and retrieving peting relational memory hypothesis, stating that in overlapping experiences both spatially and non-spa- addition to being crucial for declarative memories, the tially have been further studied in animals using in- MTL structures are also important for acquiring asso- vasive techniques including single-cell recordings and ciations among items together in time or across time selective MTL lesions. With accumulating evidence and for encoding sequences of episodic events. Sev- that the hippocampus is involved in encoding infor- eral studies have been performed using animal mod- mation about different types of episodic experiences SPRING 2010 | 41 REVIEWS

45 in the same location, Wood et al. studied the aspect (odors 5a and 5b). This finding suggests that at the of encoding overlapping spatial experiences in rats by critical choice point, the hippocampus is required to using a T-maze alternation task in combination with recall information from the earlier segment of the se- single-cell recordings of the hippocampal CA1 pyra- quence in order to successfully disambiguate between midal cells. Taking into account the number of hip- sequences after experiencing the overlapping ambig- pocampal neurons that are specifically influenced by45 uous component (odors 3 and 4). The findings from running, head and movement direction, Wood et al. these animal studies suggest and support the hypoth- found that two-thirds of the cells fired differentially esis that the hippocampus is critical for encoding and when the rat was traversing through the common, retrieving the information necessary to disambiguate central stem of the maze for both left- and right-turn between overlapping episodic representations of spa- trials. Significant differences between cell firing rates tial and non-spatial events. Given the significant evi- for both left-and right-turn trials provided evidence dence provided by these important animal studies, in- that CA1 cells show a selective response for both loca- vestigators sought to apply these findings to study the tion and context of the trial type, despite the overlap- role of human MTL in the encoding and disambiguat- ping components of animal’s behavior29 and pathways ing between overlapping representations of events by traveled. In 2007, Lipton et al. investigated the role using human brain mapping techniques. of the dorsocaudal medial entorinal cortex (dcMEC) An advantage of fMRI research, as opposed to neurons in the disambiguation of overlapping45 spatial animal studies, is that fMRI provides investigators experiences. Similar to Wood et al.’s study, rats were with a non-invasive tool to obtain a high spatial, but trained to perform a T-maze alternation task; how- moderate temporal resolution of brain activity when ever, in addition to recording the activity of the CA1 subjects engage in cognitive tasks. These important neurons, they also recorded the activity of the dcMEC techniques allow researchers to spatially map and neurons while the rats were performing this task. An locate what brain regions are active relative to the interesting robust pattern of firing of the dcMEC neu- task the subjects are performing. With regard to the rons, more so than the CA1 neurons, exhibited speci- MTL and its involvement38 in sequence learning and re- ficity for distinguishing between trial-types (left- and trieval, Ross et al. applied fMRI to investigate if the right-turn trials), whereas the CA1 neurons showed role of the human hippocampus in sequence learn- a stronger response to the location of the rat within ing and sequence retrieval. During the scan, subjects the T-maze. These findings support the MTL’s role in encoded and learned two overlapping (OL) and two encoding and disambiguating between overlapping non-overlapping (NOL) sequences, each consisting of spatial events. 2 six cropped faces per sequence. In addition to the four Agster et al. provided complementary evidence conditions, two random groups of six randomly pre- that the hippocampus is also involved in the disambig- sented faces were also intermixed to serve as controls uation of overlapping events with non-spatial stimuli. for this study. Importantly, post-scan tests revealed In this study, rats were presented with two alternat- that there was no significant difference between dif- ing partially overlapping sequences of six odors. ficulty and number of errors made in each condition Both sequences began with a distinct odor (odor 1a (100% correct in OL, 98.6% correct in NOL), thus or 1b) followed by another distinct odor (odor 2a or showing that the subjects successfully learned each 2b), indicating what sequence they were going to fol- sequence. Analyzed fMRI data showed hippocampal low (either sequence a or b). Odors 3 and 4 in both activation regardless of the degree of overlap of infor- sequences were kept constant to provide the degree mation, thus suggesting a role of the hippocampus in of overlap and ambiguity between the two sequences. both encoding and retrieval memory processes. Fur- Odors 5a and 5b were used as a test probe, known as ther analysis provided evidence that there was great- the critical choice point, to indicate whether or not er hippocampal activity for OL than NOL condition in the rats could successfully disambiguate between the both the encoding and learned phases of the study, two partially overlapping sequences. By comparing as well as greater hippocampal activity for OL than the performance of the control rats to the rats with NOL at the critical choice phase. These findings sug- selective hippocampal lesions, experimenters found gest that overlapping sequences of events demands that rats with hippocampal damage were significantly a greater activation of the hippocampus during re- impaired when attempting to successfully disambigu- trieval because participants are required to recall the ate between sequences at the critical choice point necessary information from the earlier component of 42 | THE NERVE REVIEWS

5 the sequence to successfully disambiguate between ing the retrograde tracer horseradish peroxidase . overlapping episodic events. 28 Barbas and Blatt5 identified ipsilateral projections In a similar study, Lehn et al. hypothesized that from the hippocampal complex (hippocampus, pre- the MTL is sensitive to recalling naturalistic sequence subiculum, and parasubiculum) to distinct areas in of events, and aimed to evaluate the contribution of the the lateral, medial and orbital PFC. Further analysis of subregions in the human MTL to the recall of temporal their results have shown that the medial PFC receives sequences of related events. To test their hypothesis, the most input from the hippocampal region, suggest- participants watched a novel movie depicting “true- ing the role of the medial PFC in mnemonic processes. to-life” characters and “life-like” events, explicitly tell- Outside of the MTL, anatomical connectivity studies in ing them that they would be tested on this informa- rhesus monkeys have identified projections from the tion the next day. During the scan, participants were early and late stages of sensory processing cortices to presented with four scenes, either from different time both the PFC and the OFC, suggesting that these areas points (retrieve/reconstruct test) or close together in integrate, converge and communicate the necessary time (infer/logic test), from the movie and then were information4 for constructing and retrieving episodic asked to place them in the correct order in which they memories . occurred. After each test, subjects reported their level In humans, white matter connections, integrity, of effort (1 = little effort, 5 = a lot of effort) and the degree of diffusivity and the direction of diffusion strategy they used to reconstruct the sequences of along white matter tracts can be assessed using DTI. In events (remembered the order, used logic, or other). a study of the relationship between episodic12 memory Intermixed with these two test conditions, a control and white matter integrity, Charlton et al. measured condition asked the subjects to evaluate a simple the mean diffusivity (MD), fractional anisotropy (FA) math equation. The results from this study showed and white matter hyper-intensities (WMH) of the dis- a significantly greater activation of the hippocampus tributed network of white matter pathways support- and the parahippocampal cortex (PHC) during the ing episodic memory in normal aging participants. Re- retrieve test when compared to the infer and control sults revealed a significant decrease in immediate and tasks. In combination with the behavioral reports, delayed memory performance, as well as a decrease in activity in the right hippocampus was positively cor- FA and an increase in MD and WMH as age increased, related with the accuracy of sequence recall, whereas further supporting a similar finding from a DTI study the bilateral PHC activation did not. Most importantly, on the relationship31 between white matter and LTM in when comparing the data from the retrieve to the in- adolescents . Interestingly, this study showed that fer tasks, significant bilateral activation of the hippo- hippocampal volume did not decrease when com- campus and the PHC during the retrieve trials reflects pared to baseline, thus suggesting that hippocampal various mnemonic processes including the retrieval atrophy does not significantly contribute to LTM de- of temporal order, recollection of spatial and non- cline in normal aging subjects. This finding suggests spatial contexts, and scene and landmark6, 27, 16, 42, 25, recognition, 18 that memory decline is not specifically related to hip- concurrent with similar studies . Though pocampal atrophy, but may be attributed to the re- these findings of MTL activation for different aspects duction of integrity of the white matter connections of sequence learning and retrieval have implied that between the PFC and the MTL. Though these anatomi- these structures are critical for encoding and integrat- cal connectivity studies identified that the PFC, OFC, ing episodic events across time, perception, attention, sensory cortices, and MTL structures communicate executive function and connectivity studies have pro- critical information for normal memory functioning, vided insight to a network of areas outside of the MTL the specific role of these areas and their contribution that also importantly contribute to the support8, 10, of3 nor- to navigational processes were later investigated. mal functioning of these memory processes . Computational models of the PFC’s involvement In order to understand the network involved in in- in goal-directed actions and connection to the hip- tegrating various types of sensory information into an pocampus provide evidence that these areas must episodic experience, we must investigate the anatomi- integrate and communicate information in24 order to cal and functional connections of MTL to surrounding successfully navigate a spatial environment13 . In sup- cortices. Similar to the human prefrontal cortex (PFC), port of these models, Churchwell et al. studied the anatomical connections of prefrontal cortex (PFC) in prefrontal-hippocampal pathway in rats and its role rhesus monkeys to the MTL have been identified us- in the navigation of a modified Hebb-Williams maze. FALL 2010 | 43 REVIEWS

To test the contribution of the medial PFC, OFC and contexts, its role in spatial navigation appears to be the hippocampus in spatial navigation, researchers evident. However, when studying the OFC in humans, utilized a deactivation procedure involving lidocaine PET has been shown to be advantageous when com- infusion to these specific areas. Rats with deactivated pared to fMRI. Studies have proven that fMRI is sus- medial PFC, as well as rats with deactivated hippocam- ceptible to signal-loss as a result of the sinus cavities pal cortex, were significantly impaired when encoding in this area, thus making it difficult to investigate the and retrieving the necessary information to success- OFC’s contribution21 to memory processes. Frey and fully navigate through the maze to the goal box. How- Petrides utilized PET, an invasive imaging technique ever, the rats with OFC deactivation did not show any that involves the injection of a radioactive isotope, to disruption of memory processes, suggesting a disso- examine OFC activity while subjects encoded abstract, ciation of function in spatial navigation between the non-spatial, non-verbal drawings. The researchers “aOFC and confounding medial PFC. These findings suggest that problem the hypothesized that with if the demand animal for active encoding studies on episodic memory is that animals cannot explicitly describe their declarative experience”

interaction of the medial PFC and the hippocampus is increases, activity of the OFC must increase as well. critical for encoding and retrieving crucial contextual Four encoding conditions were implemented, ranging information, concurrent with evidence from an11 MEG from a minimal, control encoding task (condition 1) to study on the prefrontal-hippocampal pathway . Al- a maximal encoding task (condition 4). In conditions though there is an ample amount of evidence from an- 1 and 2, subjects viewed random single presentations imal studies showing that33, the45, 20, hippocampus 2, 29 is critical of familiar stimuli, whereas in conditions 3 and 4, for in spatial navigation, other studies have subjects viewed random single presentations of novel suggested that the OFC and medial PFC differentially5, 4, 13 stimuli. However, condition 4 subjects were instruct- contribute to long-term memory processes. ed to explicitly memorize the novel stimulus during In a review of the19 dissociable functions of the me- scanning. A surprise subsequent recognition memory dial and lateral OFC , the authors provide evidence test was administered to participants after each scan- that patients with OFC damage display an impairment ning condition, which was used to assess their encod- in decision making, choice responses, complex rea- ing performance. In support of their hypothesis, PET soning, and rule switching relative to reward values. analysis revealed that as encoding demands increase, Simple delayed match to sample tasks reveal an en- activation of the OFC increases as well. Importantly, hanced activity in the medial OFC, whereas the lateral there was no other area within the frontal cortex that OFC exhibits enhanced activity when19 subjects per- was significantly activated during encoding condi- form a delayed non-matching task . Such evidence tions. This finding suggests a relationship between of the lateral OFC being involved in non-matching OFC and the level of encoding novel material, which processes suggests that this area is involved in the also supports OFC anatomical4 connections to the MTL flexible expression of a behavioral choice in the con- in the rhesus monkeys . Concurrent with OFC studies text where an outcome is ambiguous. With the OFC on memory organizational strategies, condition 4 and showing a flexibility of response choices relative to subsequent memory results show that a greater use of stimuli-reward associations in novel and familiar verbal and semantic association strategies of partici- 44 | THE NERVE REVIEWS

pants to memorize material resulted in a better recall to such a problem when investigating the relationship of the material. Although Frey and Petrides did not ob- between a brain area and its function is by applying serve any other significant activity in the frontal cor- a non-invasive technique with a precise temporal and tex, they hypothesized that the PFC, an area involved spatial resolution such as TMS to human brain map- in executive functions, differentially contributes to ping studies. An important aspect of TMS is that single various mnemonic processes. or repetitive pulses (rTMS) transiently disrupts nor- The role of PFC in delayed non-match to sample mal brain activity when applied to a given22 brain re- tasks has provided insight to a dissociation of func35- gion, thus inducing a ‘reversible lesion’ . tion between the dorsolateral and ventrolateral PFC . In order to assess the time course of the ven- A result from this study demonstrates that the dor- trolateral PFC’s 32 involvement in memory formation, solateral PFC is responsible for holding onto the in- Machizawa et al. applied a double-pulse TMS to both formation of a stimulus in the absence of that stimu- the left and right anterior inferior frontal gyrus, as lus and motor planning of goal-directed behaviors, well as to the control vertex site, during the encoding whereas the ventrolateral PFC is involved in making of sequences of words. Behavioral probes showed that decisions and judgments based on the stimulus infor- participants who received TMS pulses to the PFC were mation that is actively monitored by the dorsolateral significantly affected when encoding and consolidat- PFC. Although dissociated in function, both areas are ing sequences of words, which paralleled the subjects highly connected and are critical for normal memory decrease in recognition accuracy. Results strongly functioning. Such a connection between these areas suggest that the left inferior frontal gyrus is crucial allows the communication of the necessary informa- for long-term memory consolidation and the creation tion to select the appropriate response in familiar and of an organizational mnemonic strategy to remember21 novel contexts. Another critical function of the PFC words, a finding similar to Frey and Petrides . An- in memory was identified in clinical cases involving other TMS study investigated the role of the dorsolat- patients with frontal lobe damage. One deficit these eral PFC in memory-guided26 responses during a spatial patients exhibit is an impaired ability to freely recall recognition task . Application of rTMS to the partici- lists of pictures or words. Interestingly, further exami- pant’s right dorsolateral PFC resulted in a decrease in nation revealed that these frontal lobe patients lacked performance on spatial recall probes, thus suggesting an organizational strategy when attempting to recall a role in spatial memory. However, it is important to a list of words by randomly8 recalling words instead note that the authors attribute this deficit of spatial of grouping3 words together . Parallel to this finding, recall in subjects to the impairment of preparation Badre et al. provided significant fMRI evidence that and execution of the memory-guided motor response the PFC is organized hierarchically and is critical for and not to a deficit in retrieval. Evidence of the critical executive functions and cognitive control in both ab- involvement and contribution32 of the PFC in memory stract and concrete contexts, a critical component of formation, retrieval strategies26, 3 , decision making and spatial navigation in a novel environment. Patients goal-directed responses from both clinical cases with PFC damage were tested using four types of and human brain mapping studies strongly suggests a higher order cognitive processing tasks consisting critical role in spatial navigation of familiar and novel of a response task, feature task, dimension task and environments. a context task. Each task was designed to assess and The role of the MTL in spatial navigation has been test the hierarchical organization of the PFC and its thoroughly tested and well-established as a critical site function in concrete and abstract contexts, respective- for learning sequences and associations and33 45 retriev 20 2 29 28- ly. Analysis of the fMRI results shows an interesting ing distinct episodic events and sequences . organization and dissociation of function between the Additional studies on the OFC and PFC’s function and anterior and posterior PFC. Patients with anterior PFC contribution to monitoring and manipulating various lesions were affected more on abstract than concrete stimuli, memory encoding support, retrieval strate- tasks, whereas patients with posterior PFC lesions gies, and memory-guided responses provides strong were affected more on concrete than abstract tasks. evidence that these areas are equally as important as Though these clinical cases provide ample evidence of the MTL structures8 26 3 32 when navigating to a destination the PFC’s involvement in memory, widespread dam- of our choice . In a recent fMRI study of remote age to other areas found in these patients may also memory for spatial relations and landmark identity in contribute to impaired memory processes. A solution former taxi drivers with Alzheimer’s disease (AD) and FALL 2010 | 45 REVIEWS

37 encephalitis, Rosenbaum et al. revealed a network of overlap of streets between these familiar routes, we of areas that differentially contribute to the support often make mistakes when trying to navigate to our of spatial memory functions. The focus of this study intended destination. In order to successfully reach was on two patients with widespread damage to areas our point of interest, our brain must overcome this in- involved in mnemonic processes. Patient S.B.’s wide- terference by separating, or disambiguating, between spread atrophy of the hippocampus, parahippocam- overlapping pathways. In a recent study performed pal cortex, occipitotemporal cortex, inferior parietal in our lab, Brown et al.7 studied the effects of contex- and orbitofrontal cortex was a result of AD, whereas tual retrieval on the disambiguation of well-learned Patient I.R.’s atrophy of the hippopcampus, left para- overlapping navigational routes. The researchers pos- hippocampal cortex, and anterior temporal cortex tulated that the hippocampus and parahippocampal was a result of viral encephalitis. Both patients were cortex would be activated for the retrieval of contex- matched for age, education, and both served as taxi tual cues and associations which aids in the success- drivers in downtown Toronto for approximately 42 ful disambiguation between routes, and that the OFC years. Controls were matched for age and education. would also be activated when subjects were required Performance results from experiments requiring both to make the correct response after traversing the patients to mentally navigate through remote memo- overlapping component of the maze. Prior to scan- ries of spatial layouts suggested that despite MTL ning, participants learned to successfully navigate atrophy, only a limited proportion of old allocentric through overlapping (OL) and non-overlapping (NOL) spatial memories are spared and accessible. This find- mazes. The OL conditions consisted of six mazes that ing suggests that remote memories are stored and ac- were split into three pairs. The OL mazes had distinct cessible outside of the MTL, supporting fMRI evidence start and end points, but converged in the middle to from a study on MTL activity43 during the recall of re- provide the degree of overlap between these mazes. mote semantic memories . A major dissociation in Importantly, after traversing down the overlapping performance regarding landmark identification and hallways, subjects were required to make the correct landmark memories was found between Patients S.B decision at the critical choice point (where the mazes and I.R. Patient S.B.’s landmark agnosia was identified diverged) to reach the correct end point relative to during the recognition and identification landmark where they began. The NOL condition consisted of task. The inability to perceive and imagine familiar six distinct mazes, with no overlapping components. landmarks was attributed to his occipitotemporal cor- Unique spatial cues were provided in each hallway for tex damage,23 a region found to be involved in object rec- both conditions to serve as contextual cues that al- ognition . Importantly, when both Patient S.B. and I.R. lowed the participants to identify the specific maze were required to learn and navigate through a novel they were in and which end point they have to navi- environment, Patient S.B. was significantly impaired gate to. Post-scan interviews consisted of question when identifying alternate routes between start and regarding their use of landmark objects, how they end points after a delay, whereas Patient I.R. perfor- identified the mazes, and the strategy the employed to mance improved from five errors to no errors on the make the correct decision at the critical choice point second day of testing. In addition to S.B.’s landmark ag- after navigating through the overlapping hallways. nosia, significant atrophy of S.B.’s right hippocampus, fMRI analysis of the first hall period showed a greater involved in spatial memory, provides evidence of why activation of all three hypothesized brain areas in the this patient could not encode and navigate through OL condition when compared to the NOL condition. the novel test environment. This study provides evi- This finding suggests that these areas are important dence of a relation between widespread brain atrophy for the retrieval of spatial context, which supports evi- and memory dysfunction when navigating through dence from similar studies9 27 37 41. environments; however, it does not reveal the active At the critical choice point, the right hippocam- memory network underlying navigational processes pus and right parahippocampal activation, as well as in healthy individuals, and does not directly test how bilateral OFC activation, was also greater for the OL one disambiguates between routes that share com- than NOL condition. Right hippocampal and para- mon elements. hippocampal cortex activation suggests the retrieval In everyday life, we rely on a widespread net- of distinguishing contextual features from the first work of brain areas to successfully navigate from one hall period, where as the OFC activation reflects the place to another. However, because there is a degree participants selection of the correct navigational re- 46 | THE NERVE REVIEWS

sponse based on the contextual cues and associations cortices. Brain Res. Bull. 52, 319-330. retrieved by the MTL. In addition to these areas, the 5. Barbas, H., and Blatt, G.J. (1995). Topographically specific medial parietal and retrosplenial cortices were also hippocampal projections target functionally distinct pre- active in both first and critical halls. Based on the re- frontal areas in the rhesus monkey. Hippocampus 5, 511- trieval strategies used by the participants, both areas 533. have been suggested to play a role in thinking about 6. Brown, M.W., Aggleton, J.P. (2001). Recognition memory: one’s future, autobiographical memory, and response what are the roles of the perirhinal cortex and hippocam- planning, thus aiding in the successful disambiguation pus?. Nat. Neurosci. 2, 51-61. of overlapping routes9 10 37 1. 7. Brown, T.I., Ross, R.S., Keller, J.B., Hasselmo, M.E., Stern, Groundbreaking evidence from animal studies C.E. (2010). Which way was I going? Contextual retrieval on memory has facilitated an overwhelming amount supports the disambiguation of well-learned overlap- of research on the human memory network. Although ping navigation routes. J. Neurosci. 21, 7414-7422. it was believed that the MTL was specific to memory 8. Buckner, R.L., Wheeler, M.E. (2001). The cognitive Nat. processes, human brain mapping techniques allowed Neurosci. of remembering. Nat. Neurosci. 2, 624-634. investigators to identify a network of areas that are 9. Burgess, N., Maguire, E.A., Spiers, H.J., O’Keefe, J. (2001). equally important and critical for supporting spatial A Temporoparietal and Prefrontal Network for Retriev- navigation. More importantly, studying spatial navi- ing the Spatial Context of Lifelike Events. Neuroimage 14, gation allows researchers to breakdown this simple, 439-453. yet complex process that we engage in everyday. Dis- 10. Cabeza, R., Ciaramelli, E., Olson, I.R., Moscovitch, M. secting this phenomenon provides researchers with (2008). The parietal cortex and episodic memory: an at- a better understanding of how we successfully navi- tentional account. Nat. Neurosci. 9, 613-625. gate through our environment, as well as understand- 11. Campo, P., Maestu, F., Ortiz, T., Capilla, A., Fernandez, S., ing the similarities and differences of neural activity Fernandez, A. (2005). Is the medial temporal lobe activa- across species during a spatial navigation task. With tion specific for encoding long-term memories?. Neuro- the use of human brain mapping techniques, the rela- image 25, 32-42. tionship between mnemonic processes and brain ar- 12. Charlton, R.A., Barrick, T.R., Markus, H.S., Morris, R.G. eas can be further investigated safely and accurately. (2009). The relationship between episodic long-term However, one must be wary when interpreting an au- memory and white matter integrity in normal aging. thor’s evidence and conclusions. Thus, I propose that Neuropsychologia 48, 114-122. when reading these studies, one should always read 13. Churchwell, J.C., Morris, A.M., Musso, N.D., Kesner, R.P. with a critical eye and mind, questioning and compar- (2010). Prefrontal and hippocampal contributions to ing result and methods to avoid any misinterpreta- encoding and retrieval of spatial memory. Neurobio. of tion of the data. Despite these caveats, as task designs Learning and Memory 93, 415-421. and brain mapping technology advances, researchers 14. Cohen, N. J. & Eichenbaum, H. Memory, Amnesia and the hope to decode and model this neural network under- Hippocampal System (MIT Press, Cambridge, MA, 1993). lying all cognitive processes with accurate and valid 15. Corkin, S. (2002). What’s new with amnesic patient evidence. H.M.?. Nat. 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Dissociable Hierarchial cognitive control deficits following damage Functions in the Medial and Lateral Orbitofrontal Cor- to the human frontal lobe. Nat. Neurosci. 14, 515-522. tex: Evidence from Human Neuroimaging Studies. Cereb. 4. Barbas, H. (2000). Connections underlying the synthesis Cortex 10, 308-317. of cognition, memory, and emotion in primate prefrontal 20. Fortin, N.J., Agster, K.L., Eichenbaum, H. (2002). Criti-

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cal role of the hippocampus in memory for sequences of of mnemonic information within the primate frontal cor- events. Nat. Neurosci. 5, 458-462. tex. Philos. Trans. R. Soc. Lond. B 351, 1455-1462. 21. Frey, S., and Petrides, M. (2002). Orbitofrontal Cortex 36. Rosenbaum, R.S., Ziegler, M., Winocur, G., Grady, C.L., and Memory Formation. Neuron 36, 171-176. Moscovitch, M. (2004). “I Have Often Walked Down This 22. Grafman, J., Wassermann, E. (1999). Transcranial mag- Street Before”: fMRI Studies on the Hippocampus and netic stimulation can measure and modulate learning Other Structures During Mental Navigation of an Old En- and memory. Neuropsychologia 37, 159-167. vironment. Hippocampus 14, 826-835. 23. Grill-Spector, K. (2003). The neural basis of object per- 37. Rosenbaum, R.S., Gao, F., Richards, B., Black, S.E., Mosco- ception. Current Opinion in Neurobio. 13, 159-166. vitch, M. (2005). “Where to?” Remote memory for spatial 24. Hasselmo, M.E. (2005). A model of prefrontal cortical relations and landmark identity in former taxi drivers mechanisms for goal-directed behavior. J. Cog. Neurosci. with Alzheimer’s Disease and Enchephalitis. J. Cog. Neu- 17, 1115-1129. rosci 17, 446-462. 25. Hasselmo, M.E. & Eichenbaum, H. (2005). Hippocampal 38. Ross, R.S., Brown, T.I., Stern, C.E. (2009). The Retrieval of mechanisms for the context-dependent retrieval of epi- Learned Sequences Engages the Hippocampus: Evidence sodes. Neural Netw. 18, 1172-1190. From fMRI. Hippocampus 19, 790-799. 26. Hamidi, M., Tononi, G., Postle, B.R. (2008). Evaluating 39. Ross, R.S., and Slotnick, S.D. (2008). The Hippocampus is with role of prefrontal and parietal cortices in memory- Preferentially Associated with Memory for Spatial Con- guided response with repetitive transcranial magnetic text. J. Cogn. Neurosci. 20, 432-446 stimulation. Neuropsychologia 47, 295-302. 40. Schendan, H.E., Searl, M.M., Melrose, R.J., Stern, C.E. 27. Kohler, S., Crane, J., Milner, B. (2002). Differential con- (2003). An FMRI study of the role of the medial temporal tributions of the parahippocampal place area and the lobe in implicit and explicit sequence learning. Neuron anterior hippocampus to human memory success. Hip- 37, 1013-1025. pocampus 12, 718-723. 41. Schon, K., Tinaz, S., Somers, D.C., Stern, C.E. (2008). De- 28. Lehn, H., Steffenach, H.A., van Strien, N.M., Veltman, D.J., layed match to object or place: An event-related fMRI Witter, M.P., Haberg, A.K. (2009). A Specific Role of the study of short-term stimulus maintenance and the role Human Hippocampus in Recall of Temporal Sequences. J. of stimulus pre-exposure. Neuroimage 39, 857-872. Neurosci. 29, 3475-3484. 42. Schon, K., Hasselmo, M.E., LoPresti, M.L., Tricarico, M.D., 29. Lipton, P.A., White, J.A., Eichenbaum, H. (2007). Disam- Stern, C.E. (2004). Persistence of parahippocampal rep- biguation of overlapping experiences by neurons in the resentations in the absence of stimulus input enhances medial entorhinal cortex. J. Neurosci. 27, 57875795. long-term memory encoding: A functional magnetic 30. LoPresti, M.L., Schon, K., Tricarico, M.D., Swisher, J.D., resonance imaging study of subsequent memory after Celone, K.A., Stern, C.E. (2008). Working Memory for So- a delayed match-to-sample task. J. Neurosci. 24, 11088- cial Cues Recruits Orbitofrontal Cortex and Amygdala: 11097. A Functional Magnetic Resonance Imaging Study of De- 43. Smith, C.N., Squire, L.R. (2009). Medial temporal lobe ac- layed Matching to Sample for Emotional Expressions. J. tivity during retrieval of semantic memory is related to Neurosci. 28, 3718-3728. the age of the memory. J. Neurosci. 29, 930-938. 31. Mabbott, D.J., Rovet, J., Noseworthy, M.D., Smith, M.L., 44. Squire, L.R., Zola-Morgan, S. (1991). The medial temporal Rockel, C. (2009). The relations between white matter lobe memory system. Science 253, 1380-1386. and declarative memory in older children and adoles- 45. Wood, E.R., Dudchenko, P.A., Robitsek, R.J., Eichenbaum, cents. Brain Research 1294, 80-90. H. (2000). Hippocampal neurons encode information 32. Machizawa, M.G., Kalla, R., Walsh, V., Otten, L.J. (2010). about different types of memory episodes occurring in The time course of ventrolateral prefrontal cortex in- the same location. Neuron 27, 623-633. volvement in memory formation. J. Neurophysiol. 103, 1569-1570. 33. Morris, R.G.M., Garrud, P., Rawlins, J.P., O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nat. Neurosci. 297, 681-683. 34. Norman, K.A., Polyn, S.M., Detre, G.J., Haxby, J.V. (2006). Beyond mind-reading: multi-voxel pattern analysis of fMRI data. Trends in Cog. Neurosci. 10, 424-430. 35. Petrides, M. (1996). Specialized systems for processing

48 | THE NERVE OPINION

Evolutionary Psychology on the Couch

by Devyn Buckley

FALL 2010 | 49 OPINION

Evolutionary Psychology on the Couch

by Devyn Buckley

In Brief

volutionary psychology (EP) is the predomi- cial and class levels by making them natural law. nant lens of interpretation in psychology today Freudian psychologists emphasized the influence and is expanding into the general public as a of early childhood and the multiplicity of conflicting contemporary thought trend. As you may guess, it at- motives within an individual psychology. The Behav- tempts to apply Darwin’s Theory of Evolution to the iorists at the turn of the 20th century held the radical field of psychology. It explains observed behavior in position that all aspects of psychology, including per- contemporary humans as results of hard-wired pre- sonality and intelligence could be attributed to varia- dispositions produced by natural selection. While tions of Pavlov’s conditioning, or learning strictly in speculation has its merits, many of E.P.’s claims seem terms of reward and punishment. In the 1950’s, hu- Ereactionary and guided by an agenda, as is evidenced manism provided an almost limitless encouragement by the claims’ poor believability and the lack of data of self-actualization, positing that a well-socialized, that support them. As a result of an ideological polar- happy being was attainable through unconditional ization occurring between modern religious extrem- positive regard and a general atmosphere of goodwill. ists and their counter Darwinian fundamentalists,. E.P. Meanwhile Cognitive psychology overlapped greatly performs logical acrobatics to justify its speculation as with neuroscience and studied the structures under- fact. I aim to demonstrate the logically fallacious na- lying cognition. The passing of time and the formation ture of E.P. and its ideological character, particularly as of new schools of thought did not reject each system, a counter-ideological reaction to the social sciences, but dethroned it as the principle means of psychologi- Thereligiosity, Evolution and feminism.of Psychology cal analysis as soon as the next came along. E.P. emerged at the end of the 20th century, first in the form of Sociobiology. It began around 1975 when Edward O. Wilson proposed that human psychology, The multitude of previous schools of thought in in addition to physiology, could be explained in terms psychology mostly relied on the premise that the hu- of evolutionary adaptations2 in his book Sociobiology: man mind was a malleable thing. Many disciplines The New Synthesis. It was initially unpopular due to emphasized psychological malleability out of a dual a fear of returning social injustice. It reemerged un- motive for truth and social justice. Even John Scopes, der the new title of E.P. in the 1990’s with books such who was favored by scientific intellectuals in the 1925 as The Adapted Mind (1992) by John Tooby and Leda Tennessee vs. Scopes trial, which accused him of un- Cosmides and David Buss’s Evolutionary Psychology: lawfully teaching evolution in Tennessee, taught from Reactionthe New Science to the “Social”of the Mind Sciences (1995). or the SSSM the textbook Civic Biology, which made racist sugges- tions and endorsed ideas such as sterilization of epi- leptics and the mentally1 feeble from the then popular field of eugenics. Anthropology and craniometry had Dylan Evans and Oscar Zarate, who write in Intro- long sought to justify social inequities on both the ra- ducing Evolutionary Pscyhology, published 1999, that 50 | THE NERVE OPINION

“In the future, the study of human psychology will be as evidence uses the same observational techniques completely transformed by the Darwinian approach... deemed “quack” in order to legitimatize it, namely it won’t be called ‘Evolutionary3 Psychology’. It will just it observes and interprets behavior in the mode of a be called ‘psychology’.” David Buss titles one of his soft science. Furthermore, if observation is in the eye papers, “Evolutionary Psychology:4 A New Paradigm of the beholder, then wouldn’t claims concerning unfor Psychological Science.” The Handbook of Evolu- observable behavior 100,000 years ago be even more tionary Psychology, edited by Buss describes E.P. as a so? The only difference then is that E.P. imagines itself “scientific revolution, a profound paradigm shift in the to supersede the others because it provides a creation field of5 psychology,” and a “paradigm within biology story for behavior, rather than stopping at what is ob- itself.” servable and imagines itself to be a science because its All prior schools of thought are dismissed. In The I,vocabulary Robot incorporates biological terms. Handbook, Buss labels socio-cultural outlook “mainstream psychology,” which he defines as being “por- tioned into subdisciplines—cognitive, social, personality, developmental, clinical, and hybrid areas such as Right at the time of Darwinism’s reawakening cognitive neuroscience,” that5 E.P. reveals to lack “logi- a revolution was occurring in technology affecting cal or scientific warrant.” To all of them Buss grants fields from computer science to biology. The mind be- a false premise: the human mind is a “blank slate”. He came the brain the more the brain could be measured. states, “The human mind can no longer be conceived David Marr, a British neuroscientist helped interpret as it has been in mainstream psychology as a blank the visual processing5 system from a computational7 slate onto which 5parents, teachers, and cultures im- standpoint. Noam Chomsky’s 1968 study of infants pose their script.” Buss refers to non-evolutionary6 ex- demonstrated the existence of innate linguistic capa- planation as the “myth of cultural causation.” All non- bilities, revealing the power of inborn mechanisms or evolutionary facets of “mainstream psychology” are modules within the mind, signaling the commence- united under the appellation5 of the Standard Social ment of the cognitive revolution, or the mechanistic Science Model (SSSM) , meaning that they attempt to treatment of the mind. Module is a term often used explain aspects of human behavior by external influ- in technological and economic fields because it deals ences rather than internal predeterminations. Those with highly structured mechanisms. It is a general opposing the revelation of sociobiology by Wilson are systems concept, meaning, it refers to “complexes of described in the Handbook5 as “intellectuals wedded elements or components, which mutually condition to the blank slate.” and constrain one another, so that the whole complex While previous approaches did not rely on bio- works together, with8 some reasonably clearly defined logical explanations, largely out of technological lim- overall function.” . Neurological modules exist mostly itations, to say they viewed the human as entirely a within the realm of comprehending physical relations, blank slate would be a stretch, excepting the behavior- analyzing visual data, processing speech and emotion. ists. Freud, for one, acknowledged uncontrollable im- These are all areas with minimal variability among pulses and the strength of unconscious instincts. Ad- individuals in the same way that the pumping heart ditionally, despite the radicalism of the Behaviorists, is more or less unvarying. E.P. grasped the notion of their conditioning experiments were integral to an modularity and applied it universally to the point that understanding of learning and cannot be dismissed. the human being is a preprogrammed machine. Pink- Steven Pinker quotes philosopher Nelson Goodman er states that “the brain is not just like a computer—it in the foreword of The Handbook to describe alter- is a computer” and that “the evolved function5 of a psy- native psychological explanations as “a pretender, chological mechanism is computational.” an imposter, a quack.” According to him, they are ut- Universal modularity seems to go against neu- terly false because they rely on “similarity, frequency, rological fact and observed behavior. Modularity is salience, and regularity” to make conclusions about not synonymous with cognition. It details rigid, pre- behavior, explanations5 Pinker states are “in the eye programmed, unchanging systems. Pinker writes of the beholder.” They do not address the “why” of “humans are intelligent7 not because we have fewer behavior. However, the same methods are employed instincts, but more.” Instincts are innate for every by E.P. in their observation of behavior in order to de- member of the species, yet, human behavior and per- vise explanations for its existence. What they claim sonality vary vastly among individuals. How can such FALL 2010 | 51 OPINION

a high degree of flexibility exist in an organism entirely etc. It contrasts with scientism, an outlook which ac- composed of modular instinct? Either each individual cepts only the quantifiable experience of being: that possesses her or his own set of instincts or there is a which can be measured and subjected to the scientific multitude of strongly deviating mutants. This is not to method. Scientism has become increasingly popular as say that modularity does not exist within the human technology rapidly develops and more people invest mind, only that the model of its universality fails. Mod- their education in the expanding sciences and areas ularity may operate within the realms of language, of practical skill, partly out of economic reasons, leav- perception, and emotion, while other more complex ing many schools to shut down programs in the lib- psychology involves the interaction of memory, feel- eral arts. The University of Louisiana, Lafayette ended ing and consciousness, without being the product of a its philosophy major, and Michigan State University rigid, preprogrammed and definitive process. eliminated10 its major in American Studies and Classics recently. Public figures posit scientistic views that A modular system works in a deductive fash- collectively shape public opinion. For example, some ion—arriving at a conclusion through a rigid reason- have taken Richard Dawkins to suggest in The Selfish ing system with a defined premise. The human con- Gene that all human behavior is reducible to geneti- sciousness, on the other hand, behaves mostly in an cally selfish foundations, reawakening Darwinism and “We have the power to turn against our own creators” - Richard Dawkins, The Selfish Gene

inductive fashion. That is, conclusions are not reached contributing to E.P. Such an outlook comes from the through linear computation, but through a constant desire to push against age-old western notions of hu- modification of experience and probabilistic deter- man nature, particularly those revered by religious minations. Self-awareness is the critical ingredient to extremists. Evolutionary psychologists label them as non-modularity. Jerry Fodor, a cognitive scientist and stubborn, irrational, and imposing to the acquisition original proponent of modularity, gives the example of a truth. that, although we cannot force our modular visual Western Culture finds humans to have some system to stop perceiving an optical illusion, the fact elect quality that gives them superiority not only in that we can understand that it is an illusion and reject skill but also in essence over animals. E.P. tries to de- it or modify our relationship to 7it illustrates complex stroy the notion of the elect human being by placing cognition outside of modularity. him within the animal kingdom, but with such over- The computational model of the human mind emphasis that it frames human nature as uniform and seems incongruous with observation, yet E.P. denies it instinctual, ignoring the defining factors of humanity: for reasons unconscious to itself. E.P. reacts as it did to self-awareness and culture. It attempts to crush any the social sciences, to religious and western notions. It utopian notion of a human-invented paradigm toward represents a facet of the polarization marking this era which we progress, by over-emphasizing negative as- Thebetween Fall ofscientism Man and metaphysics. pects of human behavior. The Handbook of Evolution- ary Psychology takes a missionary tone, stating that “EP challenges5 the foundations of crucial enlighten- ment values.” Daniel Dennet, a philosopher and advo- Metaphysics deals with non-quantifiable experi- cate of Dawkins’ strict adaptationism, explains in Dar- ence such as philosophy, art, literature, psychology, win’s Dangerous Idea natural selection as a “universal 52 | THE NERVE OPINION

acid”: universal referring to its global explanatory are they separate from the supposed biological deter- power12 and acid to its corrosion of traditional Western minism that shapes all thought and behavior? The par- belief. adox arises from the profound error of rejecting the It is a testament to the power of cultural influence essence of human existence, partly out of radicalized as well as to the influence of the unconscious to ob- counter-ideology to religion and traditional Western serve that while E.P. fights traditional western values, beliefs; that essence being metaconsciousness or the it maintains them in its methodology. As regards love feeling of “I” that is so intimately infused with the also of reasoning, they are in full conformity, for they treat rejected concept of culture. They are not to be denied their conjectures as absolute truth, indicating none in simplistic systematization, as their rejection leads other than a total faith in the purity and omnipotence to impossible paradoxes and incongruities with hu- of their human reasoning. As regards the elect status man experience. of the human being, it is evident that they see their How can a trait be biologically determined if it is school of thought as superior to any other and in this not necessarily expressed? Steven Gould addresses manner treat themselves as a chosen elect. As regards the conundrum in The Mismeasure of Man, stating, “if the notion of paradigm, they treat their system as fi- innate only means possible…then everything we do is nalized and refer to it as paradigmatic. Additionally, innate and the word has no meaning…flexibility is the evolution itself is often treated as purposeful, direct- hallmark of human evolution.” He goes on to say, “we ed, and perfect. The adapted machine understanding should be wary of…viewing all brain capacities as di- of the human mind conforms not only to the desire for rect adaptations…additional capacities are ineluctable a paradigm, but also to the desire for an anthropomor- consequences of structural design, not adaptations… phic, willful designer found in the religious psychol- our vastly more complex organic computers were ogy. The religious personality is explicitly evident in also built for reasons, but possess an almost terrifying Pinker’s own statement:5 “Darwin’s prophetic vision is array of additional capacities—including,18 I suspect, being realized.” most of what makes us human.” Thus, there are basic Most fascinating of fallacies, however, is E.P.’s du- structures which are universally found, but complex, alistic understanding of human nature despite its de- variable behavior made possible by basic structures terminism. Rejecting cultural influence and free will, is not a modular adaptation, but an expression of an evolutionary psychologists perceive what Ivan fore- incredible plethora of possibilities. A potential to act worns in Dostoyevsky’s The Brothers Karamazov14 that one way or the other renders both possibilities essen- without God “everything is permitted.” God, in this tially non-determining. case, can be understood not only as metaphysical im- Once the existence of systematized thinking is dis- petus for morality, but also as the concept of free will. covered, people accuse it of masking truth in the rigid- To preserve morality, evolutionary psychologists sep- ity of its dogma, and shatter it by revealing a complete arate self from self and ethics from nature. In How the opposite of its creed to be true, and in their excitement Mind Works Pinker states that science and ethics are fall unknowingly into another system as fierce as the “two self-contained systems…science treats people as first in its conviction and as sensitive towards criti- material objects and its rules are the physical process- cism. Polarized against the SSSM, traditional Western es that cause behavior through natural selection…eth- notions of human nature and anti-scientific religious ics treats people as15 equivalent, sentient, rational, free- extremism, E.P. falls into the error of counter-ideolo- willed agents…” He proposes two separate, equal, gy. E.P. forcefully defends conjecture out of ideological and entirely contradicting ways to understand the imperative rather than objectivity and claims conjec- human being. Dawkins states in The Selfish Gene that Boysture as versus fact through Girls faith in its dogmatic axioms. “we have the16 power to turn against our own creators”, the genes. Pinker writes of his choice to never have children and how it is an “evolutionary mistake,” but that if7 his “genes don’t like it, they can go jump in the E.P. focuses primarily on sex and supposed sex lake.” What kind of a machine has the power to defy differences. The most frequently used words in the its hardwire? What modular, goal-oriented, reduction- titles of over 800 articles in two journals, Ethology ist system creates a being that can behave counter to and Sociobiology and Evolution and Human Behavior its biological fitness? If ethics are not metaphysical or include sex, differences, human, and male in that or- religious delusions, but possess real value, then how der from 1997-2002 and attractiveness, sexual, facial, FALL 2010 | 53 OPINION

19 sex, men, female, male from 2003-2008 in that order. most specifically child-rearing. To EP, female sexual E.P.’s narrow window of focus indicates an almost fa- desire is stupefying, if not ignored completely, and the natical devotion to naturalizing sex stereotypes as monogamy of men is seen as a female victory or ef- Robert Wright, who initially popularized 21 E.P. in his feminacy. Christopher Ryans, author of Sex at Dawn, book The Moral Animal, predicted it would. titles an entry on his blog on Psychology Today’s web- E.P. defines the biologically determined or pro- site, “Why Does Female Orgasm Exist?” and states how grammed mating strategies of men and women to be its existence has baffled evolutionary psychologists. inherently opposing. The textbook Psychology and David Buss’ book Why Women Have Sex presumes in Life outlines the perspective of E.P. to be such, citing its title the perplexing nature of the female pursuit of Buss stating “Human males could reproduce hun- sex. Yet a sexual desire in women would seem more dreds of times a year if they could find willing mates. evolutionarily advantageous. To produce a child all they need to invest is a teaspoon While the premise of E.P. is that an observed be- of sperm and a few minutes of intercourse. Women havior is adapted, they refuse to acknowledge female can reproduce at most once a year and each child…re- orgasm as an adaptation, but regard it as an enigma quires a huge amount of time investment and energy… or as vestigial. This demonstrates the a priori nature the basic problem facing a male animal is to maximize of their beliefs, which shape interpretation through the number of offspring he produces by mating with a pre-established conviction of gender roles, making the largest number of females possible…but females them decide what is or is not an adaptation by pref- have the problem of selecting…the biggest, strongest, erence. If females had choice in selecting mates of smartest, most highest-status, 22 most thrilling mate… high-status, then wouldn’t they have just as much of but also the most committed…” Men, as Buss posits, a choice in pursuing sexual pleasure and preferences? have an evolved strategy to “seduce and abandon as The confusion over female orgasm is really confusion many women as possible…” and the female strategy over whether females have choice in pursuing sex or is to seek out resources and men of high-status. In not. E.P. grants women choice only when it allows essence, women are commitment loving and child- them to explain the evolution of a pre-existing stereo- oriented, whereas men are stunted by commitment in type. the pursuit of their biological imperative to impreg- EP is the naturalizes of female objectification, and nate as many youthful, attractive women as possible. makes women natural means to ends in the eyes of Women seek resources,6 status, and “men who are men, rather than a fellow human being whom they older,” according to Buss. In the scheme of E.P. the relate to, empathize with and depend on. Their per- words “willing mate” are unnecessary, but used to pre- spective places the male as a champion of fitness and empt extreme controversy, as happened when Craig T. esteems him through a worship of his potential to mas- Palmer and Randy Thornhill, whose paper “Why Men sively procreate. Warlords and keepers of harems who Rape,” stated rape was not in its essence a violent act, enslaved women are cited as examples of male fitness but “natural, biological phenomenon.” They advised and sexual strategy. Psychology and Life gives as an the New York Times, “a woman’s risk of attack rises example of a Moroccan despot, King Ismail the Blood along with her hemline, and her willingness to26 social- Thirsty, who possessed many harems and fathered ize without the company of ‘male protectors.’” They over 3,000 children, ignoring the fact that a warlord suggested men be instructed to repress natural feel- from several hundred years ago is not an exemplar for ings to prevent the act. Like other violent criminal the biologically determined psychology of every hu- acts, rape is not a global behavior, or an evolved trait, man male anymore than a stay at home dad from the but one behavior out of many coming from a cogni- 21st century is. Buss cites the Turkmen of Persia to tively flexible species. justify women’s resource-oriented strategy and men’s E.P. perpetuates stereotypes and sexual inequi- sex-oriented one: the males in the wealthier half of the ties by making the dream of social justice a farce in the population left 75 percent more offspring than males face of fact. By claiming that certain behaviors are in- in the poorer counterparts. Interpreting this as a ful- nate and modular, the human will becomes ineffectual fillment of evolutionary roles ignores the entire cul- to change them. A double standard is, thus, justified tural background which was, like the majority of soci- in which the male is irresponsible, freewheeling, and eties throughout history and the world, possessive of self-indulgent, while the female is a natural care-taker, women, selling them into marriage and denying them a fulfiller of responsibilities, and bearer of burdens, equitable societal status. To say that the enslavement, 54 | THE NERVE OPINION

domination, and objectification of women is natural A study in Psychology and Life involved over justifies sexual inequity and preempts social change. 16,000 participants from 52 nations about their inter- The same textbook Psychology and Life lists exem- est in “short-term sexual relationships,” in which men plary power hierarchies as: “parent-child, teacher- reported22 greater desire for sexual variety than did student, doctor-patient, boss-worker,22 male-female.” women. The survey does not validate an evolution- This exemplifies attitudes of E.P. ary narrative, but reveals merely what those partici- The aggressive anti-feminist tone of E.P. is illus- pants at that point in time and space revealed about trated by Ryan who states, “boys will be boys, and men their personal motives. Take this as a testament to the will be the way they are, despite the23 many ways our so- nature of surveys: “In 1953, Alfred Kinsey, Ph.D., the ciety tries to make them change.” Ryan quotes Don- famous sexuality researcher, found that nearly 40 per- ald Symons saying “The sexually insatiable woman is cent of the 5,628 women he interviewed experienced to be found primarily, if not exclusively, in the ideology at least one nocturnal orgasm (orgasms during sleep), of feminism, the hopes of boys, and the fears of men.” or “wet dream,” by the time they were forty-five years The stereotypes naturalized by E.P. are facts of old. A smaller study published in the Journal of Sex current culture. Women are shown to be “resource Research in 1986 found that 85 percent of the women obsessive,”pursuing shoes, handbagsand men with who had experienced nocturnal orgasms had done great wealth. A popular T-shirt depicts a man and so by the age of 29twenty-one, some even before they woman getting married with the words “game over” turned thirteen.” The dramatic increase was not due underneath. A poster for the show Entourage on to a biological change, but a change in what partici- Spike, the men’s channel, shows two female bodies pants stated about themselves and also, likely, chang- in bikinis outlining authoritative male figures in suits ing societal attitudes about women’s sexuality. with the caption, “where every guy can get some.” The EP’s most fatal error is its denial of humanity. It Evolutionist describes it as “a flood of magazines and places women and men in psychological sexual con- television programmes celebrating the distinct fea- flict in which they must attempt to trick one another tures of “maleness” - ogling, drinking, fighting, playing to achieve satisfaction. Buss states “One of the key in- football...” It describes this as a reaction to the failed6 sights of evolutionary psychology is that humans have attempt to modify male behavior by sociologists. inherent conflicts of interest with other individuals, An article in The Economist titled “Sex, Shopping, with members of their own family, with members and Thinking in pink” argued that women were evolu- of the opposite sex, and members of their own sex,” tionarily programmed to enjoy shopping and to be at- and describes his major6 interest as “topic of conflict tracted to pink, a color designated27 feminine in Europe between the sexes.” E.P. attitude sees all elements of and America around 1950 , since it signified the color nature in conflict, including the supposed modules of berries and emotional28 states on faces, making them within oneself or “scores of instincts assembled7 into good empathizers. programmes and pitted in competition,” as described Once again, the errors lie in the foundational by Pinker. This misinterprets not only the relation be- mistakes of E.P. The dismissal of obvious social and tween the genders, but evolution as a whole and criti- cultural phenomena does not come from reason, but cal aspects of a social humanity. from adherence to dogma and a desire to make ste- Adaptation can result from mutually beneficial reotypes irrefutable. What they designate as evidence relationships between individuals who share the is behavior selected by them to be interpreted with a same needs. The parts of the brain, as well, work very priori conclusions. Perhaps a uniform history of deny- nicely together, not because they are in competition, ing women equal career opportunity could have made but because their harmony gives rise to a well func- attaching oneself to an economically stable, older man tioning whole. In the system of E.P. there is hardly more conservative for women. Equitable social and need for men to fall in love or for women to experience economic status for women is fairly new, and limited orgasm, as Ryans notes, yet this occurs anyway. Why geographically. A cross-cultural examination may re- not incorporate them into one’s evolutionary schema? veal universal cultural phenomena than a biological Perhaps men and women form lasting bonds out of reality. The poor status and treatment of women, for mutual emotional and physical need as many seem example, is similar throughout history and through- to do. Maybe it is through supporting these needs to- out culture. Would this not lead to similar behavioral gether that ensures the success of both? Though we phenomena? may only speculate, isn’t it probable that cave people FALL 2010 | 55 OPINION

in their small social groups facing a threatening cli- er people, as well as the motives of the unconscious, mate similarly needed steady bonds with other mem- present the greatest obfuscations to truth, while at the bers both to survive as well as ensure the health of same time are least detected, by virtue of the very fact their offspring? Perhaps the attentiveness of a man that they are not conscious. Societal convention and to his mate and offspring ensures their success more self-serving belief, the two often one in the same, con- than those who abandon them to the environment? It stitute the great Lochness of the depths of the uncon- would seem the thing of greatest need in small groups scious, powerful, ageless, and hidden, churning the struggling to survive would be trust and ritual culture. waters of consciousness in the minds of even the most Perhaps E.P. could be more appreciable if had a set earnest. In the excitement of a new school of thought, of varied narratives, but it does not. Its emphasis on it is often easy to forget that the present is also part conflict neglects the various complex emotional and of history and that the current era, since it is always social needs that are satisfied by relationships unique the most modern, does not signify an arrival at final to human beings. Relations between the genders are truth, but the most current contribution to a succes- about more than just procreation, and successful hu- sion of imperfect perspectives. Deconstructing E.P.’s man procreation is about more than just copulation. methods one finds the symptoms of the ideological or By treating people as animals, not only in taxonomy, religious personality, whose most integral aspect the but in essence of spirit, we lose the defining quality circular logic of faith. E.P.’s assumptions concerning of humanity—that is, the self-awareness and all the biological determinism and modularity are in opposi- psychological complexity that comes with a reasoning tion to the facts of behavioral flexibility, the human- Toand Err emoting is Human conscious. ity of self-awareness, and culture. Its beliefs are often counter-ideology to the social sciences, religiosity, and feminism. Understanding what is false is one way It is important to remember that in the noble of understanding what is true. Deconstructing E.P. il- quest to uncover the basis of our psychology, we some- lumines the social politics of our era and practices a times overlook our psychology. The influences of oth- critical skepticism that aids scientific objectivity.

1. Black, Edwin. _War Against the Weak: Eugenics and America’s Campaign ford University Press, 1976. to Create a Master Race_. New York, N.Y.: Avalon Publishing Group Inc., 17. Welton, James and Alexander James Monahan. _An Intermediate Logic_. 2003. [75.] E.M. Whetnall. 3. The University of Michigan: W.B. Cliver, 1928. 2. Webster, Gregory. “What’s in a Name?: Is “Evolutionary Psychology” Eclips- 18. Gould, Stephen J. _The Mismeasure of Man_. 500 Fifth Avenue, New York, ing “Sociobiology” in Scientific Literature?.” Evolutionary Psychology NY: W.W. Norton & Company, Inc., 1981. [360-1]. Journal Volume 5(3) (2007): 683-684. 19. Webster, Gregory D. “Hot Topics and Popular Papers in Evolutionary Psy- 3. Evans, Dylan and Oscar Zarate. _Introducing Evolutionary Psychology_. chology.” Evolutionary Psychology 7 (2009). Duxford, Cambridge: Icon Books Ltd., 1999. [169] 20. Herrnstein, Richard J. and Charles Murray. _The Bell Curve_. United States 4. Buss, David, ed. “Evolutionary Psychology: A New Paradigm for Psychologi- of America: Free Press Paperbacks, 1994. cal Science.” Psychological Inquiry 6 (1) (1995): 1-30. 21.Wright, Robert. _The Moral Animal: Evolutionary Psychology and Every- 5. Buss, David. _The Handbook of Evolutionary Psychology_. Hoboken, New day Life_. The University of Michigan: Pantheon Books, 1997. Jersey: John Wiley & Sons, Inc., 2005. 22. Zimbardo, Philip and Richard J. Gerrig. _Psychology and Life_. 18. N.p.: 6. The Evolutionist. (1996). [Interview with David Buss, author of The Evolu- Pearson Education, Inc., 2008. [363]. tion of Desire]. Darwin@LSE. 23. Ryan, Christopher, “Sex at Dawn: Exploring the Evolutionary Origins of 7. Malik, Kenan. “Darwinian Fallacies.” Prospect. 1998. Modern Sexuality.” Psychology Today. May 4, 2010. (http://www.psy- 8. Edquist, Charles. _Systems of innovation: technologies, institutions, and chologytoday.com/blog/sex-dawn?page=1) organizations_. N.p.: Pinter, 1997. 24. Maines, Rachel. The Technology of Orgasm: “Hysteria,” the Vibrator, and 9. Addington, Larry. _America’s War in Vietnam: a short, narrative history_. Women’s Sexual Satisfaction. The Johns Hopkins University Press, Bloomington, Indiana: Indiana University Press, 2000. 1998. 10. Zerinke Kate. “Making College Relevant.” The New York Times (2010): 25. McCaughey, Martha. The Caveman Mystique. National Sexuality Resource ED16. Center. October 20, 2008. (http://nsrc.sfsu.edu/article/caveman_mys- 11. Aristotle. _Nicomachean Ethics_. Martin Ostwald. N.p.: Prentice Hall, 1962. tique_evolution_psychology) [17]. 26. Pozner, Jennifer. “In Rape Debate, Controversy Trumps Credibility.” Extra! 12. Gould, Stephen J. “Darwinian Fundamentalism,” The New York Review, (May/June 2000). June 12, 1997, pp. 34-37. 27. Peril, Lynn. Pink Think: Becoming a Woman in Many Uneasy Lessons. New 13. Connecting Christians Www.connectingchristians.co.za. Web. 10 July York, N.Y.: W.W. Norton & Company, 2002. 2010. . 28. “Sex, Shopping and Thinking Pink; Evolutionary Psychology.(What Wom- 14. Dostoevsky, Fyodor. The Brothers Karamazov. Pevear, Richard and Larissa en Want, Evolutionarily Speaking).” The Economist (2007). Economist Volokhonsky. First Farrar, Straus and Giroux paperback edition. U.S. & Newspaper Ltd. Web. Canada: Douglas & McIntyre Ltd., 2002. [649]. 29. Health Services at Columbia, “Go Ask Alice”. Columbia University’s Health 15. Pinker, Steven. _How the Mind Works_. N.p.: W.W. Norton & Company, Q&A Internet Service. . 16. Dawkins, Richard. The Selfish Gene. Great Clarendon Street, Oxford: Ox-

56 | THE NERVE OPINION

Does the Brain Run Algorithms?

by Kayla Ritchie

FALL 2010 | 57 OPINION Does the brain run algorithms?

by Kayla Ritchie

Introduction What is an algorithm? Computer algorithms

omputation, or information For the purpose of this article, Though a general purpose processing, can be defined it is appropriate to use a general dictionary will explain that an al- as that which describes the purpose definition with a few clari- gorithm consists of a step-by-step changes which occur in the natu- fications. First, an algorithm must problem solving procedure, the ral world. Typically an algorithm consist of precise, unambiguous computational meaning of the or equation, such as the ones used steps which require no subjective word has not yet been agreed upon. in neural modeling, are employed interpretation, and, resultantly, the Computation, in its most basic defi- for such processing due to their execution of the algorithm must al- nition, occurs in a system which is ability to describe the behavior of ways yield the same outcome given designed to process information Ca system according to certain de- Intentionala particular setUse of of inputs. Algorithms in the form of simple symbol ex- pendent and independent condi- change, as in the 0-1 coding para- tions. Due to the recent increase digm used in digital computers. A in processing capacity of modern certain combination of such for- computers, neuroscientists and While executing even the sim- mally defined symbols correlates computer scientists have attempt- plest tasks such as brushing one’s to certain commands, which can ed to model large scale brain archi- teeth, or navigating to a desired, take the form of stepwise algorith- tectures that include entire popula- familiar destination, application mic functions. tions of neurons, or in the case of a of an algorithm is essential for In most modern comput- team of Swiss researchers, the en- successful completion of the task. ers, this symbol exchange corre- tire human brain, in hopes of simu- More complex tasks, such as using sponds to the presence or absence lating the processes in the brain to the quadratic formula, require sim- of electrical current. Hardware is a point that higher cognitive func- ilar use of step-by-step processes. designed so that input generates tions would arise from the models. However the algorithms we draw current fluctuations in a vast ar- While this is an exciting prospect, on to accomplish such everyday ray of transistors, which eventually it is unclear whether running the tasks are learned through many leads to some output mechanism. “Brain Program”, would actually experiences of trial and error; each This output can be expressed, for yield genuine cognitive processes, algorithm was developed indirect- example, through a mechanical de- simply because the brain is not ly through intentional, goal-driven vice that takes the current fluctua- necessarily a digital computer, behavior, and so is not inherent to tions and converts them to light on and its functions not necessar- the architecture of the brain. In a monitor. It can also be converted ily computational. In this paper, I other words, the processes which into signals that direct the motion pose the question: Does the brain govern the underlying functions of of the mechanical arm that writes run algorithms? I will argue that the brain, i.e. protein synthesis and on the hard disc. Note, however, this question stems from a deeper the physical and chemical basis for that transistors are not strictly uncertainty of whether cognitive generating action potentials are necessary for a formal symbol ex- processes are computational, and neither learned, nor controllable change. Theoretically, any system explore the implications that this through intentional behavior. Such upon which a formal symbol defini- may have on our ability to model processes are inherent in the phys- tion can be imposed can be a com- the mind with computers. ics of the system. puter. 58 | THE NERVE OPINION

What is the difference between human and computer algorithms? val determined by force of gravity stances that make it through are and mass of rock } small enough to pass, and do so Until(terminal_velocity ==velocity) because of a chemical gradient, or Move towards center of the earth because they are chemically suited The human method of fol- at terminal_velocity to pass through a specific chan- lowing an algorithm requires } nel. Similarly, a cell membrane is consciousness. Humans are con- not round because the cell actively sciously aware of the task that they Why is it clear to us that the maintains its shape due to the fact are supposed to complete, and use rock is not following this algo- that this enables higher internal the meaning of their instructions rithm? For one, we know that organization, but rather because to drive their behavior. Comput- a rock does not have an input/ it is the lowest energy configura- ers run algorithms in a completely output system. It neither has way tion of the hydrophilic heads and different manner due to their lack of measuring its own velocity, nor hydrophobic tails of each phospho- of consciousness. The computer a way to alter its velocity, and so lipid molecule in the membrane. In “performs” algorithms simply could not follow the do… until other words, there are no instruc- through following a formal sym- instruction, or any of the oth- tions written somewhere to govern bol definition that precipitates ers. Additionally, a rock does not these behaviors; they are results of changes in the hardware and soft- propel itself; rather, gravity exerts physical and chemical processes. ware. Though both humans and a force on the rock that causes it Unfortunately, accepting that computers can use the same exact to move in a particular direction all things are results of physical algorithm to find the value of vari- at a particular speed. In other and chemical processes does not ables in a quadratic equation, the words, we know that a rock cannot by itself refute the proposal that processes which underlie their detect its progress, and aside from the brain is computational. Indeed, behavior are radically different. not having a propulsion system, it it is still possible to assert that all But the question still remains: Are wouldn’t be able to execute com- things in nature are intrinsically there any nonconscious algorithms mands if it did have a propulsion Iscomputational. everything intrinsically com- (i.e. computational processes) in system. putational? Whatthe brain? things in nature are poten- But does there exist anything tially capable of algorithmic be- in nature that does follow algo- havior? rithms? Immediately, it should occur to us that there is one prime This viewpoint has been fur- candidate: Life. Even the most thered by such prominent phi- basic life forms have organization losophers as Daniel Dennett, who In the post-Newtonian era, all which functions as an input/out- proposed that evolution was an al- of us can observe a natural process, put system. Paramecia have the gorithmic process. Others debate such as a rock falling from a cliff ability to sense changes internally this claim, however. John Searle, an overhang, and can imagine a ba- and in the environment, and thus opponent of this type of thinking sic set of laws or equations which can perform certain behaviors, e.g. stated in his book The Rediscov- could accurately model the rock’s food acquiring. Yet this by itself ery of the Mind, “…notions such as motion. It is also clear to us that does not indicate that any algo- computation, algorithm, and pro- the rock is not following an algorithm is being followed. Biological gram do not name intrinsic physi- rithm, which could look something processes are unique in their in- cal features of a system. Compu- like this: put/output organization, but this tational states are not discovered does not contradict the fact that all within physics, they are assigned Detach oneself from cliff face things that occur are still based on to the physics”. While(collision with chemical and physical processes. In order to understand this, let ground=FALSE) A cell membrane is not selectively us remember that computation can { permeable because it detects each be defined as a system of informa- Do{ substance on its exterior and pass- tion processing that relies on the Move towards the center of the es judgment on whether or not to mindless exchange of symbols, i.e. earth, increasing velocity by inter- let it through, but because the sub- the use of syntax. In much of his FALL 2010 | 59 OPINION

work, Searle vehemently points to brain contains “programs” of be- ficulties. Often times when such the fact that syntax is a formally havior which are somehow distinct a system is encountered, descrip- defined system which is imposed from neurobiology will never offer tions which focus on behavior, that upon a natural system. By this he explanations of how behaviors ac- is, on the input-output relationship means that the voltage levels of a tually arise from the neurobiology, displayed by the system, are put computer which we encode as 0’s and so are limited in their ability to forward, rather than explanations and 1’s, and in fact all state changes realistically portray what the brain which are based purely on physi- in any natural system, are not in Couldactually a does.network of Ordinary Dif- cal properties of the system. An themselves indicative of anything. ferential Equations constitute indispensable tool used in nearly Rather, we as observers assign real consciousness? all math and science, the algorithm, symbolic meanings to each state. is often used to generate similar In this sense, nothing is intrinsi- input-output relationships in a vir- cally computational. tual environment. Considering any given pattern Top-down approach aside, Upon first examination, it found in the brain, we could read- there are those whose efforts re- seems obvious that brains “run” ily ascribe a computational inter- volve around reconstructing the algorithms, simply because a brain pretation. But this does not mean brain from the bottom-up using appears to us as a black box func- that the brain is a digital computer, computers to simulate its most ba- tion, i.e. an entity which, when giv- or that it has a separate “program sic components. Networks of or- en specific input, produces specific2 level”, as has been the assumption dinary differential equations have output with some predictability . since Marr proposed a model of the been used to mimic the changes However, the same could be said brain that separated the neurobiol- in individual neurons as they for many other natural phenom- ogy from the other “higher” func- fire. But even this only provides ena, such as a projectile moving tions. As Searle said, “You don’t a simulation of the processes that through the air, or the formation need to suppose that there are any occur in the brain. There is still of phospholipid membranes. Each rules on top of the neurophysiolog- this assumption that the physiol- of these systems can be reduced Whatic structures.” does it mean for computer ogy that causes the brain to func- to a set of inputs or initial condi- science models of the brain if the tion is somehow incidental. On tions, which after a series of steps brain isn’t algorithmic? the contrary, the physicality of any or computations that are defined system is what causes it to behave by physical rules produce a pre- as it does. To suppose otherwise is dictable set of output. Indeed, unscientific. Thus efforts like Tom one can write algorithms which If the brain lacks any intrinsic Markram’s Blue Brain project may describe the behavior of each of algorithmic processes, then there succeed in simulating all processes these systems. But we have seen is no algorithm we’ll invent that in the brain perfectly, but such a that our unique position as observ- will recreate any fundamental pro- feat would not amount to creating ers creates the notion of a symbol, cesses in the brain. Computational a mind any more than simulating a and this predisposes us towards models that emphasize a top-down tornado1 will amount to creating a believing that nature contains its approach may be valuable for aca- Conclusiontornado . own inherent language of compu- demic fields that wish to use brain- tation. Were it not for the philo- like behavior for the purpose of sophical analysis of such problems, improving mechanical and com- we would forever be limited in our putational systems. But the top- With a certain degree of com- ability to understand the universe. down method of devising a compu- plexity, it is often difficult or impos- Though the implications of the tational model that represents the sible to decipher the processes of a brain’s lack of intrinsic algorithmic relationship between higher level system. Because the human brain processes may seem inconsequen- brain architectures and behaviors is radically more complex than tial, many areas of research oper- will fail to provide an ultimate ex- most natural phenomena, attempts ate under the assumption that the planation of how the brain works. to explain the operations and phys- brain is a computer. Of course, the Methods that operate under the ical processes which cause a brain majority of these projects are not mistaken assumption that the to function fall victim to these dif- concerned with creating a truly 60 | THE NERVE OPINION

Notes: conscious mind, but rather focus on Current research programs developing applications for small- that wholly embrace the philo- 1. That is not to say that it will scale artificial intelligence soft- sophical considerations related not provide valuable data on how ware, in which a simulation of be- to science are rare. Even Boston the brain works. Simulations are havior is appropriate. Projects that University’s own Cognitive and created and used for their ability to do aim to create a conscious mind, Neural Systems department barely supply vast amounts of knowledge however, may be faced with severe considers the myriad philosophi- about a particular system, knowl- difficulty unless they adapt their cal problems associated with the edge which may be otherwise inac- methods to reduce or eliminate the study of the mind. Institutions that cessible. But that is the extent of modeling of higher-level structures care only about the utility of the their abilities. in the brain. Henry Markram’s fruits of an experiment dominate 2. The mathematical definition Blue Brain project, for example, is the realm of scientific funding, as of a function requires that specific attempting to model the brain at they should. What these institu- input will always produce the same the molecular level, and so has a tions (and the scientists who ap- output, that is, the relation must much higher chance of creating a peal to them) tend to forget is that be totally predictable. While it can mind than if he were to model the robust theoretical deliberation be assumed that minute processes brain at a higher-level. In addition, improves the chances of practical, which occur in the brain during there may be success in attempts scientific success. It should be the normal operation respond predict- to build a physical recreation of aim of every research effort, then, ably to given inputs, the unpredict- the brain with synthetic materials to develop a solid theoretical para- ability of processes in the brain as analogous to the biological ones. digm that places their experiments a whole (due to the vast number This approach would excel not in context, and clearly defines the of contingencies within the brain) only because it emphasizes the im- domain in which results may ap- causes us to view the brain’s re- portance of the brain’s physicality, pear. Still, the scientific study of sponses as probabilistic rather but also because it would enable a the mind is relatively young. With than deterministic. Note however view into the precise relationships any luck, neuro-researchers will that if by some terrific feat of neu- and connections between the parts begin to recognize the significance roscience we could view how all of of the brain, and possibly explain of the philosophy of mind in time to these contingencies interacted, it how such relationships contribute guarantee the success of their sci- may be more appropriate to think to consciousness. entific endeavors. of the brain as deterministic.

Interested in Graduate Programs in Neuroscience? Check out Neuroscience at BU: bu.edu/neuro

FALL 2010 | 61 Undergraduate Program in Neuroscience:

The Undergraduate Program in Neuroscience is an interdisciplinary major leading to a Bachelor of Arts in Neuroscience that takes advantage of the rich neuroscience mission of multiple departments and campuses of Boston University. As a field, neuroscience has grown considerably over the last few decades through its integration of multiple disciplines; and, a current understanding of the field requires knowledge that spans traditional approaches while moving into the intersection between far- reaching technologies and new computational methods. This program combines breadth of exposure to the field as a whole with the opportunity for depth of experience in one of three central domains of neuroscience: Cellular and Systems, Cognition and Behavior, and Computational Neuroscience

Neuroscience students will have access to the extensive resources and expertise of affiliated faculty across multiple departments and colleges throughout the university. A wide array of courses are offered through the departments of Biology, Cognitive & Neural Systems, Computer Science, Mathematics & Statistics, Psychology, and Health Sciences in Sargent College. Together more than 50 upper level neuroscience elec- tives are offered, including laboratory courses and seminars.

Opportunities for independent laboratory research are available through multiple departments in the Colleges of Arts and Sciences and Engineer- ing, and at Boston University School of Medicine, including Anatomy and Neurobiology, Biochemistry, Neurology, Pathology, Pharmacology & Experimental Therapeutics, Physiology and Biophysics, and Psychia- try. Undergraduate research opportunities in neuroscience laboratories expand throughout the university across both the Charles River and Medical campuses. Don’t toss out that term paper! Submit it to The Nerve!

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