Dario Dieguez, Jr, PhD – Brain Blogger http://brainblogger.com Health and Science Blog Covering Brain Topics Wed, 30 May 2018 15:00:03 +0000 en-US hourly 1 https://wordpress.org/?v=4.9.6 Memories Are Made of These http://brainblogger.com/2014/07/21/memories-are-made-of-these/ http://brainblogger.com/2014/07/21/memories-are-made-of-these/#respond Mon, 21 Jul 2014 11:00:15 +0000 http://brainblogger.com/?p=16882 Since the early 1900s, scientists have pondered an age old question: what are memories made of? In the 1920s, Karl Lashley embarked on his famous journey to find “the engram” – the place in the brain where memories are stored. In 1949, Donald Hebb proposed his famous postulate of how memories could be formed, insisting that brain “cells that fire together, wire together” as part of a “cell assembly.” Since those early days of neuroscience, scientists have worked extensively to characterize brain mechanisms that could support memory formation.

The first support for Hebb’s idea was the demonstration of long-term potentiation (LTP), an increase in strength between connected groups of brain cells after artificial high-frequency stimulation. While this was an important demonstration that scientists would work to explain for the next several decades, they have not always agreed on whether LTP is a memory mechanism. Carol Barnes, Ph.D., Regents’ Professor of Psychology & Neurology at Arizona State University, posed the famous question – what would constitute proof? After decades of research, we finally have the answer.

The study was led by Nobel laureate Roger Y. Tsien, Ph.D., Professor of Pharmacology at the University of California at San Diego School of Medicine and Roberto Malinow, Ph.D., Professor of Neuroscience at the University of California at San Diego and National Academy of Sciences member. The study was published online in the June 2014 issue of Nature.

To investigate, the researchers trained rats to fear a tone by pairing it with a foot shock, which resulted in freezing behavior indicative of fear learning. Subsequently, the researchers replaced the tone with a pulse of blue light that could be used to stimulate specific inputs to the lateral amygdala, part of the brain’s fear learning center.

In these rats, the lateral amygdala had previously been injected with a virus containing a gene capable of producing light-sensitive channels that could respond to light stimulation, an approach known as optogenetics. In this paradigm, pairing the pulse of light (aimed at the rats’ lateral amygdalae) with a foot shock produced robust fear learning, as indicated by freezing behavior.

Interestingly, cells of the lateral amygdala showed LTP, indicating that the light-driven stimulation of the amygdala was capable of inducing in LTP in rats that learned to fear. Interestingly, this light-driven fear memory could be inactivated by light stimulation capable of inducing long-term depression (a pattern opposite of LTP) in the amygdala. In this case, freezing behavior was not observed, indicating that LTP is an essential component of inducing fear memory in the amygdala. Importantly, light stimulation that re-induced LTP in the lateral amygdala was capable of reinstating the fear memory. These observations indicate that LTP of the lateral amygdala is necessary for fear learning.

While many previous studies have demonstrated parallels between LTP, LTD, and memory, this is the first study to directly manipulate specific populations of brain cells to demonstrate the relationship between LTP and behavioral memory.

“This is the best evidence so far, period,” said Eric R. Kandel, M.D., Nobel laureate and Professor of Brain Science at Columbia University. Indeed, “no previous studies showed definitively that LTP is a basis for and required for memory,” said Robert Malenka, M.D., Ph.D., Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine and National Academy of Sciences member.

Dr. Malinow is clearly happy that the experiments worked. “It’s a bit of a relief and we can celebrate a little too,” he said.

References

Barnes CA (1995). Involvement of LTP in memory: are we “searching under the street light”? Neuron, 15 (4), 751-4 PMID: 7576624

Callaway, E. (2014). Flashes of light show how memories are made Nature DOI: 10.1038/nature.2014.15330

Ciocchi S, Herry C, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, Ehrlich I, Sprengel R, Deisseroth K, Stadler MB, Müller C, Lüthi A. (2010). Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468(7321): 277-282. PMID: 21068837.

Hebb DO. (1949). The organization of behavior. John Wiley & Sons.

Josselyn SA (2010). Continuing the search for the engram: examining the mechanism of fear memories. Journal of psychiatry & neuroscience : JPN, 35 (4), 221-8 PMID: 20569648

Bliss TV, & Lomo T (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. The Journal of physiology, 232 (2), 331-56 PMID: 4727084

Lin JY, Knutsen PM, Muller A, Kleinfeld D, & Tsien RY (2013). ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation. Nature neuroscience, 16 (10), 1499-508 PMID: 23995068

Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, & Tonegawa S (2012). Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature, 484 (7394), 381-5 PMID: 22441246

Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, & Malinow R (2014). Engineering a memory with LTD and LTP. Nature PMID: 24896183

Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, Ryan TJ, & Tonegawa S (2013). Creating a false memory in the hippocampus. Science (New York, N.Y.), 341 (6144), 387-91 PMID: 23888038

Shors TJ, & Matzel LD (1997). Long-term potentiation: what’s learning got to do with it? The Behavioral and brain sciences, 20 (4) PMID: 10097007

Stevens CF (1998). A million dollar question: does LTP = memory? Neuron, 20 (1), 1-2 PMID: 9459434

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Young Blood Revitalizes the Aging Brain http://brainblogger.com/2014/06/13/young-blood-revitalizes-the-aging-brain/ http://brainblogger.com/2014/06/13/young-blood-revitalizes-the-aging-brain/#respond Fri, 13 Jun 2014 11:00:41 +0000 http://brainblogger.com/?p=16645 Have neuroscientists found the proverbial fountain of youth? The idea may not be as far-fetched as you think. Researchers recently reported that infusing blood from young mice into the circulation of elderly mice is sufficient to reverse brain aging.

Considering the increase in the proportion of elderly humans, the identification of new ways to maintain or enhance cognition during aging is of primary importance. Normal brain aging is marked by cellular and molecular changes thought to mediate cognitive decline. Researchers have long sought to increase the integrity of the aged brain in animal models. However, only recently, researchers have revived a century-old method, known as parabiosis, to help rescue the aging brain from decline.

The study, conducted by Tony Wyss-Coray, Professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine, in collaboration with researchers at the University of California at San Francisco, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, the AfaSci Research Laboratory, and the VA Palo Alto Health Care System, was published in the May 2014 issue of Nature Medicine.

To facilitate the transfer of blood from young (3 months) to aged (18 months) mice, the researchers surgically joined young and aged mice (so that they shared the same circulatory system) for five weeks or injected young blood into the tails of aged mice. Previously, the researchers utilized similar methods to show that exposure to young blood increased stem cell function in the brains of aged mice. In the current studies, the researchers sought to investigate whether exposure to young blood could improve molecular, physiological, and behavioral measures of learning and memory in aged mice.

Aged mice exposed to young blood for five weeks showed a significant increase in the number of cells in the hippocampus, a structure important for learning and memory, positive for signaling molecules (including Erg-1, c-Fos, and pCREB) important for learning processes. In addition, these aged mice showed a significantly increased number of dendritic spines, portions of brain cells that receive signals in order to help transmit information, in the dentate gyrus of the hippocampus. In brain slices prepared from these mice, a physiological process that underlies learning, known as long-term potentiation, was significantly enhanced in the dentate gyrus of aged mice exposed to young blood. Importantly, the parabiosis procedure itself did not cause significant changes in general health, behavior, or stress response in the mice that were surgically fused together.

“We’ve shown that at least some age-related impairments in brain function are reversible. It was as if these old brains were recharged by young blood,” said Dr. Wyss-Coray.

Additional studies showed that aged mice exposed to young blood showed enhanced learning in two behavioral models of memory that depend on the hippocampus – the radial arm water maze and contextual fear conditioning. Lastly, the researchers showed that CREB signaling was necessary for the increase in dendritic spines observed in the dentate gyrus of aged mice and contributes significantly to the enhancement of behavioral learning and memory in aged mice.

“There are factors present in blood from young mice that can recharge an old mouse’s brain so that it functions more like a younger one,” said Dr. Wyss-Coray. “We’re working intensively to find out what those factors might be and from exactly which tissues they originate. We don’t know yet if this will work in humans,” he said.

References

Bishop NA, Lu T, & Yankner BA (2010). Neural mechanisms of ageing and cognitive decline. Nature, 464 (7288), 529-35 PMID: 20336135

Bliss TV, & Collingridge GL (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361 (6407), 31-9 PMID: 8421494

Conboy MJ, Conboy IM, & Rando TA (2013). Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging cell, 12 (3), 525-30 PMID: 23489470

Hebert LE, Scherr PA, Bienias JL, Bennett DA, & Evans DA (2003). Alzheimer disease in the US population: prevalence estimates using the 2000 census. Archives of neurology, 60 (8), 1119-22 PMID: 12925369

Rosenzweig ES, & Barnes CA (2003). Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Progress in neurobiology, 69 (3), 143-79 PMID: 12758108

Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, & Wyss-Coray T (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477 (7362), 90-4 PMID: 21886162

Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, & Wyss-Coray T (2014). Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature medicine PMID: 24793238

Image via Fer Gregory / Shutterstock.

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Can a Blood Test Predict Alzheimer’s disease? http://brainblogger.com/2014/05/25/can-a-blood-test-predict-alzheimers-disease/ http://brainblogger.com/2014/05/25/can-a-blood-test-predict-alzheimers-disease/#comments Sun, 25 May 2014 11:00:23 +0000 http://brainblogger.com/?p=16581 Alzheimer’s disease (AD) is an irreversible brain disease that causes progressive dementia. It currently affects over 35 million people worldwide and is expected to affect 115 million by 2050. A recent report indicates that AD claimed over 503,000 lives in Americans aged 75 and older in 2010. Abnormal changes in the brain are thought to begin several years prior to behavioral manifestations of the disease. This extended “pre-clinical phase” of AD represents a unique window of opportunity for therapeutic intervention.

However, at present, there are no known cures or therapies that can reduce the abnormal brain changes associated with AD (amyloid plaques and neurofibrillary tangles). This is likely due, at least in part, to the inability to accurately diagnose AD prior to the emergence of marked behavioral changes and memory loss. The results of a new study offer hope that this may now be possible.

In the past two decades, remarkable progress has been made in the ability to detect biomarkers for early AD, including measurement of plaques and tangles in cerebrospinal fluid, structural and functional magnetic resonance imaging of the abnormal AD brain, and the recent use of brain amyloid imaging. However, these methods are of limited utility since they are either invasive, time consuming, or expensive. Therefore, identification of useful blood-based biomarkers for pre-clinical AD would be ideal to facilitate the development of disease-modifying or preventative therapies.

A study led by Howard J. Federoff, M.D., Ph.D., Executive Vice President for Health Sciences, Executive Dean, and Professor of Neurology at Georgetown University Medical Center, has accomplished just that. The study, conducted in a collaboration among investigators at Georgetown University, University of Rochester School of Medicine, Unity Health System, Rochester General Hospital, University of California at Irvine, Temple University School of Medicine, and Regis University School of Pharmacy, was published in the April 2014 issue of Nature Medicine.

The researchers followed 525 study participants as part of the Rochester/Orange County Aging Study over the course of the 5-year observational study period. All participants were community-dwelling adults living in the Rochester, NY and Irvine, CA communities. For inclusion in the study, participants had to be aged 70 or older, proficient with written and spoken English, and have corrected vision and hearing necessary to complete the battery of cognitive tests.

Individuals who fulfilled any of the following conditions were excluded from the study: presence of major psychiatric or neurological disorders (including AD, stroke, epilepsy, or psychosis) at the time of study enrollment, current or recent use of anticonvulsants, neuroleptics, highly active antiretroviral therapy, antiemetics, or antipsychotics, or presence of any serious blood diseases. All study participants underwent an annual blood test and an annual battery of tests to assess five cognitive domains, including attention, executive function, language, memory, and visuospatial perception. Results of all cognitive tests were adjusted for age, sex, education, and visit.

Classification of study participants as part of either the amnesic mild cognitive impairment or mild AD (aMCI/AD) or normal control group was based on measures of memory performance. The normal control group included participants who matched those in the aMCI/AD group for age, sex, and education. Over the course of the study, 74 participants met criteria for aMCI/AD. Of these, 46 were incidental cases upon study entry and 28 converted from non-impaired memory to aMCI/AD (“Converters”) during the study. The average time for such conversion was 2.1 years.

In the third year of the study, 53 participants with either aMCI or AD (including 18 Converters) were selected to participate in the blood biomarker discovery studies. An additional 41 participants, consisting of the remaining 21 participants in the aMCI/AD group (including 10 Converters), and 20 matched NC participants, were included in subsequent validation studies. Remarkably, a panel of ten lipids in the blood were found to be at significantly lower levels in those destined to become Converters (previously described above), as compared to that in  normal participants, predicted conversion (from normal) to either aMCI or AD within a two to three year timeframe with 90% accuracy.

These lipids normally function to provide structural and functional support to normal cell membranes (the outer, protective layers of cells). Therefore, reduced levels of these ten lipids in the blood may represent a breakdown of normal cell membrane integrity in participants destined to acquire aMCI or AD. In addition, they may mark the transition period from normal to aMCI or AD when abnormal changes in the brain may first become associated with changes in memory.

“We consider our results a major step towards the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify individuals at risk for AD,” said Dr. Federoff.

“If successful, it would be a major step in assisting the pharmaceutical industry in producing disease-modifying therapies at both early and late preclinical stages of dementia,” said Gisele Wolf-Klein, M.D., Director of Geriatric Education at North Shore-LIJ Health System, who was not involved in the study.

References

Hulstaert F, Blennow K, Ivanoiu A, Schoonderwaldt HC, Riemenschneider M, De Deyn PP, Bancher C, Cras P, Wiltfang J, Mehta PD, Iqbal K, Pottel H, Vanmechelen E, & Vanderstichele H (1999). Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF. Neurology, 52 (8), 1555-62 PMID: 10331678

James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K, & Bennett DA (2014). Contribution of Alzheimer disease to mortality in the United States. Neurology, 82 (12), 1045-50 PMID: 24598707

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, & Långström B (2004). Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Annals of neurology, 55 (3), 306-19 PMID: 14991808

Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, Macarthur LH, Hall WJ, Fisher SG, Peterson DR, Haley JM, Nazar MD, Rich SA, Berlau DJ, Peltz CB, Tan MT, Kawas CH, & Federoff HJ (2014). Plasma phospholipids identify antecedent memory impairment in older adults. Nature medicine, 20 (4), 415-8 PMID: 24608097

McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, & Phelps CH (2011). The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 7 (3), 263-9 PMID: 21514250

Small SA, Perera GM, DeLaPaz R, Mayeux R, & Stern Y (1999). Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Annals of neurology, 45 (4), 466-72 PMID: 10211471

Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, & Phelps CH (2011). Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 7 (3), 280-92 PMID: 21514248

Thambisetty M, & Lovestone S (2010). Blood-based biomarkers of Alzheimer’s disease: challenging but feasible. Biomarkers in medicine, 4 (1), 65-79 PMID: 20387303

World Health Organization. Dementia: A Public Health Priority (World Health Organization, Geneva, 2012).

Image via Africa Studio / Shutterstock.

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Remembering Henry Molaison http://brainblogger.com/2014/03/03/remembering-henry-molaison/ http://brainblogger.com/2014/03/03/remembering-henry-molaison/#comments Mon, 03 Mar 2014 12:00:37 +0000 http://brainblogger.com/?p=16014 Henry Gustav Molaison (1926-2008) was perhaps the best-known and most studied patient in the history of neuroscience. Henry became the subject of a scientific article which would become one of the most cited articles in the history of medical literature.

At around the age of ten, Henry began having epileptic seizures, which became more severe over time, compromising his health, school performance, and social life. As an adult, Henry’s ability to work and function independently were severely impaired by his seizures in spite of taking high doses of anticonvulsant medications. In an effort to alleviate Henry’s seizures, neurosurgeon William Beecher Scoville performed an experimental brain operation on Henry, then 27, to remove portions of his medial temporal lobes, including a large portion of the hippocampus, which may have been the source of his seizures.

The article showed that, while Henry’s seizures were reduced in frequency, he acquired unexpected amnesia after his surgery. Henry was a normal, intelligent young man who had no memory impairments prior to his surgery. His acquired amnesia, therefore, was attributed to the surgical removal of his medial temporal lobes. This would prove to be a medical breakthrough, since the neurological substrate of memory in the brain was unknown at the time of Henry’s operation.

Thanks to Henry’s willingness to undergo extensive scientific testing, the modern era of memory research essentially began with evidence from his case. He was unexpectedly unable to retain new information – a condition known as anterograde amnesia, which prevents the process of consolidation, which transfers short-term into long-term memories. Reminiscent of the main character in the movie Memento, Henry was able to hold information in his mind through rehearsal, but could not store that information in long-term memory. Therefore, for all practical purposes, Henry lived only in the present tense. For example, Henry could not recognize members of the hospital staff who cared for him extensively during his stay. In fact, from recorded interviews with Henry, it is clear that he could not remember what he had eaten for lunch on any given day, or identify the current President of the United States.

Prior to his death from respiratory failure on December 2, 2008 in a Connecticut nursing home at the age of 82, he was popularly known as Patient H.M., Henry M., or, simply H.M. Shortly before Henry’s death, his guardians authorized the release of audio recordings made of him in the early 1990s, which were made available online by National Public Radio. These audio recordings represented the first opportunity for the general public to hear his voice and poignantly captured the essence of his existence, which included discernable optimism and good will – all in spite of his profound surgery-induced memory impairments.

After Henry’s death, his full name was made publicly available and the story of his life was published by neuroscientist Suzanne Corkin, Ph.D., Professor of Neuroscience, Emerita, at the Massachusetts Institute of Technology, in her book, Permanent Present Tense: The Unforgettable Life of the Amnesic Patient, H.M., which details Henry’s remarkable contributions to neuroscience.

Henry’s profound memory impairment had an enormously negative impact on his quality of life. Although Henry’s semantic memory (conscious recollections of facts and general knowledge about the world) for the years before his surgery was preserved, especially that for major world events, he was unable to recall any autobiographical memories from that time. In spite of this, Henry’s personality, language, attention, intellectual abilities, and short-term memory all remained unaffected. In fact, based on tests performed ten months after his surgery, Henry’s IQ was above average. Interestingly, further testing revealed that Henry had a number of preserved learning and memory functions (including normal performance in motor skill learning, perceptual learning, and visuoperceptual priming), even while claiming he could not recall these learning experiences and, therefore, lacked that declarative knowledge (“knowing that”). This revealed, for the first time, that non-declarative or procedural learning (“knowing how”), which was normal in Henry, relied on memory circuits separate from those in the medial temporal lobe and that it did not require conscious memory processes.

Since brain imaging technology was not available at the time of Henry’s surgery, the nature and extent of his brain lesions could not be visualized until much later. Computerized tomography (CT) scans of Henry’s brain were first published in 1984, although they did not clearly reveal the nature and extent of tissue damage in his medial temporal lobes. Later, in the 1990s, magnetic resonance imaging (MRI) indicated that his lesions included most of the amygdaloid complex and entorhinal cortex, as well as a large portion of the hippocampal formation. These MRI scans, however, did not reveal the exact anatomical boundaries of the lesions in Henry’s medial temporal lobes.

After Henry’s death, his brain was donated to science and sent to The Brain Observatory at the University of California at San Diego, where, as part of Project HM, it could be expertly cut and simultaneously recorded in a series of high resolution neuroanatomical images. From these images, it was possible to construct a detailed microscopic level mapping and to make 3D measurements from a digital model of Henry’s brain.

A research team, led by neuroanatomist Jacopo Annese, Ph.D., Founder and Director of The Brain Observatory, and Matthew Frosch, M.D., Ph.D., Director of Neuropathology Service at Massachusetts General Hospital, performed histological sectioning and digital 3D reconstruction of Henry’s brain. Project H.M., funded by the National Science Foundation, Dana Foundation, National Eye Institute, and National Institute of Mental Health, clearly delineated the exact anatomical locations of Henry’s brain lesions for the first time.

The findings, published online in Nature Communications, were based on 2,401 digital images of Henry’s brain, which was cut in an uninterrupted 53-hour procedure that was streamed live on the internet on the one-year anniversary of Henry’s death. “I didn’t sleep for three days,” said Dr. Annese. “It was probably the most engaging, most exciting thing I’ve ever done,” he said.

The results show that there was complete removal of Henry’s anterior hippocampus and most of his entorhinal cortex, although a substantial portion of presumably non-functional hippocampal tissue remained. “These initial results confirm what we already knew about the size and shape of Henry’s brain lesions,” said Dr. Corkin. In addition, there was a near-complete removal of the amygdala, which may explain Henry’s dampened expression of emotions, poor motivation, lack of initiative, and inability to identify internal states such as pain, hunger, and thirst. Moreover, the results showed that Henry had a small lesion in the left frontal lobe of unknown origin that had never previously been identified. Whether this newly discovered frontal lobe lesion had any influence on Henry’s behavior is currently unknown.

Also noteworthy was the visualization of atrophy of the cerebellum, which had been previously identified via brain imaging and which Henry acquired as a side effect of long-term use of Dilantin, part of Henry’s seizure management both before and after his surgery. Lastly, the results also showed that Henry had diffuse damage to deep white matter (insulation for parts of brain cells) underlying the removed medial temporal lobes, which appeared to be a recent age-related phenomenon attributable to medical conditions, including hypertension.

Henry Molaison lived solely in the present tense for 55 years, during which time he taught us more about memory and the brain than we had ever thought possible. By all accounts, Henry enjoyed participating in the research being conducted on him and expressed happiness, saying: “What they find out about me helps them to help other people.”

Undoubtedly, Henry’s contributions to neuroscience will never be forgotten, but rather will last forever. “Henry’s disability, a tremendous cost to him and his family, became science’s gain,” said Dr. Corkin.

References

Annese J, Schenker-Ahmed NM, Bartsch H, Maechler P, Sheh C, Thomas N, Kayano J, Ghatan A, Bresler N, Frosch MP, Klaming R, & Corkin S (2014). Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction. Nature communications, 5 PMID: 24473151

Buchen L (2009). Famous brain set to go under the knife. Nature, 462 (7272) PMID: 19940891

Corkin S. (2013). Permanent Present Tense: The Unforgettable Life of the Amnesic Patient, H.M. Jackson, TN: Basic Books.

Corkin S (2002). What’s new with the amnesic patient H.M.? Nature reviews. Neuroscience, 3 (2), 153-60 PMID: 11836523

Corkin S, Amaral DG, González RG, Johnson KA, & Hyman BT (1997). H. M.’s medial temporal lobe lesion: findings from magnetic resonance imaging. The Journal of neuroscience : the official journal of the Society for Neuroscience, 17 (10), 3964-79 PMID: 9133414

Corkin S, Amaral DG, González RG, Johnson KA, & Hyman BT (1997). H. M.’s medial temporal lobe lesion: findings from magnetic resonance imaging. The Journal of neuroscience : the official journal of the Society for Neuroscience, 17 (10), 3964-79 PMID: 9133414

Hughes, V. (2014, January 28). After death, H.M.’s brain uploaded to the cloud. National Geographic RSS. Retrieved February 2, 2014.

Newhouse, B. (2007, February 24). H.M.’s brain and the history of memory. National Public Radio. Retrieved February 2, 2014.

SCOVILLE WB, & MILNER B (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of neurology, neurosurgery, and psychiatry, 20 (1), 11-21 PMID: 13406589

Thomson, H. (2014, January 28). Neuroscience’s most famous brain is reconstructed. New Scientist RSS. Retrieved February 2, 2014.

Image via Oliver Sved / Shutterstock.

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Drug-Induced Mystical Experience http://brainblogger.com/2012/02/27/drug-induced-mystical-experience/ http://brainblogger.com/2012/02/27/drug-induced-mystical-experience/#comments Mon, 27 Feb 2012 13:00:27 +0000 http://brainblogger.com/?p=10120 Psilocybin, a naturally occurring hallucinogen, is the main psychoactive component of psilocybe and other hallucinogenic mushrooms (so called “magic mushrooms”). Like other classic hallucinogens, such as d-lysergic acid diethylamide (LSD) and mescaline, psilocybin exerts its psychoactive effects through a sub-type of serotonin receptors (called 5-HT2a) in the brain. In some cultures, psilocybin has historically been used in religious contexts — likely for millennia. Psilocybin has a number of effects, including changes in perception, cognition, affect, and decision-making. Clinical research on psilocybin dates back to at least the 1950s, with variable effects on the perceived affective character of the experience. Research on psilocybin administration in humans has occurred in psychotherapeutic contexts in terminally ill cancer patients dating back to the 1970s and continues today. A surprising new study reveals that, under specific conditions, acute exposure to psilocybin can elicit long-lasting positive changes and increases in mystical-type experience.

A research team headed by Rolland R. Griffiths, PhD, professor of neuroscience in the Department of Neuroscience at Johns Hopkins University School of Medicine, performed the study in collaboration with Robert Jesse, founder of The Council on Spiritual Practices in San Francisco. The study was published in a recent issue of Psychopharmacology.

To investigate, the researchers sought study volunteers from the local community through flyers announcing a study of states of consciousness induced by psilocybin. Two-hundred seventy-nine people were screened by telephone and 31 were further screened in person. Eighteen study volunteers, eight of which were males, were tested for physical and mental health prior to initiation of the study. Volunteers were tested for common drugs of abuse and those with current alcohol or drug dependence (including nicotine) were excluded, as were those with a past history within the past 20 years of alcohol or drug dependence (excluding nicotine). Study volunteers had never used a hallucinogenic drug, except for one who had used psilocybin mushrooms on two occasions over 20 years previously. Study volunteers did not receive monetary compensation for participation in the study. Rather, their only motivation was curiosity about the effects of psilocybin and the opportunity for extensive self-reflection within the context of the study.

The double-blind study involved the administration of multiple doses of psilocybin (0, 5, 10, 20, and 30 mg for every 70 kilograms) during five 8-hour sessions conducted at 1-month intervals and a 14-month follow-up. Study volunteers were randomly assigned to receive either increasing or decreasing doses of psilocybin (in capsule form), with nine volunteers in each group. Drug sessions occurred in an aesthetic living room-like environment in the presence of two study “monitors,” who were present throughout all drug exposure periods for a given study volunteer but were unaware of the drug dose sequences. For most of the time during the drug sessions, volunteers were encouraged to lie down on the couch, use an eye mask to block external visual stimuli, and use headphones through which a music program was played. Volunteers were encouraged to focus their attention on their inner experiences throughout the drug sessions. At multiple time points throughout the study, blood pressure and heart rate were recorded for each volunteer. In addition, at the same time points, study monitors rated each volunteer’s mood and behavior. At seven hours after initial drug exposure (when drug effects had worn off), volunteers completed three questionnaires designed to assess subjective aspects of the hallucinogenic experiences, as well as two questionnaires to assess mystical experience.

At 14 months after the last drug session, study volunteers were interviewed to gain information about their study experiences and life situation. At this time, the volunteers filled out a questionnaire (which included some items related to mystical experience) and were also asked to provide written descriptions about the drug sessions, including how their behavior changed in response to the drug experiences. As an additional measure, three adults having regular contact with each study volunteer (“community observers”) were interviewed multiple times after the study to rate different aspects of the study volunteer’s behavior. At the conclusion of the study, the study monitors were asked to rate any enduring changes in the volunteer’s attitude and behavior they believed resulted directly from the drug sessions.

The research team reports that psilocybin produced significant dose- and time-related effects on blood pressure and heart rate in study volunteers over a six-hour period after initial drug exposure. During this time, monitors rated significant changes in study volunteers due to overall drug effects, including, stimulation/arousal, peace/harmony, distance from ordinary reality, and joy/intense happiness. For about 39% of study volunteers, monitors rated a significant, psilocybin-induced, unpredictable course of extreme anxiety or fearfulness, mostly at the higher drug doses. About 44% of study volunteers reported transient delusional or paranoid thinking, mostly at the higher doses, including some of those who experienced anxiety or fear. However, as noted by Dr. Griffiths, “if we reduce the dose a little, we have just as much of the same positive effects and the properties of the mystical experience remain the same, but there is a five-fold decrease in anxiety and fearfulness.”

At seven hours after initial drug exposure, study volunteers filled out three questionnaires about the drug experience, in which they reported a variety of significant dose-related effects typical of hallucinogens. These included perceptual changes (eg., visual pseudo-hallucinations and illusions), labile moods (eg., feelings of transcendence, grief, joy, and/or anxiety), and cognitive changes (eg., sense of meaning or insight). At this time, study volunteers also reported significant dose-related effects on measures of states of consciousness (eg., internal and external unity, sacredness, transcendence of time and space, and deeply felt positive mood) and mystical experience.

The long-term effects of the psilocybin sessions are perhaps even more striking. At 14 months after initial drug exposure, study volunteers rated significant dose-related effects of the drug sessions. These included positive ratings of attitudes about life and the self, mood, social and behavioral effects, well-being, life satisfaction, spirituality, a sense of continuity after death, as well as the personal and spiritual meaningfulness of the drug experience. In addition, at this time, the positive ratings reported about states of consciousness and mystical experience at seven hours after initial drug exposure were still present. Interestingly, at this time, most volunteer questionnaires about the drug experience indicated increased physical and psychological self-care, as well as increased spiritual practice. Post-study ratings of study volunteers by study monitors and community observers at 14 months after initial drug exposure were consistent with all of the aforementioned changes. Importantly, clinical interviews with study volunteers indicated that none reported clinically significant post-study adverse events or non-study hallucinogen use since study enrollment. At this time, all of the study volunteers appeared to be psychologically healthy, high-functioning, productive members of society.

Remarkably, most of the study volunteers (including the volunteer who experienced the highest level of transient psilocybin-induced anxiety) rated the highest dose drug sessions as the single most personally meaningful and spiritually significant event of their lives. This psilocybin-induced spirituality appears similar to that reported in case studies of individuals reporting spontaneous mystical experience. The authors suggest that, based on these and other studies, therapeutic use of psilocybin may be clinically useful in psychiatric settings when administered under specific, controlled conditions, but acknowledge that this is controversial.

“The important point here is that we found the sweet spot where we can optimize the positive effects of psilocybin while avoiding the fear and anxiety,” said Griffiths. Jerome H. Jaffe, MD, clinical professor of psychiatry at the University of Maryland School of Medicine, who served as the first White House “Drug Czar” but was not involved in the study, said “the Hopkins psilocybin studies clearly demonstrate significant and lasting benefits, but this route to the mystical is not to be walked alone.”

Griffiths and colleagues do warn against casual use of psilocybin (especially at high doses) and caution that the present results may be limited to the study population — a group of hallucinogen-naïve, well-educated, psychologically stable, mostly middle-aged adults, most of whom participate in religious or spiritual activities on a weekly basis. The authors conclude by highlighting that 70% of study volunteers reported having a “complete” psilocybin-induced mystical experience, which is considerable in comparison to what they refer to as “the rarity of spontaneous mystical experiences in the general population.”

References

Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, & Jesse R (2011). Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology, 218 (4), 649-65 PMID: 21674151

Griffiths R, Richards W, Johnson M, McCann U, & Jesse R (2008). Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of psychopharmacology (Oxford, England), 22 (6), 621-32 PMID: 18593735

Griffiths RR, Richards WA, McCann U, & Jesse R (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187 (3) PMID: 16826400

Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, & Greer GR (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of general psychiatry, 68 (1), 71-8 PMID: 20819978

Johnson, M., Richards, W., & Griffiths, R. (2008). Human hallucinogen research: guidelines for safety Journal of Psychopharmacology, 22 (6), 603-620 DOI: 10.1177/0269881108093587

LEARY T, LITWIN GH, & METZNER R (1963). REACTIONS TO PSILOCYBIN ADMINISTERED IN A SUPPORTIVE ENVIRONMENT. The Journal of nervous and mental disease, 137, 561-73 PMID: 14087676

Richards WA, Grof S, Goodman LE, and Kurland AA (1972). LSD-assisted psychotherapy and the human encounter with death. Journal of Transpersonal Psychology 4:121–150.

Image via chantal de bruijne / Shutterstock.

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The NeuroSocial Network http://brainblogger.com/2011/09/08/the-neurosocial-network/ http://brainblogger.com/2011/09/08/the-neurosocial-network/#comments Thu, 08 Sep 2011 07:50:48 +0000 http://brainblogger.com/?p=7098 Social neuroscience is a rapidly growing discipline that examines the relationship between the brain and social behavior. The “social brain hypothesis” posits that, over evolutionary time, living in large, social groups favored the physical growth of brain regions important for social behavior. In non-human primates, some evidence indicates that the size of the amygdala is related to social behavior. Little is known, however, about this relationship in humans. A provocative new study finds that the volume of a key component of the social brain, the amygdala, is directly related to the size and complexity of social networks in adult humans.

A research team headed by Lisa F. Barrett, Ph.D., Distinguished Professor of Psychology at Northeastern University, used brain imaging to study the relationship between the volume of the amygdala and social network size and complexity in both males and females.

To investigate, the researchers recruited 58 healthy adults (22 women and 36 men, aged 19-83 years, with average age of 53) with normal intelligence and no major mental disorders to participate in the study. Each participant underwent magnetic resonance imaging (MRI) in order to assess the volume of multiple brain regions, including the amygdala (important for emotions such as fear) and the hippocampus (important for learning and memory). Importantly, head size was corrected for in the measurement of each participant’s brain volume. In addition, the researchers used two versions of a questionnaire called the Social Network Index to evaluate the size (reflected by the total number of contacts), as well as the complexity (reflected by the number of different groups that contacts belong to), of each participant’s social network. Subsequently, the research team used advanced statistical methods to evaluate the relationship between the volume of different brain regions and social network size and complexity.

In a study published in a recent issue of Nature Neuroscience, the research team reports that people having larger and more complex social networks have larger amygdala volumes. These results persisted even when biological (such as age and amygdalae on different sides of the brain) and social (such as life satisfaction and perceived social support) factors were taken into account. Importantly, the volume of the hippocampus (measured for purposes of comparison) was not related to either the size or complexity of social networks. Further analyses also demonstrated a similar lack of relationship between the size of additional brain regions and social network variables. Amygdala volume was not related to other social variables, such as life satisfaction or perceived social support. These results demonstrate the specificity of the relationship between amygdala volume and social network parameters. Interestingly, when the participants were considered separately by age and sex, the relationship between amygdala volume and social networks was less pronounced in older participants, as well as in males (regardless of age).

This study is the first to report that the volume of the amygdala is related to social network variables within a single species. The researchers suggest that this phenomenon may have served, in evolutionary time, to facilitate greater social intelligence in order to accommodate the demands of an increasingly complex social life. It should be noted, however, that the results merely indicate a correlation; that is, people who have greater amygdala volumes have larger social networks, but it is unknown whether having greater amygdala volume leads to having a larger and more complex social network, or vice versa. Dr. Barrett said “it is probably a little of both.”

Imaging studies of amygdala volume as related to social behavior have mostly been conducted in individuals with autism or psychopathy/antisocial personality and have yielded variable results. Even in normal humans lacking any such disorders, the exact relationship between amygdala volume and social functioning has remained somewhat elusive. So, is a bigger amygdala better? The answer remains to be definitely determined. However, a bigger amygdala is likely to be better equipped to accommodate more social information from more people in more contexts. In this sense, a bigger amygdala may facilitate greater social intelligence.

The research findings have potential significance for a growing body of literature suggesting that emotional memories in the amygdala can be rewired during a process known as “reconsolidation” (during which time old memories can be updated with new information) in order to help people suffering from post-traumatic stress disorder. “We hope to be able to discover how abnormalities in the amygdala and related brain regions may impair social behavior in psychiatric and neurological conditions,” said Dr. Barrett.

References

Bickart KC, Wright CI, Dautoff RJ, Dickerson BC, & Barrett LF (2011). Amygdala volume and social network size in humans. Nature neuroscience, 14 (2), 163-4 PMID: 21186358

Hartley CA, & Phelps EA (2010). Changing fear: the neurocircuitry of emotion regulation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 35 (1), 136-46 PMID: 19710632

Lewis KP, & Barton RA (2006). Amygdala size and hypothalamus size predict social play frequency in nonhuman primates: a comparative analysis using independent contrasts. Journal of comparative psychology (Washington, D.C. : 1983), 120 (1), 31-7 PMID: 16551162

Monfils MH, Cowansage KK, Klann E, & LeDoux JE (2009). Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science (New York, N.Y.), 324 (5929), 951-5 PMID: 19342552

Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, & Phelps EA (2010). Preventing the return of fear in humans using reconsolidation update mechanisms. Nature, 463 (7277), 49-53 PMID: 20010606

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Imaging the Musical Brain http://brainblogger.com/2011/03/04/imaging-the-musical-brain/ http://brainblogger.com/2011/03/04/imaging-the-musical-brain/#comments Fri, 04 Mar 2011 12:00:09 +0000 http://brainblogger.com/?p=6190 Humans experience pleasure from a variety of stimuli, including food, money, and psychoactive drugs. Such pleasures are largely made possible by a brain chemical called dopamine, which activates what is known as the mesolimbic system — a network of interconnected brain regions that mediate reward. Most often, rewarding stimuli are biologically necessary for survival (such as food), can directly stimulate activity of the mesolimbic system (such as some psychoactive drugs), or are tangible items (such as money). However, humans can experience pleasure from more abstract stimuli, such as art or music, which do not fit into any of these categories. Such stimuli have persisted across countless generations and remain important in daily life today. Interestingly, the experience of pleasure from these abstract stimuli is highly specific to cultural and personal preferences.

Recent brain imaging studies indicate that dopamine-rich areas of the brain become activated when people listen to music or during learning when food and money are presented as rewards. However, these studies cannot exclude the possibility that chemicals other than dopamine contribute to this brain activity. In addition, animal studies indicate that reward can occur in the brain even in the absence of dopamine. The precise role of dopamine in eliciting brain activity that mediates pleasurable experiences has not been well-studied with brain imaging techniques, especially in humans actively engaged in these pleasurable experiences.

A research team headed by Robert J. Zatorre, Ph.D., Professor of Neurology and Neurosurgery at McGill University, used multiple brain imaging techniques — positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) — to study dopamine activity in the brain while people listened to pleasurable music. PET was used to identify brain areas having dopamine activity while fMRI was used to measure blood flow in the brain over time. The researchers hoped to combine the power of PET to identify brain regions showing increased dopamine activity with the power of fMRI to determine the precise timing of these changes while participants listened to pleasurable music.

To investigate, the researchers recruited eight participants having a wide range of musical experience for participation in the study. The participants were aged 19-24 and provided 10 pieces of instrumental music they found pleasurable and to which they experienced chills. The music used in the study included a wide range of genres – classical, folk, jazz, electronica, rock, punk, techno, and tango. For inclusion in the study, the participants must experience chills of similar magnitude at times of extreme pleasure consistently at the same point throughout the music regardless of environment or association with a specific memory. People having a history of medical or psychiatric illness, or substance abuse, were excluded from the study.

During PET scanning, participants listened to self-selected pleasurable music in one session and neutral music in another. In order to utilize similar sets of stimuli throughout the study, as well as for purposes of comparison, one participant’s pleasurable music was used as another’s neutral music. For each PET session, participants listened to music for 15 minutes, were injected with a radiolabeled substance (that competes with dopamine for binding to certain dopamine receptors), and listened to music for another 60 minutes. While listening to music in the PET scanner, participants provided subjective ratings of pleasure by pressing a button when they experienced a chill, and rated both the intensity of each chill and the degree of pleasure felt on a 10-point scale  (1 = neutral; 10 = extremely pleasurable). Also during PET scanning, the researchers simultaneously measured a number of other physiological indicators of arousal, including chills, heart rate, respiration (breathing) rate, and skin conductance (electrical impulses on the skin indicative of heightened emotional state).

During subsequent fMRI scanning, participants listened to alternations of their self-selected pleasurable music and other participants’ neutral music over a 40-minute period. Here, participants pressed a button when experiencing a chill and rated the degree of pleasure they experienced while listening to music on a scale of 1 to 3 (1 = Neutral, 2 = Low Pleasure, 3 = High Pleasure).

In a study published in the February 2011 issue of Nature Neuroscience, the research team reports that participants rated their experience of the pleasurable music condition as being more pleasurable than the neutral music condition. Also, the more chills experienced by the participants, the greater the pleasure they reported experiencing while listening to music. In addition, several indicators of physiological arousal, including heart rate, respiration, and skin conductance, increased significantly during the pleasurable music condition as compared to the neutral music condition. Furthermore, the greater the intensity of the chills experienced by participants while listening to music, the greater the degree to which they experienced increases in the aforementioned indicators of physiological arousal.

PET scans showed increased dopamine activity in the striatum (part of the mesolimbic system) during the pleasurable music condition as compared to the neutral music condition. fMRI scans showed that different parts of the striatum released dopamine to ‘want’ or ‘like’ the music at different times. During peak pleasure experiences (as indicated by chills while listening to music), there was increased blood flow in the nucleus accumbens, which may signal liking of the music. By contrast, there was increased blood flow in the caudate during periods of anticipation of peak pleasure experiences (15 seconds before each chill), which may signal wanting (anticipating) the music.

This study provides the first direct evidence that pleasure experienced while listening to music is associated with dopamine activity in the mesolimbic reward system. This phenomenon may be made possible by the ability of music to modulate emotional states and may help to explain why it has remained so highly valued across generations. “These findings provide neurochemical evidence that intense emotional responses to music involve ancient reward circuitry in the brain,” said Dr. Zatorre. “This study paves the way for future work to examine non-tangible rewards that humans consider rewarding for complex reasons,” he said.

References

Blood AJ, & Zatorre RJ (2001). Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proceedings of the National Academy of Sciences of the United States of America, 98 (20), 11818-23 PMID: 11573015

Cannon CM, & Palmiter RD (2003). Reward without dopamine. The Journal of neuroscience : the official journal of the Society for Neuroscience, 23 (34), 10827-31 PMID: 14645475

Egerton A, Mehta MA, Montgomery AJ, Lappin JM, Howes OD, Reeves SJ, Cunningham VJ, & Grasby PM (2009). The dopaminergic basis of human behaviors: A review of molecular imaging studies. Neuroscience and biobehavioral reviews, 33 (7), 1109-32 PMID: 19481108

Salimpoor VN, Benovoy M, Larcher K, Dagher A, & Zatorre RJ (2011). Anatomically distinct dopamine release during anticipation and experience of peak emotion to music. Nature neuroscience, 14 (2), 257-62 PMID: 21217764

Valentin VV, & O’Doherty JP (2009). Overlapping prediction errors in dorsal striatum during instrumental learning with juice and money reward in the human brain. Journal of neurophysiology, 102 (6), 3384-91 PMID: 19793875

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The Neuroscience of Fear and Loathing http://brainblogger.com/2011/01/19/the-neuroscience-of-fear-and-loathing/ http://brainblogger.com/2011/01/19/the-neuroscience-of-fear-and-loathing/#comments Wed, 19 Jan 2011 22:20:22 +0000 http://brainblogger.com/?p=5993 Fear is an innate emotion that is triggered by environmental stimuli perceived as potentially threatening or harmful. This emotion is so basic to human existence that its expression on a human face can be accurately recognized by anyone in the world. Thus, fear is a highly evolved, universal emotion whose existence is critical to survival.

Fear has long been thought to arise due to activity of cells in the amygdala, an almond-shaped brain structure located in the medial temporal lobe. In 1939, Heinrich Klüver and Paul Bucy reported that surgical removal of both temporal lobes (including the amygdalae) in monkeys produced a dramatic behavioral condition now referred to as the Klüver-Bucy syndrome. After surgery, the monkeys, who previously feared humans, no longer showed such fear. They also showed a number of other behavioral changes, including hyperorality (a compulsion to examine objects by mouth), hypersexuality (excessive sexual behavior), hypermetamorphosis (excessive tendency to react to visual stimuli), and visual agnosia (inability to recognize familiar objects). The exact role of the amygdala in human fear, however, has not been fully established (perhaps) until now.

For over two decades, researchers at the University of Iowa have been studying an extraordinary woman known only as patient SM, who acquired damage to both amygdalae (due to a rare congenital genetic condition known as Urbach-Wiethe disease). The researchers sought to examine the induction and experience of fear in SM (now a 44-year old woman) in a variety of experimental settings. Specifically, the researchers exposed SM to live snakes and spiders, took her on a tour of a haunted house, and showed her clips from several scary movies (including The Ring, Halloween, Seven, and Silence of the Lambs). SM provided her written consent to participate and the researchers took great pains to only expose SM to situations capable of inducing fear with little risk of direct harm. Additional studies were conducted utilizing self-report questionnaires (over a period of three years) and experience sampling (over three months). In experience sampling studies, SM provided input to a computerized emotional diary, in which she rated her current emotional state utilizing a set of 50 randomly presented emotional terms. The emotional terms included a wide range of both positive and negative emotional states and were derived from the Positive and Negative Affect Schedule – Expanded Form (PANAS-X).

In a study published in the January 11, 2011 issue of Current Biology, the researchers report that SM did not show fear in any of the aforementioned scenarios. When taken to an exotic pet store, SM voluntarily held a large snake for three minutes even though she has often said that she “hates” them and “tries to avoid them.” She seemed fascinated with the snake and said, “this is so cool!” while holding it. SM asked the store employee 15 times if she could also hold a larger, more dangerous snake, but this was not allowed to avoid the possibility of her being harmed. SM also attempted to touch a tarantula but was stopped so that she would not be bitten. When asked why she would want to touch a dangerous snake in spite of claiming to hate snakes, SM indicated that she was overcome with “curiosity.” When taken to a Halloween haunted house at the Waverly Hills Sanatorium in Louisville, Kentucky (ranked as “one of the most haunted places in the world”), SM voluntarily led a group of five strangers through the haunted house and showed no signs of fear or hesitation. “This way guys, follow me!” she repeatedly exclaimed. Ironically, SM scared one of the monsters by poking it in the head because she was “curious.” When asked about her experience at the haunted house, SM likened it to the excitement felt while riding a roller coaster — an activity she claims to enjoy. When shown a set of 10 different fear-inducing film clips, SM showed no behavior indicative of fear. She found the fear-inducing films to be exciting and, in one case, asked the name of the movie so that she could rent it later that day. Interestingly, SM commented that most people would fear the content of the films even though she did not. Importantly, SM was also shown a number of other film clips intended to evoke disgust, anger, happiness, and surprise and, in each case, reported experiencing high levels of the respective emotions during the films. It is also worth noting that, over the past two decades, SM has consistently performed in the normal range in terms of IQ, memory, language, and perception.

In support of these behavioral observations, SM scored consistently below normal on eight well-validated self-report questionnaires intended to evaluate the level of fear a person may experience in a variety of scenarios (such as public speaking or dying). In addition, in studies of experience sampling, SM’s PANAS-X score was at the lowest possible level. SM consistently rated feeling the lowest possible levels of the following: “afraid,” “scared,” “fearful,” “nervous,” “guilty,” and “ashamed.” She also reported feeling the highest average rating for “fearless.” Importantly, for all basic emotions other than fear, SM reported experiencing them on numerous occasions to varying degrees — from “a little” to “quite a bit.”

Despite SM’s apparent deficit, she does understand what fear is and reports having felt fear on multiple occasions before the age of 10 — likely around the time that her congenital condition resulted in amygdala damage. During adulthood, SM had multiple experiences that may be considered traumatic (such as being held up at knife point and gun point and being nearly killed in an act of domestic violence) to which she responded with a marked lack of fear or urgency. It is clear that SM’s impaired ability to detect dangerous situations likely contributes greatly to her high incidence of life-threatening experiences. Regardless, SM appears unaware of her deficit and is unable to elaborate about why she is being studied (other than to indicate that the researchers studying her want to understand how her brain damage affects her behavior).

Several limitations of this study limit the conclusions that can be drawn from its findings. First, brain imaging indicates that SM’s brain damage is not entirely limited to the amydgalae and extends into nearby brain regions. Second, this study provides only preliminary evidence about whether SM’s experience of emotions other than fear is in the normal range. Third, SM is a single case and, ideally, these findings should be replicated in other similar cases.

In sum, these findings indicate that patient SM exhibits a significant deficit in the ability to experience fear across a wide variety of situations. As SM is capable of experiencing other emotions normally, she is not emotionless, but rather fearless. This case study, when coupled with data acquired in amydgala-damaged animals, indicates that the amygdala is critical for triggering the experience of fear. As indicated by the authors, SM’s unique case suggests that, without the amygdala, the evolutionary value of fear is lost.

SM’s amygdala damage appears to render her immune to the effects of post-traumatic stress disorder (PTSD), an intriguing hypothesis that is supported by results from recent studies in amygdala-damaged war veterans. “This finding points us to a specific brain area that might underlie PTSD,” said senior study author Daniel Tranel, Ph.D., Director of University of Iowa’s Interdisciplinary Graduate Program in Neuroscience. “Psychotherapy and medications are the current treatment options for PTSD and could be refined and further developed with the aim of targeting the amygdala,” said Dr. Tranel.

References

Ekman P, Sorenson ER, & Friesen WV (1969). Pan-cultural elements in facial displays of emotion. Science (New York, N.Y.), 164 (3875), 86-8 PMID: 5773719

Elfenbein HA, & Ambady N (2002). On the universality and cultural specificity of emotion recognition: a meta-analysis. Psychological bulletin, 128 (2), 203-35 PMID: 11931516

Feinstein JS, Adolphs R, Damasio A, & Tranel D (2011). The human amygdala and the induction and experience of fear. Current biology : CB, 21 (1), 34-8 PMID: 21167712

Klüver H, and Bucy PC. (1939). Preliminary analysis of functions of the temporal lobe in monkeys. Archives of Neurology & Psychiatry 42: 979-1000.

Koenigs M, Huey ED, Raymont V, Cheon B, Solomon J, Wassermann EM, & Grafman J (2008). Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nature neuroscience, 11 (2), 232-7 PMID: 18157125

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Love Can Alleviate Pain http://brainblogger.com/2010/12/24/love-can-alleviate-pain/ http://brainblogger.com/2010/12/24/love-can-alleviate-pain/#comments Fri, 24 Dec 2010 12:00:07 +0000 http://brainblogger.com/?p=5853 The early stages of a new, romantic relationship are associated with feelings of euphoria, which likely arise from brain mechanisms responsible for sensations of pleasure or reward. Imaging studies have shown that viewing pictures of a new, romantic partner elicits brain activity in multiple reward processing centers in the brain. Interestingly, these findings have now been replicated in a sample of Chinese participants, suggesting that patterns of brain activation elicited by viewing pictures of a romantic partner may be universal.

A research team headed by Sean Mackey, M.D., Ph.D., Chief of Stanford University School of Medicine’s Pain Management Division, wondered whether viewing pictures of a new, romantic partner could reduce experimentally induced pain. The research team examined whether or not viewing pictures of a new, romantic partner would be associated with specific patterns of brain activity that may mediate reward or relief of pain.

To investigate, Dr. Mackey’s team recruited 15 students to participate in the study during the first nine months of a new, romantic relationship. Each participant reported being intensely in love, which was confirmed numerically by use of the Passionate Love Scale. The participants included eight women and seven men, aged 19-21 years. Each participant underwent functional magnetic resonance imaging (fMRI) of the brain, which measures change in blood flow due to changes in brain activity. While in the brain scanner, each participant was asked to concentrate on each of the following: a picture of their romantic partner, a picture of an acquaintance of the same gender and similar attractiveness as the romantic partner, and a non-emotional word-association task.

Each condition was presented while the participants were made to experience no, moderate, or high levels of pain induced by exposure to varying levels of heat on the non-dominant hand for 15 seconds. Each pairing of condition and pain level was repeated six times in random order. Immediately after each pairing, participants used their dominant hand to rate the level of pain they experienced on a scale of 0 to 10 (0 = no pain at all and 10 = worst pain imaginable). After each pain rating, participants counted backwards for 13 seconds to minimize sensory and emotional carryover between trials.

In a study published in a recent issue of PLoS One, the research team reports that viewing pictures of a new, romantic partner significantly reduced pain, but viewing pictures of the acquaintance did not. fMRI results showed that several brain regions implicated in reward and emotion increased in activity during viewing of the romantic partners, including the frontal cortex, amygdala, and hypothalamus. In addition, fMRI data showed that brain regions implicated in the processing of pain, such as the insula, decreased in activity during viewing of the romantic partners. Interestingly, increased activation of brain regions such as the caudate and nucleus accumbens was associated with pain relief during viewing of the romantic partners but not during the word-association task. The caudate and nucleus accumbens have been consistently implicated in reward and include both classic brain reward pathways (namely, the “mesolimbic” and “nigrostriatal” pathways).

Not all of the patterns of brain activation induced by viewing pictures of romantic partners, however, were specific to reward. For example, some brain regions activated by the “love task” described here are also associated with activation of brain areas responsible for memory, attention, and sexual arousal. In addition, the researchers had no way to determine how much attention a given participant was paying to the pictures during the experiment. Surprisingly, there was no specific brain region that increased in activity during viewing pictures of a romantic partner to a degree similar to the extent of the pain relief experienced.

Overall, the results indicate that specific behavioral experiences can reduce pain without drugs. “When patients are doing markedly better and I find out they are in a new, passionate relationship, I may be less likely to think it’s the new medication I put them on, said Dr. Mackey. “I realize that maybe it has nothing to do with me,” he said.

The authors suggest that the pain relief associated with activation of brain reward systems described here may confer an evolutionary advantage in humans. Specifically, the alleviation of pain during the pursuit of a rewarding stimulus (in this case, the romantic partner) may facilitate attempts to attain specific goals even in spite of facing potentially harmful stimuli.

References

Altier N, & Stewart J (1998). Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. The Journal of pharmacology and experimental therapeutics, 285 (1), 208-15 PMID: 9536012

Aron A, Fisher H, Mashek DJ, Strong G, Li H, & Brown LL (2005). Reward, motivation, and emotion systems associated with early-stage intense romantic love. Journal of neurophysiology, 94 (1), 327-37 PMID: 15928068

Kelley AE, & Berridge KC (2002). The neuroscience of natural rewards: relevance to addictive drugs. The Journal of neuroscience : the official journal of the Society for Neuroscience, 22 (9), 3306-11 PMID: 11978804

Master SL, Eisenberger NI, Taylor SE, Naliboff BD, Shirinyan D, & Lieberman MD (2009). A picture’s worth: partner photographs reduce experimentally induced pain. Psychological science : a journal of the American Psychological Society / APS, 20 (11), 1316-8 PMID: 19788531

Xu, X., Aron, A., Brown, L., Cao, G., Feng, T., & Weng, X. (2010). Reward and motivation systems: A brain mapping study of early-stage intense romantic love in Chinese participants Human Brain Mapping DOI: 10.1002/hbm.21017

Younger J, Aron A, Parke S, Chatterjee N, & Mackey S (2010). Viewing pictures of a romantic partner reduces experimental pain: involvement of neural reward systems. PloS one, 5 (10) PMID: 20967200

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Are Rhesus Monkeys Self-Aware? http://brainblogger.com/2010/11/18/rhesus-monkeys-self-aware/ http://brainblogger.com/2010/11/18/rhesus-monkeys-self-aware/#comments Thu, 18 Nov 2010 12:00:45 +0000 http://brainblogger.com/?p=5698 Conventional wisdom from cognitive science posits that a variety of animals can recognize themselves in the mirror and, therefore, possess self-awareness. Traditionally, macaque monkeys have not been included among them, but a new study utilizing refined behavioral methods reveals that rhesus monkeys can indeed recognize themselves in the mirror. The results appear to reconcile a decades-old conundrum about presumably variable self-recognition abilities among evolutionarily distinct primates.

Traditionally, scientists have assessed mirror self-recognition abilities in animals based on their performance on the “mark test.” In this test, marks are placed on an animal’s face and, subsequently, its behavior in front of a mirror is observed. If the animal spends increased time touching the marks or looking at them in the mirror, then it passes the mark test and is assumed to possess at least a rudimentary form of self-awareness. Select chimpanzees, orangutans, elephants, dolphins, and even magpies pass the mark test while gorillas and macaque monkeys do not.

A research team headed by Dr. Luis C. Populin at the University of Wisconsin-Madison suspected that macaque monkeys might be self-aware even though they fail the mark test consistently, even in their own laboratory. This suspicion arose when the researchers noticed the macaques grooming themselves while looking in the mirror after having a surgical implant affixed to their skulls.

Rhesus monkeys that had been exposed to mirrors throughout most of their lives were videotaped during exposure to one of the following hung outside their cage: a small mirror, a large mirror, or a mirror covered with black, non-reflective plastic. Multiple independent observers viewed and scored the videotapes for the occurrence of social and self-directed behaviors. Occurrence of the former (for example, signs of aggression such as open-mouth threats) suggests that a monkey may interpret his mirror image as another monkey, while the latter (self-examination, for example) indicates mirror self-recognition. All of the monkeys studied had previously been prepared with skull implants to facilitate physiological recordings from their brains. However, for purposes of comparison, some monkeys were also observed prior to receiving their skull implants.

In a study recently published in PLoS One, the research team reports that macaques looked at the small mirror at an increased rate, and at an even greater rate in the large mirror. These effects were not observed when the mirrors were covered with black, non-reflective plastic. In addition, the rate at which the monkeys touched unseen body parts was increased almost tenfold with either the small or large mirror compared to when no mirror was present. Moreover, when the large mirror was present, the rate at which social behaviors occurred declined significantly while the rate of self-directed behaviors remained elevated and stable. Interestingly, monkeys without skull implants did not observe themselves in the mirror, but proceeded to do so after the implants were affixed to their skulls.

Mirror-self recognition is a learned ability. Even in children at a specific developmental stage, its expression varies depending on intelligence level, cultural background, and testing conditions. The findings of this study indicate that, although macaque monkeys fail the traditional mark test, they are nonetheless able to recognize themselves in the mirror when the saliency of the mirror image is increased (in this case, with the skull implant). The researchers suggest that the skull implant serves as a “super mark” which facilitates learning of mirror self-recognition in rhesus monkeys. Thus, the traditional mark test may not be an adequate way to assess mirror self-recognition in all species and this ability indeed appears to exist on an evolutionary continuum.

References

Plotnik JM, de Waal FB, & Reiss D (2006). Self-recognition in an Asian elephant. Proceedings of the National Academy of Sciences of the United States of America, 103 (45), 17053-7 PMID: 17075063

Prior H, Schwarz A, & Güntürkün O (2008). Mirror-induced behavior in the magpie (Pica pica): evidence of self-recognition. PLoS biology, 6 (8) PMID: 18715117

Rajala AZ, Reininger KR, Lancaster KM, & Populin LC (2010). Rhesus monkeys (Macaca mulatta) do recognize themselves in the mirror: implications for the evolution of self-recognition. PloS one, 5 (9) PMID: 20927365

Reiss D, & Marino L (2001). Mirror self-recognition in the bottlenose dolphin: a case of cognitive convergence. Proceedings of the National Academy of Sciences of the United States of America, 98 (10), 5937-42 PMID: 11331768

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Translational Neuroscience – Untapped Potential for Education and Policy http://brainblogger.com/2010/10/10/translational-neuroscience-%e2%80%93-untapped-potential-for-education-and-policy/ http://brainblogger.com/2010/10/10/translational-neuroscience-%e2%80%93-untapped-potential-for-education-and-policy/#comments Sun, 10 Oct 2010 12:00:45 +0000 http://brainblogger.com/?p=5529 Recent decades have seen extraordinary advances in the fields of neuroscience, molecular biology, genetics, psychology, and cognitive science. In particular, the National Institutes of Health called the last 10 years of the 20th century the “Decade of the Brain.” Aside from the scientific advances made during that time, government agencies, foundations, and professional organizations put forth substantial efforts to increase public awareness about brain development and diseases. A growing number of neuroscientists indicate that these efforts need to be elevated in order for neuroscience findings to be translated into principles that can facilitate sound policymaking relevant to early childhood education.

Ten years ago, the Institute of Medicine and National Research Council published a report entitled From Neurons to Neighborhoods: The Science of Early Childhood Development, in which great emphasis was placed on the need to utilize knowledge about early childhood development to ensure the health and well-being of young children. Many are now taking this further and emphasize what they call “Neuro-Education” – the utilization of scientific findings about learning and environments to create more effective teaching methods and curricula, as well as to influence educational policy.

The lofty goals of Neuro-Education are deeply rooted in the knowledge that genes interact with both early experiences and environments to shape the structure and function of the developing brain. On this topic, neuroscience has been more informative regarding the negative consequences of these interactions in cases where, for example, early experiences and/or environments are less than ideal. For this reason, scientific contributions to policymaking have been focused on interventions in the lives of children facing considerable adversity. However, given the plethora of evidence suggesting that enriching early experiences have beneficial outcomes in terms of cognitive abilities, placing greater emphasis on this facet of policymaking holds considerable promise. In order for neuroscience to influence early childhood education and policy effectively, there must now be a focus on what can be done to increase the impacts of current educational interventions, as well as on how they can best be implemented. To this end, the power of critical periods in brain development, during which time experience has a particularly powerful influence, must be recognized and utilized as part of organized efforts to positively influence the cognitive, emotional, and social development of young children.

It is time for neuroscience to begin to realize its full translational potential in the world of educational policy. Children in the U.S. and beyond are not doing well academically. Arne Duncan, the U.S. Secretary of Education, called the state of education in America a national public health crisis. Importantly, some Neuro-Education initiatives have recently been established in order to begin to address these issues. In 2009, Dr. Thomas J. Carew, Professor of Neurobiology and Behavior at the University of California at Irvine, and then President of the Society for Neuroscience, created the Neuroscience Research in Education Summit, which gave rise to the creation of the Neuro-Education Leadership Coalition that is working to further the goals of Neuro-Education. Also, the Johns Hopkins University School of Education has established a Neuro-Education Initiative, which promotes the applicability of findings from neuroscience to inform and enrich educational practices. In addition, the Harvard Graduate School of Education offers master’s and doctoral degrees in Mind, Brain, and Education, which emphasize the applicability of the biological and cognitive sciences to pedagogy and public policy. Such efforts, however, are only a beginning.

Neuro-Education provides a framework within which science can inform education and public policy through the application of knowledge gained across multiple disciplines that have not traditionally worked in collaboration. If efforts in Neuro-Education are implemented on a large scale, they may help produce children that are better learners who can rise to the challenges required for leadership in the 21st century. Some have even argued that Neuro-Education may be financially and socially rewarding because, if successful, it may result in reduced costs associated with remedial education, clinical treatment, public assistance, and even incarceration. The existence of so many potentially favorable outcomes of Neuro-Education suggests that we, as a society, cannot afford to continue to do without it.

References

Carew TJ, & Magsamen SH (2010). Neuroscience and education: an ideal partnership for producing evidence-based solutions to Guide 21(st) Century Learning. Neuron, 67 (5), 685-8 PMID: 20826300

Shonkoff JP, & Levitt P (2010). Neuroscience and the future of early childhood policy: moving from why to what and how. Neuron, 67 (5), 689-91 PMID: 20826301

Shonkoff JP, & Phillips DA, eds. (2000). From Neurons to Neighborhoods: The Science of Early Childhood Development (Washington, DC: National Academy Press).

Society for Neuroscience (2009). Neuroscience Research in Education Summit: The Promise of Interdisciplinary Partnerships Between Brain Sciences and Education [PDF]

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Fear-Reducing Drugs – An Emerging Science? http://brainblogger.com/2010/09/19/fear-reducing-drugs-an-emerging-science/ http://brainblogger.com/2010/09/19/fear-reducing-drugs-an-emerging-science/#comments Sun, 19 Sep 2010 12:00:58 +0000 http://brainblogger.com/?p=5423 A new animal study reveals that a brain protein can reduce the expression of fear when infused into specific parts of the brain involved in behavioral responses to fear-inducing stimuli. The findings have important implications for the possible development of new drug therapies that can mimic these effects in humans with anxiety disorders or post-traumatic stress disorder.

Brain-derived neurotrophic factor (BDNF) is a brain protein that has been implicated in the expression of fearful behaviors in both humans and animals. A number of studies have shown that BDNF and related proteins play an important role in psychiatric conditions such as anxiety and depression. The role of BDNF in behavioral fear responses is currently a subject of intense investigation.

A research team headed by Dr. Gregory Quirk at the University of Puerto Rico School of Medicine thought that it might be possible to reduce the expression of fear in rats by manipulating levels of BDNF in specific parts of the brain thought to be involved in the expression of fearful behaviors.

To investigate, the research team trained rats to become fearful of a tone that was paired to a mild footshock in a procedure known as auditory fear conditioning. In order to test how fearful the rats had become of the tone, the researchers tested how much time the rats spent engaged in freezing behavior, in which rats cease physical movements and appear frozen for a brief period around the time of a fear-inducing event (in this case, the tone). On subsequent tests, the rats were trained to become less fearful of the tone by no longer pairing it to a footshock. After this so-called extinction training, freezing behavior could again be observed in order to determine the degree to which the rats no longer feared the tone.

In a study published in Science, the researchers demonstrated that, after auditory fear conditioning, fearful rats show better performance in response to extinction training (i.e., show reduced fear of the tone, as shown by reduced freezing behavior) when BDNF is infused into a part of the brain called the infralimbic pre-frontal cortex, a structure involved in behavioral expressions of fear. Remarkably, even when BDNF was given in the absence of extinction training, the rats showed reduced freezing behavior. Importantly, BDNF had no effect on the initial learning of fear, but only affected its behavioral expression.

In additional experiments, the researchers show that rats exhibiting better extinction of fear had increased levels of BNDF (than more fearful rats) in the hippocampus, a brain structure that activates the infralimbic pre-frontal cortex. Furthermore, in rats treated with drugs to inactivate the effects of BDNF in the infralimbic pre-frontal cortex, BDNF infusions no longer resulted in enhanced extinction (i.e., reduced fear behavior).

Together, the findings shed light on the workings of brain circuits responsible for behavioral expressions of fear, as well as suggest how they can be manipulated with drugs to reduce fearful behaviors. The researchers suggest that these results may help pave the way for future efforts to treat humans with anxiety disorders or post-traumatic stress disorder. This study is particularly timely because, earlier this year, other studies reported that a single change in the DNA sequence in the gene responsible for producing BDNF is associated with impaired fear extinction and increased anxiety in humans.

BDNF and related proteins have been extensively studied in humans and animals, but drugs intended to manipulate levels of BDNF in human brains have not yet been developed. The remaining challenge is to apply findings from animal studies of BDNF to drug discovery and clinical settings, where drugs can be developed and tested, respectively, for their ability to increase BDNF levels in brain circuits mediating fear behaviors in humans. Since BDNF can substitute for extinction training (i.e., training to no longer be fearful) in animals, its future applicability to pharmacotherapeutics in humans with anxiety disorders or post-traumatic stress disorder is a viable possibility.

References

Alleva E, & Francia N (2009). Psychiatric vulnerability: suggestions from animal models and role of neurotrophins. Neuroscience and biobehavioral reviews, 33 (4), 525-36 PMID: 18824030

Montag C, Basten U, Stelzel C, Fiebach CJ, & Reuter M (2010). The BDNF Val66Met polymorphism and anxiety: Support for animal knock-in studies from a genetic association study in humans. Psychiatry research, 179 (1), 86-90 PMID: 20478625

Peters J, Dieppa-Perea LM, Melendez LM, & Quirk GJ (2010). Induction of fear extinction with hippocampal-infralimbic BDNF. Science (New York, N.Y.), 328 (5983), 1288-90 PMID: 20522777

Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, Jing D, Tottenham N, Amso D, Somerville LH, Voss HU, Glover G, Ballon DJ, Liston C, Teslovich T, Van Kempen T, Lee FS, & Casey BJ (2010). A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science (New York, N.Y.), 327 (5967), 863-6 PMID: 20075215

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