Heavy marijuana users have abnormal brain structure and poor memory

Drug abuse appears to foster brain changes that resemble schizophrenia CHICAGO --- Teens who were heavy marijuana users -- smoking it daily for about three years -- had abnormal changes in their brain structures related to working memory and performed poorly on memory tasks, reports a new Northwestern Medicine® study. A poor working memory predicts poor academic performance and everyday functioning. The brain abnormalities and memory problems were observed during the individuals' early twenties, two years after they stopped smoking marijuana, which could indicate the long-term effects of chronic use. Memory-related structures in their brains appeared to shrink and collapse inward, possibly reflecting a decrease in neurons. The study also shows the marijuana-related brain abnormalities are correlated with a poor working memory performance and look similar to schizophrenia-related brain abnormalities. Over the past decade, Northwestern scientists, along with scientists at other institutions, have shown that changes in brain structure may lead to changes in the way the brain functions. This is the first study to target key brain regions in the deep subcortical gray matter of chronic marijuana users with structural MRI and to correlate abnormalities in these regions with an impaired working memory. Working memory is the ability to remember and process information in the moment and -- if needed -- transfer it to long-term memory. Previous studies have evaluated the effects of marijuana on the cortex, and few have directly compared chronic marijuana use in otherwise healthy individuals and individuals with schizophrenia. The younger the individuals were when they started chronically using marijuana, the more abnormally their brain regions were shaped, the study reports. The findings suggest that these regions related to memory may be more susceptible to the effects of the drug if abuse starts at an earlier age. "The study links the chronic use of marijuana to these concerning brain abnormalities that appear to last for at least a few years after people stop using it," said lead study author Matthew Smith, an assistant research professor in psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine. "With the movement to decriminalize marijuana, we need more research to understand its effect on the brain." Alcoholism and Drug Abuse Counselors Continuing Education The paper will be published Dec. 16 in the journal Schizophrenia Bulletin. In the U.S., marijuana is the most commonly used illicit drug and young adults have the highest -- and growing -- prevalence of use. Decriminalization of the drug may lead to greater use. Because the study results examined one point in time, a longitudinal study is needed to definitively show if marijuana is responsible for the brain changes and memory impairment. It is possible that the abnormal brain structures reveal a pre-existing vulnerability to marijuana abuse. But evidence that the younger a subject started using the drug the greater his brain abnormality indicates marijuana may be the cause, Smith said. The groups in the study started using marijuana daily between 16 to 17 years of age for about three years. At the time of the study, they had been marijuana free for about two years. A total of 97 subjects participated, including matched groups of healthy controls, subjects with a marijuana use disorder, schizophrenia subjects with no history of substance use disorders, and schizophrenia subjects with a marijuana use disorder. The subjects who used marijuana did not abuse any other drugs. Few studies have examined marijuana's effect on the deep regions in the brain -- the 'subcortical gray matter' below the noodle-shaped cortex. The study also is unique in that it looked at the shapes of the striatum, globus pallidus and thalamus, structures in the subcortex that are critical for motivation and working memory. The Marijuana and Schizophrenia Connection Chronic use of marijuana may contribute to changes in brain structure that are associated with having schizophrenia, the Northwestern research shows. Of the 15 marijuana smokers who had schizophrenia in the study, 90 percent started heavily using the drug before they developed the mental disorder. Marijuana abuse has been linked to developing schizophrenia in prior research. "The abuse of popular street drugs, such as marijuana, may have dangerous implications for young people who are developing or have developed mental disorders," said co-senior study author John Csernansky, M.D., chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. "This paper is among the first to reveal that the use of marijuana may contribute to the changes in brain structure that have been associated with having schizophrenia." Chronic marijuana use could augment the underlying disease process associated with schizophrenia, Smith noted. "If someone has a family history of schizophrenia, they are increasing their risk of developing schizophrenia if they abuse marijuana," he said. While chronic marijuana smokers and chronic marijuana smokers with schizophrenia both had brain changes related to the drug, subjects with the mental disorder had greater deterioration in the thalamus. That structure is the communication hub of the brain and is critical for learning, memory and communications between brain regions. The brain regions examined in this study also affect motivation, which is already notably impaired in people with schizophrenia. "A tremendous amount of addiction research has focused on brain regions traditionally connected with reward/aversion function, and thus motivation," noted co-senior study author Hans Breiter, M.D., professor of psychiatry and behavioral sciences and director of the Warren Wright Adolescent Center at Feinberg and Northwestern Memorial. "This study very nicely extends the set of regions of concern to include those involved with working memory and higher level cognitive functions necessary for how well you organize your life and can work in society." "If you have schizophrenia and you frequently smoke marijuana, you may be at an increased risk for poor working memory, which predicts your everyday functioning," Smith said. ### The research was supported by grants R01 MH056584 and P50 MH071616 from the National Institute of Mental Health and grants P20 DA026002 and RO1 DA027804 from National Institute of Drug Abuse, all of the National Institutes of Health.

Gene found to be crucial for formation of certain brain circuitry

Identified using new technique that can speed identification of genes, drug candidates Using a powerful gene-hunting technique for the first time in mammalian brain cells, researchers at Johns Hopkins report they have identified a gene involved in building the circuitry that relays signals through the brain. The gene is a likely player in the aging process in the brain, the researchers say. Additionally, in demonstrating the usefulness of the new method, the discovery paves the way for faster progress toward identifying genes involved in complex mental illnesses such as autism and schizophrenia — as well as potential drugs for such conditions. A summary of the study appears in the Dec. 12 issue of Cell Reports. "We have been looking for a way to sift through large numbers of genes at the same time to see whether they affect processes we're interested in," says Richard Huganir, Ph.D., director of the Johns Hopkins University Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, who led the study. "By adapting an automated process to neurons, we were able to go through 800 genes to find one needed for forming synapses — connections — among those cells." Although automated gene-sifting techniques have been used in other areas of biology, Huganir notes, many neuroscience studies instead build on existing knowledge to form a hypothesis about an individual gene's role in the brain. Traditionally, researchers then disable or "knock out" the gene in lab-grown cells or animals to test their hypothesis, a time-consuming and laborious process. In this study, Huganir's group worked to test many genes all at once using plastic plates with dozens of small wells. A robot was used to add precise allotments of cells and nutrients to each well, along with molecules designed to knock out one of the cells' genes — a different one for each well. "The big challenge was getting the neurons, which are very sensitive, to function under these automated conditions," says Kamal Sharma, Ph.D., a research associate in Huganir's group. The team used a trial-and-error approach, adjusting how often the nutrient solution was changed and adding a washing step, and eventually coaxed the cells to thrive in the wells. In addition, Sharma says, they fine-tuned an automated microscope used to take pictures of the circuitry that had formed in the wells and calculated the numbers of synapses formed among the cells. The team screened 800 genes in this way and found big differences in the well of cells with a gene called LRP6 knocked out. LRP6 had previously been identified as a player in a biochemical chain of events known as the Wnt pathway, which controls a range of processes in the brain. Interestingly, Sharma says, the team found that LRP6 was only found on a specific kind of synapse known as an excitatory synapse, suggesting that it enables the Wnt pathway to tailor its effects to just one synapse type. "Changes in excitatory synapses are associated with aging, and changes in the Wnt pathway in later life may accelerate aging in general. However, we do not know what changes take place in the synaptic landscape of the aging brain. Our findings raise intriguing questions: Is the Wnt pathway changing that landscape, and if so, how?" says Sharma. "We're interested in learning more about what other proteins LRP6 interacts with, as well as how it acts in different types of brain cells at different developmental stages of circuit development and refinement." Another likely outcome of the study is wider use of the gene-sifting technique, he says, to explore the genetics of complex mental illnesses. The automated method could also be used to easily test the effects on brain cells of a range of molecules and see which might be drug candidates Continuing Education for Social Workers ### Other authors on the paper are Se-Young Choi, now of Seoul National University School of Dentistry; Yong Zhang, Shunyou Long and Min Li of Johns Hopkins University School of Medicine; and Thomas J.F. Nieland, now of the Broad Institute of Harvard and MIT. This work was supported by grants from the Howard Hughes Medical Institute and the National Institute of Mental Health (grant numbers P50MH084020 and 5U54MH084691). Related stories: Gene Found to Foster Synapse Formation in the Brain http://www.hopkinsmedicine.org/news/media/releases/gene_found_to_foster_synapse_formation_in_the_brain Study Refutes Accepted Model of Memory Formation http://www.hopkinsmedicine.org/news/media/releases/study_refutes_accepted_model_of_memory_formation____ Newly Discovered "Switch" Plays Dual Role in Memory Formation http://m.hopkinsmedicine.org/news/media/releases/newly_discovered_switch_plays_dual_role_in_memory_formation

Aging and gene expression -- possible links to autism and schizophrenia in offspring

Advanced paternal age has been associated with greater risk for psychiatric disorders, such as schizophrenia and autism. With an increase in paternal age, there is a greater frequency of certain types of mutations that contribute to these disorders in offspring. Mutations are changes in the genetic code. Recent research, however, looks beyond the genetic code to "epigenetic effects", which do not involve changes in the genes themselves, but rather in how they are expressed to determine one's characteristics. Such epigenetic changes in sperm, related to ageing, have been linked with psychiatric disorders in offspring. Maria Milekic, PhD, reported today, at the American College of Neuropsychopharmacology annual meeting in Hollywood Florida, that old mice have an epigenetic change ‒ a loss of DNA methylation at the locations where the genetic code starts being transcribed. DNA methylation is a biochemical process that plays an important regulatory role in development and disease. The work was done by a research team in the Department of Psychiatry at Columbia University. Offspring of old fathers showed the same deficit in DNA methylation, and they differed in their behavior from the offspring of the young fathers. They showed less exploratory activity and differed in the startle response and in habituation. Two groups, with 10 breeder mice per group, were tested. The breeders were either old (12 month) or young (3 month) males, each bred with two young (3 month) female mice. Then the behavior of the offspring was tested when they were 3 months old. DNA methylation also was tested in the young and old fathers' sperm, and brains of the offspring were tested for DNA methylation as well as gene expression. "We were interested in understanding the mechanism of the paternal age effect", said Dr. Milekic."The risk for schizophrenia increases 2-fold when a father is over 45 years of age, and the risk for autism increases 2-5-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism." Not only did the offspring of the old fathers differ from their counterparts with young fathers in DNA methylation, they also showed significant differences in the expression of genes that have been implicated in autism spectrum disorders and that are known to regulate the development and function of the brain. These findings point to possible factors that can lead to autism spectrum disorders and schizophrenia, and ultimately may lead to more effective therapeutic interventions. With respect to studies in the immediate future, Dr. Milekic said,"We are trying to evaluate changes in different brain regions. Our studies before did not compare brain regions. Most of the genes that have altered expression are in the cerebellum. We are interested in how DNA methylation in the cerebellum is affected by paternal age." Social Worker CEUs ### The work was supported by grants from NIMH and the Simon Foundation to Jay Gingrich, MD, PhD, and a NARSAD Young Investigator Awa rd from the Brain and Behavior Research Foundation to Dr. Milekic.

Mental stress + heart disease: Stronger presence in women under 50

Patients with recent heart attack tested with public speaking task Researchers have found that women younger than 50 with a recent heart attack are more likely to experience restricted blood flow to the heart (myocardial ischemia) in response to psychological stress. The finding may partly explain why younger women who are hospitalized after a heart attack face a greater risk of complications and dying, compared to men of the same age. The results are scheduled to be presented Wednesday, Nov. 20 at the American Heart Association Scientific Sessions meeting in Dallas. Researchers at Emory University have been studying the responses of patients who recently had a heart attack to exercise stress and mental stress, in the form of public speaking on an emotional topic. They have found that women age 50 and below are more likely to experience mental stress-induced ischemia, compared to men of the same age (52 percent compared to 25 percent). The MIMS (Myocardial Infarction and Mental Stress) study included 49 men and 49 women, age-matched pairs who all had a heart attack in the last six months. Their ages ranged from 38 to 59. Among study participants older than 50, there were no significant sex differences in mental stress-induced ischemia;, however, men older than 50 had a rate of exercise-induced ischemia that was twice as high as women of a similar age. "This is the first study to examine the cardiovascular effects of psychological stress as a possible mechanism for the greater mortality after myocardial infarction among younger women," says study leader Viola Vaccarino, MD, PhD, professor and chair of the Department of Epidemiology, Rollins School of Public Health. "We saw a dramatic difference in mental stress-induced ischemia specifically in younger women. In addition, when ischemia was graded in a continuous way, we saw that it was twice as severe among the younger women." Women who experience a heart attack before age 50 are relatively rare, suggesting that perhaps those who do simply have more severe heart disease. However, even when investigators adjusted for different rates of traditional heart disease risk factors such as smoking and diabetes, the disparity remained. In fact, women tended to have less severe coronary artery disease, measured by examining the degree of blockage in their coronary arteries. One possible explanation the Emory investigators considered was a higher burden of psychosocial stress, Vaccarino says. In the study, the younger women were more often poor, of minority race, with a history of sexual abuse and with higher levels of depressive symptoms. "Yet if we look at the statistics, factors such as poverty, race and depression do not explain the difference," she says. "Yes, women have more stressors. But our data show that women also may be more vulnerable to the effects of mental stress on the heart." "This could be an added stimulus to the medical community to pay more attention to the emotional factors in cardiac patients. We are now taking a closer look at potential physiological factors that account for the additional susceptibility in younger women." Emory researchers working with Vaccarino have identified two areas where there are specific differences in younger women who had a recent heart attack: inflammation and heart rate variability, a measure of the responsiveness of the autonomic nervous system. Low heart rate variability has been previously linked to greater heart disease risk. The inflammation data is being presented in a poster by postdoctoral researcher Cherie Rooks, PhD on Sunday, Nov. 17 and the heart rate variability data in a poster by assistant professor Amit Shah, MD on Tuesday, Nov. 19. Interleukin-6 is a marker of inflammation that goes up and down quickly depending on someone's environmental exposures including mental stress, even in healthy individuals. In the MIMS study, women age 50 and below had much higher levels of IL-6 in their blood, compared to age-matched men, both before the mental stress test and afterwards. Women and men older than 50 had similar levels of IL-6. Heart rate goes up in response to physical or psychological stress, but the beats also become more evenly spaced. Heart rate variability is a measure of how much moment-to-moment fluctuation is present; higher heart rate variability is a marker of a more flexible, and thus healthier, autonomic system. In the MIMS study, younger women had their heart rate variability dip more in response to stress, compared to men the same age. This is additional evidence that young women after a heart attack may be more vulnerable to the adverse effects of psychological stress on the heart. Vaccarino and her colleagues are continuing to investigate mental stress-induced ischemia, including how it affects mortality and complication rates, in a second phase of the MIMS study at Emory, which will include a larger sample with patient follow-up Alcoholism and Drug Abuse Counselors Continuing Education ### How the study was conducted The mental stress test part of the study was a public speaking task involving an emotional topic. Participants were asked to imagine a real-life stressful situation, such as a close relative been mistreated in a nursing home. They had to quickly prepare a speech and deliver it in front of a video camera and an audience wearing white coats, while their blood pressure and other vital signs were monitored. Immediately afterwards, cardiac imaging was performed to assess blood flow within the heart via SPECT (single photon emission computed tomography). On a separate day, study participants performed a standard exercise test on a treadmill; a few were unable to exercise at a high heart rate and had to have a "pharmacological" stress test with a drug that dilates coronary arteries. The research was supported by the National Heart Lung and Blood Institute and the National Institute for Mental Health (R21HL093665, R21HL093665-01A1S1, R01 HL109413, K24HL077506, and K24 MH076955).

Brain connectivity study reveals striking differences between men and women

Penn Medicine brain imaging study helps explain different cognitive strengths in men and women PHILADELPHIA—A new brain connectivity study from Penn Medicine published today in the Proceedings of National Academy of Sciences found striking differences in the neural wiring of men and women that's lending credence to some commonly-held beliefs about their behavior. In one of the largest studies looking at the "connectomes" of the sexes, Ragini Verma, PhD, an associate professor in the department of Radiology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues found greater neural connectivity from front to back and within one hemisphere in males, suggesting their brains are structured to facilitate connectivity between perception and coordinated action. In contrast, in females, the wiring goes between the left and right hemispheres, suggesting that they facilitate communication between the analytical and intuition. "These maps show us a stark difference--and complementarity--in the architecture of the human brain that helps provide a potential neural basis as to why men excel at certain tasks, and women at others," said Verma. For instance, on average, men are more likely better at learning and performing a single task at hand, like cycling or navigating directions, whereas women have superior memory and social cognition skills, making them more equipped for multitasking and creating solutions that work for a group. They have a mentalistic approach, so to speak. Past studies have shown sex differences in the brain, but the neural wiring connecting regions across the whole brain that have been tied to such cognitive skills has never been fully shown in a large population. In the study, Verma and colleagues, including co-authors Ruben C. Gur, PhD, a professor of psychology in the department of Psychiatry, and Raquel E. Gur, MD, PhD, professor of Psychiatry, Neurology and Radiology, investigated the gender-specific differences in brain connectivity during the course of development in 949 individuals (521 females and 428 males) aged 8 to 22 years using diffusion tensor imaging (DTI). DTI is water-based imaging technique that can trace and highlight the fiber pathways connecting the different regions of the brain, laying the foundation for a structural connectome or network of the whole brain. This sample of youths was studied as part of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children's Hospital of Philadelphia. The brain is a roadmap of neural pathways linking many networks that help us process information and react accordingly, with behavior controlled by several of these sub-networks working in conjunction. In the study, the researchers found that females displayed greater connectivity in the supratentorial region, which contains the cerebrum, the largest part of the brain, between the left and right hemispheres. Males, on the other hand, displayed greater connectivity within each hemisphere. By contrast, the opposite prevailed in the cerebellum, the part of the brain that plays a major role in motor control, where males displayed greater inter-hemispheric connectivity and females displayed greater intra-hemispheric connectivity. These connections likely give men an efficient system for coordinated action, where the cerebellum, which involves perception, and the front of the brain, which involves action, are bridged together, according to the authors. The female connections likely facilitate integration of the analytic and sequential processing modes of the left hemisphere with the spatial, intuitive information processing modes of the right side. The authors observed only a few gender differences in the connectivity in children younger than 13 years, but the differences were more pronounced in adolescents aged 14 to 17 years and young adults older than 17. The findings were also consistent with a Penn behavior study, of which this imaging study was a subset of, that demonstrated pronounced sexual differences. Females outperformed males on attention, word and face memory, and social cognition tests. Males performed better on spatial processing and sensorimotor speed. Those differences were most pronounced in the 12 to 14 age range. "It's quite striking how complementary the brains of women and men really are," said Dr. Ruben Gur. "Detailed connectome maps of the brain will not only help us better understand the differences between how men and women think, but it will also give us more insight into the roots of neuropsychiatric disorders, which are often sex related." Next steps are to quantify how an individual's neural connections are different from the population; identify which neural connections are gender specific and common in both; and to see if findings from functional magnetic resonance imaging (fMRI) studies fall in line with the connectome data Professional Counselor Continuing Education ### Co-authors of the study include Madhura Ingalhalikar, Alex Smith, Drew Parker, Theodore D. Satterthwaite, Mark A. Elliott, Kosha Ruparel, and Hakon Hakonarson of the Section of Biomedical Image Analysis and the Center for Biomedical Image Computing and Analytics. This study was funded by in part by the National Institutes of Mental Health: MH089983, MH089924, MH079938, and MH092862.

PTSD raises risk for obesity in women

Women with PTSD gain weight more rapidly than women without disorder Women with post-traumatic stress disorder (PTSD) gain weight more rapidly and are more likely to be overweight or obese than women without the disorder, find researchers at Columbia University's Mailman School of Public Health and Harvard School of Public Health. It is the first study to look at the relationship between PTSD and obesity over time. Results appear online in JAMA Psychiatry. One in nine women will have PTSD at sometime over the course of their lifetime—twice as often as men. Women are also more likely to experience extreme traumatic events like rape that carry a high risk for the disorder. "PTSD is not just a mental health issue," says study senior author Karestan Koenen, PhD, Mailman School associate professor of Epidemiology. "Along with cardiovascular disease and diabetes, we can now add obesity to the list of known health risks of PTSD." PTSD - Clinical Practice Guideline for Management of Post Traumatic Stress CEU Course "The good news from the study is that it appears that when PTSD symptoms abate, risk of becoming overweight or obese is also significantly reduced," says first author Laura D. Kubzansky, PhD, Professor of Social and Behavioral Sciences at Harvard School of Public Health. However, despite the growing evidence of potential far-reaching problems associated with PTSD, it's estimated that only half of women in the United States with the disorder are ever treated. "Hopefully, wider recognition that PTSD can also influence physical health will improve this statistic, leading to better screening and treatments, including those to prevent obesity," says Dr. Kubzansky. While it's known that women with PTSD have high rates of obesity, it has been unclear whether PTSD was actually driving the weight gain. To explore the issue, the researchers analyzed data collected from 50,504 women, aged 22-44 years, taking part in the Nurses' Health Study II between 1989 and 2009. Participants were asked about the worst trauma they experienced and if they had related post-traumatic stress symptoms. The threshold for PTSD was the persistence of four or more symptoms over a month or longer. Common symptoms include re-experiencing the traumatic event, feeling under threat, social avoidance, and numbness. Normal-weight women who developed PTSD during the study period had 36% increased odds of becoming overweight or obese compared with women who experienced trauma but had no symptoms of PTSD. The higher risk was evident even for women with sub-threshold symptoms levels and remained after adjusting for depression, which has also been proposed as a major risk factor for obesity. In women with PTSD that began prior to the study period, body mass index increased at a more rapid pace than women without PTSD. The observed effect of PTSD on obesity is likely stronger in the general population of women than in nurses, notes Dr. Koenen. "Nurses are great for studies because they report health measures like BMI with a high degree of accuracy. But they are also more health conscious and probably less likely to become obese than most of us, which makes these results more conservative than they would otherwise be." Symptoms of PTSD rather than the trauma itself seemed to be behind the weight gain. "We looked at the women who developed PTSD and compared them to women who experienced trauma but did not develop PTSD. On the whole, before their symptoms emerged, the rate of change in BMI was the same as the women who never experienced trauma or did experience trauma but never developed symptoms," says Dr. Kubzansky. How exactly does PTSD lead to weight gain? The biological pathway is unknown, but scientists have a number of guesses. One is through the over-activation of stress hormones. PTSD may lead to disturbances in functioning of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, each of which are involved in regulating a broad range of body processes, including metabolism. Another is through unhealthy behavior patterns that may be used to cope with stress. Ongoing research is looking at whether PTSD increases women's preference for processed foods and decreases their likelihood of exercising Social Worker Continuing Education ### Co-authors include Pula Bordelois, MPH, and Andrea Roberts, PhD, at Harvard School of Public Health; Hee Jin Jun, DrPH, at the Channing Division of Network Medicine at Brigham and Women's Hospital; Noah Blustone, BA, at Harvard Medical School and Boston University; and Magdalena Cerda, DrPH, at Columbia's Mailman School. The study was supported by grants from the National Institute of Mental Health to Dr. Koenen (MH078928 and MH093612). The authors declare no conflict of interest.

Focusing on faces

Researchers find neurons in amygdala of autistic individuals have reduced sensitivity to eye region of others' faces Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals. "We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team's findings. "We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally." The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD. By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown. "It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment." "We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs. To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs. "At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says MHC Continuing Education ### Funding for the research outlined in the Neuron paper, titled "Single-neuron correlates of abnormal face processing in autism," was provided by the Simons Foundation, the Gordon and Betty Moore Foundation, the Cedars-Sinai Medical Center, Autism Speaks, and the National Institute of Mental Health. Additional coauthors were Caltech postdoctoral scholar Oana Tudusciuc and graduate student Shuo Wang.