Our brains are made of the same stuff, despite DNA differences

Gene expression databases reveal “consistent molecular architecture”

Despite vast differences in the genetic code across individuals and ethnicities, the human brain shows a “consistent molecular architecture,” say researchers supported by the National Institutes of Health. The finding is from a pair of studies that have created databases revealing when and where genes turn on and off in multiple brain regions through development counselor ceus

“Our study shows how 650,000 common genetic variations that make each of us a unique person may influence the ebb and flow of 24,000 genes in the most distinctly human part of our brain as we grow and age,” explained Joel Kleinman, M.D., Ph.D., of the National Institute of Mental Health (NIMH) Clinical Brain Disorders Branch.

Kleinman and NIMH grantee Nenad Sestan, M.D., Ph.D. of Yale University, New Haven, Conn., led the sister studies in the Oct. 27, 2011 issue of the journal Nature.

“Having at our fingertips detailed information about when and where specific gene products are expressed in the brain brings new hope for understanding how this process can go awry in schizophrenia, autism and other brain disorders,” said NIMH Director Thomas R. Insel, M.D.

Both studies measured messenger RNAs or transcripts. These intermediate products carry the message from DNA, the genetic blueprint, to create proteins and differentiated brain tissue. Each gene can make several transcripts, which are expressed in patterns influenced by a subset of the approximately 1.5 million DNA variations unique to each of us. This unique set of transcripts is called our transcriptome – a molecular signature that is unique to every individual. The transcriptome is a measure of the diverse functional potential that exists in the brain.

Both studies found that rapid gene expression during fetal development abruptly switches to much slower rates after birth that gradually decline and eventually level off in middle age. These rates surge again as the brain ages in the last decades, mirroring rates seen in childhood and adolescence, according to one of the studies. The databases hold secrets to how the brain’s ever-changing messenger chemical systems, cells and development processes are related to gene expression patterns through development.

For example, if a particular version of a gene is implicated in a disorder, the new resources might reveal how that variation affects the gene’s expression over time and by brain region. By identifying even distant genes that may be turning on and off in-sync, the databases may help researchers discover whole modules of genes involved in the illness. They can also reveal how variation in one gene influences another’s expression.

Prefrontal cortex

Kleinman’s team focused on how genetic variations are linked to the expression of transcripts in the brain’s prefrontal cortex, the area that controls insight, planning and judgment, across the lifespan. They studied 269 postmortem, healthy human brains, ranging in age from two weeks after conception to 80 years old, using 49,000 genetic probes. The database on prefrontal cortex gene expression alone totals more than 1 trillion pieces of information, according to Kleinman.

Among key findings in the prefrontal cortex:
Individual genetic variations are profoundly linked to expression patterns. The most similarity across individuals is detected early in development and again as we approach the end of life.

Different types of related genes are expressed during prenatal development, infancy, and childhood, so that each of these stages shows a relatively distinct transcriptional identity. Three-fourths of genes reverse their direction of expression after birth, with most switching from on to off.

Expression of genes involved in cell division declines prenatally and in infancy, while expression of genes important for making synapses, or connections between brain cells, increases. In contrast, genes required for neuronal projections decline after birth – likely as unused connections are pruned.

By the time we reach our 50s, overall gene expression begins to increase, mirroring the sharp reversal of fetal expression changes that occur in infancy.

Genetic variation in the genome as a whole showed no effect on variation in the transcriptome as a whole, despite how genetically distant individuals might be. Hence, human cortexes have a consistent molecular architecture, despite our diversity.


In previous studies, Kleinman and colleagues have found that all genetic variations implicated to date in schizophrenia are associated with transcripts that are preferentially expressed in the fetal brain. This adds to evidence that the disorder originates in prenatal development. By contrast, he and his colleagues are examining evidence that genetic variation implicated in affective disorders may be associated with transcripts expressed later in life. They are also extending their database to include all transcripts of all the genes in the human genome, examining 1000 post-mortem brains, including many of people who had schizophrenia or other brain disorders.

Multiple brain regions

Sestan and colleagues characterized gene expression in 16 brain regions, including 11 areas of the neocortex, from both hemispheres of 57 human brains that spanned from 40 days post-conception to 82 years – analyzing the transcriptomes of 1,340 samples. Using 1.4 million probes, the researchers measured the expression of exons, which combine to form a gene’s protein product. This allowed them to pinpoint changes in these combinations that make up a protein, as well as to chart the gene’s overall expression.

Among key findings:
Over 90 percent of the genes expressed in the brain are differentially regulated across brain regions and/or over developmental time periods. There are also widespread differences across region and time periods in the combination of a gene’s exons that are expressed.

Timing and location are far more influential in regulating gene expression than gender, ethnicity or individual variation.

Among 29 modules of co-expressed genes identified, each had distinct expression patterns and represented different biological processes. Genetic variation in some of the most well-connected genes in these modules, called hub genes, has previously been linked to mental disorders, including schizophrenia and depression.

Telltale similarities in expression profiles with genes previously implicated in schizophrenia and autism are providing leads to discovery of other genes potentially involved in those disorders.

Sex differences in the risk for certain mental disorders may be traceable to transcriptional mechanisms. More than three-fourths of 159 genes expressed differentially between the sexes were male-biased, most prenatally. Some genes found to have such sex-biased expression had previously been associated with disorders that affect males more than females, such as schizophrenia, Williams syndrome, and autism.


The Sestan study was also funded by NIH’s National Institute on Child Health and Human Development, National Institute on Neurological Disorders and Stroke, and National Institute on Drug Abuse. Data for the Sestan study are posted at www.humanbraintranscriptome.org and at http://www.developinghumanbrain.org, as part of a larger ongoing study, BrainSpan, funded by NIMH under the American Recovery and Reinvestment Act to create an Atlas of Human Brain Development.

The Kleinman study data on genetic variability are accessible to qualified researchers at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v1.p1, while the gene expression data can be found at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc5GSE30272. In addition, BrainCloud, a web browser application developed by NIMH to interrogate the Kleinman study data, can be downloaded at http://www.libd.org/braincloud.


Our brains are all made of the same stuff. Despite individual and ethnic genetic diversity, our prefrontal cortex shows a consistent molecular architecture. For example, overall differences in the genetic code (“genetic distance”) between African -Americans (AA) and caucasians (cauc) showed no effect on their overall difference in expressed transcripts (“transcriptional distance”). The vertical span of color-coded areas is about the same, indicating that our brains all share the same tissue at a molecular level, despite distinct DNA differences on the horizontal axis. Each dot represents a comparison between two individuals. The AA::AA comparisons (blue) generally show more genetic diversity than cauc::cauc comparisons (yellow), because caucasians are descended from a relatively small subset of ancestors who migrated from Africa, while African Americans are descended from a more diverse gene pool among the much larger population that remained in Africa. AA::cauc comparisons (green) differed most across their genomes as a whole, but this had no effect on their transcriptomes as a whole.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Individual genetic variation likely affects the expression of genes. For example, across all ages and ethnicities studied, expression of a gene called ZSWIM7 stays low, medium or high in the prefrontal cortex, depending on which of three versions (A/A, A/G, G/G) is inherited. The versions are created by a tiny variation in the letters of the genetic code (DNA) at a location in the gene called rs1045599.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Overall gene expression plummets 5-fold in infancy and 90-fold in childhood from its prenatal peak. The decline levels-off during the middle years, but expression surges again in the last decades of life, as the brain ages. Note: The fetal/infant graph at left is based on a different scale than the lifespan graph at right, so the two are not visually comparable.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Males show more sex-biased gene expression. More genes differentially expressed (DEX) between the sexes were found in males than females, especially prenatally. Some genes found to have such sex-biased expression had previously been associated with disorders that affect males more than females, such as schizophrenia, Williams syndrome, and autism. Eleven of the brain areas shown are in the neocortex (NCX), or outer mantle.
Source: Nenad Sestan, M.D., Ph.D., Yale University Department of Neurobiology and Kavli Institute for Neuroscience


Profiling developmental processes. The expression data can be used to create trajectories for the expression of genes involved in particular processes, such as the development of synapses (structures that underlie communication between neurons). These expression trajectories can be compared for different regions, such as the NCX and cerebellar cortex (CBC).
Source: Nenad Sestan, M.D., Ph.D., Yale University Department of Neurobiology and Kavli Institute for Neuroscience

References

Colantuoni c, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, Colantuoni EA, Elkahloun AG, Herman MM, Weinberger DR, Kleinman JE. Temporal Dynamics and Genetic Control of Transcription in the human prefrontal cortex. Nature 2011. Oct 27

Kang HJ, Kawasawa1YI, Cheng F, Zhu Y, Xu X, Li M, Sousa1 AMM, Pletikos M, Meyer KA, Sedmak G, Guennel G, Shin Y, Johnson MB, Krsnik Z, Fertuzinhos MS, Umlauf S, Lisgo SN, Vortmeyer A, Weinberger DR, Mane S, Hyde TM, Huttner A, Reimers M, Kleinman JE, Šestan N. Spatiotemporal transcriptome of the human brain. Nature 2011. Oct 27.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world's research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to inform policy and improve practice. Fact sheets on the health effects of drugs of abuse and information on NIDA research and other activities can be found on the NIDA home page at www.drugabuse.gov. To order publications in English or Spanish, call NIDA's new DrugPubs research dissemination center at 1-877-NIDA-NIH or 240-645-0228 (TDD) or fax or email requests to 240-645-0227 or drugpubs@nida.nih.gov. Online ordering is available at http://drugpubs.drugabuse.gov. NIDA's new media guide can be found at http://drugabuse.gov/mediaguide/.

NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

The activities described in this release are funded in part through the American Recovery and Reinvestment Act. More information about NIH's Recovery Act grant funding opportunities can be found at http://grants.nih.gov/recovery/. To track the progress of HHS activities funded through the Recovery Act, visit www.hhs.gov/recovery. To track all federal funds provided through the Recovery Act, visit www.recovery.gov.

Perinatal antidepressant stunts brain development in rats

Miswired brain circuitry traced to early exposure – NIH-funded study

Rats exposed to an antidepressant just before and after birth showed substantial brain abnormalities and behaviors, in a study funded by the National Institutes of Health.

After receiving citalopram, a serotonin-selective reuptake inhibitor (SSRI), during this critical period, long-distance connections between the two hemispheres of the brain showed stunted growth and degeneration. The animals also became excessively fearful when faced with new situations and failed to play normally with peers – behaviors reminiscent of novelty avoidance and social impairments seen in autism. The abnormalities were more pronounced in male than female rats, just as autism affects 3-4 times more boys than girls.

“Our findings underscore the importance of balanced serotonin levels – not too high or low -- for proper brain maturation,” explained Rick Lin, Ph.D., of the University of Mississippi Medical Center, Jackson, a Eureka Award grantee of the NIH’s National Institute of Mental Health.

Lin and colleagues report on their discovery online during the week of Oct. 24, 2011, in the Proceedings of the National Academy of Sciences.

Last July, a study reported an association between mothers taking antidepressants and increased autism risk in their children. It found that children of mothers who took SSRI’s during the year prior to giving birth ran twice the normal risk of developing autism – with treatment during the first trimester of pregnancy showing the strongest effect. A study published last month linked the duration of a pregnant mother’s exposure to SSRIs to modest lags in coordination of movement – but within the normal range – in their newborns counselor ceus

“While one must always be cautious extrapolating from medication effects in rats to medication effects in people, these new results suggest an opportunity to study the mechanisms by which antidepressants influence brain and behavioral development,” said NIMH Director Thomas R. Insel, M.D. “These studies will help to balance the mental health needs of pregnant mothers with possible increased risk to their offspring.”

Earlier studies had hinted that serotonin plays an important role in shaping the still-forming brain in the days just after a rat is born, which corresponds to the end of the third trimester of fetal development in humans. Experimental manipulations of the chemical messenger during this period interfered with formation of sensory-processing regions of the cortex, or outer mantle, and triggered aggressive and anxiety-related behaviors in rodents.

There is also recent evidence in humans that serotonin from the placenta helps shape development of the fetal brain early in pregnancy. Disrupted serotonin has been linked to mood and anxiety disorders. SSRIs, the mainstay medication treatment for these disorders, boost serotonin activity.

Lin and colleagues gave citalopram to male and female rat pups prenatally and postnatally and examined their brains and behavior as they grew up. Male, but not female, SSRI exposed rat pups abnormally froze when they heard an unfamiliar tone and balked at exploring their environment in the presence of unfamiliar objects or scents. These behaviors persisted into adulthood. The male pups especially also shunned normal juvenile play behavior – mimicking traits often seen in children with autism.

A key brain serotonin circuit, the raphe system, known to shape the developing brain during the critical period when the animals were exposed to the drug, showed dramatic reductions in density of neuronal fibers. Evidence of stunted development in the circuit coursed through much of the cortex and other regions important for thinking and emotion, such as the hippocampus.

The researchers also discovered miswiring in the structure responsible for communications between the brain’s left and right hemispheres, called the corpus collosum. Extensions of neurons, called axons, through which such long-distance communications are conducted, were deformed. A protective sheath, called myelin, that normally wraps and boosts axons’ efficiency-- like insulation on an electrical wire – was reduced by one-third in the treated animals. This damage was three times worse in male than in female pups and would likely result in abnormal communication between the two hemispheres, say the researchers.

Moreover, the perinatally exposed animals showed evidence of neurons firing out of sync and other electrophysiological abnormalities, suggesting faulty organization of neuronal networks in the cortex.

The research also was supported by the NIH’s National Center for Research Resources, National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Human Development.


Cross-sections of the part of the rat brain that connects the left and right hemisphere (corpus collosum) show stunted development of neuronal wiring, called axons, in an animal that received an antidepressant (right) during a critical period around the time of birth. A protective sheath, called myelin (visible in normal animal at left), that normally wraps the axons and boosts their efficiency, failed to develop normally in the treated animal. The resultant inefficient neuronal communications could underlie the pattern of deficits seen in autism.
Source: Rick C.S. Lin, Ph.D., University of Mississippi Medical Center

Reference

Perinatal antidepressant exposure alters cortical network function in rodents. Simpson KL, Weaver KJ, de Villers-Sidani E, Lu JY-F, Cai Z, Pang Y, Rodriguez-Porcel F, Paul IA, Merzenich M, Lin RCS. 2011, Oct. 24, PNAS.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The National Center for Research Resources (NCRR), a part of NIH, provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat and prevent a wide range of diseases. NCRR supports all aspects of translational and clinical research, connecting researchers, patients and communities across the nation. For more information, visit www.ncrr.nih.gov. NINDS is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov/.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

White House Names NIMH a “Champion of Change” for its Suicide Prevention Efforts

Source: White House

The National Institute of Mental Health (NIMH) was named by the White House as a “Champion of Change” on August 25, 2011, for its efforts in supporting research on suicide prevention. Jane Pearson, Ph.D., and Kevin Quinn, Ph.D., of NIMH accepted the award at a ceremony and roundtable event at the White House, where they joined White House policy officials and others for a discussion of suicide prevention best practices. In addition to NIMH, the Suicide Prevention Resource Center (SPRC); Suicide Prevention Action Network; SAVE Foundation; the American Foundation for Suicide Prevention; National Suicide Prevention Lifeline; Blue Star Families; the Gay, Lesbian, and Straight Education Network (GLSEN); the Creative Coalition; and the Trevor Project, all of whom are dedicated to preventing suicide, were honored.

The White House Champions of Change initiative celebrates individuals and organizations from all walks of life who are making an impact in communities and helping the country rise to the challenges of the 21st century.

The roundtable discussion was moderated by Pamela J. Hyde, Administrator of the Substance Abuse and Mental Health Services Administration (SAMHSA); Andrea Palm, Senior Advisor for Health at the White House Domestic Policy Council; and Deborah Temkin, Research and Policy Coordinator for Bullying Prevention Initiatives at the Department of Education. The discussion focused on numerous issues important to suicide prevention including:
Media influences: how the media—including social media—has encouraged people to show their support of individuals in crisis ceus for counselors

Best practices: how the SPRC, which acts as a clearinghouse of evidence-based information related to suicide prevention, helps spread the word. The National Suicide Prevention Lifeline also continues to improve counseling services by using best practices.
Working Together: how each organization learns from the others. For instance, NIMH funds research associated with the National Suicide Prevention Lifeline, including research on the training of crisis counselors in an effort to improve counselors’ assessment and referral skills.
Prioritizing Next Steps: including identifying technological opportunities to help reduce suicide,(e.g., developing and testing phone apps for helping someone in crisis).
Early intervention: all agreed that for children, early intervention programs aimed at decreasing aggression and improving problem-solving skills are vital to ensuring children do not become bullies or reach a suicidal crisis.

NIMH is deeply honored to be identified as a Champion of Change. If you or someone you know is in crisis or considering suicide, call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255), a free, 24-hour hotline that seamlessly connects anyone in suicidal crisis or emotional distress with their nearest crisis center.

National Survey Dispels Notion that Social Phobia is the Same as Shyness

Source: NIMH

Normal human shyness is not being confused with the psychiatric anxiety disorder known as social phobia, according to an NIMH survey comparing the prevalence rates of the two among U.S. youth. The study was published online ahead of print October 17, 2011, in the journal Pediatrics.

Background

Social phobia is a disabling anxiety disorder characterized by overwhelming anxiety and excessive self-consciousness in everyday social or performance situations. Critics of the diagnosis have suggested that psychiatrists and pharmaceutical companies publicize social phobia, also known as social anxiety disorder, in order to increase sales of psychotropic medications, especially among youth. In addition, some have debated whether social phobia is just a “medicalization” of a normal variation in human temperament.

In response, Marcy Burstein, Ph.D., and colleagues at NIMH examined the rate of normal shyness among youth and its overlap with social phobia using data from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey of more than 10,000 teens aged 13-18 sponsored by NIMH. Social phobia was assessed using standard diagnostic criteria set by the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-IV). To assess shyness, teens were asked to rate how shy they felt around peers that they did not know well.

Results of the Study

The authors found that while about half of youth identified themselves as shy, only 12 percent of shy youth also met criteria for social phobia in their lifetime. Moreover, among youth who did not identify themselves as shy, about 5 percent met criteria for social phobia, suggesting that social phobia and shyness are not necessarily directly related. Rather, the presence of social phobia may be independent of shyness in some instances.

In addition, those with social phobia were consistently more likely to also have another psychiatric disorder in their lifetime, like depression or a behavior or drug use disorder, compared to those who identified themselves as shy. Those with social phobia also showed higher levels of impairment in work or school, or among family or peers, though they were no more likely to be receiving professional treatment than those who were shy.

Finally, rates of prescribed medication use were low for all groups. Only about 2.3 percent of those with social phobia were taking the antidepressant paroxetine (commonly used to treat anxiety disorders), while 0.9 percent who described themselves as shy were taking it. In addition, those with social phobia were no more likely to be taking any prescribed psychiatric medication compared to the other groups.

Significance

The results suggest that social phobia is not simply shyness that has been inappropriately medicalized. Rather, social phobia affects a minority of youth and only a fraction of those who consider themselves to be shy. In addition, despite the greater disability that youth with social phobia experience and the greater likelihood that they will have another disorder, they are not more likely to be getting treatment compared to their peers, questioning the notion that these youth are being unnecessarily medicated continuing education for counselors

Citation

Burstein M, Ameli-Grillon L, Merikangas M. Shyness versus social phobia in U.S. youth. Pediatrics. Online ahead of print Oct 17, 2011.

Adding Psychotherapy to Medication Treatment Improves Outcomes in Pediatric OCD

Source: NIMH

Youth with obsessive compulsive disorder (OCD) who are already taking antidepressant medication benefit by adding a type of psychotherapy called cognitive behavior therapy (CBT), according to an NIMH-funded study published September 21, 2011, in the Journal of the American Medical Association social worker continuing education

Background

Several studies have shown that, among adults with OCD, a form of CBT involving controlled exposure to feared situations plus training that helps the person refrain from compulsions is effective both alone and in combination with antidepressant medication. However, few studies of this type of combination therapy have been conducted among children. In addition, many children with OCD tend to respond only partially to antidepressant medication. Studies have found that among adults who only partially respond to antidepressant medication, adding CBT can be effective. However, until now, there have been no studies testing this same approach in youth.

Martin Franklin Ph.D., of the University of Pennsylvania, Jennifer Freeman Ph.D., of Brown University, John March M.D.,MPH, of Duke University, and colleagues set out to determine whether CBT can effectively augment antidepressant treatment in children who partially respond to the medication. Among 124 children ages 7-17, they compared three treatment options:
Medication management only (MM), prescribed and managed by a physician. All patients were taking a type of antidepressant known as a selective serotonin reuptake inhibitor (SSRI).
MM plus Instructional CBT (I-CBT), a shorter, less intensive version of CBT administered by the prescribing physician.
MM plus CBT provided by a trained CBT therapist. The CBT included a type of therapy called exposure plus response prevention (ERP), in which children are exposed to feared situations and taught how to respond to the resulting anxiety without engaging in compulsions.

Results

After 12 weeks of treatment, nearly 69 percent of those receiving MM+CBT had responded to treatment, compared to 34 percent receiving MM+I-CBT and 30 percent receiving MM. Those receiving MM+CBT showed more improvement in all respects, compared to those receiving MM and MM+I-CBT.

Significance

The findings are consistent with other studies demonstrating that ERP is an effective treatment strategy for OCD, both alone and in combination with SSRIs. The researchers conclude that the full version of CBT with ERP should be widely disseminated as opposed to a brief version that may not be effective.

What’s next

The researchers were unsure why there was so little difference in treatment response between the MM group and the MM+I-CBT group. They reasoned that the I-CBT was generally ineffective because it was brief and less intensive than the CBT. It also did not include key treatment components that are central to the full CBT protocol, such as exposure practices during the treatment sessions themselves. Future efforts should focus on making the full CBT with ERP more widely available in community settings, they concluded.

Citation

Franklin ME, Sapyta J, Freeman JB, Khanna M, Compton S, Almirall D, Moore P, Choate-Summers M, Garcia A, Edson AL, Foa EB, March JS. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive compulsive disorder: the Pediatric OCD Treatment Study (POTS II) randomized controlled trial. Journal of the American Medical Association. 21 Sept 2011

Brain Chemical Linked to Joylessness Provides Insight Into Teen Depression

Depressed teens with anhedonia, or the inability to experience pleasure, have lower levels of the neurotransmitter GABA in a key mood-regulating region of the brain, according to an NIMH-funded study published online October 3, in the Archives of General Psychiatry. The researchers note that focusing on specific symptoms and using different types of measures may offer new clues to the pathways and processes underlying depression and other mental disorders continuing education for social workers

Background

Symptoms of depression in teens can be highly varied and tend to overlap with signs of other disorders. Because of this, adolescent depression can be hard to study using conventional research tools and methods.

Guided by findings in adults, Vilma Gabbay, M.D., of New York University School of Medicine, and colleagues decided to focus on the neurotransmitter GABA. GABA has many important roles throughout the body and is involved in regulating communication between brain cells. Abnormalities in GABA production or function in the brain have been linked to several mental disorders, including schizophrenia and postpartum depression, and possibly learning disorders. GABA has also been linked to anhedonia, a symptom present in up to 59 percent of depressed teens.

The researchers used a type of specialized MRI to measure GABA levels in the brain region known as the anterior cingulate cortex (ACC) in 20 teens with depression, half of whom also had anhedonia. They were compared to 21 matched controls who did not have depression or anhedonia. Levels of anhedonia were scored numerically according to clinician- and self-rated assessments.

Results of the Study

Compared to controls, teens with depression and anhedonia had significantly lower ACC GABA levels. Lower ACC GABA levels were associated with more severe anhedonia symptoms among all participants.

Significance

The findings support a role for GABA in anhedonia and depression among teens. Also, by correlating GABA levels with numeric measures of anhedonia severity, the researchers were able to assess participants’ symptoms along a continuum. Compared to traditional measures that categorize symptoms only as being either present or absent, such continuous or “dimensional” measurements may provide greater specificity to disease evaluations in research.

What’s Next

Additional studies in larger populations are needed to confirm these findings. Advances in imaging techniques and technology may help to identify differing roles for other neurotransmitters associated with depression.

Reference

Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, Panzer AM, Alonso CM, Shungu DC. Anterior Cingulate Cortex {gamma}-Aminobutyric Acid in Depressed Adolescents: Relationship to Anhedonia. Arch Gen Psychiatry. 2011 Oct 3. [Epub ahead of print] PubMed PMID: 21969419.