Mapping Brain Circuits Provides Clues to Schizophrenia, Earlier Detection of Psychosis

Two regions in the brain have been linked to schizophrenia and psychosis, which may lead to earlier detection of this disorder and symptom, reported an imaging study funded by the National Institute of Mental Health (NIMH) that was published online last month in Biological Psychiatry. Background Patients with schizophrenia experience decreased activity in the prefrontal cortex ( blue, top figure) and excess activity in the basal ganglia (red, bottom figure). The greater the disconnect between these two regions, the higher the level of psychosis seen in these patients. Psychosis is a loss of contact with reality that usually includes false beliefs about what is taking place or who one is (delusions) and seeing or hearing things that aren’t there (hallucinations). Numerous medical problems can cause psychosis such as substance abuse, brain tumors, and certain mental disorders such as schizophrenia and bipolar disorder. Treatment approaches include hospitalization, antipsychotic drugs, and various psychosocial treatments. Too often, psychosis is not diagnosed or treated early enough. The longer this duration of untreated psychosis, the poorer the patient’s long-term functioning and response to treatment. In the United States, the average time between the first onset of psychotic symptoms and the initiation of treatment is about 110 weeks, or over 2 years. Disordered thinking and psychosis often go hand-in-hand in patients with the chronic brain disorder schizophrenia. A popular and long-standing theory in the field implicates the prefrontal cortex, the brain area just behind the forehead that normally supports higher-order capabilities such as prioritizing, categorizing, and strategizing. Damage to this area causes not only disordered thinking but also leads to psychosis from the excess release of the neurotransmitter dopamine into regions deep inside the brain. While this theory offers a compelling explanation for the co-occurrence of these two symptoms in schizophrenia, there have been only a small handful of studies that have directly supported this theory. Identification of the exact circuit(s) involved has so far remained elusive Professional Counselor Continuing Education “Schizophrenia is a very complex condition, involving a constellation of diverse symptoms. This diversity presents both a challenge and a constraint for figuring out the neurobiological root causes of schizophrenia. There is likely not just one lesion but a number of lesions that are present across different brain regions that are the proximal causes for these symptoms.” explained Jong H. Yoon, M.D., at the University of California, Davis, and lead author of the study. Yoon’s study focused on the prefrontal cortex and the basal ganglia. The basal ganglia is a subcortical collection of neuron clusters, including the ventral tegmental area and substantia nigra, which produce the majority of the brain’s dopamine, and the striatum, an important site of action of dopamine. Using functional magnetic resonance imaging (fMRI), the researchers examined the brain activity within the prefrontal cortex and basal ganglia of 18 individuals with schizophrenia and 19 healthy controls. The subjects completed a memory task in which they had to remember images of faces across a brief delay period to determine if subsequently presented faces were the same faces; it was hypothesized that patients with schizophrenia would have more difficulty performing this task. Results of the Study Patients with schizophrenia experienced excess activity in the substantia nigra, decreased activity in the prefrontal cortex, and diminished functional connectivity between these regions, suggesting that communication among these regions was out of sync. Additionally, the higher the level of connectivity between the substantia nigra and the striatum, the higher the level of psychosis seen in the patients with schizophrenia. Significance These findings suggest that the prefrontal cortex-basal ganglia circuit may be a common pathway linking cognitive deficits and psychosis in schizophrenia. It also points to a more widespread use of fMRI in diagnosis and treatment. Compared to other neuroimaging techniques such as positron emission tomography (PET), fMRI yields more detailed images, does not use radiation, and is relatively widely available since most university-based brain imaging centers have this technology. These findings could also lead to the creation of a better animal model of psychosis, of which there currently are few. Biomedical research has shown that early detection and intervention could preempt later stages of diseases. This concept of “treatment as prevention” is seen in the NIMH-supported North American Prodrome Longitudinal Study (NAPLS), which is using biological assessments, such as neuroimaging, to predict who will convert to psychosis and to develop new treatment and prevention approaches. Another NIMH study, Recovery After an Initial Schizophrenia Episode (RAISE), supports the development and testing of two complementary models for early intervention in schizophrenia. Research is also underway to identify genes and environmental elements associated with schizophrenia. What’s Next Because the study involved patients with established illness who are already on antipsychotic medications, it needs replication in patients with schizophrenia who are not medicated and/or in the early phases of illness. The study should also be performed in individuals at high risk of developing psychosis to see if these findings could help identify individuals in the earliest stages of illness when interventions to prevent or significantly ameliorate schizophrenia can be instituted. To obtain greater precision in localizing brain regions, the study also warrants replication with high-resolution fMRI. Furthermore, the techniques in this study could also be applied to other disorders that can have psychosis as one of its symptoms, such as mood disorders, and post-traumatic stress disorder. Reference Yoon JH, Minzenberg MJ, Raouf S, D’Esposito M, Carter CS. Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia. Biological Psychiatry, published online January 14, 2013.

Imaging Biomarker Predicts Response to Rapid Antidepressant

Signals Dysfunction in Brain System Targeted by Scopolamine – NIH Study A telltale boost of activity at the back of the brain while processing emotional information predicted whether depressed patients would respond to an experimental rapid-acting antidepressant, a National Institutes of Health study has found. NIMH’s Dr. Maura Furey talks about scopolamine research “We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients,” explained Maura Furey, Ph.D., of NIH’s National Institute of Mental Health (NIMH). Furey, NIMH’s Carlos Zarate, M.D., and colleagues, reported on their functional magnetic resonance imaging (fMRI) study of a pre-treatment biomarker for the antidepressant response to scopolamine, Jan. 30, 2013, online in JAMA Psychiatry. Scopolamine, better known as a treatment for motion sickness, has been under study since Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Unlike ketamine, scopolamine works through the brain’s acetylcholine chemical messenger system. The NIMH team’s research has demonstrated that by blocking receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, spurring interest in a predictive biomarker Alcoholism and Drug Abuse Counselors Continuing Education The acetylcholine system plays a pivotal role in working memory, holding information in mind temporarily, but appears to act by influencing the processing of information rather than through memory. Imaging studies suggest that visual working memory performance can be enhanced by modulating acetylcholine-induced activity in the brain’s visual processing area, called the visual cortex, when processing information that is important to the task. Since working memory performance can predict response to conventional antidepressants and ketamine, Furey and colleagues turned to a working memory task and imaging visual cortex activity as potential tools to identify a biomarker for scopolamine response. Depressed patients have a well-known tendency to process and remember negative emotional information. The researchers propose that this bias stems from dysregulated acetylcholine systems in some patients. They reasoned that such patients would show aberrant visual cortex activity in response to negative emotional features of a working memory task. They also expected to find that patients with more dysfunctional acetylcholine systems would respond better to scopolamine treatment. Before receiving scopolamine, participants performed a working memory task while their brain activity was monitored via fMRI. For some trials, it required that they pay attention to, and remember, the emotional expression (sad, happy, etc.) of faces flashing on a computer monitor. For other trials, they had to pay attention to only the identity, or non-emotional feature, of the faces. After scanning, and over the following several weeks, 15 patients with depression and 21 healthy participants randomly received infusions of a placebo (salt solution) and/or scopolamine. Mood changes were monitored with depression rating scales. Overall, scopolamine treatment reduced depression symptoms by 63 percent, with 11 of the patients showing a significant clinical response. The strength of this response correlated significantly with visual cortex activity during key phases of the working memory task – while participants were paying attention to the emotional content of the faces. There was no such correlation for trials when they attended to the identity of the faces. The findings suggest that acetylcholine system activity drives visual cortex activity that predicts treatment response – and that differences seen between depressed patients and controls may be traceable to acetylcholine dysfunction. Overall, patients showed lower visual cortex activity than controls during the emotion phase of the task. Patients showing activity levels most dissimilar to controls experienced the greatest antidepressant response to scopolamine treatment. Visual cortex activity in patients who didn’t respond to scopolamine more closely resembled that of controls. As hypothesized, the pretreatment level of visual cortex activity appears to reflect the extent of patients’ acetylcholine system dysfunction and to predict their response to the experimental medication, say the researchers. Preliminary evidence suggests that such visual cortex activity in response to emotional stimuli may also apply to other treatments and may prove to be a shared biomarker of rapid antidepressant response, according to Furey. The level of increased activity in left and right visual cortex (blue), while attending to emotional faces in a working memory task, predicted depressed patients’ responsiveness to the experimental antidepressant scopolamine. View from the back of the brain shows fMRI data superimposed on anatomical MRI scan data. Source: Maura Furey, Ph.D., NIMH Experimental Therapeutics and Pathophysiology Branch Working memory task: Over several trials, participants were required to attend to either the identity (non-emotional feature) or the emotion of a face, remember it during a 9 second delay, and match the feature to a subsequent face. Neural activity in the visual cortex elicited by the emotion trials predicted a patient’s subsequent responsiveness to scopolamine treatment. Source: Maura Furey, Ph.D., NIMH Experimental Therapeutics and Pathophysiology Branch References Potential of Pretreatment Neural Activity in the Visual Cortex During Emotional Processing to Predict Treatment Response to Scopolamine in Major Depressive Disorder. Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA. JAMA Psychiatry. 2013 Jan 30:1-11. doi: 10.1001/2013.jamapsychiatry.60. [Epub ahead of print] PMID:23364679 Cholinergic Modulation of Cognition and Emotion in Mood Disorders ### 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. 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.

Astrocytes identified as target for new depression therapy

Tufts neuroscientists find that starry brain cells can be used to mimic sleep deprivation BOSTON (January 23, 2013) — Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies. Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting Marriage and Family Therapist Continuing Education During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known. Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior. Haydon's team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects. During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness. "In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours," said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM). "By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior," continued Hines. "Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms," said Naomi Rosenberg, Ph.D., dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. "The team's next step is to further understand the other receptors in this system and see if they, too, can be affected." ### Senior author, Phillip G. Haydon, Ph.D., is the Annetta and Gustav Grisard professor and chair of the department of neuroscience at Tufts University School of Medicine (TUSM). Haydon is also a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts. Additional authors are Luke I. Schmitt, B.S., a Ph.D. candidate in neuroscience at the Sackler School; Rochelle M. Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at TUSM; and Stephen J. Moss, Ph.D., a professor of neuroscience at Tufts University School of Medicine and a member of the neuroscience program faculty at the Sackler School. Hines DJ, Schmitt LI, Hines RM, Moss SJ, Haydon PG. Translational Psychiatry. "Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling." (2013) 3, e212; doi:10.1038/tp.2012.136. Published online 15 January 2013. This research was supported by award number R01MH095385 from the National Institute of Mental Health, part of the National Institutes of Health, as well as by award number R01NS037585 from the National Institute of Neurological Disorders and Stroke, both of the National Institutes of Health. Dustin Hines was partially funded by the Heart and Stroke Foundation of Canada. Haydon is co-founder and president of GliaCure Inc., which has licensed a pending patent application filed by Tufts University claiming compounds that modulate the signaling cascades, and related methods of use, described in this paper. About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science. If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine or another Tufts health sciences researcher, please contact Siobhan Gallagher.

Brain Imaging Predicts Psychotherapy Success in Patients with Social Anxiety Disorder

Treatment for social anxiety disorder or social phobia has entered the personalized medicine arena—brain imaging can provide neuromarkers to predict whether traditional options such as cognitive behavioral therapy will work for a particular patient, reported a National Institute of Mental Health (NIMH)-funded study that was published in the January 2013 issue of JAMA Psychiatry. Background Social anxiety disorder (SAD)— the fear of being judged by others and humiliated— is the third most prevalent psychiatric disorder in Americans, after depression and alcohol dependence, according to the National Comorbidity Survey, a U.S. poll on mental health. This fear can be so strong that it interferes with daily life activities like going to work or school. If left untreated, some sufferers use alcohol, food, or drugs to reduce the fear at social events, which often leads to other disorders such as alcoholism, eating disorders, and depression. The NIMH claims that 6.8 percent of U.S. adults and 5.5 percent of 13- to 15-year-olds, the age of onset for this chronic disorder, are annually afflicted Social Worker Continuing Education Although psychotherapy and drugs, such as antidepressants and benzodiazepines, exist as treatments for SAD, current behavioral measures poorly predict which would work better for individual patients. “Half of social anxiety disorder patients have satisfactory response to treatment. There is little evidence about which patient would benefit from a particular form of treatment,” said John D. Gabrieli, Ph.D., lead author of the study. “Currently, there is no rational basis for prescribing one treatment over the other. Which treatment a patient gets depends on whom they see.” Enter personalized medicine, the use of genetic or other biological markers to tailor treatments to those who would actually benefit from them, thus sparing the expense and side effects for those who would not. Brain imaging could identify neuromarkers or targeted areas of the brain that could one day optimize treatment for individual patients. Neuromarkers are being used in other areas of mental illness, for instance, to predict the onset of psychosis in schizophrenia and the likelihood of relapse in drug addiction. In this study, Gabrieli, at the Massachusetts Institute of Technology in Cambridge, and his colleagues, used functional magnetic resonance imaging (fMRI) in 39 SAD patients before a 12-week course of cognitive behavioral therapy. The patients viewed angry versus neutral faces and scenes while undergoing fMRI examination (see first slide). Compared to neutral faces, angry faces convey disapproval and are likely to prompt excessive fear responses and negative connotations in SAD patients; cognitive behavioral therapy teaches these patients ways to downregulate their responses. The patients’ brain images were then compared to their scores on a conventional clinical measure, the Liebowitz Social Anxiety Scale (LSAS), a questionnaire which they took before and after therapy completion. Results of the Study SAD patients responded more to the images of faces and not scenes, which is characteristic for the social basis of this disorder. Patients whose brains reacted strongly to the facial images before treatment benefitted more from the therapy than those who reacted to these the least (see second slide). Specifically, changes in two occipitotemporal brain regions—areas involved in early processing of visual cues such as faces—correlated with positive cognitive behavioral therapy outcome. These neuromarkers predicted treatment outcome better than the currently used LSAS. Significance This study is the first of its kind to use neuroimaging to predict treatment response in SAD patients. Neuromarkers may become a practical clinical tool to guide the selection of optimal treatments for individual patients. Integration of neuromarkers with genetic, behavioral, and other biomarkers is likely to further refine the prediction. What’s Next A larger study comparing people with SAD with normal participants is needed to verify the results. fMRI studies using other facial expressions (disgust or fear) might be better predictors. Studies that look at other treatment options, such as drugs, are also needed to confirm which treatment is optimal. Researchers asked patients with social phobia to undergo functional magnetic resonance imaging (fMRI) while viewing images of neutral versus angry faces and scenes. The patients’ brains showed more activity when they viewed the faces. Source: Gabrieli Lab, MIT Patients with social phobia whose brains “lit” up the most, particularly in two regions towards the back of the brain that process what we see, responded the best to psychotherapy. Source: Gabrieli Lab, MIT Reference Doehrmann O, Ghosh SS, Polli FE, Reynolds GO, Horn F, Keshavan A, Triantafyllou C, Saygin ZM, Whitfield-Gabrieli S, Hofmann SG, Pollack M, Gabrieli JD. Predicting Treatment Response in Social Anxiety Disorder from Functional Magnetic Resonance Imaging. JAMA Psychiatry. January 2013. 70(1):87–97.