eBriefing

Advances in the Neurobiology of Mental Illness

Advances in the Neurobiology of Mental Illness
Reported by
Alla Katsnelson

Posted February 10, 2017

Presented By

The New York Academy of Sciences

Overview

Mental health disorders are the leading cause of disability worldwide and take an enormous toll on individuals who suffer from them, their families and caregivers, and society at large. The global economic burden of mental illness is estimated to be a staggering $2.5 to 8.5 trillion in lost productivity. Recent advances in neuroscience and an evolving understanding of the etiology of many of these conditions is raising hopes for new therapies.

On October 7, 2016, the Academy convened a symposium at which researchers from academia and the pharmaceutical industry met to discuss the latest developments in understanding the underlying neurobiology of these conditions and in developing new treatments. Speakers discussed ongoing research in conditions including depression, schizophrenia, autism, anxiety, and anorexia nervosa. Talks focused on basic research, clinical trials, and biomarker development, as well as the connection between mental illnesses and other medical conditions. Several speakers touched on the burgeoning use of mobile technologies to continuously monitor symptoms.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Tyrone D. Cannon (Yale University)
K. Ranga Rama Krishnan (Rush Medical College)
Husseini Manji (Janssen Research & Development, LLC)
Vaibhav Narayan (Janssen Research & Development, LLC)
Daniel Pine (National Institute of Mental Health, US National Institutes of Mental Health)
B. Timothy Walsh (New York State Psychiatric Institute, Columbia University)


How to cite this eBriefing

The New York Academy of Sciences. Advances in the Neurobiology of Mental Illness. Academy eBriefings. 2016. Available at: www.nyas.org/MentalIllness2016-eB

Overview: State of the Science in Mental Illness


Husseini Manji (Janssen Research and Development, LLC)
  • 00:01
    1. Introduction
  • 04:43
    2. Mental illnesses are global and very costly
  • 09:02
    3. Tremendous advances in science
  • 16:31
    4. Using human induced pluripotent stem cells to create neural cells
  • 23:35
    5. Targeting AMPA receptors in a very regionally selective manner
  • 29:35
    6. Long term recovery will require integrative solutions and holistic car

Medical Consequences of Depression and Neuroimmune Interactions


K. Ranga Rama Krishnan (Rush Medical College)
  • 00:01
    1. Introduction
  • 03:33
    2. Interplay medical illness and depression
  • 09:05
    3. Interferons and mood
  • 14:06
    4. Depression affects many systems
  • 18:02
    5. Conclusion

Prediction and Prevention of Psychosis: The Schizophrenia Prodrome


Tyrone D. Cannon (Yale University)
  • 00:01
    1. Introduction
  • 05:05
    2. North American prodrome longitudinal study
  • 10:47
    3. Web-based application
  • 18:56
    4. Individualized prevention approaches in psychosis
  • 23:24
    5. Activated microglia as a potential unifying mechanism
  • 29:05
    6. Questions for ongoing and future wor

Using Neuroscience to Inform Clinical Thinking: Applications in Pediatric Anxiety


Daniel S. Pine (National Institute of Mental Health, U.S. National Institutes of Health)
  • 00:01
    1. Introduction
  • 03:49
    2. Focus on anxiety
  • 08:38
    3. Task context
  • 12:37
    4. Attention training therapy
  • 15:30
    5. The science of hitting and baseball
  • 18:40
    6. Conclusion

The Emerging Neurobiology of Anorexia Nervosa


B. Timothy Walsh (New York State Psychiatric Institute, Columbia University)
  • 00:01
    1. Introduction
  • 02:56
    2. Why anorexia nervosa is difficult to treat
  • 07:55
    3. Persistent behavior
  • 14:36
    4. Is dieting in anorexia nervosa habitual?
  • 21:34
    5. Assessment of self control
  • 27:04
    6. Summar

Harnessing Mobile and Sensor Technology to Help Patients with Diseases of the Brain and Central Nervous System


Vaibhav Narayan (Janssen Research and Development, LLC)
  • 00:01
    1. Introduction
  • 03:47
    2. Neurodegenerative and neuropsychiatric changes
  • 10:18
    3. Real world technology driven assessment of episodic memory
  • 16:19
    4. Longitudinal study to develop predictive models of near term relapse in depression
  • 20:33
    5. The data driven learning engine
  • 24:22
    6. From diagnose and treat to predict and preemp

Resources

Manji

World Health Organization — Global Burden of Disease

The Global Economic Burden of Noncommunicable Diseases

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Krishnan

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Cannon

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Zarate

Cornwell BR, Salvadore G, Furey M, et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 2012 Oct 1;72(7):555-61.

Duncan WC, Sarasso S, Ferrarelli F, et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int J Neuropsychopharmacol. 2013 Mar;16(2):301-11.

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Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016 Aug 1;173(8):816-26.

Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016 May 4;533(7604):481-6.

Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.

Dawson

Dawson G, Rogers S, Munson J, et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics. 2010 Jan;125(1):e17-23.

Dawson G, Jones EJ, Merkle K, et al. Early behavioral intervention is associated with normalized brain activity in young children with autism. J Am Acad Child Adolesc Psychiatry. 2012 Nov;51(11):1150-9.

Orekhova EV, Elsabbagh M, Jones EJ, et al. EEG hyper-connectivity in high-risk infants is associated with later autism. J Neurodev Disord. 2014;6(1):40.

Young AM, Chakrabarti B, Roberts D, et al. From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition. Mol Autism. 2016 Jan 20;7:9.

Autism Biomarkers Consortium for Clinical Trials

European Autism Interventions

Pine

Bar-Haim Y, Lamy D, Pergamin L, et al. Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol Bull. 2007 Jan;133(1):1-24.

Bar-Haim Y, Holoshitz Y, Eldar S, et al. Life-threatening danger and suppression of attention bias to threat. Am J Psychiatry. 2010 Jun;167(6):694-8.

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LeDoux JE, Pine DS. Using neuroscience to help understand fear and anxiety: a two-system framework. Am J Psychiatry. 2016 Nov 1;173(11):1083-1093.

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Walsh

Foerde K, Steinglass JE, Shohamy D, Walsh BT. Neural mechanisms supporting maladaptive food choices in anorexia nervosa. Nat Neurosci. 2015 Nov;18(11):1571-3.

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Walsh BT. The enigmatic persistence of anorexia nervosa. Am J Psychiatry. 2013 May;170(5):477-84.

Narayan

Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016 Apr 9;387(10027):1561-72.

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Manji HK, Insel TR, Narayan VA. Harnessing the informatics revolution for neuroscience drug R&D. Nat Rev Drug Discov. 2014 Aug;13(8):561-2.

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Martínez-Pérez B, de la Torre-Díez I, López-Coronado M. Mobile health applications for the most prevalent conditions by the World Health Organization: review and analysis. J Med Internet Res. 2013 Jun 14;15(6):e120.

Villemagne VL, Burnham S, Bourgeat P, et al. Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013 Apr;12(4):357-67.

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Speakers

Tyrone D. Cannon, PhD

Yale University
website | publications

Tyrone D. Cannon is the Clark L. Hull Professor of Psychology and Psychiatry at Yale University. Cannon earned his bachelor's degree at Dartmouth College and his doctoral degree at the University of Southern California. He took his first academic appointment at the University of Pennsylvania. He joined the faculty at University of California Los Angeles as professor of psychology and psychiatry and biobehavioral sciences, before moving to his current position at Yale in 2012. Cannon's research addresses the interplay between psychological-level phenomena and neurobiological mechanisms as they relate to disturbances of perception, belief, motivation, and emotional processing in people with mental illness, principally schizophrenia. A primary aim of his work, which incorporates structural, functional, metabolic, and neurochemical brain imaging, as well as behavioral and genetics approaches, aims to identify the mechanisms underlying the emergence of psychosis during adolescence and early adulthood and to develop effective intervention and prevention strategies targeting these mechanisms.

Geraldine Dawson, PhD

Duke University School of Medicine
website | publications

Geraldine Dawson is a professor in the departments of psychiatry and behavioral sciences, pediatrics, and psychology and neuroscience at Duke University as well as director of the Duke Center for Autism and Brain Development. She is also president of the International Society for Autism Research. She serves as a member of the US National Institutes of Health Interagency Autism Coordinating Committee, which develops the federal strategic plan for autism research, services, and policy. Dawson is a fellow of the American Psychological Society and American Psychological Association. Her scientific research was recognized by the National Institutes of Health as a Top Advance in Autism Research in 2007, 2008, 2009, 2010, 2012, 2013, 2014, and 2015, and by TIME magazine as one of the top 10 medical breakthroughs of 2012. Dawson received a PhD in Developmental and Child Clinical Psychology from University of Washington and completed a clinical internship at the University of California, Los Angeles Neuropsychiatric Institute.

Husseini Manji, MD, FRCPC

Janssen Research & Development, LLC
website | publications

Husseini K. Manji is the global therapeutic head for neuroscience at Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson. He was previously chief of the Laboratory of Molecular Pathophysiology & Experimental Therapeutics at the United States National Institutes of Health (NIH), and director of the NIH Mood and Anxiety Disorders Program, the largest program of its kind in the world. He is also a visiting professor at Duke University.

Manji received his BS (Biochemistry) and MD from the University of British Columbia. Following residency training, he completed fellowship training at the US National Institute on Mental Health and obtained extensive additional training in cellular and molecular biology at the US National Institute of Diabetes and Digestive and Kidney Diseases. The major focus of his research has been the investigation of disease- and treatment-induced changes in gene and protein networks that regulate synaptic and neural plasticity in neuropsychiatric disorders.

Vaibhav Narayan, MBA, PhD

Janssen Research & Development, LLC
website | publications

Vaibhav is senior director of the Neuroscience Therapeutic Area at Janssen R&D and currently head of Neuroscience Integrated Solutions and Informatics at Janssen Pharmaceutical Companies of Johnson & Johnson, where his group is developing science-based, technology-enabled solutions for early diagnosis, relapse prediction, and adherence management in Alzheimer's disease, depression, and schizophrenia. Vaibhav joined Johnson & Johnson from Eli Lilly and Co., where he was the head of Discovery and Medical Informatics group. Prior to Lilly, Vaibhav held multiple leadership roles at Celera Genomics where he participated in the sequencing, assembly, and analysis of the human genome. Vaibhav obtained his PhD from Yale University jointly from the Departments of Chemistry and Molecular Biophysics & Biochemistry in 1998, and an Executive MBA from Kellogg School of Management, Northwestern University in 2009.

Daniel S. Pine, MD

National Institute of Mental Health, US National Institutes of Mental Health
website | publications

Daniel S. Pine is chief of the Section on Development and Affective Neuroscience, in the National Institute of Mental Health Intramural Research Program. Pine moved to this position in 2000, after 10 years of training, teaching, and research at Columbia University. Since graduating from the University of Chicago, Pine has been engaged continuously in research on pediatric mental disorders, as reflected in more than 400 peer-reviewed papers. Currently, his group examines the degree to which pediatric mood and anxiety disorders are associated with perturbed neural circuitry function. Pine served as the chair of the Psychopharmacologic Drug Advisory Committee for the Food and Drug Administration, chair of the Child and Adolescent Disorders Work Group for the DSM-5 Task Force, and president of the Society of Biological Psychiatry. He is a member of the Institute of Medicine of the National Academy of Sciences and has received many other awards.

K. Ranga Rama Krishnan, MBBS

Rush Medical College
website | publications

K. Ranga Rama Krishnan is dean and senior vice president of Rush University Medical Center. Previously, Krishnan served for seven years as the dean at the Duke–NUS Graduate Medical School Singapore, and as the school's executive vice dean.

Krishnan earned his medical degree in 1978 and completed a rotating internship at Government General Hospital and Madras Medical College in Madras, India. He then served as senior house officer at Queen Elizabeth Hospital, University of West Indies, Barbados, West Indies.

He is an elected member of the Institute of Medicine. He has been the recipient of many awards and honors, including the 2008 C. Charles Burlingame Award, which recognizes outstanding leadership and lifetime achievement in psychiatric research and education, and the Edward Strecker award from the University of Pennsylvania 2011.

At Duke University, Krishnan created a translational research center focused on depression in the elderly, the only such center in the US funded by the National Institutes of Health.

B. Timothy Walsh, MD

New York State Psychiatric Institute, Columbia University
website | publications

B. Timothy Walsh received his undergraduate degree in chemistry from Princeton University and MD from Harvard Medical School. After completing an internship at Dartmouth College, and a residency and research fellowship at Albert Einstein College of Medicine, he joined the psychiatry department at Columbia University. Over the course of his career, he has published several hundred papers, and received numerous grants from US National Institutes of Health. He has served as president of both of the major international eating disorders associations, and was a member of both the Diagnostics and Statistics Manual (DSM)-IV and DSM-5 Task Forces, for which he chaired the eating disorders work group. He has received awards from the American Psychiatric Association, the Academy for Eating Disorders, and the Association for Behavior and Cognitive Therapies.

At Columbia, he has held leadership positions including co-chair of the Institutional Review Board. He has been director of the Division of Clinical Therapeutics since its creation in 2007.

Carlos A. Zarate, Jr., MD

National Institute of Mental Health, US National Institutes of Health; The George Washington University
website | publications


Alla Katsnelson

Alla Katsnelson is a freelance science writer and editor, specializing in health, biomedical research, and policy. She has a doctorate in developmental neuroscience from Oxford University and a certificate in science communication from the University of California, Santa Cruz, and writes regularly for scientists and non-scientists alike.

Sponsors

Presented by

NYAS

Platinum Sponsor

Janssen Neuroscience

Speakers

Husseini Manji

Janssen Research & Development

K. Ranga Rama Krishnan

Rush Medical College

Highlights

Mental illness has a demonstrably negative impact on many health conditions, such as heart disease, cancer, type 2 diabetes, and osteoporosis.

Inflammation has been proposed as one connection between medical illness and mental illness.

Antagonists of pro-inflammatory cytokines may treat depression in a subset of patients who experience inflammation.

The state of the science in mental illness

Mental illness takes an enormous toll on individuals and populations worldwide, said Husseini Manji of Janssen Research & Development. According to the World Health Organizations' Global Burden of Disease study, major depression is the number one cause of disability in the western world today, and it is projected to become the number one cause worldwide by 2030. The global economic burden of mental illness is estimated to be a staggering $2.5 to 8.5 trillion in lost productivity. Because these conditions generally strike in adolescence and young adulthood, they rob society of its members' most productive years.

Several new and powerful techniques have emerged for visualizing brain structure and function in unprecedented detail.

The body and brain are not separate, said Manji—mental illness has an enormously deleterious effect on many health conditions. People are several-fold times more likely to die in the six months following a heart attack if they are depressed than if they are not; depression is also a predictor of disease progression in cancer, type 2 diabetes, osteoporosis, and many other conditions.

Despite the magnitude of medical need, the National Institutes of Health is underinvesting in neuroscience, and few pharmaceutical companies currently maintain neuroscience programs. That may be because brain disorders are seemingly more complex and therefore more daunting than other conditions.

Manji noted, however, that neuroscience today is progressing at a spectacular rate and that this progress must be harnessed to identify novel therapies. Mental illness is far more heritable than other common conditions, such as breast cancer, hypertension and lung disease, and gene studies powered by the falling cost of sequencing are identifying key signaling pathways involved in brain disease pathology. Researchers are also beginning to understand the environmental contributions to mental illness and to identify so-called epigenetic targets for treatment, Manji said. New tools for visualizing and manipulating brain function are emerging, and the ability to make patient-specific cells with the help of induced pluripotent cell techniques is providing the means to test disease and treatment hypotheses in human tissue.

Neuroscientists studying brain function are abandoning their focus on neurotransmitter levels and are instead embracing a model in which synaptic plasticity builds the circuitry of the brain. A growing understanding of how neurotransmitter receptors drive synaptic plasticity, strengthening or weakening the flow of information between neurons, is pushing researchers to ask whether this process can be targeted to promote learning and memory or to treat certain illnesses. Awareness of how brain circuitry interacts with stress and immune function is also increasing. In addition to scientific advances in understanding mental illness, great strides have been made in harnessing the technology revolution for data collection.

Manji closed by pointing to HIV research as a model of progression for the field to follow. Just a few decades ago, HIV infection was a death sentence, but through the efforts of researchers, companies and activists, AIDS in the western world has become a chronic disease. "True progress is only going to be made if we can work together," he said, "and I'm very optimistic that we can."

The medical consequences of depression and neuroimmune interactions

Mental illness and substance abuse are too often treated separately from other medical illnesses, but these conditions are closely intertwined, said K. Ranga Rama Krishnan of Rush Medical College. Many symptoms that arise in depression—feeling tired, losing interest in life activities, poor sleep, and reduced appetite—also occur in medical illnesses. Depression, anxiety and substance abuse are major drivers of hospital readmission rates following medical illnesses, and conversely, the longer an illness lasts, the more likely is a patient to become depressed. Large-scale studies conducted decades ago also show that at least for cardiovascular disease patients, additionally having depression increases the risk of death.

Inflammation has been proposed as one connection between medical illness and mental illness. Substances that activate pro-inflammatory cytokines, elicit symptoms of major depression. In healthy adults injected with lipopolysaccharides, for example, activation of proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interneulin 10 strongly increased while mood and memory worsened. Cytokines injected therapeutically, such as interferon and interleukin 2, also negatively affect mood. Antidepressants, on the other hand, dampen pro-inflammatory cytokine activation.

Inflammation might cause depression-like sickness behaviors by activating cytokines either in the periphery or directly in the brain.

Stress can affect mental health via the immune system. Stress stimulates the production of cortisol, but it can also directly affect immune function, which increases the production of pro-inflammatory markers as well as a substance produced in the liver called C-reactive protein. C-reactive protein is linked with cardiac disease, vascular disease, and many other medical conditions, and it also acts as a proxy variable for inflammation. One stress-related modulator of both inflammation and depression is the hypothalamic-pituitary-adrenal axis of the endocrine system, which regulates cortisol levels. Many changes to this system both influence and are influenced by depression—for example, the adrenal and the pituitary glands increase in size in depression, and cortisol levels increase. Stress also decreases serotonin levels.

Inflammation is a factor in many disorders, including depression, Krishnan said, and several studies have explored the therapeutic effect of blocking pro-inflammatory cytokines. About 15 years ago, in a trial testing a tumor necrosis factor inhibitor called etanercept in treating rheumatoid arthritis, clinicians noted that patients who took it felt better and reported a lessening of fatigue even before their arthritis improved. When the drug, acquired by Amgen, began trials for psoriasis, Krishnan and his colleagues convinced the company to include measures of fatigue and depression. In one of the largest studies of depression treatment at the time, the researchers found that depression, ranging from mild to severe, was widely present in the patient group, and that depression and fatigue symptoms improved in patients who received the drug—often before their psoriasis began to resolve.

Other studies since then have explored the effects of therapeutically administered cytokine inhibitors on depression. Antagonists of interleukin 6, used in treating a lymph node disorder called Castleman disease and rheumatoid arthritis, also improved depression symptoms. When cytokine blockers were used to treat depression directly, they ameliorated symptoms selectively in patients who had elevated C-reactive protein levels—a marker of inflammation. This suggests that inflammation could provide a therapeutic target in a subset of patients with depression. Krishnan noted that these studies have initially spurred limited follow-up, in part because some of the cytokine inhibitors tested were generic medicines and or had significant risk, and therefore would be difficult to commercialize. But such data reveal that "there is a story there, and it's worth exploring."

Speakers

Tyrone D. Cannon

Yale University

Carlos A. Zarate Jr.

National Institute of Mental Health, U.S. National Institutes of Health; The George Washington University

Highlights

Risk calculators predicting the onset of psychosis are improving, but treatments for preventing the condition do not yet exist.

Next generation antidepressants such as ketamine can elicit effects within hours, unlike the 6–8 week timeframe of current antidepressants.

Prediction and prevention of psychosis

Current approaches for treating people with schizophrenia do not address the underlying disease process or prevent future psychotic episodes and often carry significant side effects. The ability to predict and prevent the onset of psychosis would fill a great unmet medical need, said Tyrone D. Cannon of Yale University.

Several groups have attempted to develop tools that identify people at imminent risk of psychosis by pinpointing early symptoms that precede their first psychotic episode—a so-called prodrome. This might include deterioration of social or scholastic function or an up-ramp in psychotic thoughts. Early work showed that in people age 15–25 who showed prodromal symptoms, about 15% converted to full-blown psychotic disorder within one year and 25% converted within two years. Most such patients develop schizophrenia, while others develop a mood disorder with psychotic features.

Cannon is a primary investigator of the North American Prodrome Longitudinal Study (NAPLS2), a consortium of nine research centers in the US and Canada that is developing a prediction calculator for psychosis that could be applied to individual cases in the clinic. The tool was based on risk calculators for cancer and coronary heart disease developed by a statistician at the Cleveland Clinic.

The psychosis risk calculator uses variables including unusual thought content, decline in social function, age, and performance drops in verbal learning, processing speed, and digit symbol matching. It was developed with data from 596 help-seeking, at-risk individuals.

The tool performed similarly to those used for coronary heart disease and cancer. The group then replicated it in 176 subjects in another study that included many of the same variables, and found that the risk calculator worked similarly and thus generalized beyond the population in which it was developed. The tool needs more validation before use in a clinical setting, but could be used to enroll patients in clinical trials, Cannon said. Screening for subjects with a higher risk of converting to psychosis mitigates against false positives.

This "low tech" device is valuable, Cannon said, but biomarkers could improve it further. A small study suggests that structural MRI could further refine risk prediction. Blood markers of inflammation, oxidative stress, and hypothalamic–pituitary–adrenal axis dysregulation are also under preliminary investigation. This work must be validated in large studies, however. While the ability to predict conversion to psychosis is improving, individuals thus identified have few options for preventive treatments.

Over-active microglia (green and yellow) may be pruning too many synaptic connections in the brains of people with schizophrenia.

The brains of people in their late teens and early 20s are in a period of dynamic development. Neurons develop exuberant synaptic connections in childhood that are later pruned in adolescence. But MRI data shows that the cerebral cortex of schizophrenia patients is thinner than those of people without the condition, suggesting that excessive pruning of neuronal connections may play a part in psychosis. Cannon and his colleagues are exploring the hypothesis that immune cells in the brain called microglia are scavenging synapses at an abnormally fast rate. Microglia are activated by proinflammatory cytokines, and data from NAPLS shows that higher levels of proinflammatory cytokines at baseline predict higher brain tissue loss in people with psychosis.

NAPLS is currently exploring whether microglial activation precedes and predicts changes in brain circuitry related to psychosis and whether interfering with this process will provide therapeutic benefits. The group is also examining whether synapses are more likely to be inactive when synaptic plasticity is dysregulated, and whether this increases their propensity to be pruned.

Rapid relief from severe depression

Mood disorders disrupt many facets of patients' lives and often become chronic. A big limitation in current treatments is the lag of onset; antidepressants take up to 6–8 weeks to take effect. The goal of next generation treatments is to be efficacious within hours, said Carlos A. Zarate Jr. of the National Institute of Mental Health and the George Washington University.

Most efforts to develop new treatments for mood disorders target genes, cells, circuits, or behavior, but these approaches are limited by a lack of pathophysiological knowledge. Another possible strategy is to focus on drugs that have a strong and surprising effect. One such drug is ketamine, an anesthetic which produces a rapid antidepressant effect. Developing biomarkers of response to ketamine will allow researchers to fill in pathophysiological knowledge gaps.

Zarate and his colleagues are conducting double-blind proof of concept studies of ketamine and polamine, another fast-acting agent. They focus on modulators of the neurotransmitter glutamate, where targets include presynaptic glutamate release; postsynaptic neurons, glia and astrocytes; and glutamate synthesis and release.

The fast-acting effect of ketamine has long been recognized; a 2006 study conducted by Zarate and his colleagues showed a 50% reduction of symptoms within 6–24 hours. Later studies confirmed the finding, showing an anti-suicidal effect within one hour with improvements in associated comorbidities. Ketamine's fast effects appear to endure at least a week, and studies are now trying to determine the best way of administering it along with existing treatments. Several biomarkers are under investigation to track response to ketamine and relapse.

Multiple glutamate modulators could serve as targets for mood disorder therapies.

In one proposed mechanism of action for ketamine, the drug's effect is mediated by a burst of glutamate release that potentiates plasticity. Zarate and colleagues showed that several markers—EEG recaptured by EEG recordings of slow wave activity, shifts in patients' bias towards negative words and faces, cortical excitability as measured with magnetoencephalography—had potential as biomarkers that differentiate ketamine responders from nonresponders. The researchers will soon launch an in-depth biophenotyping study to evaluate these and other biomarkers.

Zarate's lab set out to systematically examine the role of ketamine's metabolites. Identifying their pharmacological and behavioral effects could give clues about ketamine's mechanism of action and determine whether these downstream molecules have their own therapeutic properties. They interfered with ketamine's metabolism by strengthening one of the compound's carbon bonds with deuterium and found that its antidepressant properties are diminished in animal studies. That and further work suggests that one metabolite, hydroxynorketamine plays a role in its therapeutic effect.

Speakers

Geraldine Dawson

Duke University School of Medicine

Daniel S. Pine

National Institute of Mental Health, US National Institutes of Health

Highlights

Researchers are identifying biomarkers for autism to identify children with the disorder as early as possible and to use as measures for determining therapeutic efficacy in clinical trials.

Video games that train a person's instantaneous reflexive response to threat can help treat anxiety disorder.

Innovative biomarkers and clinical indicators in autism spectrum disorder

Autism wears many faces—from individuals who don't speak and require constant care, to those employed as university professors. Yet people with the condition share a struggle to navigate the social world. Drugs to treat core symptoms of the disorder are on the horizon, said Geraldine Dawson of Duke University School of Medicine. But to develop them, the field needs better outcome measures and a better infrastructure for clinical trials.

Autism researchers are on the hunt for biomarkers of the condition.

Several ongoing projects are looking for biomarkers in infant siblings of children with autism, who are at high risk of developing the condition. Early detection may make interventions more effective. In one study of 14-month old children, Dawson and her colleagues used high-density electroencephalography (EEG) to identify a pattern of hyperconnectivity in the brains of babies who went on to develop autism. Other findings suggest that reduced connectivity between specific brain areas thought to mediate speech, so the brain in children with autism appear to not be specializing normally. Electrophysiological signals called event-related potentials (ERPs) offer another promising predictive biomarker. In children with autism, ERP response to faces is disrupted, and in a recent study Dawson and her colleagues compared ERPs to faces versus objects to predict autism diagnoses in 6-month-old high-risk infants.

Biomarkers can help evaluate interventions in clinical trials. A 2-year study in high-risk children starting at 2.5 years of age that included behavioral and electrophysiological outcome measures showed that children who received an intensive behavioral intervention called the Early Start Denver Model showed improved IQ, language, social abilities and adaptive behavior compared to those that received the control condition of standard community intervention. Another study showed that early intensive behavioral intervention can normalize brain activity in children with autism, and that such changes correlate with improvements in social behavior. Early intervention in young children can thus bring them back to the social world, Dawson said.

Even with the best behavioral interventions, however, a significant percentage of children with autism still have significant impairments. For example, 30% of children with autism never learn to speak. Therefore, medicinal interventions are also key. Dawson and her colleagues recently completed a phase I open-label trial of autologous cord blood to treat autism in 25 children. Evidence suggests that neuroinflammation plays a role in the disorder, and umbilical cord blood has been shown to reduce microglial activation and stimulate myelin repair, perhaps through anti-inflammatory or neurotrophic mechanisms. The study evaluated eye-tracking, EEG, and magnetic resonance imaging, and found promising improvements in social behavior at 6 months and 12 months after infusion.

Dawson also described several novel techniques for measuring behavior that can collect a so-called digital phenotype of a child, providing objective, quantitative, continuous and scalable data. One such tool, LENA, is a small computer worn in a child's pocket that records her and her parents' vocalizations at home and measures who speaks and how often. Another approach, called EthoVision, tracks how often a child approaches a parent or objects in the lab. A third tool measures facial expressions in babies and children.

Researchers are developing a range of new methods for obtaining so-called digital phenotypes of participants in clinical trials.

A handful of consortia have formed to identify and validate biomarkers and to develop ways of using such technology-based measures. Dawson and her team are members of the Janssen Autism Knowledge Engine, which is creating tools including a phenotyping portal for parents and clinicians, a new measure that allows parents to monitor autism-related symptoms on their smartphones, and a biosensor worn by the child that collects sleep, heart rate and other data that can be correlated to behavior. Other efforts include the NIH Autism Biomarkers Consortium for Clinical Trials and the European Autism Interventions Consortium. "These large-scale efforts will be critical for companies coming into this space to have confidence in which biomarkers they should be incorporating into their clinical trials," Dawson said.

Using neuroscience to inform clinical thinking in pediatric anxiety

Mental illnesses are currently classified by symptom, but researchers must begin understand them based on brain function, said Daniel S. Pine of the U.S. National Institute of Mental Health. Unraveling the relationship between clinically relevant behaviors and brain processes in the lab can provide clinical insight, he said.

Anxiety is a good starting point for this approach because its brain-behavior relationship is strongly conserved across species and can therefore be compared in humans versus nonhuman organisms. Understanding how different aspects of anxiety relate to different brain perturbations and differentiating risk from disorder can help improve treatment.

Pine's work rests on the hypothesis that an anxious person pays more attention to threats than a non-anxious person. Responding to a threatening stimulus has two consecutively-occurring components. The first, a reflex like pulling your hand away from a hot stove, occurs without conscious perception, while the second involves realizing what has occurred. Understanding the two-step nature of this process has profound implications for treatment, Pine said.

His team studied this early reflex component using the so-called dot-probe task, which measures response times to a probe after viewing a stimulus such as an angry face versus a neutral face. Subjects who have high behavioral inhibition—that is, who are more likely to experience distress from novel stimuli—respond faster to angry faces, while subjects with low behavioral inhibition respond faster to happy faces. Behavioral inhibition reflects anxiety, suggesting that anxiety increases the tendency to monitor threat. The researchers found that lower levels of sustained attention at 14 months of age predicted increased levels of behavioral inhibition and anxiety over the next 7–10 years of a child's life.

In the two-system framework of fear and anxiety (bottom), a "defensive survival circuit" kicks in reflexively, without cognitive awareness.

However, this finding is reversed when people are in dangerous circumstances. Pine and his colleagues discovered in 2009, during the Gaza war in Israel, that people who did the dot-probe test right after running to a bomb shelter experienced an avoidance of attention to the novel stimuli rather than an elevation of it. The researchers have since replicated these findings. In one study using this paradigm, they reported that soldiers who go on to develop post-traumatic stress disorder show a baseline bias towards increased threat detection from the start of their time in the military, but in instances when they are actually exposed to threat, they experience attention avoidance.

Attention avoidance is an automatic reflex that turns out to be mediated by a circuit that connects the amygdala to the prefrontal cortex, Pine said. Talk therapy won't work in helping people with anxiety to normalize it because they are not even aware they experience it. Pine and his team therefore came up with a different technique—a video game that retrains players' attention. In multiple studies, they showed that in anxious children and adults, this training game alleviates anxiety symptoms. Based on the results of a small randomized clinical trial published last year led by Pine's Israeli collaborators, all Israeli defense force soldiers now receive this training before they go into combat. However, there is yet insufficient evidence to understand who such treatment would potentially benefit and who it might harm, Pine said. Still, its use does reflect its clinical relevance, he believes, and that ultimately it will become an essential part of treating anxiety disorders.

Speakers

B. Timothy Walsh

New York State Psychiatric Institute, Columbia University

Vaibhav Narayan

Janssen Research & Development, LLC

Highlights

In anorexia nervosa, dieting becomes habitual, and treatment thus requires breaking the habit.

Digital apps and technologies are providing ecologically valid, continuous data that can be used to monitor central nervous system disease.

The emerging neurobiology of anorexia nervosa

Anorexia nervosa, which affects about 1% of women, is extremely difficult to treat. B. Timothy Walsh of New York State Psychiatric Institute, Columbia University described a cognitive neuroscience-based approach to understanding the behaviors driving the illness and their underlying neural circuitry.

The brain circuit for goal-directed learning (red) shifts to more dorsal and lateral regions (orange) of the prefrontal cortex and the striatum.

Treating anorexia nervosa is deceptively simple: simply get people to eat. Upon being admitted to Walsh's treatment facility, patients are asked to partake of a buffet lunch, where most consume about 300 self-chosen calories. After 2–3 months of treatment they improve, eating closer to 500 self-chosen calories. However, that does not approach control subjects' caloric intake of 800 calories. Clinicians know that people with anorexia nervosa avoid foods containing fat, and that recovery is associated with eating a greater variety of foods with higher fat content. The persistence of dieting is thus the condition's core behavior.

To better understand its persistence, Walsh and his colleagues turned to the neural basis of making choices. Persistent behavior that we are not born with is learned via one of two processes: Goal-directed learning, in which a behavior is repeated because it elicits a reward, and habit-formation, in which the behavior becomes fixed through overtraining, and begins to occur automatically, dissociated from the reward. "Habits are very powerful mechanisms that we as mammals are very prone to develop with training," Walsh said.

The circuit governing goal-directed learning includes the amygdala, the ventral striatum, and the prefrontal cortex. But as a behavior becomes more habitual, the circuit shifts toward more dorsal and lateral regions of the striatum and frontal cortex. Walsh's team hypothesized that anorexia nervosa, initially a learned behavior in young girls who feel good dieting, becomes habitual—explaining the condition's persistence and why it can be so hard to treat.

The team tested the hypothesis with a food choice task that examines the neural mechanism for self-control. They showed subjects a series of food pictures, asking them to rate how healthy, then how tasty, each item was. Then, a computer program chose a food the viewer judged neutral in both health and taste, and paired that image consecutively with all the other foods.

Subjects with anorexia nervosa generally reported food to be less healthy than controls did, but both they and control subjects deemed low-fat food healthier than high-fat food. However, for anorexia subjects, the higher the fact content, the less tasty they considered a food to be. When subjects were offered a choice, controls picked tasty foods while anorexia subjects selected healthy foods, going for high fat foods just 20% of the time. Finding high-fat foods less tasty thus reduced the need to exert self-control in not eating them. But when self-control was called upon, anorexia subjects were much better at it, exercising it 50–60% of the time while control subjects did so less than 20% of the time.

The researchers examined the eating preferences of people with anorexia nervosa with a food choice task including high-fat and low-fat foods.

When the researchers conducted the study in a functional magnetic resonance imaging scanner, controls engaged the ventral striatum while subjects with anorexia engaged the dorsal striatum, supporting the hypothesis that habit underlies their diet behavior. What's more, this connectivity pattern was correlated with how much they ate the next day. This task thus provides a tool for probing a habitualized behavior and its underlying neural circuitry. Better understanding of these circuits may point the way to helping people change this and other maladaptive behaviors, Walsh said.

Mobile and sensor technology for brain and CNS diseases

Medicine is on the cusp of a technological revolution, and neuroscience is the therapeutic area best positioned to take advantage of it, said Vaibhav Narayan of Janssen Research & Development. He discussed the promise and the challenge of harnessing continuous monitoring technologies for central nervous system disorders in an evidence-based and clinically-relevant manner.

These technologies could be applied to two types of disorders—neurodegenerative, in which change happens slowly over a lifetime, and neuropsychiatric, which is much more dynamic in nature and inconsistent in timescale.

In a neurodegenerative disease such as Alzheimer's, pathology takes root in the brain decades before symptoms appear, and the trajectory of memory and cognitive loss from mild cognitive impairment and dementia diverges from that in normal aging. Two studies in which people were followed for 15–20 years until their death suggested that a decline in verbal episodic memory is caused by the disease. Numerous apps and technologies now exist for capturing these markers in an ecologically valid, continuous, and often passive way. Narayan and his colleagues, for example, developed an app that automates a widely-used test for verbal episodic memory, performing as well as a trained psychologist.

Many apps and tools are being developed to continuously measure episodic memory.

Functional tasks such as ability to take medication or handle everyday finances can also be used as markers. Even something as simple as computer use can track the disorder: In people who had mild cognitive impairment, amount of daily computer use plummeted month by month, presumably because it taxed cognitive functions like episodic memory, executive function, and attention. Narayan and his colleagues are also investigating whether performance on an immersive video game correlates with known markers of Alzheimer's disease in people who report memory complaints. Such serious, validated tests will soon be available on our smart phones and computers to help determine whether the decline a person experiences is normal or disease-driven.

Digital tools are also useful for neuropsychiatric disorders, which are marked by a long prodromal period as well as precipitous events like depressive or manic episodes over days or weeks. This dynamic paradigm offers opportunities to improve outcome by intervening both presymptomatically and during relapses if they can be detected. Risk factors include constants, such as family history, as well as changing ones such as circadian rhythm, mood, sleep, and psychosocial functioning that can be tracked through a cell phone.

Narayan's group is currently conducting a study following more than 300 people with major depressive disorder for 12 months, continuously collecting data on sleep, activity cycle, and speech to look for a detectable technology-driven signature of relapse. Ultimately, he says, such data will have to be well-integrated with clinical information gleaned from medical visits. It must also be collected longitudinally, so that each person can be their own control.

Thousands of apps are being developed to monitor mood, predict disease-related events, and even offer therapeutic intervention, but so far, the number of them backed by science is miniscule. In 2013, for example, more than 1500 apps related to depression could be found in commercial app stores, but there were just 32 published research studies about them. Reputable companies can thrive in this space only if researchers can ensure the validity of such measures, Narayan said. The learning engine for developing such technologies starts out with controlled studies, clinical validation, and replication studies, and then involves the use of scalable IT platforms and testing in real-world populations. Ultimately, he said, the algorithm will be able to learn from the population as a whole and to make predictions for individuals.

Finally, Narayan said, with data from people's daily lives being used to make medical decisions, "we would have to make very clear that the owners of these data are the patients themselves—it's they who should decide how these data are shared and utilized." Janssen is leading a consortium of 24 organizations that span computer companies, biotech and medical device companies, patient advocates, and ethics experts to address how these technologies should navigate ethics and privacy concerns.

How will drugs that treat inflammation stand up as therapies for depression, and how can researchers identify the subset of patients most likely to respond to them?

What role do microglia play in the disease process of psychosis?

How can blood biomarkers be used to predict schizophrenia and other mental illnesses?

What kinds of continuous monitoring tools that collect a so-called digital phenotype of patients will be most helpful in clinical trials?

How should attentional training be used therapeutically to alleviate anxiety?

Can understanding the neural circuitry of core behaviors in mental illness point to new therapies?

How can digital monitoring tools be translated into use in the real world while maintaining patient privacy?

Might glutamate targets besides ketamine, such as some ketamine metabolites, also have therapeutic possibilities as fast-acting antidepressants?