347 Applications - 40 Grants - $4M Funded
Hailing from nine countries and 33 institutions, 40 mid-career scientists will apply powerful new technologies and new insights to study mental illnesses such as anxiety, autism spectrum disorder, bipolar disorder, depression and schizophrenia. We are delighted to be able to support their work and take pleasure in introducing them to you.
BASIC RESEARCH - To understand what happens in the brain to cause mental illness
Garret D. Stuber, Ph.D., University of North Carolina at Chapel Hill, will examine circuit connectivity within the bed nucleus of the stria terminalis (BNST), a component of the amygdala, the brain’s center for fear-related illnesses such as panic disorder, obsessive-compulsive disorder and generalized anxiety disorder. The study will determine the precise neural circuits within the BNST that selectively process threat-related stimuli.
BIPOLAR DISORDER (BP)
Benjamin I. Goldstein, M.D., Ph.D., Sunnybrook Health Sciences Centre, University of Toronto, will conduct a trial to determine how oxidative stress and blood-vessel functioning relate to cognitive problems in adolescents with BP. Oxidative stress––an imbalance between production of reactive oxygen species (free radicals) and antioxidant defenses––is increased in BP, while the proper functioning of blood vessels is reduced. These effects are associated with cognitive problems, both during episodes of depression and mania as well as during remission.
Tracey L. Petryshen, Ph.D., Massachusetts General Hospital, Harvard University, will investigate the function of a gene called Ankryin 3 (ANK3) in BP. Abnormally expressed, ANK3 is one of the strongest BP risk genes in response to stress, a major risk factor for the disorder. The study will probe ANK3 regulation of stress hormone expression in susceptible mice to pinpoint brain regions where ANK3 is believed to function.
Maura Boldrini, M.D., Ph.D., Columbia University, seeks to advance understanding of how inflammation influences depression. Studies of animal models of depression show that inflammation is detrimental to neurogenesis, the birth of new neurons, in the hippocampal region of the brain. Selective serotonin reuptake inhibitor (SSRI) antidepressants appear to work by spurring neurogenesis. The study will compare expression of inflammatory chemicals called cytokines in the hippocampus of postmortem brains of untreated depression patients, SSRI-treated patients and healthy controls.
Kathryn L. Evans, Ph.D., University of Edinburgh, seeks to clarify the effect of factors that alter gene expression in the development of major depressive disorder. The binding of chemicals such as a methyl group to a gene’s DNA in reaction to environmental influences changes the amount of protein the gene produces (a field of study referred to as epigenetics,* where gene expression is affected without an alteration to the underlying DNA sequence). This study will compare DNA methylation in siblings where one has depression and the other does not.
Erika E. Forbes, Ph.D., University of Pittsburgh, will investigate the neural circuitry underlying the influence of inflammation on the onset of depression in a pilot study of youths at risk due to family mental health history. Recent findings with adults have shown that inflammation can lead to anhedonia (the inability to experience pleasure) and altered response to reward, responses that commonly occur in depression.
Roxann Roberson-Nay, Ph.D., Virginia Commonwealth University, will examine the association between early-onset major depressive disorder and DNA methylation, a process that alters genetic activity (“epigenetics”* per above). The study will examine DNA methylation in adolescent and young adult twins, with and without depression histories, to learn whether it leaves a lasting genetic imprint, if it is associated with the number of lifetime depression episodes and if it can predict depression development.
Daniel J. Smith, M.B., Ch.B., M.D., University of Glasgow, aims to identify new genetic risk factors for co-morbid (co-occurring) major depressive disorder and cardiometabolic disorders. He will approach the problem by analyzing findings from the UK Biobank, in which 500,000 men and women aged 40 to 69 years were studied to learn how genetics, lifestyle, diet and environment contribute to illness.
Alberto Bacci, Ph.D., Brain and Spine Institute, Paris, is looking into the role of cells called PV basket cells* in schizophrenia. His lab previously found that PV basket cells are massively self-connected by inhibitory autapses. (Autapses are synapses that a neuron makes with itself rather than with another neuron.) The research will examine how PV-cell autaptic self-inhibition malfunction affects cognitive functioning in schizophrenia.
Oleg V. Evgrafov, Ph.D., University of Southern California, will investigate aberrations in brain development that result in noticeable differences in brain structure in people with schizophrenia. To learn how differences in gene expression of neural progenitor cells (or precursor cells) are translated into structural differences in the brain, the research will explore the effects of abnormally high expression of a calcium channel gene, CACNA1C, one of the few genes proven to be involved in the origin of schizophrenia.
David Glahn, Ph.D., Yale University, will assess the influence of the glutamatergic genetic pathway* on cognitive deficits in schizophrenia as a step toward clarifying how modulating glutamate* neurotransmission might work as a treatment. The glutamate hypothesis of schizophrenia suggests that there is disrupted functioning of the N-methyl-D-aspartate (NMDA) receptors for glutamate, the brain’s major excitatory neurotransmitter. NMDA receptors are thought to mediate cortical connectivity, which is critical for cognitive functioning.
Kathryn Grace Commons, Ph.D., Children’s Hospital, Boston, proposes to visualize and quantify the network of axons that controls the activity of serotonin neurons to identify features of the network that change in animal models of psychiatric illnesses. Axons are the projections that receive signals carried by neurotransmitters across the synapse, the junction between neurons. The neurotransmitter serotonin is implicated in many mental illnesses, including depression, anxiety, obsessive compulsive disorder and schizophrenia.
Alysson Renato Muotri, Ph.D., University of California, San Diego, will examine the interplay between astrocytes and neurons in psychiatric illnesses. Once believed to be passive support cells, astrocytes have been found to secrete molecules that stimulate synapse formation and function throughout the brain. The research will create and analyze stem cells derived from patients’ neurons and astrocytes to explore genetic alterations that are common to autism spectrum disorder and schizophrenia.
Anju Vasudevan, Ph.D., McLean Hospital, Harvard University, is investigating a signaling pathway of the neurotransmitter GABA* that works independently of the classical, better known GABA pathway. The two pathways diverge during early embryogenesis, with far-reaching consequences for brain development. Understanding abnormalities in this novel pathway may provide new understanding of mechanisms underlying neuropsychiatric disorders such as schizophrenia, epilepsy, autism spectrum disorder and mood- and anxiety-related disorders.
- EATING DISORDERS
Benjamin R. Arenkiel, Ph.D., Baylor College of Medicine, will expand his examination of brain circuits underlying obesity and metabolic dysfunction and eating disorders such as anorexia and bulimia. The proposed study is based on his lab’s discovery that loss of cholinergic neurons (cells of the acetylcholine neurotransmitter system) from the basal forebrain leads to increased food intake and severe obesity in mice.
NEW TECHNOLOGIES - to advance or create new ways of studying and understanding the brain
BIPOLAR DISORDER (BP)
Benicio N. Frey, M.D., Ms.C., Ph.D., McMaster University, Canada, will conduct a clinical trial using a novel method of magnetic resonance imaging (MRI) to determine whether patients with BP exhibit abnormalities in the myelin of the cerebral cortex. Myelin is the substance that sheathes axons, the projections on neurons responsible for receiving neurotransmission signals. The study is based on the possibility that disruptions in myelination could disrupt brain connectivity.
Vincent A. Magnotta, Ph.D., University of Iowa, will apply a functional imaging tool, called T1 relaxation in the rotating frame (T1ρ), developed in his lab, to study metabolic changes in BP; studies previously hindered by limitations in imaging technology. Preliminary findings suggest an abnormal neurovascular coupling that is contributing to observed symptoms. Results from this study may lead to novel diagnostic and therapeutic approaches.
Dimitri Van De Ville, Ph.D., Ecole Polytechnique Federale de Lausanne, Switzerland, will use functional magnetic resonance imaging (fMRI) to obtain periodic measures of brain activity in patients with BP, and apply novel analytical techniques developed in his lab to diagnose and anticipate mood changes. The guiding hypothesis is that large-scale patterns of dynamic functional connectivity can unveil the direction of mood alterations and might be a reliable predictive marker for mood fluctuations.
Romina Mizrahi, M.D., Ph.D., Centre for Addiction and Mental Health, University of Toronto, will conduct the first brain imaging studies to examine possible alterations in endocanabinoid metabolism in patients with schizophrenia. Numerous studies have shown that the use of cannabis (marijuana or hashish) is associated with increased incidence of schizophrenia. The active components of cannabis mimic the effects of endocannabinoids, brain compounds that regulate neurotransmitters, including dopamine and glutamate, which are altered in schizophrenia.
Adam G. Carter, Ph.D., New York University, will study the impact of chronic stress in mental illnesses, including schizophrenia, anxiety and depression, as it affects the prefrontal cortex, a brain structure critical in the regulation of cognition and emotion. The project will use a combination of electrophysiology, microscopy and optogenetics* to explore how stress perturbs structure and function of cortical neurons in neuropsychiatric illness.
David J. Foster, Ph.D., Johns Hopkins University, is using a rapid neural assay he helped develop to study hippocampal “replay” memory in mice. The hippocampus is a key brain memory structure. Recent rodent studies reveal a pattern across hippocampal neurons in which experiences are “replayed” at later times. Dr. Foster hypothesizes that impairments to the episodic memory and future planning functions of hippocampal replay/preplay may be of major significance in psychiatric disease.
John M. Hettema, M.D., Ph.D., Virginia Commonwealth University, will expand on his neuroimaging studies of brain abnormalities in mood and anxiety disorders by examining at-risk twins at the critical period between ages nine to 13. He will use functional magnetic resonance imaging (fMRI) brain scans to assess activation patterns in the amygdala and prefrontal cortex while subjects respond to psychological tasks. Twins are ideal subjects for determining the differential effects of genes and environment and their shared versus specific contributions.
Sheena A. Josselyn, Ph.D., Hospital for Sick Children, University of Toronto, will explore brain mechanisms involved in the association of environmental stimuli, such as a neighborhood or song, with the rewarding properties of cocaine. The goal of the research is to determine whether disrupting the memory can prevent addiction relapse. Dr. Josselyn’s project will use molecular tools to erase reward memory in a mouse analogue of drug-seeking, as well as the new technology called CLARITY to examine impact on the 3-D brain-wide “cocaine map.”
NEXT GENERATION THERAPIES - to reduce symptoms of mental illness and retrain the brain
Rajeshwar Awatramani, Ph,D., Northwestern University, will study subtypes of neurons that produce dopamine, a neurotransmitter implicated in a number of neuropsychiatric disorders. Current treatments that affect the dopaminergic system lack target specificity, with often undesirable results. One subtype, DAS6, appears to project to the amygdala, the brain’s seat of fear and anxiety. The research goal is to define DAS6 involvement in fear behaviors so as to improve treatment outcomes.
Thomas Kash, Ph.D., University of North Carolina Chapel Hill, will explore the effect of the brain chemical dynorphin and its receptor, kappa opioid receptor (KOR), on the neurotransmitter glutamate and anxiety-like behavior. The aim is to demonstrate a causal role for dynorphin and KORs in a key anxiety circuit so as to identify potential targets within the system for novel treatments of anxiety and stress disorders.
BIPOLAR DISORDER (BP)
Carla Torrent, Ph.D., Clinica de la Salud, Spain, will test the usefulness of an online e-neurocognitive module that can be used at home as an adjunct to other remediation in the treatment of BP. Between 40 and 60 percent of patients with BP experience cognitive impairment during acute mood episodes and also during remission periods. The program, which has been used successfully with neurological and schizophrenia patients, will be altered for content specifically geared to BP.
Rodrigo A. Cunha, Ph.D., University of Coimbra, Portugal, will explore the effect of stress in depression, based on the hypothesis that repeated stress impairs brain circuits mediating positive emotion (reward learning), while bolstering circuits mediating negative emotion (aversion learning). The goal is to develop a therapy that targets a system regulated by a receptor for the chemical adenosine, which simultaneously corrects impaired reward and aversive behaviors.
Flavio Frohlich, Ph.D., University of North Carolina, Chapel Hill, will conduct a trial of a non-invasive brain stimulation method developed in his lab for the treatment of patients with major depressive disorder. This method uniquely provides adaptive, individualized stimulation. Called “feedback transcranial alternating current stimulation,” it manipulates brain activity through a weak electric current, not detectable by the patient, applied to the scalp in response to pathological brain-activity signals measured by a standard electroencephalogram (EEG).
Dimitris N. Kiosses, Ph.D., Weill Cornell Medical College, Cornell University, plans to adapt Problem Adaptation Therapy (PATH), a home-delivered psychosocial intervention, to reduce depression and prevent suicide in at-risk older adults with treatment-resistant major depressive disorder and cognitive impairment. PATH addresses patient, caregiver and home environment. The proposed pilot trial will add new cognitive, behavioral and support techniques to reduce suicide ideation (thinking about suicide) and feelings of hopelessness.
Katherine E. Burdick, Ph.D., Icahn School of Medicine at Mount Sinai, will test the calcium channel blocker isradipine, normally used to treat high blood pressure, as a potential treatment for the cognitive deficits of schizophrenia. A variant form of the gene that encodes a subunit of a calcium channel has been shown to impair cognitive ability in schizophrenia patients, suggesting that calcium channel dysregulation may be a central feature of schizophrenia.
Erika Jääskeläinen, M.D., Ph.D., University of Oulu, Finland, will utilize data from the Northern Finland 1966 and 1986 Birth Cohort population studies to determine the effects of lifetime antipsychotic medication on the course of schizophrenia, including number of symptoms and hospitalizations, recoveries, cognitive and occupational functioning, other health problems and death. The research will also examine whether outcomes differ between these two generations.
Einat Liebenthal, D.Sc., Brigham & Women’s Hospital, Harvard Medical School, is interested in the neural mechanisms that underlie psychotherapy’s positive effects in treating schizophrenia. This study, which will explore neural response to threat words, should help determine, among other findings, the types of patients most likely to respond to psychotherapy and the aspects of therapy likely to be most effective.
Steffen Moritz, Ph.D., University Hospital Hamburg-Eppendorf, will conduct a trial to assess the efficacy and feasibility of using individualized Metacognitive Therapy (MCT+) to treat psychotic symptoms of schizophrenia in patients who refuse medications or fail to take them as prescribed. MCT+ is a new form of psychotherapy that addresses reasoning biases and is derived from both individualized cognitive behavioral therapy and group metacognitive training, which has been described as “thinking about thinking.”
Yuri Rassovsky, Ph.D., University of California, Los Angeles, plans to try a brain stimulation method called transcranial direct current stimulation (tDCS) as a means of improving cognitive deficits in schizophrenia patients. In the clinical trial, tDCS will be applied over the dorsolateral prefrontal cortex, a brain area significantly involved in cognitive dysfunction. The research will also seek to determine whether deficits in this area involve neuronal hyperactivity or underactivity.
Joshua Roffman M.D., M.MSc., Massachusetts General Hospital, hopes to determine how specific genes, abnormally expressed during fetal development, influence later development of schizophrenia. Folic acid, a B vitamin, supplies chemical precursors for gene expression regulated through a process called methylation. Folic acid deficiency is a risk factor for developing schizophrenia. Findings from the study might therefore support studies of folic acid augmentation as an early preventive measure for people at risk.
Jason Tregellas, Ph.D., University of Colorado Anschutz Medical Campus, will investigate whether the anti-epilectic drug leviteracetam (LEV) will help reduce cognitive deficits in patients with schizophrenia, a problem that has eluded effective treatment. His lab recently demonstrated that the hippocampus, a brain region important for learning and memory, is hyperactive in schizophrenia. The proposed trial is based on evidence that LEV at a low dose reduces hippocampal hyperactivity and improves memory in individuals with mild cognitive impairment.
Aristotle Voineskos, M.D., Ph.D., Centre for Addiction and Mental Health, University of Toronto, will conduct brain imaging studies with schizophrenia patients to study the effects on brain structure of the use of repetitive transcranial magnetic stimulation (rTMS), a promising potential treatment for impairments in working (short-term) memory. This symptom of schizophrenia is difficult to treat. Magnetic resonance imaging (MRI) scans before and after treatment will be used to reveal how rTMS changes the brain to improve memory performance.
Angel Barco, Ph.D., Institute of Molecular Biology of Barcelona, Spanish Research Council, will explore the biological mechanism of histone deacetylase inhibitors (HDACIs), a family of neuropsychiatric medications that appear to reduce cognitive deficits and degeneration in animal models of neurodegenerative diseases. How HDACIs affect neurons in degenerative illnesses such as Alzheimer’s disease, congenital and age-related cognitive impairment, mood disorders, addiction and schizophrenia remains largely unknown; this information is needed for future development efforts.
Benjamin Cheyette, M.D., Ph.D., University of California, San Francisco, will investigate a proposed biochemical feedback circuit in the brain based on his hypothesis that disruption of this circuit in neurons of the prefrontal cortex plays a part in schizophrenia, autism spectrum disorder and possibly other psychiatric conditions. He seeks to determine if this disruption causes changes in synapse development and function that lead to behavioral disruption. He will explore whether pharmacologic intervention that normalizes this circuit can reverse pathological changes.
Allison D. Redlich, Ph.D., State University of New York, Albany, will focus on the escalating problem of the overrepresentation of people with severe, untreated mental illnesses in the criminal justice system. The research will analyze a large database of information on special Mental Health Courts that mandate treatment. Dr. Redlich’s study will assess the validity of the rationale behind establishment of these courts––that treatment reduces crime.