Covering a broad spectrum of mental illnesses, these NARSAD Young Investigator Grants function as catalysts to get new ideas off the ground that may not otherwise be supported. Every year, applications are reviewed by members of the Foundation’s Scientific Council, which is comprised of 145 brain and behavior research experts who volunteer their time to select the most promising research ideas to fund. We are very grateful to all of our donors whose contributions make the awarding of these grants possible.
To understand what happens in the brain to cause mental illness
Andrew L. Eagle, Ph.D., Michigan State University, is working to identify neural mechanisms within the hippocampus involved in resilience to depression and in antidepressant function. Preliminary research in his lab showed that a transcription factor, ΔFosB, is induced in the hippocampus by chronic fluoxetine (Prozac®) use and identified its role in brain reward regions. Transcription factors bind to DNA to control the rate at which genetic information is expressed.
Attention-Deficit Hyperactivity Disorder (ADHD)
Marta Ribases, Ph.D., Vall d'Hebron Research Institute VHIR, will use genome-wide research technology and polymerase chain reaction, a technique for amplifying DNA to add exploration of gene expression, to identify potential microRNA (miRNA) biomarkers for ADHD in blood samples from ADHD patients. MicroRNAs are small, non-coding RNA molecules that play key roles in the regulation of gene expression. The research may help to identify the 30 percent of infants diagnosed at risk for ADHD who will develop the disorder.
Autism Spectrum Disorder (ASD)
Elise Brooks Robinson, SC.D., M.P.H., Massachusetts General Hospital, Harvard University, will use a unique set of medical, behavioral and genetic data obtained from participants with ASD and their families to try to clarify the diversity across the spectrum of ASD. There can be many differences in presentation of symptoms, severity and comorbidities with other disorders, as well as differences in the genetic risk factors involved. The purpose of this project is to link differences in presentation to differences in genetic architecture.
Yijing Su, Ph.D., Johns Hopkins University, will study epigenetic regulation of gene expression in the development of ASD. Epigenetic regulation changes gene expression through various means, including DNA methylation, the attachment of methyl chemicals to DNA. Dr. Su will investigate dysregulation of epigenetic processes by Gadd4, a gene that plays important roles in DNA demethylation, in mice. Gadd4 has been shown to be abnormally expressed in postmortem tissue from patients with ASD.
Simone Tomasi, M.D., Ph.D., Yale University, will explore embryonic development of the prefrontal cortex in the mouse brain to look for alterations in the process that may be linked to ASD. A major goal of the study is to reveal the role of fibroblast growth factors in typical development and in ASD. Fibroblast growth factors and their receptors are essential for proliferation and maturation of embryonic progenitor cells.
Ryan K.C. Yuen, Ph.D., The Hospital for Sick Children, University of Toronto, will conduct a large-scale genome screening to look for a genetic abnormality called trinucleotide repeat (TNR) expansion that disrupts early brain development. TNR is known to be linked to Fragile X syndrome and TNR expansion has been found in ASD-associated genes and in individuals with ASD, suggesting that it may present a significant risk factor for the development of ASD.
Bipolar Disorder (BP)
Seth A. Ament, Ph.D., Institute for Systems Biology, hopes to advance currently sparse knowledge of the genetics of bipolar disorder risk by studying the Amish, an isolated population descended from a small number of founders with reduced genetic heterogeneity. The Amish also tend to have large families and maintain careful genealogical records.
Jacob C. Garza, Ph.D., Massachusetts General Hospital, Harvard University, aims to elucidate the behavioral changes in bipolar disorder that are induced by suppression of the Ankyrin-3 gene. The goal is to provide a framework for explaining the interaction of Ankyrin-3 and GSK-3β—a key signaling molecule implicated in BP―that causes the changes in both behavior and in the regulation of neurogenesis (the generation of new nerve cells) in BP.
Marla Kay Perna, Ph.D., Vanderbilt University, will explore how imbalances in stress responses in mitochondria can result in insufficient energy for maintaining normal cellular function in the brain, leading to BP in susceptible people. Mitochondria are the cellular structures that generate energy, and neurons in the brain need the highest amount of energy, in particular in the hippocampus region, essential for memory and cognition.
Diana I. Simeonova, Dipl.-Psych., Ph.D., Emory University School of Medicine, will focus on early determinants of resilience to and risk for BP. Half of offspring of parents with BP develop mental illness, and half do not. The study will assess and compare social emotional development, resilience and the oxytocin system (a natural hormone involved in emotional bonding) of infants of mothers with BP.
Abdullah Cagri Yuksel, M.D., McLean Hospital, Harvard University, will conduct a trial using a noninvasive metabolism measure to explain an abnormality in energy metabolism that may be involved in BP. Dr. Yuksel will be looking specifically at abnormal activity of creatine kinase—an enzyme critical to the metabolism of high-energy phosphate in the brain—that generates the compound adenosine triphosphate (ATP). ATP is essential for all energy requirements in living tissues.
Anita Ellen Autry, Ph.D., Harvard University, will focus on the role of a brain circuit, PeFA Ucn3, in stress-related postpartum depression. Preliminary findings show that activation of Ucn3 neurons induces aggression toward their pups in normally maternal female mice. She will use a mouse model of chronic social stress to induce deficits in mood and maternal care similar to those of postpartum depression, and examine the impact on PeFA Ucn3 neurons.
Mounira Banasr, Ph.D., Yale University, proposes to identify the molecular and cellular mechanism involved in the effect of stress on astrocytes—brain cells of the type called glia—which provide support and insulation for neurons. Stress-induced glial anomalies, including astrocyte dysfunction, have been implicated in major depressive disorder and other stress-related neuropsychiatric illnesses.
Joanna M. Chango, Ph.D., McLean Hospital, Harvard University, will examine the impact of peer behavior as a means of establishing risk factors for depression in adolescent girls. Neural responses observed in brain imaging following peer criticism and praise will be utilized to probe neurobiological mechanisms. Identifying biomarkers of adolescent depression may improve early identification of depression risk.
Itzamarie Chevere-Torres, Ph.D., Rutgers University, hopes to unravel how changes in microtubules—structures that help shape and support cells—may affect synaptic structure and function and contribute to symptoms of depression. The proposal is based on findings that dysfunction in the activity of stathmin, a negative regulator of microtubular stability, at synaptic sites in the hippocampus leads to symptoms of postpartum depression.
Hyong Jin Cho, M.D., Ph.D., University of California, Los Angeles, will investigate sleep deprivation as a vulnerability factor for inflammation-induced depressive symptoms in older women. Older women have higher rates of inflammation and depression than older men; however, not all older women with inflammation develop depression. Defining the factors that explain this variability may identify individuals at risk for depression when exposed to heightened inflammatory states.
Victoria Stephanie Dalton, B.Sc., Ph.D., Trinity College Dublin, will examine epigenetic control of a gene called FK506 binding protein 5 (FKBP5), a key regulator of stress response. (Epigenetics involves changes in gene expression without alteration to the DNA sequence.) FKBP5 levels are changed in patients with depression and have an epigenetic profile different from non-depressed people. The study will include patients before and after antidepressant treatment.
Simone de Jong, Ph.D., Institute of Psychiatry, King's College London, will conduct one of the largest studies to date of common and rare genetic variation and gene expression in depression, based on data from 900 patients. Dr. Jong will assess which genes differ in expression level correlated with treatment response or with suicidality, with particular focus on symptoms induced or reduced by antidepressants.
Susanne Rosalie de Rooij, Ph.D., University of Amsterdam, wants to determine the effects of maternal depression on the mental health of children. She will investigate whether maternal mood changes the form of the fetus’s brain or causes epigenetic changes (changes in gene expression that do not alter DNA sequence) using brain imaging. Dr. de Rooij will compare brain scans of babies from depressed mothers who received psychological therapy during pregnancy to babies from mothers who did not.
Dani Dumitriu, M.D., Ph.D., Icahn School of Medicine at Mount Sinai, will explore why some people are more resilient to stress that, in others, induces depression. The research will focus on the prefrontal-limbic circuit, which is impaired in both human depression and in animal models, based on the hypothesis that resilient animals will show stronger circuit connections capable of resisting the effects of stress.
Carrie R. Ferrario, Ph.D., University of Michigan, will explore the degree to which insulin-resistance and obesity contribute to depression-like behaviors in a rodent model. Alterations in excitatory inputs to the nucleus accumbens (NAc) area of the brain are thought to contribute to depression; activation of insulin receptors decreases excitatory transmission. This study will determine potential differences in NAc function regulation by insulin in the normal and insulin-resistant state.
Peter Matthew Kaskan, Ph.D., National Institute of Mental Health, National Institutes of Health, is studying dysfunction in the amygdala—a brain center involved in reward—that may cause anhedonia, which is diminished pleasure in response to stimuli previously perceived as pleasurable and is a core symptom of depression. Dr. Kaskan hopes to uncover aspects of information processing compromised by amygdala pathology and an overall picture of brain areas under amygdala influence.
Ian Sutherland Maze, Ph.D., The Rockefeller University, seeks to identify genes and gene networks with altered epigenetic status that relate to depression. Epigenetics refers to modifications of gene expression that occur in response to various stimuli that do not alter the gene’s underlying DNA sequence. Dr. Maze will explore the epigenetic dynamics of a variant histone (histones are proteins found in association with DNA in chromosomes)—H3.3—and its potential contribution to vulnerability for depression.
Divya Deepak Mehta, Ph.D., University of Queensland, plans to establish a collaboration between researchers in Australia and the U.S. to perform genome-wide genetic profiling of 300 samples to identify early predictive biomarkers for postpartum depression. The study is designed to confirm results of a pilot study by the Mehta lab demonstrating that gene expression profiles in blood samples from the third trimester of pregnancy could predict postpartum depression with 88 percent accuracy.
Therese Marion Murphy, Ph.D., University of Exeter, will explore epigenetic pathways linking major depressive disorder and chronic inflammation. The research will compare epigenetic variation in individuals with lifetime depression and chronic inflammatory condition(s) to individuals with depression alone, individuals with chronic inflammation alone, and healthy controls.
Thalia K. Robakis, M.D., Ph.D., Stanford University, wants to find predictors of postpartum depression. Half of women who develop the disorder have no depression history. Adult attachment insecurity is suggested as a strong predictor and is highly related to suboptimal early parenting that can cause epigenetic changes through which environmental factors affect gene expression. Dr. Robakis will test this hypothesis in pregnant women by looking for the epigenetic “signature” associated with adult attachment insecurity.
Marianne Louise Seney, Ph.D., University of Pittsburgh, is investigating the impaired balance in excitatory and inhibitory neurotransmission in depression possibly resulting from decreased gamma-aminobutyric acid (GABA)-mediated inhibition. The study will follow up earlier studies indicating that reduction in the function of the somatostatin cells of the GABA system (in a brain hub critical for processing and regulating emotion) induces increased anxiety and depression-like behavior that can be reversed with a boosting of somatostatin cell function.
William Kyle Simmons, Ph.D., Laureate Institute for Brain Research, will conduct a trial to explore brain mechanisms linking depression and declining body function, and whether interoception, the perception and integration in the brain of signals about the body, may be the critical link that is, whether people with depression experience an interoceptive stimulus differently from controls. Functional MRI data will show brain region differences as participants recall the interoceptive experience.
Nicholas Stavropoulos, Ph.D., New York University School of Medicine, is using a fruit fly model to explore why we sleep and the mechanisms responsible for sleep disorders, including depression. Dr. Stavropoulos previously identified insomniac, a gene that regulates sleep in interactions with another gene called Cul3, which encodes a protein that modulates other proteins in sleep function. Since humans have similar genes, Dr. Stavropoulos hopes to identify and analyze the proteins that insomniac and Cul3 target.
Marcus Stephenson-Jones, Ph.D., Cold Spring Harbor Laboratory, will work with mice to explore oversensitivity to negative feedback, a core symptom of depression. Findings implicate interaction of the lateral habenula (LHb), a brain region involved in decision making, and a structure called the globus pallidus (GPh). Dr. Stephenson-Jones’s hypothesis is that while the rate of GPh neuronal activity encodes how “bad” something is, increased strength of connection between the GPh and the LHb may determine the degree of sensitivity to this negative information.
Makoto Taniguchi, Ph.D., McLean Hospital, Harvard University, will test the hypothesis that Npas4, a “transcription factor” (a protein that regulates gene expression), plays a key role in stress-induced depressive behavior in mice models that lack Npas4 function in the prefrontal cortex of the brain. Npas4 and its target gene play a key role in inhibitory synapse function; dysfunction in inhibitory synapses may be an underlying mechanism of depression.
Eva Haimo Telzer, Ph.D., University of Illinois at Urbana-Champaign, is examining how a history of peer victimization shapes neural processing of social threat and may be linked to adolescent depression and risk of long-term depression. Dr. Telzer will work with functional MRI data from an existing sample of adolescent girls who were victimized across an eight-year period, and follow them for an additional two years to complete diagnostic interviews and measure the development of depression.
Junqian Xu, Ph.D., Icahn School of Medicine at Mount Sinai, will study the neuroimmunology of anhedonia, the inability to experience pleasure, in adults with major depressive disorder. This research project will build upon findings in the Xu lab that in adolescents with depression, activation of the immune system, inflammation and accompanying neurometabolic alterations are specifically linked to severity of anhedonia.
Post-Traumatic Stress Disorder (PTSD)
Joanna Izabella Giza, Ph.D., Cornell University, will investigate the molecular mechanism by which a common genetic variation affects the neural circuitry of fear extinction, a current treatment for PTSD (and anxiety disorders). The variation alters one amino acid in the growth factor BDNF and impairs fear extinction. (Amino acids are the building blocks of proteins.)
Stephanie Sillivan, Ph.D., The Scripps Research Institute, proposes to identify the microRNA (miRNA) mechanisms unique to traumatic memories associated with PTSD that create dysfunction in fear processing, including hyper-activation of the amygdala, the brain’s emotional memory center. miRNAs biologically regulate gene expression; their irregular functioning has been implicated in numerous disease states and previous work has suggested miRNAs are key participants in the formation of long-term memory.
Jessica A. Bernard, Ph.D., University of Colorado, Boulder, is studying the prodrome, the ambiguously symptomatic period before a first psychotic episode, seeking markers to identify the 30 percent of those with prodromal symptoms who will go on to develop psychosis. Cognitive dysmetria is a symptom of thought difficulties seen in schizophrenia patients. The study will ascertain whether dysmetria is present during the prodrome stage as a potential predictor of later schizophrenia.
Hong Goo Chae, Ph.D., Cold Spring Harbor Laboratory, will investigate neuronal mechanisms underlying olfactory deficits. Olfactory hallucinations or poor odor detection are prime signatures of schizophrenia. The study will determine the effect of suppressing cortical feedback on the dynamics of nerve cells in the brains of mice with schizophrenia-like symptoms, laying the groundwork for the investigation of bulb-to-cortex dynamics in schizophrenia.
Joshua J. Chiappelli, M.D., Maryland Psychiatric Research Center, University of Maryland, plans to extend his findings that stress causes abnormally high levels of kynurenic acid (KYNA) in saliva, suggesting that this may be a novel, therapeutically useful biomarker of stress reactivity. Stress-induced high KYNA in lab mice can cause cognitive impairment, a major, and to date, largely untreatable symptom of schizophrenia.
Lot de Witte, M.D., Ph.D., University Hospital Utrecht, Utrecht University, will pursue studies of immune system involvement in schizophrenia through studies of synaptic pruning, a natural process in brain development that eliminates unnecessary neurons. Microglia are immune cells thought to play a major role in synaptic pruning; this study will examine microglia in postmortem brain material and additional cells from patients with schizophrenia and control subjects.
Laurie R. Earls, Ph.D., St. Jude Children's Research Hospital, will study a gene called Pants (for plasticity-associated neural transcript short) that her lab uncovered within a defective chromosomal region associated with schizophrenia. Mice studies suggest that Pants is responsible for deficits in synaptic plasticity, a neural process thought to underlie learning and memory. Understanding the mechanisms of these deficits may lead to better understanding of the cognitive deficits of schizophrenia.
Suleyman I. Gulsuner, M.D., Ph.D., University of Washington, will integrate genetic data from his lab and elsewhere, including data on de novo mutations in patients, to understand the extreme genetic heterogeneity of schizophrenia. (De novo mutations arise spontaneously and are not inherited from parents.) His lab recently demonstrated that genes harboring damaging de novo mutations in people with schizophrenia formed highly interconnected networks in the fetal prefrontal cortex region of the brain.
Libi Hertzberg, M.D., Ph.D., Tel Aviv University, wants to help explain the mechanisms of variant genes that have been identified as associated with schizophrenia. While a specific variant increases risk for developing the illness only marginally, interaction between genes could be synergistic, working through common pathways. Dr. Hertzberg will extend previous studies that appeared to show schizophrenia-associated gene expression correlated with calcium-related genes, suggesting interaction through calcium-related pathways.
Yongsung Kim, Ph.D., Salk Institute for Biological Studies, aims to elucidate mitochondrial dysfunction in the pathogenesis of schizophrenia. Mitochondria are cellular organelles that regulate energy production, among other key biological functions. Recent studies suggest that mitochondrial dysfunction may play a primary role in schizophrenia, and if so, mitochondrial regulation could be a potential target for curing or delaying progression of the disease.
Sehba Husain-Krautter, M.B.B.S., Ph.D., Zucker Hillside Hospital, The Feinstein Institute for Medical Research, is investigating the relationship between immune cells called proinflammatory cytokines and gene-regulating molecules called microRNAs (miRNAs). Their interaction appears to be abnormal in first-episode schizophrenia patients. Finding a mechanism through which the interaction operates would establish a foundation for investigating events that follow inflammation in schizophrenia and whether existing schizophrenia treatments alter cytokine and/or miRNA expression.
Aaron R. Jeffries, Ph.D., University of Exeter, will seek to identify the potential role in schizophrenia of random monoallelic expression of a gene associated with schizophrenia susceptibility. In monoallelic expression only one of the two copies of a gene is activated. Monoallelic expression may influence schizophrenia risk and also help to explain why it can happen that only one identical twin will develop schizophrenia despite sharing the same genetic inheritance with the other twin.
Eunchai Kang, Ph.D., Johns Hopkins University School of Medicine, will examine neurons with a deficiency in the disrupted-in-schizophrenia 1 (DISC1) gene, whose normal function includes regulating various aspects of neuronal development during adult hippocampal neurogenesis. Based on her previous findings of DISC1-induced synapse malformation, she will explore the critical role of DISC1 in synaptogenesis, the formation of synapses, and of mechanisms that may lead to neural connectivity deficits contributing to the pathogenesis of schizophrenia.
Ada Ledonne, Ph.D., IRCCS Fondazione Santa Lucia, will investigate the potential role of dysregulated dopamine neurotransmission in the midbrain, induced by altered genetic signaling (of neuregulin 1 or NRG1 and ErbB), and its effect on glutamate transmission in schizophrneia. NRG1, which modulates glutamatergic neurotransmission in the hippocampus and the prefrontal cortex, has been repeatedly linked to schizophrenia, and alterations in NRG1/ErbB expression have been reported in patients with schizophrenia as well as in animal models.
Matthew Luke MacDonald, Ph.D., University of Pittsburgh, seeks to understand the glutamate signaling abnormalities correlated with auditory-cortex dendritic spine loss in schizophrenia. Dendritic spines are structures that receive neuronal signals, and it has been postulated that spine loss underlies cortical processing deficits observed in schizophrenia. Enhancing glutamatergic signaling by targeting synaptic glutamate receptors is currently a strategy for the development of novel treatments.
Jacob J. Michaelson, Ph.D., University of Iowa, will use genome-wide approaches to define the role of neuronal PAS (Npas) domain proteins in mental illness, including schizophrenia. In mice, mutated Npas3 virtually removes postnatal neurogenesis---the birth of new nerve cells---in the hippocampus, the brain’s memory center, while mutated Npas1 increases it. The underlying basis for this striking effect between two closely related proteins remains to be explained.
Simon Trent, Ph.D., Cardiff University, will investigate genes implicated in schizophrenia that encode synaptic proteins in complexes that include cytosolic FMRP interacting protein 1 (CYFIP1) and its binding partner, the Fragile X syndrome-causing FMRP protein, with another protein called ARC. Working with rodents, Dr. Trent hopes to further current understanding of CYFIP1 and ARC interactions involved in memory and learning processes and in schizophrenia-relevant mechanisms.
Brooke Viertel, Ph.D., University Medical Center Hamburg-Eppendorf, University of Hamburg, will assess deficits in schizophrenia in the area of social cognition, the mental processes associated with perception, interpretation and response to social stimuli. Dr. Viertel will compare subjective and objective social cognition performance of patients with schizophrenia and control subjects, with an aim of improving understanding of the underlying biological processes.
Guangying K. Wu, Ph.D., George Washington University, will probe genetic mechanisms underlying auditory hallucinations in a mouse model of schizophrenia involving 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, which is caused by DNA deletions on chromosome 22. The 22q11.2 deletion syndrome is highly associated with abnormal brain circuitry.
Wenchi Zhang, Ph.D., Johns Hopkins University, will expand studies of the gene known as Arc that is essential for learning and memory. The research will test the hypothesis that Arc binds directly to genes linked to schizophrenia. Dr. Zhang will assess the mechanisms that regulate its binding; if the hypothesis is confirmed, Arc’s binding pocket could possibly serve as a schizophrenia treatment target.
Monica Aas, Ph.D., University of Oslo, will explore the role of childhood trauma in the development of mental illness, particularly schizophrenia and bipolar disorder. She will seek biological correlates of childhood trauma and their relationship to clinical characteristics in patients with psychotic disorders and examine potential links between particular genes, childhood trauma and psychosis.
Simona L. Buetti, Ph.D., University of Illinois at Urbana-Champaign, will conduct the first systematic study of how people with and without mood disorders respond to the experience of control and the associated neural circuit. Depression and mania are thought to be related to distorted perception of control; for example, depressed individuals tend to feel little control over events in their life. This research may open a path toward improving cognitive and emotion regulation in mood disorders.
Yongku P. Cho, Ph.D., University of Connecticut-Storrs, aims to develop a novel approach for rapid and reversible knockout of target genes to study how dynamically regulated protein levels affect brain circuits. This approach will be applied to study the mechanism of GABAA receptor dysfunction, implicated in diseases such as schizophrenia and epilepsy. GABAA is the receptor for GABA, the primary inhibitory neurotransmitter.
Sebastien Delcasso, Ph.D., Massachusetts Institute of Technology, proposes to characterize a newly discovered learning signal in the striatum region of the brain involving dopamine, a neurotransmitter critically involved in reward-motivated behaviors and learning. Dysfunction of the dopaminergic system is implicated in schizophrenia, depressive and anxiety disorders, and obsessive-compulsive disorders.
Santhosh Girirajan, M.B.B.S., Ph.D., Pennsylvania State University, University Park, PA, aims to identify genetic risk variants for neurodevelopmental disorders such as autism spectrum disorder, intellectual disability and schizophrenia, studying families with a particular variant that by itself can lead to relatively mild neuropsychiatric features in a parent, but inherited with additional gene variants at another location in the genome, can result in severe illness in an affected child.
Brad Alan Grueter, Ph.D., Vanderbilt University, will explore his hypothesis that certain immune-system receptors regulate mechanisms in the nucleus accumbens (NAc), an area of the brain involved in emotion and reward, to contribute to susceptibility to affective disorders, including depression. His long-term goal is to map the complex reward circuitry and better understand how these circuits interact with their environment to produce normal and pathological behavioral outcomes.
Matthew C. Judson, Ph.D., University of North Carolina at Chapel Hill, will investigate pathogenic mechanisms underlying subplate abnormalities associated with a variety of neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. The subplate is a largely transient layer of neurons that aids development of the structural and functional architecture of synaptic connections within the overlying neocortex, the brain site for most higher-thinking functions.
Marija Kundakovic, Ph.D., Columbia University, will use mouse models to determine the interaction of early life and adolescent stress in inducing depression and anxiety-like behavior and exaggerated stress response in adulthood. Dr. Kundakovic will examine how DNA methylation is affected in the adult hippocampus at 48 genomic regions of relevance to depression and anxiety (methylation is a so-called “epigenetic” mechanism in which external factors, such as stress, alter gene expression without altering the underlying DNA sequence).
Julien Muffat, Ph.D., Whitehead Institute for Biomedical Research, will study glia, brain cells that support neurons and, when improperly functioning, can contribute to Rett Syndrome, a neurodevelopmental disorder that shares some characteristics with ASD. Facilitated by the lab’s development of methods to generate genetically-matched controls for any mutant cells under study, the research will examine both the effects of mutant glia on healthy neurons and the effects of healthy glia on mutant neurons.
Shraddha Pai, Ph.D., Centre for Addiction and Mental Health, University of Toronto, will examine DNA asymmetry in epigenetic processes in schizophrenia and bipolar disorder. Epigenetic mechanisms can alter which genes in a cell are expressed. Although it was previously assumed that both strands of DNA in a cell were identical, evidence shows that neurons have flags that sometimes mark only one strand. This asymmetric marking may indicate brain processes relevant to psychosis.
Kanaka Rajan, Ph.D., Princeton University, will investigate the mechanisms the brain uses in timing tasks, how this activity arises in healthy brains and how pathologies in timing occur. Almost all behaviors executed by the brain require sequences of actions over time and many demand that time intervals be judged, remembered and incorporated into behavioral responses. Deficits in time estimation and working memory occur in several brain disorders, including schizophrenia and Alzheimer’s disease.
Alma I. Rodenas-Ruano, Ph.D., Albert Einstein College of Medicine of Yeshiva University, is studying N-methyl-D-aspartate receptors (NMDARs), which are essential to the brain’s development and its synaptic plasticity, which functions as the basis for healthy brain activity. NMDAR malfunction is associated with early-onset neuropsychiatric disorders. This research will explore how stress can prevent maturation in cells crucial to NMDAR function.
Laura J. Sittig, Ph.D., University of Chicago, is working to identify so-called epistatic modifier genes and their role in risk for heritable mental illnesses. Genetic interactions, or epistasis, may explain the missing information about heritability in mental illness. Mutations in the CACNA1C gene, for example, contribute to risk for bipolar disorder, schizophrenia and depression. Dr. Sittig will work with mice without the CACNA1C gene to look for epistatic modifiers of susceptibility or resilience to developing mental illness.
Karin Johanna Hendrika Verweij, Ph.D., VU Medisch Centrum, Vrije Universiteit Amsterdam, will explore genetic overlap between vulnerability to developing conduct disorder and addictive behaviors, both of which have been shown to be heritable in studies with twins. Dr. Verweij will use data from two large studies to determine whether genetic variants underlying addictive behaviors can also explain individual differences in conduct disorder.
Melanie von Schimmelmann, Ph.D., Icahn School of Medicine at Mount Sinai, will seek insight into how neuronal memory forms at the single neuron level in response to the neurotransmitter dopamine. Dopamine dysfunction is known to be involved in schizophrenia and mood disorders. Dr. von Schimmelmann will trace neurons responding to dopamine and determine their transcriptional (transcription is the first step in gene expression) and epigenetic (epigenetics is a mechanism for regulating the expression of genes) states compared to non-responding cells.
Sindy Cole, Ph.D., Boston College, will use a rodent model to dissect the neural mechanisms that underlie cue-potentiated overeating—overeating driven by environmental and social factors—as a step toward understanding human eating disorders. The study seeks to define the role of the medial prefrontal cortex region of the brain and of orexin, a neurotransmitter that regulates arousal, wakefulness and appetite.
Marcelo Dietrich, M.D., Ph.D., Yale University, is working to identify the biological processes that trigger anorexia nervosa, which has the highest mortality rate among psychiatric illnesses, to help develop effective treatments. With a mouse model created in his lab, Dr. Dietrich will examine the interplay between hunger-inducing neurons of the hypothalamus and the food-stimulated reward circuitry in the brain that his studies point to as being altered in people susceptible to anorexia.
Seung Tae Baek, Ph.D., University of California, San Diego, seeks to identify how a genetic mutation causes developmental brain defects and abnormal neuronal activities that underlie hemimegalencephaly, a malformation of cortical development responsible for most pediatric epilepsy. Surgical removal of the affected brain region is the only current treatment for the intractable seizures of the disorder, but can cause complications and side effects.
Ramon Y. Birnbaum, Ph.D., Ben-Gurion University of the Negev, hopes to advance genetic diagnoses and treatments for epilepsy by exploring the 98 percent of the human genome that is non-coding (does not contain genes), but that contains gene regulatory elements, such as enhancers, that instruct gene activity and in which mutations can arise to cause illness. Most enhancers associated with epilepsy remain unknown.
Justin S. Feinstein, Ph.D., Laureate Institute for Brain Research, will investigate the neural pathways that generate interoceptive fear, which is fear and anxiety in response to threats from within the body, as opposed to exteroceptive fear in response to external threats. He seeks to identify how interoceptive fear is played out in the brain, an important step toward understanding conditions such as panic disorder, known to involve a dysregulated and hyper-sensitized interoceptive fear-response system.
Hao Wu, Ph.D., Johns Hopkins University School of Medicine, studies Rett syndrome, a neurodevelopmental disorder caused by mutations in MECP2, a gene on the X chromosome. Males have one X chromosome and one Y; females have two X chromosomes. In women, either one or both copies of MECP2 can be affected. Dr. Wu will use mouse models to explore the ways in which the two differing forms of MECP2 interact to cause variable symptoms of the disorder.
to advance or create new ways of studying and understanding the brain
Avishek Adhikari, Ph.D., Stanford University, will use optogenetics—a technology that allows for controlling brain cell activity and observing effects on behavior in laboratory animals―to determine whether a connection from the brain’s ventral medial prefrontal cortex (vmPFC) to the amygdala, the brain’s fear center, suppresses learned fear and innate anxiety. Brain imaging in humans has shown that higher vmPFC activation correlates with lower amygdala activation and decreased fear, but to confirm a causal relationship requires precise targeted control.
Johanna Molly Jarcho, Ph.D., National Institute of Mental Health, National Institutes of Health, will apply functional magnetic resonance imaging (fMRI) to a longitudinal (extended period) study of the neural modulators of social anxiety in bullied adolescents to distinguish transient from persistent changes in their brain function, an important step toward developing targeted interventions to limit symptom severity and persistence.
Dilja Krueger, Ph.D., Max-Planck-Institute for Experimental Medicine/Max-Planck Society/Max Planck Institutes, will use novel genetic tools to identify synapses affected by mutations in the neuroligin2 (NLGN2) protein involved in anxiety circuitry and behavior. Neuroligins mediate the formation and maintenance of synapses between neurons; mutations in neuroligins have been linked to autism spectrum disorder, schizophrenia and anxiety disorders. Dr. Krueger seeks to determine whether anxiety is reversible if NLGN2 function is restored.
Attention-Deficit Hyperactivity Disorder (ADHD)
Nikola Todorov Markov, Ph.D., Princeton University, will use a combination of techniques, including electrophysiology and optogenetics, in mouse models to dissect the circuit mechanisms that support attentional filtering to provide a deeper understanding of how these mechanisms are disrupted in ADHD. The study will also test the mechanisms of action of current ADHD medications and facilitate development of new therapies.
Redmond O'Connell, Ph.D., Trinity College Dublin, will conduct a trial to pinpoint the neural mechanisms linked to a hallmark symptom of ADHD called intra-subject variability, or difficulty in maintaining consistent performance levels. The research will employ a technique developed in the O’Connell lab for simultaneous monitoring of critical stages of sensory encoding, decision formation and motor preparation, as well as supporting factors of attention and arousal, while participants perform a simple perceptual task.
Autism Spectrum Disorder (ASD)
Brenda L. Bloodgood, Ph.D., University of California, San Diego, will combine optogenetic strategies for activating neurons with genome analysis and brain imaging to determine how excitatory-inhibitory balance is regulated in a neuron. The goal is to identify pathways and molecules that will be useful for the treatment of ASD and other disorders that emerge from imbalance of excitation and inhibition. Of particular interest, NPAS4 is a molecule that acts as a master regulator of excitatory-inhibitory balance.
Denis Jabaudon, M.D., Ph.D., University of Geneva, is studying a pivotal cell type in Fragile X syndrome, the most common cause of inherited male mental retardation and a leading cause of autism spectrum disorder. Abnormal assembly of neurons in the somatosensory cortex is thought to play a central role, and layer 4 (L4) cortical neurons appear most affected. A technique developed in the Jabaudon laboratory enables fluorescent tagging of L4 in newborn mice models of Fragile X as neuronal circuits are forming.
Brian J. O'Roak, Ph.D., Oregon Health and Science University, proposes to develop new technologies that will allow testing for the functional effect of all possible mutations of a gene called PTEN, which plays a major role in cancers, overgrowth syndromes and ASD, to learn how mutations in a single gene can result in such diverse clinical outcomes. Understanding the functional effect of an individual mutation is a key part of developing personalized medicine.
Kaustubh Satyendra Supekar, Ph.D., Stanford University, plans to integrate and analyze behavioral, cognitive and brain imaging data from a large sample of 50,000 individuals—both with ASD and without (control subjects)—supplied by the National Institute of Mental Health. Dr. Supekar seeks to identify factors that explain the diversity of symptoms in ASD, to characterize the neuroprotective factors in girls (underlying the four-times-less-frequent occurrence of ASD in girls than in boys), and to find a potential biomarker for female ASD.
Lucina Q. Uddin, Ph.D., University of Miami, will use a developmental framework to provide the first characterization of patterns of brain connectivity in ASD. ASD is believed to be associated with alterations in brain connectivity, but the precise nature of these alterations is debated. Understanding the onset, development and progression of ASD would provide information that can be used to guide discovery of biomarkers for the disorder.
Nan Yang, Ph.D., Stanford University, proposes to generate human inhibitory neurons from pluripotent stem cells. Inhibitory neurons are affected in many psychiatric illnesses, including ASD. To date, studies of brain processes have relied on animal models, imaging or human postmortem tissues. This new approach will be used to explore cellular characteristics associated with neuropsychiatric disorders, and the cells generated may also be useful for screening of new medications.
Bipolar Disorder (BP)
Danai Dima, Ph.D., Institute of Psychiatry, King's College London, aims to use novel and sophisticated neuroimaging and genetics methods to map the brain changes that make it possible for many first degree relatives of people with BP to avoid developing the illness, which can be highly heritable. The changes may arise through epigenetic changes, which are changes in gene regulation and expression caused by environmental factors acting on genes without altering the DNA sequence.
Luciano Minuzzi, M.D., Ph.D., St. Joseph's Hospital, McMaster University, will use a new magnetic resonance imaging method developed in his lab to conduct the first study to learn whether patients with BP have abnormalities in cortical myelin in the brain. Myelin is the fatty and protective sheath around axons, the hair-like projections from neurons that relay the neuron’s signals. It is believed that disruptions in myelination disrupt brain connectivity.
Jessica Andrews-Hanna, Ph.D., University of Colorado, Boulder, will use mobile phone technology and ultra-fast functional MRI (fMRI) to characterize self-generated thoughts (mind-wandering thoughts unrelated to the context in which they occur). She seeks to identify brain mechanisms underlying dysfunctional thoughts in people with depression that might serve as biomarkers for depression risk, diagnosis and treatment strategies.
Rosemary Bagot, Ph.D., Icahn School of Medicine at Mount Sinai, is studying a brain region called the nucleus accumbens (NAc) and its role in depression. Dr. Bagot will examine how communication between NAc and other brain regions is altered in mice exhibiting depressive-like states and how manipulating this communication with optogenetic techniques affects the animal’s behavior.
Chun-hui Chang, Ph.D., University of Pittsburgh, will study rat models of human depression with the aim of providing a first step in delineating the neural circuitry underlying the abnormal activity of the dopamine neurotransmitter system. The study will apply optogenetics, to control the animals’ neuronal activity and observe the effects on behavior, combined with behavioral assays to determine whether a particular mediator of the dopaminergic system (the BLA-VP pathway in the brain) is critical and sufficient to induce depression-like behaviors.
Jonathan J. Nassi, Ph.D., Salk Institute for Biological Studies, will explore neural-circuit mechanisms underlying disruption of attention in schizophrenia; specifically, visual selective attention. The study will use the new technology optogenetics, which offers a means of controlling cell activity and observing the effects on living, behaving animals. Dr. Nassi will manipulate the relevant cortical circuit while a lab animal performs an attention-demanding sensory discrimination, and test for a causal relationship between the circuits and the neural and behavioral signatures of attention.
Karen Ryan, Ph.D., Trinity College Dublin, using an animal model, will apply the powerful new approach of deep sequencing for genetic analysis to investigate the effects of electroconvulsive therapy (ECT)—used for treating resistant depression—on microRNAs (miRNAs). miRNAs are small molecules abundant in the brain that control half of all protein-coding mammalian genes; this study is based on preliminary research indicating that miRNAs likely to contribute to brain disorders, including depression, and to their effective treatment.
Jennifer Tropp Sneider, Ph.D., McLean Hospital, Harvard University, will use proton magnetic resonance spectroscopy with depressed women and healthy controls while they perform a memory task to examine activation in brain regions important for memory and executive functioning. The purpose is to pursue evidence of reduced levels of the neurotransmitter gamma-amino butyric acid (GABA) in depression and to evaluate the relationships between GABA levels, brain activation, symptom severity and cognitive ability in depression.
Brendon Omar Watson, M.D., Ph.D., Weill Cornell Medical College, will apply special techniques of silicon probe-based recordings to investigate how the medication ketamine works to treat depression. This will be the first use of this tool for pharmacological inquiry. By implanting probes in the rat prefrontal cortex and the hippocampus, regions heavily involved in depression, the research will provide data regarding depression-related circuitry at a timescale directly related to the likely mechanism of ketamine action.
Obsessive-Compulsive Disorder (OCD)
Yen-Yu Ian Shih, Ph.D., University of North Carolina at Chapel Hill, will use novel brain imaging and genetic tools, including optogenetics, in rat models of OCD to dissect brain circuits modulated by deep brain stimulation (DBS). Dr. Shih’s goal is to learn how DBS modulates neural activity in different brain regions to alleviate symptoms of OCD.
Post-Traumatic Stress Disorder (PTSD)
Chadi Abdallah, M.D., Yale University, will use advanced brain imaging called carbon-13 magnetic resonance spectroscopy to examine the effects of PTSD on the functioning of glia and on glutamate neurotransmission. Glia are brain cells that provide support and protection for neurons; glutamate is the brain’s main excitatory neurotransmitter. Glia functioning and glutamate neurotransmission are impaired in animal models of stress and have been linked to psychiatric illness.
Joshua Cisler, Ph.D., University of Arkansas for Medical Sciences, will use computational modeling of brain and behavioral data to characterize specific, modifiable patterns of family dynamics among adolescent assault victims. Violence experienced in early life is a risk factor for developing mental illness, including PTSD. Patterns of family behavior that promote recovery and their effect on mediating neural processing in adolescents are currently unknown.
Jonathan Richard Epp, Ph.D., The Hospital for Sick Children, University of Toronto, hopes to gain better understanding of how PTSD develops by modeling fear symptoms in mice and analyzing brain-wide activity patterns at the cellular level. He will compare the normal fear memory network to that of pathological fear. Once the difference between the two is identified, he will attempt to normalize network activity and behavioral response.
Jonathan Paul Fadok, Ph.D., Friedrich Miescher Institute, will combine optogenetics and electrophysiology to further understand the neural networks disrupted in PTSD and anxiety disorders by studying in mice the little-known circuits mediating or modulating learned active fear strategies, such as flight. In preliminary research he discovered that corticotropin-releasing factor neurons project to brain areas vital for flight responses and how these neurons respond to auditory cues that evoke fear behavior.
Léma Massi, Ph.D., Friedrich Miescher Institute, has developed a method combining single-cell extracellular recordings, optogenetic stimulation and trans-synaptic tracing to determine, in mice models, the morphology, or structure, of a cell and cell-type connectivity of fear circuits involved in PTSD and anxiety disorders. The goal is to zero in on specific single neurons involved in distinct aspects of fear learning and fear extinction and define molecular markers useful for new strategies for study and treatment of fear disorders.
Joshua W. Cordeira, Ph.D., Harvard Medical School, Harvard University, will test whether activation of brain cells called parvalbumin-positive gamma-aminobutyric acid neurons in the basal forebrain enhances cortical gamma oscillations and cognition. Gamma band oscillations facilitate attention and memory. People with schizophrenia have decreased gamma band oscillations and impaired attention and memory. The research will use state-of-the-art optogenetic techniques to manipulate brain cells in mice engaged in an attention-requiring task.
Fei Du, Ph.D., Harvard Medical School, Harvard University, will apply advanced imaging technologies developed in the lab to explore white-matter abnormalities in schizophrenia. White matter, consisting of nerve fibers and a protective sheath called myelin, appears to be reduced in schizophrenia. Beginning with first-episode patients, the study is expected to advance the ability to probe white-matter changes as illness progresses.
Colin Shaun Hawco, Ph.D., Centre for Addiction and Mental Health, University of Toronto, will conduct a clinical trial to examine disruptions in prefrontal brain activity that results in deficits in working, or short-term, memory in patients with schizophrenia. Dr Hawco will use an innovative brain imaging technique that works by modulating brain activity via a magnetic pulse while measuring brain activity with functional magnetic resonance imaging (fMRI).
Conrad Iyegbe, Ph.D., Institute of Psychiatry, King's College London, will combine a multimodal biomarker screen for psychosis with the Psychiatric Genomic Consortium's polygenic risk score for schizophrenia to facilitate identification of biological signatures of psychosis among high-risk subjects. Participants for the study will be recruited from southeast London, a community with the world’s highest incidence of schizophrenia. The biomarkers will then be tested as predictors of who will go on to develop schizophrenia within two years.
Youngcho Kim, Ph.D., University of Iowa, will study dysfunctional dopamine signaling in schizophrenia involved in cognition. Performance on interval timing tasks, a cognitive process that depends on dopamine signaling in the prefrontal cortex, is markedly impaired in schizophrenia. Activity of relevant neurons in the prefrontal cortex of lab animals can be manipulated with laser light and monitored with recording electrodes. The impaired circuits that are identified could then be targeted by therapeutic brain-stimulation therapies.
Felice Reddy, Ph.D., VA Greater Los Angeles Healthcare System—West Los Angeles, University of California, Los Angeles, will conduct a trial with patients playing the Cyberball game, a tested social exclusion paradigm, to examine the physical and cognitive costs of social exclusion for people with schizophrenia. Studies indicate that distress from social exclusion not only negatively impacts cognitive abilities, but also that inflammatory cytokines may be a measureable physiological indicator of heightened vulnerability to social stress.
Yuri B. Saalmann, Ph.D., University of Wisconsin-Madison, will utilize magnetic resonance imaging (MRI) and electrophysiology to explore cognitive control, the ability to flexibly adapt behavior to a current situation, which is impaired in schizophrenia. He proposes that changes in the brain region of the thalamus in schizophrenia produce abnormal synchrony between cells in the prefrontal cortex, the seat of higher brain function, and consequently may perturb information processing, giving rise to deficits in cognitive control.
Peter Savadjiev, Ph.D., Brigham and Women's Hospital, Harvard University, has created novel imaging and computational methods for in vivo investigation and for identifying biomarkers of neurodevelopmental processes leading to brain structure abnormalities and schizophrenia risk. His research is motivated by theories that link development of the cortex—the site of higher thought processes—to the development and geometrical structure of white matter, the axonal projections from neurons through which brain signals are dispatched.
Ilana Witten, Ph.D., Princeton University, will investigate working, or short-term memory, which is compromised in schizophrenia. The neurotransmitter dopamine is implicated, but medications that target dopamine have limited effect on working memory. Dr. Witten will use the new technique of optogenetics to control dopamine neurons in mouse models of schizophrenia to explore specific temporal and spatial patterns of neuronal activity important to working memory that she believes are eluded by current therapies.
Tracy L. Young-Pearse, Ph.D., Brigham and Women's Hospital, Harvard University, will study a chromosomal translocation (a process whereby chromosomes swap broken-off fragments) in the disrupted-in-schizophrenia ( DISC1) gene, a major risk gene for schizophrenia. Dr. Young-Pearse will examine the chr(1;11) translocation in human stem cells engineered in her lab to learn which DISC1 translocations may be perturbed in neuronal development and likely contribute to the development of mental illness.
Borderline Personality Disorder
Sarah Kathryn Fineberg, M.D., Ph.D., Yale University, will use tools from cognitive neuroscience to explore a phenomenon experienced by people with borderline personality disorder: they have difficulties feeling that they know their own bodies. A computer game will measure social and nonsocial learning in women with borderline personality disorder, and also will test whether they use bodily mimicry to understand emotions as often as do women without the disorder.
Cendra Agulhon, Ph.D., Université René Descartes, proposes to establish whether inflammation during postnatal brain development can cause brain cells called astrocytes to trigger abnormal release of the neurotransmitter glutamate and inflammatory mediators. The study, in rodents, will use a powerful new tool called chemogenetics for remotely controlling neuron function with electrophysiology to determine whether this string of events causes abnormal, long-term changes in neurotransmission leading to schizophrenia and bipolar disorder.
Philip G. Browning, Ph.D., Icahn School of Medicine at Mount Sinai, will explore, in monkeys, brain regions involved in retrieving memories. Impairments in memory are a significant feature in human depression, schizophrenia and drug addiction. The study will use a new method of silencing neurons to identify pathways essential for memory retrieval so as to provide a new target for therapies aimed at augmenting memory compromised by brain disorders.
Yongku P. Cho, Ph.D., University of Connecticut, Hartford Hospital, aims to develop a novel approach for rapid and reversible knockout of target genes to study how dynamically regulated protein levels affect brain circuits. This approach will be applied to study the mechanism of GABAA receptor dysfunction, implicated in diseases such as schizophrenia and epilepsy. GABAA is the receptor for GABA, the primary inhibitory neurotransmitter in the brain.
Jeremiah Yaacov Cohen, Ph.D., Johns Hopkins University School of Medicine, will use an approach he developed, combining techniques from physiology and genetics, to explore two fundamental questions about neural circuits involving the neurotransmitter serotonin and mood disorders. Working with mice, he will seek to identify what serotonin does in the brain in mood-changing behaviors and how serotonin-releasing neurons combine inputs from other brain regions to send their own signals.
Lauren Celia Faget, Ph.D., University of California, San Diego, will build on her previous discovery of a novel excitatory neural circuit connecting two key brain structures known to be perturbed in schizophrenia and other psychiatric illness. She plans to carefully map the circuit, using sophisticated mouse genetic tools, and will then apply the new technique of optogenetics, using light to rapidly control the activity of neurons and observe the effect on behavior.
Jennifer H. Foss-Feig, Ph.D., Connecticut Mental Health Center, Yale University, will investigate imbalance in neural excitatory and inhibitory signaling in the cortex in adults with autism spectrum disorder and people with early-course schizophrenia. Using computationally and biologically grounded experimental paradigms and cutting-edge functional neuroimaging techniques, the study will seek to relate behavioral and neural markers of this imbalance to both shared and distinct clinical symptoms across the two illnesses.
Virginia Garcia-Marin, Ph.D., New York University, is developing a new approach for studying specific anatomical circuits and will examine circuit mechanisms of visual information processing that may underlie deficits in visual perceptual processing in people with schizophrenia, dyslexia and autism spectrum disorder; specifically, deficits related to changes in the functioning of the magnocellular-(M-) visual pathway, which conducts low-resolution visual information rapidly to the cortex.
Ozgun Gokce, Ph.D., Stanford University, will investigate the effects of cocaine on neural circuits involved in addiction and in stress-induced depression by genetically tracing neuronal circuits that are activated by cocaine exposure, using a mouse line that allows active neurons to be genetically labeled. The insights derived may have the potential to guide the development of precisely targeted pharmacological interventions.
Ian Cameron Gould, D.Phil., University of New South Wales, will establish whether distinct biological and genetic changes differentially affect novel subgroups of schizophrenia and bipolar disorder patients, defined according to their patterns of cognitive deficits. He will use brain-structure scans and genetic analysis to identify neuroanatomical changes and genetic risks in patients with severe cognitive deficits compared with patients with relatively spared cognitive abilities.
R. Matthew Hutchison, Ph.D., Harvard University, aims to identify disruptions in the brain's dynamic functional network architecture that occur in patients with psychosis and to develop biomarkers for accurate patient classification. Psychotic disorders, including bipolar disorder, schizophrenia and schizoaffective disorder are characterized by a wide array of symptoms. He will apply tools he developed to characterize slow-varying, large-scale activity patterns combined with functional imaging data to pursue growing evidence pointing toward a large-scale functional disconnection of brain areas.
Roozbeh Kiani, M.D., Ph.D., New York University, will investigate the decision-making process and its adaptive regulation to better understand decision-making deficits in mental illnesses, focusing on neural computations that afford behavioral flexibility in face of uncertainty. Dr. Kiani will examine how errors and negative feedback influence future decisions and how the decision-making network detects and adjusts to changes in environment. Lack of such flexibility is common in schizophrenia, anxiety disorders and obsessive-compulsive disorder.
Markita Patricia Landry, Ph.D., Massachusetts Institute of Technology, will combine newly developed neurotransmitter sensors with fiber-optic probes inserted into the brain—nano materials the size of molecules—to examine neurotransmitter activity at the scale of a single neuron. This new tool will collect real-time information on neuron-to-neuron communication to shed new light on neurological function and its malfunction in diseases such as Parkinson's disease and schizophrenia.
Elena Michaelovsky, Ph.D., Tel Aviv University, will use newly developed genomic microarrays and next-generation technologies to identify unknown genetic variations of the 22q11.2 deletion syndrome (22q11.2DS), a syndrome resulting from deletions to chromosome 22 and the strongest known genetic risk factor for developing schizophrenia. 22q11.2DS can also contribute to anxiety disorders and ADHD. The research will focus on a large, multi-generation family whose members carry the 22q11.2 deletion.
Jacqueline Morris, Ph.D., University of Pennsylvania, will use a technology called single cell nuclear mRNA capture to identify events that contribute to susceptibility to glutamate toxicity. Glutamate is the major excitatory neurotransmitter used by the central nervous system to communicate information between cells. Disruptions in glutamatergic signaling has been linked to a number of psychiatric illnesses, including mood disorders
Alexandre Mourot, Ph.D., University Pierre and Marie Curie, will use a technology called optogenetic pharmacology to study neuromodulations, or events that govern neuronal development and plasticity. Impairment of neuromodulation leads to many neuropsychiatric disorders such as schizophrenia, addiction and depression. Potential applications of optogenetic pharmacology range from mapping adult neural circuits to artificially perturbing neuronal activity during brain development or during exposure to medications.
Ligia Assumpcao Papale, Ph.D., University of Wisconsin-Madison, will utilize state-of-the-art approaches to test the hypothesis that DNA methylation mediates genome-wide gene expression in response to stress. Dr. Papale will study the gender-specific role of epigenetics in stress-related psychiatric illnesses, including anxiety and depression (epigenetics refers to mechanisms that regulate gene expression without altering the underlying DNA sequence).
Ludovic Tricoire, Ph.D., University Pierre and Marie Curie, will use multiple strategies, including electrophysiology, optogenetics and advanced microscopy, to explore dysfunctional interactions between the neurotransmitters dopamine and glutamine that confer risk for schizophrenia and autism; specifically, the role of mutations in a gene called Grid1, which codes for a protein called GluD1. Loss of GluD1 function leads to impaired glutamate transmission and a large decrease in dopamine neuronal activity.
Carmen Varela, Ph.D., Massachusetts Institute of Technology, will use state-of-the-art techniques of pharmacogenetics to manipulate thalamic activity and test its role in sleep interactions between the hippocampus and neocortex regions of the brain. The work will build on evidence suggesting that the hippocampus and neocortex interact during sleep to consolidate memories. Disrupted functional coupling in the hippocampus-prefrontal cortex network has been proposed to explain some of the cognitive problems in schizophrenia and depression.
Qi Wang, Ph.D., Columbia University, will use advanced functional magnetic resonance imaging (fMRI) brain scans to measure the dynamics of neural circuits integrating visual and tactile information in patients with schizophrenia and autism spectrum disorder (ASD). Higher-order cognitive functions require the brain to integrate information from multiple sources, and deficits in this ability characterize schizophrenia and ASD. The study may reveal targets for therapeutic intervention as well as neural signals to use as biological markers of treatment response.
Kevin Wang, Ph.D., Oregon Health and Science University, is working to understand the dopamine transporter, the site where cocaine acts primarily to inhibit dopamine—a neurotransmitter involved in mood and motor function—uptake into neurons. His study will visualize the structural rearrangements that occur as the transporter uptakes dopamine and the dopamine transporter will be crystallized in a complex with cocaine and dopamine with X-ray crystallography.
Fragile X Syndrome
Emma Puighermanal, Ph.D., INSERM, will combine powerful mouse transgenic lines, molecular biology and rodent behavioral tasks to identify key proteins in neurons that play a crucial role in the memory deficits produced by exposure to cannabinoids, including delta9-tetrahydrocannabinol, the main psychoactive compound of marijuana. The elucidation of the mechanisms involved might provide a better understanding of other neurological diseases, including Fragile X syndrome.
Deanna Jacquelyn Greene, Ph.D., Washington University School of Medicine, will use neuroimaging and sophisticated analysis strategies to identify markers in the brain that can distinguish children with Tourette syndrome―a condition of pathological tics that can become permanent―from typically developing children with tics. The ability to make that distinction would allow early intervention for those children most likely to need treatment for Tourette syndrome.
Next Generation Therapies
to reduce symptoms of mental illness and retrain the brain
Christine Elizabeth Gould, Ph.D., VA Palo Alto Health Care System, Stanford University, will test a system for reducing late-life anxiety, which affects more elderly people than depression, and improving their psychological and physical functioning with self-directed relaxation. Using the system, called BREATHE (Breathing, Relaxation, and Education for Anxiety Treatment in the Home Environment), participants will learn diaphragmatic breathing and progressive muscle relaxation.
Tija Carey Jacob, Ph.D., University of Pittsburgh, will investigate the cellular mechanisms that are altered in the GABA neurotransmitter system by benzodiazepines, clinical medications widely used to treat anxiety disorders and as adjunct therapy in schizophrenia and depression. While safe and initially effective, benzodiazepine use is severely limited by tolerance. The goal of this study is to aid in the development of new anti-anxiety therapies that avoid this limitation.
Ting Lu, Ph.D., University of Illinois at Urbana-Champaign, plans to engineer probiotic bacteria to treat anxiety; specifically, a lactic acid bacterial strain that will enable autonomous production of Neuropeptide Y. Neuropeptide Y is a small molecule that is highly potent in anxiety suppression but in its natural form is unstable in circulation and low in functional specificity. Dr. Lu will examine the efficacy of the engineered probiotics in both in vitro and in vivo animal tests.
Attention-Deficit Hyperactivity Disorder (ADHD)
Agatha Lenartowicz, Ph.D., University of California, Los Angeles, will test a computer-based training course for people with ADHD. She will use multimodal brain imaging to discern the atypical interactions between neural networks involved in attention control in ADHD, and which interactions are most predictive of improvement, beyond the effects of medication, after completion of the training.
Stephanie Dunkel Smith, Ph.D., Connecticut Mental Health Center, Yale University, will conduct a trial to determine the effects of an integrated brain, body and social (IBBS) intervention for children with ADHD on neural markers of attention and inhibitory control and on changes in symptom severity following treatment. The IBBS intervention is designed to foster interconnections between attentional subsystems and ADHD-compromised brain areas through computerized cognitive remediation, physical exercise, and a classroom-based behavior management strategy.
Autism Spectrum Disorder (ASD)
Lior Brimberg, Ph.D., Zucker Hillside Hospital campus of The Feinstein Institute for Medical Research, will follow up evidence from her lab that mothers of children with ASD are four times more likely than average to have brain-reactive antibodies and other features of autoimmunity that were transferred to the fetus during pre-gnancy. She plans to identify the antibodies and develop molecules to bind them and neutralize their toxicity to the fetal brain.
Latha Soorya, Ph.D., Rush University, will evaluate a novel pharmacological augmentation of a behavioral intervention for deficits in social information processing, a core symptom of ASD. The study will enroll pre-adolescents with ASD in a 12-week trial in which oxytocin, which shows promise as a cognitive and social enhancer, is administered prior to sessions of Seaver-NETT (Nonverbal synchrony, Emotion recognition, and Theory of mind Training).
Brittany Gail Travers, Ph.D., University of Wisconsin, will conduct a clinical study using an exploratory video game-based motor intervention that trains balance for patients with ASD, in whom motor difficulties are common. The training will target the corticospinal tract based on evidence suggesting the white-matter microstructure of the corticospinal tract predicts both motor symptoms and core ASD symptoms. The white matter contains the axonal projections from neurons that convey the neuronal signals of brain communication.
Bipolar Disorder (BP)
Nao Jennifer Gamo, Ph.D., Johns Hopkins University, will investigate the disrupted circadian rhythms associated with BP by characterizing oscillations in the expression of the circadian rhythm-related genes ARNTL and PER2 in cells from patients. The study will also look at how treatments like lithium affect circadian oscillations and the potential role in these processes of cyclic adenosine monophosphate, an important amplifier of cellular communication.
Alison R. Berent-Spillson, Ph.D., University of Michigan, will investigate the relationship between insulin resistance and increased risk of depression in women. The study will compare placebo and insulin-sensitizing treatments to determine the effect on brain activation patterns and mood symptoms. If the earliest stages of insulin resistance appear to be associated with an increased risk of depression, this might present an opportunity for preventive measures.
Becky Catherine Carlyle, Ph.D., Yale University, plans to further research to characterize the brain’s response to ketamine, a fast and effective antidepressant that works for people with intractable depression but has some undesirable side effects. She will explore the inhibiting effect of ketamine on an enzyme, EF2K, toward potential use of EF2K inhibitors in a newly designed treatment for depression with fewer negative side effects than ketamine.
Shun-Chiao Chang, Sc.D., Brigham and Women’s Hospital, Harvard University, will use data from 11,500 women who have been participating in the Nurses' Health Study, established in 1976, to investigate interactions between genetic and environmental factors in depression risk for mid-life women. Findings from the work may offer insight for preventive measures through lifestyle changes.
Dipesh Chaudhury, Ph.D., Icahn School of Medicine at Mount Sinai, will conduct the first systematic investigation of the links between the circadian and sleep/wake centers of the brain and aberrations in associated neural circuitry that lead to depression-related behaviors. The study, based on the known property of sleep deprivation as therapy for depression, may lead to a faster-acting form of antidepressant treatment than currently available.
Sharon Dekel, Ph.D., Massachusetts General Hospital, Harvard University, will conduct a clinical trial to examine the preventive potential of the hormone oxytocin administered intranasally to mothers at risk of peripartum (the period immediately before or after giving birth) or postpartum depression for which current treatments are limited. Oxytocin has multiple functions related to emotional bonding.
Christine Ann Denny, M.S., Ph.D., Columbia University, will seek to identify how ketamine, a rapid-acting, still experimental antidepressant, impacts the hippocampus in mice models of depression. Her lab has developed a transgenic mouse that can permanently label neurons activated by a particular experience to reveal how hippocampal function is impaired in depression and how ketamine affects hippocampal circuits to alleviate depressive-like symptoms in the mice.
Faranak Farzan, Ph.D., Centre for Addiction and Mental Health, will test whether electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) improve symptoms in patients with refractory depression by potentiation of inhibition of neuronal activity in the prefrontal cortex, a brain area associated with depression. Dr. Farzan will examine whether this effect is mediated by improvement in neuronal connectivity, and if so, whether pre-treatment measures of neuronal connectivity could predict which patients would benefit from ECT or MST.
Jennifer C. Felger, Ph.D., Emory Clinic, Emory University, will examine changes in brain circuitry that may underlie inflammation-induced anhedonia in patients with depression. Recent evidence suggests a cause-and-effect relationship between inflammatory chemicals called cytokines and symptoms relevant to a number of psychiatric illnesses. While seeking to establish brain biomarkers of inflammation, the study will assess therapeutic strategies to reverse inflammatory effects on behavior.
Allyson Kimberly Friedman, Ph.D., Icahn School of Medicine at Mount Sinai, is exploring mechanisms in the brain’s reward pathways that underlie the effect of social support in preventing and treating depression toward finding therapeutics that are more naturally acting than current antidepressants. Recent research in her lab and elsewhere suggest that oxytocin is crucial in mediating social behavior and in mitigating neuroendocrine response to stress.
Miguel Angel García-Cabezas, M.D., Ph.D., Boston University, will investigate the abnormalities in the way brain area 25 communicates with nearby brain areas in depression. Dr. Garcia-Cabezas will explore the roles of NMDA, a receptor for the brain’s most common excitatory neurotransmitter, glutamate, and of glia, brain cells that absorb glutamate after neurotransmission. Recent studies have shown that selectively blocking this specific type of NMDA receptor accounts for the effectiveness of ketamine in relieving the symptoms of depression.
Stefan Goetz, Ph.D., Duke University Medical Center, Duke University, is working to characterize and modulate the effects of transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique that is used to treat depression and is showing promise for the treatment of several other psychiatric illnesses. In preliminary research, Dr. Goetz has shown that TMS can be enhanced to be more clinically effective.
Mira Alexandra Jakovcevski, Ph.D., Max-Planck Institute for Psychiatry, Max-Planck Society/Max Planck Institutes, wants to determine which behavioral and molecular aspects of stress vulnerability and resilience are mediated by broad spectrum histone deacetylase inhibitors, compounds that, interacting with astrocytes, improve depression symptoms. Astrocytes, nervous-system cells that insulate and support neurons, play a major role in stress-related neuropsychiatric disorders and in the response to antidepressant medications.
Chung Sub Kim, Ph.D., University of Texas at Austin, is exploring the effects of chronic unpredictable stress in depression, and in particular, the expression of a protein―HCN1 channel―found to be significantly increased in an animal model of depression. Dr. Kim will explore whether reducing HCN1 channel expression produces resilience to the depressive effects of chronic unpredictable stress.
Yevgenia Kozorovitskiy, Ph.D., Northwestern University, wants to determine how ketamine, a medication that provides fast-acting relief from depression, alters the structure and function of excitatory connections between neurons and the classes of neurons most sensitive to its effects. Since ketamine can have serious side effects, another goal of this project is to study a second promising medication, currently in clinical trial, to compare its effects to those of ketamine.
Chun Hay Alex Kwan, Ph.D., Yale University, will use time-lapse two-photon microscopy to image antidepressant medication effect on dendritic spines, the neuronal protrusions that receive signals from other neurons across the synapse. Because the antidepressant ketamine stimulates synaptic activity and spine proliferation, Dr. Kwan will test whether spine density indicates general antidepressant efficacy by imaging the same sets of spines in mouse models of depression before and after treatments with different antidepressants.
Benjamin Bruce Land, Ph.D., Yale University, will use traditional pharmacological approaches and novel light-based strategies that allow cells to be turned on and off to learn whether the opioid system influences measures of pain and depression. The brain areas underlying depression may also play a role in the perception of pain. This effect, mediated by opioids, has not been extensively tested in depression and may offer a new target for treatment.
Joelle LeMoult, Ph.D., Stanford University, will develop and test a novel intervention that specifically targets rumination, a persistent and unproductive way of thinking about feelings of distress and a key determinant of the course of major depressive disorder. The trial will build on cognitive bias modification methods to improve the patient’s ability to remove negative information from working memory.
Margarita Rivera, Ph.D., Hospital Universitario San Cecilio, will use genetic information and data on environmental factors to try to predict obesity in people with depression and gain a more comprehensive understanding of why the two disorders tend to cluster together. Factors may include antidepressant medication, lifestyle and socioeconomic status, as well as stress, biological imbalances and genetic risk. Identification of patients at risk of obesity-related disorders will inform programs to prevent their development and improve treatment.
Benjamin A. Samuels, Ph.D., Research Foundation for Mental Hygiene, Inc., NYSPI, Columbia University, is exploring a potential treatment for intractable depression, based on his findings with a mouse model that activity by a growth factor in the brain called TGFβ is different in responders and non-responders to antidepressant treatment. He will characterize TGFβ; signaling in depression patients to determine if manipulation of its signaling is a potential treatment for treatment-resistant depression.
Marina Lopez Sola, Ph.D., University of Colorado, Denver, will assess the effectiveness of an eight-week trial of mindfulness-based cognitive therapy (MBCT) in preventing depression relapse in highly vulnerable postpartum women with a history of depression. She will characterize the neural and psychological mechanisms that underlie the positive effects of MBCT, and develop brain-based predictors of depression relapse six months after MBCT intervention.
Giulia Treccani, Ph.D., University of Milano Bicocca, will investigate changes induced by ketamine in glutamate neurotransmission in a rat model of depression. Glutamate is the most important excitatory neurotransmitter in the brain; glutamate system dysfunction is considered a core component of mood disorders. The study will seek to explain how a single infusion of ketamine causes rapid and sustained antidepressant effect, reversing stress-induced enhanced glutamate release and the resulting effects on dendrites (structures on neurons that receive neural transmissions) synapses.
Hongyu Yang, Ph.D., University of California, Los Angeles, will conduct a trial of memantine and of escitalopram (Lexapro®), medications that target the systems of the neurotransmitters glutamate and GABA, in patients with late-life depression, a condition that can lead to cognitive impairment and dementia. Dr. Yang seeks to determine whether the medications improve cognitive performance and the response to standard pharmacological treatments.
Kymberly D. Young, Ph.D., Laureate Institute for Brain Research, will conduct a trial with real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf)―a non-invasive potential treatment for intractable depression, in which the patient’s own brain controls the fMRI signal. The target brain region will be an area of the amygdala, essential to the processing of memory, decision-making and emotional reactions.
Obsessive-Compulsive Disorder (OCD)
Carolyn I. Rodriguez, M.D., Ph.D., Research Foundation for Mental Hygiene, Inc., NYSPI, Columbia University, will test a compound called GLYX-13 with the aim of improving treatment options for OCD. Currently available medications rarely produce complete remission and take months to work; GLYX-13 modulates activity of the receptor for glutamate, the major excitatory neurotransmitter. Dr. Rodriguez hopes to determine its mechanism of action within neural circuits implicated in OCD.
Post-Traumatic Stress Disorder (PTSD)
Antoine Besnard, Ph.D., Massachusetts General Hospital, Harvard University, will explore the potential of treating PTSD by stimulating neurogenesis, the birth of new nerve cells, in the hippocampus. Hippocampal neurogenesis contributes to mood regulation and also to pattern separation, a process by which we distinguish between similar experiences. Since patients with PTSD overreact to ambiguous trauma-related cues, enhancing pattern separation ability may be a strategy for easing PTSD symptoms.
Lorenzo Diaz-Mataix, Ph.D., New York University, will explore the potential of the medications gabapentin (Neurontin®) and pregabalin (Lyrica®) to prevent PTSD from developing in patients who have been exposed to trauma. Dr. Diaz-Mataix will test their effect in the consolidation of threat memories and study the mechanisms and brain areas involved to learn if they have potential as preventive treatments.
Raül Andero Galí, Ph.D., Emory University, will expand his studies of a brain pathway called Tac2 to further explore its role in fear conditioning. Tac2 appears to block fear memory development and consolidation and therefore may be a candidate for therapeutic intervention to prevent the development of PTSD after trauma.
Linda Isaac, Ph.D., Stanford University, will conduct the first study of combat veterans with PTSD, using a brief, non-invasive, cost-effective method for retraining abnormal brain-wave patterns. Through a brain-computer interface, the study will use electroencephalographic (EEG) biofeedback to make the intentional control of one's own brain activity possible. The computer monitor becomes a virtual mirror of real-time electrical oscillations produced by neurons in the cortex recorded by an electroencephalogram.
Sandra Jurado, Ph.D., University of Maryland School of Medicine, wants to further understand the release mechanism of the natural opioid dynorphin, based on increasing evidence that dynorphin and its receptor, the kappa opioid receptor contribute to both formation and extinction of aversive memories. Dr. Jurado will explore the potential of the dynorphin-release regulation mechanism as a target for therapies to treat PTSD and other fear-related disorders.
Imanuel Ruvin Lerman, M.D., M.S., University of California, San Diego, will test the efficacy of a therapy called burst spinal cord stimulation (bSCS) in reducing affective pain in patients with PTSD. bSCS uses stimulation via implanted electrodes in the spine to decrease affective and sensory pain in patients with chronic pain and it is postulated that it decreases affective pain through modulation of circuitry that overlaps with dysregulated brain circuitry in PTSD.
Alik Sunil Widge, M.D., Ph.D., Massachusetts General Hospital, Harvard University, will test a new form of deep brain stimulation (DBS) for PTSD, designed to be activated by the patient’s own thoughts. DBS is a technology that alters electrical activity in the brain and is currently in trials for the treatment of intractable depression. Existing DBS parameters can be changed only by a physician, and so is not effective for disorders like PTSD with rapidly fluctuating symptoms.
John Daniel Cahill , MBBS, Yale University, is exploring pregnenolone, a natural hormone precursor, as a defense against the effects of cannabis, which is believed to interact with brain abnormalities to exacerbate or precipitate psychosis. Marijuana use is high among people with and/or at risk for developing schizophrenia. The study will first explore the interaction between pregnenolone and THC, the principal active component of cannabis, in healthy volunteers to test the potential link between pregnenolone and THC-induced psychosis-like effects.
Hsun-Hua Chou, M.D., Ph.D., University of California, San Diego, will test an intervention called Targeted Cognitive Therapy (TCT), for adolescents with early-onset schizophrenia to improve schizophrenia-related problems of cognition, such as attention, learning and memory, which are not significantly improved by current schizophrenia medications. TCT is based on the ability of an individual to learn to increase the accuracy and speed of processing simple sensory information.
Charmaine Demanuele, Ph.D., Massachusetts General Hospital, Harvard University, will investigate the possible contributions of abnormal sleep to cognitive deficits in schizophrenia. She will expand on her preliminary findings that reductions in a brain activity called sleep spindles during sleep correlates with worsened memory, and that the sleep medication eszopiclone (Lunesta®) increased sleep spindles and improved memory in patients with schizophrenia.
Anna Rose Docherty, Ph.D., Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, hopes to improve the ability to predict who may develop schizophrenia. She will combine extensive recent data on genetic risk factors and early symptoms observed in a large sample of young people, a quarter of whom typically will go on to develop psychosis. Better prediction would aid in early intervention and avoid unnecessary treatments and side effects.
Paolo Fusar-Poli, Ph.D., Institute of Psychiatry, King's College London, will conduct a trial to evaluate the mechanism of action of the hormone oxytocin on social cognition and emotional processing in individuals at high risk for schizophrenia during the prodromal phase before psychosis appears. Oxytocin has been shown to promote social interactions and emotional bonding in healthy volunteers, and improve psychotic symptoms in patients with schizophrenia.
Rachel A. Hill, Ph.D., University of Melbourne, will explore the cognitive-enhancing effects of estradiol, a major estrogen hormone that appears to protect women with schizophrenia from the more severe cognitive impairments experienced by men with the disorder. Current schizophrenia medications do not alleviate the cognitive deficits of schizophrenia. Dr. Hill wants to find alternative treatment strategies that would exploit estradiol’s protective traits without its unacceptable side effects.
Dennis Kaetzel, Ph.D., Institute of Neurology/University College London, University of London, will assess whether and which symptoms of schizophrenia may be related to deficits in the synchronous, oscillatory firing of nerve cells, to test both this concept of causation as well as the possibility that its pharmacological reversal would be effective against the cognitive and negative symptoms of schizophrenia for which there are currently no effective medications.
Sarah Christine McEwen, Ph.D., Neuropsychiatric Institute and Hospital, University of California, Los Angeles, will develop and test a comprehensive home-based exercise program to improve cognition in patients with schizophrenia to be delivered through the patients’ smartphones. Along with the known benefits in combating these patients’ increased vulnerability to heart disease, regular exercise has been shown to elevate neurochemical mechanisms that result in better memory function.
Brent Gregory Nelson, M.D., University of Minnesota, will explore transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, for reducing hallucinations, one of the hallmark symptoms of schizophrenia. The study will specifically investigate whether random noise stimulation would be effective in reducing auditory hallucinations, and if so, Dr. Nelson will use brain imaging to see how the brain changes as a result of the stimulation.
Nichole Marie Neugebauer, Ph.D., Northwestern University, is working to facilitate treatment for the cognitive impairments of schizophrenia, considered to be the most enduring, treatment-resistant and predictive-of-future-functioning symptoms. Current atypical antipsychotic medications enable some cognitive improvement in some patients. This study will address gaps in knowledge regarding adjunctive agents to antipsychotic medications that may contribute to more effective therapy.
Maria V. Puig, Ph.D., Massachusetts Institute of Technology, will use mice models to unravel neural mechanisms underlying the actions of the atypical antipsychotic medications clozapine and risperidone in the prefrontal cortex, the brain’s site of higher learning. Dr. Puig will specifically assess the effects of the medications on the neurotransmitter serotonin—a major modulator of prefrontal cortex function—and neural oscillations—brain waves that synchronize the activity of neuronal networks.
Jianping Zhang, M.D., Ph.D., Zucker Hillside Hospital, Feinstein Institute for Medical Research, will conduct a clinical trial to determine mechanisms of action of clozapine, an antipsychotic medication used for treatment of refractory schizophrenia. Thirty to 40 percent of patients with schizophrenia do not respond to other antpsychotic medications. The study will investigate potential biomarkers that can predict which patients will respond to which medication.
Wesley Brian Asher, Ph.D., Columbia University, hopes to help develop better antipsychotic drugs for schizophrenia and disorders. He will apply an assay his lab developed to study aripiprazole (Abilify®) and similar drugs that do not block the activity of proteins called arrestins, which other antipsychotics do block, thus avoiding side effects common to other antipsychotics. The aim is to understand the relationship between arrestin and drug efficacy.
Valeria Gazzola, Ph.D., University of Groningen, will focus on the neural mechanism of empathy to determine whether changing brain activity using transcranial direct current stimulation in empathy-related brain regions can change moral behavior. Such knowledge might pave the way to scientifically guided therapies to help normalize antisocial behaviors in psychopathic individuals and in adolescents with conduct disorders.
Lior Greenbaum, M.D., Chaim Sheba Medical Center, Tel Aviv University, will examine the effects of a second-generation antipsychotic medication, risperidone, on sexual behavior and testosterone levels, and of the aromatase inhibitor letrozole, which blocks conversion of testosterone to estradiol, in mice. Driving this research is the huge increase in prescriptions for these medications for anxiety, affective disorders and other conditions for adolescents, possibly risking their adult sexual and reproductive life.
Michy Kelly, Ph.D., University of South Carolina, is exploring a recently discovered enzyme, called Phosphodiesterase 11A (PDE11A), found in the hippocampus, that is critical to the formation of memories. Dr. Kelly believes that understanding PDE11A function and dysfunction will have implications for treating issues with long- and short-term memory, including in patients with epilepsy and PTSD. Dr. Kelly hypothesizes that PDE11A has the potential to selectively restore aberrant signaling in a key memory-related brain region without unwanted side effects.
Shalini Lal, Ph.D., Montreal General Hospital, McGill University, will evaluate the first online system, HORYZONS, designed to maintain clinical and psychosocial benefits of early intervention for youths with psychotic disorders, including schizophrenia, bipolar disorder and depression, after discharge from first-episode psychosis services in four Canadian sites. Studies have shown that the benefits of early intervention are not sustained after patients are transferred to routine mental health care.
Benjamin C. Nephew, Ph.D., Tufts University, will study the effects of intranasal oxytocin and vasopressin for treating the negative behavioral and physiological effects in a rodent model of postpartum depression and anxiety. These hormones are powerful mediators of maternal behavior, social bonding, aggression and lactation. Decreased oxytocin during pregnancy is associated with increased risk for postpartum depression and anxiety.
Stephanie Perreau-Lenz, Ph.D., SRI International, will develop mouse models of alcohol abuse to test potential compounds that target sleep regulators as therapy for the treatment of sleep disruption and disruptions in biological rhythms and in the functioning of the body’s circadian clock gene brought on by alcohol abuse. Normal sleep and expression of circadian clock genes have been found to be crucial to prevent the development of multiple mental illnesses.
Ann Polcari, Ph.D., Northeastern University, will test a new approach to cognitive behavioral therapy for people who suffered emotional abuse during childhood. The therapy will focus on the negative self-image resulting from internalization of adult criticism experienced in early life that can lead to depression, anxiety and suicide. Effects of treatment will be measured in default mode network connectivity, the resting-state network implicated in processing brain operations, especially related to thoughts about the self.
Seethalakshmi Ramanathan, M.D., Hutchings Psychiatric Center, will investigate how socioeconomic stress translates into childhood developmental difficulties and its long-term affect on mental health. The study will focus on socioeconomic depreciation, a downward shift in the family’s economic state, through analysis of two large, national datasets to understand the mechanisms underlying the effect on an infant's social, cognitive and emotional development. Results from these analyses can be used to develop early intervention strategies.
Alessandra Raudino, Ph.D., University of New South Wales, will seek markers of childhood development that represent vulnerability to developing adult psychiatric illness in offspring of parents with psychotic and severe mood disorders. The study will use data on 87,000 New South Wales children whose teachers completed the Australian Early Development Index on their behalf in 2009. Identification of such markers is a necessary step toward determining appropriately timed targets of preventive interventions.
Ling Shan, Ph.D., University of California, Los Angeles, will investigate opiate medications as a new approach to treat the sleep disorders of narcolepsy and Parkinson's disease and as a novel treatment for depression. Patients with narcolepsy and Parkinson’s disease have excessive loss of hypocretin/orexin (Hcrt) neuron function, which is involved in regulating arousal. Reduced Hcrt levels have been linked to suicide attempts, and Dr. Shan’s findings indicate Hcrt levels are linked to mood.
Sonal G. Thakar, Ph.D., University of California, San Diego, will explore the regulatory pathways of the synapse, the site where neurons exchange information, with an aim of identifying targets for new pharmacological treatments for psychiatric illnesses linked to synaptic dysfunction. The Thakar lab has identified a molecule called Celsr3 as essential for synapse formation, plasticity and maintenance. This study seeks to precisely define the roles of Celsr3 at the molecular level and in living animals.
Carmelo Mario Vicario, Ph.D., Bangor University, will test the efficacy of transcranial direct current stimulation (tDCS), a noninvasive brain stimulation method, for treating nicotine addiction. The tDCS treatment will target what is called the mother tongue area of the brain’s corticobulbar tract, based on new evidence linking this region with the effect of nicotine on the reward system.
Sanjeev Kumar, M.D., Centre for Addiction and Mental Health, University of Toronto, will conduct a clinical trial of repetitive transcranial magnetic stimulation (rTMS), a brain stimulation technology that has shown promise in treating the cognitive problems of Alzheimer’s disease. The goal is to uncover brain-area targets for rTMS that will enhance brain neuroplasticity (the brain’s capacity to remodel its architecture) and working memory of individuals with mild to moderate Alzheimer’s disease.
Borderline Personality Disorder (BPD) and Suicide
Anthony Charles Ruocco, Ph.D., Centre for Addiction and Mental Health, University of Toronto, will conduct a trial of magnetic seizure therapy (MST) with patients with BPD who are suicidal. MST is an innovative brain stimulation technique that shows promise for treating suicidal thinking and behaviors. The treatment target will be the dorsolateral prefrontal cortex, the brain region responsible for managing emotions and controlling impulsive behaviors.
Hyeong-Min Lee, Ph.D., University of North Carolina at Chapel Hill, will work to identify and characterize small molecules that restore normal function to the MECP2 gene. Mutations in MECP2 cause Rett syndrome, a brain disorder that affects females. Symptoms can include loss of speech, seizures, irregular breathing and mental retardation. Discovery of such compounds, while providing insights into the precise mechanisms of the disease, may also lead to safe, effective treatment.