2016 NARSAD Independent Investigator Grantees

We are proud to announce $3.9 million has been awarded in NARSAD Independent Investigator Grants to 40 mid-career scientists from 30 institutions in 16 countries for basic research to understand what happens in the brain to cause mental illness; new technologies to advance or create new ways of studying and understanding the brain; and next-generation therapies that reduce symptoms of mental illness and ultimately cure and prevent brain and behavior disorders.

Covering a broad spectrum of brain and behavior disorders, the NARSAD Independent Investigator Grants provide $50,000 per year for up to two years to support investigators during the critical period between the initiation of research and the receipt of sustained funding. Every year, applications are reviewed by members of the Foundation’s Scientific Council, which is comprised of 150 leading experts across disciplines in brain and behavior research 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.

 
 

Anxiety

Basic Research: to understand what happens in the brain to cause mental illness

Johannes Gräff, Ph.D., Ecole Polytechnique Fédérale de Lausanne (EPFL), seeks to improve treatment for anxiety disorders by uncovering how memories are updated in the brain. Dr. Gräff hopes to lead the first published study to investigate which connections in the brain make it possible for old, fearful memories to be revised with new information. Looking at mice, his team will track the activity of brain cells in the hippocampus, a crucial brain region for memory formation.

Andrew Tapper, Ph.D., University of Massachusetts, will study connections throughout the brain that contribute to anxiety disorders. Dr. Tapper’s team will focus on a group of brain cells that contributes to the brain’s reward system by releasing the neurotransmitter dopamine. They hope to produce evidence that this dopamine release helps to regulate the experience of anxiety. Confirming this prediction would point to this specific neuron group as a possible target for anxiety treatment. The results will also shed light on the underlying pathology of this common disorder.

 

Autism Spectrum Disorder (ASD)

Next Generation Therapies: to reduce symptoms of mental illness and retrain the brain

Peter Gregory Enticott, Ph.D., Deakin University, is seeking a biological treatment for autism that targets its core symptoms. Using transcranial magnetic stimulation (TMS), he will target the disrupted communication between brain cells that is a hallmark of autism. He will then compare efficacy of TMS when applied to two different brain regions, to determine which areas hold promise for new interventions. Dr. Enticott’s team will focus on adolescents and young adults with autism, a crucial population whose autism symptoms can interfere with the transition to adulthood.

 

Bipolar Disorder

Basic Research: to understand what happens in the brain to cause mental illness

Ana Cristina Andreazza, Ph.D., University of Toronto, will explore genetic abnormalities that lead to bipolar disorder. Her team will look specifically at genetic defects that interfere with the activity of mitochondria, which produce energy for cells. Sometimes these defects produce a disease specific to mitochondria, and other times they appear to contribute to bipolar disorder. Dr. Andreazza will use stem cell reprogramming technology to compare the cells from bipolar disorder patients who have these defects with cells from their relatives who instead have mitochondrial disease.

Manpreet Singh, M.D., Stanford University, will explore the potential negative side effects of antidepressant medication given to youth at high risk for psychiatric disorders. In youths with emotional dysregulation, side effects have been noted including irritability, agitation, elevated mood. For some youth, these adverse events lead to the development of lifelong psychiatric disorders such as bipolar disorder (BD). Looking at youth with family histories of BD, Dr. Singh will investigate how antidepressant use, combined with typical psychotherapy, alters brain activity and triggers negative side effects.

Jun-Feng Wang, M.D., Ph.D., University of Manitoba, hopes to identify mechanisms in the brain that lead to bipolar disorder (BD) in order to improve treatments for the illness. Dr. Wang’s team will look at brain cells that may be degraded by stress and inflammation to determine whether these cells show impaired activity in bipolar disorder. They will also test whether any such impaired activity fails to respond to the gold standard treatment for BD, lithium, and whether interfering with this system in mice produces depression- and bipolar-like symptoms.

Next Generation Therapies: to reduce symptoms of mental illness and retrain the brain

Benedikt Lorenz Amann, M.D., Ph.D., FIDMAG Research Foundation, aims to improve treatment for people with bipolar disorder who have experienced traumatic events, which often worsen their experience of the disease. His work will test the effectiveness of a possible treatment, called Eye Movement Desensitization Reprocessing, that starts by directing patients’ eye movements in particular pattern. Bipolar patients will either undergo EMDR or more traditional therapy. Dr. Amann predicts that EMDR will be more effective at reducing troubling emotional events in the short- and long-term, making it a strong treatment option for traumatized bipolar patients.

Peter L. Franzen, Ph.D., University of Pittsburgh, will investigate the potential of dialectical behavior therapy (DBT), a psychosocial treatment, in reducing suicides among adolescents with bipolar disorder. Dr. Franzen’s team will focus on DBT’s therapeutic value in reducing sleep disturbances, both a risk factor and symptom of bipolar. They will compare the effects of DBT, which targets emotion regulation processes, by looking at brain imaging and measures of sleep quality in adolescents both with and without bipolar disorder.

Kerning Gao, M.D., Ph.D., Case Western Reserve University, will try to explain why only some individuals respond to the gold standard treatment for bipolar disorder, lithium. Dr. Gao will use highly sensitive tests to track how gene expression within white blood cells differs between people with bipolar whose symptoms improve with lithium, and people whose do not. If his team is able to pinpoint these differences, researchers may in the future be able to use this blood test to predict whether patients will respond well to lithium and tailor their treatment accordingly.

 

Depression

Basic Research: to understand what happens in the brain to cause mental illness

Christine DeLorenzo, Ph.D., Stony Brook University School of Medicine, hopes to improve treatment for depression by identifying what makes antidepressants effective. Most antidepressant medication targets levels of the brain chemical serotonin. Dr. DeLorenzo believes the effectiveness of this medication depends on the balance between two other chemicals: glutamate, which promotes communication throughout the brain, and GABA, which inhibits communication. Her team will study whether that balance changes after eight weeks on typical antidepressants that alter serotonin levels.

Kirsten A. Donald, M.D., University of Cape Town, South Africa, will investigate how depression can be “passed on” from parent to child, given that children of depressed mothers are especially likely to develop the disorder. A mother’s depression may affect the child through passed-on genes, other changes to the child’s physiology, and environmental factors stemming from the mother’s symptoms. Dr. Donald’s team will use imaging to study the brains of toddlers whose mothers have depression, and compare that information to images of their brain activity during pregnancy.

Timothy York, Ph.D., University of British Columbia, will investigate the biological mechanisms underlying postpartum depression. His project seeks to identify chemical changes in gene expression that may contribute to development of the disorder. His team will look for patterns in these chemical changes that can predict whether mothers will develop depression before or after giving birth. They will also test whether improvements in depression symptoms correspond with reversal of these chemical changes to gene expression.

New Technologies: to advance or create new ways of studying and understanding the brain

Vincent P. Ferrera, Ph.D., Columbia University, will study a non-invasive brain therapy that holds promise for treating different psychiatric conditions, including depression that does not respond to usual forms of treatment. This non-invasive therapy, called focused ultrasound, uses targeted sound waves to stimulate or limit the activity of brain cells. Dr. Ferrera’s team will investigate the mechanisms underlying focus ultrasound’s ability to improve performance on a decision-making task in monkeys.

Next Generation Therapies: to reduce symptoms of mental illness and retrain the brain

Olivier Berton, Ph.D., Icahn School of Medicine at Mount Sinai, will test the potential for combining drug therapy with deep brain stimulation for cases of depression that do not respond to psychotherapy and antidepressants. Deep brain stimulation has already shown promise but the relief it provides is not always consistent. Dr. Berton will try to make these effects stronger and more stable by giving patients a drug that alters genetic activity in neurons that is usually changed by deep brain stimulation itself.

Paul Holtzheimer, M.D., Dartmouth-Hitchcock Medical Center, will try to distinguish between two kinds of treatment-resistant depression to better tailor treatments to symptoms. He will look at a population whose depression has not improved in response to typical treatments. Dr. Holtzheimer predicts refractory depression is rooted in one of two distinct brain areas, requiring two distinct kinds of treatment. His team will test this idea by applying transcranial magnetic stimulation (TMS), an alternative treatment, to the two different brain areas in people with depression and then measuring how it affects their symptoms and behavior.

Maria Lindskog, Ph.D., Karolinska Institute, will build on a new wave of depression treatment focusing on the antidepressant effects of an anesthetic drug, ketamine. Ketamine may produce antidepressant effects by altering the brain’s levels of the chemical glutamate. This work will investigate how inflammatory chemical signals that the body produces in response to stress affect glutamate levels throughout the brain. Dr. Lindskog predicts that a particular inflammatory signal acts on support cells in the brain that regulate glutamate levels. Testing this prediction will help determine whether this particular signaling can be targeted, in the body’s immune response system, to improve depression treatments.

Peter Nagele, M.D., Washington University, St. Louis, seeks to identify the ideal dose of a potential new medication to treat intractable depression. He will test the efficacy of “laughing gas,” the anesthetic often used in dental treatment, which produces antidepressant effects by altering levels of the brain chemical N-methyl-D-aspartate, or NMDA. The team will give people with treatment-resistant depression different doses of laughing gas. They can then compare the success of each dose in relieving depression symptoms while producing the fewest side effects, which might include psychosis, the feeling of disconnect from reality, and euphoria.

Roland Zahn, M.D., Ph.D., King’s College London, will explore a potential new treatment for treatment-resistant depression. Dr. Zahn will test the efficacy of “neurofeedback” in patients who haven’t responded to treatment. This technique involves patients viewing their own brain activity as viewed through functional magnetic resonance imaging, and then using this activity as a guidepost for behaving differently to reduce their symptoms. The project will compare this technique against a psychological, thought-based training technique, to isolate any unique improvements from the neurofeedback not caused by purely psychological effects. If successful, these tests will support neurofeedback as a promising new treatment, especially for currently intractable depression.

 

Obsessive-Compulsive Disorder (OCD)

Basic Research: to understand what happens in the brain to cause mental illness

Stephanie Dulawa, Ph.D., University of California-San Diego, hopes to shed light on the genetic basis of obsessive compulsive disorder (OCD). Dr. Dulawa will study BTBD3, a gene thought to be a contributing factor; it regulates the forging of connections in the brain based on experience. Using a mouse model, Dr. Dulawa’s team will test whether certain activity levels of the target gene are needed to produce all the treatment effects of standard antidepressants, and at which points in development this gene’s role has notable impact.

 

Post-Traumatic Stress Disorder (PTSD)

Basic Research: to understand what happens in the brain to cause mental illness

Kelly Patricia Cosgrove, Ph.D., Yale University, will examine differences in brain chemistry between individuals with and without PTSD using a combination of brain imaging techniques: positron emission tomography (PET), which measures molecules of interest in the living brain; and functional magnetic resonance imaging (fMRI) which measures brain activation in response to a task. They will focus on levels of an enzyme called 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme in the stress pathway that modulates the amount of stress hormones present in the brain, as well as activation of the amygdala relative to subjects’ recollection of a traumatic event in their life.

New Technologies: to advance or create new ways of studying and understanding the brain

Daniela Kaufer, Ph.D., University of California-Berkeley, aims to identify one of the biological bases of post-traumatic stress disorder that can help predict the development of the disease. She will use a rat model of PTSD to compare brain activity in rats that have not been exposed to trauma, rats that have been trauma-exposed but have not developed PTSD, and rats that have PTSD as a result of trauma. She predicts that PTSD symptoms will be linked to an excess of myelin, fatty material that facilitates communication throughout the brain. They will investigate how this material may overdevelop in the pathology of PTSD, whether this overproduction can predict PTSD, and the potential for reversing overproduction as a treatment.

Next Generation Therapies: to reduce symptoms of mental illness and retrain the brain

Isabelle Rosso, Ph.D., Harvard University, will test riluzole, a new potential treatment for post-traumatic stress disorder (PTSD), which does not always respond to current treatments. Riluzole reduces activity of the brain chemical glutamate, which facilitates much of the symptoms by reducing abnormally high glutamate levels and increasing low levels of a chemical biomarker of brain cell health, called NAA. The trial is based on the theory that high levels of glutamate injure brain cells, perhaps helping to account for the well documented shrinkage of the brain’s hippocampus in patients with PTSD.

 

Schizophrenia

Basic Research: to understand what happens in the brain to cause mental illness

Stewart Alan Anderson, M.D., University of Pennsylvania, will study the possible role of mitochondria, the “power plants” of human cells, in schizophrenia. He will study a genetic irregularity that increases the risk of schizophrenia and its link to the activity of mitochondria. He will use advanced technology to reprogram stem cells from skin samples of healthy individuals (controls), and from patients with a genetic variation on chromosome 22 previously linked with the illness. He will force the stem cells to rapidly mature into active neurons and compare measures of bioenergetic health in neurons from the patients compared to controls. He hopes these studies will open up a new way of thinking about the neuropathology, prevention, and treatment of schizophrenia.

Kristen Jennifer Brennand, Ph.D., Icahn School of Medicine at Mount Sinai, will explore a possible new route to treating schizophrenia, focusing on a gene mutation associated with the illness. Dr. Brennand will use a technology called hiPSC to reprogram stem cells from four individuals with mutations in the NRXN1 risk gene. Her team will characterize aberrant NRXN1 expression in neurons and astrocytes derived from patients with deletions in the gene and then restore NRXN1 expression to normal levels, to better understand the mechanisms that produce schizophrenia.

Mathieu Wolff, Ph.D., University of Bordeaux, France, will investigate brain areas possibly involved in generating cognitive symptoms of schizophrenia, which are not sufficiently relieved by current treatment options. Dr. Wolff will focus on the brain’s medial prefrontal cortex and hippocampus. The team will interfere with cells that connect to those regions and then test for any resulting changes in the activity of both brain regions. They will also test for any resulting cognitive impairment and try to reverse the disruption to the target group of cells. Their findings will help determine the role, and potential therapeutic value, of these cells in schizophrenia.

Next Generation Therapies: to reduce symptoms of mental illness and retrain the brain

Brian James Miller, M.D., Ph.D., Georgia Regents University, will explore a possible new treatment for schizophrenia that may help relieve cognitive symptoms of the illness. Dr. Miller’s work will test the efficacy of a drug that breaks down immune system chemicals that the body produces in response to stress, and which have been linked to cognitive impairments in schizophrenia. The team will administer the drug once a month to schizophrenia patients, who will continue on their antipsychotic medications.

Rafael Penades, Ph.D., University of Barcelona, Spain, will investigate how a treatment method called cognitive remediation helps reduce cognitive impairments in schizophrenia. Dr. Penades’ team will test whether cognitive remediation achieves its therapeutic effects by changing a brain chemical in a way that has been previously associated with psychotherapy. They will study those changes, as well as whether related changes in gene expression affect the success of cognitive remediation in treating schizophrenia.

Marta Rapado-Castro, Ph.D., CIBERSAM, Madrid, Spain, will lead efforts to develop a new treatment for the cognitive symptoms of psychosis, which do not respond strongly to current antipsychotics. Dr. Rapado-Castro’s team will test a combination therapy: a drug targeting glutamate, the chemical that drives much of the communication in the brain, plus auditory training based on the brain’s ability to adapt.

Thomas Weickert, Ph.D., University of New South Wales, Australia, will study the role of the body’s immune system in schizophrenia. He will test for anti-schizophrenia effects of a drug that reduces levels of a protein the body releases as part of its immune response. This protein has previously been linked to schizophrenia and related symptoms, including an inability to experience pleasure, memory impairments, and social dysfunction. Dr. Weickert’s team predicts that the drug will reduce symptoms and cognitive impairment in people with schizophrenia by regulating specific brain activity. Such findings would confirm their target drug as a viable new treatment for schizophrenia among patients who show irregular immune responses.

Todd Woodward, Ph.D., University of British Columbia, will test a combination treatment for delusions in schizophrenia. The treatment combines a technique called metacognitive training, where schizophrenia patients must question the reality of everyday experiences, and electrical stimulation of particular brain regions. Dr. Woodward predicts that simultaneous electrical stimulation will make metacognitive training more effective. His team will also test whether the brain regions targeted by electrical stimulation respond with a difference in activity. They hope their findings will expand and encourage the use of non-pharmacological treatments for psychotic symptoms in schizophrenia.

 

Multiple Disorders

Basic Research: to understand what happens in the brain to cause mental illness

Arie Kaffman, M.D., Ph.D., Yale University, will study how early life stress impairs function in the hippocampus, a brain region important for memory formation. In mice, Dr. Kaffman’s team will eliminate a protein that regulates gene expression needed to reduce the profusion of neuronal connections in the brain during childhood. This is important for healthy brain development. Dr. Kaffman hypothesizes that deleting this protein will have the same impact on hippocampal development as early life stress. (Mood Disorders)

Linda Booji, Ph.D., Concordia University, hopes for the first time to measure levels of a protein in the brain, HDAC, that may contribute to a range of psychiatric disorders. The protein affects the way genetic material is packaged in cells, influencing gene activity. Dr. Booji’s team will study how levels of this protein vary in relation to childhood trauma, which is known to impact gene expression. The project will also investigate the connection between the target protein and the size of brain regions linked to emotion regulation.

Joseph D. Dougherty, Ph.D., Washington University School of Medicine, will study the basis of sex differences across common psychiatric disorders. While depression and anxiety are more prevalent among women, both autism and attention deficit hyperactivity disorder occur more among men. Dr. Dougherty’s team will search for possible differences in brain cell activity, and possibly structure, that give rise to these sex differences. In particular, they will look for genetic differences between men and women in a specific brain region, the locus coeruleus, which is a key treatment target for many psychiatric conditions.

Kyung-An Han, Ph.D., University of Texas at El Paso, will help define the cellular mechanisms driving dysfunctional response inhibition, a deficit common to many psychiatric disorders. Response inhibition refers to the ability to suppress impulses or the thought of actions that will not help the current situation. Studying a fly population, Dr. Han’s team will manipulate genetic, environmental, and social factors that affect response inhibition to identify the brain structures and chemicals involved in this crucial behavior. They will focus especially on dopamine, the chemical that controls the brain’s reward system, and the pathways in the brain that change response inhibition in response to social context.

Colleen Ann McClung, Ph.D., University of Pittsburgh, aims to help improve treatment for bipolar disorder, major depression, and schizophrenia by examining disruptions to sleep patterns, which can destabilize mood. Dr. McClung’s team will study coordinated patterns of brain activity tied to the stages of consciousness and sleep—in particular, how these stages look irregular in major depression, bipolar, and schizophrenia. The researchers will also test how strongly these disruptions are linked to outcomes such as suicide and psychosis. These findings will shed light on the underlying pathology of sleep irregularities in psychiatric disorders, laying the groundwork for new treatments.

Gleb P. Shumyatsky, Ph.D., Rutgers University, will investigate gene activity crucial for long-term memory, which degrades in a range of neurological illness including Alzheimer’s disease, autism, and mood disorders. Dr. Shumyatsky will study a particular protein that helps facilitate gene expression, active during learning and other activities relevant to memory. His team will test how the intensity of memory training and strength of activity in the brain’s memory center, the hippocampus, relate to the activity of the target protein. They hope this work will further elucidate the mechanisms of long-term memory and identify a new means of enhancing memory, through this particular gene expression.

Rudolph Uher, M.D., Ph.D., Dalhousie University, Nova Scotia, will study specific connections in the brain that may provide paths to treating many forms of psychiatric illness by expanding on the predictive factors of family history and early symptoms. Dr. Uher’s team will test whether emotional training in youth improves connections between the brain’s emotion and memory centers, and whether training to reduce psychotic symptoms improves connections between the sensory processing and executive control centers. This work may point toward new measures that help prevent schizophrenia, bipolar disorder, and other serious adolescent brain disorders.

Larry Zweifel, Ph.D., University of Washington, Seattle, will explore genetic mutations previously linked to mental illness that change activity in the brain’s reward system, implicated in disorders from addiction to depression. These mutations regulate the activity of brain cells that produce the reward-regulating chemical dopamine. Dr. Zweifel’s team seeks to better understand how these genes regulate activity in the brain’s reward areas and influence behavior. Their findings will lay the groundwork for intervening within the dopamine system to treat psychiatric disorders.

 

Other

Next Generation Therapies: to reduce symptoms of mental illness and retrain the brain

Rachel Alison Adcock, M.D., Ph.D., Duke University, will investigate a possible treatment for nicotine dependence, an addiction especially common among those with schizophrenia and other chronic mental disorders. Addiction causes the brain’s reward system to respond more strongly to drugs, but less strongly to typically pleasurable non-drug stimuli. Dr. Adcock’s research will attempt to teach patients to respond more positively to non-drug stimuli by altering their levels of dopamine, a chemical in the brain that regulates our response to rewards. She hopes this work will lead to the development of personalized interventions for addiction and other disorders involving the dopamine system, including depression. (Addiction)

New Technologies: to advance or create new ways of studying and understanding the brain

Nadia Micali, M.D., Ph.D., Icahn School of Medicine, will study girls at high risk for the eating disorder anorexia nervosa due to family history, in the hopes of identifying biological signs that can help predict development of the disease. Her team’s work will be the first to look for features of brain structure, brain connections, and cognitive performance that may serve as biological predictors of anorexia in girls aged 10 to 15, specifically those whose mothers have had the illness and may pass down genetic susceptibility. Dr. Micali’s team predicts that these high-risk girls will show impairments in processing visual and spatial cues, controlling their behaviors, and understanding social situations. (Eating Disorders)