The 2018 NARSAD Young Investigator grantees from the Brain and Behavior Research Foundation include four faculty members from the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai. Their research aims are listed below.

Rebecca Sue Hofford, PhD, hopes to lay the groundwork for a drug to treat addiction to cocaine and other psychostimulants. She previously found a link between cocaine-induced behaviors and the activity of granulocyte-colony stimulating factor, or G-CSF, which is a cytokine—a signaling protein released by the immune system. Her team now hopes to identify which neurons are affected by G-CSF in the nucleus accumbens, a brain region that is associated with reward processing and involved in addiction. They will study how affected neurons change their activity in response to G-CSF.

Eva Velthorst, PhD, will explore how parental genes that are not passed on to the child may nevertheless help explain the link between childhood adversity and the development of psychosis. It is theorized that such non-inherited genes are able to affect the child through their parents’ contribution to the child’s environment. This phenomenon, called “genetic nurturing,” has been largely ignored in genetic studies but may point to preventable exposures, Dr. Velthorst suggests. Leveraging the Avon Longitudinal Study of Parents and Children study, the team will integrate genetic and developmental data on 3,000+ individuals followed from birth up to age 24, and their parents. This will provide the opportunity to examine the effect of non-transmitted genes of the mother and father separately (accounting for the transmitted genes) in the childhood adversity-psychosis relationship.

This year’s American College of Neuropsychopharmacology (ACNP) conference takes place December 9-13 in Hollywood, Florida. Faculty from the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai will be contributing via panels, study groups, and posters. The schedule of panels and study groups is listed below.

René Kahn, MD, PhD, left, and Dolores Malaspina, MD, MPH, MSc

Panels

Novel Technological Strategies to Assess Suicidality and Develop Suicidal Phenotypes
Co-chair: M. Mercedes Perez-Rodriguez, MD, PhD
When: Monday, 3 – 4:15 pm
Where: Diplomat 1-2

Neural Computations as Markers of Stress, Anxiety, and Trauma
Co-chair and presenter: Daniela Schiller, PhD
When: Monday, 3 – 5:30 pm; Dr. Schiller presents 4:20 – 4:55 pm
Where: Atlantic Ballroom 3

Larger-Scale Transcriptome and Epigenome Mappings, Modeling and Analyses in Developing and Diseased Human Brain
Presenters: Schahram Akbarian, MD, PhD, and Kiran Girdhar, PhD
When: Tuesday, 8:30 – 11 am; Dr. Akbarian presents 8:30 – 8:40 am; Dr. Girdhar presents 9:50 – 10:25 am
Where: Atlantic Ballroom 2

Neuroimaging as a Novel Tool to Enhance the Development of Psychotherapeutic Strategies
Chair: Harold Koenigsberg, MD
When: Thursday, 8 – 8:10 am; Dr. Koenigsberg presents 8:10 – 8:45 am
Where: Diplomat 1-2

Genomic Mechanisms in the Etiology of Bipolar Disorder
Presenter: Eli Stahl, PhD
When: Thursday, 8 – 10:30 am; Dr. Stahl presents 9:20 – 9:55 am
Where: Atlantic Ballroom 2

Challenges and Solutions to Elucidating Psychiatric Disease Biology From Genomic Association Using Human Induced Pluripotent Stem Cell-Based Assays
Presenter: Kristen Brennand, PhD  
When: Thursday, 12 – 2:30 pm; Dr. Brennand presents 12:10 – 12:45 pm
Where: Regency Ballroom 3

Study Groups

What is the Importance of Animal Models to Neuropsychiatric Disease?
Participant: Eric Nestler, MD, PhD
When: Tuesday, 8:30 – 11 am
Where: Great Hall 5

No Longer Tarred With the Same Brush? Evidence for the Therapeutic Potential of Cannabidiol: Implications for Regulatory Policy
Participant: Yasmin Hurd, PhD
When: Tuesday, 3 – 5:30 pm
Where: Atlantic Ballroom 3

Challenges and Strategies for Strengthening the Pipeline of Physician Scientists in Psychiatry and Neuroscience
Participants: René Kahn, MD, PhD, and Eric Nestler, MD, PhD
Moderator: Antonia New, MD
Co-chair: M. Mercedes Perez-Rodriguez, MD, PhD
When: Tuesday, 3 – 5:30 pm
Where: Great Hall 5

The Debate Regarding Maintenance Treatment With Antipsychotics In Schizophrenia
Participants: René Kahn, MD, PhD, and Dolores Malaspina, MD, MPH, MSc
When: Wednesday, 3 – 5:30 pm
Where: Great Hall 5

Lotje De Witte, MD, PhD, is one of the few experts on “mini brains,” or cerebral organoids—stem cells grown into small balls of human brain tissue. This video shows a mini brain in her lab, showing the dividing cells in red. Video courtesy of Dilara Ilhan.

Until very recently, there was no way to watch human brain activity in action. Imaging, postmortem brain specimens, and animals, though useful in many respects, can only reveal so much about how a live human brain functions. Enter the “mini brain,” or cerebral organoids: stem cells grown into small balls of human brain tissue.

Aided by a biochemical cocktail of proteins and minerals, they grow and self-assemble in the lab dish, mimicking the development of fetal brains in the womb and forming regions such as the hippocampus and retina. Cerebral organoids were first used in 2013 to model microcephaly, and are now used for studying neurological and psychiatric conditions such as autism and schizophrenia. An important distinction between mini brains and real ones is their lack of vasculature and an immune system—both vital aspects.

Rapid evolution

In March of this year, researchers at the UC Davis Institute for Regenerative Cures found a way to induce vascularization. They encased the mini brains in a nutritious gel containing endothelial cells (the cells that line the insides of blood vessels) so the organoids could grow their own blood vessels. After marinating for three weeks, they were implanted into rodent brains. Over the course of their time in vitro and then for two weeks in the rodents, the endothelial cells grew into functioning blood vessels that expanded into the organoid.

The following month, researchers at the Salk Institute for Biological Studies showed in Nature that organoids implanted in mice connected to the hosts’ circulatory systems. The organoid’s neurons fired in conjunction with the mouse-host’s neurons, suggesting a level of integration that could illuminate long-elusive secrets about many brain conditions.

Dr. De Witte’s breakthrough

Lotje de Witte, MD, PhD, one of the few experts in this field, is interested in the role of microglia cells, the immune cells of the brain. Microglia are involved in both inflammation and construction of the brain (believed to be associated with schizophrenia). Incredibly, she and her team discovered that these cells can innately develop within organoids. This greatly increases the potential of mini brains to illuminate how microglia contribute to human brain development and disease. Dr. De Witte’s team published their groundbreaking findings in Nature Communications in October.

“We have known for a long time that the immune system is somehow involved in causing neurodevelopmental disorders such as schizophrenia and autism. Now, we finally have a human model to study how microglia contribute to neurodevelopment and neurodevelopmental disorders. This is very exciting because if we find a disease mechanism, these organoids can be used to screen for potential new drugs to help our patients,” said Dr. De Witte.

The ethics of mini brains

Understandably, ethical and philosophical concerns have been raised, most notably in Nature earlier this year. What are the ethics of working with these organoids? Could a mini brain feel pain, or achieve consciousness?

“I’ve read about these issues with great interest,” said Dr. De Witte. “If it’s even possible to create a fully functioning brain or fetus in a dish, it’s far, far in the future. Regardless, it’s certainly critical to think ahead and discuss where the boundaries should be drawn. Our ultimate goal is always to more effectively treat the millions of people worldwide afflicted with neurological and psychiatric conditions, and mini brains are uniquely valuable for research in service of that goal. Optimizing the protocols to use this technology should be encouraged.”

Dr. De Witte is Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai, where her lab investigates the connection between the immune system and the pathogenesis of psychiatric disorders. She is also affiliated with the MIRECC at the James J. Peters VA Medical Center in the Bronx, where she is establishing a lab to culture organoids. Her PhD is in molecular biology and immunology.

The Department of Psychiatry at the Icahn School of Medicine at Mount Sinai has put together a fantastic lineup for the 2018-2019 Grand Rounds season—check out some of the highlights below.

February 5: Mark Solms, PhD, from the University of Cape Town, will discuss how and why consciousness arises. Dr. Solms is Director of Neuropsychology at the University of Cape Town, and Director of Training of the South African Psychoanalytical Association.

February 19: Maurizio Fava, MD, from Massachusetts General Hospital/Harvard Medical School, will discuss novel pharmacological approaches to treatment-resistant depression. Dr. Fava is Slater Family Professor of Psychiatry at Harvard Medical School, Executive Vice Chair of Psychiatry at Massachusetts General Hospital (MGH), Executive Director of Clinical Trials Network and Institute at MGH, and Director of the Division of Clinical Research at MGH.

March 19: Francis S. Lee, MD, PhD, from Weill Cornell Medical College, will discuss treating the developing versus the developed brain. Dr. Lee is Professor of Molecular Biology in Psychiatry, Vice Chair for Research Psychiatry, and Interim Director of the Sackler Institute for Developmental Psychobiology Psychiatry/Pharmacology at Weill Cornell Medicine. Photo credit: Jesse Winter

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David Kimhy, PhD, joined the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai In September of 2017 as an Associate Professor, Leader in New Interventions in Schizophrenia, and Director of the Experimental Psychopathology Laboratory.

Dr. Kimhy’s current focus is on improving daily function in people with psychosis. In 2017 he received, along with co-investigator Dr. T. Scott Stroup of Columbia University, a 4-year, $6.2 million research grant from the National Institute of Mental Health for a multi-site, single-blind, randomized clinical trial entitled Improving Cognition via Exercise in Schizophrenia, the largest study of its kind. The goal of the study is to confirm the impact of aerobic exercise training on cognitive functioning, along with examining its impact on daily functioning and biomarkers of neuroplasticity and cognitive change.

Background

Schizophrenia is commonly characterized by psychotic symptoms such as hallucinations and delusions. However, it is often the accompanying cognitive deficits (e.g., difficulties with poor attention, memory, processing speed, and executive functioning) that lead to life-long functional difficulties and disability. Such deficits can get in the way of attending school, gaining and maintaining employment, as well as developing relationships with family, friends, and romantic partners. While antipsychotic medications have been found to relieve psychotic symptoms, available treatments offer limited benefits for cognitive deficits.

Targeting these deficits, in 2014 Dr. Kimhy demonstrated that such deficits in people with schizophrenia are closely associated with poor aerobic fitness. A year later, he tested a novel intervention to improve cognitive functioning in people with schizophrenia. Completing a small clinical trial, he demonstrated that individuals with schizophrenia who participated in a 12-week aerobic exercise program using active-play video games (i.e., Xbox Kinect) improved their cognitive functioning by 15% (compared to minimal change in the control group). The cognitive improvements were associated with upregulation of Brain rived Neurotrophic Factor (BDNF), a biomarker of neuroplasticity.

Beyond Medication: Hope for Patients

In the present study, Dr. Kimhy is aiming to replicate these results in a larger cohort, employing a similar intervention to study 200 participants with schizophrenia across four sites in New York, North Carolina, Georgia, and California. Participants engage in a 12-week, 3 times per week, 1-hour training program with a trainer using active-play video games along with traditional exercise equipment. “Our innovative use of active-play video games as part of exercise is fun, as well as inexpensive and scalable,” said Dr. Kimhy.

“This study is important for a number of reasons. Primarily, it highlights poor aerobic fitness as a modifiable risk factor for cognitive deficits in schizophrenia, for which aerobic exercise is a safe, non-stigmatizing, and nearly side-effect free intervention,” said Dr. Kimhy. Additionally, aerobic exercise may potentially improve mood symptoms and poor physical health, as well as minimize the risk of premature death—all issues that are prevalent among people with schizophrenia. Results from this efficacy study will inform policy makers’ “go/no-go” decisions regarding the dissemination of aerobic exercise to target cognitive deficits in people with schizophrenia.