Video » Laura Padilla, Ph.D., Winner of the 2018 NIMH Three-Minute Talks Competition

Laura Padilla, Ph.D., Winner of the 2018 NIMH Three-Minute Talks Competition

 

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>> LAURA PADILLA:

Severe neuropsychiatric illnesses involve drastic changes in experiencing rewards from increased risk-taking behaviors, like gambling and addiction, to a lack of finding things enjoyable. Many of these same illnesses, including substance abuse, depression, and schizophrenia emerge during or soon after puberty, which itself is considered a time of increased risk taking and reward seeking even in healthy adolescence. However, little is known about how the process of puberty may affect the brain's circuits involved in reward processing. The nucleus accumbens, shown here, is a key reward processing region in the brain. It has been shown that in adolescence this region is more sensitive to rewards compared to both children and adults. Although, most studies focus on age and do not define puberty per say. The hormonal events that make up the puberty transition may specifically alter nucleus accumbens sensitivity to reward and could contribute to the observed increase in adolescent risk-taking behavior.

To better characterize the changes in reward processing, I was interested in whether the onset of puberty alters how the nucleus accumbens interacts with the rest of the brain when a person anticipates a reward. As part of a large scale, NIMH longitudinal study of pubertal neuro development, I study typically developing children and adolescents between the ages of 8 and 18 in eight to 10-month intervals. At each visit, participants complete a comprehensive neuro imaging protocol and clinical assessments including characterization of puberty endocrine events and physician determine puberty status. To study reward related changes in brain function during puberty, I analyzed data from a reward processing game and compared brain connectivity of our prepubescent 8-year-old children with a cohort of 12-year-old adolescents in a preliminary cross-sectional design. Because I was specifically interested in nucleus accumbens activity during reward, I use it as a seed region to probe its functional interactions across the whole brain.

I found that functional connectivity between the nucleus accumbens and two brain regions, including the hippocampus and right inferior frontal gyrus differed between children and adolescents. Specifically, I found that pre-pubertal children showed minimal connectivity between the nucleus accumbens and both of these regions, while adolescence showed that as nucleus accumbens activity increased, hippocampus and frontal gyrus activity decreased. These data provide preliminary evidence of changes in reward related functional connectivity with the nucleus accumbens from pre to post onset of puberty, which may contribute to the increased impulsive behaviors observed during this critical developmental period. However, using this cross-sectional design, we cannot associate the impact of puberty related hormonal events from those that age. We are currently collecting longitudinal data and future analysis will attempt to disentangle the roles of age, puberty stage, and hormonal events of puberty in the development of reward processing.

Original Article

Science News » Gene Regulators Work Together for Oversized Impact on Schizophrenia Risk

Researchers have discovered that gene expression regulators work together to raise an individual’s risk of developing schizophrenia. Schizophrenia-like gene expression changes modeled in human neurons matched changes found in patients’ brains. The researchers, led by Kristen Brennand, of the Icahn School of Medicine at Mount Sinai, New York City, report on their findings in Nature Genetics. The work was funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health.

Genome-wide association studies have revealed at least 143 chromosomal sites associated with risk for schizophrenia. However, individually, each of these sites can explain only a small fraction of the risk. Even when the effects of disease-linked rare genetic variants are factored in, most of schizophrenia’s known high inheritance remains unexplained. One possible clue: more than 40% of the suspect chromosomal sites contain regulators, called expression quantitative trait loci, or eQTLs, that govern the expression of multiple genes.

“Individually, these gene regulators have a modest effect on the brain. Working in concert, they exert different and more significant effects on the brain—effects that boost schizophrenia risk,” explained David Panchision, chief of the Developmental Neurobiology Program at NIMH. “Learning more about the downstream cellular and molecular effects of such synergy holds hope for advances in precision psychiatry and more personalized medicine.”

To explore the role of these regulators, Brennand and colleagues studied them in induced neurons using a molecular modeling technology. This induced pluripotent stem cell method makes it possible to grow a person’s unique neurons in a petri dish using stem cells derived from their skin cells. The researchers used the model to take a closer look at the downstream molecular consequences of gene expression changes known to occur in schizophrenia, and compared them with changes seen in postmortem brains and similarly modeled neurons of people with the illness.

The researchers experimentally mimicked the interaction of multiple risk genes thought to contribute to schizophrenia. They used the gene editing tool CRISPR to simultaneously increase or decrease expression of four schizophrenia-implicated genes known to harbor eQTLs. The genes were selected because they were deemed most likely to confer disease risk by regulating gene expression. To trigger changes in the direction predicted to heighten risk for schizophrenia, expression was increased for three of the genes and decreased for one.

Manipulating expression of the four genes altered expression of 1,261 other genes – 665 increased and 596 decreased. This was many more than would be expected if the genes had been merely acting individually, suggesting an underlying mechanism that is synergistic rather than additive.

“This unexpected synergy between gene variants demonstrated how even subtle genetic variations can impact neuronal function,” said Brennand. “These interactions emphasize the importance of considering the complex nature of schizophrenia and other psychiatric disorders, where a combination of gene variants contributes to disease.”

Many of the genes affected downstream contained variants that had been linked to autism spectrum disorder or bipolar disorder, in addition to schizophrenia – consistent with other research suggesting genetic overlap across mental disorders.

The experimentally induced gene expression changes mirrored those seen in postmortem brains of people with the three mental illnesses. The same changes were also seen in induced pluripotent stem cell neurons from people with childhood-onset schizophrenia, a rare form of the illness thought to be more genetic in origin.

“Notably, all of these gene changes resulted in loss-of-brain-function effects when screened one-at-a-time in a zebrafish model,” said Brennand. “We have added several of them to a list of genes worthy of further study for possible involvement in schizophrenia. There is an overwhelming need for future studies to similarly model such multi-gene interactions in complex cells and circuits.”

microscopic image of an induced human neuron

Induced human neuron. Source: Seok-Man Ho, Icahn School of Medicine at Mount Sinai

Grants

MH101454, MH106056, MH109897

Reference

Schrode N, Ho S-M, Yamamuro K, Dobbyn A, Huckins L, Matos MR. Cheng E, Deans PJM, Flaherty E, Barretto N, Topol A, Alganem K, Abadali S, Gregory J, Hoelzli E, Phatnani H, Singh V, Girish D, Aronow B, Mccullumsmith R, Hoffman GE, Stahl EA, Morishita H, Sklar P, Brennand KJ. Synergistic effects of common schizophrenia risk variants. Nature Genetics, September 23, 2019. DOI: 10.1038/s41588-019-0497-5

For more information:
Mount Sinai video
Faculty Spotlight: Kristen Brennand, Ph.D.

About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

NIH…Turning Discovery Into Health®

Original Article

Science News » NIH Announces Funding Awards for National Early Psychosis Learning Community

The National Institutes of Health (NIH) awarded six research grants for studies to develop a learning health care system for the treatment of early psychosis. The awards are part of a broad research initiative called Early Psychosis Intervention Network (EPINET), which aims to develop models for the effective delivery of coordinated specialty care (CSC) services for early psychosis. The grants are administered by the National Institute of Mental Health (NIMH), part of NIH.

The word psychosis is used to describe conditions that affect the mind, where there has been some loss of contact with reality. About 100,000 youth and young adults in the United States experience a first episode of psychosis each year. Left untreated, psychotic symptoms can lead to disruptions in school and work, strained family relations, and separation from friends. The longer the symptoms go untreated, the greater the risk of additional problems.

CSC is a recovery-oriented treatment program for people with early psychosis (i.e., those in the early stages of a psychotic illness). It promotes shared decision making and uses a team of specialists who work with the client to create a personal treatment plan. Through these EPINET awards, NIMH aims to establish regional scientific hubs each connected to six or more community-based CSC programs that endorse measurement-based early psychosis treatment. A national data coordinating center will support and extend the work of the regional hubs by integrating data obtained from 58 CSC programs across nine states.

The groundwork for EPINET was laid by NIMH’s Recovery After an Initial Schizophrenia Episode (RAISE) initiative. RAISE demonstrated the superiority of team-based, multi-component CSC treatment compared to usual care for early psychosis and the feasibility of implementing CSC programs in U.S. community settings. Individuals in the RAISE studies who received CSC stayed in treatment longer and experienced greater improvement in their symptoms, interpersonal relationships, quality of life, and involvement in work and school compared with those who received typical care.

“The RAISE findings have been replicated by other studies, adding momentum to early intervention programs in America,” said Robert K. Heinssen, Ph.D., director of NIMH’s Division of Services and Intervention Research (DSIR). “EPINET represents the next chapter in a science-to-service story that started with RAISE but is moving toward learning health care that fosters recovery in early serious mental illness.”

Today, over 260 early psychosis specialty care programs have been established in 49 states. NIMH is seeking to build on states’ investments by supporting practice-based research that promotes high quality, continuously improving care across all CSC programs.

“As the number of early intervention programs expands, it is essential that we learn how to ensure those receiving these services get the best possible care,” said Joshua A. Gordon, M.D., Ph.D., director of NIMH. “Through EPINET, we hope to learn how best to deliver cutting edge care in real-world, community-based settings. This will help us rapidly translate scientific advances into the clinic."

NIMH has awarded over $40 million in funding for EPINET over five years. The grants that have been awarded include:

EPINET Regional Scientific Hubs

EPINET National Data Coordinating Center

Each regional hub will have one or more studies focused on reducing delays in accessing care, improving cognitive functioning, preventing suicide, increasing treatment adherence, and sustaining clinical gains over time. Each CSC program participating in EPINET will use standard clinical measures and uniform data collection and analysis methods to facilitate learning about the most effective ways to deliver early psychosis treatment. The EPINET National Data Coordinating Center will enable large-scale, practice-based research using data shared by the regional hubs to improve early identification, diagnosis, clinical assessment, intervention effectiveness, and health outcomes in clinics offering evidence-based care to persons in the early stages of psychotic illness.

Grants

MH120555-01; MH120594-01; MH115846-01A1S1; MH120597-01; MH120589-01; MH120591-01

About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

NIH…Turning Discovery Into Health®

Original Article

Concept Clearance » Behavioral Tasks Targeting Brain Subsystems Relevant to Anhedonia

Behavioral Tasks Targeting Brain Subsystems Relevant to Anhedonia

NAMHC Concept Clearance •

Presenter:

Andrew F. Rossi, Ph.D.
Division of Neuroscience and Basic Behavioral Science

Goal:

This initiative seeks to develop task-based behavioral measures, which will be validated with neuroimaging and then used as behavioral readouts serving as a proxy for engagement of brain subsystems relevant to anhedonia. The goal is to use these newly developed behavioral tasks as quantitative tools to advance treatment development. Studies may include healthy volunteers and clinical populations. Projects that focus on early development and adolescence are strongly encouraged. Research projects should aim to: 1) propose behavioral tasks that target brain subsystem(s) relevant to anhedonia assessed with neuroimaging and/or other brain activity recording techniques; 2) demonstrate that chosen task(s) engage the targeted brain subsystem through neuroimaging or other brain measure; and 3) show active modification of the targeted brain system through behavioral training or other means (e.g., noninvasive neuromodulation). This initiative strongly encourages development of novel behavioral tasks that go beyond the Research Domain Criteria (RDoC) positive valence domain (e.g., reward valuation, reward sensitivity and reward learning) and those that target novel candidate subconstructs. Candidate behavioral tasks should be quantifiable and reliable (test-retest). The extent of correlation with existing clinical measures (e.g., Snaith–Hamilton Pleasure Scale, DARS) for the domain of anhedonia being targeted should be addressed unless there are no established clinical measures for the investigated construct. Importantly, behavioral tasks and targeted brain system measures should be robust and have sensitivity to detect change due to treatment interventions (although treatment trials are beyond the scope of this concept). Candidate behavioral tasks are expected to tap into altered functional domains relevant to anhedonia that can be reliably identified at neurobiological levels and serve as a more precise way of defining clinical features of anhedonia for use in both diagnosis and treatment development.

Rationale:

Anhedonia is associated with a wide range of disorders and its clinical presentation varies greatly. Research over the last two decades suggests that anhedonia is not a unitary symptom, but rather the result of a failure of one or several brain subsystems underlying reward, motivation, and hedonic processing. This is a timely opportunity for NIMH to support research to develop behavioral tasks targeting functional subconstructs of anhedonia that can be validated with imaging and/or other neural measures, thus serving as quantitative tools to assess treatment efficacy. This initiative will complement prior NIMH initiatives that have focused on:

  • Dimensional and computational approaches to understanding mental illness (RDoC);
  • Targeting impaired cognition as a potential therapeutic target for schizophrenia (CNTRICS);
  • Computationally defined behaviors;
  • The NIMH FAST-MAS trial that used behavior- and brain-based measures for demonstrating engagement of neural circuitry related to the hedonic response in anhedonia patients.

Thus, the proposed concept will build on the aforementioned investments while addressing a gap in NIMH portfolio by encouraging studies that aim to develop a battery of neural imaging-validated behavioral tasks for use as quantitative measures (or tools) to advance treatment development.

Original Article