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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Transcript

>> 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

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

Franchesca Kuhney, Ph.D., Winner of the 2018 NIMH Three-Minute Talks Competition

 

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Transcript

>> FRANCESCA KUHNEY:

Today, I'm going to talk to you about how genes impact brain development, and one approach that we can take to understanding this is a very rare genetic disorder called Williams Syndrome. Williams Syndrome allows us to study genetic influence on the brain in a very special way because it's clearly defined and very specific genetic and clinical profiles. Williams Syndrome is caused by a hemi deletion of approximately 25 genes on chromosome seven and results in a very specific pattern of hyper sociability, non-social anxiety, and cognitive deficits. So, by setting this very specific genetic deletion in its resulting impact on brain development we can better understand how genes work through the brain to result in complex behaviors.

The amygdala highlighted in red and the hippocampus highlighted in green are involved in emotion regulation and cognition respectively. Adults with Williams Syndrome have shown altered activation patterns, metabolism, and shape in these structures compared to healthy adults. And while it's known that the genetic features of Williams Syndrome impact brain development, the details of this process have not been studied in children over time. So, I wanted to know how the relative volume of the hippocampus and amygdala differ in children's Williams Syndrome compared to typically developing children across adolescence.

Each line on this plot represents a child that participated in our longitudinal study. In each dot on that line represents one of their two-year visits at which structural MRI scans were collected. These scans were longitudinally processed, and the hippocampus and amygdala were segmented to estimate their volume. These volumes were then normalized and applied to growth curve models which estimate nonlinear longitudinal trajectories. These graphs represent growth curve models of volume of the hippocampus and amygdala with volume on the y axis and age on the x axis. These are absolute volumes, and we can see that children with Williams syndrome have a smaller amygdala and hippocampus compared to typically developing children over time.

However, people with Williams Syndrome have a smaller total brain volume and it's important to consider these data in the context of this fact. So, now, I will show you these data normalized by total brain volume and we can see that children with Williams syndrome actually have a larger percentage of their brains dedicated to the hippocampus and amygdala compared to typically developing children over time. These data provide early indication of the structural differences seen in the hippocampus and amygdala and can be related to these social and cognitive phenotypes seen in Williams Syndrome adults. Future work will investigate the relationship between these findings and neuropsychological tests and anxiety scales because little is known about how the brain changes across childhood and adolescence and how genes influence this process. This longitudinal study of Williams syndrome begins to shed light on the complex neuro genetic mechanisms underlying adolescent brain development as a whole. Thank you.

Original Article

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

Elisa Dumett, Ph.D., Winner of the 2018 NIMH Three-Minute Talks Competition

 

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>> ELISA DUMETT TORRESS:

The study of hippocampal function is important for understanding the basic processes of memory encoding and how they are altered in psychiatric illness. A way that we can look more closely at the role of the hippocampus and memory is by using ephemera-based functional coupling of the hippocampus to the rest of the brain during encoding. This shows us the brain regions that are activated or deactivated in parallel to the hippocampus. It is also interesting to look at how brain function is influenced by environmental and genetic factors. Importantly, gene environment interactions helped to better model systems under some genetic control, like hippocampal function.

Therefore, I chose to look a hippocampal functional coupling through the lens of environmental factor of urbanicity and the genetic factor BDNF. Life in cities carries both positives, like better quality of life and decreased infant mortality rate, as well as negatives, like increased risk of cardiovascular or psychiatric illnesses. Urbanicity quantifies the extent of urban exposure during childhood based on the relative population size people are raised in. Brain-derived neurotropic factor, or BDNF is critical for hippocampal function. There is allelic variation in the BDNF gene that swaps a methionine for a valine. As seen here and these cultured hippocampal neurons, the Val BDNF genotype is trafficked well across the cell and into its dendrites, unlike the Met BDNF genotype.

People with even one copy of the Met allele display poor hippocampal mediated memory performance. I chose a visual memory encoding task known to activate the hippocampus to identify any urbanicity by the BDNF genotype interactions. Because of the difference in health outcomes for people from urban environments and the differences in synaptic and cellular function for the Met BDNF enough genotype, I predicted that urban Met BDNF genotype individuals might be distinct from other groups. I found two brain regions that displayed a significant interaction between urbanicity and BDNF genotype on right hippocampal functional coupling. The first region was the inferential parietal labial, known to be involved in episodic memory encoding. Urban Met carriers showed reduced hippocampal functional coupling opposite to that found in rural met carriers.

The second region we found to show a significant interaction was a lateral geniculate nucleus, a region of the thalamus involved in vision. The interaction in this region followed a different pattern, although, still highlighting a difference between urban and rural groups. Among urban reared subjects, Met carriers showed increased coupling, whereas no difference was found among rural-reared subjects. The fact that these two interactions followed different patterns reinforces the idea that the environmental factor of urbanicity can alter the coupling relationships across BDNF genotypes. Ultimately, this study provides a template for exploring the effects of gene environment interactions for general brain function and how this might be altered in psychiatric illness.

Original Article

Science News » NIH Announces Winners of High School Mental Health Essay Contest

The National Institutes of Health announces 10 winners of the “Speaking Up About Mental Health! This Is My Story” national essay challenge, which was designed to spur conversations among youth about mental health and encourage them to seek support for themselves and others.

“Only about half of young adults with a mental illness receive treatment,” said Joshua A. Gordon, M.D., Ph.D., director of the National Institute of Mental Health (NIMH). “We issued this essay contest to jump-start a conversation about the impact of mental illness among high school teens, barriers faced when seeking treatment, and innovative approaches to overcome those barriers.”

The NIMH and the National Institute on Minority Health and Health Disparities (NIMHD), both part of NIH, led the contest in collaboration with the Calvin J. Li Memorial Foundation. A panel of judges from NIMH and NIMHD and the award approving officials selected the winning essays based on their organization, creativity, clarity, and quality of writing. Selected from more than 160 entries from 38 states and Puerto Rico, the essay winners and those receiving honorable mention awards addressed the challenges of stigma, fear, and improving mental health education and treatment, particularly in vulnerable populations. NIH will award cash prizes to the contest winners and certificates to those receiving honorable mention.

Although the contest was open to all high school students nationwide, it started as part of the Healthy Mind Initiative, which aims to increase mental health awareness and promote suicide prevention in Asian American and Pacific Islander youth. The goal of the initiative is to reach a population that may view mental health care negatively, or may not consider it at all, due to stigma, lack of awareness and education, or differences in cultural conceptualization of mental health. The winning and honorable mention essays are available at https://www.nimhd.nih.gov/programs/edu-training/hmi/winners.html.

“I found the creative solutions from this diverse group of teens to help raise awareness of mental health challenges that many of our young people encounter to be a reason for optimism that we will reduce the burden of mental illness in the future,” said NIMHD Director Eliseo J. Pérez-Stable, M.D. “These essays can motivate all teenagers to address the gaps in mental health care that youth and young adults face, especially those from racial or ethnic minorities, disadvantaged communities, and sexual gender minorities.”

For anyone in crisis and in need of immediate help, the National Suicide Prevention Lifeline (NSPL) through https://suicidepreventionlifeline.org and 1-800-273-8255 is available. The deaf and hard of hearing can contact to the Lifeline via TTY at 1-800-799-4889. Your confidential and toll-free call goes to the nearest crisis center in the Lifeline national network, where trained crisis workers are available to talk 24 hours a day, seven days a week. These centers provide crisis counseling and mental health referrals. If the situation is potentially life-threatening, callers should dial 911 or go to a hospital emergency room immediately.

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 Institute on Minority Health and Health Disparities (NIMHD): NIMHD leads scientific research to improve minority health and eliminate health disparities by conducting and supporting research; planning, reviewing, coordinating, and evaluating all minority health and health disparities research at NIH; promoting and supporting the training of a diverse research workforce; translating and disseminating research information; and fostering collaborations and partnerships. For more information, visit the NIMHD 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 » 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