David Kimhy, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): In this revised application for a Mentored Patient-Oriented Research Career Development Award (K23), Dr. David Kimhy will pursue training and research in the cognitive and neurobiological mechanisms of stress regulation and psychosis in schizophrenia. The goals of the training and research plan are integrated around the hypothesis that cognitive coping strategies mediate the link between stress and psychotic symptoms during recovery from psychosis in schizophrenia. Under the sponsorship of Dr. Dolores Malaspina, the training plan capitalizes on the resources of NYSPI/Columbia University, combining formal coursework, direct supervision, and clinical research experience and training. The plan involves mentorship and didactic instruction in key areas including: 1) psychosis research in schizophrenia using of Experience Sampling Method (ESM), 2) clinical methodologies for assessment of stress-regulating systems, 3) data analysis using multilevel linear modeling, and 4) cognitive-behavior therapy for psychosis (CBTp). Current methodologies have limited ecological validity to establish causal links between momentary changes in stress and psychosis. Dr. Kimhy will study simultaneously the real-time physiological and psychological correlates of psychosis using ambulatory assessment of cardiac autonomic regulation (Heart Rate Variability; HRV) synchronized with data collected using Experience Sampling Method (ESM) with Palm handheld computers. The research plan involves simultaneous probing of momentary psychotic symptoms, subjective stress, HRV, and cognitive coping strategies. Assessments will be conducted before and after pharmacological and CBTp treatments of psychosis. This methodology translates basic science into use in real-time, real-world environments (in-vivo and in-situ), allowing for the assessment of psychosis as part of the ebb-and-flow of daily functioning. Understanding these interactions will advance our understanding of the mechanisms of recovery from psychosis in schizophrenia. The proposed training and research plan will provide Dr. Kimhy with the knowledge, training, and experience necessary to develop as an independent researcher focusing on the neurobiological and psychological mechanisms of stress regulation and psychosis in schizophrenia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Schizophrenia has a population incidence of 1%, but it is the 9th leading cause of disability worldwide. Individuals with schizophrenia display a broad range of cognitive deficits that have been identified as major determinants of poor daily functioning and disability, thus representing a serious public health concern. Current pharmacological and cognitive remediation treatments offer limited to modest efficacy in improving these deficits. However, data from animal and human research strongly support the positive influence of Aerobic Exercise (AE) on cognitive functioning. As individuals with schizophrenia typically display cognitive deficits along with a highly sedentary lifestyle, and preliminary evidence suggest that AE training is both feasible and effective in increasing aerobic fitness in this population, it is reasonable to hypothesize that AE may also improve cognitive functioning. However, this association has hardly been investigated in schizophrenia. To elucidate this putative link, we propose to evaluate the influence of AE on cognitive functioning in schizophrenia using a single-blind, randomized clinical trial. Outpatient individuals with schizophrenia (n=48) receiving treatment at a large academic medical center in New York City will be randomly assigned to Aerobic Exercise (AE) training or Treatment As Usual (TAU). Participants in the AE training will undergo a 12-week, 3 times per week, 1-hour AE sessions at the medical center. All patients will receive appropriate pharmacological and counseling treatment. Assessments of neurocognitive and daily functioning abilities, along with symptom severity, and physiological and behavioral measures of aerobic fitness will be completed before and after the 12-week program by raters blind to treatment status. This study will allow determining the putative positive influence of AE on cognitive and daily functioning in individuals with schizophrenia. PUBLIC HEALTH RELEVANCE: Individuals with schizophrenia suffer from cognitive impairments that have been identified as major determinants of poor functioning and disability. Aerobic Exercises (AE) have been shown to improve cognition in healthy individuals, but their influence in schizophrenia have not been studied. Elucidating the link between AE and cognition in schizophrenia may lead to development of novel behavioral treatments targeting cognitive deficits in schizophrenia.

Project Summary DESCRIPTION (provided by applicant): The goal of the proposed study is to examine the impact of aerobic exercise (AE) training on cognitive functioning in people with schizophrenia (SZ). People with SZ display a broad range of cognitive impairments that have been identified as major determinants of poor functional outcome and disability, thus representing an important public health concern and a target for interventions. At present, available treatments offer only minimal to limited benefits to ameliorate these deficits. Extensive animal and human research literatures converge in supporting the positive influence of AE training on cognitive functioning. Preliminary data indicate that AE training is effective in improving cognitive functioning in people with SZ. However, previous studies employed small samples, making it difficult to ascertain the potential impact of relevant biological variables. Additional limitations include focus on a single or limited range of cognitive domains and insufficient information on daily functioning or putative biomarkers underlying cognitive change. Finally, previous studies tended to view AE as a uniform intervention, with limited attention given to intervention characteristics, an issue critical to reproducibility. Thus, we lack fully powered studies to provide information to inform decisions regarding the effectiveness of AE training to ameliorate cognitive deficits in SZ. Altogether, these limitations hinder our ability to make informed decisions regarding the efficacy of AE to address cognitive deficits in people with SZ. To tackle this very specific need, the proposed research focuses on three major aims - AIM 1: confirm the efficacy of AE training to improve cognition in people with SZ; AIM 2: examine the impact of AE on daily functioning; and AIM 3: examine brain-derived neurotrophic factor (BDNF) as an AE-related biomarker of cognitive-change. Employing a single-blind, randomized clinical trial design, we will randomly assign 200 individuals with SZ from 4 U.S. sites to one of two 12-week, 3x-week, 1-hour treatment programs: 1) AE or 2) A stretching and toning (ST) control condition. All participants will undergo assessments of aerobic fitness, cognition, daily functioning, BDNF, and other putative biomarkers of cognitive change before the training and after 6- and 12-weeks of interventions.

Project Summary DESCRIPTION (provided by applicant): The goal of the proposed study is to examine the impact of aerobic exercise (AE) training on cognitive functioning in people with schizophrenia (SZ). People with SZ display a broad range of cognitive impairments that have been identified as major determinants of poor functional outcome and disability, thus representing an important public health concern and a target for interventions. At present, available treatments offer only minimal to limited benefits to ameliorate these deficits. Extensive animal and human research literatures converge in supporting the positive influence of AE training on cognitive functioning. Preliminary data indicate that AE training is effective in improving cognitive functioning in people with SZ. However, previous studies employed small samples, making it difficult to ascertain the potential impact of relevant biological variables. Additional limitations include focus on a single or limited range of cognitive domains and insufficient information on daily functioning or putative biomarkers underlying cognitive change. Finally, previous studies tended to view AE as a uniform intervention, with limited attention given to intervention characteristics, an issue critical to reproducibility. Thus, we lack fully powered studies to provide information to inform decisions regarding the effectiveness of AE training to ameliorate cognitive deficits in SZ. Altogether, these limitations hinder our ability to make informed decisions regarding the efficacy of AE to address cognitive deficits in people with SZ. To tackle this very specific need, the proposed research focuses on three major aims - AIM 1: confirm the efficacy of AE training to improve cognition in people with SZ; AIM 2: examine the impact of AE on daily functioning; and AIM 3: examine brain-derived neurotrophic factor (BDNF) as an AE-related biomarker of cognitive-change. Employing a single-blind, randomized clinical trial design, we will randomly assign 200 individuals with SZ from 4 U.S. sites to one of two 12-week, 3x-week, 1-hour treatment programs: 1) AE or 2) A stretching and toning (ST) control condition. All participants will undergo assessments of aerobic fitness, cognition, daily functioning, BDNF, and other putative biomarkers of cognitive change before the training and after 6- and 12-weeks of interventions.

Project Summary: The goal of this study is to investigate the impact of sleep on neurocognitive and daily functioning in people with schizophrenia (SZ). Individuals with SZ display a broad range of neurocognitive impairments that have been identified as major determinants of poor functioning and disability, thus representing an important public health concern and a focal target for interventions. Extensive animal, preclinical and clinical research literatures converge in highlighting the critical role insomnia and sleep disturbances play in degrading neurocognitive functioning. Such sleep disturbances, which have been linked to reduced slow wave sleep oscillations and thalamo- cortical sleep spindles, result in clinical presentations that are in line with the neurocognitive difficulties commonly observed in people with SZ. Consistent with these findings, insomnia and sleep disturbances are highly prevalent in people with SZ. However, despite their chronic and ubiquitous nature, there are scant data on the impact sleep disturbances on neurocognition in SZ and there are no data quantifying their influence on daily functioning. Thus, sleep disturbances remain poorly understood and modeled in SZ, their impact is rarely considered in clinical trials, and they remain largely unaddressed by clinicians. To address this gap in the literature, the primary aim of this study is to characterize sleep in individuals with SZ and quantify its impact on neurocognition and daily functioning. Employing an experimental, within-person, repeated assessment design, we will characterize sleep architecture, duration, and quality along with cognitive, electrophysiological, biomarkers and daily functioning sequalae in 40 individuals with SZ. Participants will first complete a week-long, in-home characterization of sleep duration and quality using actigraphy and a sleep diary. Next, they will complete two overnight polysomnography examinations employing two sleep schedules: 1) undisturbed sleep; and 2) restricted sleep (4 hours). As part of these assessments, participants will provide blood samples for biomarkers analyses and complete EEG-indexed memory tasks pre- and post-sleep, along with a post-sleep battery of neurocognitive functioning. Finally, participants will complete a 36- hour ambulatory assessment using actigraphy and smartphones employing Experience Sampling Method (ESM) to explore the impact of sleep on ?real-world? daily functioning including symptoms, emotion regulation, and mood. PublicHealth Relevance Statement:This study will provide experimental characterization of the links between sleep neurocognition and functioning in individuals with SZ, informing the development of treatments of neurocognitive deficits in SZ.