Sohee Park, Ph.D. - US grants

DESCRIPTION (Adapted from applicant's abstract): The major goal of this project is to analyze the neurocognitive components of working memory deficits in schizophrenia. The three proposed studies are designed to specify parameters of the prefrontal working memory systems and to characterize their possible links to the expression of the symptoms of schizophrenia. The investigator's global hypothesis is that an inability to regulate behavior by prefrontal working memory systems may demarcate cardinal features of schizophrenia. Growing evidence supports this view but the role of working memory in clinical symptoms is unclear, because of the functional heterogeneity of the frontal lobes, multiplicIty of the working memory systems and diffuse definitions of symptoms. The roles of the dorsolateral prefrontal and ventral/orbitofrontal systems in schizophrenia will be probed, using a series of specific experiments designed to assess dissociation and integration of the multiple working memory systems. Spatial working memory is mediated by a neural circuitry including the dorsolateral prefrontal cortex, whereas visual (nonspatial) and olfactory working memory systems are associated with the integrity of the ventral/orbitofrontal system. There are 3 studies, consisting of 3 experiments each. Study 1 is focused on examining spatial, visual (nonspatial) and olfactory working memory systems separately in schizophrenia patients in order to determine which systems are consistently impaired independent of fluctuating symptoms versus which systems are linked to the symptoms. Young siblings of schizophrenia patients will be tested to see if they show similar patterns of deficit. Study 2 is concerned with determining how these anatomically and psychologically separable working memory systems are dissociated, coordinated or inhibited to guide action by a control mechanism (the "central executive"). In Study 3, the integrity of the connections between orbitofrontal and dorsolateral prefrontal systems will be examined by inspecting the roles of affect, arousal and reward on working memory. Ultimately, all the components of working memory and subdivisions of frontal systems must be integrated in an organism with intact personality and self-regulating behaviors. The key to understanding cognitive deficits and symptoms of schizophrenia may be found in the patterns of dissociation and integration of these multiple systems, in response to specific task demands. In summary, this project will enable the investigator to further identity and elucidate neurocognitive components of schizophrenia and thus contribute towards our understanding of the complex interplay between cortical functions, cognitive deficits and clinical syndromes in men and women with schizophrenia.

DESCRIPTION (Adapted from applicant's abstract): The major goal of this project is to analyze the neurocognitive components of working memory deficits in schizophrenia. The three proposed studies are designed to specify parameters of the prefrontal working memory systems and to characterize their possible links to the expression of the symptoms of schizophrenia. The investigator's global hypothesis is that an inability to regulate behavior by prefrontal working memory systems may demarcate cardinal features of schizophrenia. Growing evidence supports this view but the role of working memory in clinical symptoms is unclear, because of the functional heterogeneity of the frontal lobes, multiplicIty of the working memory systems and diffuse definitions of symptoms. The roles of the dorsolateral prefrontal and ventral/orbitofrontal systems in schizophrenia will be probed, using a series of specific experiments designed to assess dissociation and integration of the multiple working memory systems. Spatial working memory is mediated by a neural circuitry including the dorsolateral prefrontal cortex, whereas visual (nonspatial) and olfactory working memory systems are associated with the integrity of the ventral/orbitofrontal system. There are 3 studies, consisting of 3 experiments each. Study 1 is focused on examining spatial, visual (nonspatial) and olfactory working memory systems separately in schizophrenia patients in order to determine which systems are consistently impaired independent of fluctuating symptoms versus which systems are linked to the symptoms. Young siblings of schizophrenia patients will be tested to see if they show similar patterns of deficit. Study 2 is concerned with determining how these anatomically and psychologically separable working memory systems are dissociated, coordinated or inhibited to guide action by a control mechanism (the "central executive"). In Study 3, the integrity of the connections between orbitofrontal and dorsolateral prefrontal systems will be examined by inspecting the roles of affect, arousal and reward on working memory. Ultimately, all the components of working memory and subdivisions of frontal systems must be integrated in an organism with intact personality and self-regulating behaviors. The key to understanding cognitive deficits and symptoms of schizophrenia may be found in the patterns of dissociation and integration of these multiple systems, in response to specific task demands. In summary, this project will enable the investigator to further identity and elucidate neurocognitive components of schizophrenia and thus contribute towards our understanding of the complex interplay between cortical functions, cognitive deficits and clinical syndromes in men and women with schizophrenia.

DESCRIPTION (provided by applicant): Cannabis sativa is the most widely used illicit drug in the United States with about 7 million people using it at least once a week. Although the acute effects of cannabis on neuropsychological functions seem reversible, long-term neurocognitive effects and potential psychiatric consequences are not yet fully understood. However, it is important to specify the potential long-term effects of cannabis for several reasons: (1) Cannabis might be used as a treatment for certain conditions in the future, so it is important to determine whether or not cannabis produces long-lasting neurotoxicity; (2) Cannabis use among young people may result in long-term permanent neuropsychological consequnces including cognitive deficits and increased risk of schizophrenia. The present proposal seeks support to examine neurocognitive and psychiatric consequences of cannabis use in young adults. Attention, inhibitory control, and social cognition will be investigated in current and past cannabis users and nonusers at the beginning of the first year of college. They will be monitored regulary during the first year to track changes in behavior in relation to cannabis. In addition, schizotypal personality will be examined in young cannibus users. Cannabis use is implicated in increased risk for schizophrenia and schizotypal personality but it is unclear whether pre-existing liability for psychosis may be a major factor. We will assess schizotypal traits and cannabis use in first year college students and re-examine them a year later to test whether cannabis use increases psychosis-proneness or whether pre-existing schizotypal personality increases the probability of using cannabis. In sum, this project will enable us to further identify and elucidate the potential neurocognitive and psychiatric consquences of cannabis use in young, healthy people and pinpoint possible neural circuits that may be affected by cannabis. The outcome of this project will enable us to design and conduct focused functional and structural neuroimaging studies of adolescent and young adult cannabis users in the future in order to understand how cannabis use may affect neural circuits in late adolescence and early adulthood and whether these potential changes are permanent. Thus the outcome of this proposal will directly form the basis for systematic neuroimaging investigations of the origins of cannabis neurotoxicity and cannabis potential role in psychosis.

DESCRIPTION (provided by applicant): Neurocognitive deficits are core features of schizophrenia (SZ) that may determine functional outcome. Working memory (WM) deficit has been identified as one of the most important components of the neurocognitive deficits in SZ. WM is a limited-capacity, active short-term memory system that guides and controls behavior. A majority of SZ patients and about half of their healthy first-degree relatives have WM deficits and these deficits are linked to poor social and adaptive functioning yet the origins and consequences of WM deficit are unclear. Thus it has not been possible to develop targeted interventions that might ameliorate WM deficits and improve adaptive functioning. The present proposal seeks support to investigate components of WM deficits in SZ from a cognitive neuroscience approach, to identify the factors are central to WM deficit, their neural correlates and the effects of WM deficit on social functioning. Cognitive and neuroanatomical data suggest that selective attention and affect modulate encoding and maintenance in WM but SZ patients are unable to effectively integrate attention and affect to guide goal-directed behavior. In Study 1, the roles of perceptual, attentional and affective factors in encoding will be examined to specify both optimal and detrimental encoding conditions with a series of cognitive experiments. Encoding affects all forms of memory and thus has far-reaching consequences. In addition to impaired encoding there is good evidence for abnormal maintenance in SZ. In Study 2, the effects of attentional control and affect on maintenance will be examined to identify where vulnerabilities of SZ lie. In Study 3, the roles of prefrontal and parietal cortices in normal and abnormal WM will be investigated with even-related fMRI experiments. The neural correlates of correct and incorrect performance will be observed to elucidate the difference between remembering and forgetting in the brain. In sum, the current proposal aims to identify the key components of WM deficits in SZ subjects, and their unaffected siblings. Identification and elucidation of core neurocognitive deficits of SZ will contribute towards the understanding of the complex interplay between cortical functions and cognitive deficits in SZ. Moreover, specifying abnormal mechanisms within WM in relation to attention, affect and brain activation patterns could lead to targeted strategies that might ameliorate WM deficits and improve adaptive functioning in SZ.

? DESCRIPTION (provided by applicant): Social impairments are core features of schizophrenia that lead to poor outcome. Social skills and competence improve quality of life and protect against stress-related exacerbation of symptoms, while supporting resilience, interpersonal interactions, and social affiliation. To improve outcome, we must remediate social deficits. Existing psychosocial interventions are moderately effective but the effort-intensive nature (high burden), low adherence, and weak transfer of skills to everyday life present significant hurdles toward recovery. Thus, there is a dire need to develop effective, engaging and low-burden social interventions for people with schizophrenia that will result in better compliance rates and functional outcome. We will test the effectiveness of a novel adaptive virtual reality (VR) intervention in improving targeted social cognitive function (social attention as indexed by eye scanning patterns) in individuals with schizophrenia. VR technology offers a flexible alternative to conventional therapies, with several advantages, including a simplified and low-stress social interaction environment with targeted opportunities to simulate, exercise and reinforce basic elements of social skills in a very wide range of realistic scenarios, and to repea exposure to naturalistic situations from multiple angles. Our desktop VR `game' is designed as an `intelligent' system that adaptively adjusts the difficulty of social training tasks based on participant's physiological, eye tracking and performance data in real time. Such dynamic feedback-based, `closed-loop' VR supports and enhances training because it adjusts and personalizes the learning environment in real time for each participant so that he/she always learns at an optimal arousal and attentional state. Furthermore, the VR environment can potentially simulate any social scenarios, which allows the participants to exercise social skills n a wide variety of situations. Such simulation exercises can help generalize learned skills to everyday life. The R21 phase will aim to implement the social intervention VR task, test its efficacy on improving social attention (target) in schizophrenia, and determine an optimal `dose'. We hypothesize that the VR training will engage social attention and improving social attention will lead to better social outcome. The R33 phase will test the adaptive social VR game against an active control condition in a pilot randomized controlled trial to evaluate the relative efficac of the social VR on enhancing social attention and associated neural circuitry. We will also examine social outcome. If this initial work is successful, our long-term goals are to develop VR social skills training modules that are personalized, accessible, and portable so that social remediation can become an integral part of one's daily life.

PROJECT SUMMARY Schizophrenia is a severe and debilitating disorder that affects about 51 billion people worldwide, and costs more than $60 billion annually in United States (Salomon and al., 2013). Despite the more spectacular psychotic symptoms of schizophrenia (e.g., hallucinations), it is the cognitive impairments that largely drive the poor outcomes from the illness, such as preventing patients from keeping jobs, due to the inability of medications to effectively treat these cognitive impairments (Gold and Weinberger, 1995; Green, 1996; Elvevag and Goldberg, 2000). Failures of adaptive control are a hallmark of the cognitive impairments in schizophrenia. Adaptive control allows healthy individuals to follow rules and to override compelling competing responses. Impairments of adaptive control result in errors and an inability to change following negative feedback. In systems neuroscience, a growing body of evidence demonstrates that adaptive control processes are supported by oscillatory activity in the healthy brain (Luu et al., 2003; Wang et al., 2005; Cavanagh et al., 2009; van Driel et al., 2012; Anguera et al., 2013; Narayanan et al., 2013; Cavanagh and Frank, 2014), and that certain patterns of oscillatory dynamics might be useful for understanding the cognitive impairments in schizophrenia (Ford and Mathalon, 2008; Uhlhaas and Singer, 2010; Lesh et al., 2011). In this project, we propose to use a causal neuroscientific technique, noninvasive electrical brain stimulation, combined with measurements of electroencephalographic oscillations to determine whether modifying certain oscillatory rhythms in patients with schizophrenia can improve cognitive abilities. Our preliminary data are highly encouraging and indicate that we can selectively manipulate the phase of oscillatory activity and cause improvements in the adaptive control exhibited by patients with schizophrenia. The goals of our research are to use the tools and insights from basic neuroscience to gain a deeper understanding the cognitive impairments in schizophrenia, and achieve concrete translational progress toward a non-pharmacological therapy for boosting cognitive function in schizophrenia.  1