Adolescence is a peak time for the emergence of the core symptoms of psychopathology. Cognitive disorganization (CD) is a key symptom dimension of psychosis that emerges most commonly in adolescence, reflects a disorganization of thought and is defined by the presence of bizarre behavior, alogia, and impaired attention. CD transcends DSM diagnostic categories, predicts the onset and severity of psychotic disorders, and is associated with neuropsychological impairment. Genetic studies have reported that CD is highly heritable, and therefore has been proposed as a promising phenotype for molecular genetic studies. Despite its critical role in heralding risk for psychosis, little is knon about the neurobiological underpinnings of CD in adolescents. It has been reported however that adolescents experiencing disorganization have significant deficits in working memory capacity (WMC) and arousal/stress regulation (ASR). These two behavioral constructs show dramatic maturational changes during adolescence, which are necessary for the transition to higher-level cognition, affect regulation and psychosocial adaptation. Despite the strong epidemiologic evidence for the role of stress in the etiology of psychosis, and the centrality of working memory impairments in psychosis, little is known about their contribution to CD in adolescence. Examining the neural and physiological systems associated with working memory and stress regulation in adolescence, and their contribution to CD severity, offers a critical step in elucidating the pathophysiological mechanisms that contribute to the onset of psychosis. This approach is consistent with the RDoC framework, which encourages using converging measurements to study the underlying neurobiology of domains (Cognitive System and Arousal Regulation in this proposal), and constructs (working memory capacity and stress regulation) that represent fundamental behaviors expressed by individuals with clinical risk symptoms for psychosis. We will use a multimodal approach integrating functional neuroimaging, electrophysiological, and behavioral measures to ascertain converging measures of working memory and arousal/stress regulation constructs across neural, physiological, and behavioral units, and to characterize the contributions of atypical ASR and impaired WMC in the severity of CD symptoms measured through clinical scales.
In Aim 1, we will evaluate the contributions of working memory impairments and atypical arousal/stress regulation in 180 adolescents (ages 9-16) to the severity of CD symptom.
In AIM 2 we will model the relationship between WM and ASR constructs and their impact on CD severity.
In AIM 3, we will examine the longitudinal trajectory of CD symptom severity, behavioral and electrophysiological measures of WM and ASR, and their associations with baseline neural, behavioral, and physiological measures acquired in AIMs 1 and 2. For each aim, we will explore the modulatory role of sex differences and pubertal maturation on stress-regulation and working memory during adolescence, and their influence in determining functional outcomes. IMPACT: Understanding the neural and physiological systems associated with working memory capacity and stress regulation in adolescence, and their contribution to CD severity, is a crucial step for elucidating the core pathophysiological mechanisms that promote the emergence and exacerbation of psychosis.

Public Health Relevance

Adolescence is a critical period for brain maturation and the emergence of cognitive disorganization symptoms that precede many psychotic disorders. While the neurobiological mechanisms that cause cognitive disorganization in adolescence are unknown, abnormal stress regulation and cognitive deficits often accompany these manifestations. In this project we will examine the biological mechanisms that are known to underlie aberrant stress regulation and working memory impairments, and identify their association with severity of cognitive disorganization in adolescents. We will study adolescents of 9-16 years of age with varying severity of cognitive disorganization, and examine the contributions of neural, physiological and behavioral deficits in stress regulation and working memory capacity domains. This project will help us identify biological measures associated with severity of a key symptom dimension that preceded and predicts psychosis onset, and hence may ultimately pave the way for the development of better treatments for vulnerable young people with cognitive disorganization.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Friedman-Hill, Stacia
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Andersen, Elizabeth H; Lewis, Gregory F; Belger, Aysenil (2018) Aberrant parasympathetic reactivity to acute psychosocial stress in male patients with schizophrenia spectrum disorders. Psychiatry Res 265:39-47