Aysenil Belger

Despite the range of symptoms, one clinical dimension that is core to psychotic disorders and transcends diagnostic categories (Allardyce, McCreadie et al. 2007; Allardyce, Suppes et al. 2007) is cognitive disorganization (CD). CD is defined as disorganized and incoherent patterns of thought and behavior. Factor analyses (Bell, Low et al. 1994; Emsley, Niehaus et al. 2001; Rijsdijk, Gottesman et al. 2011; Demjaha, Valmaggia et al. 2012; Potuzak, Ravichandran et al. 2012; Russo, Levine et al. 2014; Stefanovics, Krystal et al. 2014) identify it as a key psychopathological dimension of psychosis. CD is highly hereditary (Cardno, Rijsdijk et al. 2008; Rijsdijk, Viding et al. 2010), present in at risk relatives (Cardno, Rijsdijk et al. 2008; Rijsdijk, Gottesman et al. 2011), and predicts onset of psychosis in at-risk individuals (Demjaha, Valmaggia et al. 2012) better than other dimensions, and therefore is a promising phenotype for genetic studies. As such, variations in CD are clinically highly relevant, yet little is known about the neurobiological underpinnings of CD symptom dimension. Because CD is often accompanied by a decline in domains of cognition and arousal regulation, we posit that the biological mechanisms associated with impaired working memory capacity (WMC) and atypical arousal/stress-regulation (ASR) may play a critical role in the emergence and severity of CD in adolescence. Despite compelling epidemiologic evidence that stress plays a significant role in the development or aggravation of psychotic symptoms (van Os, Krabbendam et al. 2005; van Os, Kenis et al. 2010), the contribution of atypical stress regulation to the severity of CD in adolescence re-mains unknown. We propose that the biological mechanisms underlying impaired WMC and atypical stress regulation lead to sustained increases in cortisol. This in turn disrupts function in frontal and limbic regions necessary for stress regulation and working memory (WM), contributing to the severity of CD. Here we propose to systematically evaluate the relationship between neural, physiological and behavioral measures of WMC and ASR, and examine their contribution to CD severity in adolescents. This project fills a critical gap in our knowledge of the biological underpinnings of cognitive disorganization and its role in the onset of psychosis. We are therefore requesting funds to use novel sophisticated methodology to characterize stress regulation in adolescents at risk.

CD is defined as disorganized and incoherent patterns of thought and behavior. Factor analyses (Bell, Low et al. 1994; Emsley, Niehaus et al. 2001; Rijsdijk, Gottesman et al. 2011; Demjaha, Valmaggia et al. 2012; Potuzak, Ravichandran et al. 2012; Russo, Levine et al. 2014; Stefanovics, Krystal et al. 2014) identify it as a key psychopathological dimension of psychosis. CD is highly hereditary (Cardno, Rijsdijk et al. 2008; Rijsdijk, Viding et al. 2010), present in at risk relatives (Cardno, Rijsdijk et al. 2008; Rijsdijk, Gottesman et al. 2011), and predicts onset of psychosis in at-risk individuals (Demjaha, Valmaggia et al. 2012) better than other dimensions, and therefore is a promising phenotype for genetic studies. As such, variations in CD are clinically highly relevant, yet little is known about the neurobiological underpinnings of CD symptom dimension. Because CD is often accompanied by a decline in domains of cognition and arousal regulation, we posit that the biological mechanisms associated with impaired working memory capacity (WMC) and atypical arousal/stress-regulation (ASR) may play a critical role in the emergence and severity of CD in adolescence. Despite compelling epidemiologic evidence that stress plays a significant role in the development or aggravation of psychotic symptoms (van Os, Krabbendam et al. 2005; van Os, Kenis et al. 2010), the contribution of atypical stress regulation to the severity of CD in adolescence re-mains unknown. We propose that the biological mechanisms underlying impaired WMC and atypical stress regulation lead to sustained increases in cortisol. This in turn disrupts function in frontal and limbic regions necessary for stress regulation and working memory (WM), contributing to the severity of CD. Here we propose to systematically evaluate the relationship between neural, physiological and behavioral measures of WMC and ASR, and examine their contribution to CD severity in adolescents. This project fills a critical gap in our knowledge of the biological underpinnings of cognitive disorganization and its role in the onset of psychosis. We are therefore requesting funds to use novel sophisticated methodology to characterize stress regulation in adolescents at risk.

Dear Kevin and Maria, Thank you both your comments and support. I would like to specifically address Maria's thoughtful comment. As you know, the current gold standard for diagnosing psychiatric disorders is the identification of specific clinical symptoms for specific durations, many of which are ascertained through clinical interviews and rely on subjective assessments based on clinician observations and patient self-reports. There are no biological measures, no identified pathophysiological mechanisms, and therefore no targeted cures. Our lab, as many others around the country at outstanding Instotutions, is committed to identifying objective biological markers associated with the currently recognized and widely accepted subjective clinical indices of pathology. In this project we focus on identifying the objective neurobiological measures that can represent markers of increased risk or vulnerability in adolescents at risk for psychosis. Please allow me to explain why we focus on adolescence, on cognitive disorganization, and finally on stress regulation. First, adolescence is a time of remarkable physical and behavioral changes, including steep cortical maturation in frontal and limbic circuitry necessary for adaptation to higher order cognitive and emotional processes, as well as the emergence of many psychotic disorders. Inability to adapt to cognitive and affective challenges, a decline in function and psychosocial adaptation, and an increase in stress vulnerability represent shared characteristics of adolescents with clinical or familial high risk for psychotic disorders, and they predict future psychosis. Examination of specific dimensions of psychosis during adolescence has potential to inform our understanding of the emergence of psychosis. Despite the range of symptoms, one clinical dimension that is core to psychotic disorders and transcends diagnostic categories (Allardyce, McCreadie et al. 2007; Allardyce, Suppes et al. 2007) is cognitive disorganization (CD).

Thank you Kevin, we appreciate your support. I will upload a project update shortly.