John G. Kerns - US grants

The purpose of this study is to determine if either active memory or inhibition is a causal neurocognitive mechanism of formal thought disorder (FTD). Even though FTD has been considered an important symptom of schizophrenia since the formation of the schizophrenia concept (Andreasen, 1979; Bleuler, 1911/1950; Kraepelin, 1919/1971), it has been often noted that progress in understanding the causes of FTD has been slow (Maher, 1991; Rochester and Martin, 1979). We propose that much of the previous theory and research of FTD has been consistent in implicating two potential causal mechanisms of FTD: active memory and inhibition. However, previous research has confounded their measurement. This project will separately measure and manipulate active memory and inhibition. Two parts of the project will provide converging evidence about which of these two processes are causal mechanisms of FTD. In the first part, we will determine whether active memory or inhibition is associated with FTD in people with schizophrenia. In the second part of the project, active memory and inhibition will be directly manipulated in an analogue study to determine which process could be a causal mechanism of FTD.

[unreadable] DESCRIPTION (provided by applicant): Formal thought disorder (FTD), or disorganized and incoherent speech, has long been considered a central symptom of schizophrenia, is an important target for cognitive rehabilitation, and is increased in people at risk for schizophrenia. The long-term objective of this application is to understand the cognitive and neural mechanisms that contribute to FTD. Previous research suggests that FTD is associated with deficits in cognitive control. However, cognitive control is a broad construct that encompasses multiple component processes. In this proposal, deficits in 2 cognitive control component processes, context processing and interference resolution, will be examined as possible mechanisms of FTD in 2 studies, 1 involving people with schizophrenia, the other involving psychosis-prone as well as healthy college students. The application will test whether: 1. Performance on a context processing task (Missing Letter), an interference resolution task (Sternberg with Interference), or both, are associated with baseline amount of FTD in an interview; and FTD is specifically associated with poor context processing rather than only with poor performance on a general working memory task (2-back); 2. Context processing and interference tasks are specifically associated with baseline amount of FTD (i.e., not due to a generalized deficit), assessed using psychometrically matched tasks; 3. Increased context processing and interference resolution demands on an experimental speech task cause an increase in FTD; in contrast, an increase in general cognitive demand (increased sustained attention) does not cause an increase in FTD; 4. Performance on context processing and interference resolution tasks (but not matched control tasks) predict increased amount of FTD on the experimental speech task. Collectively, these 2 studies have the potential to provide compelling converging evidence that context processing and interference resolution deficits contribute to FTD in people with schizophrenia and in people at-risk for psychosis.

Cognitive control refers to a set of processes involved in complex, non-automatic thought and behavior and[unreadable] cognitive control is thought to play a critical role in many cognitive and behavioral domains. Deficits in[unreadable] cognitive control are thought to be involved in a number of psychiatric (e.g., schizophrenia) and cognitive[unreadable] (e.g., Parkinson's) disorders. Cognitive control is a broad construct and most researchers believe it is[unreadable] comprised of multiple subcomponents and multiple brain regions. Two brain regions that are known to be[unreadable] centrally involved in cognitive control are the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC).[unreadable] However, the exact contributions of these brain regions to cognitive control are still unresolved. One goal of[unreadable] this research is to critically test conflict-control loop theory, which is one theory about the components of[unreadable] cognitive control and contributions of the ACC and PFC to cognitive control. In addition, another goal of this[unreadable] research is to examine whether specific components of cognitive control are associated with cognitive[unreadable] disorganization which is related to risk for schizophrenia. Specifically, in two brain imaging studies, the[unreadable] current proposal will examine whether:[unreadable] 1. ACC is associated with conflict monitoring (Botvinick et al., 2001) and not with[unreadable] providing an attentional boost to relevant items (Weissman et al., 2005);[unreadable] 2. the PFC but not the ACC is associated with preparation for overcoming a prepotent[unreadable] response;[unreadable] 3. level of ACC or PFC activity is associated with cognitive disorganization which is[unreadable] associated with risk for schizophrenia.[unreadable] Overall, this research is designed to provide a strong test of conflict-control loop theory and can provide[unreadable] important evidence about the functioning of brain regions centrally involved in cognitive control, information[unreadable] that could potentially help improve the treatment of a number of serious neuropsychiatric conditions.

DESCRIPTION (provided by applicant): There is evidence that binge or extreme drinking episodes are associated with neural and cognitive deficits (Courtney &Polich, 2009). Preclinical animal studies have found evidence of neurodegeneration, reduced neurogenesis, and cognitive deficits after extreme ethanol exposure, especially in adolescent animals (Crews &Nixon, 2009). Two brain regions that appear especially sensitive to extreme exposure are the prefrontal cortex (PFC) and hippocampus (Crews &Nixon, 2009), brain regions involved in executive control and long- term memory (Eichenbaum et al., 2007;Miller &Cohen, 2001). Extreme drinking is particularly common among young adults (Ziegler et al., 2005). For example, one common drinking event is to attempt to have at least 21 drinks on one's 21st birthday (Lewis et al., 2009;Neighbors et al., 2005;Neighbors et al., 2006;Rutledge et al., 2008). Young adulthood is also a time of important brain development changes (Brown et al., 2008). There is evidence that alcohol abuse in young adulthood is associated with problems in brain and cognitive development (Clark et al., 2008;Squeglia et al., 2009). Therefore, the effects of extreme drinking might be especially harmful in young adults. However, to our knowledge most research with young adults has been cross-sectional and has not directly and prospectively examined brain and cognitive changes after a single and well-documented extreme drinking episode. The current research will examine whether a single extreme drinking episode in young adults is associated with dysfunctional brain and cognitive changes. We will study naturalistic extreme drinking associated with turning 21 years of age. 70 participants will be scanned at three different time points. We will examine whether after an extreme drinking episode young adults exhibit: 1) decreased focal brain activity in PFC and hippocampus when performing executive control and long-term memory encoding tasks, assessed with fMRI;and 2) loss of PFC and hippocampal gray and white matter, assessed with structural MRI. Overall, the current translational research based on preclinical animal studies and cognitive neuroscience research will provide evidence about the harmful biological and cognitive consequences of extreme drinking in young adults. PUBLIC HEALTH RELEVANCE: The goal of this research is to examine whether extreme drinking in young adults results in neural injury. This research could have important implications for understanding the adverse effects of alcohol on the developing brain.

DESCRIPTION (provided by applicant): The over-arching aim of this proposal is to identify an impairment in neural mechanisms involved in emotion regulation and examine its relationship to emotional distress symptoms in people's daily lives. Emotional distress symptoms are found in a range of disorders (e.g., major depression, borderline personality disorder, and anxiety disorders), in part explaining extremely high comorbidity across these disorders. These disorders can be very common (e.g., combined prevalence over 1/3 of US population), are associated with intense personal suffering, and are associated with great costs to society (e.g., depression one of the leading causes of disability; anxiety disorders double medical care costs). Emotion regulation involves attempts to influence the presence, type, experience, and expression of emotion and emotional distress psychopathology is often posited to reflect impaired emotion regulation. Converging human and animal research has identified top-down ventromedial prefrontal cortex (vmPFC) regulation of amygdala activation as a critical neural emotion regulation mechanism, with some evidence that deficits in this mechanism are related to emotional distress psychopathology. Unlike possibly all previous research that examined the functional consequences of impaired vmPFC-amygdala functional connectivity, this neural deficit will be identified with functional magnetic resonance imaging (fMRI) by using both resting state data as well two different emotion regulation task paradigms, one implicit and the other explicit. This will provide converging evidence across very different functional imaging contexts to assess the breadth of this neural deficit. However, the relationship between this neural emotion dysregulation deficit and its manifestation in people's daily lives is still unknown. Previous research suggests that key emotional distress symptoms and correlates are often inaccurately recalled. Ambulatory assessment (AA) is a powerful, innovative way to assess affective, behavioral, and physiological symptoms and correlates in real world environments reliably (e.g., with smart phones), while minimizing the inaccuracy of retrospective self-reports. The use of AA will allow accurate characterization of how impaired vmPFC-amygdala functional connectivity translates into people's daily life experiences, such as self-reported negative affect affective instability, and behavioral dysregulation. In addition, physiological assessment is a critical complement to self-reported affect in order to validly assess emotional states. The current study will use wireless and continuous physiological assessment to provide converging evidence to self-reported emotional distress symptoms. Furthermore, this study will examine the relationship between this neural emotion dysregulation endophenotype with the frequency and duration (i.e., emotional recovery time) of real world emotional distress episodes measured objectively with continuously recorded physiological activity. Understanding the specific relationship between this neural emotion dysregulation and emotional distress psychopathology will have important implications assessment and treatment.