Scott R. Sponheim - US grants

[unreadable] DESCRIPTION (provided by applicant): The neural signature of abnormal controlled processing in schizophrenia must be written into the electrical activity of cerebral neurons. A nonhuman primate model of controlled processing can serve as a bridge linking minute physiological events in cortical neurons to patterns of altered cognitive control that are indicative of cognitive deficits in schizophrenia. The first step in the proposed translational endeavor is to develop tasks for cross-species studies. We will implement a spatial working memory task developed in the context of single-cell recordings in nonhuman primates, and a sustained visual attention task used to reveal reliable vigilance deficits in schizophrenia patients and their first-degree relatives, to study visual controlled processes in schizophrenia patients, control subjects, and nonhuman primates. Through behavioral studies we will identify characteristics of spatial working memory and sustained visual attention tasks that allow for study of specific visual controlled processing deficits in schizophrenia. Next, we will identify candidate neural signals associated with visual controlled processing through the use of functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). We will require candidate neurophysiological signals characterized by fMRI or MEG to exhibit dependency on the amount of controlled processing performed, selective synchrony between prefrontal cortex and visual stream activity, and associations with augmented sensory activity and controlled processing deficits in schizophrenia. From the results of these studies we will design a task that allows for clear delineation of neural mechanims underlying visual controlled processing in humans and nonhuman primates, and apply the task in future studies of schizophrenia. We hypothesize that high frequency neural activity (gamma) serves as a neurophysiological signal of activity in cortical networks mediating visual controlled processing. [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We will implement a spatial working memory task developed in the contest of single-cell recordings in nonhuman primates, and a sustained visual attention task used to reveal reliable vigilance deficits in schizophrenia patients and their first-degree relatives, to study visual controlled processes in schizophrenia patients, control subjects, and nonhuman primates. Next, we will identify candidates neural signals associated with visual controlled processing through the use of functional magnetic resonance imaging (fMRI) at the Center for Magnetic Resonance Research and magnetoencephalography (MEG) at the VAMC in Minneapolis. From the results of these studies, we will design a task that allows for cleear delineation of neural mechanisms underlying visual controlled processing humans and nonhuman primates, and apply the task in future studies of schizophrenia.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Brain injury from explosive blast is a prominent feature of contemporary combat. We will use sophisticated measures of brain function and structure to characterize brain injury from explosive blasts in a sample of Operation Iraqi Freedom (OIF) National Guard soldiers who returned from deployment in the fall of 2007. Biological measures that directly assess neural disruption will be used to characterize differences in brain structure and function between blast-related brain injury and post-traumatic psychopathology. To fully characterize the effects of blast on the brain and differentiate them from post-traumatic stress disorder, we will contrast groups of soldiers exposed to blast with groups experiencing post-traumatic stress disorder. It is expected that this DoD-funded study may take up to four years. This study will provide a means for separating co-occurring conditions of brain injury and psychological distress due to explosive blast and post-traumatic psychopathology. The results of this research will help clinicians better differentiate between post-traumatic stress disorder and brain injury due to explosive blast by increasing our understanding of the essential features of the conditions in terms of neural function and structure. Better differentiation between the two conditions will allow clinicians to design more appropriate treatment protocols. Results of this research will be used to inform diagnosis and characterize mechanisms of recovery after blast-related neural injury to allow the creation of interventions that return soldiers to maximum levels of functioning.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this novel study is to elucidate the relationship between abnormalities in prefrontal structure and impairments in executive functioning by conducting a study of schizophrenia patients compared to controls using multi-modal magnetic resonance imaging (MRI) techniques. Background: Genes associated with vulnerability to schizophrenia may affect neurodevelopment and result in abnormalities in prefrontal structure and function. The prefrontal cortex occupies approximately one quarter of the human cortex and is part of the brain that is most unique to humans. It is the one of the last parts of the brain to mature, but is typically also the first part of the brain to suffer with age. The prefrontal cortex regulates executive processes such as attention, planning, judgment, impulse control, self-monitoring, and problem solving. Studies have demonstrated reduced prefrontal gray matter in schizophrenia patients and their healthy relatives compared to controls suggesting a genetic component (Cannon et al., 1998). In addition, problems in executive functioning are a fairly robust correlate of the schizophrenia diathesis (Snitz et al., 2006) and reduced prefrontal brain activity is also a reliable correlate of schizophrenia (Snitz et al., 2005). To date, most studies have analyzed structural and functional data in isolation. The purpose of this study is to examine the relationship between abnormalities in prefrontal cortical structure and BOLD response in schizophrenia patients, first-degree biological relatives of schizophrenia patients, and control subjects. We hypothesize that schizophrenia patients with prefrontal abnormalities in either structure or hemodynamic responses will have a similar regional abnormality in the complementary domain. Similar regional associations between structure and BOLD response will be observed in first-degree biological relatives of schizophrenia patients suggesting the abnormalities are related to the diathesis for schizophrenia. Covariation of structure and hemodynamic response will be less robust in control subjects.

DESCRIPTION (provided by applicant): ICOSR - Project Summary/Abstract Young investigators within the first five years of their careers are the future of schizophrenia research. Beginning and then sustaining a career to better understand and treat schizophrenia can be a daunting task. To assist young people in advancing through the maze of establishing a research career, the International Congress on Schizophrenia Research (ICOSR) has created and overseen a Young Investigator Program which has paid the expenses of young, academically-oriented investigators and provided career support at its biennial meetings. The ICOSR was initiated in 1987 as a part of the National Plan for Schizophrenia Research and now welcomes nearly 1,500 active scientists to its four-day meeting. Young Investigators are an integral part of the meeting - all presenting their work while participating in a mentorship program. During the last 20 years, the ICOSR has supported 334 Young Investigators - many of whom have gone on to be leaders in the field. The Congress now seeks support for this Program for its next 3 meetings (2013, 2015, and 2017). With this support the ICOSR will continue to improve the Program for young scientists and provide a beginning network for their careers.

? DESCRIPTION (provided by applicant): Severe mental disorders are associated with poor cognitive control that is evident in a failure to update responses for new circumstances, effectively use short-term memory, and inhibit behavioral responses. Limited goal-oriented control over cognition and behavior creates measurable difficulties in the day-to-day functioning of people with severe psychopathology. Despite accumulating evidence of a network of cortical regions underlying cognitive control functions, the dynamic interaction of brain regions that yield these functions are unknown. The overarching goal of the proposed work is to better understand the neural basis of compromised context updating, working memory, and response inhibition in severe psychopathology by detailing the strength and timing of bioelectrical oscillations within cortical regions composing the neural network underlying cognitive control. As part of this project, we will first identify cortical regions and frequencies pertinent to cognitive control. Through combined use of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data gathered from people with severe psychopathology, their first-degree biological relatives, and healthy controls we will identify cortical sources common to context updating and response inhibition and identify bioelectrical oscillations in these brain regions instrumental to cognitive control. Second, we will test the generalization of oscillatory abnormalities to other samples of participants and other tasks (e.g., working memory) in order to fully determine common aspects of the cortical network governing cognitive control and what abnormalities exist in severe psychopathology. The broader samples will include individuals with severe mood dysregulation and psychosis. Third, we will test neural network oscillations for relevance to symptom, behavioral, and genetic elements of severe psychopathology. Specifically, we will investigate the significance of abnormal oscillatory activity during cognitiv control in severe psychopathology by examining associations with dimensions of symptomatology, additional behavioral measures of cognitive control, and polygenic predictors of risk for severe psychopathology as well as candidate genes identified as related to cognitive control and severe psychopathology. Completion of the aims will identify abnormalities in the temporal dynamics of activity within cortical regions underlying impaired cognitive control in severe psychopathology. New knowledge gained from this work will enable more effective interventions that target specific neural circuits in severe mental disorders and may involve the direct manipulation of brain activity. Project Units of Analysis: Units of analysis include circuit, physiology, behavior, genes, self-report.

The NOSI and RFA for this application do not require a project abstract or narrative. However, these two documents are marked as required in the online application and generate error messages if no documents have been uploaded, thereby preventing the submission of the application. This document has been uploaded to remove the error messages.

Project Summary It is unknown how functions of the brain give rise to psychotic experiences in severe psychopathology. Consequently, available treatments for psychotic disorders are often marginally effective. Abnormal visual perception is evident in psychosis (e.g., hallucinations) and noted in people with genetic liability for psychotic psychopathology (e.g., heightened illusions). Current evidence points to early visual abnormalities in psychosis that may trigger a cascade of errant neural activity creating distortions in one's visual experience; however, it is unclear how basic visual and complex guidance functions of the brain separately contribute to visual misperception in psychotic psychopathology. The overarching goal of the proposed work is to use sophisticated psychophysical tasks and neuroimaging to a) precisely characterize behavioral and neural abnormalities in individuals with psychotic disorders during visual perception, b) detail the mechanisms of visual hallucinations and distortions through the development and testing of a computational model c) determine if the mechanistic anomalies also mark genetic liability for psychosis. The goal will be accomplished by studying individuals with psychotic disorders (IPDs), one first-degree biological sibling of each IPD (SibIPDs), and healthy controls (HCs) demographically similar to the other two groups. We hypothesize that individuals prone to visual hallucinations exhibit stable neural abnormalities in early visual cortex (V1, V2) causing errors in the processing of visual elements, and that visual hallucinations occur in IPDs when contextual influences of more anterior regions (LOC/fusiform, prefrontal cortex) on visual perception become deviant. Individuals prone to anomalous visual illusions but without a psychotic disorder are hypothesized to exhibit a stable decrement in high-level influences on visual perception reflected in anomalies of inter-regional neural synchronization. We will employ contrast discrimination, surround suppression, attention regulation, and ambiguous object tasks to assess early visual perceptual processes, with and without contextual modulation, in IPDs, their unaffected biological siblings (SibIPDs), and healthy controls (HCs), to determine when task performance predicts self-reported visual misperceptions. We will compute cortical source signals from 248-channel MEG data functionally localized through 7 Tesla (T) fMRI to detail the location, timing, and synchronization of neural responses during visual perceptual tasks assessing local and long-range processes in IPDs, SibIPDs, and HCs, as well as determine how neural responses elicited by tasks predict variation in self-reported visual misperception. We will also characterize visual responses in all tasks using the Gaussian Scale Mixture model originally published by Schwartz et al (2009) and recently extended in our work to generalize across multiple scene segmentation cues (Qiu, 2013). We will use this model to test whether terms reflecting local inhibition are selectively reduced in all IPDs and whether the strength of the term representing long-range modulation correlates with frequency of visual hallucinations.