Katharine Natasha Thakkar - US grants

[unreadable] DESCRIPTION (provided by applicant): A substantial body of literature indicates that impairments in cognitive control play a central role in schizophrenia but the mechanisms underlying these deficits are still undetermined. The overarching goal of the proposed work is to understand two core components of self-control of action, response inhibition and response monitoring, in schizophrenia. The saccade countermanding paradigm provides an ideal framework for the quantification of the mechanisms of control of action by indexing one's ability to stop an initiated movement. Research on both the computational model and neurophysiology of saccade countermanding is being conducted at Vanderbilt University. Combination of work in humans and non-human primates provides unprecedented leverage on these crucial questions of the specificity of executive control dysfunction in schizophrenia as it allows the application of sophisticated models of behavior, as well as spatially and temporally precise measures of brain activity, to understanding the processes and their underlying mechanisms that are impaired and preserved in schizophrenia. The specific aims of this project are to specify the behavioral and neural markers of response inhibition and performance monitoring deficits using the countermanding task in schizophrenia and to articulate how these two processes are related in healthy controls and patients. Deficits in performance monitoring and response inhibition in patients with schizophrenia will be examined, and the relationship between trial-by-trial reaction time adjustments based on prior responses and quantitative measures of response inhibition will be examined in healthy controls and patients with schizophrenia. To elucidate the neural basis of difficulties in control of action, the electrophysiological correlates of performance monitoring and response inhibition will be investigated in patients with schizophrenia and healthy controls. PUBLIC HEALTH RELEVANCE: Implications for public health: Cognitive deficits predict functional outcome better than clinical symptoms and the remediation of cognitive deficits in schizophrenia is an urgent and important public health challenge. Thus, more specific understanding of the components of cognitive deficits has the potential to allow avenues for improved behavioral and pharmacological treatment and intervention. [unreadable] [unreadable] [unreadable]

Sensory and motor deficits represent core features of autism spectrum disorder (ASD) and contribute to significant functional impairment. In the current application, we hypothesize a relationship between alterations in sensation and action in ASD, highlighting the importance of sensorimotor loops in attempting to understand mechanisms of impairment. In particular, we predict - to our knowledge, for the first time - that a breakdown in the link between action and perception leads to a different perceptual quality of self-generated motor acts in ASD. We propose a battery of translational experimental paradigms to test this novel hypothesis. All mobile organisms are equipped with a mechanism that serves to attenuate the sensory consequences of self-generated action, allowing enhanced processing of external information. Specifically, corollary discharge (CD) signals are sent to sensory brain areas and represent a copy of movement signals sent to lower motor regions. CD signals allow organisms to predict the sensory consequences of an imminent movement, such that sensory brain regions can attenuate their response to self-initiated action. In the auditory domain, CD allows dampening of the sensory response to self-generated sounds (e.g., speech). In the oculomotor domain, CD allows the visual system to prepare for change in retinal input following an eye movement. We propose that ASD is characterized by disturbances in CD signaling, such that affected individuals experience increased response to their own actions, potentially resulting in hypo-responsiveness to external sensory stimuli and internal preoccupation. Critically, these putative consequences of CD deficits are well- replicated ASD features, but CD itself has never been tested in ASD. Our approach is to capitalize on elegant behavioral paradigms derived from animal neurophysiology, in combination with eye tracking and electrophysiology (EEG), to evaluate the integrity of CD signals in children and adolescents with ASD, as compared to well-matched typically developing controls. We hypothesize that disturbances in CD in ASD will be evidenced in: (1) reduced attenuation of auditory EEG responses to self-generated sounds; and (2) altered visual perception and movement planning following a saccadic eye movement, consistent with a failure to use CD to compensate for this movement. We will explore whether CD deficits relate to clinical features, including not only sensory and motor symptoms, but also higher order deficits in social and empathic functioning, which could reflect downstream effects of basic sensorimotor alterations. To our knowledge, this study is the first investigation of CD in ASD. Thus, this innovative, translationally- grounded project addresses a key gap in ASD research and knowledge, using cognitive neuroscience techniques to probe a specific, well-characterized brain mechanism that may underlie core ASD features. Our findings have the potential to link core ASD features to activity of single neurons, providing unique insight into potential neural mechanisms driving symptoms in ASD and potentially offering novel targets for intervention.

PROJECT SUMMARY Disturbances in a sense of self are a hallmark of schizophrenia. These disturbances can be characterized by a distorted sense of agency?the subjective sense that I cause the actions I produce. Agency distortions are manifest in many psychotic symptoms of schizophrenia, for example, the delusion that one is being controlled by aliens. The physiological mechanisms of these agency disturbances have been difficult to identify. The most convincing biological explanation for agency distortions is a disturbance in corollary discharge (CD). CD refers to ?copies? of motor signals. Rather than being sent to the muscles, CD signals are sent to sensory areas and allow the organism to anticipate the sensory consequences of the impending action. A match between the anticipated and actual sensory events following an action engenders a sense of agency, whereas a mismatch results in the subjective experience that sensations are caused by an external agent. The oculomotor system provides an ideal framework in which to investigate CD. The most robust behavioral paradigms for studying CD as well as the only neurophysiological evidence for CD signals in primates has come from eye movement research. This body of work provides an unprecedented translational framework for understanding the agency disturbances that characterize psychosis and allows us to translate single-cell findings in animals to studies of the mechanisms of self-related symptoms characterizing psychosis. Recently, we have shown evidence for disturbed CD in the saccadic eye movement system in patients with chronic schizophrenia. Informed by neurophysiology studies, these behavioral findings generate testable hypotheses about dysfunctional networks that might be giving rise to CD abnormalities in schizophrenia. This 4-year proposal has three major aims. The first is to identify the neural correlates of disrupted CD in chronic schizophrenia patients using structural and functional neuroimaging and state-of-the-art connectivity analyses. The second is to examine whether CD impairments are also present in recent-onset schizophrenia patients, as the conditions for detecting relevant pathophysiological mechanisms are better in this sample. The third is to investigate whether CD impairments are specific to schizophrenia or represent a trans-diagnostic mechanism of psychosis by including patients with bipolar disorder with a history of psychosis. A fourth exploratory aim explores the implications of this CD abnormality for impaired cognition in psychosis. These findings have the potential to link core phenomenological experiences in schizophrenia to activity of single neurons and to understand shared and distinct biological substrates of psychosis across a range of syndromes. In addition, finding abnormalities in specific neural pathways that are known to convey CD signals holds the promise to inform pharmacological treatments. Finally, our behavioral paradigms can provide a useful translational and quantitative measure of treatment targets and aid in early illness detection.