Working Memory-Related Prefrontal Activity Measured with Magnetoencephalography: Abnormalities in Schizophrenia and Relationship to Dopamine

Rubinstein, Daniel Yehonatan

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Year:: 2017
Contributor:: Rubinstein, Daniel Yehonatan (creator); Berman, Karen (Advisor); Coppola, Richard (Reader); Sheinberg, David (Reader); Horwitz, Barry (Reader); Brown University. Department of Neuroscience (sponsor)
Genre:: theses
Subject:: Genetics; Schizophrenia; Schizophrenics; Dopamine; Dopamine--Receptors; Antipsychotic drugs; Tomography, Emission; Magnetoencephalography; Short-term memory; Beta Band; Prefrontal cortex
Extent:: xv, 124 p.
DOI: https://doi.org/10.7301/Z0DB8099

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Abstract:: Prefrontal cortical dysfunction is well-established in schizophrenia and is thought to contribute to working memory (WM) impairment, which occurs early in development before the onset of other symptoms. Clarification of the neurophysiology underlying this impairment is thus essential for identifying biomarkers, developing more targeted therapies, and ultimately prevention through early identification and treatment of high risk individuals. Involvement of dysfunctional dopamine (DA) signaling in the etiology of schizophrenia is well-established and, when considered with evidence of DAergic modulation of WM-related activity in the dorsolateral prefrontal cortex (DLPFC), is hypothesized to contribute to prefrontal dysfunction and WM deficits in individuals with schizophrenia. To elucidate the relationships between these systems, I used MEG to measure neural activity at high spatiotemporal resolution in healthy volunteers (HVs) and patients with schizophrenia in a blinded antipsychotic medication withdrawal protocol to determine the effects of diagnosis and medication on WM-related electrophysiology. HVs exhibited robust beta band desynchronization in the DLPFC while drug-free patients showed no such DLPFC response. Antipsychotic medication “normalized” patients’ neural responses in a time-specific manner, such that medication significantly altered activity only during epochs exhibiting abnormal DLPFC desynchronization in the drug-free condition. To further investigate DAergic modulation of WM-related activity, I used PET imaging and genetic analyses to assess distinct components of the DAergic system. In HVs, D1-like, but not D2-like receptor availability, as well as variance in the dopamine D1 receptor gene, was associated with the degree of DLPFC desynchronization. The results are among the most direct evidence of a relationship between DLPFC-specific neural activity and DA receptor function in humans, supporting primate studies demonstrating a privileged role of D1 receptors in the modulation of DLPFC WM-related activity. The findings further support development of time-specific neural oscillation-based biomarkers, and combined D1/D2-targeted treatments for cognitive impairments in schizophrenia. Future research will further investigate the relationship between DA-related genes/function and beta band activity in patients to help determine the primary mechanisms underlying their prefrontal dysfunction.
Notes:: Thesis (Ph. D.)--Brown University, 2017

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Rubinstein, Daniel Yehonatan, "Working Memory-Related Prefrontal Activity Measured with Magnetoencephalography: Abnormalities in Schizophrenia and Relationship to Dopamine" (2017). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0DB8099

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Neuroscience Theses and Dissertations

Theses and Dissertations for the Neuroscience department.
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