This project responds to PAR 14-153, Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits in Brain Disorders. As described in the RFA, a rich body of evidence suggests that cognitive processes are associated with particular patterns of neural activity. These data indicate that oscillatory rhythms, their co-modulation across frequency bands, spike-phase correlations, spike population dynamics, and other patterns might be useful drivers of therapeutic development for cognitive improvement in neuropsychiatric disorders. This project uses parallel human and non-human primate (NHP) investigations to evaluate effects of transcranial direct current stimulation (tDCS)/transcranial alternating current stimulation (tACS) on neural oscillatory patterns underlying auditory cognitive impairments in schizophrenia (Sz), with particular emphasis on impairments in theta and delta phase reset mechanisms and delta/gamma phase amplitude coupling. In addition it evaluates the role of N- methyl-D-aspartate receptors (NMDAR) in the etiology of oscillatory dysfunction in Sz, as well as the ability of tDCS/tACS to reverse NMDAR antagonist-induced impairments in NHP as a model for future therapeutic development. The project addresses Topic 1 of the RFA by mapping neuro-oscillatory patterns underlying impaired auditory information processing in Sz using parallel human and NHP studies; Topic 2 by investigating mechanisms underlying NMDAR antagonist-induced effects; Topic 3 by evaluating tDCS/tACS effects on neuro-oscillatory function in both NHP and Sz; and Topic 4 by evaluating relative effects of high definition (HD-tDCS) and conventional tDCS using neurocomputational mapping approaches. The project includes active manipulations in both humans and NHP, and tests specific hypotheses regarding low frequency (delta, theta) oscillation and cross-frequency (e.g. delta/gamma) phase-amplitude coupling impairments as a basic mechanism of neurocognitive impairment in Sz. The recording methods detect neural activity directly using multichannel surface/intracranial electrodes in humans and NHP, respectively, and employ spectral analyses of EEG data along with quantitative behavioral measures as the primary outcome variables. Auditory dysfunction, as reflected both behaviorally and by impaired generation of mismatch negativity (MMN) and other auditory potentials is a prominent and severe feature of Sz and contributes directly to global functional outcome via direct impact on processes such as auditory hallucinations, phonological processing impairments and social cognition. Deficits in MMN generation, moreover, predict conversion to psychosis among at risk individuals. The proposed stimulation approaches including HD- tDCS and delta frequency tACS are highly novel and will have direct, real-world impact not only on neurocognitive dysfunction in Sz, but also on related forms of neurocognitive impairments across relevant associated neuropsychiatric disorders.
Schizophrenia is a severe neuropsychiatric disorder associated with prominent impairments in the pattern of brain rhythmic activity (?neurooscillations?). Transcranial direct current stimulation (tDCS) is a novel approach for modulation for modulating neurooscillatory activity. This project evaluates the ability of tDCS and related methods to reverse neurooscillatory impairments both in schizophrenia and in animal models.
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