University of Pittsburgh Endowed Professor in Translational Neuroscience; Chairman, Department of Psychiatry; Medical Director and Director of Research, Western Psychiatric Institute and Clinic; Director, Translational Neuroscience Program; Director, NIMH Conte Center for the Neuroscience of Mental DisordersDr. Lewis' research focuses on understanding the organization and functional properties of the neural circuitry of the prefrontal cortex and interconnected brain regions, and the alterations of this circuitry in schizophrenia. This work links up with neuropsychological perspectives that identify "working memory" deficits as a key etiological factor.
A Neural Circuitry Basis for Impaired Cortical Network Oscillations and Cognitive Dysfunction in Schizophrenia
Deficits in cognitive control, the ability to adjust thoughts or behaviors in order to achieve goals, are now considered to be a core feature of schizophrenia and to be the best predictor of long-term functional outcome. Cognitive control depends on the coordinated activity of a number of brain regions, including the dorsolateral prefrontal cortex (DLPFC). Subjects with schizophrenia exhibit altered activation of the DLPFC, and reduced frontal lobe gamma band (~40 Hz) oscillations, when performing tasks that require cognitive control. Gamma oscillations require robust activity in the reciprocal connections between the parvalbumin-containing basket cell class of cortical GABA neurons and neighboring pyramidal neurons. Thus, alterations in either the excitatory or inhibitory synapses in this circuit could contribute to impaired gamma oscillations and cognition in schizophrenia. This presentation will review the evidence for these types of alterations in the DLPFC of subjects with schizophrenia, and the convergent findings indicating which alterations might be primary disturbances and which are compensatory responses. Together, the findings suggest a mechanistic model of "re-set" excitatory-inhibitory balance in DLPFC circuitry that could give rise to impaired gamma oscillations and could explain the developmental course of functional disturbances in individuals with schizophrenia.