Deficient Neural Plasticity and its Functional Consequences in Schizophrenia

Veterans Affairs Med Ctr San Francisco, San Francisco CA

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Abstract

While antipsychotic medications are useful for ameliorating psychotic symptoms of schizophrenia, they have little effect on cognitive dysfunction, which is a core feature of the illness and a major determinant of functional disability and poor community outcomes. Although recent research has shown some promise in using cognitive training and cognitive-behavioral techniques to target cognition and clinical symptoms, responses to these interventions are highly variable and likely depend on intact basic mechanisms of neuroplasticity to achieve success. Several recent theoretical perspectives and observations implicate abnormalities in basic mechanisms of neuroplasticity in the pathophysiology of schizophrenia, contributing to cognitive deficits and potentially interfering with the efficacy of cognition-based interventions. Specifically, N- methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP), which is a mechanism of experience-dependent synaptic plasticity and a leading candidate cellular mechanism of learning and memory, is predicted to be compromised in schizophrenia based on NMDAr hypofunction models of the disorder. Recently, sensory stimulation paradigms have been developed that allow for the assessment of LTP-like plasticity in humans in vivo. Analogous to electrical stimulation in animals, repeated visual stimulation can induce repetitive synchronous afferent activity that results in LTP-like effects, including persistent potentiation of scalp-recorded visual evoked potentials (VEPs). A few studies using variants of this paradigm have now demonstrated deficient LTP-like visual plasticity in schizophrenia as well as mood disorders, reflected by reduced potentiation of VEPs relative to healthy individuals. Despite these promising initial findings, however, further work is needed to both optimize and validate the visual stimulation paradigm as a probe of the integrity of LTP-like plasticity in schizophrenia. Accordingly, this Career Development Award study aims to further optimize and validate the visual stimulation paradigm as a probe of LTP-like visual plasticity and examine the clinical and functional consequences of deficient LTP-like plasticity in Veterans with schizophrenia. The training plan will further develop the Principal Investigator's expertise in psychiatric neuroimaging through a tailored combination of coursework, methodological workshops, and collaboration with established investigators with expertise in schizophrenia and the integration of functional neuroimaging methods. This study combines neuroimaging modalities (EEG and fMRI) to achieve four specific aims: 1) to identify when and where LTP-like visual plasticity effects, and their deficiencies in schizophrenia, occur in the brain; 2) to test the hypothesis that variation in LTP-like visual plasticity is associated with variation in visual perceptual learning; 3) to examine whether the integrity of LTP-like visual plasticity predicts gains following cognitive training, and 4) to explore whether greater deficits in LTP-like visual plasticity are correlated with more severe symptoms and poorer functional outcomes in schizophrenia. This study has the potential to provide a mechanistic account for why cognitive training fails to improve cognition in some patients or produces limited gains in others. These advances may facilitate 1) the development of personalized medicine approaches that prescribe cognitive training to those most likely to benefit from it, and 2) the identification of neurophysiological targets for novel interventions specifically aimed at ameliorating deficient neuroplasticity, thereby restoring the capacity of Veterans with schizophrenia to benefit from treatments that rely on new learning.