A neurobiological investigation of cannabis use and misuse in Veterans

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In individuals with psychosis cannabis is associated with worse prognosis, exacerbation of psychotic symptoms, impaired cognition, functional disability, violence, increased frequency and duration of hospitalizations, and elevated healthcare costs. Despite this, there are high rates of co-occurring cannabis use in psychosis, and rising cannabis use amongst Veterans. With legalization, commercialization, and increasing potency of cannabis and decreasing risk perception, there is cause for alarm especially for those with psychosis. Critically, there are no proven or approved treatments for cannabis use disorder in individuals with psychosis. While antipsychotic medications are useful for decreasing psychotic symptoms, they have little effect on decreasing cannabis use. Although nascent research suggests that repetitive transcranial magnetic stimulation (rTMS) and psychosocial interventions (i.e., motivational enhancement therapy) may reduce cannabis use and/or psychosis, responses have been mixed. One possible reason that treatments may fail is that they may rely on intact synchronized neural activity necessary for information processing, learning and memory. Converging evidence suggest deficits in neural synchrony in regions involved in learning and memory are implicated in the pathophysiology of psychosis and psychoactive effects of cannabis. In those with psychosis, deficits in coordinated neural activity in theta (4-7Hz) and gamma (30-80Hz) ranges, which are centrally involved in learning and cognition and particularly working memory (WM), have been observed. In vitro and in vivo studies and our experimental work in healthy controls have shown cannabinoid receptor type 1 agonists decrease theta and gamma synchrony and increase noise (random activity), as well as alter functional connectivity in the working memory network (WMN). While a scant literature, experimental studies in psychosis have shown cannabinoids increase cognitive dysfunction and reduced hippocampal-striatal functional connectivity during a learning task. Despite these initial findings, further work is needed on the impact of cannabinoids on neural synchrony in those with psychosis, as identifying implicated neural mechanisms may lead to development of new interventions. Powerful tools previously used to investigate neural synchrony and functional connectivity (coordinated activity), such as electroencephalography (EEG) and functional magnetic resonance imaging, can be complemented with magnetoencephalography (MEG). MEG is a non-invasive, functional measure of magnetic fields produced by neural activity with excellent temporal and spatial resolution. MEG has been critical for understanding neural synchrony and working memory in other disorders, like Alzheimer’s Disease. While MEG is sensitive to tangential currents, EEG is sensitive to tangential and radial currents. Together, MEG and EEG provide complementary information for more accurate determination of neural mechanisms. Despite this, there have been no studies using MEG/EEG to investigate neural synchrony, cannabis, and psychosis in Veterans. To address these gaps, this CDA-2 aims to compare neural synchrony and clinical outcomes of cognition, psychiatric symptoms (i.e., psychosis, trauma, and anxiety), and function in Veterans with psychosis and regular cannabis use compared to non-using peers using simultaneous MEG/EEG, available for the first time within the VA at VA Connecticut. The proposal will build on the Principal Investigator’s expertise in cannabis use and cognition and provide the unique skills to support her long-term career goal of using advanced multimodal neuroscience tools to investigate the impact of cannabinoids on Veterans as an independent VHA investigator. This study has the potential to reveal a sophisticated account of neural synchrony in this population with insight into how it relates to cognition, psychiatric symptoms, and function. This advance in scientific knowledge may yield significant translational clinical utility such that findings about regions of altered synchrony may provide targets for the development of novel, more effective, interventions, such as cognitive remediation or rTMS to address neural synchrony and enhance cognition in Veterans with psychosis and co-occurring cannabis use.