Project Summary/Abstract Persons with HIV (PWH) living in the western world have a life expectancy near that of the general population, but remain at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Substance use disorders (SUD) are also more prevalent in PWH, yet their contribution to the increased rate of cognitive impairment in this group remains poorly understood. A major barrier to progress has been the historic lack of diagnostic tests and biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded quantification of the additive impact of SUD comorbidity. This lack of tests and markers is at least partially attributable to the field’s limited consensus on the key neuropathological features of HIV-infection. For example, whether HIV-related cognitive decline is primarily attributable to cortical or subcortical circuits remains widely debated, despite literally hundreds of neuroimaging studies over the past 20 years. We recently received a NIH S10 High-End Instrumentation award from the Office of the Director to acquire a next-generation magnetoencephalography (MEG) system. This $3M instrument was the third such unit installed in the United States and remains the only one being used for HIV and/or SUD research. This award follows on the heels of several remarkable discoveries in our ongoing effort to develop quantitative neuro-metrics that can distinguish impaired from unimpaired PWH. Briefly, these findings revealed highly specific cortical oscillatory deficits in PWH, which generated significant excitement and were published in a series of high-impact papers. Most recently, we have shown that regular cannabis use is associated with a normalization of these oscillatory deficits in PWH. While remarkable, all of this work was based on MEG measurements acquired with a previous generation system (circa 2008), which was far more sensitive to cortical versus subcortical neural responses. Of note, this greater sensitivity to cortical activity is true of many modern neuroimaging tools and consequently the extensive evidence supporting cortical aberrations in virally suppressed PWH could be mistaken. Our new next- generation MEG system provides an unprecedented opportunity to quantify human brain dynamics with enhanced precision across multiple parameters, including far greater sensitivity to subcortical brain responses. Thus, through this project we will determine whether HIV-related deficits in cortical oscillatory and spontaneous activity are a primary or secondary neural abnormality in PWH, and whether the apparently beneficial effects of cannabis use on neuronal dynamics in PWH are primarily attributable to modulation of cortical or subcortical neurophysiological activity. While the pathological spontaneous and oscillatory neural activity observed in PWH could arise from increased subcortical drive from the thalamus, we hypothesize that these cortical deficits will be independent of any subcortical aberrations and that the beneficial effects of cannabis will be limited to the cortex.

Project Narrative Magnetoencephalographic (MEG) imaging is a noninvasive method for mapping human brain dynamics that has been used with major success, by our group and others, to identify neural markers of HIV-related cognitive decline and cannabis use disorder. The first next-generation MEG instruments were recently released, and these systems have significantly improved the precision of dynamic functional brain mapping and enabled many longstanding questions to be rigorously tested. The proposed project will examine such questions by probing whether HIV-related cognitive decline is primarily due to cortical or subcortical aberrations and whether the seemingly beneficial effects of regular cannabis use on brain function in adults with HIV are due to alterations in cortical or subcortical dynamics and circuitry.