Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals. Research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). While the mechanisms underlying these deficits are not well understood, numerous human neuroimaging studies have examined the brain areas that may be involved, and overall these studies have been largely successful in identifying the critical hubs and networks. However, many questions remain regarding basic circuit dysfunction within these brain regions, and consequently there is a clear and common need to further investigate the neural dynamics and connectivity, as well as other key physiological parameters that may underlie the development and progression of HIV-related cognitive dysfunction. This proposal responds to RFA-MH-18-610, which requests proposals that “advance knowledge of the etiology of mild to moderate forms of HIV-related cognitive dysfunction by clarifying the role played by altered neuronal circuits, receptors, and networks,” using “novel neuro-electrophysiological and neuroimaging techniques.” The Multimodal Imaging of NeuroHIV Dynamics (MIND) Consortium responds to this call with an innovative, large- scale multimodal neuroimaging study that uses the latest breakthroughs in instrumentation and data analyses to identify the pathophysiology of neuroHIV in virally-suppressed adults. Specifically, the consortium will use advanced magnetoencephalographic (MEG) imaging to quantify the region- and circuit-level neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map areal brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to quantify GABA levels in multi-voxel slabs of interest identified by the functional modalities. The investigative team includes a unique combination of experts in MEG, MRI/fMRI, MRSI, and cognitive psychology from the University of Nebraska and University of Pittsburgh Medical Centers (UNMC/UPMC). In addition, this consortium will harness existing resources such as the Multicenter AIDS Cohort Study (MACS) database and the National NeuroAIDS Tissue Consortium (NNTC) and, consistent with the RFA, will follow the Research Domain Criteria (RDoC) framework to define cognitive constructs. The consortium’s overarching hypothesis is that HIV-infected adults will exhibit aberrations in local inhibitory circuits, and that these deficits will alter gamma oscillations and thereby impair neuronal coding and interregional functional connectivity in the theta range. Such gamma deficits would provide robust explanatory power for the breadth of pathophysiological findings in the existent literature, and the MIND study is uniquely powered to investigate the underlying sources of these deficits, which are likely multifactorial (e.g., medical history, lifestyle factors, CNS viral penetration).

Project Narrative HIV-infection has become a chronic manageable condition with a life expectancy that approaches that of the general population, but affected adults remain at a significantly elevated risk of developing cognitive disorders. Previous imaging studies have mapped the brain regions that may be involved in these cognitive disorders, but many basic questions remain about the local physiology and connectivity, and how it might differ in those with cognitive impairments. The Multimodal Imaging of NeuroHIV Dynamics (MIND) Consortium will use advanced dynamic functional brain mapping methods, along with the latest in structural, functional, and spectroscopic MRI to evaluate brain circuity and cognitive dysfunction in a large sample of HIV-infected and uninfected adults.