HIV-associated neurocognitive disorders (HAND) remain a major public health concern despite effective suppression of plasma viremia by antiretroviral therapy (ART). Although HIV dementia is now rare, less severe but prevalent forms of HAND adversely impact quality of life. Motor function and multiple cognitive domains are often impaired in HIV+ patients. Elucidating the pathogenesis of HAND is crucial to development of optimal treatments. While reduced basal ganglia volumes are a hallmark of HIV/AIDS, atrophy of the cortex is also seen in ART- treated patients today. We have preliminary data from a structural magnetic resonance imaging (MRI) study of non-demented, virally suppressed HIV+ subjects. Significant thinning of the insula and other cortical regions, as well as of subcortical and cerebellar gray matter, was associated with detectable levels of peripheral blood mononuclear cell HIV DNA. As the insula plays a key role in attention and psychomotor ability, its dysfunction has potential implications for HAND. Alterations in functional connectivity between the insula and other brain regions affected by HIV may shed light on the mechanism behind neurocognitive decline. Using a data-driven choice of insular sub-regions based on our recent work, we propose to determine their intrinsic functional connectivity with other relevant brain structures. This project will use resting-state functional MRI to: 1) relate atrophy of the insula to altered intrinsic functional connectivity between the insula and target brain regions, and assess connectivity differences between HIV+ subjects and healthy controls; 2) determine the relation between resting-state functional insular connectivity and measures of neurocognitive function; and 3) explore the possible association of resting-state functional insular connectivity with HIV DNA. Changes in insular structure and function will be evaluated as potential markers of neurocognitive impairment. Structural atrophy and disrupted functional connectivity will be quantified by MRI-based morphometry and resting-state functional MRI, respectively. An imaging marker of HAND would potentially identify and monitor patients at risk or in early stages of neurocognitive decline. Therapy aimed at halting or reversing brain atrophy or disrupted functional connectivity may eventually become possible with knowledge of the underlying processes.