Abstract Summary Neurocognitive disorders are a devastating consequence of HIV infection, which occur despite active antiretroviral treatment. The central nervous system (CNS) can serve as a reservoir for HIV, and continued immune activation of macrophages and microglia in the brain can lead to central neurological signs and symptoms, including HIV-associated neurocognitive disorder (HAND). HIV treatment may also have neurological effects. Reliable biomarkers of CNS effects in HIV infection and treatment are essential to diagnose and track this debilitating consequence of HIV. Traditionally, neurocognitive test batteries are used, which can be time-consuming, labor-intensive, and sometimes stressful for the patient. These conventional test batteries can be insensitive to early or subclinical changes and complicated by comorbidities (ADHD, learning disabilities). An alternate way to assess central nervous system function in HIV infection may be through the physiological assays of the central auditory network. In our NIDCD-funded research in both Tanzania and Shanghai, China we have shown that HIV+ individuals have signs of a central auditory processing deficit, including a strong negative relationship between cognitive performance and the ability to understand speech in background noise (despite normal peripheral hearing determined by audiometric thresholds), higher gap detection thresholds (another sign of a central auditory deficit) in HIV+ adults even though peripheral hearing is intact, and changes on neuro-electrophysiological tests (frequency-following response). These findings likely reflect dysfunction in the auditory network in these patients, since detecting gaps, processing sound, and interpreting speech in noise are demanding CNS tasks involving the auditory network and its connections to other circuits and centers. This offers the possibility of assessing the CNS effects of HIV infection and treatment using central auditory test batteries. Central auditory effects might appear earlier than or independently from other neurological or neuropsychological test findings, so detecting these changes could complement or enhance current testing methods. For central auditory effects to be used as a biomarker, however, the changes in the auditory network need to be correlated with central auditory findings and neurocognitive testing results. The Shanghai Public Health Clinical Center follows a cohort of over 6000 HIV positive individuals and has extensive neuroimaging capabilities. In collaboration with Dartmouth, they have established the ability to make detailed central auditory processing measures. Our study will perform neuroimaging of the auditory network and its connections in HIV+ people both with (n=60) and without (n=60) HAND, including resting-state and auditory task-based fMRI, neuro-electrophysiological testing, and diffusion basis spectral imaging, which will be correlated to performance on behavioral central auditory tests and compared to results from an HIV- group. These data will show whether central auditory tests could serve as a “window” to assess the CNS co-morbidities of HIV infection.

Project Narrative This study will show whether changes in the brain’s auditory network could provide a “window” into the central nervous system effects of HIV infection. Diagnosing and monitoring of central nervous system co- morbidities is essential in HIV infection, and central auditory tests of auditory network function may offer an earlier or more accurate way to assess this than current techniques. This could alter clinical practice if central auditory tests can shown to be useful for diagnosing or tracking central nervous system effects in HIV+ individuals.