Nearly half of all HIV patients eventually develop neuropsychiatric difficulties, despite advances in combined antiretroviral therapy (cART) permitting greater control of viral migration into the brain post-infection. Increased importance has thus been placed on understanding the role that comorbid conditions play in the etiology of HIV-related neurocognitive and psychological disorders in the cART era. This K23 proposal takes the novel approach of investigating early-life stress (ELS), as a comorbid risk factor for increased neuropsychiatric impairments in HIV patients. Such an investigation is critical given that high ELS, which is known to cause significant brain abnormalities, is common among HIV+ individuals. Preliminary structural MRI findings indicate that HIV and high ELS have combined effects on brain volume, specifically in the amygdala, which correlate with cognitive impairments in HIV patients. The proposed K23 study will investigate the independent and combined effects of HIV and high ELS on amygdala function using functional magnetic resonance imaging (fMRI), which offers a more direct method of examining brain dysfunction than structural MRI. The study employs a cross sectional 2x2 design that will include 50 HIV+ and 50 HIV-seronegative control participants, with and without high ELS (4 groups of 25 participants). The primary dependent variables will be measures of fMRI blood oxygen level dependent (BOLD) response during cognitive and emotional tasks, and performances on cognitive and psychological measures assessed outside of the MRI scanner. The study will test whether HIV and high-ELS interact to: 1) increase abnormalities in amygdala fMRI BOLD response, and 2) reduce the functional connectivity between amygdala and frontal lobe regions. It will also test whether these two fMRI measures are associated with cognitive and psychological dysfunction in HIV patients. Exploratory analyses will test the relation of fMRI measures to plasma biomarkers of inflammation (e.g., cytokines). It is hypothesized that HIV+ high-ELS patients will display increased amygdala BOLD response and reduced amygdala-frontal lobe connectivity, which will correlate with cognitive and psychological dysfunction and biomarker abnormalities. The long-term objective of this research program is to better understand the mechanisms through which high ELS increases neural dysfunction in HIV patients, in order to improve our ability to prevent, assess, and treat HIV-related neuropsychiatric disorders. This 5-year award aims to foster the PI's transition into becoming an independent fMRI investigator whose research examines the etiology of neuropsychiatric disorders in HIV patients. The PI is trained in clinical neuropsychology and structural MRI investigations of HIV-related neural abnormalities. The proposed training plan will provide coursework and mentorship at Brown University to build the PI's expertise in 3 vital areas: fMRI methodology, the cognitive sequelae of neuroAIDS, and the biological correlates of ELS. This K23 addresses key issues in the etiology of neuroAIDS, and will fully prepare the PI to conduct independent patient-oriented research in this field.
This study will provide valuable information about the lasting effects of high levels of childhood adversity ('early-life stress') on brain functions in adults wih and without HIV. We will obtain a novel understanding of the biological mechanisms associated with high levels of early-life stress that lead to increased risk for cognitive and emotional dysfunction in HIV+ patients and otherwise healthy adults. This research will build the necessary groundwork for future studies that aim to reduce and prevent brain abnormalities that result from high levels of early-life adversity.
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