Pain, Negative Affect, and Cognitive Dysfunction at the Intersection of HIV and AUD Risk

Lsu Health Sciences Center, New Orleans LA

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Linked publications & trials

Abstract

Alcohol use disorder (AUD) is characterized by neurological deficits, negative affective/emotional states, and a profound escalation of drinking despite these harmful consequences. The cognitive and affective behavioral deficits associated with alcohol use are attributed to functional and persistent changes in specific brain regions including the prefrontal cortex (PFC). Despite its short-term analgesic properties, alcohol also damages the peripheral nervous system over time to produce a characteristic neuropathy, and the resulting hyperalgesia (increased pain sensitivity) is hypothesized to potentiate negative affect (e.g., anxiety and depression symptoms) and negative reinforcement processes to increase motivation for continued alcohol use. Alcohol use also represents a major exacerbating factor for human immunodeficiency virus (HIV) disease. Even in the postantiretroviral therapy (ART) era, neurocognitive deficits remain prevalent in persons with HIV (PWH), and HIVassociated neurocognitive disorder (HAND) and co-occurring AUD can exacerbate these deficits. PWH also frequently suffer from neuropathic pain and other pain-related symptoms that disrupt physical and emotional function, interfere with ART adherence, and increase the chance of virologic failure. Pain symptoms in PWH are associated with specific changes in the brain and correspondingly associate with numerous psychosocial factors in this population, including anxiety and depression. While cognitive deficits and pain are closely linked in PWH, few studies have examined the biobehavioral factors that drive these interactions or how alcohol and HIV exacerbate these conditions. The PFC represents and executes the highest forms of goal-directed behavior, and its function is compromised in motivational disorders such as AUD. As a potential neurobiological locus at the intersection of pain and cognitive impairment in PWH, preclinical and clinical studies have implicated a functional potentiation of the anterior cingulate cortex (ACC) in association with alcohol drinking, cognitive dysfunction, and chronic pain. From a mechanistic perspective, alterations in neurotrophic support and excitability of vulnerable cognition- and pain-related brain areas such as the ACC may represent a unifying mechanism contributing to these pathologies. Our overarching hypothesis is that alcohol and HIV/ART exposure additively increase pain, negative affect, and cognitive deficits over time in PWH in association with decreased neurotrophic signaling and hyperexcitability within the ACC. We will examine these factors using a bidirectional translational experimental design incorporating humans and nonhuman primates. Biobehavioral interventions aimed at reducing alcohol use and enhancing neurotrophic adaptations in vulnerable brain regions represent a critically underexplored area of HIV research in the public interest that will also be featured in this proposal.