The Neural Underpinnings of Depression and Cannabis Use in Young PLWH

PROJECT SUMMARY / ABSTRACT In response to RFA-DA-21-012, ?Elucidation of mechanisms underlying complex morbidities of SUD and other mental Illnesses in people living with HIV/AIDS? (PLWH), we propose to investigate reward and pain circuitry in cannabis use and depression comorbidity, two highly prevalent conditions in PLWH. We will focus on young adults (ages 18-34) to minimize HIV neuronal chronicity effects and in light of the high rates of substance use and reduced adherence to HIV treatment in this age group. Our proposed model is: 1) Both reward dysfunction (deficits in reward learning, expectancy, attainment, positive prediction errors) and pain hypersensitivity (pain sensitivity, aversion, negative prediction errors) contribute to cannabis use and depression comorbidity in young PLWH. 2) The habenula (Hb), a small limbic hub, plays a pivotal regulatory role in these processes by inhibiting ventral tegmental area (VTA) reward signals to the nucleus accumbens (NAc) following pain and loss. 3) THC, a major component of cannabis, exerts its psychoactive analgesic effects by binding to cannabinoid 1 receptors in the reward and pain systems, including the anterior cingulate (ACC), periaqueductal gray (PAG), thalamus, amygdala, VTA, NAc, and Hb, creating temporary relief of mood and pain symptoms but resulting in long-term alterations in reward circuitry that exacerbate depression and substance use. 4) Capitalizing on improvements in fMRI resolution, our novel imaging methods overcome prior technical constraints to study the Hb and other small structures critical to reward and pain processing. Supporting data from PLWH ages 18-34 in our health system show that 43% have depression, 21% have cannabis use disorders, and only 68% had undetectable HIV viral load (VL). Using the reward flanker (RFT) and reward prediction error (RPET) fMRI tasks, we documented distinct brain activity during reward anticipation, attainment and prediction error, which predicted future depression severity. Further, we detected Hb activation during RPET and a pain task, and mapped Hb intrinsic functional connectivity (iFC) with regions critical to reward (VTA), pain (insula, PAG), or both circuits (NAc, ACC). Distinct Hb iFC were documented in relation to depression, anhedonia and cannabis use. We hypothesize that cannabis use and depression in young PLWH have an additive effect, inducing both reward deficits and pain hypersensitivity and that this pattern will predict worse outcomes at 1 year follow-up. We will utilize a 2×2 factorial design: 1) 70 depressed cannabis users; 2) 70 depressed cannabis non-users; 3) 70 non-depressed cannabis users; and 4) 70 non-depressed cannabis non-users. Participants will have comprehensive evaluations at baseline, 6- and 12-months including depression, substance, reward, pain, anxiety, trauma, HIV treatment, CD4+ count, and VL. Baseline cognitive testing and fMRI (resting-state, RFT, RPET, pain) will be performed. Analytical approaches will include machine learning classifications.