Presentation Title:

Acute Alcohol Effects on the Functional Neural Correlates of Pain Processing

Abstract:

Alcohol has well-documented analgesic effects. In individuals both with and without chronic pain, acute alcohol intake produces significant increases in pain threshold, decreases in pain intensity, and perceived pain relief during laboratory-based quantitative sensory testing. Evidence suggests these effects are dose-dependent, consistent with increased risk for alcohol-related consequences in individuals using alcohol for pain self-management. However, the functional neural mechanisms underlying alcohol analgesia remain poorly understood. N=97 healthy social drinkers (52.6% women) 21-45 years of age completed two laboratory sessions in which they received placebo or alcohol (.08 g/dL target breath alcohol concentration) in counterbalanced order. ~25 minutes after beverage consumption, they were positioned in a Siemens Prisma 3T MRI. Over each of three task fMRI runs, seven 10s blocks painful heat were applied to the glabrous skin of the foot. Participants rated pain intensity after each stimulus and perceived relief from pain from consuming their beverage after each run. Alcohol- induced change in pain-related functional activation and functional connectivity, including cerebral network topology, was assessed.

Alcohol significant reduced pain-related functional activation of the dorsolateral prefrontal cortex in men, but not women (pFDR=.035). dlPFC connectivity with regions including insula, supramarginal gyrus, and primary motor cortex was also disrupted (pFDR<.024). Alcohol also disrupted pain-related functional activation and functional connectivity of the insula, with effects differing between anterior and posterior insula.

Finally, alcohol reduced the inter-connectedness of the broader cerebral network (p=.014) and increased the average distance separating network nodes (p=.05) during pain processing. Overall, results provide new evidence that acute alcohol intake significantly perturbs not just localized pain- related functional activation and functional connectivity, but also the broad organization of pain-related cerebral networks.

Presentation Title:

Cortical Opioids: Top-Down Regulation of Affect, Motivation, and Cognition

Abstract:

Opioid use disorder is associated with persistent deficits in reward valuation, motivation, and behavioral flexibility, implicating prefrontal circuits that guide adaptive decision-making. The orbitofrontal cortex (OFC) integrates reward value to support flexible, goal-directed behavior and expresses high levels of mu-opioid peptide receptors (MOPRs). Although local opioid signaling in the OFC modulates reward consumption, whether endogenous OFC MOPRs are necessary for associative learning, effort-based motivation, and value-based decision-making, and whether this is reflected in the functional heterogeneity of OFC subregions, remains unknown. To answer these questions, we use a complementary suite of pharmacological, genetic, CRISPR, in situ hybridization, and in vivo imaging approaches to isolate the mechanisms of MOPRs on unconditioned and complex operant behaviors. Data so far indicate that MOPRs in medial versus lateral subregions have specialized roles in regulating behavior, and this is further driven by their actions on distinct OFC interneuron populations. Looking forward, we plan to assess how these endogenous OFC MOPR mechanisms impact the development and expression of motivated drug seeking, and whether modulating this system can alleviate the motivational and cognitive deficits observed in opioid and substance use disorders.

Presentation Title:

From Prenatal Exposures to Polysubstance Use: Neurodevelopmental Findings from the ABCD Study

Abstract:

The Adolescent Brain Cognitive Development (ABCD) Study provides an unprecedented opportunity to examine how biological, environmental, and developmental factors shape risk for substance use and mental health outcomes during adolescence. This presentation will highlight findings from a series of ABCD investigations examining neurodevelopmental pathways to substance use risk, with a particular focus on prenatal substance exposure, brain maturation, impulsivity, psychopathology, and polysubstance use. First, I will present work characterizing the impact of prenatal exposures and early-life adversity on trajectories of brain development and mental health. Next, I will discuss studies identifying neurobiological, genetic, and environmental predictors of substance use initiation and progression, including factors associated with impulsivity and emerging polysubstance use. Finally, I will review evidence linking these developmental risk factors to later substance use patterns and psychiatric outcomes. Together, these findings illustrate how risk for substance use disorders emerges through the interaction of prenatal influences, neurodevelopment, and environmental exposures. The results have important implications for identifying vulnerable youth, informing prevention strategies, and advancing our understanding of the developmental origins of addiction.

Presentation Title:

Targeting Brain Circuits in Addiction: Toward Personalized and Adaptive Neuromodulation

Abstract:

Substance use disorders arise from dysfunction across distributed neural circuits involved in reward processing, cognitive control, craving, and decision-making. Noninvasive brain stimulation provides a unique opportunity to causally engage these circuits. Still, variability in brain anatomy, functional organization, and stimulation-induced electric fields remains a major challenge for translating neuromodulation into effective and reproducible interventions. This talk will present a research framework for moving from conventional stimulation protocols toward circuit-informed, personalized, and adaptive neuromodulation for addiction. 

Using studies combining transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) with functional MRI, EEG, intracranial electrophysiology, and computational electric-field modeling, I will discuss approaches for identifying therapeutic targets and understanding how stimulation engages distributed brain networks. Work in opioid use disorder demonstrates that theta-band frontoparietal stimulation can modulate cortico-striatal-amygdala circuitry associated with drug-cue processing and craving, while electric-field modeling provides a framework for examining interindividual variability in neural and behavioral responses. Complementary work based on closed-loop and traveling-wave stimulation and invasive and noninvasive electrophysiology examines how the spatial and temporal organization of stimulation can be optimized to influence cognitive networks.

Finally, I will discuss emerging strategies that use neuroimaging and electrophysiological signals to personalize stimulation targets, parameters, and timing, including fMRI-guided targeting and closed-loop approaches. Together, these studies support a shift from applying standardized stimulation protocols toward precision neuromodulation, in which the target, dose, timing, and brain state are selected based on individual circuit characteristics. This framework may provide a path toward more mechanistically informed and adaptive interventions for substance use disorders.

Presentation Title:

From Diabetes to Addiction: Evaluating Metformin as a Treatment for Substance Use Disorders

Abstract:

Chronic cocaine use results in maladaptive brain changes that promote an enduring vulnerability to relapse even after extended abstinence. Currently there is no FDA-approved treatment for cocaine use disorder (CUD) contributing to high rates of treatment attrition and relapse. Because cocaine alters brain energy metabolism, metabolic regulators may provide a promising new avenue for therapy. In pursuit of novel pharmacotherapies, our lab began investigating the utility of the FDA-approved type II diabetes drug metformin (MET, dimethyl-biguanide) for attenuating cocaine-mediated behaviors. In this talk, I will present accumulating evidence from our laboratory that metformin regulates cocaine-mediated behaviors in addition to converging evidence collected by others demonstrating metformin effects with other rewarding substances. Although the mechanism of action underlying MET effects remains unclear, I will present data demonstrating that metformin crosses the blood-brain-barrier and accumulates in reward-relevant brain regions. Finally, I will conclude with recent work using electronic health records from the UMN health system to explore how metformin use impacts mental health outcomes in cocaine and cannabis users. We believe this work is important because metformin is a safe, affordable drug with the potential to increase treatment access for individuals with substance use disorders.