Electrophysiological Dynamics of Acute Opioid Use in Human Reward, Affect, and Pain Pathways - ABSTRACT Opioid use disorder (OUD) and chronic pain (CP) are interrelated, both impacting the brain's reward, affect, and pain circuits. OUD is prevalent among CP patients, and the euphoric effects and negative reinforcement properties of opioids are significant factors contributing to an increased risk of abuse in this population. The neural circuitry of OUD has been extensively studied using animal models and human neuroimaging, and an overall reduced functional connectivity within the reward network has been found among CP patients and those with OUD. However, the dynamic changes in connectivity from acute opioid use, and how these differ for CP patients who are at risk of developing OUD remain largely unknown. To address this gap in knowledge, we aim to uncover how acute opioid use impacts neural connectivity by directly recording human neuronal signals from regions associated with OUD. These regions encompass interconnected and overlapping circuits involved in reward, affect, and pain processing, and include: amygdala, hippocampus, insula, orbitofrontal cortex (OFC), medial and ventrolateral and dorsolateral prefrontal cortex (mPFC, VLPFC, DLPFC), anterior cingulate cortex (ACC), sensory thalamus, and periaqueductal gray matter (PAG). To achieve this, we will leverage a unique ability to directly record local field potentials (LFP) from awake humans, who have electrodes implanted for clinical purposes in deep brain regions, that opportunistically overlap with areas implicated in OUD. These recordings will be obtained from two patient groups: 1) epilepsy patients implanted with temporary brain electrodes for seizure monitoring (for 1-2 weeks), covering reward and affect processing areas, and 2) deep brain stimulation (DBS) patients undergoing awake DBS placement surgery, covering pain processing areas. Both groups routinely receive opioids to manage surgical pain, and both includes a subset of patients who have chronic pain (CP). This enables us to compare neural activity during acute opioid administration across individuals with varying degrees risk for developing OUD. In this project, patients will rate their pain and mood levels on a scale (0-10) before and after receiving opioid pain medications, and the change in reward/affect (Aim1) and pain (Aim2) network connectivity will be assessed, and further explored across patients with varying degrees of risk in developing OUD (Aim3). Through this K01 award, Dr. Ryu will lead the project and receive valuable mentored training by an interdisciplinary team specializing in substance use disorder, neuromodulation, human brain signal processing, and computational modeling. By the conclusion of the K01 award period, this research will reveal the neurophysiological signatures within the addiction circuitry related to acute opioid use, offering valuable insights for the development of future neuromodulatory treatments for OUD, and will further guide Dr. Ryu toward achieving independence in this research field.
