Neurobiological Threat Reactivity as a Biomarker of Chronic Pain and Alcohol Use Disorder

About This Grant

PROJECT SUMMARY/ABSTRACT Chronic pain and alcohol use disorder (AUD) frequently co-occur, leading to worse outcomes than either condition alone. Although treatments for chronic pain and AUD exist, they often prove ineffective for individuals suffering from both conditions. The unmet treatment needs in this group highlight the urgent necessity for developing effective mechanism-driven interventions for chronic pain and AUD comorbidity. Prior research suggests that a maladaptive response to uncertain threat may be a shared pathway linking chronic pain and AUD. The unpredictability of a potentially painful impending threat can increase pain intensity and sensitivity (hyperalgesia), elicit anticipatory anxiety, and activate the interoceptive brain circuit anchored in the anterior insular cortex (AIC). The candidate previously showed that AIC circuit hyperreactivity to uncertain threat predicts coping-motivated binge drinking in youth and characterizes individuals with AUD, and her preliminary data further suggest that the AIC may also be a key region targeted by comorbid chronic pain and AUD. However, no study has directly tested this hypothesis in individuals with chronic pain with and without AUD. To fill this knowledge gap, the K99/R00 proposal will combine functional imaging probe of neural circuitry with longitudinal real-time tracking of daily fluctuations in pain symptoms and alcohol use behaviors (consumption and craving) in adults with and without chronic pain and AUD. The first aim will examine if individuals with both conditions show greater AIC activation and connectivity than either condition alone compared with controls. The second aim will assess how AIC circuit function correlates with the severity of chronic pain and AUD symptoms, hypothesizing that higher symptom severity in both conditions will correspond to greater AIC activation and connectivity, with a stronger effect for individuals with concurrent symptoms. The third aim will evaluate if AIC circuit function predicts real-world chronic pain and AUD symptoms and, thus, is a useful treatment target. Completing this study will support the candidate's transition to an independent investigator with a focused program of neuroimaging alcohol and chronic pain research. Her career goals are to investigate coping strategies and mechanisms that develop and maintain AUD in comorbid populations and to translate the knowledge gained from her research into more effective prevention, intervention, and treatment strategies. To achieve these goals, the candidate will complete formal coursework, and receive structured mentoring and supervised training in research and professional development by experts in clinical phenomenology and neuroscience of chronic pain and AUD (Dr. Rajita Sinha, primary mentor, and Dr. Declan Barry), machine learning and connectome-based-predictive modeling (Dr. Dustin Scheinost), and through collaboration with a biostatistician with expertise in intensive real-time longitudinal data collection and analysis (Dr. Eugenia Buta). The outstanding research environment and intellectual resources at Yale University will provide the candidate with ample training in novel neuroimaging and analytical techniques and guidance on data dissemination, networking, oral communication, and grant writing.