Travis E. Baker, Ph.D. - US grants

Project Summary Cognitive control appears to be one of the most consistently and severely affected functions in opioid use disorder (OUD), putting opioid users at higher risk of treatment dropout and drug relapse. While treatment programs for OUD typically focus on the cessation of substance use, there is now a firm basis for treatment programs to consider cognitive control difficulties in order to provide more neurocognitive targeted support for people seeking treatment for OUD. Our long-term goal is to improve cognitive control functioning in OUD with the aim to increase opioid users' success in treatment and maintaining abstinence, as well as achieving broader life changes. The main scientific premise is that cognitive control functioning may be improved in OUD by modulating the activity of the anterior cingulate cortex (ACC) with a non-invasive brain stimulation method called robot-assisted transcranial magnetic stimulation (TMS). This premise has been formulated on the basis of strong empirical and theoretical support, as well as recent findings produced by the applicant. Foremost, the ACC is a brain area centrally concerned with cognitive control and implicated in a variety of psychiatric disorders, including substance use disorders. In humans, the reward processing function of the ACC can be investigated using an event-related brain potential called the reward positivity, and numerous reward positivity studies have demonstrated that substance abusers, regardless of drug type, exhibit abnormal ACC activity to rewards. Importantly, TMS delivered to the left dorsal lateral prefrontal cortex has been shown to enhance neuronal activity in the ACC. We recently demonstrated that TMS can modulate the amplitude of the reward positivity in abstinent smokers, bolstering the utility of TMS as a tool to treat substance use disorders. Building on this empirical support, the overall objective in this application is to examine and improve cognitive control functioning in OUD. The rationale for the proposed research is that combining EEG with TMS provides an unprecedented opportunity for the systematic examination of the ACC reward function in OUD, and the potential role of TMS in modulating the level of reward value assigned by the ACC to goal-directed behaviors in OUD. This hypothesis will be tested by pursuing two specific aims. Because the reward positivity has not yet been investigated in an OUD population, our first aim is to use the reward positivity as a means to evaluate the reward function of the ACC in opioid users. Our second aim is to modulate the ACC reward function through the frontal-cingulate circuit via TMS to enhance the reward response by ACC in OUD, as evaluated by reward positivity. The approach is innovative because it would highlight an important yet under-investigated role of ACC dysfunction in OUD, and adapt an existing TMS technique to provide a novel treatment for OUD. Given that the US is in the midst of an OUD epidemic, the empirical findings obtained here would underscore such a need for continued research of the utility of TMS in the understanding and treatment of this disorder.

1. Abstract Intensive curative chemotherapy is associated with subacute neurotoxicity, which can adversely affect brain functioning. These adverse treatment sequelae add to the significant lifelong impact on survivors and families, and may entail a measurable cost to societal, medical, and educational systems. To date, converging evidence shows that 40?70% of childhood survivors who have gone through central nervous system (CNS) chemotherapy exhibit deficits in attention, working memory, and information processing speed, deficits believed to be caused by the neurotoxicity of the treatment. While non-CNS solid tumors (NST) collectively account for over one third of cancer diagnoses among children, little is known about the neurotoxic effects of chemotherapy in NST survivors. The overarching goal of this project is to examine the impact of chemotherapy-related neurotoxicity on well-established neural, cognitive, and computational indices of reward processing, cognitive control and working memory in pediatric NST survivors. To achieve our goal, we aim to recruit 30 survivors of childhood NTS (e.g., osteosarcomas, lymphomas, carcinomas, and neuroblastomas) aged 6?17 years old and 30 age-matched typically developing children. The specific aims of this project will be to examine group differences between electrophysiological, behavioral, and computational biomarkers associated with reward responsiveness (Aim 1a), reward valuation (Aim 1b), cognitive control (Aim 2a) and working memory (Aim 2b). Our overarching hypothesis is that chemotherapy for NST alters neural activity and brain structures involved in specific cognitive functions (reward processing, cognitive control, working memory), and we predict that our selected neurocognitive indices of these functions will reveal unique patterns of abnormal neural and computational processes compared to healthy, age- and sex-matched controls. We believe that the diversity in these areas of research, such as engaging multiple neural systems, enables us to address basic, translational, and applied questions, including those at the intersection of the brain, computation, and behavior. Our long-term goal will be to find out whether this cross-cutting research model will aid in the development of a more targeted and efficient chemotherapy treatments for pediatric NST, as well as aftercare for cognitive deficits. By identifying such neurocognitive phenotypes, this research will help develop future research and grant strategies aimed at reducing the adverse effects of chemotherapy as well as tailor therapeutic interventions for the specific cognitive profile of this population.