Project Summary / Abstract This study seeks to investigate mechanisms underlying treatment responses in individuals with obesity (OB) and binge-eating disorder (BED), a group of individuals with OB particularly refractory to existing treatments and associated with steep weight gain trajectories and significant morbidity. Specifically, we aim to add neural, cognitive and behavioral measures to a recently funded staged randomized clinical trial (RCT) to investigate alone and in combination lisdexamfetamine (LDX -the only medication with an FDA indication for BED) and cognitive behavioral therapy (CBT – the best established behavioral therapy for BED that has demonstrated efficacy in reducing binges but not in generating weight loss). The proposed study benefits from leveraging data about to be collected in a RCT funded by NIH and will provide insight into neural, cognitive and behavioral mechanisms linked to OB and BED and the proposed treatments. The data also provide the potential to examine and explore conceptually and empirically supported predictors, moderators, and mediators of outcomes. The aim is to use fMRI to identify pre-treatment brain activations across several domains (preoccupation with food, cognitive control, reward processing, and negative affect) and changes in those activations during three 12-week treatment conditions (CBT, LDX, CBT/LDX) associated prospectively and over time with outcomes acutely (i.e., at post-treatment) and at longer terms (i.e., 6, 12 and 18 month follow-up assessments). A similar approach will assess cognitive and behavioral measures to examine and explore how these domains will relate to treatment outcomes. This study will provide new and novel information regarding possible “mechanistic” factors through which these distinct pharmacological and behavioral interventions achieve outcomes. The proposed study will examine N=120 OB patients with BED recruited from a RCT of LDX and CBT. fMRI will be performed pre- and post-treatment to identify brain activations underlying food-cue reactivity (Preoccupation Phase), cognitive control (Impaired Control Phase), reward processing (Binge Episode Phase), and emotion regulation (Negative Affect Phase). Pre-treatment levels and changes in these domains and their neural correlates that occur with treatment will be examined prospectively in relation to acute- and long- term outcomes. Exploratory measures will assess other brain measures (white matter, gray matter, resting state, circuitry) in relation to treatment outcomes. Measures assessing impulsivity, compulsivity and dopamine- dependent and dopamine-independent cognitive and behavioral processes will be obtained to explore “predictors” of treatment responses to CBT and LDX, identify changes over time associated with LDX and CBT treatments and probe moderation and mediation models to identify who might respond best to specific treatments and potential mechanisms of action for CBT and LDX.

Project Narrative / Relevance to Public Health This grant application seeks funds to add measures to a randomized clinical trial comparing the efficacies of two leading treatments for binge-eating disorder (BED), cognitive behavioral therapy (CBT) and lisdexamfetamine (LDX) in persons with BED and obesity. The proposed study will integrate state-of-the-art functional magnetic resonance imaging (fMRI) tasks before and after treatment to assess neural processes underlying cue reactivity and craving to energy-dense food cues, cognitive control, non-food reward processing, and emotional regulation in relation to treatment outcomes and identify mechanisms underlying treatment responses, with additional measures proposed to assess psychological and behavioral constructs of impulsivity, compulsivity, executive functioning. This study has significance for developing an understanding of the mechanisms of leading treatments for BED, which will inform the refinement of interventions for binge eating in obesity.