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BACKGROUND: Depression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements. OBJECTIVES: The aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors. METHODS: Adults (n = 108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression. RESULTS: Compared with usual care, PST led to reductions in left amygdala activation (−0.75; 95% CI: −1.49, −0.01) and global scores of the negative affect circuit (−0.43; −0.81, −0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized β-coefficients were −0.67 in usual care and −0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and −2.02 in usual care and −0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized β-coefficients were −0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and −1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet. CONCLUSIONS: Short-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413).

Background Depression exerts a staggering toll that is worsened with co-occurring chronic conditions such as obesity. It is imperative to develop more effective interventions for depression and to identify objective and biological plausible neural mechanisms to understand intervention outcomes. The current study uses functional neuroimaging to determine whether a behavioural intervention changes the negative affect circuit and whether these changes relate to subsequent improvements in both symptom and problem-solving outcomes in depressed patients with co-occurring obesity. Methods This study (‘ENGAGE’) was a pre-planned element of the randomized controlled trial, ‘RAINBOW’ (ClinicalTrials.gov NCT02246413). 108 depressed patients with obesity were randomized to receive an integrated collaborative care intervention (I-CARE) or usual care. Participants underwent functional neuroimaging using an established facial emotion task at baseline and two months (coinciding with the first two months of intervention focused on problem-solving therapy (‘PST’)). Amygdala, insula and anterior cingulate cortex activation was extracted using pre-planned definitions and standardized methods. The primary health and behavioural outcomes were depression symptom severity and problem-solving ability respectively, assessed at baseline, the main 6-month outcome point and at 12-month follow up. Mediation analyses used an intent-to-treat approach. Findings PST, relative to usual care, reduced amygdala activation engaged by threat stimuli at two months. This reduction mediated subsequent improvements in depression severity in an intervention-dependent manner. PST did not change insula activation at two months but did temper the strength of the relationship between insula activation and improvements in problem-solving ability. Interpretation The negative affect circuit may be an important neural target and potential mediator of PST in patients with comorbid obesity. Funding US National Institutes of Health/National Heart Lung and Blood Institute R01 HL119453 and UH2/UH3 HL132368

Background: Behavioral interventions for obesity have modest and variable effectiveness. Emotion dysregulation may hinder effective weight loss interventions, especially among those with comorbid depression. Whether neural mechanisms related to emotion dysregulation mediate the effect of behavioral intervention on improving health behaviors in obesity combined with depression is unknown. Hyperactivation of the amygdala and loss of functional connectivity with the anterior cingulate regions are neural characteristics of unhealthy responses to negative emotion and accompanying emotion dysregulation. Methods: Using data from a randomized clinical trial of 108 primary care adult patients with obesity and depression, we investigated whether changes in amygdala activity and connectivity following problem solving therapy for depression over 2 months mediate weight loss, physical activity, and/or dietary outcomes at 6 and 12 months. Results: Compared with controls (n=49), intervention participants (n=59) had a significant blunting of the otherwise unhealthy increase in activity of the bilateral amygdala at 2 months (right: -0.83, 95% CI -1.55 to -0.11; left: -0.86, -1.63 to -0.10). While increases in amygdala activity significantly correlated with decreases in leisure-time physical activity levels and total energy expenditure at 12 months in the control group, this relationship was tempered or reversed among intervention participants (for physical activity, right: usual care -692.9, -1365.3 to -20.6; interaction 652.2, -115.4 to 1419.9; left: usual care -686.0, -1127.9 to -244.1; interaction 664.7, 73.1 to 1256.4; for energy expenditure, right: usual care -1.82, -3.08 to -0.56; interaction 1.94, 0.50 to 3.38; left: usual care -1.72, -2.51 to -0.93; interaction 1.89, 0.84 to 2.94). Compared with controls, intervention participants had a significant increase of the otherwise unhealthy loss of amygdala-subgenual anterior cingulate connectivity at 2 months (0.78, 0.05 to 1.52). This increase in functional connectivity significantly correlated with a decrease in BMI at 6 months among intervention participants (usual care 0.04, -0.42 to 0.50; interaction -0.61, -1.20 to -0.02) and an increase in fruit and vegetable intake at 12 months across all participants (usual care 1.42, 0.27 to 2.57; interaction -0.95, -2.36 to 0.46). Conclusions: These findings highlight potential neural mechanism for optimizing the efficacy of behavioral intervention in comorbid obesity and depression.Trial registration: ClinicalTrials.gov#NCT02246413.URL: https://clinicaltrials.gov/ct2/show/NCT02246413.

Despite evidence for effective integrated behavior therapy for treating comorbid obesity and depression, treatment response is highly variable and the underlying neurobiological mechanisms remain unknown. This hampers efforts to identify mechanistic targets in order to optimize treatment precision and potency. Funded within the NIH Science of Behavior Change (SOBC) Research Network, the 2-phased ENGAGE research project applies an experimental precision medicine approach to address this gap. The Phase 1 study focused on demonstrating technical feasibility, target engagement and potential neural mechanisms of responses to an integrated behavior therapy. This therapy combines a video-based behavioral weight loss program and problem-solving therapy for depression, with as-needed intensification of antidepressant medications, and its clinical effectiveness was demonstrated within a parent randomized clinical trial. Here, we describe the ENGAGE Phase 2 (ENGAGE-2) study protocol which builds on Phase 1 in 2 ways: (1) pilot testing of an motivational interviewing-enhanced, integrated behavior therapy in an independent, primarily minority patient sample, and (2) evaluation of a priori defined neural targets, specifically the negative affect (threat and sadness) circuits which demonstrated engagement and malleability in Phase 1, as mediators of therapeutic outcomes. Additionally, the Phase 2 study includes a conceptual and methodological extension to explore the role of microbiome-gut-brain and systemic immunological pathways in integrated behavioral treatment of obesity and depression. This protocol paper documents the conceptualization, design and the transdisciplinary methodologies in ENGAGE-2, which can inform future clinical and translational research in experimental precision medicine for behavior change and chronic disease management. Trial registration: ClinicalTrials.gov #NCT 03,841,682.

Introduction: Neural mechanisms underlying behavior therapy in obesity are poorly understood, particularly in patients with comorbid depression. Putative targets include neural circuits for conscious and nonconscious emotion regulation. Hypothesis: Changes in a priori neural circuits for emotion regulation from baseline (0) to 2 mo (mediators, M) mediate changes in BMI, physical activity, and eating behaviors from 0 to 6 or 12 mo (outcomes, Y). Methods: In a trial of integrated behavior therapy, adults with obesity and depression were randomized to intervention (n=59) or usual care (n=49). The yearlong intervention included 6 in-person problem solving therapy (PST) sessions for depression by 2 mo, 3 additional PST sessions for depression and 11 home videos on lifestyle changes for weight loss by 6 mo, and 6 maintenance calls by 12 mo. Participants completed validated conscious and nonconscious facial emotion viewing tasks in fMRI at 0 and 2 mo (time point corresponding to initial PST for depression in the intervention) and weight and height (baseline only) measurements, 7-day physical activity recalls, and 24-hour dietary recalls at 0, 6, and 12 mo. Analyses tested mediation as showing both a significant treatment effect (X) of the intervention vs. usual care on the mediator (X->M, path a ) and a significant correlation of the mediator with the outcome either as a main effect or an interaction effect by treatment group (M->Y, path b ). Results: Compared with usual care, the intervention led to significantly reduced nonconscious reactivity to threat-related facial emotions (fear, anger) at 2 mo for the left (-0.89, 95% CI -1.64 to -0.14; P =.02) and right amygdala (-0.84, 95% CI -1.54 to -0.13; P =.02) ( path a ). These reductions correlated significantly with increased leisure-time physical activity (MET minutes/wk) at 12 mo: main effect -686.0 (95% CI -1127.9 to -244.1; P =.003) and interaction effect 664.7 (95% CI 73.1 to 1256.4; P =.03) for the left amygdala and main effect -692.9 (95% CI -1365.3 to -20.6; P= .04) for the right amygdala. Similarly, the reductions correlated significantly with increased energy expenditure (kcal/kg/d) at 12 mo: main effect -1.72 (95% CI -2.49 to -0.95; P P P =.006) and interaction effect 1.94 (95% CI 0.50 to 3.38; P =.01) for the right amygdala ( path b ). Nonconscious reactivity to threat in bilateral amygdala did not correlate significantly with changes in BMI or eating behaviors. Conclusions: Reduced nonconscious reactivity to threat in bilateral amygdala in response to initial PST for depression significantly mediated improvements in leisure-time physical activity and energy expenditure. Results advance the understanding of neural mechanisms underlying behavior therapy in obesity and inform intervention optimization to enhance efficacy.