Early changes in neural circuit function engaged by negative emotion and modified by behavioural intervention are associated with depression and problem-solving outcomes: A report from the ENGAGE randomized controlled trial

Andrea N Goldstein-Piekarski, Joseph Wielgosz, Lan Xiao, Patrick Stetz, Carlos G Correa, Sarah E Chang, Nan Lv, Lisa G Rosas, Philip W Lavori, Mark B Snowden, Elizabeth M Venditti, Janine M Simmons, Joshua M Smyth, Trisha Suppes, Megan A Lewis, Olusola Ajilore, Jun Ma, Leanne M Williams, Andrea N Goldstein-Piekarski, Joseph Wielgosz, Lan Xiao, Patrick Stetz, Carlos G Correa, Sarah E Chang, Nan Lv, Lisa G Rosas, Philip W Lavori, Mark B Snowden, Elizabeth M Venditti, Janine M Simmons, Joshua M Smyth, Trisha Suppes, Megan A Lewis, Olusola Ajilore, Jun Ma, Leanne M Williams

Abstract

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.

Keywords: Amygdala; Depression; Insula; Neuroimaging; Obesity; Problem-solving.

Conflict of interest statement

Declaration of Competing Interest LMW is on the Scientific Advisory Board for One Mind Psyberguide and the External Advisory Board for the Laureate Institute for Brain Research. JM is a paid scientific consultant for Health Mentor, Inc. (San Jose, CA). OA is the co-founder of Keywise AI and the servers on the advisory boards of Blueprint Health and Embodied Labs. TS reports in the last 36 months grants from Merck, grants from National Institute on Drug Abuse, grants from National Institute of Health, grants from Palo Alto Health Sciences, grants from Stanley Medical Research Institute, grants from Pathways Genomics, personal fees from Sunovion Pharmaceuticals, Inc., personal fees from American Society of Clinical Psychopharmacology, personal fees from Impel NeuroPharma Inc., personal fees from Intracellular Therapies, personal fees from Servier (Australia), personal fees from Allergan, Inc., personal fees from Medscape (WebMD), personal fees from CME Institute (Physicians Postgraduate Press, Inc.), personal fees from CMEology, personal fees from American Psychiatric Association Publishing, personal fees from Hogrefe Publishing, personal fees from Jones and Bartlett, personal fees from Wolters Kluwer Health (UpToDate), outside the submitted work.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
CONSORT chart for participant inclusion in the primary sample.
Fig. 2
Fig. 2
PST-induced target engagement of amygdala engaged by nonconscious threat and subsequent depression symptom change at 6 months. Amygdala engagement by nonconscious threat stimuli at 2 months mediates subsequent depressive symptom improvements at 6 months. (Path a) Early change in bilateral amygdala engagement for PST versus usual care. (Path B) Association of early change in bilateral amygdala engagement with subsequent change in depression symptoms. All changes are relative to baseline session. For the box plots, the central thick black bar represents the mean, grey shaded boxes represent standard error (dark grey) and standard deviation (lighter grey) of the mean, and the whiskers represent 2 standard deviations of the mean. The impact on the intervention on clinical variables are reported in Ma et al. 2019 for the full RAINBOW trial and presented for the RAINBOW/ENGAGE sub-sample in supplement. aBOLD activation vs. neutral cue, z-scored. Abbreviations: ACC = Anterior Cingulate Cortex; sgACC = subgenual ACC; Ant Insula = Anterior Insula; Amyg = Amygdala; R = right; L = left; SCL-20 = Depression Symptom Checklist, 20-item; PST = initial 2-month intervention phase of the I-CARE program focused on a 7-step problem-solving therapy process.
Fig. 3
Fig. 3
PST-induced target engagement of anterior insula engaged by sad and subsequent problem-solving behaviour change at 6 months. Anterior insula engagement by conscious sad stimuli at 2 months is associated with subsequent change in problem-solving ability at 6 months (Path a) Early change in anterior insula engagement for PST versus usual care. (Path b) Association of early change in anterior insula engagement with subsequent change in problem-solving ability. All changes are relative to baseline session. For the box plots, the central thick black bar represents the mean, grey shaded boxes represent standard error (dark grey) and standard deviation (lighter grey) of the mean, and the whiskers represent 2 standard deviations of the mean. The impact on the intervention on clinical variables are reported in Ma et al. 2019 for the full RAINBOW trial and presented for the RAINBOW/ENGAGE sub-sample in supplement. aBOLD activation vs. neutral cue, z-scored; b Social Problem-Solving Inventory, Revised – Short form. Abbreviations: ACC = Anterior Cingulate Cortex; pgACC = pregenual ACC; Ant. Insula = Anterior Insula; Amyg = Amygdala; R = right; L = left; PST = initial 2-month intervention phase of the I-CARE program focused on a 7-step problem-solving therapy process.

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