Association of Changes in Neural Targets and Dietary Outcomes among Patients with Comorbid Obesity and Depression: Post hoc Analysis of ENGAGE-2 Mechanistic Clinical Trial

Nan Lv; Hagar Hallihan; Lan Xiao; Leanne M Williams; Olusola A Ajilore; Jun Ma

doi:10.1016/j.tjnut.2023.01.022

. 2023 Jan 23;153(3):880–896. doi: 10.1016/j.tjnut.2023.01.022

Association of Changes in Neural Targets and Dietary Outcomes among Patients with Comorbid Obesity and Depression: Post hoc Analysis of ENGAGE-2 Mechanistic Clinical Trial

Nan Lv ^1,^†, Hagar Hallihan ^1,^†, Lan Xiao ², Leanne M Williams ^3,⁴, Olusola A Ajilore ^5,^‡, Jun Ma ^1,^∗,^‡

PMCID: PMC10196721 PMID: 36931755

Abstract

Background

Disruptions in brain circuits that regulate cognition and emotion can hinder dietary change and weight loss among individuals with obesity and depression.

Objective

The study aimed to investigate whether changes in brain targets in the cognitive control, negative affect, and positive affect circuits after 2-mo problem-solving therapy (PST) predict changes in dietary outcomes at 2 and 6 mo.

Methods

Adults with obesity and depression from an academic health system were randomly assigned to receive PST (7-step problem-solving and behavioral activation strategies) over 2 mo or usual care. Seventy participants (mean age = 45.9 ± 11.6 y; 75.7% women, 55.7% Black, 17.1% Hispanic, 20.0% White; mean BMI = 36.5 ± 5.3 kg/m²; mean Patient Health Questionnaire-9 depression score = 12.7 ± 2.8) completed functional MRI and 24-h food recalls. Ordinary least square regression analyses were performed.

Results

Among intervention participants, increased left dorsal lateral prefrontal cortex (dLPFC) activity of the cognitive control circuit at 2 mo was associated with increased diet quality (β: 0.20; 95% CI: −0.02, 0.42) and decreased calories (β: −0.19; 95% CI: −0.33, −0.04), fat levels (β: −0.22; 95% CI: −0.39, −0.06), and high-sugar food intake (β: −0.18; 95% CI: −0.37, 0.01) at 6 mo. For the negative affect circuit, increased right dLPFC–amygdala connectivity at 2 mo was associated with increased diet quality (β: 0.32; 95% CI: −0.93, 1.57) and fruit and vegetable intake (β: 0.38; 95% CI: −0.75, 1.50) and decreased calories (β: −0.37; 95% CI: −1.29, 0.54), fat levels (β: −0.37; 95% CI: −1.50, 0.76), sodium concentrations (β: −0.36; 95% CI: −1.32, 0.60), and alcohol intake (β: −0.71; 95% CI: −2.10, 0.68) at 2 but not at 6 mo. The usual care group showed opposing associations. The 95% CIs of all between-group differences did not overlap the null, suggesting a significant treatment effect.

Conclusions

Among adults with obesity and depression who underwent PST compared with those under usual care, improved dLPFC–amygdala regulation of negative affective brain states predicted dietary improvements at 2 mo, whereas improvements in dLPFC-based cognitive control predicted dietary improvements at 6 mo. These findings warrant confirmatory studies.

This trial was at clinicaltrials.gov as NCT03841682.

Keywords: dorsal lateral prefrontal cortex, amygdala, cognitive control, negative affect, functional neuroimaging, diet, obesity, depression

Introduction

Obesity is a major public health problem and often comorbid with prevalent mental health disorders, such as depression. Adults with obesity experience a 55% increased risk of developing depression, compared with those with normal weight [1]. Depression can interfere with participant adherence and response to standard behavior weight loss treatment [2, 3].

Until recently, effective integrated treatments for obesity with comorbid depression were lacking [4]. The Research Aimed at Improving Both Mood and Weight trial, the largest randomized behavioral intervention clinical trial of comorbid obesity and depression to date (N = 409), showed that an integrated collaborative care intervention led to significant improvements in weight loss and depressive and anxiety symptoms over 12 mo, compared with usual care [5, 6]. The ENGAGE-2 trial, a follow-on neural mechanistic trial, further showed that a refined version of that integrated intervention led to significantly improved depressive and anxiety symptoms over 6 mo but not weight loss, in an independent, more racially and ethnically diverse sample than the Research Aimed at Improving Both Mood and Weight sample [7]. To enhance weight loss outcomes, a better understanding of the underlying neural mechanisms of treatment effects on dietary behaviors may guide more personalized treatment approaches.

Studies have evaluated the role of brain function in eating and obesity; however, little is known about how neural changes in response to depression treatment affect dietary changes among adults with obesity and comorbid depression. Disruption in brain circuits involved in cognitive control and emotion regulation not only contribute to depression but may also hinder effective eating behavior change. Alterations in cognitive control have been linked with an impaired ability to anticipate the consequences of overeating and control over the actual behavior, leading to weight gain and obesity [8]. Similarly, emotion dysregulation may increase vulnerability to maladaptive behaviors, such as overeating and binge eating that accompany stress and negative affective states, thus limiting the effectiveness of weight loss interventions [9, 10]. In particular, selective activation of the central amygdala involved in negative affect might also increase overeating accompanied by stress, confining effective weight loss interventions [11]. In addition, abnormal activity in the dorsolateral prefrontal cortex (dLPFC) has been shown to negatively affect behavior regulation, such as overeating and less interest toward weight loss interventions [12]. Furthermore, excessive consumption of palatable food may trigger neuroadaptive responses in brain reward circuitry, and such vulnerabilities in brain reward systems can increase predisposition to obesity [13, 14].

Leveraging data from the ENGAGE-2 trial, this post hoc analysis investigated how changes in neural targets in the cognitive control, negative affect, and positive affect circuits after a brief psychotherapy compared with those after usual care predicted changes in dietary outcomes.

Materials/Subjects and Methods

The institutional review board for the University of Illinois (UI)–Chicago approved this study. All participants provided written informed consent. The trial protocol [15] and primary outcomes [7] were previously published.

Participants

Participants were recruited from the internal medicine outpatient care clinics at the UI Health, a minority-serving academic health system. Adults were eligible if they recorded a BMI of ≥30 kg/m² (≥27 kg/m², if Asian) and a Patient Health Questionnaire-9 score of ≥10, without serious medical or psychiatric comorbidities or other exclusions. Participants were recruited between 1 March 2019 and 19 March 2020; the date of the final 6-mo follow-up was 31 August 2020. To comply with NIH reporting requirements, participants were asked to self-identify their race and ethnicity from fixed categories.

Study Procedures, Randomization, and Blinding

Detailed study procedures were as previously published [15]. Participants (N = 106) were randomly assigned in a 2:1 ratio to receive the refined Integrated Coaching for Better Mood and Weight (I-CARE, version 2) intervention or usual care using a validated online system [16] based on covariate-adaptive minimization (Figure 1) [17]. This method was used to achieve better-than-chance marginal balance across multiple baseline characteristics: age, sex, race/ethnicity, education, BMI, Depression Symptom Checklist 20-item score, and current use of antidepressant medication (yes/no). Investigators, the data and safety monitoring board, outcome assessors, and the data analyst were blinded to participant treatment assignment until after completing the primary data lock.

Patient flow from enrollment and follow-up to the data analysis.

Intervention

The intervention was refined based on the I-CARE intervention, previously shown to be effective for treating comorbid obesity and depression [5]. The updated version (I-CARE2) included specific refinements as described in the protocol [15]. I-CARE2 combined the Group Lifestyle Balance video program [18] for weight loss and problem-solving therapy (PST) involving the 7-step problem-solving and behavioral activation strategies for depression care management [19, 20]. The intervention focused on depression first with 6 one-on-one PST sessions with a trained health coach over 2 mo, followed by 3 additional PST sessions plus 11 home-viewed Group Lifestyle Balance videos over the next 4 mo. Participants self-monitored weight and diet and synchronized activity tracker data through the Fitbit application throughout the intervention. Results on intervention participant engagement and feedback were published previously [21].

Usual Care

During enrollment, participants in both the intervention and usual care control groups were advised to continue routine medical care and received a handout on behavioral health and weight management services at the UI Health.

Outcome Measures

Trained study staff interviewed participants to conduct 2–3 multiple-pass 24-h dietary recalls using the Nutrition Data System for Research (NDSR) [22, 23] at the baseline and at 2 and 6 mo. Multiple-pass 24-h dietary recalls have been validated in diverse populations, including those with obesity or other comorbidities [24, 25]. The DASH diet is recommended by the USDA as a healthy dietary pattern [26]. As an index of overall diet quality, the DASH score was computed based on 9 nutrients (total fat, saturated fat, protein, cholesterol, fiber, magnesium, calcium, sodium, and potassium levels) [27] provided by the NDSR software. NDSR also provided total calories. Daily servings of fruit and vegetables; low-fat/fat-free dairy food; whole grains; nuts, seeds, and legumes; high-sugar food, and alcohol intake were calculate using the Food Group Serving Count System Output File generated by NDSR. The averages of the dietary values from a participant’s recalls at each time point were used in the analysis.

Participants underwent fMRI at the baseline and at 2 mo, following a previously established fMRI protocol [28, 29] (Supplemental Methods). The cognitive control circuit was engaged using a go/no-go task. The target regions of interest (ROIs) were the activity of dLPFC (bilaterally) and connectivity between dLPFC and dorsal anterior cingulate cortex (dACC). The negative affect circuit was engaged by viewing threat faces in the nonconscious viewing condition. Informed by previous findings [2, 30], the ROIs were activation of the amygdala (bilaterally) and connectivity between dLPFC and amygdala. The positive affect circuit was engaged by conscious happy face–viewing task. ROIs in this circuit included activation of the ventral medial prefrontal cortex (vMPFC) and ventral striatum (vStriatum, bilaterally).

Patient-level activation of the ROIs for each contrast of interest for each task (i.e., no-go compared with go, threat compared with neutral, and happy compared with neutral) were derived in a manner consistent with the methods used for a healthy reference sample [[31], [32], [33]]. Similarly, psychophysiological interaction [34] analyses were used to quantify functional connectivity between ROIs. These activation and connectivity values were winsorized using ±3 SDs. Of the 106 participants, 70 had the NDSR and fMRI data and were included in the analysis.

Statistical Analysis

An ordinary least square regression ( $Δ Y_{t = 2 o r 6} = Y_{0} + X + Δ M_{t = 2} + X Δ M_{t = 2} + ε$ ) analysis was used to test the association of changes in a neural target at 2 mo ( $Δ M_{t = 2}$ ) with changes in a dietary outcome at 2 and 6 mo separately ( $Δ Y_{t = 2 o r 6}$ ), adjusting for the baseline value of the outcome measure ( $Y_{0}$ ). The regression models also included a test of the treatment effect ( $X$ with usual care = 0, intervention = 1) and the interaction of treatment by change in the neural target ( $X Δ M_{t = 2}$ ). For a uniform comparison of effect sizes across dietary measures with different units, each dietary outcome was standardized using the baseline SD of the ENGAGE-2 sample. Each model included all participants with follow-up data on the neural target at 2 mo and the outcome at 2 or 6 mo, and participants were analyzed based on the group to which they were assigned. No imputation of fMRI and diet data was conducted because of the small sample size and the challenges of imputing fMRI data [35]. Model-based adjusted mean differences with 95% CIs were reported.

This post hoc analysis study was hypothesis generating by nature. Thus, we focused on standardized mean estimates with 95% CIs rather than P values as recommended in the American Statistical Association Statement and a recent position article [36, 37] and discussed effects of medium or larger size, especially where the findings were consistent across related outcome measures. In particular, we highlighted associations where the 95% CIs of the interaction effects did not include the null, indicating meaningful between-group differences. Nonetheless, to aid transparent interpretation, we reported unadjusted and adjusted P values (P_adj) using the false discovery rate procedure [38] to control the family-wise error rates across tests of similar hypotheses. In particular, the tests involving the neural targets within each neural circuit for all dietary outcomes at each time point separately (2 or 6 mo) were considered a family, and the false discovery rate procedure was applied accordingly. All analyses were conducted using SAS, version 9.4 (SAS Institute).

Changes in Protocol Owing to the COVID-19 Pandemic

Recruitment and baseline data collection were not affected by the pandemic. Baseline and 2-mo fMRI scans occurred before the COVID-19 lockdown date, 16 March 2020, in Illinois. Of the 70 participants included in the analysis, 1 completed the 24-h dietary recalls after the lockdown date at 2 mo and 31 completed the recalls after the lockdown at 6 mo. After 16 March 2020, delivery of the intervention sessions was changed from in-person to telephone or Zoom video conference.

Results

Sample Characteristics

The mean age of the 70 participants included in this study was 45.9 ± 11.6 y. Most of the participants were women (75.7%), 55.7% were African American, and 17.1% were Hispanic. Participants recorded moderately severe obesity (mean BMI = 36.5 ± 5.3 kg/m²) and mild depression (mean Symptom Checklist 20-item score = 1.2 ± 0.7) (Table 1). The baseline diet quality was low, with a mean DASH score of 1.6 ± 1.0. The baseline characteristics of the included participants were not significantly different from the participants who were not included in the analysis.

TABLE 1.

Baseline characteristics of adults with obesity and depression

Characteristic	Overall (n = 106)	Analysis cohort		P
Characteristic	Overall (n = 106)	With data (n = 70)	Without data (n = 36)	P
Age (y), mean (SD)¹	47.0 ± 11.9	45.9 ± 11.6	49.0 ± 12.4	0.21
Female sex (%)¹	76.4	75.7	77.8	0.81
Race/ethnicity (%)¹				0.56
Non-Hispanic White	17.9	20.0	13.9
African American	54.7	55.7	52.8
Asian/Pacific Islander	1.9	2.9	0.0
Hispanic	19.8	17.1	25.0
Other (e.g., decline to state, multirace)	5.7	4.3	8.3
Education (%)¹				0.40
High school/GED or less	13.2	11.4	16.7
College: 1–3 y	40.6	37.1	47.2
College: ≥4 y	27.4	28.6	25.0
Postcollege	18.9	22.9	11.1
Income (%)				0.11
<$35,000	32.1	24.3	47.2
$35,000 to <$55,000	24.5	28.6	16.7
$55,000 to <$75,000	14.2	15.7	11.1
≥$75,000	29.2	31.4	25.0
BMI (kg/m²), mean (SD)¹	37.1 ± 6.0	36.5 ± 5.3	38.2 ± 7.3	0.23
Weight (kg), mean (SD)	101.5 ± 15.2	100.3 ± 13.4	103.7 ± 18.2	0.33
Waist circumference (cm), mean (SD)	112.7 ± 12.6	112.4 ± 11.2	113.4 ± 15.2	0.75
PHQ-9 score, mean (SD)	12.8 ± 2.8	12.7 ± 2.8	13.2 ± 2.8	0.40
SCL-20 score, mean (SD)¹	1.2 ± 0.7	1.2 ± 0.7	1.2 ± 0.6	0.83
Current use of ADM (%)¹	17.9	17.1	19.4	0.77
SBP (mm Hg), mean (SD)	122.5 ± 16.8	121.6 ± 14.3	124.5 ± 21.0	0.46
DBP (mm Hg), mean (SD)	77.0 ± 11.0	76.7 ± 9.5	77.7 ± 13.5	0.70
DASH score, mean (SD)	1.6 ± 1.0	1.6 ± 1.0	1.6 ± 0.9	0.85

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ADM, antidepressant medication; DBP, diastolic blood pressure; GED, general educational development; PHQ-9, Patient Health Questionnaire-9; SBP, systolic blood pressure; SCL-20, Depression Symptom Checklist-20.

Prognostic factors for randomization: age, sex, race/ethnicity, education, BMI, SCL-20 score, and current use of antidepressant medication.

Association of Neural Targets With Dietary Outcomes

Cognitive control circuit

TABLE 2, TABLE 3 summarize associations between changes of neural targets in the cognitive control circuit at 2 mo and changes of dietary outcomes at 2 and 6 mo, respectively, in the intervention and usual care groups and between-group differences. Between-group differences in these associations were primarily noted for changes of dietary outcomes at 6 mo. An increase in the left dLPFC activity was associated with an increase in DASH scores (β: 0.20; 95% CI: −0.02, 0.42) and decreases in calories (β: −0.19; 95% CI: −0.33, −0.04), fat levels, (β: −0.22; 95% CI: −0.39, −0.06), and high-sugar food intake (β: −0.18; 95% CI−0.37, 0.01) in the intervention group; these associations were opposite in the usual care control group, and the 95% CIs of the interaction effects did not include the null (Table 3). A decrease in connectivity between the left dLPFC and medial dACC was associated with increased DASH scores (β: −0.28; 95% CI: −0.57, 0.02) and decreased sodium intake (β: 0.22; 95% CI: −0.04, 0.48) in the intervention group; these associations were opposite in the usual care group, and the 95% CIs of the interaction effects did not include the null (Table 3). Moreover, for whole grain intake, the 95% CIs of between-group differences did not overlap with the null for both the left dLPFC activity (β: −0.64; 95% CI: −1.01, −0.27) and connectivity between the left dLPFC and medial dACC (β: 0.51; 95% CI: 0.07, 0.95).

TABLE 2.

Associations between changes of neural targets in cognitive control circuit (GONOGO) at 2 mo and changes of dietary outcomes at 2 mo between the PST intervention and usual care patients with obesity and depression¹

Neural target	Hemisphere²	Dietary outcome change³	Intervention⁴			Usual care effect			Interaction (between-group difference)
Neural target	Hemisphere²	Dietary outcome change³	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj
dLPFC	L	Energy (kcal/d)	−0.08 (−0.26, 0.10)	0.38	0.82	0.10 (−0.31, 0.52)	0.61	0.91	−0.19 (−0.64, 0.27)	0.41	0.86
	R		0.02 (−0.24, 0.28)	0.89	0.98	−0.01 (−0.49, 0.47)	0.98	0.99	0.02 (−0.52, 0.57)	0.93	0.98
dLPFC to dACC	L–M		0.17 (−0.07, 0.41)	0.16	0.63	0.23 (−0.18, 0.63)	0.27	0.78	−0.06 (−0.53, 0.42)	0.81	0.96
	R–M		0.21 (−0.04, 0.45)	0.10	0.53	−0.05 (−0.47, 0.37)	0.82	0.96	0.26 (−0.23, 0.75)	0.30	0.78
dLPFC	L	DASH score	0.12 (−0.13, 0.37)	0.33	0.79	−0.33 (−0.89, 0.23)	0.24	0.78	0.45 (−0.16, 1.06)	0.15	0.60
	R		0.12 (−0.23, 0.48)	0.49	0.89	−0.36 (−1.01, 0.29)	0.27	0.78	0.48 (−0.25, 1.22)	0.19	0.72
dLPFC to dACC	L–M		−0.16 (−0.48, 0.17)	0.35	0.80	−0.31 (−0.87, 0.26)	0.28	0.78	0.15 (−0.50, 0.80)	0.65	0.93
	R–M		−0.35 (−0.69, −0.01)	0.04	0.39	−0.05 (−0.63, 0.53)	0.87	0.97	−0.30 (−0.96, 0.36)	0.37	0.82
dLPFC	L	Fruit and vegetable (servings/d)	0.07 (−0.17, 0.30)	0.57	0.90	0.05 (−0.48, 0.58)	0.85	0.97	0.01 (−0.57, 0.59)	0.96	0.99
	R		0.15 (−0.18, 0.48)	0.36	0.80	−0.24 (−0.88, 0.39)	0.44	0.87	0.40 (−0.31, 1.10)	0.26	0.78
dLPFC to dACC	L–M		−0.09 (−0.40, 0.22)	0.56	0.90	−0.27 (−0.82, 0.27)	0.32	0.78	0.18 (−0.43, 0.80)	0.56	0.90
	R–M		0.15 (−0.17, 0.46)	0.36	0.80	0.38 (−0.17, 0.92)	0.17	0.67	−0.23 (−0.86, 0.40)	0.47	0.89
dLPFC	L	Low-fat/fat-free dairy (servings/d)	−0.05 (−0.21, 0.10)	0.50	0.89	−0.14 (−0.49, 0.22)	0.44	0.87	0.08 (−0.30, 0.47)	0.66	0.94
	R		0.04 (−0.18, 0.27)	0.69	0.95	−0.12 (−0.53, 0.30)	0.57	0.90	0.16 (−0.32, 0.64)	0.50	0.89
dLPFC to dACC	L–M		0.29 (0.10, 0.48)	0.003	0.16	0.14 (−0.19, 0.47)	0.41	0.86	0.15 (−0.23, 0.54)	0.43	0.87
	R–M		0.26 (0.06, 0.47)	0.01	0.27	−0.19 (−0.54, 0.16)	0.28	0.78	0.46 (0.06, 0.86)⁵	0.03	0.39
dLPFC	L	Fat (g/d)	−0.04 (−0.27, 0.18)	0.69	0.95	0.13 (−0.38, 0.63)	0.61	0.91	−0.17 (−0.73, 0.38)	0.53	0.90
	R		0.06 (−0.26, 0.38)	0.70	0.95	0.03 (−0.56, 0.61)	0.93	0.98	0.03 (−0.63, 0.70)	0.92	0.98
dLPFC to dACC	L–M		0.15 (−0.14, 0.45)	0.30	0.78	0.23 (−0.27, 0.73)	0.36	0.80	−0.08 (−0.65, 0.50)	0.79	0.96
	R–M		0.33 (0.04, 0.62)	0.03	0.39	−0.17 (−0.67, 0.34)	0.51	0.89	0.50 (−0.09, 1.08)	0.09	0.53
dLPFC	L	Sodium (mg/d)	−0.08 (−0.25, 0.10)	0.38	0.83	0.16 (−0.23, 0.55)	0.43	0.87	−0.23 (−0.66, 0.19)	0.28	0.78
	R		−0.02 (−0.28, 0.24)	0.88	0.98	0.04 (−0.41, 0.50)	0.85	0.97	−0.06 (−0.60, 0.47)	0.82	0.96
dLPFC to dACC	L–M		0.03 (−0.20, 0.26)	0.81	0.96	0.07 (−0.32, 0.47)	0.72	0.95	−0.04 (−0.50, 0.42)	0.85	0.97
	R–M		0.25 (0.01, 0.49)	0.04	0.39	−0.12 (−0.52, 0.27)	0.53	0.90	0.37 (−0.09, 0.84)	0.11	0.53
dLPFC	L	Whole grain (servings/d)	−0.05 (−0.30, 0.21)	0.71	0.95	0.48 (−0.11, 1.08)	0.11	0.53	−0.53 (−1.17, 0.11)	0.11	0.53
	R		0.07 (−0.30, 0.44)	0.71	0.95	−0.04 (−0.73, 0.66)	0.92	0.98	0.11 (−0.68, 0.89)	0.79	0.96
dLPFC to dACC	L–M		−0.04 (−0.39, 0.31)	0.82	0.96	0.02 (−0.59, 0.63)	0.95	0.98	−0.06 (−0.77, 0.65)	0.87	0.97
	R–M		−0.09 (−0.45, 0.27)	0.62	0.91	0.17 (−0.45, 0.80)	0.58	0.90	−0.27 (−0.99, 0.46)	0.46	0.89
dLPFC	L	Nuts, seeds, and legumes (servings/d)	0.12 (0.01, 0.23)	0.03	0.39	0.13 (−0.12, 0.38)	0.31	0.78	−0.01 (−0.28, 0.26)	0.94	0.98
	R		0.08 (−0.08, 0.24)	0.32	0.78	0.06 (−0.24, 0.37)	0.68	0.95	0.02 (−0.32, 0.36)	0.91	0.98
dLPFC to dACC	L–M		−0.02 (−0.17, 0.14)	0.84	0.97	−0.14 (−0.41, 0.12)	0.29	0.78	0.13 (−0.18, 0.44)	0.42	0.86
	R-M		0.04 (−0.12, 0.20)	0.58	0.90	−0.02 (−0.29, 0.26)	0.91	0.98	0.06 (−0.26, 0.38)	0.70	0.95
dLPFC	L	High-sugar food (servings/d)	−0.15 (−0.39, 0.10)	0.24	0.78	−0.15 (−0.71, 0.42)	0.61	0.91	0.00 (−0.62, 0.62)	1.00	1.00
	R		−0.01 (−0.37, 0.34)	0.93	0.98	−0.41 (−1.06, 0.25)	0.22	0.77	0.39 (−0.35, 1.14)	0.30	0.78
dLPFC to dACC	L–M		0.22 (−0.14, 0.57)	0.23	0.77	0.30 (−0.27, 0.86)	0.30	0.78	−0.08 (−0.74, 0.58)	0.81	0.96
	R–M		−0.08 (−0.43, 0.27)	0.64	0.93	0.15 (−0.45, 0.74)	0.62	0.91	−0.23 (−0.92, 0.46)	0.51	0.89
dLPFC	L	Alcohol (servings/d)	−0.00 (−0.28, 0.27)	0.98	0.99	0.72 (0.09, 1.36)	0.03	0.39	−0.72 (−1.41, −0.04)⁵	0.04	0.39
	R		−0.02 (−0.42, 0.39)	0.93	0.98	0.45 (−0.30, 1.21)	0.23	0.77	−0.47 (−1.32, 0.38)	0.27	0.78
dLPFC to dACC	L–M		−0.20 (−0.57, 0.18)	0.30	0.78	0.57 (−0.08, 1.21)	0.09	0.53	−0.76 (−1.51, −0.01)⁵	0.047	0.42
	R–M		−0.18 (−0.58, 0.23)	0.39	0.83	0.06 (−0.62, 0.74)	0.86	0.97	−0.24 (−1.04, 0.56)	0.55	0.90

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dACC, dorsal anterior cingulate cortex; dLPFC, dorsal lateral prefrontal cortex; L, left; M, medial, PST, problem-solving therapy; R, right.

The ordinary least square regression was used to test the association of change in a neural target at 2 mo with change in a dietary outcome at 2 or 6 mo within the usual care group and the difference in the size of the treatment effect between the intervention and usual care groups at different levels of the neural target, adjusting for the baseline value of the outcome measure. Each outcome was standardized using the baseline SD of the ENGAGE-2 sample for uniform comparison of effect sizes across measures with different units. Analyses on cognitive control circuit were conducted with n_total = 64 participants with baseline and 2-mo follow-up data.

Single letter indicates task activation; paired letters indicate task-related connectivity.

The DASH score was computed based on 9 nutrient targets (total fat, saturated fat, protein, cholesterol, fiber, magnesium, calcium, sodium, and potassium) [38] provided by the NDSR software. Daily servings of fruit and vegetable; low-fat/fat-free dairy food; whole grains; nuts, seeds, and legumes; high-sugar food; and alcohol intake were calculate using the Food Group Serving Count System Output File generated by NDSR.

⁴

The initial 2-mo intervention phase of the I-CARE program that implemented a 7-step problem-solving process as its core component.

⁵

The 95% CIs of the interaction effects did not include the null.

TABLE 3.

Associations between changes of neural targets in cognitive control circuit (GONOGO) at 2 mo and changes of dietary outcomes at 6 mo between the PST intervention and usual care patients with obesity and depression¹

Neural target	Hemisphere²	Dietary outcome change³	Intervention⁴			Usual care effect			Interaction (between-group difference)
Neural target	Hemisphere²	Dietary outcome change³	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj
dLPFC	L	Energy (kcal/d)	−0.19 (−0.33, −0.04)	0.01	0.27	0.25 (−0.06, 0.57)	0.11	0.53	−0.44 (−0.79, −0.09)⁵	0.01	0.28
	R		−0.20 (−0.42, 0.02)	0.08	0.53	−0.05 (−0.41, 0.31)	0.79	0.96	−0.15 (−0.57, 0.27)	0.48	0.89
dLPFC to dACC	L–M		0.17 (−0.04, 0.38)	0.10	0.53	−0.16 (−0.5, 0.17)	0.33	0.79	0.33 (−0.06, 0.73)	0.10	0.53
	R–M		0.11 (−0.12, 0.33)	0.34	0.80	0.02 (−0.35, 0.38)	0.93	0.98	0.09 (−0.33, 0.52)	0.67	0.94
dLPFC	L	DASH score	0.20 (−0.02, 0.42)	0.08	0.53	−0.38 (−0.85, 0.09)	0.11	0.53	0.58 (0.05, 1.10)⁵	0.03	0.39
	R		0.19 (−0.14, 0.53)	0.26	0.78	−0.13 (−0.67, 0.40)	0.62	0.91	0.33 (−0.31, 0.96)	0.31	0.78
dLPFC to dACC	L–M		−0.28 (−0.57, 0.02)	0.07	0.52	0.32 (−0.17, 0.80)	0.20	0.73	−0.59 (−1.15, −0.03)⁵	0.04	0.39
	R–M		−0.32 (−0.65, 0.01)	0.05	0.46	0.09 (−0.42, 0.61)	0.72	0.95	−0.42 (−1.02, 0.19)	0.17	0.67
dLPFC	L	Fruit and vegetable (servings/d)	0.06 (−0.15, 0.27)	0.55	0.90	−0.14 (−0.60, 0.32)	0.54	0.90	0.21 (−0.30, 0.71)	0.42	0.86
	R		0.15 (−0.13, 0.43)	0.30	0.78	−0.74 (−1.21, −0.28)	0.002	0.13	0.89 (0.36, 1.43)⁵	0.002	0.12
dLPFC to dACC	L–M		0.03 (−0.25, 0.32)	0.82	0.96	−0.08 (−0.56, 0.40)	0.73	0.96	0.11 (−0.44, 0.66)	0.68	0.95
	R–M		0.27 (−0.03, 0.56)	0.07	0.53	0.38 (−0.09, 0.84)	0.11	0.53	−0.11 (−0.66, 0.44)	0.69	0.95
dLPFC	L	Low-fat/fat-free dairy (servings/d)	0.11 (−0.07, 0.28)	0.22	0.77	−0.13 (−0.51, 0.25)	0.50	0.89	0.23 (−0.18, 0.65)	0.27	0.78
	R		0.17 (−0.09, 0.43)	0.19	0.71	0.00 (−0.42, 0.43)	0.99	0.99	0.17 (−0.34, 0.68)	0.50	0.89
dLPFC to dACC	L–M		−0.09 (−0.33, 0.14)	0.44	0.87	0.05 (−0.34, 0.45)	0.79	0.96	−0.14 (−0.61, 0.32)	0.54	0.90
	R–M		0.03 (−0.23, 0.28)	0.83	0.96	−0.14 (−0.55, 0.28)	0.51	0.89	0.16 (−0.32, 0.65)	0.50	0.89
dLPFC	L	Fat (g/d)	−0.22 (−0.39, −0.06)	0.01	0.27	0.28 (−0.07, 0.64)	0.12	0.53	−0.51 (−0.90, −0.12)⁵	0.01	0.27
	R		−0.24 (−0.49, 0.01)	0.06	0.49	0.00 (−0.41, 0.41)	1.00	0.99	−0.24 (−0.72, 0.24)	0.32	0.79
dLPFC to dACC	L–M		0.21 (−0.02, 0.44)	0.08	0.53	−0.19 (−0.56, 0.19)	0.33	0.79	0.39 (−0.05, 0.83)	0.08	0.53
	R–M		0.20 (−0.05, 0.45)	0.12	0.53	−0.06 (−0.47, 0.34)	0.75	0.96	0.26 (−0.21, 0.74)	0.27	0.78
dLPFC	L	Sodium (mg/d)	−0.03 (−0.23, 0.17)	0.76	0.96	0.27 (−0.17, 0.70)	0.22	0.77	−0.30 (−0.77, 0.18)	0.21	0.77
	R		0.04 (−0.26, 0.34)	0.79	0.96	0.14 (−0.33, 0.62)	0.55	0.90	−0.10 (−0.68, 0.47)	0.72	0.95
dLPFC to dACC	L–M		0.22 (−0.04, 0.48)	0.09	0.53	−0.32 (−0.74, 0.11)	0.14	0.59	0.54 (0.04, 1.03)⁵	0.04	0.39
	R–M		0.03 (−0.26, 0.33)	0.83	0.96	−0.12 (−0.59, 0.34)	0.60	0.91	0.16 (−0.40, 0.71)	0.58	0.90
dLPFC	L	Whole grain (servings/d)	0.05 (−0.11, 0.20)	0.53	0.90	0.69 (0.35, 1.03)	<0.001	0.048	−0.64 (−1.01, −0.27)⁵	0.001	0.12
	R		0.07 (−0.18, 0.31)	0.59	0.91	0.46 (0.07, 0.86)	0.02	0.39	−0.40 (−0.86, 0.07)	0.09	0.53
dLPFC to dACC	L–M		0.03 (−0.19, 0.25)	0.81	0.96	−0.48 (−0.86, −0.11)	0.01	0.27	0.51 (0.07, 0.95)⁵	0.02	0.39
	R–M		0.06 (−0.19, 0.31)	0.64	0.92	−0.19 (−0.59, 0.22)	0.36	0.80	0.25 (−0.23, 0.72)	0.30	0.78
dLPFC	L	Nuts, seeds, and legumes (servings/d)	0.04 (−0.02, 0.10)	0.15	0.61	−0.02 (−0.15, 0.11)	0.80	0.96	0.06 (−0.08, 0.20)	0.41	0.86
	R		0.09 (0.01, 0.18)	0.03	0.39	0.08 (−0.05, 0.22)	0.23	0.77	0.01 (−0.15, 0.17)	0.90	0.98
dLPFC to dACC	L–M		−0.05 (−0.12, 0.03)	0.24	0.78	−0.11 (−0.24, 0.03)	0.12	0.53	0.06 (−0.10, 0.21)	0.45	0.88
	R–M		−0.07 (−0.15, 0.02)	0.11	0.53	−0.19 (−0.32, −0.06)	0.004	0.17	0.13 (−0.02, 0.28)	0.10	0.53
dLPFC	L	High-sugar food (servings/d)	−0.18 (−0.37, 0.01)	0.07	0.52	0.31 (−0.11, 0.73)	0.14	0.59	−0.49 (−0.95, −0.03)⁵	0.04	0.39
	R		−0.10 (−0.39, 0.20)	0.51	0.89	−0.03 (−0.51, 0.45)	0.90	0.98	−0.07 (−0.63, 0.50)	0.81	0.96
dLPFC to dACC	L–M		0.14 (−0.16, 0.43)	0.35	0.80	0.12 (−0.32, 0.57)	0.58	0.90	0.01 (−0.51, 0.54)	0.96	0.99
	R–M		0.03 (−0.26, 0.33)	0.81	0.96	0.12 (−0.35, 0.59)	0.61	0.91	−0.08 (−0.64, 0.47)	0.76	0.96
dLPFC	L	Alcohol (servings/d)	−0.10 (−0.39, 0.18)	0.47	0.89	0.05 (−0.57, 0.67)	0.87	0.97	−0.15 (−0.84, 0.53)	0.66	0.94
	R		−0.11 (−0.53, 0.30)	0.59	0.91	−0.10 (−0.78, 0.59)	0.78	0.96	−0.01 (−0.82, 0.79)	0.97	0.99
dLPFC to dACC	L–M		−0.29 (−0.66, 0.09)	0.13	0.58	−0.04 (−0.67, 0.59)	0.90	0.98	−0.25 (−0.99, 0.49)	0.51	0.89
	R–M		−0.03 (−0.45, 0.39)	0.90	0.98	0.11 (−0.56, 0.77)	0.75	0.96	−0.13 (−0.92, 0.65)	0.73	0.96

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dACC, dorsal anterior cingulate cortex; dLPFC, dorsal lateral prefrontal cortex; L, left; M, medial, PST, problem-solving therapy; R, right.

The ordinary least square regression was used to test the association of change in a neural target at 2 mo with change in a dietary outcome at 2 or 6 mo within the usual care group and the difference in the size of the treatment effect between the intervention and usual care groups at different levels of the neural target, adjusting for the baseline value of the outcome measure. Each outcome was standardized using the baseline SD of the ENGAGE-2 sample for uniform comparison of effect sizes across measures with different units. Analyses on cognitive control circuit were conducted with n_total = 61 participants with baseline and 2-mo follow-up data.

Single letter indicates task activation; paired letters indicate task-related connectivity.

⁴

The initial 2-mo intervention phase of the I-CARE program that implemented a 7-step problem-solving process as its core component.

⁵

The 95% CIs of the interaction effects did not include the null.

Negative affect circuit

TABLE 4, TABLE 5 tabulate associations between changes of neural targets in the negative affect circuit at 2 mo and changes of dietary outcomes at 2 and 6 mo, respectively, in the intervention and usual care groups and between-group differences. Between-group differences in these associations were primarily noted for changes of dietary outcomes at 2 mo. An increase in connectivity between the right dLPFC and right amygdala was associated with increases in DASH scores (β: 0.32; 95% CI: −0.93, 1.57) and fruit and vegetable intake (β: 0.38; 95% CI: −0.75, 1.50) and decreases in calories (β: −0.37; 95% CI: −1.29, 0.54), fat levels (β: −0.37; 95% CI: −1.50, 0.76), sodium concentrations (β: −0.36; 95% CI: −1.32, 0.60), and alcohol intake (β: −0.71; 95% CI: −2.10, 0.68) in the intervention group; these associations were opposite in the usual care group, and the 95% CIs of the interaction effects did not include the null (Table 4).

TABLE 4.

Associations between changes of neural targets in negative affect circuit engaged by nonconscious threat face–viewing tasks at 2 mo and changes of dietary outcomes at 2 mo between the PST intervention and usual care patients with obesity and depression¹

Neural target	Hemisphere²	Dietary outcome change³	Intervention⁴			Usual care effect			Interaction (Between-group difference)
Neural target	Hemisphere²	Dietary outcome change³	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj
Amygdala	L	Energy (kcal/d)	0.15 (−0.04, 0.34)	0.13	0.99	0.08 (−0.23, 0.39)	0.61	0.99	0.07 (−0.30, 0.43)	0.72	0.99
	R		0.26 (0.05, 0.48)	0.02	0.51	0.14 (−0.18, 0.46)	0.40	0.99	0.13 (−0.26, 0.52)	0.52	0.99
dLPFC to amygdala	L–L		0.00 (−0.98, 0.98)	0.99	1.00	−0.55 (−2.80, 1.69)	0.63	0.99	0.55 (−1.90, 3.01)	0.65	0.99
	R–R		−0.37 (−1.29, 0.54)	0.42	0.99	2.35 (0.23, 4.47)	0.03	0.55	−2.73 (−5.05, −0.41)⁵	0.02	0.53
Amygdala	L	DASH score	0.01 (−0.24, 0.27)	0.91	0.99	−0.03 (−0.45, 0.39)	0.89	0.99	0.04 (−0.45, 0.54)	0.86	0.99
	R		−0.03 (−0.33, 0.26)	0.83	0.99	0.00 (−0.45, 0.45)	0.99	1.00	−0.03 (−0.58, 0.52)	0.91	0.99
dLPFC to amygdala	L–L		0.78 (−0.57, 2.13)	0.25	0.99	1.84 (−1.05, 4.72)	0.21	0.99	−1.06 (−4.34, 2.22)	0.52	0.99
	R–R		0.32 (−0.93, 1.57)	0.61	0.99	−2.67 (−5.42, 0.07)	0.06	0.71	3.00 (0.01, 5.99)⁵	0.049	0.65
Amygdala	L	Fruit and vegetable (servings/d)	0.24 (0.01, 0.47)	0.04	0.60	−0.26 (−0.67, 0.15)	0.21	0.99	0.51 (0.05, 0.96)⁵	0.03	0.55
	R		0.29 (0.01, 0.56)	0.04	0.60	0.08 (−0.33, 0.49)	0.70	0.99	0.21 (−0.28, 0.69)	0.40	0.99
dLPFC to amygdala	L–L		0.29 (−0.94, 1.53)	0.64	0.99	0.12 (−2.65, 2.89)	0.93	0.99	0.18 (−2.86, 3.22)	0.91	0.99
	R–R		0.38 (−0.75, 1.50)	0.50	0.99	−3.40 (−5.94, −0.86)	0.01	0.40	3.78 (1.00, 6.55)⁵	0.01	0.40
Amygdala	L	Low-fat/fat-free dairy (servings/d)	0.12 (−0.04, 0.28)	0.14	0.99	0.15 (−0.12, 0.41)	0.28	0.99	−0.03 (−0.34, 0.28)	0.86	0.99
	R		0.13 (−0.05, 0.32)	0.15	0.99	0.23 (−0.05, 0.51)	0.10	0.91	−0.10 (−0.43, 0.24)	0.57	0.99
dLPFC to amygdala	L–L		0.15 (−0.70, 1.01)	0.72	0.99	−0.55 (−2.45, 1.35)	0.56	0.99	0.71 (−1.36, 2.77)	0.50	0.99
	R–R		0.36 (−0.47, 1.19)	0.38	0.99	0.36 (−1.49, 2.20)	0.70	0.99	0.01 (−2.03, 2.04)	1.00	1.00
Amygdala	L	Fat (g/d)	0.20 (−0.03, 0.43)	0.08	0.87	0.15 (−0.23, 0.52)	0.44	0.99	0.06 (−0.39, 0.50)	0.80	0.99
	R		0.33 (0.06, 0.59)	0.02	0.51	0.19 (−0.20, 0.58)	0.34	0.99	0.14 (−0.34, 0.61)	0.57	0.99
dLPFC to amygdala	L–L		0.06 (−1.15, 1.28)	0.92	0.99	−0.85 (−3.59, 1.89)	0.54	0.99	0.91 (−2.11, 3.94)	0.55	0.99
	R–R		−0.37 (−1.50, 0.76)	0.51	0.99	2.64 (0.02, 5.25)	0.048	0.65	−3.01 (−5.85, −0.17)⁵	0.04	0.60
Amygdala	L	Sodium (mg/d)	0.15 (−0.06, 0.35)	0.15	0.99	0.16 (−0.17, 0.49)	0.34	0.99	−0.01 (−0.40, 0.37)	0.95	0.99
	R		0.20 (−0.03, 0.44)	0.09	0.87	0.11 (−0.24, 0.46)	0.53	0.99	0.09 (−0.33, 0.51)	0.67	0.99
dLPFC to amygdala	L–L		−0.31 (−1.35, 0.74)	0.56	0.99	−1.28 (−3.63, 1.07)	0.28	0.99	0.97 (−1.61, 3.55)	0.45	0.99
	R–R		−0.36 (−1.32, 0.60)	0.46	0.99	3.04 (0.82, 5.26)	0.01	0.40	−3.40 (−5.79, −1.00)⁵	0.01	0.40
Amygdala	L	Whole grain (servings/d)	0.02 (−0.24, 0.29)	0.86	0.99	−0.02 (−0.47, 0.43)	0.92	0.99	0.05 (−0.48, 0.57)	0.86	0.99
	R		0.12 (−0.20, 0.43)	0.46	0.99	−0.17 (−0.65, 0.31)	0.49	0.99	0.29 (−0.30, 0.87)	0.33	0.99
dLPFC to amygdala	L–L		0.50 (–0.85, 1.86)	0.46	0.99	−1.78 (−4.99, 1.43)	0.27	0.99	2.29 (−1.19, 5.76)	0.19	0.99
	R–R		0.21 (−1.11, 1.54)	0.75	0.99	2.01 (−0.99, 5.00)	0.19	0.99	−1.79 (−5.06, 1.48)	0.28	0.99
Amygdala	L	Nuts, seeds, and legumes (servings/d)	−0.05 (−0.18, 0.08)	0.43	0.99	−0.02 (−0.23, 0.18)	0.82	0.99	−0.03 (−0.27, 0.22)	0.83	0.99
	R		−0.01 (−0.16, 0.14)	0.89	0.99	0.01 (−0.21, 0.24)	0.91	0.99	−0.02 (−0.30, 0.25)	0.87	0.99
dLPFC to amygdala	L–L		−0.03 (−0.67, 0.62)	0.94	0.99	0.11 (−1.37, 1.58)	0.88	0.99	−0.13 (−1.75, 1.48)	0.87	0.99
	R–R		−0.43 (−1.05, 0.19)	0.17	0.99	−0.18 (−1.58, 1.23)	0.80	0.99	−0.25 (−1.79, 1.28)	0.74	0.99
Amygdala	L	High-sugar food (servings/d)	0.03 (−0.24, 0.29)	0.83	0.99	−0.05 (−0.49, 0.38)	0.81	0.99	0.08 (−0.43, 0.59)	0.75	0.99
	R		0.06 (−0.26, 0.37)	0.72	0.99	0.01 (−0.45, 0.48)	0.95	0.99	0.04 (−0.52, 0.61)	0.88	0.99
dLPFC to amygdala	L–L		0.04 (−1.31, 1.39)	0.95	0.99	0.56 (−2.50, 3.62)	0.71	0.99	−0.52 (−3.85, 2.81)	0.75	0.99
	R–R		0.64 (−0.68, 1.96)	0.34	0.99	0.70 (−2.24, 3.65)	0.64	0.99	−0.07 (−3.31, 3.18)	0.97	0.99
Amygdala	L	Alcohol (servings/d)	0.06 (−0.23, 0.36)	0.67	0.99	−0.25 (−0.75, 0.24)	0.31	0.99	0.32 (−0.26, 0.89)	0.28	0.99
	R		0.13 (−0.22, 0.47)	0.47	0.99	−0.23 (−0.75, 0.29)	0.38	0.99	0.36 (−0.27, 0.99)	0.26	0.99
dLPFC to amygdala	L–L		−0.67 (−2.19, 0.84)	0.38	0.99	−0.52 (−3.95, 2.91)	0.76	0.99	−0.16 (−3.91, 3.59)	0.93	0.99
	R–R		−0.71 (−2.10, 0.68)	0.31	0.99	4.62 (1.51, 7.73)	0.004	0.40	−5.33 (−8.73, −1.94)⁵	0.003	0.40

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dLPFC, dorsal lateral prefrontal cortex; L, left; M, medial, PST, problem-solving therapy; R, right.

The ordinary least square regression was used to test the association of change in a neural target at 2 mo with change in a dietary outcome at 2 or 6 mo within the usual care group and the difference in the size of the treatment effect between the intervention and usual care groups at different levels of the neural target, adjusting for the baseline value of the outcome measure. Each outcome was standardized using the baseline SD of the ENGAGE-2 sample for uniform comparison of effect sizes across measures with different units. Analyses on cognitive control circuit were conducted with n_total = 62 participants with baseline and 2-mo follow-up data.

Single letter indicates task activation; paired letters indicate task-related connectivity.

⁴

The initial 2-mo intervention phase of the I-CARE program that implemented a 7-step problem-solving process as its core component.

⁵

The 95% CIs of the interaction effects did not include the null.

TABLE 5.

Associations between changes of neural targets in negative affect circuit engaged by nonconscious threat face–viewing tasks at 2 mo and changes of dietary outcomes at 6 mo between the PST intervention and usual care patients with obesity and depression¹

Neural target	Hemisphere²	Dietary outcome change³	Intervention⁴			Usual care effect			Interaction (between-group difference)
Neural target	Hemisphere²	Dietary outcome change³	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj
Amygdala	L	Energy (kcal/d)	−0.06 (−0.23, 0.11)	0.47	0.99	−−0.08 (−0.33, 0.18)	0.56	0.99	0.01 (−0.29, 0.32)	0.93	0.99
	R		−0.00 (−0.22, 0.21)	0.96	0.99	−0.10 (−0.36, 0.16)	0.45	0.99	0.09 (−0.24, 0.43)	0.58	0.99
dLPFC to amygdala	L–L		−0.13 (−0.94, 0.67)	0.74	0.99	1.46 (−0.21, 3.14)	0.09	0.87	−1.60 (−3.46, 0.26)	0.09	0.87
	R–R		−0.48 (−1.28, 0.31)	0.23	0.99	0.04 (−1.77, 1.85)	0.96	0.99	−0.53 (−2.50, 1.45)	0.60	0.99
Amygdala	L	DASH score	0.04 (−0.20, 0.28)	0.76	0.99	0.09 (−0.28, 0.46)	0.63	0.99	−0.05 (−0.49, 0.39)	0.81	0.99
	R		0.14 (−0.15, 0.43)	0.35	0.99	0.12 (−0.25, 0.50)	0.51	0.99	0.01 (−0.47, 0.49)	0.96	0.99
dLPFC to amygdala	L–L		−0.95 (−2.15, 0.25)	0.12	0.98	−1.29 (−3.70, 1.11)	0.29	0.99	0.35 (−2.44, 3.13)	0.81	0.99
	R–R		−1.36 (−2.49, −0.23)	0.02	0.51	−0.17 (−2.57, 2.24)	0.89	0.99	−1.19 (−3.81, 1.43)	0.37	0.99
Amygdala	L	Fruit and vegetable (servings/d)	−0.03 (−0.25, 0.20)	0.80	0.99	−0.27 (−0.64, 0.09)	0.14	0.99	0.24 (−0.18, 0.66)	0.25	0.99
	R		0.05 (−0.23, 0.33)	0.71	0.99	−0.20 (−0.55, 0.15)	0.27	0.99	0.25 (−0.20, 0.70)	0.27	0.99
dLPFC to amygdala	L–L		−0.52 (−1.63, 0.59)	0.35	0.99	−0.98 (−3.27, 1.30)	0.39	0.99	0.47 (−2.09, 3.02)	0.72	0.99
	R–R		−0.68 (−1.75, 0.39)	0.21	0.99	0.68 (−1.70, 3.07)	0.57	0.99	−1.37 (−3.97, 1.24)	0.30	0.99
Amygdala	L	Low-fat/fat-free dairy (servings/d)	0.05 (−0.14, 0.25)	0.59	0.99	0.03 (−0.27, 0.34)	0.82	0.99	0.02 (−0.35, 0.38)	0.92	0.99
	R		0.11 (−0.13, 0.36)	0.36	0.99	−0.02 (−0.33, 0.28)	0.87	0.99	0.14 (−0.25, 0.53)	0.49	0.99
dLPFC to amygdala	L–L		0.60 (−0.38, 1.58)	0.23	0.99	−0.80 (−2.79, 1.19)	0.42	0.99	1.40 (−0.79, 3.59)	0.21	0.99
	R–R		−0.37 (−1.32, 0.58)	0.44	0.99	0.80 (−1.29, 2.90)	0.45	0.99	−1.17 (−3.49, 1.14)	0.32	0.99
Amygdala	L	Fat (g/d)	−0.10 (−0.29, 0.10)	0.33	0.99	−0.11 (−0.41, 0.18)	0.45	0.99	0.02 (−0.34, 0.37)	0.93	0.99
	R		−0.02 (−0.26, 0.22)	0.87	0.99	−0.16 (−0.46, 0.15)	0.30	0.99	0.14 (−0.25, 0.53)	0.48	0.99
dLPFC to amygdala	L–L		−0.25 (−1.18, 0.69)	0.60	0.99	1.79 (−0.15, 3.73)	0.07	0.80	−2.04 (−4.21, 0.14)	0.07	0.79
	R–R		−0.55 (−1.47, 0.37)	0.23	0.99	−0.35 (−2.45, 1.75)	0.74	0.99	−0.20 (−2.48, 2.07)	0.86	0.99
Amygdala	L	Sodium (mg/d)	−0.04 (−0.26, 0.17)	0.69	0.99	0.05 (−0.28, 0.37)	0.78	0.99	−0.09 (−0.48, 0.30)	0.65	0.99
	R		0.02 (−0.25, 0.29)	0.88	0.99	0.10 (−0.23, 0.43)	0.55	0.99	−0.08 (−0.51, 0.35)	0.71	0.99
dLPFC to amygdala	L–L		−0.09 (−1.13, 0.95)	0.87	0.99	1.24 (−0.91, 3.39)	0.25	0.99	−1.33 (−3.74, 1.08)	0.28	0.99
	R–R		−0.24 (−1.27, 0.79)	0.64	0.99	0.21 (−2.13, 2.54)	0.86	0.99	−0.45 (−2.96, 2.07)	0.72	0.99
Amygdala	L	Whole grain (servings/d)	0.04 (−0.15, 0.23)	0.68	0.99	0.14 (−0.15, 0.43)	0.33	0.99	−0.11 (−0.45, 0.24)	0.54	0.99
	R		0.07 (−0.16, 0.30)	0.54	0.99	0.19 (−0.11, 0.49)	0.20	0.99	−0.12 (−0.50, 0.26)	0.52	0.99
dLPFC to amygdala	L–L		0.26 (−0.67, 1.18)	0.58	0.99	0.57 (−1.44, 2.59)	0.57	0.99	−0.32 (−2.54, 1.91)	0.78	0.99
	R–R		0.12 (−0.79, 1.02)	0.80	0.99	0.01 (−2.01, 2.02)	1.00	1.00	0.11 (−2.10, 2.32)	0.92	0.99
Amygdala	L	Nuts, seeds, and legumes (servings/d)	0.04 (−0.03, 0.10)	0.29	0.99	0.08 (−0.02, 0.19)	0.10	0.91	−0.05 (−0.17, 0.07)	0.43	0.99
	R		0.09 (0.01, 0.17)	0.03	0.55	0.07 (−0.04, 0.17)	0.20	0.99	0.02 (−0.11, 0.16)	0.73	0.99
dLPFC to amygdala	L–L		0.08 (−0.25, 0.42)	0.63	0.99	0.10 (−0.62, 0.81)	0.79	0.99	−0.01 (−0.80, 0.78)	0.97	0.99
	R–R		0.04 (−0.29, 0.37)	0.81	0.99	−0.20 (−0.93, 0.53)	0.59	0.99	0.24 (−0.56, 1.04)	0.55	0.99
Amygdala	L	High-sugar food (servings/d)	−0.10 (−0.32, 0.12)	0.36	0.99	0.01 (−0.32, 0.35)	0.94	0.99	−0.11 (−0.51, 0.29)	0.58	0.99
	R		−0.18 (−0.45, 0.10)	0.21	0.99	−0.05 (−0.39, 0.28)	0.75	0.99	−0.12 (−0.56, 0.32)	0.59	0.99
dLPFC to amygdala	L–L		0.49 (−0.56, 1.54)	0.35	0.99	1.78 (−0.39, 3.96)	0.11	0.91	−1.29 (−3.69, 1.10)	0.28	0.99
	R–R		−0.07 (−1.13, 0.99)	0.90	0.99	0.54 (−1.80, 2.87)	0.65	0.99	−0.61 (−3.18, 1.97)	0.64	0.99
Amygdala	L	Alcohol (servings/d)	0.06 (−0.21, 0.34)	0.64	0.99	−0.08 (−0.50, 0.34)	0.71	0.99	0.14 (−0.36, 0.65)	0.57	0.99
	R		0.06 (−0.29, 0.40)	0.75	0.99	−0.15 (−0.57, 0.28)	0.50	0.99	0.20 (−0.35, 0.75)	0.47	0.99
dLPFC to amygdala	L–L		−0.04 (−1.39, 1.31)	0.95	0.99	0.35 (−2.45, 3.15)	0.80	0.99	−0.39 (−3.50, 2.72)	0.80	0.99
	R–R		0.19 (−1.12, 1.50)	0.77	0.99	−1.46 (−4.35, 1.43)	0.32	0.99	1.65 (−1.51, 4.81)	0.30	0.99

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dLPFC, dorsal lateral prefrontal cortex; L, left; M, medial, PST, problem-solving therapy; R, right.

The ordinary least square regression was used to test the association of change in a neural target at 2 mo with change in a dietary outcome at 2 or 6 mo within the usual care group and the difference in the size of the treatment effect between the intervention and usual care groups at different levels of the neural target, adjusting for the baseline value of the outcome measure. Each outcome was standardized using the baseline SD of the ENGAGE-2 sample for uniform comparison of effect sizes across measures with different units. Analyses on cognitive control circuit were conducted with n_total = 58 participants with baseline and 2-mo follow-up data.

Single letter indicates task activation; paired letters indicate task-related connectivity.

⁴

The initial 2-mo intervention phase of the I-CARE program that implemented a 7-step problem-solving process as its core component.

Positive affect circuit

TABLE 6, Table 7 present associations between changes of neural targets in the positive affect circuit at 2 mo and changes of dietary outcomes at 2 and 6 mo, respectively, in the intervention and usual care groups and between-group differences. Between-group differences in these associations were primarily noted for changes of dietary outcomes at 2 mo. The 95% CIs of between-group differences did not overlap with the null for the associations between changes in the right vStriatum activity and sodium intake (β: 0.39; 95% CI: 0.01, 0.77) and between changes in the right vStriatum activity and low-fat/fat-free dairy food intake (β: −0.35; 95% CI: −0.67, −0.03) (Table 6). Moreover, the 95% CIs of between-group differences did not overlap with the null for the associations between changes in the medial vMPFC activity and DASH scores (β: −0.62; 95% CI: −1.23, −0.01) and between changes in the medial vMPFC activity and sodium intake (β: 0.62; 95% CI: 0.15, 1.08) (Table 6).

TABLE 6.

Associations between changes of positive affect circuit engaged by happy face–viewing tasks at 2 mo and changes of dietary outcomes at 2 mo between the PST intervention and usual care patients with obesity and depression¹

Neural target	Hemisphere²	Dietary outcome change³	Intervention⁴			Usual care effect			Interaction (between-group difference)
Neural target	Hemisphere²	Dietary outcome change³	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj
vMPFC	M	Energy (kcal/d)	0.01 (−0.16, 0.19)	0.89	0.95	−0.21 (−0.65, 0.24)	0.36	0.72	0.22 (−0.26, 0.70)	0.36	0.72
vStriatum	L		0.05 (−0.09, 0.19)	0.50	0.79	0.08 (−0.28, 0.44)	0.66	0.84	−0.03 (−0.42, 0.35)	0.87	0.95
	R		0.07 (−0.06, 0.21)	0.29	0.69	−0.04 (−0.40, 0.33)	0.84	0.95	0.11 (−0.28, 0.50)	0.57	0.81
vMPFC	M	DASH score	−0.03 (−0.25, 0.20)	0.81	0.95	0.59 (0.02, 1.16)	0.04	0.54	−0.62 (−1.23, −0.01)⁵	0.048	0.54
vStriatum	L	DASH score	−0.12 (−0.30, 0.06)	0.19	0.68	0.31 (−0.16, 0.78)	0.19	0.68	−0.43 (−0.94, 0.08)	0.10	0.68
	R		−0.10 (−0.28, 0.08)	0.28	0.69	0.32 (−0.15, 0.79)	0.17	0.68	−0.42 (−0.92, 0.08)	0.10	0.68
vMPFC	M	Fruit and vegetable (servings/d)	0.13 (−0.09, 0.34)	0.23	0.69	0.18 (−0.38, 0.73)	0.53	0.80	−0.05 (−0.64, 0.55)	0.88	0.95
vStriatum	L		0.15 (−0.02, 0.32)	0.09	0.68	0.19 (−0.24, 0.62)	0.37	0.72	−0.05 (−0.51, 0.42)	0.84	0.95
	R		0.18 (0.02, 0.34)	0.03	0.54	0.21 (−0.21, 0.64)	0.32	0.72	−0.03 (−0.49, 0.42)	0.88	0.95
vMPFC	M	Low-fat/fat-free dairy (servings/d)	0.04 (−0.11, 0.19)	0.63	0.83	0.14 (−0.25, 0.52)	0.48	0.77	−0.10 (−0.52, 0.32)	0.63	0.83
vStriatum	L		−0.01 (−0.13, 0.12)	0.93	0.97	0.13 (−0.18, 0.44)	0.41	0.72	−0.13 (−0.46, 0.19)	0.42	0.73
	R		0.00 (−0.11, 0.12)	0.96	0.98	0.35 (0.06, 0.65)	0.02	0.54	−0.35 (−0.67, −0.03)⁵	0.03	0.54
vMPFC	M	Fat (g/d)	0.07 (−0.15, 0.28)	0.53	0.80	−0.32 (−0.86, 0.22)	0.24	0.69	0.39 (−0.19, 0.97)	0.19	0.68
vStriatum	L		0.06 (−0.12, 0.23)	0.51	0.80	0.04 (−0.39, 0.48)	0.84	0.95	0.01 (−0.46, 0.48)	0.95	0.98
	R		0.08 (−0.09, 0.25)	0.36	0.72	0.01 (−0.43, 0.45)	0.97	0.98	0.07 (−0.40, 0.54)	0.77	0.91
vMPFC	M	Sodium (mg/d)	0.08 (−0.09, 0.25)	0.34	0.72	−0.54 (−0.97, −0.10)	0.02	0.54	0.62 (0.15, 1.08)⁵	0.01	0.54
vStriatum	L	Sodium (mg/d)	0.09 (−0.05, 0.22)	0.22	0.69	−0.38 (−0.73, −0.03)	0.03	0.54	0.47 (0.09, 0.84)⁵	0.02	0.54
	R		0.09 (−0.04, 0.23)	0.17	0.68	−0.30 (−0.65, 0.06)	0.10	0.68	0.39 (0.01, 0.77)⁵	0.046	0.54
vMPFC	M	Whole grain (servings/d)	0.10 (−0.12, 0.31)	0.37	0.72	−0.30 (−0.84, 0.25)	0.28	0.69	0.40 (−0.19, 0.98)	0.18	0.68
vStriatum	L		0.05 (−0.13, 0.22)	0.59	0.83	−0.14 (−0.60, 0.32)	0.54	0.80	0.19 (−0.30, 0.68)	0.44	0.75
	R		0.04 (−0.13, 0.21)	0.64	0.83	−0.26 (−0.72, 0.19)	0.25	0.69	0.30 (−0.18, 0.78)	0.21	0.69
vMPFC	M	Nuts, seeds, and legumes (servings/d)	0.00 (−0.11, 0.11)	0.94	0.97	−0.08 (−0.37, 0.21)	0.59	0.83	0.07 (−0.23, 0.38)	0.63	0.83
vStriatum	L		−0.04 (−0.13, 0.05)	0.38	0.72	−0.04 (−0.27, 0.18)	0.69	0.87	0.01 (−0.23, 0.24)	0.97	0.98
	R		−0.00 (−0.09, 0.08)	0.94	0.97	−0.08 (−0.31, 0.15)	0.48	0.77	0.08 (−0.16, 0.32)	0.53	0.80
vMPFC	M	High-sugar food (servings/d)	−0.07 (−0.31, 0.17)	0.56	0.81	0.10 (−0.50, 0.70)	0.74	0.90	−0.17 (−0.82, 0.48)	0.60	0.83
vStriatum	L		−0.03 (−0.22, 0.15)	0.72	0.88	0.32 (−0.16, 0.80)	0.18	0.68	−0.35 (−0.87, 0.16)	0.17	0.68
	R		0.00 (−0.19, 0.19)	>0.99	1.00	0.11 (−0.38, 0.60)	0.65	0.84	−0.11 (−0.63, 0.41)	0.68	0.86
vMPFC	M	Alcohol (servings/d)	−0.15 (−0.42, 0.12)	0.27	0.69	−0.20 (−0.89, 0.49)	0.56	0.81	0.05 (−0.69, 0.79)	0.90	0.95
vStriatum	L	Alcohol (servings/d)	−0.09 (−0.31, 0.13)	0.40	0.72	−0.24 (−0.79, 0.32)	0.40	0.72	0.14 (−0.46, 0.74)	0.64	0.83
	R		−0.09 (−0.31, 0.12)	0.38	0.72	−0.42 (−0.98, 0.13)	0.13	0.68	0.33 (−0.27, 0.93)	0.28	0.69

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L, left; M, medial, PST, problem-solving therapy; R, right; vMPFC, ventral medial prefrontal cortex; vStriatum, ventral striatum.

The ordinary least square regression was used to test the association of change in a neural target at 2 mo with change in a dietary outcome at 2 or 6 mo within the usual care group and the difference in the size of the treatment effect between the intervention and usual care groups at different levels of the neural target, adjusting for the baseline value of the outcome measure. Each outcome was standardized using the baseline SD of the ENGAGE-2 sample for uniform comparison of effect sizes across measures with different units. Analyses on cognitive control circuit were conducted with n_total = 58 participants with baseline and 2-mo follow-up data.

Single letter indicates task activation; paired letters indicate task-related connectivity.

⁴

The initial 2-mo intervention phase of the I-CARE program that implemented a 7-step problem-solving process as its core component.

⁵

The 95% CIs of the interaction effects did not include the null.

Table 7.

Associations between changes of positive affect circuit engaged by happy face–viewing tasks at 2 mo and changes of dietary outcomes at 6 mo between the PST intervention and usual care patients with obesity and depression¹

Neural target	Hemisphere²	Dietary outcome change³	Intervention⁴			Usual care effect			Interaction (between-group difference)
Neural target	Hemisphere²	Dietary outcome change³	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj	β (95% CI)	P	FDR P_adj
vMPFC	M	Energy (kcal/d)	0.11 (−0.03, 0.26)	0.13	0.68	−0.07 (−0.44, 0.30)	0.70	0.87	0.18 (−0.21, 0.58)	0.35	0.72
vStriatum	L		0.14 (0.02, 0.25)	0.02	0.54	−0.06 (−0.34, 0.23)	0.68	0.86	0.20 (−0.11, 0.50)	0.20	0.69
	R		0.12 (−0.00, 0.23)	0.05	0.54	−−0.15 (−0.43, 0.12)	0.27	0.69	0.27 (−0.03, 0.56)	0.07	0.67
vMPFC	M	DASH score	−0.15 (−0.36, 0.07)	0.17	0.68	0.19 (−0.35, 0.73)	0.48	0.77	−0.34 (−0.92, 0.24)	0.25	0.69
vStriatum	L		−0.14 (−0.31, 0.03)	0.10	0.68	0.23 (−0.20, 0.66)	0.29	0.69	−0.37 (−0.84, 0.09)	0.12	0.68
	R		−0.09 (−0.26, 0.07)	0.27	0.69	0.27 (−0.14, 0.68)	0.19	0.68	−0.36 (−0.81, 0.08)	0.11	0.68
vMPFC	M	Fruit and vegetable (servings/d)	0.10 (−0.09, 0.30)	0.29	0.69	−0.23 (−0.74, 0.27)	0.35	0.72	0.34 (−0.20, 0.88)	0.21	0.69
vStriatum	L		0.07 (−0.08, 0.23)	0.35	0.72	−0.04 (−0.44, 0.36)	0.85	0.95	0.11 (−0.31, 0.54)	0.60	0.83
	R		0.08 (−0.07, 0.24)	0.29	0.69	−0.20 (−0.58, 0.18)	0.30	0.69	0.28 (−0.12, 0.69)	0.17	0.68
vMPFC	M	Low-fat/fat-free dairy (servings/d)	0.06 (−0.12, 0.23)	0.52	0.80	−0.17 (−0.61, 0.26)	0.43	0.74	0.23 (−0.24, 0.70)	0.34	0.72
vStriatum	L		0.01 (−0.12, 0.15)	0.85	0.95	−0.24 (−0.58, 0.10)	0.16	0.68	0.25 (−0.11, 0.62)	0.17	0.68
	R		0.01 (−0.13, 0.14)	0.91	0.96	−0.18 (−0.51, 0.15)	0.28	0.69	0.19 (−0.17, 0.54)	0.29	0.69
vMPFC	M	Fat, g/d	0.15 (−0.01, 0.32)	0.07	0.65	−0.02 (−0.43, 0.39)	0.93	0.97	0.17 (−0.27, 0.61)	0.44	0.75
vStriatum	L		0.15 (0.02, 0.28)	0.02	0.54	−0.02 (−0.34, 0.30)	0.88	0.95	0.18 (−0.17, 0.52)	0.31	0.71
	R		0.12 (0.00, 0.25)	0.06	0.57	−0.08 (−0.39, 0.24)	0.63	0.83	0.20 (−0.14, 0.54)	0.24	0.69
vMPFC	M	Sodium (mg/d)	0.22 (0.05, 0.39)	0.01	0.54	−0.18 (−0.60, 0.24)	0.40	0.72	0.40 (−0.06, 0.86)	0.09	0.68
vStriatum	L		0.14 (−0.00, 0.28)	0.05	0.54	−0.12 (−0.46, 0.23)	0.50	0.79	0.26 (−0.11, 0.63)	0.17	0.68
	R		0.13 (−0.00, 0.26)	0.05	0.57	−0.26 (−0.59, 0.06)	0.11	0.68	0.40 (0.04, 0.75)⁵	0.03	0.54
vMPFC	M	Whole grain (servings/d)	0.08 (−0.09, 0.24)	0.36	0.72	0.31 (−0.11, 0.73)	0.15	0.68	−0.23 (−0.68, 0.22)	0.31	0.71
vStriatum	L		0.05 (−0.08, 0.19)	0.43	0.74	0.15 (−0.21, 0.52)	0.39	0.72	−0.10 (−0.48, 0.28)	0.60	0.83
	R		0.06 (−0.08, 0.19)	0.39	0.72	0.13 (−0.21, 0.47)	0.45	0.75	−0.07 (−0.43, 0.29)	0.70	0.87
vMPFC	M	Nuts, seeds, and legumes (servings/d)	−0.01 (−0.06, 0.04)	0.71	0.87	0.11 (−0.03, 0.25)	0.12	0.68	−0.12 (−0.27, 0.03)	0.12	0.68
vStriatum	L		−0.02 (−0.07, 0.02)	0.28	0.69	0.01 (−0.10, 0.12)	0.86	0.95	−0.03 (−0.15, 0.08)	0.56	0.81
	R		−0.00 (−0.05, 0.04)	0.84	0.95	0.07 (−0.03, 0.18)	0.16	0.68	−0.08 (−0.19, 0.03)	0.17	0.68
vMPFC	M	High-sugar food (servings/d)	0.03 (−0.16, 0.22)	0.76	0.91	0.16 (−0.33, 0.64)	0.52	0.80	−0.13 (−0.65, 0.39)	0.62	0.83
vStriatum	L		0.09 (−0.06, 0.24)	0.24	0.69	0.28 (−0.09, 0.65)	0.13	0.68	−0.19 (−0.59, 0.21)	0.34	0.72
	R		0.08 (−0.07, 0.23)	0.28	0.69	0.15 (−0.22, 0.51)	0.42	0.74	−0.06 (−0.46, 0.33)	0.74	0.90
vMPFC	M	Alcohol (servings/d)	−0.16 (−0.43, 0.12)	0.26	0.69	0.06 (−0.63, 0.76)	0.86	0.95	−0.22 (−0.97, 0.53)	0.56	0.81
vStriatum	L		0.03 (−0.20, 0.25)	0.82	0.95	0.06 (−0.50, 0.63)	0.83	0.95	−0.04 (−0.65, 0.58)	0.91	0.96
	R		0.02 (−0.20, 0.24)	0.84	0.95	0.24 (−0.31, 0.79)	0.39	0.72	−0.22 (−0.82, 0.38)	0.47	0.77

Open in a new tab

L, left; M, medial, PST, problem-solving therapy; R, right; vMPFC, ventral medial prefrontal cortex; vStriatum, ventral striatum.

The ordinary least square regression was used to test the association of change in a neural target at 2 mo with change in a dietary outcome at 2 or 6 mo within the usual care group and the difference in the size of the treatment effect between the intervention and usual care groups at different levels of the neural target, adjusting for the baseline value of the outcome measure. Each outcome was standardized using the baseline SD of the ENGAGE-2 sample for uniform comparison of effect sizes across measures with different units. Analyses on cognitive control circuit were conducted with n_total = 55 participants with baseline and 2-mo follow-up data.

Single letter indicates task activation; paired letters indicate task-related connectivity.

⁴

The initial 2-mo intervention phase of the I-CARE program that implemented a 7-step problem-solving process as its core component.

⁵

The 95% CIs of the interaction effects did not include the null.

Discussion

This post hoc analysis of the ENGAGE-2 trial data investigated how changes in neural targets in the cognitive control, negative affect, and positive affect circuits in response to PST predicted changes in dietary outcomes. Findings showed that improvements in both cognitive control and regulation of negative and positive emotions predicted improved dietary behaviors as a function of PST compared with those of the usual care. PST-related improvements in dLPFC engagement within the cognitive control circuit were associated with changes in dietary outcomes at 6 mo. Accompanying improvements in negative emotion regulation, reflected in greater dLPFC–amygdala connectivity within the negative affect circuit, were associated with changes in dietary outcomes at 2 mo. Moreover, changes in vStriatum and vMPFC activities for positive emotion regulation were associated with changes in dietary outcomes at 2 mo.

The dLPFC plays an essential role in the volitional appetite control [39]. Previous studies have shown that men and women with obesity have less activation in the dLPFC on the left hemisphere compared with lean men and women [[40], [41], [42], [43]] and that abnormal activity in the left dLPFC is linked to impaired ability to regulate overeating and resulting weight gain and obesity [39, 44]. Research has also shown increased activity in the dLPFC in individuals who were successful at dieting, suggesting that they voluntarily engaged top-down regulatory strategies to reduce the quantity of a food-seeking behavior [45]. The results of this study about the associations between changes in the activity of the left dLPFC for the cognitive control circuit at 2 mo and changes in dietary outcomes at 6 mo are consistent with the idea that individual’s perception and memories influenced by the cognitive control about a particular meal or dessert eaten in the past may exert a strong influence on their future intake of either a same or similar meal [8]. Dysfunction in the left dLPFC for cognitive control and emotion regulation can hinder healthy eating behavior change in patients with obesity and comorbid depression [12], and this study indicates that PST may remediate this dysfunction [7]. The results also suggest that individuals with obesity and comorbid depression showing target engagement (a meaningful change in activity of the left dLPFC) early in the depression treatment may be more likely to experience improvement in dieting and weight loss at the end of treatment. Well-designed studies to formally test this hypothesis are warranted.

Furthermore, the dLPFC plays a central role in top-down regulation of both negative emotions and reward through connections with amygdala and other subcortical structures [46, 47]. The right brain hypothesis for emotional functions and obesity posits that decreased activity in the right dLPFC can underpin a switch to self-centered mode of overeating, leading to obesity subsequently [48]. Lack of top-down dLPFC regulation of emotional reactivity has been shown to make it difficult for individuals with obesity or depression to control maladaptive health behaviors [49, 50] such that they engage in higher calorie intake and unhealthy eating choices in the context of emotion dysregulation. Studies have shown that the amygdala activity for negative emotions and functional connectivity between the amygdala and prefrontal cortex affect effective weight loss and maintenance interventions [2, 51]. The results of this study showing that changes in the connectivity between the dLPFC and amygdala for the negative affect circuit on the right hemisphere at 2 mo were associated with changes in dietary outcomes at 2 mo lend support to the right brain hypothesis by suggesting that enhanced cognitive regulation of negative emotions due to PST may have corollary benefits in eating behaviors.

In addition, the results about the associations between changes in the vStriatum activity for the positive affect circuit and dietary outcomes at 2 mo are expected because patients with obesity might use food to trigger a pleasure effect on the brain due to hedonic effect, which could be mitigated by the therapeutic effect of PST. Eating pays off by providing the brain with rewards, i.e., feeling good, in the context of mood swings or stress. Our findings extend the previous studies suggesting that reward-seeking eating is a way to attempt to “self-medicate” for depression, ultimately leading to overeating and weight gain [52], and the vStriatum is involved in the mediation of the rewarding properties of food [53].

This study generates hypotheses that can be tested in future research. If same results can be confirmed in larger, stronger studies, these evidences can offer a foundation for informing future research on personalized management of obesity with comorbid depression based on neural targets. For example, based on the finding that dietary behaviors can improve through treatment engagement of brain regions within the cognitive control, negative affect, and positive affect circuits, future trials may prospectively stratify patients based on circuit function pretreatment or based on early response in circuit function during treatment to initiate and adjust treatments for individuals in ways that optimize their prognosis. Future trials might also assess whether noninvasive brain stimulation techniques, such as transcranial direct current stimulation [[54], [55], [56]] or transcranial magnetic stimulation [57, 58], serve particularly to engage the dLPFC as a way to augment behavioral intervention for participants who have cognitive control circuit dysfunction. This study offers hypotheses to be tested in more research on neural circuits involved in successful dieting and weight control, and potential interventions aimed at reducing unhealthy dietary choices in the context of negative affective states. For example, mindfulness meditation training is implicated in the improvement of negative emotion regulation through reduction of amygdala reactivity and heightened amygdala–prefrontal cortex connectivity [59]. Hence, if this is confirmed in future research, mindfulness training might be tested as an adaptive augmentation strategy for participants with comorbid obesity and depression who do not show initial target engagement in the negative affect circuit in response to PST.

Several limitations are worth noting. First, the ENGAGE-2 trial was a pilot mechanistic study with a small sample size. The results of this post hoc analysis on a subsample are only hypothesis generating, with more research needed for verification and to test specific hypotheses based on current findings. Second, task-based neuroimaging measures have shown varying levels of within-subject reliability, which could have affected our ability to detect associations between changes in some neural targets and changes in dietary outcomes. Third, a small percentage of participants completed only one 24-h dietary recall at 2 (n = 8, 8.3%) and 6 mo (n = 12, 13.3%). One day of 24-h recalls may not adequately assess usual dietary intakes owing to day-to-day variation. Finally, despite the randomized clinical trial design, some 24-h dietary recalls were conducted after the COVID-19 lockdown, which could have confounded the results.

Nevertheless, this study suggests that in response to PST, improvements in the dLPFC-based cognitive control may produce dietary improvements at 6 mo, whereas improved dLPFC–amygdala regulation of negative affective brain states may contribute to dietary improvements at 2 mo. This study generated hypotheses to be tested in future studies about neural mechanisms underlying eating behavior change and weight control. In turn, mechanism-targeted interventions could be developed to reduce unhealthy dietary behaviors and manage obesity with comorbid depression more effectively.

Author disclosures

JM is a paid scientific consultant for Health Mentor, Inc. (San Jose, CA). LMW is on the Scientific Advisory Board for One Mind Psyberguide and the External Advisory Board for the Laureate Institute for Brain Research. OAA is the co-founder of Keywise AI and serves on the advisory boards of Blueprint Health, Sage Therapeutics, and Embodied Labs. NL, HH, and LX, no conflicts of interest.

The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Acknowledgments

We thank to the participants and their families who made this study possible. The authors’ responsibilities were as follows – NL, HH: drafted the manuscript; JM, LMW, OAA: led the study design and conduct and/or obtained funding; LX: contributed to the statistical analyses; all authors: contributed to drafting the manuscript and/or participated in critical revisions for important intellectual content; and all authors: read and approved the final version of the manuscript.

Funding

The research leading to these results has received support from National Heart, Lung, and Blood Institute (award numbers UH2HL132368 [to JM, LMW], UH3HL132368 [to JM, LMW], R61HL155160 [to JM], and T32HL134634 [to JM]).

Data Availability

Data described in the manuscript, code book, and analytic code will be made available for research purposes only under a formal data sharing and use agreement that provides for a commitment to the following: 1) using the data only for research purposes and not to identify any individual participant, 2) securing the data using appropriate computer technology, 3) destroying or returning the data after analyses are completed, 4) accepting reporting responsibilities, 5) abiding by restrictions on redistribution of the data for commercial purposes or to third parties, and 6) proper acknowledgment of the data resource. Appropriate fees may be assessed on mutual agreement on requests for information in a format other than that we intend to provide. We will not be responsible for providing any analytical support.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia components 1

mmc1.docx^{(60.6KB, docx)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Multimedia components 1

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Data Availability Statement

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PERMALINK

Association of Changes in Neural Targets and Dietary Outcomes among Patients with Comorbid Obesity and Depression: Post hoc Analysis of ENGAGE-2 Mechanistic Clinical Trial

Nan Lv

Hagar Hallihan

Lan Xiao

Leanne M Williams

Olusola A Ajilore

Jun Ma

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Materials/Subjects and Methods

Participants

Study Procedures, Randomization, and Blinding

FIGURE 1.

Intervention

Usual Care

Outcome Measures

Statistical Analysis

Changes in Protocol Owing to the COVID-19 Pandemic

Results

Sample Characteristics

TABLE 1.

Association of Neural Targets With Dietary Outcomes

Cognitive control circuit

TABLE 2.

TABLE 3.

Negative affect circuit

TABLE 4.

TABLE 5.

Positive affect circuit

TABLE 6.

Table 7.

Discussion

Author disclosures

Acknowledgments

Funding

Data Availability

Appendix A. Supplementary data

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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