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. Author manuscript; available in PMC: 2020 May 15.
Published in final edited form as: Physiol Behav. 2019 Feb 11;204:86–92. doi: 10.1016/j.physbeh.2019.02.013

The Effects of Roux En Y Gastric Bypass Surgery on Neurobehavioral Symptom Domains Associated with Severe Obesity

Dominique Musselman 1, Neeta Shenvi 2, Amita Manatunga 2, Andrew H Miller 3, Edward Lin 4, Nana Gletsu-Miller 5
PMCID: PMC6475463  NIHMSID: NIHMS1522055  PMID: 30763595

Abstract

BACKGROUND:

Neurobehavioral symptoms and cognitive dysfunction related to mood disorders are present in individuals with severe obesity. We sought to determine acute improvements in these symptoms and relationships with adiposity, inflammation, and insulin sensitivity after roux-en-y gastric bypass (RYGB) surgery.

METHODS:

The self-report Zung Depression Rating (ZDRS) and Neurotoxicity Rating (NRS) scales were administered before, and at 6-months after RYGB surgery in severely obese women (body mass index > 35 kg/m2; N=19). Symptom domains corresponding to depressed mood/suicide ideation, anxiety, cognitive, somatic, and neurovegetative symptoms were assessed. Biologic measures were of adiposity [leptin, abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue], inflammation [IL-6, C-reactive protein (CRP)], and insulin sensitivity (Si). Spearman correlations and linear regression (adjusted for biologic measures) assessed relationships between changes in biologic measures and changes in neurobehavioral domains.

RESULTS:

By 6-months after RYGB, VAT, SAT, Si, CRP, and IL-6 had improved (p <0.05). Anxiety, somatic, and neurovegetative symptoms domains improved (p <0.05), but depressed mood/suicidal ideation and cognitive domains did not. Reductions in VAT were associated with decreases in neurovegetative symptoms (beta = 295 ± 85, p < 0.01). We also found significant positive longitudinal associations between IL-6 concentrations and minor changes in cognitive symptoms.

CONCLUSION:

Anxiety, somatic and neurovegetative symptoms, improved within 6 months after RYGB, but depressed mood/suicidal ideation and cognitive symptoms did not improve. Associations between visceral adiposity, IL-6 concentrations and neurovegetative and cognitive symptoms support links between obesity, inflammation and distinct neurobehavioral symptoms.

Keywords: inflammation, visceral adipose tissue, depression, suicide risk, cognition

Introduction

Obesity, particularly when severe, is associated with disorders with major depressive and anxiety disorders and cognitive dysfunction [1–3], although the etiology is unclear [4, 5]. Severe obesity is a model of chronic innate immune system activation, e.g. increased circulating plasma concentrations of pro-inflammatory adipocytokines, and T-cell activation [6–8]. A rich database has been developed that substantiates the capacity of inflammatory cytokines, including tumor necrosis factor (TNF) alpha, interleukin (IL)-1, and IL-6, to induce a syndrome of sickness behavior [9]. Sickness behavior associated with inflammation include aspects of mood disorders (depression, suicidal ideation, anxiety/irritability), but also symptoms that are somatic, neurocognitive and neurovegetative, including increased sensitivity to pain, anorexia, cognitive dysfunction, psychomotor slowing, anergia/fatigue, and sleep alterations [10]. In prior studies by our group of patients with metastastic melanoma and hepatitis C, we have shown that administration of high-dose interferon and pegylated interferon, respectively, is associated with induction of sickness behavior and even major depression in a significant proportion of patients[11, 12]. However, in addition to the low-grade chronic inflammation associated with by severe obesity, insulin resistance and hyperglycemia may also accompany obesity and may contribute to depression and other neurobehavioral symptoms domains [13, 14].

Fortunately, bariatric surgery reliably reduces adiposity in individuals who are severely obese and investigations using this model have provided insights on longitudinal relationships between obesity and risk of disease. A recent meta-analysis demonstrated that depressive symptoms decreased after bariatric surgery [15]. However most of the studies evaluated depression using self-report questionnaires that included symptoms of depressed mood and suicidality along with somatic and neurovegetative symptomology. This inclusive approach for evaluation of depression maximizes sensitivity, but reduces specificity regarding the depressive symptom domain, including suicidal ideation [16]. We were interested specifically in suicidality since research demonstrates that bariatric surgery patients have a higher risk of suicide compared to non-surgery cohorts [17]. Moreover, only a few studies have assessed neurobehavioral symptoms at an early timepoint of 6 months after roux en y gastric bypass (RYGB) [18–20]. While some studies in bariatric populations demonstrated that changes in body mass index (BMI) are correlated with changes in total depression rating scale scores as assessed by self-report [18, 21, 22], there is limited information on whether this relationship is specifically mediated by changes in adiposity, inflammation or glucose homeostasis. Thus the acute impact of bariatric surgery on neurobiologic pathways underlying distinct facets of mood and anxiety disorders, and cognitive dysfunction is not yet clear. The conceptual utility of neurobiobehavioral symptom domains is that characterization of specific cluster of symptoms may more accurately reflect disease course, and allow more specific understanding of neurobiology pathways or treatment adverse effects, thereby stimulating interventions to reduce patient burden and improve quality of life [12]. In a previous study, we demonstrated that, within 6 months, RYGB reliably reduces adiposity, inflammation and improves glucose homeostasis [23]. In this secondary analysis, we sought to determine: a) which neurobehavioral symptom domains improve after bariatric surgery and b) whether improvements in regional adiposity, inflammation, and glucose regulation were associated with changes in neurobehavioral symptom domains.

Methods

Enrollment and Follow-up

Data was obtained from nineteen severely obese women, who underwent bariatric surgery between May 2003 and March 2009 at the Emory Bariatric Clinic and who completed the survey instruments regarding neurobehavioral symptoms. Inclusion criteria included being female, weight stable, and eligible to undergo bariatric surgery [24 ]. Symptoms of severe mental illness, significant cognitive impairment and drug/alcohol abuse, were contraindications to surgery; use of tobacco products and eating disorders were considered to be possible contraindications [25]. Other exclusion criteria for this study were male sex, since the relationship between central adiposity and depression has been demonstrated in females, but not males [26], and age less than 19 or greater than 65 years. Individuals were categorized as having normoglycemia (never treated with hypoglycemic drugs and fasting plasma glucose (FPG) < 5.6 mmol/L, n = 9), prediabetes (FPG ≥ 5.6 mmol/L, n = 1), or diabetes (physician-documented diabetes history or FPG > 7.0 mmol/L [n = 8]) [27]. All medication use was monitored throughout the study. The Emory University Institutional Review Board approved the study (#333–2002); and all participants provided written informed consent prior to enrollment.

Assessments

Participants were evaluated at baseline (before surgery) and again at 6 months following surgery. At each study visit, study participants completed self-report rating scales to assess neurobehavioral symptoms. Our research group has previously demonstrated the utility of assessing separately, distinct symptom clusters of neurobehavioral symptomology [12, 28]. Neurobehavioral symptoms were grouped into symptom dimensions corresponding to depressed mood/suicidal ideation, cognitive, anxiety, somatic and neurovegetative symptom domains (Figure 1). Magnitude of depressive symptoms was assessed using the self-report, Zung Depression Rating Scale (ZDRS) [29]. The ZDRS is widely used in the clinical setting to screen for depression and mood symptoms. The ZDRS has been validated to assesses depression globally with higher total scores indicating greater symptom severity and scores greater than 50 indicate clinical depression [30]. The scale has 20 questions designed to assess affective, psychological and somatic symptoms. Subscales within the ZDRS correspond with symptoms of depressed mood and suicidality (feeling downhearted and blue, crying spells or feeling like crying, feeling that others would be better off if I were dead). Norms for the individual items and the total ZDRS score have been developed using college students in the US [31]. The Neurotoxicity Rating Scale (NRS) was also used, given its capacity in assessing the magnitude of behavioral, cognitive, neurovegetative and somatic symptoms in response to cytokine therapy [32]. The dimension of anxiety was assessed by the single NRS item of anxiety. Cognitive dysfunction was similarly assessed by 5 NRS items: difficulty in making decisions, distractibility, episodes of confusion, word-finding problems, memory problems. Neurovegetative symptoms were assessed by 5 other NRS items: difficulty getting to sleep, difficulty staying asleep, sleeping too much, loss of appetite, slowed movements. Six items of the NRS were used to quantify somatic symptoms: nausea, vomiting, body aches, joint pain, bowel/bladder problems, and headache.

Figure 1. Grouping of Depressive Symptomology into Clusters.

Figure 1.

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Sub-items from the Zung Depression Rating Scale (ZDRS) and the Neurotoxicity Rating Scales (NRS) were included as indicated.

Anthropometry and Body Fat Composition

Body weight, height, and all other body composition measurements were obtained with participants in light clothing, without shoes, in the fasting state, and immediately after voiding in the morning [33]. Waist circumference was obtained by tape measure at the smallest point of the posterior torso between the inferior rib and the iliac crest. Abdominal fat distribution was measured by computed tomography (CT), using a GE High Speed Advantage CT scanner (General Electric Medical Systems, Milwaukee, WI) as described [23]. Volumes of VAT and subcutaneous adipose (SAT) tissue, respectively, were determined from CT scans taken from the L1 to the L5 vertebral region (140 kV, 240–340 mA.s, 10 mm slice thickness). Adipose tissue within an attenuation range of –190 to –30 Hounsfield units was highlighted and computed using software (GE Medical Systems) [23].

Adipokine and Cytokine Lab Methods

High sensitivity C-reactive protein was measured at Emory Medical Laboratory, a reference laboratory, using the SYNCHRON LX20 high sensitivity immunoassay, Beckman Coulter Life Sciences, Indianapolis, IN. The sensitivity of the assay was 0.07 mg/dl. Plasma insulin concentrations was measured by regular and ultrasensitive immunoassay; assay limits were 1μU/mL and 0.07 μU/mL, respectively with less than 1% cross reactivity to proinsulin and c-peptide (Mercordia, Winston Salem, NC). Plasma leptin was measured using a commercial human enzyme-linked immunosorbent assay (ELISA) kit, (Diagnostic Systems Laboratory, Webster, TX). Plasma IL-6 (high sensitivity) was measured using a commercial human ELISA kit (R&D Systems, Minneapolis, MN). For the kits, we found the intra- (coefficient of variation, < 5%) and inter-assay (coefficient of variation, < 5%) precision to be similar to those stated by the manufacturers.

Assessment of Insulin Sensitivity

Insulin action was assessed via a 22-sample, 4-hour, frequently sampled intravenous glucose tolerance test (FSIGTT) [34]. Patients were admitted into the Emory General Clinical Research Center on the night before FSIGTT testing and fasted overnight (12 h). At 20 minutes after the initial intravenous glucose bolus, subjects received a bolus of human insulin (0.02 units/kg body weight). Serum glucose was quantified at the Emory Medical Laboratory, using the Beckman Coulter Alex 20 automated system (Beckman Coulter, Brea, CA). The limit of the assay for glucose was 0.17 mM. Minimal modeling analysis of glucose and insulin levels [35] was used to quantify insulin sensitivity (Si) (MinMod Millennium, Los Angeles, CA).

Bariatric Surgery

Roux-en-y gastric bypass surgery was performed laparoscopically in all patients as has been described [36]. In brief, a 20–30 cc gastric pouch was formed in longitudinal fashion. The roux-limb was typically 100–150 cm in length.

Statistical Analyses

Due to the retrospective nature and the relatively small sample size of the current study, we conducted a power calculation for each objective. For assessment of changes in neurobehavioral symptoms, Dymek et al found a 45% decrease in depression, in 32 individuals, at 6 months after RYGB surgery [20]. Using this data we calculated that a sample size of 19 would provide 91% power, α = 0.05. For assessing correlative relationships, Emery et al [37] demonstrated in 13 women that reductions in depression after RYGB were related to decreases in CRP (R = 0.98, P < 0.001). Based on this data a sample size of 19 would have sufficient power to identify significant associations.

Subscores from the ZDRS and NRS scales that correspond to symptom dimensions of interest as well as the total score of the ZDRS were considered for data analysis (Figure 1). The mean score obtained by a patient in each of the depressed mood/suicidal ideation, cognitive, anxiety, somatic and neurovegetative symptom dimensions was calculated as the sum of the scores obtained by the patient in each of the symptoms in that dimension. For calculation of the total ZDRS score we had to deal with missing values for questions 5, “I eat as much as I used to”, and question 7, “I notice that I am losing weight”. Bariatric surgery influences the answers to these questions and participants were instructed not to answer them. In order to compare the total ZDRS score with reference measures, we imputed the missing data based on logical rules [38]. For example in the ZDRS question 5, we imputed a value of 4 before surgery and a value of 1 after surgery. The analysis of the data set remained the same, whether or not we used imputed measures. Fugita and colleagues generated means and standard deviations of the each of the question in the ZDRS [31] and we used this information to create reference norms for depression mood/suicidal ideation subscore. By estimating the 95% confidence interval, we deemed participants who had values > 8.85 as having abnormally high depressed mood/suicide ideation.

Spearman correlations and linear regression were used to assess relationships in changes at 6-months, between the measures of adiposity (SAT, VAT and leptin), inflammation (IL-6, CRP], Si, and the depressed mood/suicidal ideation, anxiety, cognitive, neurovegetative, and somatic symptom domains. The dependent measures were the neurobehavioral symptoms and the measures of adiposity, inflammation and Si were included in the model as predictors. Lastly, mixed model estimates were used to compare participants receiving antidepressant treatment vs. those who were not, using interaction between the groups and time. Statistical significance was set at P < 0.05.

Results

At baseline, before surgery, our study population of women participants were relatively young and premenopausal; and half fulfilled American Diabetes Association criteria for diabetes or pre-diabetes (Table 1). Nearly half were racial minorities. Based on the total score of the ZDRS, 68% of the participants were clinically depressed although only 37% of the total sample were prescribed antidepressant medication. The depressed mood and suicidal ideation symptom domain of the ZDRS was 4.5 ± 0.3 which is within the normal range [31]. The participants exhibited evidence of relatively low peripheral inflammation - their mean circulating plasma concentration of IL-6 was 2.39 pg/ml, and their mean plasma CRP was 1.48 mg/L [39]. Only 1 out of 19 participants used steroids or anti-inflammatory medication.

Table 1:

Sociodemographic and Medical Characteristics of Study Population Before Roux-en-y Bypass Surgery

CHARACTERISTICS FREQUENCY (%)
Age (years) (mean + SD) 37 ± 9
Race n (%)
 Caucasian 11 (58%)
 African American 7 (37%)
 Hispanic 1 (5%)
Diabetes n (%)
 Nondiabetic 9 (47%)
 Impaired fasting glucose 1 (5%)
 Diabetes 9 (47%)
BMI (kg/m2) (mean + SD) 47 ± 4
Waist Circumference (cm) (mean + SD) 130.2 ± 16.0
Antidepressant Treatment 7 (37%)
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Characteristics of female participants at baseline, before undergoing roux-en-y gastric bypass surgery, N = 19. BMI, body mass index

As shown in Table 2, by 6 months post-RYBG, participants exhibited marked improvement in adiposity, evidenced by decreases in waist circumference (−21%), SAT (−43%), VAT (−49%) and leptin (−70%). There were improvements in glucose homeostasis and insulin sensitivity (+120%). Blood glucose concentrations were reduced by 25%, and dysglycemia was resolved in 70% of the participants who had diabetes or prediabetes at baseline. By 6 months after RYGB, there was a marked reduction in CRP concentrations (−72%) and a smaller but significant reduction in IL-6 (−29%).

Table 2:

Baseline and Changes in Biomarkers Over Time After Roux-en-y Bypass Surgery

CHARACTERISTIC Time Point
Mean ± SE (95% CI)
Baseline 6 Months Change % Change
C-Reactive Protein (mg/L) 1.48 ± 0.23 (1.01, 1.95) 0.42 ± 0.09 (0.24, 0.60) 1.07 ± 0.20 a (0.67,1.46 ) −72
Interleukin-6 (pg/mL) 2.39 ± 0.36 (1.67, 3.11) 1.70 ± 0.36 (0.97, 2.42) * 0.69 ± 0.52 (−0.36,1.75 ) −29
Leptin (ng/mL) 115.20 ± 7.53 (99.91, 130.50) 34.56 ± 6.36 (21.66,47.45 ) 80.62 ± 6.59 a (67.27,93.98 ) −70
Insulin Sensitivity (min-1.μU-1.ml-1) 1.62 ± 0.16 (1.30, 1.94) 3.57 ± 0.33 (2.90, 4.24) −1.95 ± 0.30 a (−2.56,−1.34 ) 120
Subcutaneous Adipose Tissue (cm3) 15240 ± 940 (13340, 17150) 8700 ± 590 (7500, 9910) 6540 ± 810 a (4900,8180) −43
Visceral Adipose Tissue (cm3) 5160 ± 430 (4300, 6030) 2630 ± 310 (2000, 3250) 2540 ± 300 a (1930,3140 ) −49
Body Mass Index (kg/m2) 49.5 ± 0.9 (39.3, 54.5) 33.5 ± 1.2 (26.2, 49.0) 13.0 ± 0.7 (−19.2, −5.5) −28
Waist Circumference (cm) 130.2 ± 3.3 (123.5, 137.0) 103.6 ± 3.2 (97.1, 110.1) 26.7 ± 1.8 a (23.0,30.3 ) −21
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Adiposity, insulin sensitivity and systemic concentrations of inflammation were measured in 19 female participants before and 6 months after roux-en-y gastric bypass surgery, as described in methods. Percent change, in comparison to baseline, are calculated for each measure, superscript

a

depicts P<0.05

Anxiety (−47%), somatic (−40%) and neurovegetative (−33%) symptom domains, measured by items of the NRS, improved (Table 3). However, the depressed mood/suicidal ideation domain of the ZDRS, and the cognition symptom domain of the NRS, did not improve in the group, despite the total ZDRS score improvement (−20%), such that the proportion of participants presenting with clinical depression decreased from 68% before surgery to 32% after surgery (P < 0.05.) Of note is that by 6 months, 37% of the participants were taking antidepressant medication, a proportion identical to that before surgery. Two participants stopped using antidepressant medication, five of the participants continued this medication therapy and two participants initiated antidepressant therapy.

Table 3.

Symptom Domains Before and After Roux-en-y Bypass Surgery

CHARACTERISTIC Time Point
Mean ± SE (95% CI)
Baseline 6 Months Change % Change*
NRS Anxiety 1.7 ± 0.2 (1.2, 2.1) 0.9 ± 0.2 (0.4, 1.4) 0.8 ± 0.3 (0.3,1.3 ) a −47
NRS Somatic 6.8 ± 1.0 (4.8, 8.8) 4.2 ± 0.8 (2.5, 5.9) 2.7 ± 0.9 (0.8,4.6 ) a −40
NRS Neurovegetative 5.5 (4.0, 7.0) 3.7 ± 0.5 (2.7, 4.7) 1.8 ± 0.8 (0.3,3.4 ) a −33
ZDRS Total Score 54.8± 2.4 (39.7, 75.8) 45.1± 2.3 (32.8, 73.1) 9.7 ± 2.3 (5.2, 14.1) a −20
ZDRS Depressed mood/Suicidal Ideation 4.5 ± 0.3 (3.9, 5.0) 4.1 ± 0.4 (3.3, 4.9) 0.4 ± 0.4 (−0.4,1.2 ) −9
NRS Cognitive 3.9 (2.7, 5.2) 3.7 ± 0.8 (2.0, 5.3) 0.2 ± 0.9 (−1.5,2.0 ) −5
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Neurobehavioral symptoms were assessed using the Zung Depression (ZDRS) and Neurotoxicity Rating Scales (NRS) in 19 female participants before and after roux-en-y gastric bypass, as described in Methods. The percent change from baseline is calculated, values are arranged in order of improvement, superscript

a

depicts P<0.05

Amongst the biomarkers examined, Spearman correlations revealed that SAT and VAT were strongly correlated with CRP (r = 0.58 and r = 0.57, both p < 0.0001), and with leptin (r = 0.65, p < 0.0001, and r = 0.26, p = 0.05), respectively. However, only VAT was correlated with IL-6 (r = 0.36, p = 0.005), whereas SAT was not (r = 0.17, p = 0.20). Regarding correlations between the neurobehavioral symptom domains, only the depressed mood/suicidal ideation domain and cognitive symptom domains were significantly correlated (r = 0.59, p <0001).

The hypothesis that changes in neurobehavioral symptom domains were associated with changes in biological indices was evaluated. Spearman correlations between adiposity and systemic biomarkers and neurobehavioral symptom domains at 6 months after surgery revealed that the decrease in the neurovegetative symptom domain was associated with reduced VAT (r = 0.77; p < 0.001), and that changes in cognitive symptoms were associated with changes in IL-6 concentrations (r = 0.57; p = 0.02). After controlling for the other biomarkers (VAT, SAT, CRP, IL-6, leptin, and Si), linear regression showed that decreases in neurovegetative symptoms were associated with reduced VAT (beta = 295 ± 84; p < 0.01) and changes in cognitive symptoms were associated with changes in IL-6 (beta = 0.36 ± 0.15; p = 0.03) (Table 4).

Table 4.

Linear Regression of Change in Biomarkers and Change in Symptom Domains at 6 Months After Surgery

CHANGE IN BIOMARKER AT MONTH 6 NRS Cognitive Domain ZDRS Neurocognitive Depression Domain Neurovegetativ e Domain Somatic Domain Anxiety Domain
beta ± SE (95%CI) beta ± SE (95%CI) beta ± SE (95%CI) beta ± SE (5%CI) beta ± SE (95%CI)
C-Reactive Protein 0.042 ± .063 (−0.092,0.177) 0.0098 ± .0253 (−0.044,.0632) 0.003 ± .074 (−0.156,0.161) −0.021 ± 0.054 (−0.134,0.092) −0.183 ± 0.199 (−0.605,0.239)
Interleukin-6 0.360 ± .145 (0.051,0.669) P=0.03 −0.011 ± 0.064 (−0.146,0.125) 0.265 ± 0.185 (−0.129,0.660) −0.034 ± 0.136 (−0.320,0.252) −0.433 ± 0.532 (−1.560,0.694)
Leptin −1.400 ± 2.002 (−5.660,2.873) −0.431 ± .809 (−2.140,1.275) 3.350 ± 2.276 (−1.500,8.200) −0.621 ± 1.717 (−4.240,3.001) −3.80 ± 6.32 (−17.20,9.60)
Insulin Sensitivity 0.158 ± 0.084 (−0.022,.3378) 0.063 ± .034 (−0.009,0.135) 0.031 ± 0.109 (−0.201,0.263) 0.025 ± 0.079 (−.141,0.191) 0.152 ± 0.293 (−0.468,0.773)
Subcutaneous Adiposity 4 ± 252 (−533,541) 47 ± 99 (−162,257) 157± 306 (−495,809) −38± 211 (−484,407) 928± 757 (−677,2530)
Visceral Adiposity 77± 94 (−122,277) 55± 34 (−17,128) 295± 85 (115,475) P=<.01 70 ± 76 (−91,231) 205± 304 (−439,849)
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Associations between changes after surgery in biological and neurobehavioral symptoms were assessed using linear regression with C-reactive protein, interleukin-6, leptin, insulin sensitivity and subcutaneous and visceral adiposity included in the model. Significant relationships are highlighted in bold.

Lastly, mixed model analyses confirmed that there were no significant differences in changes in neurobehavioral symptoms at 6 months between participants receiving antidepressant treatment compared to those without.

Discussion

In this study, at 6 months, participants who underwent RYGB experienced improvements in adiposity, inflammation, and insulin sensitivity, however the impact of RYGB on distinct neurobehavioral symptom domains was mixed. The beneficial effect of RYBG upon neurobehavioral symptom domains was greatest for anxiety, somatic (pain, nausea, fatigue) and neurovegetative (sleep, movement) symptoms, however there was no effect on the depressed mood/suicidal ideation domain or on cognitive symptom domain. We observed associations between reduced visceral adiposity and improvement in the neurovegetative symptom domain, which were independent of changes in adiposity, markers of inflammation and insulin sensitivity. In this small sample of women undergoing RYGB, dramatic improvements in insulin sensitivity and reductions in the CRP marker of systemic inflammation were not associated with any neurobehavioral symptoms. Minor decreases in concentrations of IL-6 and in cognitive symptoms were associated.

Our findings refine the extant literature characterizing aspects of neurobehavioral changes after 6-month post-RYGB. Generally, studies show that depression, as indexed by total self-report rating scales, improve [15]. Except for one study by Capuron et al [40], neurobehavioral symptomology was evaluated with an inclusive approach, using the total scores of various psychometric instruments, without clustering neurobehavioral symptoms into domains which might more specifically track with neurobiologic pathways and/or patient outcomes. Using the Neuroticism-Extraversion-Openness Personality Inventory, a psychometric instrument that does not evaluate neurovegetative or somatic symptoms, Capuron and colleagues did report reductions in depression and anxiety in 70 individuals by one year after RYBG [40]. However, we demonstrated that anxiety, neurovegetative and somatic neurobehavioral symptoms domains also were reduced after surgery.

Specific information on the effect of RYGB on depressed mood/suicide ideation is limited. We showed that he depressed mood/suicidal ideation domain did not measurably respond to surgery within six months. Of note, a third of our study patients were receiving antidepressant therapy before RYBG (consistent with prior studies [41]). While depressive (as well as other) symptom domains were similar in severity in antidepressant treated compared to non-treated women, we did not have a large enough sample to adequately control for antidepressant use, which should be a goal of future studies. In addition, our sample population exhibited low scores for depressed mood and suicide ideation, which may explain why RYGB did not have an impact. Taken together, the mild levels of pre-surgical depression in the sample population (mean total Zung score of 55 at baseline) combined with the use of antidepressant therapy, may have blunted and masked the impact of surgery on depressive and cognitive symptomology. Thus, further scrutiny of the depressed mood/suicidal ideation symptom domain is warranted, as persistent and/or worsening depression, increased involvement in psychotherapy, and increased risk of suicide, in some patients after bariatric surgery has been reported [17, 42, 43].

We also did not observe improvement in the cognition symptom domain during 6 months after RYBG. A recent systematic review summarized the long-term impact of RYGB and adjustable gastric banding surgery on neurocognitive functioning [44], when measured by cognitive tests (which are more objective than the self-report instruments we used in the current study). That review provides evidence of improvement in overall neurocognitive function as early as 12 weeks after bariatric surgery. However, similar to our observations, not all aspects of cognitive function, such as attention, were improved [45].

Our findings suggest that after surgery, certain neurobiological symptom domains may improve acutely, but others may not respond or may take longer to resolve. During the first 6 months after surgery patients are adapting to their rapidly changing image, both their internalized and external image of themselves. Self-appraisals of depressed mood/suicidal ideation and cognition (which we found to be highly correlated) may lag behind the somatic, neurovegetative and anxiety symptom domains. Potentially the lack of response in depressed mood/suicidal ideation and cognitive symptoms at 6 months may be due to other (unmeasured) biologic and/or nutritional factors [46] after RYBG, despite the reduction overall from severe obesity to mild (average BMI of 34 kg/m2).

Relevant in this regard, we sought to explore obesity-associated pathways responsible for changes in neurobehavioral symptom domains after RYGB. The improvements in the neurovegetative symptom domain was associated with reduced visceral adiposity, independent of changes in subcutaneous adiposity or changes in markers of inflammation. In support of our finding, in women in the general population, VAT has been crosssectionally associated with depressive symptoms - independent of general adiposity [26, 47–49]. Visceral fat is thought to be more metabolically active compared to subcutaneous fat and may promote a proinflammatory environment [50]. We also observed that changes in both IL-6 and the cognitive symptoms domain were small, but significantly associated, in keeping with other studies documenting associations between cognitive complaints/dysfunction and IL-6 concentrations in cross-sectional [51–54] or prospective longitudinal studies [55, 56]. We suspect that the relationship between IL-6 concentrations and cognition may be more obvious in patients with more severe inflammation. For example, we have shown that by 12 weeks of high-dose interferon-alpha therapy in patients with malignant melanoma, cognitive complaints of memory disturbances and poor concentration increase significantly [28]. Taken together, our current data and prior work suggest that alleviation of inflammation-stimulated neurochemical pathways, may underlie improvement in certain neurobehavioral symptom domains of post-bariatric patients.

This study has weaknesses. This secondary analysis has a small sample population and may have been underpowered to detect changes in the specific depression/suicidal ideation and cognitive symptom domains, as well as associations between insulin sensitivity and other biologic biomarkers that are plausibly mediators of neurobehavioral symptoms. Also only female participants were included, limiting the generalizability of the study. Our study does not have long-term follow-up, and we used self-report rating scales for assessment of cognitive symptoms, and not structured neurocognitive instruments. Association, not causation, of neurobehavioral symptom domains with alterations in biologic variables was scrutinized, and we failed to account for other confounding variables such as changes in sleep apnea, physical activity and nutritional status. Nevertheless, we selected the symptom domains based on our prior studies evaluating associations of these domains with the activation of the innate immune system in patients with melanoma [28] and hepatitis C [12]. The findings of this pilot study can be used to power future studies examining whether certain neurobehavioral symptoms domains are associated with important metabolic (insulin sensitivity, waist circumference) and neuropsychiatric (suicide) outcomes.

Furthermore, our findings of associations between decreased visceral adiposity and improvement in the neurovegetative symptom domain, and IL-6 and the cognitive symptom domain, while preliminary, point to the potential role of central adiposity regarding dysregulation of mood and cognitive function. While less is known regarding the pathways of chronic “low-grade” inflammation within the CNS which may influence neurobehavioral symptoms of the severely obese person, the RYBG post-surgical patient may offer a model in which to elucidate which mechanisms mediate “failure to respond” of important symptom domains over time, in this patient population and others, such as those suffering from chronic pain and fatigue[57].

Figure 2. Associations between before and after changes in visceral adiposity and neurovegetative symptoms.

Figure 2.

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Visceral adiposity was assessed using computed tomography and neurovegetative symptoms were assessed from the Neurotoxicity Rating Scale as described in Methods, before and after roux-en-y gastric bypass surgery.

Figure 3. Associations between before and after changes in plasma concentrations of IL-6 and cognitive symptoms.

Figure 3.

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Interleukin-6 was assessed using immunoassays and cognitive symptoms were assessed from the Neurotoxicity Rating Scale as described in Methods, before and after roux-en-y gastric bypass surgery.

HIGHLIGHTS.

  • Six months post gastric bypass, anxiety, neurovegetative and somatic symptoms domains improve.

  • Depressed mood/suicide ideation and cognitive symptom domains did not improve.

  • Neurobehavioral symptom domains, visceral obesity and inflammation are associated.

Acknowledgements:

We thank the participants who were involved in the study. Brittni Pitts and Diane Sutliff assisted with cytokine measurements, and Diane Sutliff assisted with the data analysis.

Source of Funding: This work supported by R03 DK067167-01A1, R21 DK075745, and Atlanta Clinical and Translational Science Institute #UL1 RR025008.

Footnotes

Conflict of Interest Statement:

The authors do not have any conflict of interests to declare.

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