FTO variant is associated with changes in BMI, ghrelin, and brain function following bariatric surgery.

BACKGROUNDA polymorphism in the fat mass and obesity-associated gene (FTO) is linked to enhanced neural sensitivity to food cues and attenuated ghrelin suppression. Risk allele carriers regain more weight than noncarriers after bariatric surgery. It remains unclear how FTO variation affects brain function and ghrelin following surgery.METHODSResting-state functional magnetic resonance imaging and cue-reactivity functional magnetic resonance imaging with high-/low-caloric food cues were performed before surgery and at 1, 6, and 12 months after surgery to examine brain function in 16 carriers with 1 copy of the rs9939609 A allele (AT) and 26 noncarriers (TT). Behavioral assessments up to 5 years after surgery were also conducted.RESULTSThe AT group relative to the TT group had smaller BMI loss at 12-60 months after surgery and lower resting-state activity in posterior cingulate cortex following laparoscopic sleeve gastrectomy (group-by-time interaction effects). Meanwhile, the AT group relative to the TT group showed greater food cue responses in dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and insula (group effects). There were negative associations of weight loss with ghrelin and greater activation in DLPFC, DMPFC and insula in the AT but not the TT group.CONCLUSIONThese findings indicate that FTO variation is associated with the evolution of ghrelin signaling and brain function after bariatric surgery, which might hinder weight loss.TRIAL REGISTRATIONChinese Clinical Trial Registry Center, ChiCTR-OOB-15006346.FUNDINGThis work was supported by the National Natural Science Foundation of China (grant nos. 82172023, 82202252, 82302292); National Key R&D Program of China (no. 2022YFC3500603); Natural Science Basic Research Program of Shaanxi (grant nos. 2022JC-44, 2022JQ-622, 2023-JC-QN-0922, 2023-ZDLSF-07); Fundamental Research Funds for the Central Universities (grant nos. ZYTS23188, XJSJ23190, XJS221201, QTZX23093); and the Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse (grant no. Y1AA3009).

Disrupted brain state dynamics in opioid and alcohol use disorder: attenuation by nicotine use.

Substance use disorder (SUD) is a chronic relapsing disorder with long-lasting changes in brain intrinsic networks. While most research to date has focused on static functional connectivity, less is known about the effect of chronic drug use on dynamics of brain networks. Here we investigated brain state dynamics in individuals with opioid use (OUD) and alcohol use disorder (AUD) and assessed how concomitant nicotine use, which is frequent among individuals with OUD and AUD, affects brain dynamics. Resting-state functional magnetic resonance imaging data of 27 OUD, 107 AUD, and 137 healthy participants were included in the analyses. To identify recurrent brain states and their dynamics, we applied a data-driven clustering approach that determines brain states at a single time frame. We found that OUD and AUD non-smokers displayed similar changes in brain state dynamics including decreased fractional occupancy or dwell time in default mode network (DMN)-dominated brain states and increased appearance rate in visual network (VIS)-dominated brain states, which were also reflected in transition probabilities of related brain states. Interestingly, co-use of nicotine affected brain states in an opposite manner by lowering VIS-dominated and enhancing DMN-dominated brain states in both OUD and AUD participants. Our finding revealed a similar pattern of brain state dynamics in OUD and AUD participants that differed from controls, with an opposite effect for nicotine use suggesting distinct effects of various drugs on brain state dynamics. Different strategies for treating SUD may need to be implemented based on patterns of co-morbid drug use.

Neural correlates of decreased impulsivity during delay discounting task after laparoscopic sleeve gastrectomy.

OBJECTIVE: The goal of this study was to investigate laparoscopic sleeve gastrectomy (LSG)-induced changes in choice impulsivity and the neural correlates in individuals with obesity (OB). METHODS: The study employed functional magnetic resonance imaging with a delay discounting task in 29 OB tested before and 1 month after LSG. Thirty participants with normal weight matched to OB with gender and age were recruited as the control group and underwent an identical functional magnetic resonance imaging scan. Alterations in activation and functional connectivity between pre- and post-LSG were investigated and compared with participants with normal weight. RESULTS: OB exhibited significantly reduced discounting rate after LSG. During the delay discounting task, hyperactivation in dorsolateral prefrontal cortex, right caudate, and dorsomedial prefrontal cortex decreased in OB after LSG. LSG additionally engaged compensatory effects through increased activation in bilateral posterior insula and functional connectivity between caudate and dorsomedial prefrontal cortex. Those changes were associated with decreased discounting rate and BMI as well as improved eating behaviors. CONCLUSIONS: These findings indicate that decreased choice impulsivity following LSG was associated with the changes in regions involved in executive control, reward evaluation, interoception, and prospection. This study may provide neurophysiological support for the development of nonoperative treatments such as brain stimulation for individuals with obesity and overweight.

Brain functional and structural magnetic resonance imaging of obesity and weight loss interventions.

Obesity has tripled over the past 40 years to become a major public health issue, as it is linked with increased mortality and elevated risk for various physical and neuropsychiatric illnesses. Accumulating evidence from neuroimaging studies suggests that obesity negatively affects brain function and structure, especially within fronto-mesolimbic circuitry. Obese individuals show abnormal neural responses to food cues, taste and smell, resting-state activity and functional connectivity, and cognitive tasks including decision-making, inhibitory-control, learning/memory, and attention. In addition, obesity is associated with altered cortical morphometry, a lowered gray/white matter volume, and impaired white matter integrity. Various interventions and treatments including bariatric surgery, the most effective treatment for obesity in clinical practice, as well as dietary, exercise, pharmacological, and neuromodulation interventions such as transcranial direct current stimulation, transcranial magnetic stimulation and neurofeedback have been employed and achieved promising outcomes. These interventions and treatments appear to normalize hyper- and hypoactivations of brain regions involved with reward processing, food-intake control, and cognitive function, and also promote recovery of brain structural abnormalities. This paper provides a comprehensive literature review of the recent neuroimaging advances on the underlying neural mechanisms of both obesity and interventions, in the hope of guiding development of novel and effective treatments.

Habenular connectivity predict weight loss and negative emotional-related eating behavior after laparoscopic sleeve gastrectomy.

Habenular (Hb) processes negative emotions that may drive compulsive food-intake. Its functional changes were reported following laparoscopic-sleeve-gastrectomy (LSG). However, structural connectivity (SC) of Hb-homeostatic/hedonic circuits after LSG remains unclear. We selected regions implicated in homeostatic/hedonic regulation that have anatomical connections with Hb as regions-of-interest (ROIs), and used diffusion-tensor-imaging with probabilistic tractography to calculate SC between Hb and these ROIs in 30 obese participants before LSG (PreLSG) and at 12-month post-LSG (PostLSG12) and 30 normal-weight controls. Three-factor-eating-questionnaire (TFEQ) and Dutch-eating-behavior-questionnaire (DEBQ) were used to assess eating behaviors. LSG significantly decreased weight, negative emotion, and improved self-reported eating behavior. LSG increased SC between the Hb and homeostatic/hedonic regions including hypothalamus (Hy), bilateral superior frontal gyri (SFG), left amygdala (AMY), and orbitofrontal cortex (OFC). TFEQ-hunger negatively correlated with SC of Hb-Hy at PostLSG12; and increased SC of Hb-Hy correlated with reduced depression and DEBQ-external eating. TFEQ-disinhibition negatively correlated with SC of Hb-bilateral SFG at PreLSG. Increased SC of Hb-left AMY correlated with reduced DEBQ-emotional eating. Higher percentage of total weight-loss negatively correlated with SC of Hb-left OFC at PreLSG. Enhanced SC of Hb-homeostatic/hedonic regulatory regions post-LSG may contribute to its beneficial effects in improving eating behaviors including negative emotional eating, and long-term weight-loss.

Long-term changes in insula-mesolimbic structural and functional connectivity in obese patients after laparoscopic sleeve gastrectomy.

OBJECTIVE: Brain imaging studies have shown insula-related functional and structural abnormalities in patients with obesity. Laparoscopic sleeve gastrectomy is currently an effective procedure for treating obesity, which promotes acute recovery of brain functional and structural abnormalities in obese patients. The aim of this study was to investigate the long-term impact of laparoscopic sleeve gastrectomy on insula-related structural and functional connectivity. METHODS: Diffusion tensor imaging and resting-state functional magnetic resonance imaging were employed to investigate laparoscopic sleeve gastrectomy-induced changes in insula-related structural connectivity and corresponding resting-state functional connectivity in 25 obese patients prior to (PreLSG) and 12 months post-surgery (PostLSG12). RESULTS: Results showed significant increases in fractional anisotropy and axial diffusivity between the right insula and anterior cingulate cortex, and higher fractional anisotropy of left insula-putamen, left insula-caudate and anterior cingulate cortex-right posterior cingulate cortex/precuneus at PostLSG12 compared with PreLSG. There were significant negative correlations between axial diffusivity of right insula-anterior cingulate cortex and body mass index, and fractional anisotropy of right insula-anterior cingulate cortex with scores on external eating at PostLSG12. Anxiety and depressive status ratings were negatively correlated with fractional anisotropy of left insula-putamen at PostLSG12. In addition, there was a significant decrease in resting-state functional connectivity between left insula and left caudate. CONCLUSIONS: These findings demonstrate long-term changes in insula-related structural and functional connectivity abnormalities promoted by laparoscopic sleeve gastrectomy, which highlight its strong association with long-term weight loss and improvement in eating behaviors.

Habenular and mediodorsal thalamic connectivity predict persistent weight loss after laparoscopic sleeve gastrectomy.

OBJECTIVE: The aim of this study was to investigate laparoscopic sleeve gastrectomy (LSG)-induced changes in connectivity between regions involved with reward/antireward and cognitive control and the extent to which these changes persist after surgery and predict sustainable weight loss. METHODS: Whole-brain local functional connectivity density (lFCD) was studied in 25 participants with obesity who underwent resting-state functional MRI before (PreLSG), 1 month after (PostLSG1 ), and 12 months after (PostLSG12 ) LSG and compared with 25 normal-weight controls. Regions with significant time effects of LSG on functional connectivity density were identified for subsequent seed-based connectivity analyses and to examine associations with behavior. RESULTS: LSG significantly increased lFCD in the mediodorsal thalamic nucleus (MD) and in the habenula (Hb) at PostLSG12 compared with PreLSG/PostLSG1 , whereas it decreased lFCD in the posterior cingulate cortex/precuneus (PCC/PreCun) at PostLSG1 /PostLSG12 , and these changes were associated with reduction in BMI. In contrast, controls had no significant lFCD differences between baseline and repeated measures. MD had stronger connectivity with PreCun and Hb at PostLSG12 compared with PreLSG/PostLSG1 , and the increased MD-left PreCun and Hb-MD connectivity correlated with decreases in hunger and BMI, respectively. PCC/PreCun had stronger connectivity with the insula at PostLSG1-12 . CONCLUSIONS: The findings highlight the importance of reward and interoceptive regions as well as that of regions mediating negative emotions in the long-term therapeutic benefits of LSG.

Cannabis Affects Cerebellar Volume and Sleep Differently in Men and Women.

Background: There are known sex differences in behavioral and clinical outcomes associated with drugs of abuse, including cannabis. However, little is known about how chronic cannabis use and sex interact to affect brain structure, particularly in regions with high cannabinoid receptor expression, such as the cerebellum, amygdala, and hippocampus. Based on behavioral data suggesting that females may be particularly vulnerable to the effects of chronic cannabis use, we hypothesized lower volumes in these regions in female cannabis users. We also hypothesized poorer sleep quality among female cannabis users, given recent findings highlighting the importance of sleep for many outcomes related to cannabis use disorder. Methods: Using data from the Human Connectome Project, we examined 170 chronic cannabis users (>100 lifetime uses and/or a lifetime diagnosis of cannabis dependence) and 170 controls that we attempted to match on age, sex, BMI, race, tobacco use, and alcohol use. We performed group-by-sex ANOVAs, testing for an interaction in subcortical volumes, and in self-reported sleep quality (Pittsburgh Sleep Questionnaire Inventory). Results: After controlling for total intracranial volume and past/current tobacco usage, we found that cannabis users relative to controls had smaller cerebellum volume and poorer sleep quality, and these effects were driven by the female cannabis users (i.e., a group-by-sex interaction). Among cannabis users, there was an age of first use-by-sex interaction in sleep quality, such that females with earlier age of first cannabis use tended to have more self-reported sleep issues, whereas this trend was not present among male cannabis users. The amygdala volume was smaller in cannabis users than in non-users but the group by sex interaction was not significant. Conclusions: These data corroborate prior findings that females may be more sensitive to the neural and behavioral effects of chronic cannabis use than males. Further work is needed to determine if reduced cerebellar and amygdala volumes contribute to sleep impairments in cannabis users.

Deep brain stimulation of the nucleus accumbens/ventral capsule for severe and intractable opioid and benzodiazepine use disorder.

Given high relapse rates and the prevalence of overdose deaths, novel treatments for substance use disorder (SUD) are desperately needed for those who are treatment refractory. The objective of this study was to evaluate the safety of deep brain stimulation (DBS) for SUD and the effects of DBS on substance use, substance craving, emotional symptoms, and frontal/executive functions. DBS electrodes were implanted bilaterally within the Nucleus Accumbens/Ventral anterior internal capsule (NAc/VC) of a man in his early 30s with >10-year history of severe treatment refractory opioid and benzodiazepine use disorders. DBS of the NAc/VC was found to be safe with no serious adverse events noted and the participant remained abstinent and engaged in comprehensive treatment at the 12-week endpoint (and 12-month extended follow-up). Using a 0-100 visual analog scale, substance cravings decreased post-DBS implantation; most substantially in benzodiazepine craving following the final DBS titration (1.0 ± 2.2) compared to baseline (53.4 ± 29.5; p < .001). A trend toward improvement in frontal/executive function was observed on the balloon analog risk task performance following the final titration (217.7 ± 76.2) compared to baseline (131.3 ± 28.1, p = .066). FDG PET demonstrated an increase in glucose metabolism in the dorsolateral prefrontal and medial premotor cortices at the 12-week endpoint compared to post-surgery/pre-DBS titration. Heart Rate Variability (HRV) improved following the final titration (rMSSD = 56.0 ± 11.7) compared to baseline (19.2 ± 8.2; p < .001). In a participant with severe, treatment refractory opioid and benzodiazepine use disorder, DBS of the NAc/VC was safe, reduced substance use and craving, and improved frontal and executive functions. Confirmation of these findings with future studies is needed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Connectome-Based Prediction of Optimal Weight Loss Six Months After Bariatric Surgery.

Despite bariatric surgery being the most effective treatment for obesity, a proportion of subjects have suboptimal weight loss post-surgery. Therefore, it is necessary to understand the mechanisms behind the variance in weight loss and identify specific baseline biomarkers to predict optimal weight loss. Here, we employed functional magnetic resonance imaging (fMRI) with baseline whole-brain resting-state functional connectivity (RSFC) and a multivariate prediction framework integrating feature selection, feature transformation, and classification to prospectively identify obese patients that exhibited optimal weight loss at 6 months post-surgery. Siamese network, which is a multivariate machine learning method suitable for small sample analysis, and K-nearest neighbor (KNN) were cascaded as the classifier (Siamese-KNN). In the leave-one-out cross-validation, the Siamese-KNN achieved an accuracy of 83.78%, which was substantially higher than results from traditional classifiers. RSFC patterns contributing to the prediction consisted of brain networks related to salience, reward, self-referential, and cognitive processing. Further RSFC feature analysis indicated that the connection strength between frontal and parietal cortices was stronger in the optimal versus the suboptimal weight loss group. These findings show that specific RSFC patterns could be used as neuroimaging biomarkers to predict individual weight loss post-surgery and assist in personalized diagnosis for treatment of obesity.

Brain Connectivity, and Hormonal and Behavioral Correlates of Sustained Weight Loss in Obese Patients after Laparoscopic Sleeve Gastrectomy.

The biological mediators that support cognitive-control and long-term weight-loss after laparoscopic sleeve gastrectomy (LSG) remain unclear. We measured peripheral appetitive hormones and brain functional-connectivity (FC) using magnetic-resonance-imaging with food cue-reactivity task in 25 obese participants at pre, 1 month, and 6 month after LSG, and compared with 30 normal weight controls. We also used diffusion-tensor-imaging to explore whether LSG increases brain structural-connectivity (SC) of regions involved in food cue-reactivity. LSG significantly decreased BMI, craving for high-calorie food cues, ghrelin, insulin, and leptin levels, and increased self-reported cognitive-control of eating behavior. LSG increased FC between the right dorsolateral prefrontal cortex (DLPFC) and the pregenual anterior cingulate cortex (pgACC) and increased SC between DLPFC and ACC at 1 month and 6 month after LSG. Reduction in BMI correlated negatively with increased FC of right DLPFC-pgACC at 1 month and with increased SC of DLPFC-ACC at 1 month and 6 month after LSG. Reduction in craving for high-calorie food cues correlated negatively with increased FC of DLPFC-pgACC at 6 month after LSG. Additionally, SC of DLPFC-ACC mediated the relationship between lower ghrelin levels and greater cognitive control. These findings provide evidence that LSG improved functional and structural connectivity in prefrontal regions, which contribute to enhanced cognitive-control and sustained weight-loss following surgery.

Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women.

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron emission tomography (PET) with the aromatase inhibitor [11C]vorozole in a sample of 43 adult, normal-weight, overweight, or obese men and women. A subsample of 27 also completed personality measures to examine the relationship between aromatase and personality traits related to self-regulation and inhibitory control. Results indicated that aromatase availability in the amygdala was negatively associated with body mass index (BMI) (in kilograms per square meter) and positively correlated with scores of the personality trait constraint independent of sex or age. Individual variations in the brain's capacity to synthesize estrogen may influence the risk of obesity and self-control in men and women.

Personality traits in substance use disorders and obesity when compared to healthy controls.

BACKGROUND AND AIMS: Although personality traits are implicated in substance use disorders (SUDs) and obesity, differences and similarities between them have not been assessed. Our main aim was to compare personality traits between people with different SUDs, obese people and healthy controls. DESIGN: This was a secondary analysis of personality scores obtained from participants in neuroimaging studies from Brookhaven National Laboratory and the Laboratory of Neuroimaging, National Institutes of Health. SETTING: United States. PARTICIPANTS/CASES: Individuals with obesity (OB) n = 41, alcohol use disorder (AUD) n = 39, marijuana use disorder (MUD) n = 24, cocaine use disorder (CUD) n = 100, and healthy controls (HC) n = 117 (237 males and 84 females). MEASUREMENTS: The Multidimensional Personality Questionnaire, which characterizes positive emotionality (PEM), negative emotionality (NEM) and constraint (CON) traits. Adjusted covariates included cigarette smoking status, age, gender and body mass index (BMI). FINDINGS: Multivariate analysis of covariance showed a main group effect (i.e. OB, AUD, MUD, CUD and HC) only on NEM (P < 0.0001, η2  = 0.17) and CON (P = 0.005, η2  = 0.12). Specifically, NEM was higher in AUD (P < 0.0001, d = 10.4), CUD (P < 0.0001, d = 8.2) and MUD (P = 0.001, d = 9.2), but not in OB (P > 0.05, d = 2.8) relative to HC. CUD showed lower CON (P = 0.015, d = 5.4) and PEM (P = 0.018, d = 4.8) than HC; however, these differences were not significant in the other groups. NEM and CON were negatively correlated for groups combined (r = -0.26, P < 0.0001), and separately for OB (r = -0.49, P = 0.001) and CUD (r = -0.22, P = 0.03). Cigarette smoking status did not influence group differences in NEM, PEM or CON. CONCLUSIONS: Compared with healthy controls, people with substance use disorders appear to show higher negative emotionality, and people with cocaine use disorders appear to show lower positive emotionality and constraint traits. Similar findings were not found among people with obesity.

Laparoscopic sleeve gastrectomy improves brain connectivity in obese patients.

OBJECTIVE: Obese individuals have shown functional abnormalities in frontal-limbic regions, and bariatric surgery is an effective treatment for morbid obesity. The aim of the study was to investigate how bariatric surgery modulates brain regional activation and functional connectivity (FC) to food cues, and whether the underlying structural connectivity (SC) alterations contribute to these functional changes as well as behavioral changes. METHODS: A functional magnetic resonance imaging cue-reactivity task with high- (HiCal) and low-calorie (LoCal) food pictures and diffusion tensor imaging (DTI) with deterministic tractography were used to investigate brain reactivity, FC and SC in 28 obese participants tested before and 1 month after laparoscopic sleeve gastrectomy (LSG). Twenty-two obese controls (Ctr) without surgery were also tested at baseline and 1 month later. RESULTS: LSG significantly decreased right dorsolateral prefrontal cortex (DLPFC) activation to HiCal versus LoCal cues and increased FC between DLPFC and ventral anterior cingulate cortex (vACC), which are regions involved in self-regulation of feeding behaviors. LSG also increased SC between DLPFC and ACC as quantified by fractional anisotropy. Increases in SC and FC between DLPFC and ACC were associated with greater reductions in BMI, and SC changes were positively correlated with FC changes. Increased SC between right DLPFC and ACC mediated the relationship between reduced BMI and increased right DLPFC-vACC FC; likewise, increases in right DLPFC-vACC FC mediated the relationship between increased right DLPFC-ACC SC and reduced BMI. CONCLUSION: LSG might induce weight loss in part by increasing SC and FC between DLPFC and ACC, and thus strengthening top-down control over food intake.

Laparoscopic sleeve gastrectomy induces sustained changes in gray and white matter brain volumes and resting functional connectivity in obese patients.

BACKGROUND: Obesity is associated with decreased brain gray- (GM) and white-matter (WM) volumes in regions. Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery associated with neuroplastic changes in patients with obesity at 1 month postLSG. OBJECTIVE: To investigate whether LSG can induce sustained neuroplastic recovery of brain structural abnormalities, and whether structural changes are accompanied by functional alterations. SETTING: University hospital, longitudinal study. METHODS: Structural magnetic resonance imaging and voxel-based morphometry analysis were employed to assess GM/WM volumes in 30 obese participants at preLSG and 1 and 3 months postLSG. One-way analysis of variance modeled time effects on GM/WM volumes, and then alterations in resting-state functional connectivity (RSFC) were assessed. RESULTS: Significant time effects on GM volumes were in caudate (F = 11.20), insula (INS; F = 10.11), posterior cingulate cortex (PCC; F = 13.32), and inferior frontal gyrus (F = 12.18), and on WM volumes in anterior cingulate cortex (F = 15.70), PCC (F = 15.56), and parahippocampus (F = 17.96, PFDR < .05). Post hoc tests showed significantly increased GM volumes in caudate (mean change ± SEM .018 ± .005 and P = .001, .031 ± .007 and P < .001), INS (.027 ± .008 and P = .003, .043 ± .009 and P < .001), and PCC (.008 ± .004 and P = .042, .026 ± .006 and P < .001), and increased WM volumes in anterior cingulate cortex (.029 ± .006 and P < .001, .041 ± .008 and P < .001), PCC (.017 ± .004 and P < .001, .032 ± .006 and P < .001), and parahippocampus (.031 ± .008 and P =.001, .075 ± .013 and P < .001) at 1 and 3 months postLSG compared with preLSG. Significant increases in GM volumes were in caudate (.013 ± .006 and P = .036), PCC (.019 ± .006 and P = .006), and inferior frontal gyrus (.019 ± .005 and P = .001), and in WM volumes in anterior cingulate cortex (.012 ± .005 and P = .028), PCC (.014 ± .006 and P = .017), and parahippocampus (.044 ± .014 and P = .003) at 3 relative to 1 month postLSG. GM volumes in INS and PCC showed a positive correlation at 1 (r = .57, P = .001) and 3 months postLSG (r = .55, P = .001). GM volume in INS and PCC were positively correlated with RSFC of INS-PCC (r = .40 and P = .03, r = .55 and P = .001) and PCC-INS (r = .37 and P = .046, r = .57 and P < .001) at 1 month postLSG. GM volume in INS was also positively correlated with RSFC of INS-PCC (r = .44, P = .014) and PCC-INS (r = .38, P = .037) at 3 months postLSG. CONCLUSION: LSG induces sustained structural brain changes, which might mediate long-term benefits of bariatric surgery in weight reduction. Associations between regional GM volume and RSFC suggest that LSG-induced structural changes contribute to RSFC changes.

Effect of alcohol use disorder on cellular aging.

RATIONALE: Human telomeres consist of tandem repeats at chromosome ends which protect chromosomal DNA from degradation. Telomere shortening occurs as part of natural aging; however, life stressors, smoking, drug use, BMI, and psychiatric disorders could disrupt cell aging and affect telomere length (TL). In this context, studies have evaluated the effects of alcohol consumption on TL; however, results have been inconsistent, which may reflect diverse drinking cut-offs and categorizations. OBJECTIVES: To help clarify this, the present study addresses the association of TL with alcohol use disorder (AUD), drinking behaviors, lifetime stress, and chronological age. METHODS: TL was quantified as the telomere to albumin ratio (T/S ratio) obtained from peripheral blood DNA using the quantitative PCR assay, from 260 participants with AUD and 449 non-dependent healthy controls (HC) from an existing National Institute on Alcohol Abuse and Alcoholism (NIAAA) database. RESULTS: AUD participants showed shorter TL compared to HC with both, age, and AUD, as independent predictors as well as a significant AUD with age interaction effect on TL. TL was also associated with impulsiveness in AUD participants. We did not observe an association between TL and chronicity of alcohol use, alcohol doses ingested, or childhood trauma exposures in either AUD or HC, although very few HC reported a history of childhood trauma. CONCLUSION: Our results support previous findings of telomere shortening with chronic alcohol exposures and show both an effect of AUD on TL that is independent of age as well as a significant AUD by age interaction on TL. These findings are consistent with accelerated cellular aging in AUD.

Ghrelin reductions following bariatric surgery were associated with decreased resting state activity in the hippocampus.

BACKGROUND/OBJECTIVE: Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery to treat obesity, and involves removal of the gastric fundus where ghrelin is mainly produced. Ghrelin stimulates appetite and regulates food intake through its effect on the hypothalamus and hippocampus (HIPP). While ghrelin's role on the hypothalamus has been explored, little is known about its role on HIPP. We tested the hypothesis that LSG-induced reductions in ghrelin levels would be associated with changes in HIPP activity. SUBJECTS/METHODS: Brain activity was measured with amplitude of low-frequency fluctuations (ALFF) captured with resting-state functional magnetic resonance imaging (fMRI) in 30 obese participants, both before and after 1-month of LSG, and in 26 obese controls without surgery that were studied at baseline and 1-month later. A two-way analysis of variance (ANOVA) was performed to model the group and time effects on ALFF and resting-state functional connectivity. RESULTS: One-month post-LSG there were significant decreases in appetite, body mass index (BMI), fasting plasma ghrelin and leptin levels, anxiety, and ALFF in HIPP and ALFF increases in posterior cingulate cortex (PCC, PFWE < 0.05). Decreases in HIPP ALFF correlated positively with decreases in fasting ghrelin and anxiety, and increases in PCC ALFF correlated positively with decreases in anxiety. Seed-voxel correlation analysis showed stronger connectivity between HIPP and insula, and between PCC and dorsolateral prefrontal cortex (DLPFC) post-LSG. CONCLUSIONS: These findings suggest that ghrelin effects in HIPP modulate connectivity with the insula, which processes interoception and might be relevant to LSG-induced reductions in appetite/anxiety. Role of LSG in PCC and its enhanced connectivity with DLPFC in improving self-regulation following LSG requires further investigation.

Structural changes in brain regions involved in executive-control and self-referential processing after sleeve gastrectomy in obese patients.

Obesity-related brain gray (GM) and white matter (WM) abnormalities have been reported in regions associated with food-intake control and cognitive-emotional regulation. Bariatric surgery (BS) is the most effective way to treat obesity and induce structural recovery of GM/WM density and WM integrity. It is unknown whether the surgery can promote structural changes in cortical morphometry along with weight-loss. Structural Magnetic Resonance Imaging and surface-based morphometry analysis were used to investigate BS-induced alterations of cortical morphometry in 22 obese participants who were tested before and one month post-BS, and in 21 obese controls (Ctr) without surgery who were tested twice (Baseline and One-month). Results showed that fasting plasma ghrelin, insulin, and leptin levels were significantly reduced post-BS (P < 0.001). Post-BS there were significant decreases in cortical thickness in the precuneus (PFDR < 0.05) that were associated with decreases in BMI. There were also significant increases post-BS in cortical thickness in middle (MFG) and superior (SFG) frontal gyri, superior temporal gyrus (STG), insula and ventral anterior cingulate cortex (vACC); and in cortical volume in left postcentral gyrus (PostCen) and vACC (PFDR < 0.05). Post-BS changes in SFG were associated with decreases in BMI. These findings suggest that structural changes in brain regions implicated in executive control and self-referential processing are associated with BS-induced weight-loss.

Reduced plasma ghrelin concentrations are associated with decreased brain reactivity to food cues after laparoscopic sleeve gastrectomy.

The "hunger" hormone ghrelin regulates food-intake and preference for high-calorie (HC) food through modulation of the mesocortico-limbic dopaminergic pathway. Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery to treat morbid obesity. We tested the hypothesis that LSG-induced reductions in appetite and total ghrelin levels in blood are associated with reduced prefrontal brain reactivity to food cues. A functional magnetic resonance imaging (fMRI) cue-reactivity task with HC and low-calorie (LC) food pictures was used to investigate brain reactivity in 22 obese participants tested before and one month after bariatric surgery (BS). Nineteen obese controls (Ctr) without surgery were also tested at baseline and one-month later. LSG significantly decreased (1) fasting plasma concentrations of total ghrelin, leptin and insulin, (2) craving for HC food, and (3) brain activation in the right dorsolateral prefrontal cortex (DLPFC) in response to HC vs. LC food cues (PFWE < 0.05). LSG-induced reduction in DLPFC activation to food cues were positively correlated with reduction in ghrelin levels and reduction in craving ratings for food. Psychophysiological interaction (PPI) connectivity analyses showed that the right DLPFC had stronger connectivity with the ventral anterior cingulate cortex (vACC) after LSG, and changes in BMI were negatively correlated with changes in connectivity between the right DLPFC and vACC in the LSG group only. These findings suggest that LSG-induced weight-loss may be related to reductions in ghrelin, possibly leading to decreased food craving and hypothetically reducing DLPFC response to the HC food cues.

Preclinical Evaluation of the First Adenosine A1 Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

Central adenosine A1 receptor (A1R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A1R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A1R during the sleep-awake cycle. Although several human A1R PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored non-nucleoside (3,5-dicyanopyridine and 5-cyanopyrimidine) templates for developing an agonist A1R PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxyphenyl)-6-(2-(6-methylpyridin-2-yl)ethyl)pyridine-3,5-dicarbonitrile (MMPD, 22b), a partial A1R agonist of sub-nanomolar affinity. [11C]22b showed suitable blood-brain barrier (BBB) permeability and test-retest reproducibility. Regional brain uptake of [11C]22b was consistent with known brain A1R distribution and was blocked significantly by A1R but not A2AR ligands. [11C]22b is the first BBB-permeable A1R partial agonist PET radiotracer with the promise of detecting endogenous adenosine fluctuations.