History of early life adversity is associated with increased food addiction and sex-specific alterations in reward network connectivity in obesity.

BACKGROUND: Neuroimaging studies have identified obesity-related differences in the brain's resting state activity. An imbalance between homeostatic and reward aspects of ingestive behaviour may contribute to obesity and food addiction. The interactions between early life adversity (ELA), the reward network and food addiction were investigated to identify obesity and sex-related differences, which may drive obesity and food addiction. METHODS: Functional resting state magnetic resonance imaging was acquired in 186 participants (high body mass index [BMI]: ≥25: 53 women and 54 men; normal BMI: 18.50-24.99: 49 women and 30 men). Participants completed questionnaires to assess ELA (Early Traumatic Inventory) and food addiction (Yale Food Addiction Scale). A tripartite network analysis based on graph theory was used to investigate the interaction between ELA, brain connectivity and food addiction. Interactions were determined by computing Spearman rank correlations, thresholded at q < 0.05 corrected for multiple comparisons. RESULTS: Participants with high BMI demonstrate an association between ELA and food addiction, with reward regions playing a role in this interaction. Among women with high BMI, increased ELA was associated with increased centrality of reward and emotion regulation regions. Men with high BMI showed associations between ELA and food addiction with somatosensory regions playing a role in this interaction. CONCLUSIONS: The findings suggest that ELA may alter brain networks, leading to increased vulnerability for food addiction and obesity later in life. These alterations are sex specific and involve brain regions influenced by dopaminergic or serotonergic signalling.

The effect of the GLP-1 analogue Exenatide on functional connectivity within an NTS-based network in women with and without obesity.

Objective: The differential effect of GLP-1 agonist Exenatide on functional connectivity of the nucleus tractus solitaries (NTS), a key region associated with homeostasis, and on appetite-related behaviours was investigated in women with normal weight compared with women with obesity. Methods: Following an 8-h fast, 19 female subjects (11 lean, 8 obese) participated in a 2-d double blind crossover study. Subjects underwent functional magnetic resonance imaging at fast and 30-min post subcutaneous injection of 5 µg of Exenatide or placebo. Functional connectivity was examined with the NTS. Drug-induced functional connectivity changes within and between groups and correlations with appetite measures were examined in a region of interest approach focusing on the thalamus and hypothalamus. Results: Women with obesity reported less hunger after drug injection. Exenatide administration increased functional connectivity of the left NTS with the left thalamus and hypothalamus in the obese group only and increased the correlation between NTS functional connectivity and hunger scores in all subjects, but more so in the obese. Conclusions: Obesity can impact the effects of Exenatide on brain connectivity, specifically in the NTS and is linked to changes in appetite control. This has implications for the use of GLP-1 analogues in therapeutic interventions.

Sex differences in the influence of body mass index on anatomical architecture of brain networks.

BACKGROUND/OBJECTIVES: The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters. SUBJECTS/METHODS: Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age. RESULTS: In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions. CONCLUSIONS: In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.

Gene expression profiles in peripheral blood mononuclear cells correlate with salience network activity in chronic visceral pain: A pilot study.

BACKGROUND: Distinct gene expression profiles in peripheral blood mononuclear cells (PBMCs) consistent with increased sympathetic nervous system activity have been described in different populations under chronic stress. Neuroinflammatory brain changes, possibly related to the migration of primed monocytes to the brain, have been implicated in the pathophysiology of chronic pain. Irritable bowel syndrome (IBS) is a stress-sensitive gastrointestinal disorder associated with altered brain-gut interactions and increased sympathetic/vagal tone and anxiety. Reports about immune alterations in IBS are conflicting. This pilot study aimed to test how PBMC gene expression inflammatory profiles are correlated with altered brain signatures in the salience system. METHODS: Sixteen IBS and 16 healthy controls (HCs) completed resting state MRI scans. Gene expression profiles in PBMCs were assessed using human transcriptome array-2. Bioinformatic analyses determined differential expression of PBMCs between IBS and HCs. Partial least squares, a multivariate analysis technique, was used to identify disease correlations between PBMC gene expression profiles and functional activity in the brain's salience network. KEY RESULTS: Regions of the salience network, including the mid cingulate cortex, and mid and superior temporal gyrus were positively correlated with several pro-inflammatory genes (interleukin 6, APOL2) in IBS, but negatively correlated with several anti-inflammatory genes (KRT8, APOA4) in HCs. CONCLUSIONS & INFERENCES: Based on rodent studies, one may speculate that chronically activated stress signaling pathways in IBS maintain a pro-inflammatory state in the periphery. Alternatively, primed monocytes may migrate to the brain during stress, inducing regional neuroinflammatory changes in salience regions involved in the modulation of visceral sensitivity.

Altered brain responses in subjects with irritable bowel syndrome during cued and uncued pain expectation.

BACKGROUND: A majority of the subjects with irritable bowel syndrome (IBS) show increased behavioral and brain responses to expected and delivered aversive visceral stimuli during controlled rectal balloon distension, and during palpation of the sigmoid colon. We aimed to determine if altered brain responses to cued and uncued pain expectation are also seen in the context of a noxious somatic pain stimulus applied to the same dermatome as the sigmoid colon. METHODS: A task-dependent functional magnetic resonance imaging technique was used to investigate the brain activity of 37 healthy controls (18 females) and 37 IBS subjects (21 females) during: (i) a cued expectation of an electric shock to the abdomen vs a cued safe condition; and (ii) an uncued cross-hair condition in which the threat is primarily based on context vs a cued safe condition. KEY RESULTS: Regions within the salience, attention, default mode, and emotional arousal networks were more activated by the cued abdominal threat condition and the uncued condition than in the cued safe condition. During the uncued condition contrasted to the cued safe condition, IBS subjects (compared to healthy control subjects) showed greater brain activations in the affective (amygdala, anterior insula) and attentional (middle frontal gyrus) regions, and in the thalamus and precuneus. These disease-related differences were primarily seen in female subjects. CONCLUSIONS & INFERENCES: The observed greater engagement of cognitive and emotional brain networks in IBS subjects during contextual threat may reflect the propensity of IBS subjects to overestimate the likelihood and severity of future abdominal pain.

Increased attentional network functioning related to symptom severity measures in females with irritable bowel syndrome.

BACKGROUND: Increased attention to gastrointestinal (GI) symptoms and disease-specific contexts may play an important role in the enhanced perception of visceral stimuli frequently reported in patients with irritable bowel syndrome (IBS). In this study, we test the hypothesis that altered attentional mechanisms underlie central pain amplification in IBS. METHODS: To evaluate brain networks that support alerting, orienting, and executive attention, we employed the attention network test (ANT), a modified flanker task which measures the efficiency of functioning of core attentional networks, during functional magnetic resonance imaging in 15 IBS patients (mean age = 31 [11.96]) and 14 healthy controls (HCs; mean age = 31 [10.91]). KEY RESULTS: Patients with IBS, compared to HCs, showed shorter reaction times during the alerting and orienting conditions which were associated with greater activation of anterior midcingulate and insular cortices, and decreased activity in the right inferior frontal junction and supplementary motor cortex. Patients also showed activation in the dorsal medial prefrontal cortex and concurrent thalamic deactivation during the executive control portion of the ANT relative to HCs, but no group difference in reaction times were found. The activity in brain regions showing group differences during the ANT were associated with measures of GI-specific anxiety, pain catastrophizing, and fear of uncertainty. In IBS, activity in the anterior midcingulate during alerting correlated with duration of GI-symptoms and overall symptom severity. CONCLUSIONS & INFERENCES: Together, these results suggest that IBS patients have specific abnormalities in attentional network functioning and these deficits may underlie symptom-related anxiety, hypervigilance, and visceral hypersensitivity.

Altered viscerotopic cortical innervation in patients with irritable bowel syndrome.

BACKGROUND: Studies have demonstrated the existence of regional gray matter and white matter (WM) alterations in the brains of patients with irritable bowel syndrome (IBS), but the extent to which altered anatomical connectivity between brain regions is altered in IBS remains incompletely understood. METHODS: In this study, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were used to identify significant brain connectivity differences between IBS patients and healthy control (HC) subjects. Based on MRI and DTI volumes acquired from 66 IBS patients and 23 HC subjects, multivariate regression was used to investigate whether subject age, sex, cortical thickness, or the mean fractional anisotropy (FA) of WM connections innervating each location on the cortex could predict IBS diagnosis. KEY RESULTS: HC and IBS subjects were found to differ significantly within both left and right viscerotopic portions of the primary somatosensory cortex (S1), with the mean FA of WM bundles innervating S1 being the predictor variable responsible for these significant differences. CONCLUSIONS & INFERENCES: These preliminary findings illustrate how a chronic visceral pain syndrome and brain structure are related in the cohort examined, and because of their indication that IBS diagnosis is associated with anatomic neuropathology of potential neurological relevance in this patient sample.

Altered functional connectivity within the central reward network in overweight and obese women.

BACKGROUND/OBJECTIVES: Neuroimaging studies in obese subjects have identified abnormal activation of key regions of central reward circuits, including the nucleus accumbens (NAcc), in response to food-related stimuli. We aimed to examine whether women with elevated body mass index (BMI) show structural and resting state (RS) functional connectivity alterations within regions of the reward network. SUBJECTS/METHODS: Fifty healthy, premenopausal women, 19 overweight and obese (high BMI=26-38 kg m(-2)) and 31 lean (BMI=19-25 kg m(-2)) were selected from the University of California Los Angeles' Oppenheimer Center for Neurobiology of Stress database. Structural and RS functional scans were collected. Group differences in grey matter volume (GMV) of the NAcc, oscillation dynamics of intrinsic brain activity and functional connectivity of the NAcc to regions within the reward network were examined. RESULTS: GMV of the left NAcc was significantly greater in the high BMI group than in the lean group (P=0.031). Altered frequency distributions were observed in women with high BMI compared with lean group in the left NAcc (P=0.009) in a medium-frequency (MF) band, and in bilateral anterior cingulate cortex (ACC) (P=0.014, <0.001) and ventro-medial prefrontal cortex (vmPFC) (P=0.034, <0.001) in a high-frequency band. Subjects with high BMI had greater connectivity of the left NAcc with bilateral ACC (P=0.024) and right vmPFC (P=0.032) in a MF band and with the left ACC (P=0.03) in a high frequency band. CONCLUSIONS: Overweight and obese women in the absence of food-related stimuli show significant structural and functional alterations within regions of reward-related brain networks, which may have a role in altered ingestive behaviors.

Differences in brain responses between lean and obese women to a sweetened drink.

BACKGROUND: Ingestion of sweet food is driven by central reward circuits and restrained by endocrine and neurocrine satiety signals. The specific influence of sucrose intake on central affective and reward circuitry and alterations of these mechanisms in the obese are incompletely understood. For this, we hypothesized that (i) similar brain regions are engaged by the stimulation of sweet taste receptors by sucrose and by non-nutrient sweeteners and (ii) during visual food-related cues, obese subjects show greater brain responses to sucrose compared with lean controls. METHODS: In a double-blind, crossover design, 10 obese and 10 lean healthy females received a sucrose or a non-nutrient sweetened beverage prior to viewing food or neutral images. BOLD signal was measured using a 1.5 Tesla MRI scanner. KEY RESULTS: Viewing food images after ingestion of either drink was associated with engagement of similar brain regions (amygdala, hippocampus, thalamus, anterior insula). Obese differed from lean subjects in behavioral and brain responses rating both beverages as less tasteful and satisfying, yet demonstrating greater brain responses. Obese subjects also showed engagement of an additional brain network (including anterior insula, anterior cingulate, hippocampus, and amygdala) only after sucrose ingestion. CONCLUSIONS & INFERENCES: Obese subjects had a reduced behavioral hedonic response, yet a greater engagement of affective brain networks, particularly after sucrose ingestion, suggesting that in obese subjects, lingual and gut-derived signaling generate less central hedonic effects than food-related memories in response to visual cues, analogous to response patterns implicated in food addiction.

Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women.

OBJECTIVE: Alterations in serotonin signalling within the brain-gut axis have been implicated in the pathophysiology of irritable bowel syndrome (IBS) and is a treatment target. Acute tryptophan depletion (ATD) decreases brain serotonin (5-hydroxytryptamine; 5-HT) levels, and increases visceral perception and negative emotional bias in patients with IBS. The aim of the present study was to determine the effect of ATD on brain activity and connectivity during visceral stimuli in healthy women, and to compare the ATD-induced brain connectivity of an arousal circuit in female patients with IBS without ATD. METHODS: 12 healthy females (19-25 years) were studied under placebo (PLA) conditions and ATD. Functional MRI measurements were performed during a rectal barostat protocol, consisting of random non-painful and maximal tolerable distensions. Partial least squares analyses and structural equation modelling were used to evaluate the effect of ATD on functional and effective brain connectivity during distension. Results in healthy controls under ATD were compared with the effective connectivity of brain responses to 45 mm Hg rectal distension in 14 female patients with constipation-predominant IBS (IBS-C) (24-50 years). RESULTS: In healthy controls, ATD resulted in increased response of an extensive brain network to balloon distension, including the amygdala and nodes of emotional arousal and homeostatic afferent networks. The effect was greater during high inflation, suggesting greater engagement of the central serotonion system with more aversive visceral stimuli. Effective connectivity analysis revealed a profound effect of ATD on coupling between emotional arousal network nodes, resulting in loss of negative feedback inhibition of the amygdala. A near-identical pattern was identified in the patients with IBS-C. CONCLUSIONS: The findings are consistent with an ATD-induced disinhibition of and increased connectivity within an emotional arousal network during aversive stimulation. Together with the previous demonstration of ATD-induced visceral hyperalgesia in healthy controls, and the near-identical effective connectivity pattern observed in patients with IBS-C, these findings suggest that dysregulation of this brain network may play a role in central pain amplification and IBS pathophysiology.

Sex-related differences in prepulse inhibition of startle in irritable bowel syndrome (IBS).

Alterations in central networks involved in the regulation of arousal, attention, and cognition may be critical for irritable bowel syndrome (IBS) symptom maintenance and exacerbation. Differential sensitivities in these networks may underlie sex differences noted in IBS. The current study examined prepulse inhibition (PPI), a measure of sensorimotor gating, in male and female IBS patients. Relationships between PPI and symptom severity were examined, as well as potential menstrual status effects. Compared to healthy controls, male IBS patients had significantly reduced PPI; whereas female IBS patients (particularly naturally cycling women) had significantly enhanced PPI suggesting hypervigilance. Considering previously demonstrated sex-related differences in perceptual and brain imaging findings in IBS patients, the current findings suggest that different neurobiological mechanisms underlie symptom presentation in male and female IBS patients. Compromised filtering of information in male IBS patients may be due to compromised top down (prefrontal, midcingulate) control mechanisms while increased attention to threat due to increased limbic and paralimbic circuits may be characteristic of female IBS patients.

Brain imaging approaches to the study of functional GI disorders: a Rome working team report.

Progresses in the understanding of human brain-gut interactions in health and disease have been limited by the lack of non-invasive techniques to study brain activity. The advent of neuroimaging techniques has made it possible not only to study the structure and function of the brain, but also to characterize signaling system underlying brain function. This article gives a brief overview of relevant functional neuroanatomy, and of the most commonly used brain imaging techniques. It summarizes published functional brain imaging studies using acute visceral stimulation of the oesophagus, stomach and colon in healthy control subjects and patients with functional GI disorders, and briefly discusses pertinent findings from these studies. The article concludes with a critical assessment of published studies, and with recommendations for improved study paradigms and analysis strategies.

Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: a network analysis.

Differences in brain responses to aversive visceral stimuli may underlie previously reported sex differences in symptoms as well as perceptual and emotional responses to such stimuli in patients with irritable bowel syndrome (IBS). The goal of the current study was to identify brain networks activated by expected and delivered aversive visceral stimuli in male and female patients with chronic abdominal pain, and to test for sex differences in the effective connectivity of the circuitry comprising these networks. Network analysis was applied to assess the brain response of 46 IBS patients (22 men and 24 women) recorded using [15O] water positron emission tomography during rest/baseline and expected and delivered aversive rectal distension. Functional connectivity results from partial least squares analyses provided support for the hypothesized involvement of 3 networks corresponding to: 1) visceral afferent information processing (thalamus, insula and dorsal anterior cingulate cortex, orbital frontal cortex), 2) emotional-arousal (amygdala, rostral and subgenual cingulate regions, and locus coeruleus complex) and 3) cortical modulation (frontal and parietal cortices). Effective connectivity results obtained via structural equation modeling indicated that sex-related differences in brain response are largely due to alterations in the effective connectivity of emotional-arousal circuitry rather than visceral afferent processing circuits. Sex differences in the cortico-limbic circuitry involved in emotional-arousal, pain facilitation and autonomic responses may underlie the observed differences in symptoms, and in perceptual and emotional responses to aversive visceral stimuli.

Sex specific alterations in autonomic function among patients with irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is associated with increased psychological symptoms, early life stressors, and alterations in visceral perception and brain responses to noxious visceral stimuli. The autonomic nervous system (ANS) is a likely mediator for these brain-gut interactions. The few studies directly examining ANS measures have been suggestive of alterations in some IBS patients, but no studies to date have examined the potentially critical variables of sex differences or response to visceral stimulation. AIMS: (1) To test differences in ANS function during rest and during a visceral stressor (rectosigmoid balloon distension) between IBS patients and healthy control subjects. (2) To examine the role of sex on the autonomic responses of IBS patients. METHODS: Baseline autonomic measures were evaluated from 130 Rome I positive IBS patients and 55 healthy control subjects. Data were also collected from a subset of 46 IBS patients and 16 healthy control subjects during a sigmoid balloon distension study. Heart rate variability measures of peak power ratio (PPR) and peak power high frequency (PPHF) were analysed to assess sympathetic balance and parasympathetic response, respectively. Peripheral sympathetic response was measured by skin conductance. RESULTS: IBS patients showed a greater skin conductance response to visceral distension than controls. IBS patients had higher PPR and lower PPHF across conditions. Male IBS patients had higher skin conductance and PPR than females and lower PPHF. CONCLUSIONS: IBS patients have altered autonomic responsiveness to a visceral stressor, with increased sympathetic and decreased parasympathetic activity. These differences are predominantly seen in males.

The Visceral Sensitivity Index: development and validation of a gastrointestinal symptom-specific anxiety scale.

BACKGROUND: Anxiety related to gastrointestinal sensations, symptoms or the contexts in which these may occur is thought to play a significant role in the pathophysiology as well as in the health outcomes of patients with irritable bowel syndrome. AIM: To develop a valid and reliable psychometric instrument that measures gastrointestinal symptom-specific anxiety. METHODS: External and internal expert panels as well as a patient focus group evaluated a large pool of potential item stems gathered from the psychological and gastrointestinal literature. Potential scale items were then administered to 96 patients diagnosed with irritable bowel syndrome along with a set of validating questionnaires. Final item selection was based upon rigorous empirical criteria and the psychometric properties of the final scale were examined. RESULTS: A final unidimensional 15-item scale, the Visceral Sensitivity Index, demonstrated excellent reliability as well as good content, convergent, divergent and predictive validity. CONCLUSIONS: The findings suggest that the Visceral Sensitivity Index is a reliable, valid measure of gastrointestinal symptom-specific anxiety that may be useful for clinical assessment, treatment outcome studies, and mechanistic studies of the role of symptom-related anxiety in patients with irritable bowel syndrome.