Sex Differences and Commonalities in the Impact of a Palatable Meal on Thalamic and Insular Connectivity.

The neural mechanisms underlying subjective responses to meal ingestion remain incompletely understood. We previously showed in healthy men an increase in thalamocortical, and a decrease in insular-cortical connectivity in response to a palatable meal. As sex is increasingly recognized as an important biological variable, we aimed to evaluate sex differences and commonalities in the impact of a well-liked meal on thalamic and anterior insular connectivity in healthy individuals. Participants (20 women and 20 age-matched men) underwent resting-state magnetic resonance imaging (rsMRI) before and after ingesting a palatable meal. In general, the insula showed extensive postprandial reductions in connectivity with sensorimotor and prefrontal cortices, while the thalamus showed increases in connectivity with insular, frontal, and occipital cortices, in both women and men. However, reductions in insular connectivity were more prominent in men, and were related to changes in meal-related sensations (satiety and digestive well-being) in men only. In contrast, increases in thalamic connectivity were more prominent in women, and were related to changes in satiety and digestive well-being in women only. These results suggest that brain imaging may provide objective and sex-specific biomarkers of the subjective feelings associated with meal ingestion.

Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vulvodynia: a voxel-based morphometry study.

Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study, we tested the hypotheses that PVD compared with healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD vs HCs. In addition, disease specificity of GMV alterations were examined by comparing PVD with another chronic pain disorder. Finally, we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, and 29 irritable bowel syndrome [IBS]). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared with HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to patients with IBS, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional GMV alterations were associated with patient reports of pain during intercourse and muscle tenderness. The current findings provide further evidence that GMV is increased in PVD compared with HCs in several regions of the sensorimotor network and the hippocampus in patients with PVD. In addition, GMV distinct alterations in the sensorimotor network were identified between 2 pelvic pain disorders, PVD compared with IBS.

The Gut and Its Microbiome as Related to Central Nervous System Functioning and Psychological Well-being: Introduction to the Special Issue of Psychosomatic Medicine.

Accumulating evidence indicates bidirectional associations between the brain and the gut microbiome with both top-down and bottom-up processes. This article describes new developments in brain-gut interactions as an introduction to a special issue of Psychosomatic Medicine, based on a joint symposium of the American Psychosomatic Society and the American Gastroenterological Association. Literature review articles indicate that several psychiatric disorders are associated with altered gut microbiota, whereas evidence linking functional gastrointestinal disorders and dysbiosis has not been firmly established. The association between dysbiosis with obesity, metabolic syndrome, and Type 2 diabetes mellitus is still inconclusive, but evidence suggests that bariatric surgery may favorably alter the gut microbial community structure. Consistent with the literature linking psychiatric disorders with dysbiosis is that life adversity during childhood and certain temperaments that develop early in life are associated with altered gut microbiota, particularly the Prevotella species. Some studies reported in this issue support the hypothesis that brain-gut interactions are adversely influenced by reduced functional activation of the hippocampus and autonomic nervous system dysregulation. The evidence for the effects of probiotics in the treatment of Clostridium difficile colitis is relatively well established, but effects on mental health and psychophysiological stress reactivity are either inconclusive or still in progress. To conceptualize brain-gut interactions, a holistic, systems-based perspective on health and disease is needed, integrating gut microbial with environmental ecology. More translational research is needed to examine the mental and physical health effects of prebiotics and probiotics, in well-phenotyped human populations with sufficiently large sample sizes.

Transcutaneous Electrical Stimulation Increased Nitric Oxide-Cyclic GMP Release Biocaptured Over Skin Surface of Pericardium Meridian and Acupuncture Points in Humans.

OBJECTIVES: The purpose of this study was to consecutively capture and quantify nitric oxide (NO) and cGMP, the second messenger of NO, over the skin surface of acupuncture points (acupoints), meridian line without acupoint, and non-meridian control regions of the Pericardium meridian (PC) in humans, and investigate their response to transcutaneous electrical nerve stimulation (TENS) . DESIGN, SETTING, AND MAIN OUTCOME MEASURES: Adhesive biocapture tubes were attached to the skin surface along PC regions and injected with 2-Phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl solution, an NO-scavenging compound, contacting the skin surface for 20 minutes each during 4 consecutive biocapture intervals. TENS (1.0 mA, 6 Hz, 1.0 msec duration) was applied over acupoints PC 8 and PC 3 during the 2nd biocapture for 20 min. Total nitrite and nitrate (NO(x)-), the stable metabolic products of NO, and cGMP in biocaptured samples were quantified using chemiluminescence and ELISA. RESULTS: NO(x)- levels in the 1st biocapture over PC regions are almost two fold higher compared to subsequent biocaptures and are higher over PC acupoints versus non-meridian control region. Following TENS, NO(x)- concentrations over PC regions were significantly increased, and cGMP is predominantly released from the skin surface of PC acupoints. CONCLUSIONS: TENS induces elevations of NO-cGMP concentrations over local skin region with a high level at acupoints. The enhanced signal molecules improve local circulation, which contributes to beneficial effects of the therapy.

Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women.

BACKGROUND & AIMS: The study of intrinsic fluctuations in the blood oxygen level-dependent signal of functional magnetic resonance imaging can provide insight into the effect of physiologic states on brain processes. In an effort to better understand the brain-gut communication induced by the absorption and metabolism of nutrients in healthy lean and obese individuals, we investigated whether ingestion of nutritive and non-nutritive sweetened beverages differentially engages the hypothalamus and brainstem vagal pathways in lean and obese women. METHODS: In a 2-day, double-blind crossover study, 11 lean and 11 obese healthy women underwent functional magnetic resonance imaging scans after ingestion of 2 beverages of different sucrose content, but identical sweetness. During scans, subjects rested with eyes closed. RESULTS: Blood oxygen level-dependent fluctuations demonstrated significantly greater power in the highest frequency band (slow-3: 0.073-0.198 Hz) after ingestion of high-sucrose compared with low-sucrose beverages in the nucleus tractus solitarius for both groups. Obese women had greater connectivity between the right lateral hypothalamus and a reward-related brain region and weaker connectivity with homeostasis and gustatory-related brain regions than lean women. CONCLUSIONS: In a functional magnetic resonance imaging study, we observed sucrose-related changes in oscillatory dynamics of blood oxygen level-dependent fluctuations in brainstem and hypothalamus in lean and obese women. The observed frequency changes are consistent with a rapid vagally mediated mechanism due to nutrient absorption, rather than sweet taste receptor activation. These findings provide support for altered interaction between homeostatic and reward networks in obese individuals.

Stress reactivity in traditional Chinese medicine-based subgroups of patients with irritable bowel syndrome.

OBJECTIVES: This study aimed to examine differences in autonomic responses to stress, pain perception, and the role of negative affect in these responses in individuals with irritable bowel syndrome (IBS) according to Traditional Chinese Medicine (TCM) classifications. DESIGN: Fifty-nine female patients with IBS age 18-65 years diagnosed by TCM practitioners as showing primarily an excess (n=32) or an overlap (n=27) pattern (mixed excess and deficiency) were assessed for symptom differences, heart rate, and skin conductance responses to a psychosocial stressor and pain perception. SETTINGS/LOCATIONS: University of California in Los Angeles, California. RESULTS: Compared with the excess group, the overlap group showed significantly greater overall gastrointestinal symptom severity, abdominal pain, and negative affect. The excess group with higher levels of negative affect showed greater reactivity to stress, whereas the overlap group showed an opposite response pattern. The overlap group showed increased cold sensitivity. CONCLUSIONS: IBS patients with the overlap pattern have greater disease severity and comorbidity than those with excess alone. Those with excess showed a pattern of increased stress response with greater negative affect, whereas the overlap group with greater deficiency showed lower physiologic arousal with greater negative affect, consistent with depletion resulting from allostatic load.

The unique brain anatomy of meditation practitioners: alterations in cortical gyrification.

Several cortical regions are reported to vary in meditation practitioners. However, prior analyses have focused primarily on examining gray matter or cortical thickness. Thus, additional effects with respect to other cortical features might have remained undetected. Gyrification (the pattern and degree of cortical folding) is an important cerebral characteristic related to the geometry of the brain's surface. Thus, exploring cortical gyrification in long-term meditators may provide additional clues with respect to the underlying anatomical correlates of meditation. This study examined cortical gyrification in a large sample (n = 100) of meditators and controls, carefully matched for sex and age. Cortical gyrification was established by calculating mean curvature across thousands of vertices on individual cortical surface models. Pronounced group differences indicating larger gyrification in meditators were evident within the left precentral gyrus, right fusiform gyrus, right cuneus, as well as left and right anterior dorsal insula (the latter representing the global significance maximum). Positive correlations between gyrification and the number of meditation years were similarly pronounced in the right anterior dorsal insula. Although the exact functional implications of larger cortical gyrification remain to be established, these findings suggest the insula to be a key structure involved in aspects of meditation. For example, variations in insular complexity could affect the regulation of well-known distractions in the process of meditation, such as daydreaming, mind-wandering, and projections into past or future. Moreover, given that meditators are masters in introspection, awareness, and emotional control, increased insular gyrification may reflect an integration of autonomic, affective, and cognitive processes. Due to the cross-sectional nature of this study, further research is necessary to determine the relative contribution of nature and nurture to links between cortical gyrification and meditation.

Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women.

The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect- and pain-related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat-related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30-second safe ("no abdominal stimulation will be given") and threat ("abdominal stimulation may occur at anytime") periods. The experiment consisted of 2 blocks, each containing 4 safe and 4 threat periods in which the ASR or NFR was randomly probed 9-21 seconds following period onset. Unpredictable abdominal threat potentiated both ASR and NFR responses compared to periods signaling safety. SCRs to acoustic startle probes and noxious sural nerve stimulation were also significantly elevated during the threat vs safe periods. No sex differences in ASR or startle-evoked SCRs emerged. However, nociceptive responding was moderated by sex; females showed significant increases in NFR magnitudes across both safe and threat periods compared to males. Females also showed greater threat-potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect- and pain-related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect-driven ASR responses showed no such sex differentiation.

Impact of Mindfulness-Based Stress Reduction training on intrinsic brain connectivity.

The beneficial effects of mindful awareness and mindfulness meditation training on physical and psychological health are thought to be mediated in part through changes in underlying brain processes. Functional connectivity MRI (fcMRI) allows identification of functional networks in the brain. It has been used to examine state-dependent activity and is well suited for studying states such as meditation. We applied fcMRI to determine if Mindfulness-Based Stress Reduction (MBSR) training is effective in altering intrinsic connectivity networks (ICNs). Healthy women were randomly assigned to participate in an 8-week Mindfulness-Based Stress Reduction (MBSR) training course or an 8-week waiting period. After 8 weeks, fMRI data (1.5T) was acquired while subjects rested with eyes closed, with the instruction to pay attention to the sounds of the scanner environment. Group independent component analysis was performed to investigate training-related changes in functional connectivity. Significant MBSR-related differences in functional connectivity were found mainly in auditory/salience and medial visual networks. Relative to findings in the control group, MBSR subjects showed (1) increased functional connectivity within auditory and visual networks, (2) increased functional connectivity between auditory cortex and areas associated with attentional and self-referential processes, (3) stronger anticorrelation between auditory and visual cortex, and (4) stronger anticorrelation between visual cortex and areas associated with attentional and self-referential processes. These findings suggest that 8 weeks of mindfulness meditation training alters intrinsic functional connectivity in ways that may reflect a more consistent attentional focus, enhanced sensory processing, and reflective awareness of sensory experience.

Increased startle responses in interstitial cystitis: evidence for central hyperresponsiveness to visceral related threat.

PURPOSE: Hypersensitivity to visceral stimuli in interstitial cystitis/painful bladder syndrome may result from enhanced responsiveness of affective circuits (including the amygdala complex) and associated central pain amplification. Potentiation of the eyeblink startle reflex under threat is mediated by output from the amygdala complex and, therefore, represents a noninvasive marker to study group differences in responsiveness in this brain circuit. MATERIALS AND METHODS: Acoustic startle responses were examined in female patients with interstitial cystitis/painful bladder syndrome (13) and healthy controls (16) during context threat (application of muscle stimulation electrodes to the lower abdomen overlying the bladder), and cued conditions for safety (no stimulation possible), anticipation and imminent threat of aversive abdominal stimulation over the bladder. RESULTS: Patients showed significantly greater startle responses during nonimminent threat conditions (baseline, safe and anticipation periods) while both groups showed similar robust startle potentiation during the imminent threat condition. Higher rates of anxiety and depression symptoms in the patient group did not account for the group differences in startle reflex magnitude. CONCLUSIONS: Compared to controls, female patients with interstitial cystitis/painful bladder syndrome showed increased activation of a defensive emotional circuit in the context of a threat of abdominal pain. This pattern is similar to that previously reported in patients with anxiety disorders as well as those with irritable bowel syndrome. Since these circuits have an important role in central pain amplification related to affective and cognitive processes, these results support the hypothesis that the observed abnormality may be involved in the enhanced perception of bladder signals associated with interstitial cystitis/painful bladder syndrome.

Increased acoustic startle responses in IBS patients during abdominal and nonabdominal threat.

BACKGROUND AND AIMS: Visceral hypersensitivity and symptom severity in Irritable Bowel Syndrome (IBS) are both exacerbated by stress. The eye-blink startle response represents a noninvasive measure of central defensive responding. Evidence for central hyperexcitability was studied in IBS patients by examining potentiation of the startle reflex to a nociceptive threat. METHODS: Acoustic startle responses were examined in female IBS patients (n = 42) and healthy controls (n = 22) during cued periods in which an aversive abdominal or biceps stimulation was impossible (safe), possible (imminent threat) or anticipated (period just before the imminent threat), and during a threatening context (muscle stimulation pads attached but no cues for stimulation). RESULTS: Both groups showed potentiation of startle responses during the imminent threat condition compared with both the anticipation and safe conditions. Compared with controls, IBS subjects showed significantly larger startle responses during anticipation and imminent threat conditions after receiving an initial aversive stimulation. There were no group differences during the context threat manipulation. Moreover, in IBS patients but not controls, higher neuroticism was associated with larger startle responses during safe and anticipation conditions but not imminent threat, whereas anxiety symptoms were negatively associated with startle magnitude during imminent threat. CONCLUSIONS: Female IBS patients show increased startle responses to threat of aversive stimulation at both abdominal and nonabdominal sites compared with controls. The data represent the first demonstration of altered threat potentiated startle in a functional pain condition and provide support for the use of these paradigms in further evaluation of affective mechanisms in these disorders.

Visceral analgesics: drugs with a great potential in functional disorders?

Irritable bowel syndrome remains an incompletely understood, common syndrome with significant unmet medical needs. In IBS patients, abdominal pain is a primary factor related to quality of life impairment, symptom severity and health care utilization, and chronic visceral hyperalgesia has been identified as an important aspect of IBS pathophysiology. However, the development of therapies aimed at reducing this hyperalgesia (visceral analgesics) has been only partially successful despite preclinical evidence supporting the potential usefulness of several preclinical compounds aimed at peripheral as well as central targets.

Functional abdominal pain syndrome.

Functional abdominal pain syndrome (FAPS) differs from the other functional bowel disorders; it is less common, symptoms largely are unrelated to food intake and defecation, and it has higher comorbidity with psychiatric disorders. The etiology and pathophysiology are incompletely understood. Because FAPS likely represents a heterogeneous group of disorders, peripheral neuropathic pain mechanisms, alterations in endogenous pain modulation systems, or both may be involved in any one patient. The diagnosis of FAPS is made on the basis of positive symptom criteria and a longstanding history of symptoms; in the absence of alarm symptoms, an extensive diagnostic evaluation is not required. Management is based on a therapeutic physician-patient relationship and empirical treatment algorithms using various classes of centrally acting drugs, including antidepressants and anticonvulsants. The choice, dose, and combination of drugs are influenced by psychiatric comorbidities. Psychological treatment options include psychotherapy, relaxation techniques, and hypnosis. Refractory FAPS patients may benefit from a multidisciplinary pain clinic approach.

Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis.

Patients with mild chronic inflammation of the rectum or ileum have reduced perceptual responses to rectosigmoid distension compared to patients with irritable bowel syndrome (IBS). The current study sought to identify differences in regional cerebral blood flow (rCBF) during rectal distension, which might correspond to these perceptual differences. In 8 male ulcerative colitis (UC) patients with quiescent disease, 7 male IBS patients and 7 healthy male controls, rCBF was assessed using 15O-water positron emission tomography at baseline and during actual and anticipated but undelivered rectal distensions. No group differences were seen in anterior insula and dorsal anterior cingulate cortex (dACC), two regions consistently activated by painful intestinal stimuli. However, IBS patients showed greater activation of the amygdala, rostroventral ACC, and dorsomedial frontal cortical regions. In contrast, no significant differences were observed between UC and controls. When these two non-IBS groups were combined, functional connectivity analyses showed that right lateral frontal cortex (RLFC) activation positively correlated with activation of the dorsal pons/periaqueductal gray, a key region involved in endogenous pain inhibition. According to the connectivity analysis, this effect was mediated by inhibition of medial frontal cortex by the RLFC. Chronic colonic inflammation is not necessarily associated with increased visceral afferent input to the brain during rectal distension. In the sample studied, the primary difference between functional and quiescent inflammatory disease of the colon was in terms of greater activation of limbic/paralimbic circuits in IBS, and inhibition of these circuits in UC and controls by the RLFC.

Functional Somatic Syndromes: Emerging Biomedical Models and Traditional Chinese Medicine.

The so-called functional somatic syndromes comprise a group of disorders that are primarily symptom-based, multisystemic in presentation and probably involve alterations in mind-brain-body interactions. The emerging neurobiological models of allostasis/allostatic load and of the emotional motor system show striking similarities with concepts used by Traditional Chinese Medicine (TCM) to understand the functional somatic disorders and their underlying pathogenesis. These models incorporate a macroscopic perspective, accounting for the toll of acute and chronic traumas, physical and emotional stressors and the complex interactions between the mind, brain and body. The convergence of these biomedical models with the ancient paradigm of TCM may provide a new insight into scientifically verifiable diagnostic and therapeutic approaches for these common disorders.