Implementation of a Primary Prevention Program for Posttraumatic Stress Disorder in a Cohort of Professional Soldiers (PREPAR): Protocol for a Randomized Controlled Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can manifest after a traumatic event where the individual perceives a threat to his or her life or that of others. Its estimated prevalence in the European population is 0.7% to 1.9%. According to the "dose-response" model, individuals who are most exposed to traumatic events are most at risk of developing PTSD. Hence, it is unsurprising that studies have observed a higher prevalence among the military population, ranging from 10% to 18%, or even up to 45%. This project's overall goal is to evaluate the primary prevention actions that can strengthen the resilience of at-risk professionals, notably military personnel, in the short term, with the medium- to long-term aim of preventing the occurrence of PTSD and improving the patient's prognosis. OBJECTIVE: This study's objectives are (1) to design a primary prevention program for PTSD, tailored to the studied military population and compatible with operational constraints; and (2) to implement and validate the Primary Prevention of Posttraumatic Stress Disorder in Military Professionals (PREPARE) program in the short term with operational personnel belonging to the French Mountain Infantry Brigade. METHODS: This is a single-center, prospective, randomized, parallel-group controlled cohort study. The cohort is divided into 2 groups: the nonintervention group receives no training, and the intervention group follows a dedicated prevention program (structured into 8 workshops and 2 debriefing and practice reinforcement workshops). Each participant is evaluated 4 times (at inclusion, +4 months, +6 months, and +12 months). During each visit, participants complete several psychosocial questionnaires (which take 15-80 minutes to complete). Samples (a 30-mL blood sample and three 5-mL saliva samples) are collected on 3 occasions: at inclusion, +4 months, and +12 months. Emotional reactivity (electrocardiogram and electrodermal activity) is measured before, during, and after the classic and the emotional Stroop task. RESULTS: The project is currently ongoing, and results are expected to be published by the end of 2024. CONCLUSIONS: The study adopts an integrative approach to the processes that play a role in the risk of developing PTSD. Our biopsychosocial perspective makes it possible to target levers related to factors specific to the individual and socio-professional factors. The following dimensions are addressed: (1) biophysiology (by studying markers of the neurobiological stress response, wear and tear, and vulnerability phenomena and reinforcing the flexibility of the autonomic nervous system), (2) psychology (by facilitating and measuring the development of flexible coping strategies to deal with stress and evaluating the moderating role of the individual's sense of duty in the development of PTSD), and (3) social (by facilitating community strategies aimed at reducing stigmatization and supporting the use of care by professionals in difficulty, in the institutional context). TRIAL REGISTRATION: ClinicalTrials.gov NCT05094531; https://clinicaltrials.gov/study/NCT05094531. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47175.

Trauma and mental health in young adults who arrived in France as unaccompanied and separated migrant children.

OBJECTIVES: The mental health of unaccompanied and separated minors (UASC) has been widely studied but not their first years of adulthood, often characterised by uncertainty after leaving child protection. The aim of this study was to estimate the prevalence of psychiatric disorders using standardised and validated research instruments and examine the effect of exposure to trauma. METHODS: One hundred and ten youth (92.7% male, median age 19.7 [18.1-22.8]) from Chambery, Montpellier and La Rochelle were recruited to a cross-sectional exploratory study. During a face-to-face interview, somatoform disorder, anxiety, and depression were assessed using the Patient Health Questionnaire (score≥10) and post-traumatic stress disorder (PTSD) with the PTSD Checklist for DSM-5 (score≥33). Traumatic life events were assessed using the Life Events Checklist. RESULTS: Of the youth, 19.3% had a probable somatoform disorder, 17.6% anxiety, 28.7% depression, and 20% PTSD. The number of traumatic life events increased the risk of depression (multi-adjusted OR (95%CI): 1.56 (1.25-1.96)), PTSD (1.60 (1.23-2.08)), somatoform disorder (1.41 (1.10-1.82), and anxiety (1.33 (1.02-1.72)). Physical assault was the type of event positively associated with the most disorders (P≤0.01, except for anxiety), followed by witnessing sudden and violent death (P≤0.01 for depression and PTSD) and sexual assault (P=0.002 for PTSD). CONCLUSION: Our study highlights the high prevalence of psychiatric disorders in young adults who arrived as UASC and the impact on their mental health of cumulative trauma and exposure to interpersonal and violent traumatic life events. A greater focus on their mental health with regular assessments is needed in order to provide rapid and adapted care.

The burden of early life stress in chronic inflammatory bowel diseases.

The aim of this study was to evaluate the prevalence of early life stress (ELS) in a population with inflammatory bowel diseases (IBD) and to estimate its burden on mental, physical, and digestive health. Ninety-three participants with IBD were asked to anonymously complete questionnaires (Childhood Trauma Questionnaire-Short Form, Early Life Event Scale, Perceived Stress Scale, Hospital Anxiety and Depression Scale, Ways of Coping Checklist, Gastro-Intestinal Quality of Life Index questionnaire, and ad hoc questions about symptoms). The prevalence of patients with IBD who were exposed to at least one childhood abuse was 53%. Mental health and quality of life were significantly poorer in patients with IBD who were exposed to early abuse than in those who were not. Patients exposed to ELS had also more digestive perturbations and fatigue. These results suggest that early abuse should be considered a component of IBD care.

Association between uncertainty regarding right-to-stay and mental health in unaccompanied and separated migrant children (UASC) reaching adulthood: findings from France.

PURPOSE: There is substantial evidence suggesting high levels of mental health problems in unaccompanied and separated children (UASC). However, there is less focus on the first years of adulthood characterised by increased vulnerability and fear of expulsion. We aimed to describe the mental health of UASC on reaching adulthood, and how this was affected by uncertainty regarding their right-to-stay in France. METHODS: One hundred and ten youth aged 18-22 were recruited via child protection reception centres. We administered the Patient Health Questionnaire somatic (PHQ-15), anxiety (GAD-7) and depression (PHQ-9) modules, the Post-Traumatic Stress Disorder Checklist (PCL-5) and Connor-Davidson Resilience Scale (CD-RISC-10). Logistic regression analysis was performed with the dependent variable, a secure (versus uncertain) situation, defined as (1) detaining a residence permit and being in school, an apprenticeship or a salaried job, or (2) waiting for residence permit whilst occupying a salaried job. RESULTS: Of the sample, 19.3% reached criteria for a probable somatic disorder, 17.6% for anxiety and 28.7% for depression (score  ≥ 10); 41.8% were in an uncertain situation regarding their right-to-stay. Uncertainty was associated with higher anxiety ((OR per Interquartile range (95% CI), 1.77 (1.05-2.98)) and post-traumatic stress symptoms (2.05 (1.06-4.00)), lower resilience (0.50 (0.27-0.91)), and participants rating their anxiety (p = 0.02) and depressive symptoms (p = 0.003) as more severe since reaching adulthood. CONCLUSIONS: Our findings suggest uncertainty regarding right-to-stay is associated with increased mental health symptoms, specifically anxiety and trauma-induced stress, thereby highlighting the vulnerability of UASC in their first years of adulthood. This calls for greater support during this transition period with regular symptom monitoring for timely psychological interventions.

Reducing decision-making deficits in patients with brain injury: effect of slow-paced breathing.

Impairments in decision-making have been reported in brain-damaged (stroke/traumatic brain injury) patients with a wide range of lesion sites. Here, we propose that the performances of patients in complex sequential decision-making (DM) tasks can be explained by their negative affectivity, leading to deliberative processing associated with poor DM performances. We assumed that a slow-paced breathing (SPB) training, by reducing negative affectivity would improve performances in a complex DM task. For 24 days, 34 brain-damaged patients (16 males and 18 females; 12 had a hemorrhagic stroke, 17 with an ischemic stroke and 5 with a TBI), practiced either daily SPB or sham trainings for five min, three times a day. Before and after training, we assessed their vagal tone (electrocardiogram-ECG), affectivity (Positive and Negative Affect Schedule-PANAS) and certainty level (Dimensional Ratings Questionnaire-DRQ) and their performance on the Iowa Gambling Task. All participants showed initial weak performance, which improved only for patients in the SPB training condition. These results suggest that DM disorders in brain-damaged patients can be the consequence of their poor information processing strategy rather than an impairment in their DM abilities. Second, we showed that SPB could be efficient to normalize DM processes in brain injury patients.

Relaxing effects of music and odors on physiological recovery after cognitive stress and unexpected absence of multisensory benefit.

Several studies have described, often separately, the relaxing effects of music or odor on the autonomic nervous system (ANS) activity. Only a few studies compared the presentation of these stimuli and their interaction within a same experimental protocol. Here, we examined whether relaxing music (slow-paced classical pieces) and odor (lavender essential oil) either presented in isolation or in combination would facilitate physiological recovery after cognitive stress. We continuously recorded the electrocardiogram to assess the high-frequency component of heart rate variability (HF-HRV), an index of parasympathetic activity, and electrodermal activity (EDA), an index of sympathetic activity, 10 min before, during and 30 min after a cognitive stress (i.e., completing timely constrained cognitively demanding tasks) in 99 participants allocated to four recovery conditions (control N = 26, music N = 23, odor N = 24, music+odor N = 26). The stressing event triggered both a significant increase in EDA and decrease in HF-HRV (compared to baseline). During the recovery period, the odor elicited a greater decrease in EDA compared to an odorless silent control, whereas no difference in HRV was observed. Conversely, during this period, music elicited a greater increase in HF-HRV compared to control whereas no difference in EDA was observed. Strikingly, in the multimodal music+odor condition, no beneficial effect was observed on ANS indexes 30 min after stress. Overall, our study confirms that both olfactory and musical stimuli have relaxing effects after stress on ANS when presented separately only, which might rely on distinct neural mechanisms and autonomic pathways.

Gut-Brain Coupling and Multilevel Physiological Response to Biofeedback Relaxation After a Stressful Task Under Virtual Reality Immersion: A Pilot Study.

Human physiological reactions to the environment are coordinated by the interactions between brain and viscera. In particular, the brain, heart, and gastrointestinal tract coordinate with each other to provide physiological equilibrium by involving the central, autonomic, and enteric nervous systems. Recent studies have demonstrated an electrophysiological coupling between the gastrointestinal tract and the brain (gut-brain axis) under resting-state conditions. As the gut-brain axis plays a key role in individual stress regulation, we aimed to examine modulation of gut-brain coupling through the use of an overwhelming and a relaxing module as a first step toward modeling of the underlying mechanisms. This study was performed in 12 participants who, under a virtual reality environment, performed a 9-min cognitive stressful task followed by a 9-min period of relaxation. Brain activity was captured by electroencephalography, autonomic activities by photoplethysmography, and electrodermal and gastric activities by electrogastrography. Results showed that compared with the stressful task, relaxation induced a significant decrease in both tonic and phasic sympathetic activity, with an increase in brain alpha power and a decrease in delta power. The intensity of gut-brain coupling, as assessed by the modulation index of the phase-amplitude coupling between the normogastric slow waves and the brain alpha waves, decreased under the relaxation relative to the stress condition. These results highlight the modulatory effect of biofeedback relaxation on gut-brain coupling and suggest noninvasive multilevel electrophysiology as a promising way to investigate the mechanisms underlying gut-brain coupling in physiological and pathological situations.

Psychophysiological dynamics of emotional reactivity: Interindividual reactivity characterization and prediction by a machine learning approach.

The fast reaction of the autonomic nervous system (ANS) to an emotional challenge (EC) is the result of a functional coupling between parasympathetic (PNS) and sympathetic (SNS) branches. This coupling can be characterized by measures of cross-correlations between electrodermal activity (EDA) (under the influence of the SNS) and the RR interval (the interval between R peaks) (under the influence of the PNS and the SNS). Significant interindividual variability has previously been reported in SNS-PNS coupling in emotional situations, and the present study aimed to identify interindividual cross-correlation variability in ANS reactivity. We therefore studied EDA and the RR interval in 62 healthy subjects, recorded during a 24-minute EC. A Gaussian Mixture Model was used to cluster tonic EDA-RR cross-correlations during the EC. This identified two clusters that were characterized by significant or non-significant cross-correlations (SCC and NCC clusters, respectively). The SCC cluster reported higher negative emotion after the EC, while the NCC cluster reported higher scores on the Center for Epidemiologic Studies-Depression scale. The latter finding suggests that NCC is a pathological mood pattern with altered negative perception. Furthermore, a machine learning model that included three parameters indexing the functionality of both branches of the ANS, measured at baseline, predicted cluster membership. Our results are a first step in detecting dysfunctional ANS reactivity in general population.

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases.

The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn's disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.

Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), at the origin of the worldwide COVID-19 pandemic, is characterized by a dramatic cytokine storm in some critical patients with COVID-19. This storm is due to the release of high levels of pro-inflammatory cytokines such as interleukin (IL)-1 ß, IL-6, tumor necrosis factor (TNF), and chemokines by respiratory epithelial and dendritic cells, and macrophages. We hypothesize that this cytokine storm and the worsening of patients' health status can be dampened or even prevented by specifically targeting the vagal-driven cholinergic anti-inflammatory pathway (CAP). The CAP is a concept that involves an anti-inflammatory effect of vagal efferents by the release of acetylcholine (ACh). Nicotinic acetylcholine receptor alpha7 subunit (α7nAChRs) is required for ACh inhibition of macrophage-TNF release and cytokine modulation. Hence, targeting the α7nAChRs through vagus nerve stimulation (VNS) could be of interest in the management of patients with SARS-CoV-2 infection. Indeed, through the wide innervation of the organism by the vagus nerve, especially the lungs and gastrointestinal tract, VNS appears as a serious candidate for a few side effect treatment that could dampen or prevent the cytokine storm observed in COVID-19 patients with severe symptoms. Finally, a continuous vagal tone monitoring in patients with COVID-19 could be used as a predictive marker of COVID-19 illness course but also as a predictive marker of response to COVID-19 treatment such as VNS or others.

A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease.

BACKGROUND: The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months. METHODS: Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up. KEY RESULTS: After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more "healthy profile": Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorß1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor α, and some gut mucosa metabolites as taurine, lactate, alanine, and beta-hydroxybutyrate. VNS was well tolerated. CONCLUSION & INFERENCES: Vagus nerve stimulation appears as an innovative and well-tolerated treatment in moderate Crohn's disease. After 12 months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized double-blinded control study.

Interoceptive Abilities in Inflammatory Bowel Diseases and Irritable Bowel Syndrome.

Alexithymia is usually described by three main dimensions difficulty identifying feelings (DIF), difficulty describing feelings (DDF), and externally oriented thinking (EOT). The most commonly used questionnaire investigating alexithymia, the Toronto Alexithymia Scale (TAS-20), supports this three-factor structure. One important assumption is that alexithymia severity is associated to vulnerability to somatic diseases, among them gastrointestinal disorders. However, the association between alexithymia and gastrointestinal disorders is not systematic, thus questioning the role of alexithymia as a vulnerability factor for those illnesses. A recent factor analysis suggested another four-factor structure for the TAS-20: difficulties in awareness of feelings (DAF), difficulties in interoceptive abilities (DIA), externally oriented thinking (EOT), and poor affective sharing (PAS). We assume that DIA and DAF might be more relevant to investigate the association between alexithymia and gastrointestinal disorders. The rationale is that DIA and DAF reflect impairments in emotion regulation that could contribute to an inappropriate autonomic and HPA axis homeostasis in irritable bowel syndrome (IBS), ulcerative colitis (UC), or Crohn's disease (CD). The aim of this study was to investigate whether DIA and DAF are associated with the presence of IBS, UC or CD, while checking for anxiety, depression, parasympathetic (vagus nerve) activity and cortisol levels. We recruited control participants (n=26), and patients in remission who were diagnosed with IBS (n=24), UC (n=18), or CD (n=21). Participants completed questionnaires to assess anxiety, depression, and alexithymia. A blood sample and an electrocardiogram were used to measure the level of cortisol and parasympathetic activity, respectively. Logistic regressions with the four-factor structure of the TAS-20 revealed that DIA was a significant predictor of IBS (W(1)=6.27, p=.01). Conversely, DIA and DAF were not significant predictors in CD and UC patients. However, low cortisol level was a significant predictor of UC (W(1)=4.67, p=.035). Additional logistic regressions based on the original 3-factor structure of TAS-20 (DIF, DDF, and EOT) showed that only DDF was a significant predictor of CD [W(1)=6.16, p < .001]. The present study suggests that DIA is an important dimension for assessing potential risk for gastrointestinal diseases, in particular for IBS.

Importance of considering interoceptive abilities in alexithymia assessment.

BACKGROUND: Recent studies have shown that people with high alexithymia scores have decreased interoceptive abilities, which can be associated with psychological and physical disorders. Early assessments of the alexithymia trait included the evaluation of these abilities through the dimension measuring the difficulty in identifying and distinguishing between feelings and bodily sensations (the 26-item Toronto Alexithymia Scale; TAS-26). The revised version of the TAS, the TAS-20, contains a three-factor solution that does not involve a dimension assessing interoceptive abilities. However, the three items allowing the evaluation of these abilities are still present in the TAS-20. In this context, we hypothesized that the 3 items which assess interoceptive abilities in the TAS-20 should constitute an independent factor. In addition to exploring the internal structure of the TAS-20, we examined its external validity by assessing the relationships between the new factors and self-reported measures of personality trait and psychological and physical health. METHOD: Two online studies (N = 253 and N = 287) were performed. The participants completed the TAS-20 and a set of psychological questionnaires (e.g., anxiety, depression) and health questions (e.g., "Do you suffer from a somatic disorder?"). The structure of the TAS-20 was examined using exploratory factor analysis (EFA), followed by an investigation of the relationships between the resulting new factors and other psychological and health data using regressions. In both studies, EFA revealed a new structure of the questionnaire consisting of four dimensions: (1) difficulty in the awareness of feelings, (2) externally oriented thinking, (3) difficulty in interoceptive abilities, and (4) poor affective sharing. The first factor was positively associated with all self-reported psychological and personality trait measures while the third factor was associated more with somatic disorders and medication intake. RESULTS: Our results suggest the presence of a new latent factor in the assessment of alexithymia that reflects interoceptive abilities specifically related to health and personality trait outcomes. In accordance with the results and the literature, it seems important to include an assessment of interoceptive abilities when considering the evaluation of alexithymia. The next step would be to develop a valid measure of these abilities.

Vagus Nerve Stimulation at the Interface of Brain-Gut Interactions.

The vagus nerve, a key component of the cross-communication between the gut and the brain, is a major element of homeostasis sensing the "milieu intérieur" and boosting the nervous and endocrine responses to maintain the gastrointestinal health status. This nerve has anti-inflammatory properties regulating the gut through the activation of the hypothalamic-pituitary-adrenal axis and the release of cortisol and through a vagovagal reflex, which has an anti-tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway. Stimulating this nerve is an interesting tool as a nondrug therapy for the treatment of gastrointestinal diseases in which brain-gut communication is dysfunctional, such as inflammatory bowel disorders and others. This review presents the rationale of vagal gastrointestinal physiology and diseases and the most recent advances in vagus nerve stimulation. It also highlights the main issues to be addressed in the future to improve this bioelectronic therapy for gastrointestinal disorders.

The Impact of Priming on Speed Reduction on a Ski Slope.

We tested a field-adapted priming procedure (a technique used to subtly activate mental representations and guide behavior) on a ski slope, with the goal of reducing risk behavior in winter sports. At cableway stations, skiers were initially exposed eight times to a prevention poster displaying a logo and a "slow down" message. The "slow down" concept was activated on the ski slope by exposing skiers (or not) 10 times to the logo featured on the poster. We used a radar device to measure the skiers' speed data just before a slope intersection. We hypothesized that the mean speed would be lower in the presence of the logo than in its absence. As predicted, the speed was lower (by 0.9 km/h) when the skiers had been primed (i.e., exposed to the logo). This decrease was relevant, since any reduction in speed downhill will reduce kinetic (impact) energy and thus the risk of injury in a collision. The effect of priming was statistically significant at noon and in the afternoon but not in the morning. Our pilot study is the first to show that a priming procedure can influence the speed of skiers at a dangerous location. Our findings open up new perspectives for the prevention of risk behavior in winter sports.

Electroencephalographic correlates of low-frequency vagus nerve stimulation therapy for Crohn's disease.

OBJECTIVES: In the context of the first clinical trial of vagus nerve stimulation (VNS) in Crohn's disease (CD), our main objective was to quantify the acute and chronic effects of VNS on brain activity in CD patients. METHODS: We measured the electroencephalogram (EEG) in 9CD patients under VNS at 10 Hz just before VNS initiation, after 6 weeks and after 12 months of chronic VNS. RESULTS: Acute VNS induced increased spectral power in delta and theta bands on frontal, temporal and occipital electrodes. The main significant modulation was the 12 months' chronic effect of VNS which consisted mainly in a decreased power in the alpha frequency band which was correlated with the normalization of bowel mucosal inflammation, anxiety state and vagal tone. CONCLUSIONS: In addition to the activation of vagal efferent fibers that regulate the autonomic nervous system, our data suggest that chronic VNS has a regulatory action via afferent vagal fibers on anxio-depressive symptomatology associated to CD, which could be directly highlighted by the modulation of EEG alpha power known to be associated to depressed states. SIGNIFICANCE: This is the first report of the central effects of VNS in CD patients.

The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis.

The microbiota, the gut, and the brain communicate through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve (VN), the principal component of the parasympathetic nervous system, is a mixed nerve composed of 80% afferent and 20% efferent fibers. The VN, because of its role in interoceptive awareness, is able to sense the microbiota metabolites through its afferents, to transfer this gut information to the central nervous system where it is integrated in the central autonomic network, and then to generate an adapted or inappropriate response. A cholinergic anti-inflammatory pathway has been described through VN's fibers, which is able to dampen peripheral inflammation and to decrease intestinal permeability, thus very probably modulating microbiota composition. Stress inhibits the VN and has deleterious effects on the gastrointestinal tract and on the microbiota, and is involved in the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) which are both characterized by a dysbiosis. A low vagal tone has been described in IBD and IBS patients thus favoring peripheral inflammation. Targeting the VN, for example through VN stimulation which has anti-inflammatory properties, would be of interest to restore homeostasis in the microbiota-gut-brain axis.

The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract.

The vagus nerve (VN) is the longest nerve of the organism and a major component of the parasympathetic nervous system which constitutes the autonomic nervous system (ANS), with the sympathetic nervous system. There is classically an equilibrium between the sympathetic and parasympathetic nervous systems which is responsible for the maintenance of homeostasis. An imbalance of the ANS is observed in various pathologic conditions. The VN, a mixed nerve with 4/5 afferent and 1/5 efferent fibers, is a key component of the neuro-immune and brain-gut axes through a bidirectional communication between the brain and the gastrointestinal (GI) tract. A dual anti-inflammatory role of the VN is observed using either vagal afferents, targeting the hypothalamic-pituitary-adrenal axis, or vagal efferents, targeting the cholinergic anti-inflammatory pathway. The sympathetic nervous system and the VN act in synergy, through the splenic nerve, to inhibit the release of tumor necrosis factor-alpha (TNFα) by macrophages of the peripheral tissues and the spleen. Because of its anti-inflammatory effect, the VN is a therapeutic target in the treatment of chronic inflammatory disorders where TNFα is a key component. In this review, we will focus on the anti-inflammatory role of the VN in inflammatory bowel diseases (IBD). The anti-inflammatory properties of the VN could be targeted pharmacologically, with enteral nutrition, by VN stimulation (VNS), with complementary medicines or by physical exercise. VNS is one of the alternative treatments for drug resistant epilepsy and depression and one might think that VNS could be used as a non-drug therapy to treat inflammatory disorders of the GI tract, such as IBD, irritable bowel syndrome, and postoperative ileus, which are all characterized by a blunted autonomic balance with a decreased vagal tone.

Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation.

Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the ß2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα-related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation.

Uncertainty in anticipation of uncomfortable rectal distension is modulated by the autonomic nervous system--a fMRI study in healthy volunteers.

The human brain responds both before and during the application of aversive stimuli. Anticipation allows the organism to prepare its nociceptive system to respond adequately to the subsequent stimulus. The context in which an uncomfortable stimulus is experienced may also influence neural processing. Uncertainty of occurrence, timing and intensity of an aversive event may lead to increased anticipatory anxiety, fear, physiological arousal and sensory perception. We aimed to identify, in healthy volunteers, the effects of uncertainty in the anticipation of uncomfortable rectal distension, and the impact of the autonomic nervous system (ANS) activity and anxiety-related psychological variables on neural mechanisms of anticipation of rectal distension using fMRI. Barostat-controlled uncomfortable rectal distensions were preceded by cued uncertain or certain anticipation in 15 healthy volunteers in a fMRI protocol at 3T. Electrocardiographic data were concurrently registered by MR scanner. The low frequency (LF)-component of the heart rate variability (HRV) time-series was extracted and inserted as a regressor in the fMRI model ('LF-HRV model'). The impact of ANS activity was analyzed by comparing the fMRI signal in the 'standard model' and in the 'LF-HRV model' across the different anticipation and distension conditions. The scores of the psychological questionnaires and the rating of perceived anticipatory anxiety were included as covariates in the fMRI data analysis. Our experiments led to the following key findings: 1) the subgenual anterior cingulate cortex (sgACC) is the only activation site that relates to uncertainty in healthy volunteers and is directly correlated to individual questionnaire score for pain-related anxiety; 2) uncertain anticipation of rectal distension involved several relevant brain regions, namely activation of sgACC and medial prefrontal cortex and deactivation of amygdala, insula, thalamus, secondary somatosensory cortex, supplementary motor area and cerebellum; 3) most of the brain activity during anticipation, but not distension, is associated with activity of the central autonomic network. This approach could be applied to study the ANS impact on brain activity in various pathological conditions, namely in patients with chronic digestive conditions characterized by visceral discomfort and ANS imbalance such as irritable bowel syndrome or inflammatory bowel diseases.