Nicolas Mathieu

Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study

The vagus nerve (VN) is a link between the brain and the gut. The VN is a mixed nerve with anti‐inflammatory properties through the activation of the hypothalamic–pituitary–adrenal axis by its afferents and by activating the cholinergic anti‐inflammatory pathway through its efferents. We have previously shown that VN stimulation (VNS) improves colitis in rats and that the vagal tone is blunted in Crohns disease (CD) patients. We thus performed a pilot study of chronic VNS in patients with active CD. Seven patients under VNS were followed up for 6 months with a primary endpoint to induce clinical remission and a secondary endpoint to induce biological (CRP and/or fecal calprotectin) and endoscopic remission and to restore vagal tone (heart rate variability). Vagus nerve stimulation was feasible and well‐tolerated in all patients. Among the seven patients, two were removed from the study at 3 months for clinical worsening and five evolved toward clinical, biological, and endoscopic remission with a restored vagal tone. These results provide the first evidence that VNS is feasible and appears as an effective tool in the treatment of active CD.

Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn's disease and irritable bowel syndrome.

Crohn’s disease (CD) and irritable bowel syndrome (IBS) involve brain-gut dysfunctions where vagus nerve is an important component. The aim of this work was to study the association between vagal tone and markers of stress and inflammation in patients with CD or IBS compared to healthy subjects (controls). The study was performed in 73 subjects (26 controls, 21 CD in remission and 26 IBS patients). The day prior to the experiment, salivary cortisol was measured at 8∶00 AM and 10∶00 PM. The day of the experiment, subjects completed questionnaires for anxiety (STAI) and depressive symptoms (CES-D). After 30 min of rest, ECG was recorded for heart rate variability (HRV) analysis. Plasma cortisol, epinephrine, norepinephrine, TNF-alpha and IL-6 were measured in blood samples taken at the end of ECG recording. Compared with controls, CD and IBS patients had higher scores of state-anxiety and depressive symptomatology. A subgroup classification based on HRV-normalized high frequency band (HFnu) as a marker of vagal tone, showed that control subjects with high vagal tone had significantly lower evening salivary cortisol levels than subjects with low vagal tone. Such an effect was not observed in CD and IBS patients. Moreover, an inverse association (r = −0.48; p<0.05) was observed between the vagal tone and TNF-alpha level in CD patients exclusively. In contrast, in IBS patients, vagal tone was inversely correlated with plasma epinephrine (r = −0.39; p<0.05). No relationship was observed between vagal tone and IL-6, norepinephrine or negative affects (anxiety and depressive symptomatology) in any group. In conclusion, these data argue for an imbalance between the hypothalamus-pituitary-adrenal axis and the vagal tone in CD and IBS patients. Furthermore, they highlight the specific homeostatic link between vagal tone and TNF-alpha in CD and epinephrine in IBS and argue for the relevance of vagus nerve reinforcement interventions in those diseases.

Brain Processing of Emotional Scenes in Aging: Effect of Arousal and Affective Context

Research on emotion showed an increase, with age, in prevalence of positive information relative to negative ones. This effect is called positivity effect. From the cerebral analysis of the Late Positive Potential (LPP), sensitive to attention, our study investigated to which extent the arousal level of negative scenes is differently processed between young and older adults and, to which extent the arousal level of negative scenes, depending on its value, may contextually modulate the cerebral processing of positive (and neutral) scenes and favor the observation of a positivity effect with age. With this aim, two negative scene groups characterized by two distinct arousal levels (high and low) were displayed into two separate experimental blocks in which were included positive and neutral pictures. The two blocks only differed by their negative pictures across participants, as to create two negative global contexts for the processing of the positive and neutral pictures. The results show that the relative processing of different arousal levels of negative stimuli, reflected by LPP, appears similar between the two age groups. However, a lower activity for negative stimuli is observed with the older group for both tested arousal levels. The processing of positive information seems to be preserved with age and is also not contextually impacted by negative stimuli in both younger and older adults. For neutral stimuli, a significantly reduced activity is observed for older adults in the contextual block of low-arousal negative stimuli. Globally, our study reveals that the positivity effect is mainly due to a modulation, with age, in processing of negative stimuli, regardless of their arousal level. It also suggests that processing of neutral stimuli may be modulated with age, depending on negative context in which they are presented to. These age-related effects could contribute to justify the differences in emotional preference with age.

Toward a Definition of a Global Psycho-Physiological Criterion of Vulnerability to Relapse in Inflammatory Bowel Diseases

Toward a Definition of a Global Psycho-Physiological Criterion of Vulnerability to Relapse in Inflammatory Bowel Diseases

Emotional overactivity in patients with irritable bowel syndrome

Negativity is often observed in patients with irritable bowel syndrome (IBS). No study has examined their emotional expressiveness as a marker of emotional reactivity. We investigated IBS patients’ vulnerability to an emotional load by associating their expressiveness with psychological and neurophysiological assessments. We hypothesized that IBS would be characterized by a lack of expressiveness coupled with high scores in psychological and neurophysiological parameters.

Electrical vagus nerve stimulation as an innovative treatment in inflammatory bowel diseases

The vagal cholinergic anti-inflammatory pathway involves the inhibition of pro-inflammatory cytokines release. Our previous studies revealed firstly, a blunted vagus nerve activity in Crohn’s Disease (CD) patients and secondly, an improvement of colitis in rats after electrical vagus nerve stimulation (eVNS). Consequently, a clinical eVNS study was performed in CD patients (Clinical Trials.gov NCT01569503). The main goal was to evaluate the safety and efficacy of this innovative treatment. Six CD patients under intestinal active inflammation were included and equipped with a vagal nerve stimulation device (Cyberonics Inc.). Stimulation parameters were 10 Hz, 500 μs, 0,5 mA, 30 s ON, 5 min OFF. Threemain types ofmarkers weremeasured during a one-year follow-up: clinical (Crohn’s disease activity index –CDAI-), biological (C-reactive protein-CRP-) and autonomic (heart rate variability-HRV-). Currently, the study is still running and only the six first month of follow-up are presented herein. Four patients have an improvement of 1) their clinical state marked by a decrease in CDAI, 2) their parasympathetic tone (HRV) which returns to an homeostatic level, 3) their biological state by a decrease in CRP. No adverse effect of eVNS was observed. In conclusion, these results show for the first time that eVNS in CDpatients is safe andwell tolerated. Moreover, long-term eVNS induces an effective improvement over the six first month and further next resultswill showus if this improvement ismaintained over the one year follow-up. eVNS, devoided of problemof compliance, could be of interest as an alternative to classical pharmacological therapies.