Visceral Stimulation Research Articles

Amelioration of social impairments in autism: Possible role of vagal afferent stimulation in modification of the prefrontal-amygdala connectivity

Impairment in social interactions is a prominent feature of autism spectrum disorder (ASD). The present hypothesis explains the possible role of vagal afferent stimulation in the modification of prefrontal-amygdala connectivity in the amelioration of social impairments in ASD. Currently, there is no definitive treatment for ASD. However, there is documented evidence showing that interventions that increase vagal tone lead to the improvement of autism-related social symptoms. However, the exact mechanism that explains the correlation between the elevation of vagal tone and the amelioration of autism-related symptoms has not been elucidated. In the present hypothesis, it is proposed that the increase in vagal tone affects the nucleus tractus solitarius (NTS) in the brainstem. The NTS has strong connections with other brainstem nuclei, such as the locus coeruleus and dorsal raphe nucleus. The aforementioned nuclei are the main sources of norepinephrine and serotonin, with extensive projections to various brain areas, especially the prefrontal cortex (PFC) and amygdala. PFC-amygdala functional connectivity plays an important role in social behavior and emotion regulation. Therefore, visceral stimulation, which subsequently increases the vagal tone, possibly leads to the improvement of autistic social deficits through the enhancement of PFC-amygdala functional connectivity. Further investigations are needed to evaluate the function of the mentioned neural pathways during visceral stimulation in individuals with ASD.

Do we perceive sensations inside and outside of our body differently? Perceptual, emotional, and behavioral differences between visceral and somatic sensation, discomfort, and pain.

Experimental research evaluating differences between the visceral and somatic stimulation is limited to pain and typically uses different induction methods for visceral and somatic stimulation (e.g., rectal balloon distention vs. tactile hand stimulation). Our study aimed to compare differences in response time, intensity, unpleasantness, and threat between identical electrical visceral and somatic stimulations at both painful and non-painful perceptual thresholds. Electrical stimulation was applied to the wrist and distal esophagus in 20 healthy participants. A double pseudorandom staircase determined perceptual thresholds of Sensation, Discomfort, and Pain for the somatic and visceral stimulations, separately. Stimulus reaction time (ms, via button press), and intensity, unpleasantness, and threat ratings were recorded after each stimulus. General linear mixed models compared differences in the four outcomes by stimulation type, threshold, and the stimulation type-by-threshold interaction. Sigmoidal maximum effect models evaluated differences in outcomes across all delivered stimulation intensities. Overall, visceral stimulations were perceived as more intense, threatening, and unpleasant compared to somatic stimulations, but participants responded faster to somatic stimulations. There was no significant interaction effect, but planned contrasts demonstrated differences at individual thresholds. Across all delivered intensities, higher intensity stimulations were needed to reach the half-maximum effect of self-reported intensity, unpleasantness, and threat ratings in the visceral domain. Differences exist between modalities for both non-painful and painful sensations. These findings may have implications for translating paradigms and behavioral treatments from the somatic domain to the visceral domain, though future research in larger clinical samples is needed.

Menthacarin treatment attenuates nociception in models of visceral hypersensitivity.

Chronic visceral hypersensitivity is closely associated with irritable bowel syndrome (IBS), a very common disorder which significantly impairs quality of life, characterized by abdominal pain, and distension. Imaging studies have found that IBS patients show higher metabolic activities and functional differences from normal controls in the anterior cingulate cortex (ACC), in response to visceral pain stimulation. Non-clinical data and clinical data suggest that medicinal products containing essential oils such as peppermint or caraway oil exert beneficial effects on IBS symptoms. We assessed acute and long-term treatment effects of a mixture of peppermint and caraway essential oils (Menthacarin) on brain electrophysiological markers of gut pain sensitivity in two rat models of visceral hypersensitivity. Chronic administration of corticosteroids and acute repeated mechanical hyperstimulation under anesthesia induced hyperalgesia and hypersensitivity, characterized by an increase in electrophysiological excitatory responses of ACC neurons to colorectal distension (CRD) and an increase in the proportion of neurons responding to otherwise subthreshold stimulation, respectively. Long-term, but not acute, oral administration of Menthacarin (60 mg kg-1 day-1) significantly reduced the net excitatory response to CRD in normally responsive control animals and counteracted the development of visceral hyperalgesia and hypersensitivity induced by repeated corticosterone administration and acute mechanical stimulation. The present study shows that, using the CRD method, chronic Menthacarin administration at a clinically relevant dose attenuates the neuronal discharge associated with visceral pain stimuli in the rat ACC, particularly in models of hypersensitivity, suggesting a potential for treating exaggerated visceral pain sensitivity.

POSTСOLITIS ALTERATIONS IN NOCICEPTIVE PROPERTIES OF NEURONS IN THE RAT RAPHE MAGNUS AND DORSAL RAPHE NUCLEI

Dysfunction of the brain serotonergic system is thought to play a leading role in the pathogenesis of chronic abdominal pain and comorbid somatic hyperalgesia, which disturb a significant proportion of patients with digestive tract diseases, even in remission. However, the specific changes in the serotonergic structures nociceptive properties that can be initiated by organic pathology and persist after its resolution remain unclear. The aim of our neurophysiological study on anesthetized rats – healthy and recovered from colitis – was to identify the alterations in the raphe magnus (RMg) and dorsal raphe (DR) nuclei neuronal responses to visceral (colorectal distension) and somatic (squeezing of the tail) noxious stimulations that persist after resolution of intestinal inflammation. It has been shown that both nuclei contain different groups of nociceptive neurons: 1) responding with activation only to colorectal distension (visceral); 2) excited only by tail squeezing (somatic); 3) reacting with excitation to the both irritations (general); 4) responding with discharge inhibition to any of the stimulations (inhibited). Compared with healthy animals, in RMg of colitis-exposed rats the number of the inhibited cells was increased and the total proportion of excited nociceptive neurons was reduced. Distension of the inflammation-undergone intestine caused enhanced RMg neuronal inhibition, whereas squeezing of the pathology-unaffected tail led to increased excitation of the RMg selective somatic and general nociceptive cells. In turn, in the DR of postcolitis rats the inhibited neuron proportion was reduced, while the increased population of excited neurons included fewer visceral and more somatic selective cells. This was accompanied by an increase in the selective reactions of the latter to somatic pain stimuli and by an increase in non-selective DR neuron excitation by visceral and somatic pain signals. The identified neuronal alterations can contribute to the postcolitis impairment of the studied raphe nuclei functions in the endogenous control of visceral and somatic pain sensitivity.

Empty satisfaction—a social phenomenology of late modern enjoyment

Phenomenological analyses of enjoyment are relatively rare; also, the few known attempts (e.g. Levinas) are elaborated in a transcendental fashion, without reflecting on the socio-historical constituents. The article aims at filling this gap by elaborating a social phenomenology of late modern enjoyment. Firstly, the experience is analysed with the help of general phenomenological descriptions: the visceral, existential and ethical constituents are mapped. The second section explores the structural transformations affecting these constituents, based on various critical theories of modernization: the impact of the reified control over the visceral; social disintegration; persistent inequalities; over-burdening of intimacy is analysed. In the concluding section, a diagnosis of times is elaborated: the cost of controlling enjoyment on the visceral level is the giving up of its existential and ethical constituents. To break this paradoxical cycle, the “actor-networks” (Latour) of visceral stimulation need to be “hacked” by including existential and ethical dimensions as well.

To Compare the Effectiveness of Granisetron Versus Ondansetron to Control Nausea and Vomiting During Lower Segment Cesarean Section Under Subarachnoid Block.

Nausea and vomiting (NV) seen during and after lower segment cesarean section (LSCS) are due to increased intragastric pressure, hypotension, stretching the peritoneum (exteriorization of the uterus), excessive surgical manipulation and visceral stimulation, using opioids, using uterotonic agents, and the patient's mental status. Ondansetron and granisetron intravenous (i.v.) are useful for avoiding bradycardia and hypotension. The objective of this study is to study the effectiveness of granisetron versus ondansetron to control NV during LSCS under subarachnoid block. Eighty patients undergoing elective cesarean section under spinal anesthesia by intrathecal bupivacaine were randomly divided into two groups (40 pregnant females of the American Society of Anesthesiologists physical status Classes I and II in each Group). Group 1 received granisetron 40 mg.kg-1 i.v. stat after clamping the cord and Group 2 given i.v. ondansetron 8 mg stat after clamping the cord. NV were observed at the "early postoperative period (0-3 h)" and "late postoperative period (4-24 h)." Student's t-test and Chi-square test were used to find out the statistical significance, P < 0.05 was considered statistically significant. The mean age was 29.3 years with 4.15 standard deviation (SD) and 28.3 years with 4.41 SD in Groups 1 and 2, respectively. The mean duration of surgery was 53.1 min with 6.67 min SD and 57.7 min with 10.26 SD in Groups 1 and 2, respectively. In the "early postoperative period," NV observed in 7.5% and 10.0% participants in Groups 1 and 2, respectively (P > 0.05), and in "late postoperative period," NV observed in 0.0% and 22.5% participants in Groups 1 and 2, respectively (P < 0.05). Granisetron reduces the severity of spinal-induced hypotension, need for rescue vasopressor, and incidence of nausea.

Computational modelling of nerve stimulation and recording with peripheral visceral neural interfaces

Objective. Neuromodulation of visceral nerves is being intensively studied for treating a wide range of conditions, but effective translation requires increasing the efficacy and predictability of neural interface performance. Here we use computational models of rat visceral nerve to predict how neuroanatomical variability could affect both electrical stimulation and recording with an experimental planar neural interface. Approach. We developed a hybrid computational pipeline, Visceral Nerve Ensemble Recording and Stimulation (ViNERS), to couple finite-element modelling of extracellular electrical fields with biophysical simulations of individual axons. Anatomical properties of fascicles and axons in rat pelvic and vagus nerves were measured or obtained from public datasets. To validate ViNERS, we simulated pelvic nerve stimulation and recording with an experimental four-electrode planar array. Main results. Axon diameters measured from pelvic nerve were used to model a population of myelinated and unmyelinated axons and simulate recordings of electrically evoked single-unit field potentials (SUFPs). Across visceral nerve fascicles of increasing size, our simulations predicted an increase in stimulation threshold and a decrease in SUFP amplitude. Simulated threshold changes were dominated by changes in perineurium thickness, which correlates with fascicle diameter. We also demonstrated that ViNERS could simulate recordings of electrically-evoked compound action potentials (ECAPs) that were qualitatively similar to pelvic nerve recording made with the array used for simulation. Significance. We introduce ViNERS as a new open-source computational tool for modelling large-scale stimulation and recording from visceral nerves. ViNERS predicts how neuroanatomical variation in rat pelvic nerve affects stimulation and recording with an experimental planar electrode array. We show ViNERS can simulate ECAPS that capture features of our recordings, but our results suggest the underlying NEURON models need to be further refined and specifically adapted to accurately simulate visceral nerve axons.

Oxytocin antagonist induced visceral pain and corticotropin-releasing hormone neuronal activation in the central nucleus of the amygdala during colorectal distention in mice

Activation of neurons containing oxytocin and corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, the anterior cingulate cortex (ACC), and the central nucleus of the amygdala (CeA) during colorectal distention (CRD) is likely to play a crucial role in animal models of irritable bowel syndrome (IBS). Earlier studies in rodents showed that the microbiome is involved in social behavior via oxytocin expression in the brain. However, the detailed mechanism of visceral sensation and oxytocin is largely unknown. We tested the following hypotheses: (1) that oxytocin neurons in the PVN are activated by CRD, and (2) that the activation of oxytocin neurons by CRD is related to anxiety-like behavior, visceral perception, and an activation of CRH CeA neurons or ACC neurons. Oxytocin antagonist caused visceral hypersensitivity and anxiety-like behavior. In the PVN, oxytocin neurons were activated by CRD. Noxious CRD activated the CeA, basolateral nucleus of the amygdala (BLA), and ACC. High-dose oxytocin antagonist suppressed ACC activity and activated CRH CeA neurons. These results support our hypotheses. Oxytocin likely regulates CRH CeA neurons in an inhibitory manner and the ACC in an excitatory manner. Further research into the interaction of oxytocin and CRH in visceral pain and anxiety is warranted.

Concordant pattern of the HPA axis response to visceral stimulation and CRH administration

The physiological and psychological mechanisms explaining the individual variability in the stress response are poorly understood. We tested the hypothesis that hypothalamic-pituitary- adrenal (HPA) axis responses to colorectal stimulation affect HPA axis reactivity to corticotropin-releasing hormone (CRH), the visceral pain threshold, and perceived stress. We examined 31 healthy volunteers and 27 individuals with irritable bowel syndrome. According to the ACTH response to colorectal stimulation, the participants were classified into three groups: flattened, decreased, and increased. We found significant differences in the abdominal pain threshold, discomfort threshold, and sensitivity to anxiety among the groups. There were significant differences in the ACTH change and peak level after CRH administration among the groups. The area under the curve of the cortisol response to CRH was significantly different among the groups. The increased group showed a higher basal ACTH level, earlier peak level in the CRH administration test, and higher stress rating during the experiment. The increased group had an exaggerated psychological and physiological stress response, whereas the decreased group had a higher anticipatory endocrine response, stress, and sensitivity to anxiety. Further studies are needed to determine factors including gut microbiota on the individual difference in HPA response.

Common and distinct neural representations of aversive somatic and visceral stimulation in healthy individuals

Different pain types may be encoded in different brain circuits. Here, we examine similarities and differences in brain processing of visceral and somatic pain. We analyze data from seven fMRI studies (N = 165) and five types of pain and discomfort (esophageal, gastric, and rectal distension, cutaneous thermal stimulation, and vulvar pressure) to establish and validate generalizable pain representations. We first evaluate an established multivariate brain measure, the Neurologic Pain Signature (NPS), as a common nociceptive pain system across pain types. Then, we develop a multivariate classifier to distinguish visceral from somatic pain. The NPS responds robustly in 98% of participants across pain types, correlates with perceived intensity of visceral pain and discomfort, and shows specificity to pain when compared with cognitive and affective conditions from twelve additional studies (N = 180). Pre-defined signatures for non-pain negative affect do not respond to visceral pain. The visceral versus the somatic classifier reliably distinguishes somatic (thermal) from visceral (rectal) stimulation in both cross-validation and independent cohorts. Other pain types reflect mixtures of somatic and visceral patterns. These results validate the NPS as measuring a common core nociceptive pain system across pain types, and provide a new classifier for visceral versus somatic pain.

Calcium imaging in population of dorsal root ganglion neurons unravels novel mechanisms of visceral pain sensitization and referred somatic hypersensitivity.

Mechanisms of visceral pain sensitization and referred somatic hypersensitivity remain unclear. We conducted calcium imaging in Pirt-GCaMP6s mice to gauge responses of dorsal root ganglion (DRG) neurons to visceral and somatic stimulation in vivo. Intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced colonic inflammation and increased the percentage of L6 DRG neurons that responded to colorectal distension above that of controls at day 7. Colorectal distension did not activate L4 DRG neurons. TNBS-treated mice exhibited more Evans blue extravasation than did control mice and developed mechanical hypersensitivity in low-back skin and hind paws, which are innervated by L6 and L4 DRG neurons, respectively, suggesting that colonic inflammation induced mechanical hypersensitivity in both homosegmental and heterosegmental somatic regions. Importantly, the percentage of L4 DRG neurons activated by hind paw pinch and brush stimulation and calcium responses of L6 DRG neurons to low-back brush stimulation were higher at day 7 after TNBS than those in control mice. Visceral irritation from intracolonic capsaicin instillation also increased Evans blue extravasation in hind paws and low-back skin and acutely increased the percentage of L4 DRG neurons responding to hind paw pinch and the response of L6 DRG neurons to low-back brush stimulation. These findings suggest that TNBS-induced colitis and capsaicin-induced visceral irritation may sensitize L6 DRG neurons to colorectal and somatic inputs and also increase the excitability of L4 DRG neurons that do not receive colorectal inputs. These changes may represent a potential peripheral neuronal mechanism for visceral pain sensitization and referred somatic hypersensitivity.

A Photo Stability Indicating HPLC technique for Validation of Netupitant and Palonosetron in Bulk and Formulations

Analytical chemistry is the science that seeks ever improved means of measuring the chemical composition of natural and artificial materials.Netupitant Delayed emesis has been largely associated with the activation of tachykinin family neurokinin 1 receptors. Palonosetron is a selective serotonin 5-HT3 receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally and peripherally in turn inhibits the visceral afferent stimulation of the vomiting center.The mobile phase used was orthophosphoric and acetate 70% buffer pH 3 and 30% methanol.The assay of Netupitant and Palanosetron was performed with tablets and the % assay was found to be 100.08 and 100.04, The linearity was found to be linear with a correlation coefficient of 0.999, the precision 0.8 and 0.3 for Netupitant and Palanosetron which shows that the method is precise.The validation of developed method shows that the accuracy is well within the limit, which shows that the method is capable of showing good accuracy and reproducibility. The LOD and LOQ for Netupitant were found to be 3.02 and 9.98 and LOD and LOQ for Palanosetron was found to be 3.00 and 10.00. Thus, it shows that the method is stability indicating, sensitive, accurate, robust and precise. Hence, the developed HPLC method can be successfully applied to the pharmaceutical dosage form and can be used for routine analysis.&#x0D; &#x0D; &#x0D;

Resting state functional connectivity of the pain matrix and default mode network in irritable bowel syndrome: a graph theoretical analysis

Irritable bowel syndrome (IBS) is a functional disorder of brain-gut interactions. Differential brain responses to rectal distention between IBS and healthy controls (HCs) have been demonstrated, particularly in the pain matrix and the default mode network. This study aims to compare resting-state functional properties of these networks between IBS patients and HCs using graph analysis in two independent cohorts. We used a weighted graph analysis of the adjacency matrix based on partial correlations between time series in the different regions in each subject to determine subject specific graph measures. These graph measures were normalized by values obtained in equivalent random networks. We did not find any significant differences between IBS patients and controls in global normalized graph measures, hubs, or modularity structure of the pain matrix and the DMN in any of our two independent cohorts. Furthermore, we did not find consistent associations between these global network measures and IBS symptom severity or GI-specific anxiety but we found a significant difference in the relationship between measures of psychological distress (anxiety and/or depressive symptoms) and normalized characteristic path length. The responses of these networks to visceral stimulation rather than their organisation at rest may be primarily disturbed in IBS.

Stimulation of Auricular Vagal Nerves Attenuates Pressor Cardiovascular Responses through Influence on Medullary nuclei

Stimulation of the auricular branch of the vagus nerve (ABVN) is used to manage cardiovascular disorders, including elevated blood pressure. However, precise mechanisms underlying its effects remain unclear. One previous study showed that ABVN stimulation with acupuncture at the center of the inferior concha (the “heart acupoint,” CO15) activates neurons in the nucleus tractus solitarii (NTS) through vagal inputs. Still, its actions on NTS processing and downstream influence on the nucleus regulating cardiovascular function have not been studied. Thus, the present study evaluated the effect of ABVN stimulation on pressor cardiovascular responses and the underlying neural mechanisms associated with medullary nuclei. We hypothesized that ABVN stimulation with acupuncture activates the NTS and ultimately inhibits rostral ventrolateral medulla (rVLM), a critical region controlling cardiovascular function, through opioid and GABA mechanisms. In Sprague‐Dawley rats, repeated pressor cardiovascular reflexes were induced by repetitive gastric distension (GD) under anesthesia. ABVN stimulation with manual acupuncture was performed at the CO15 acupoint with gentle rotation of the acupuncture needle at a frequency of □2 Hz for four min every 10 min during a 30 min period, 2 min in each side of the ear. During sham‐ABVN stimulation, the acupuncture needle was inserted into the same site without subsequent rotation of the needle. Unilateral microinjection of the chemical (50 nl) was conducted in the NTS and rVLM. We found that GD‐induced pressor cardiovascular reflexes significantly attenuated by ABVN stimulation (n=8; P&lt;0.05), but neither by sham‐ABVN stimulation nor mechanical stimulation with the acupuncture needle applied at the HX9 acupoint, which is located at the ear tip overlying lesser occipital nerve, the auricular somatic nerve. The modulation of pressor reflexes by ABVN stimulation was significantly (P&lt;0.05) reversed by microinjection of kynurenic acid (25 mM; n=7) into the NTS as well as naloxone (1 mM; a non‐selective opioid receptor antagonist; n=8) or gabazine (27 mM; a GABAA receptor antagonist; n=8) into the rVLM, but not by their vehicles, 0.9% normal saline. Furthermore, in rats subjected to no GD intervention, we noted that ABVN stimulation induced markedly increase in c‐Fos expression in both NTS and rVLM, compared to sham‐ABVN stimulation. Our data suggest that ABVN stimulation with manual acupuncture excites the NTS through a glutamatergic mechanism, which, in turn, attenuate excitatory cardiovascular reflexes evoked by visceral stimulation through GABA and opioids in the rVLM.Support or Funding InformationThe National Center for Complementary &amp; Integrative Health, R01 grant AT009347 and diversity supplement award to this grant.

The Role of Chronic Stress in Normal Visceroception: Insights From an Experimental Visceral Pain Study in Healthy Volunteers.

Visceroception is a complex phenomenon comprising the sensation, interpretation, and integration of sensations along the gut-brain axis, including pain or defecatory urgency. Stress is considered a crucial risk factor for the development and maintenance of disorders of gut-brain signaling, which are characterized by altered visceroception. Although the broad role of stress and stress mediators in disturbed visceroception is widely acknowledged, the putative contribution of chronic stress to variations in normal visceroception remains incompletely understood. We aimed to elucidate the role of chronic stress in shaping different facets of visceroception. From a well-characterized, large sample of healthy men and women (N = 180, 50% female), volunteers presenting with low (n = 57) and elevated (n = 61) perceived chronic stress were identified based on the validated Trier Inventory for Chronic Stress (TICS). Visceral sensitivity together with perceived and recalled intensity and defecatory urgency induced by repeated rectal distensions was experimentally assessed, and compared between low and elevated stress groups. Subgroups were compared regarding state anxiety and salivary cortisol concentrations across experimental phases and with respect to psychological measures. Finally, in the full sample and in chronic stress subgroups, a recall bias in terms of a discrepancy between the perception of experimentally-induced symptoms and their recall was tested. Participants with elevated chronic stress presented with increased state anxiety and higher cortisol concentrations throughout the experimental phases compared to the group with low chronic stress. Group differences in visceral sensitivity were not evident. The elevated stress group perceived significantly higher urgency during the stimulation phase, and recalled substantially higher feelings of urgency induced by rectal distensions, while perceived and recalled intensity were comparable between groups. Volunteers with elevated stress exhibited a recall bias in terms of a higher recall relative to mean perception of urgency, whereas no such bias was observed for the intensity of experimental visceral stimulation. Our findings in healthy men and women provide first evidence that the troublesome symptom of urgency might be particularly modifiable by chronic stress and support the relevance of memory biases in visceroception. These results may help to disentangle the impact of chronic stress on altered visceroception in disturbances of gut-brain communication.

Эффекты стимуляции инфралимбической коры на реакции нейронов каудальной вентролатеральной ретикулярной формации, вызванные ноцицептивным раздражением толстой кишки крысы

The infralimbic cortex of the cerebral hemispheres is characterized by an extensive system of afferent and efferent connections with cortical, subcortical, bainstem structures and the spinal cord, which ensure its participation in the higher mechanisms of regulation of the functions of the visceral sphere. At the same time, the involvement of the infralimbic cortex in the mechanisms of cortical modulation of visceral nociception, both acute and chronic, seems to be poorly understood. In this work, using an experimental model of abdominal pain on two groups of urethane anesthetized rats (normal rats and rats with experimental colitis), we studied the effects of electrical stimulation of the infralimbic cortex on the neuronal (responses of neurons of the caudal ventrolateral reticular formation) and systemic (changes in arterial blood pressure) reactions induced by nociceptive distension of the colorectal region of colon. It has been found that in rats of both groups nociceptive colorectal distension was accompanied by both excitatory and inhibitory reactions of neurons of the ventrolateral reticular formation, as well as depressor changes in blood pressure. Electrical stimulation of the infralimbic cortex increased excitatory and decreased inhibitory neuronal responses to visceral painful stimulation and also enhanced nociceptive depressor responses in both normal rats and rats with colitis. This effect was more pronounced in the group of healthy animals. In general, the influence of the infralimbic cortex on nociceptive neurons of the ventrolateral reticular formation and vascular responses to visceral pain can be considered as facilitating visceral nociception. Quantitative differences in the effects of cortical stimulation in normal rats and rats with colitis are possibly related to differences in the brain processing of acute visceral pain and pain complicated by chronic inflammation. One of the possible mechanisms of cortical influence on visceral nociception may be modulation of the current activity of nociceptive neurons of the caudal ventrolateral reticular formation, directly or indirectly involved in the descending control of visceral pain.

Contactless Assessment of Cerebral Autoregulation by Photoplethysmographic Imaging at Green Illumination.

Accurate and practical assessment of the brain circulation is needed to adequately estimate the viability of cerebral blood flow regulatory mechanisms in various physiological conditions. The objective of our study was to examine feasibility of the contactless green-light imaging photoplethysmography (PPG) for assessing cerebral autoregulation by revealing the dynamic relationships between cortical microcirculation assessed by PPG and changes in systemic blood pressure caused by visceral and somatic peripheral stimuli. In anesthetized male Wistar rats, the PPG video images of the open parietal cortex (either with unimpaired or dissected dura mater), electrocardiogram, and systemic arterial blood pressure (ABP) in the femoral artery were continuously recorded before, during and after visceral (colorectal distension) or somatic (tail squeezing) stimulation. In the vast majority of experiments with intact and removed dura mater, both spontaneous and peripheral stimulation-evoked changes in ABP negatively correlated with the accompanying alterations in the amplitude of pulsatile PPG component (APC), i.e., an increase of ABP resulted in a decrease of APC and vice versa. The most pronounced ABP and APC alterations were induced by noxious stimuli. Visceral painful stimulation in all cases caused short-term hypotension with simultaneous increase in cortical APC, whereas somatic noxious stimuli in 8 of 21 trials produced hypertensive effect with decreased APC. Animals with pressure 50-70 mmHg possessed higher negative cerebrovascular response rate of ABP-APC gradients than rats with either lower or higher pressure. Severe hypotension reversed the negative ratio to positive one, which was especially evident under visceral pain stimulation. Amplitude of the pulsatile PPG component probably reflects the regulation of vascular tone of cerebral cortex in response to systemic blood pressure fluctuations. When combined with different kinds of peripheral stimuli, the technique is capable for evaluation of normal and elucidation of impaired cerebrovascular system reactivity to particular physiological events, for example pain. The reported contactless PPG monitoring of cortical circulatory dynamics during neurosurgical interventions in combination with recordings of changes in other physiological parameters, such as systemic blood pressure and ECG, has the appealing potential to monitor viability of the cortex vessels and determine the state of patient’s cerebrovascular autoregulation.

Insula Activity to Visceral Stimulation and Endocrine Stress Responses as Associated With Alexithymia in Patients With Irritable Bowel Syndrome.

Few studies have investigated associations between alexithymia and physiological mechanisms in psychosomatic diseases. We examined associations between alexithymia and 1) perception and brain processing of visceral stimulation and 2) the endocrine responses to corticotrophin-releasing hormone (CRH) in healthy individuals and patients with irritable bowel syndrome (IBS). The study included 29 patients with IBS and 35 age- and sex-matched healthy controls (HCs). Alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Brain responses to rectal distention and its anticipation were measured by functional magnetic resonance imaging and analyzed at a voxel-level threshold of puncorrected < .001 combined with a cluster-level threshold of pFWE-corrected < .05. On a different day, plasma adrenocorticotropic hormone and cortisol responses after intravenous CRH administration were measured. TAS-20 scores did not differ significantly between patients with IBS and HCs (p = .18). TAS-20 scores correlated positively with the individual rectal discomfort thresholds (βrobust = 0.49, p = .03) and negatively with the rating of fear before rectal distention (βrobust = -1.63, p = .04) in patients with IBS but not in HCs. Brain responses to rectal distention in the right insula and other brain regions were positively associated with TAS-20 scores to a greater extent in patients with IBS than in HCs. Individuals with higher TAS-20 scores (both patients with IBS and HCs) demonstrated stronger adrenocorticotropic hormone responses to CRH administration (F(4,224) = 3.54, p = .008). Higher alexithymia scores are associated with stronger physiological responses, but lower anticipatory fear ratings and higher discomfort thresholds, particularly in patients with IBS.

Differential responses of neurons in the rat caudal ventrolateral medulla to visceral and somatic noxious stimuli and their alterations in colitis

Visceral and somatic types of pain have been reported to manifest crucial differences not only in the experience, but also in their peripheral and central processing. However, the precise neuronal mechanisms that responsible for the modality-specific transmission of pain signals, especially at the supraspinal level, remain unclear. Very little is known also about the potential involvement of such mechanisms in the development of viscero-somatic hyperalgesia. Therefore, in the present study performed on urethane-anesthetized adult male Wistar rats we examined responses of neurons in the caudal ventrolateral medulla (CVLM)—the first site for supraspinal processing of both internal and external pain signals—to visceral (colorectal distension, CRD) and somatic (squeezing of the tail) noxious stimulations and evaluated alterations in response properties of these cells after the induction of colitis. It has been found out that the CVLM of healthy control rats, along with harboring of cells excited by both stimulations (23.7%), contained neurons that were activated by either visceral (31.9%) or somatic noxious stimuli (44.4%). In inflamed animals, the percentages of the visceral and somatic nociceptive cells were decreased (to 18.3% and 34.3%, correspondingly) and the number of bimodal neurons was increased (up to 47.4%); these alterations were associated with substantially enhanced responses of both the modality-specific and convergent CVLM neurons not only to CRD, but also to squeezing of the tail. Under these conditions, visceral and somatic pain stimuli induced similar changes in arterial blood pressure and respiratory rate, whereas in the absence of intestinal inflammation noxious CRD and tail stimulation evoked predominantly divergent autonomic reactions. The data obtained can benefit to a deeper understanding of the neuronal mechanisms that underlie differential supraspinal processing of visceral and somatic noxious stimuli and can potentially contribute to the realization of specific cardiovascular and respiratory accompaniments inherent to a particular type of pain. Therewith, results of the study elucidate colitis-induced alterations in these mechanisms, which may be responsible for the combined development of visceral hypersensitivity and somatic hyperalgesia.

Gastric stimulation drives fast BOLD responses of neural origin

Functional magnetic resonance imaging (fMRI) is commonly thought to be too slow to capture any neural dynamics faster than 0.1 Hz. However, recent findings demonstrate the feasibility of detecting fMRI activity at higher frequencies beyond 0.2 Hz. The origin, reliability, and generalizability of fast fMRI responses are still under debate and await confirmation through animal experiments with fMRI and invasive electrophysiology. Here, we acquired single-echo and multi-echo fMRI, as well as local field potentials, from anesthetized rat brains given gastric electrical stimulation modulated at 0.2, 0.4 and 0.8 Hz. Such gastric stimuli could drive widespread fMRI responses at corresponding frequencies from the somatosensory and cingulate cortices. Such fast fMRI responses were linearly dependent on echo times and thus indicative of blood oxygenation level dependent nature (BOLD). Local field potentials recorded during the same gastric stimuli revealed transient and phase-locked broadband neural responses, preceding the fMRI responses by as short as 0.5 s. Taken together, these results suggest that gastric stimulation can drive widespread and rapid fMRI responses of BOLD and neural origin, lending support to the feasibility of using fMRI to detect rapid changes in neural activity up to 0.8 Hz under visceral stimulation.