Mathieu Piché

Cerebral and spinal modulation of pain by emotions

Emotions have powerful effects on pain perception. However, the brain mechanisms underlying these effects remain largely unknown. In this study, we combined functional cerebral imaging with psychophysiological methods to explore the neural mechanisms involved in the emotional modulation of spinal nociceptive responses (RIII-reflex) and pain perception in healthy participants. Emotions induced by pleasant or unpleasant pictures modulated the responses to painful electrical stimulations in the right insula, paracentral lobule, parahippocampal gyrus, thalamus, and amygdala. Right insula activation covaried with the modulation of pain perception, consistent with a key role of this structure in the integration of pain signals with the ongoing emotion. In contrast, activity in the thalamus, amygdala, and several prefrontal areas was associated with the modulation of spinal reflex responses. Last, connectivity analyses suggested an involvement of prefrontal, parahippocampal, and brainstem structures in the cerebral and cerebrospinal modulation of pain by emotions. This multiplicity of mechanisms underlying the emotional modulation of pain is reflective of the strong interrelations between pain and emotions, and emphasizes the powerful effects that emotions can have on pain.

Cerebral and Cerebrospinal Processes Underlying Counterirritation Analgesia

Pain is a complex experience involving extensive interactions between brain and spinal cord processes. Various interventions that modulate pain, such as the application of a competing noxious stimulus (counterirritation), are thought to involve cerebrospinal regulation through diffuse noxious inhibitory controls (DNICs). However, no study has yet examined the relation between brain and spinal cord activity during counterirritation analgesia in humans. This fMRI study investigates brain responses to phasic painful electrical stimulation administered to the sural nerve to evoke a spinal nociceptive response (RIII reflex) before, during and after counterirritation induced by the immersion of the left contralateral foot in cold water. Responses are compared with a control condition without counterirritation. As expected, counterirritation produced robust pain inhibition with residual analgesia persisting during the recovery period. In contrast, RIII reflex amplitude was significantly decreased by counterirritation only in a subset of subjects. Modulatory effects of counterirritation on pain perception and spinal nociception were paralleled by decreased shock-evoked activity in pain-related areas. Individual changes in shock-evoked brain activity were specifically related to analgesia in primary somatosensory cortex (SI), anterior cingulate cortex and amygdala, and to RIII modulation in supplementary motor area and orbitofrontal cortex (OFC). Moreover, sustained activation induced by the counterirritation stimulus in the OFC predicted shock-pain decrease while sustained activity in SI and the periaqueductal gray matter predicted RIII modulation. These results provide evidence for the implication of at least two partly separable neural mechanisms underlying the effects of counterirritation on pain and spinal nociception in humans.

Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome

&NA; The mechanisms of chronic pain in irritable bowel syndrome (IBS) have been widely investigated but remain unclear. The present study investigated the relation between visceral hypersensitivity, cutaneous thermal sensitivity, and central pain mechanisms. Rectal sensitivity was assessed with a barostat, and forearm and calf sensitivity with a contact thermode. Central mechanisms were assessed by counterirritation using sustained cold‐pain to the hand and painful electric shocks to the ankle. Psychological symptoms were also assessed, using questionnaires. Female volunteers with diarrhea‐predominant IBS (n = 27) and healthy controls (n = 25) participated in the study. IBS patients had lower rectal and calf pain thresholds compared to controls (p’s < 0.05). IBS patients also reported more pain than controls for rectal distensions, and heat pain on the calf and forearm (all p’s < 0.001). Cold‐pain inhibited shock‐pain in controls but not IBS patients (controls: −13.5 ± 5.3 vs IBS: +1.9 ± 10.5; p < 0.01). In addition, visceral hypersensitivity was significantly correlated to cutaneous thermal hypersensitivity and pain inhibition deficits, although effects were only weak and moderate, respectively. Furthermore, covariance analyses indicated that psychological factors accounted for group differences in visceral hypersensitivity and pain inhibition deficits. In conclusion, this study confirms the relation between altered pain inhibition processes and widespread hypersensitivity in IBS. The present results also suggests that psychological symptoms and altered pain processing in IBS patients may reflect at least in part, common underlying mechanisms.

Decreased pain inhibition in irritable bowel syndrome depends on altered descending modulation and higher-order brain processes

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abdominal pain and bowel dysfunction. IBS pain symptoms have been hypothesized to depend on peripheral and central mechanisms, but the pathophysiology is still unclear. The aim of the present study was to assess the contribution of cerebral and cerebrospinal processes to pain inhibition deficits in IBS. Fourteen female patients with diarrhea-predominant IBS (IBS-D) and 14 healthy female volunteers were recruited. Acute pain and the nociceptive withdrawal reflex (RIII reflex) were evoked by transcutaneous electrical stimulation of the right sural nerve with modulation by hetero-segmental counter-irritation produced by sustained cold pain applied on the left forearm. Psychological symptoms were assessed by questionnaires. Shock pain decreased significantly during counter-irritation in the controls (P<0.001) but not in IBS patients (P=0.52). Similarly, RIII-reflex amplitude declined during counter-irritation in the controls (P=0.009) but not in IBS patients (P=0.11). Furthermore, pain-related anxiety increased during counter-irritation in IBS patients (P=0.003) but not in the controls (P=0.74). Interestingly, across all subjects, counter-irritation analgesia was positively correlated with RIII-reflex inhibition (r=0.39, P=0.04) and negatively with pain-related anxiety (r=-0.61, P<0.001). In addition, individual differences in counter-irritation analgesia were predicted independently by the modulation of RIII responses (P=0.03) and by pain catastrophizing (P=0.01), with the latter mediating the effect of pain-related anxiety. In conclusion, these results demonstrate that pain inhibition deficits in female IBS-D patients depend on two potentially separable mechanisms reflecting: (1) altered descending modulation and (2) higher-order brain processes underlying regulation of pain and affect.

Dissection of perceptual, motor and autonomic components of brain activity evoked by noxious stimulation

&NA; In the past two decades, functional brain imaging has considerably advanced our knowledge of cerebral pain processing. However, many important links are still missing in our understanding of brain activity in relation to the regulation of pain‐related physiological responses. This fMRI study investigates the cerebral correlates of pain (rating), motor responses (RIII‐reflex) and autonomic activity (skin conductance response; SCR) evoked by noxious electrical stimulation. Stimulus intensity was adjusted individually based on the RIII threshold to control for differences in peripheral processes and baseline spinal activation. Covariance analyses were used to reveal individual differences in brain activity uniquely associated with individual differences in pain, RIII and SCR. Shock‐evoked activity in cingulate, medial orbitofrontal and parahippocampal regions predicted pain sensitivity. Moreover, lateral orbitofrontal and cingulate areas showed strong positive associations with individual differences in motor reactivity but negative associations with autonomic reactivity. Notably, individual differences in OFC activation was almost fully accounted by the combination of individual measures of autonomic and motor reactivity (R2 = 0.93). Additionally, trial‐to‐trial fluctuations of RIII‐reflex and SCR (within‐subjects) were proportional to shock‐evoked responses in subgenual cingulate cortex (RIII), anterior insula (SCR) and midcingulate cortex (SCR and RIII). Together, these results confirm that individual differences in perceptual, motor, and autonomic components of pain reflect robust individual differences in brain activity. Furthermore, the brain correlates of trial‐to‐trial fluctuations in pain responses provide additional evidence for a partial segregation of sub‐systems involved more specifically in the ongoing monitoring, and possibly the regulation, of pain‐related motor and autonomic responses.

Auditory responses in the visual cortex of neonatally enucleated rats.

A number of studies on humans and animals have demonstrated better auditory abilities in blind with respect to sighted subjects and have tried to define the mechanisms through which this compensation occurs. The aim of the present study, therefore, was to examine the participation of primary visual cortex (V1) to auditory processing in early enucleated rats. Here we show, using gaussian noise bursts, that about a third of the cells in V1 responded to auditory stimulation in blind rats and most of these (78%) had ON-type responses and low spontaneous activity. Moreover, they were distributed throughout visual cortex without any apparent tonotopic organization. Optimal frequencies determined using pure tones were rather high but comparable to those found in auditory cortex of blind and sighted rats. On the other hand, sensory thresholds determined at these frequencies were higher and bandwidths were wider in V1 of the blind animals. Blind and sighted rats were also stimulated for 60 min with gaussian noise, their brains removed and processed for c-Fos immunohistochemistry. Results revealed that c-Fos positive cells were not only present in auditory cortex of both groups of rats but there was a 10-fold increase in labeled cells in V1 and a fivefold increase in secondary visual cortex (V2) of early enucleated rats in comparisons to sighted ones. Also, the pattern of distribution of these labeled cells across layers suggests that the recruitment of V1 could originate at least in part through inputs arising from the thalamus. The ensemble of results appears to indicate that cross-modal compensation leading to improved performance in the blind depends on cell recruitment in V1 but probably also plastic changes in lower- and higher-order visual structures and possibly in the auditory system.

Characterization of cardiac-related noise in fMRI of the cervical spinal cord.

Magnetic resonance imaging (MRI) has recently been applied to study spinal cord function in humans. However, spinal functional MRI (fMRI) encounters major technical challenges with cardiac noise being considered a major source of noise. The present study relied on echo-planar imaging of the cervical cord at short TR (TR=250 ms; TE=40 ms; flip=45 degrees), combined with plethysmographic recordings to characterize the spatiotemporal properties of cardiac-induced signal changes in spinal fMRI. Frequency-based analyses examining signal change at the cardiac frequency confirmed mean fluctuations of about 10% (relative to the mean signal) in the spinal cord and surrounding cerebrospinal fluid (CSF), with maximal responses reaching up to 66% in some voxels. A spatial independent component analysis (sICA) confirmed that cardiac noise is an important source of variance in spinal fMRI with several components showing a response coherent with the cardiac frequency spectrum. The time course of the main cardiac components approximated a sinusoidal function tightly coupled to the cardiac systole with at least one component showing a comparable temporal profile across runs and subjects. Spatially, both the frequency-domain analysis and the sICA demonstrated cardiac noise distributed irregularly along the full rostrocaudal extent of the segments scanned with peaks concentrated in the ventral part of the lateral slices in all scans and subjects, consistent with the major channels of CSF flow. These results confirm that cardiac-induced changes are a significant source of noise likely to affect the detection of spinal Blood Oxygen Level Dependent (BOLD) responses. Most importantly, the complex spatiotemporal structure of cardiac noise is unlikely to be accounted for adequately by ad hoc linear methods, especially in data acquired using long TR (i.e. aliasing the cardiac frequency). However, the reliable spatiotemporal distribution of cardiac noise across scanning runs and within subjects may provide a valid means to identify and extract cardiac noise based on sICA methods.

Environmental enrichment enhances auditory takeover of the occipital cortex in anophthalmic mice

Enrichment of the environment is an effective means of enhancing neuronal development and plasticity but its effect on the cross‐modal compensation resulting from sensory deprivation has never been investigated. The present study used c‐Fos immunohistochemistry and dextran–biotin neuronal tracing to examine the reorganization of sensory modalities in the brain of anophthalmic mutant mice (ZRDCT/An) raised in either enriched or standard environments. Auditory stimulation was found to elicit strong neuronal activation in thalamic and cortical structures that are normally visual. An important finding was that the latter auditory‐evoked cortical activity was considerably enhanced in blind mice raised in the enriched environment. The axonal tracing study demonstrated auditory inputs from the inferior colliculus to the visual thalamus. This animal model will be useful for understanding neuronal mechanisms underlying some cross‐modal sensory phenomena observed in blind or deaf humans.

Thicker Posterior Insula Is Associated With Disease Duration in Women With Irritable Bowel Syndrome (IBS) Whereas Thicker Orbitofrontal Cortex Predicts Reduced Pain Inhibition in Both IBS Patients and Controls

UNLABELLED Patients with irritable bowel syndrome (IBS) are affected by chronic abdominal pain and show decreased pain inhibition. Moreover, they exhibit differences in brain morphology compared with healthy volunteers. The aim of this study was to examine whether decreased pain inhibition is associated with altered brain morphology in IBS patients. Structural magnetic resonance imaging scans were acquired in 14 female patients with diarrhea-predominant IBS and 14 controls. Pain and anxiety modulation were characterized using electrical stimulation of the sural nerve and heterotopic noxious counterstimulation. IBS patients reported decreased pain inhibition (P = .02) as well as increased shock anxiety, pain catastrophizing, depressive symptoms, and trait anxiety (Ps ≤ .05). IBS patients also showed a thicker right posterior insula (pINS), associated with longer IBS duration (r = .67, P = .02). In addition, thicker right lateral orbitofrontal cortex was strongly associated with less pain inhibition in both IBS patients (r = .70, P = .02) and controls (r = .68, P = .01). Results are consistent with the role of the insula in interoception and pain and suggest that IBS may induce thickening of the pINS. Reduced pain inhibition may further involve a modification of the regulatory influence of the orbitofrontal cortex on pain-related processes. PERSPECTIVE This study investigated the brain morphology of IBS patients. IBS patients showed thicker right pINS, associated with longer disease duration but not with psychological symptoms. This suggests that IBS induces thickening of pINS, which may contribute to its pathophysiology, consistent with the role of the pINS in interoception and pain.

Reduction of physiological noise with independent component analysis improves the detection of nociceptive responses with fMRI of the human spinal cord

The evaluation of spinal cord neuronal activity in humans with functional magnetic resonance imaging (fMRI) is technically challenging. Major difficulties arise from cardiac and respiratory movement artifacts that constitute significant sources of noise. In this paper we assessed the Correction of Structured noise using spatial Independent Component Analysis (CORSICA). FMRI data of the cervical spinal cord were acquired in 14 healthy subjects using gradient-echo EPI. Nociceptive electrical stimuli were applied to the thumb. Additional data with short TR (250 ms, to prevent aliasing) were acquired to generate a spatial map of physiological noise derived from Independent Component Analysis (ICA). Physiological noise was subsequently removed from the long-TR data after selecting independent components based on the generated noise map. Stimulus-evoked responses were analyzed using the general linear model, with and without CORSICA and with a regressor generated from the cerebrospinal fluid region. Results showed higher sensitivity to detect stimulus-related activation in the targeted dorsal segment of the cord after CORSICA. Furthermore, fewer voxels showed stimulus-related signal changes in the CSF and outside the spinal region, suggesting an increase in specificity. ICA can be used to effectively reduce physiological noise in spinal cord fMRI time series.