Fasting prevents medetomidine-induced hyperglycaemia and alterations of neurovascular coupling in the somatosensory cortex of the rat during noxious stimulation.

Medetomidine and isoflurane are commonly used for general anaesthesia in fMRI studies, but they alter cerebral blood flow (CBF) regulation and neurovascular coupling (NVC). In addition, medetomidine induces hypoinsulinemia and hyperglycaemia, which also alter CBF regulation and NVC. Furthermore, sudden changes in arterial pressure induced by noxious stimulation may affect NVC differently under medetomidine and isoflurane anaesthesia, considering their different effects on vascular functions. The first objective of this study was to compare NVC under medetomidine and isoflurane anaesthesia during noxious stimulation. The second objective was to examine whether fasting may improve NVC by reducing medetomidine-induced hyperglycaemia. In male Wister rats, noxious electrical stimulation was applied to the sciatic nerve in fasted or non-fasted animals. CBF and local field potentials (LFP) were recorded in the somatosensory cortex to assess NVC (CBF/LFP ratio). The CBF/LFP ratio was increased by medetomidine compared with isoflurane (p = 0.004), but this effect was abolished by fasting (p = 0.8). Accordingly, medetomidine produced a threefold increase in blood glucose (p < 0.001), but this effect was also abolished by fasting (p = 0.3). This indicates that isoflurane and medetomidine anaesthesia alter NVC differently, but the undesirable glucose dependent effects of medetomidine on NVC can be prevented by fasting.

Structural brain plasticity induced by early blindness.

It is well established that early blindness results in behavioural adaptations. While the functional effects of visual deprivation have been well researched, anatomical studies are scarce. The aim of this study was to investigate whole brain structural plasticity in a mouse model of congenital blindness. Volumetric analyses were conducted on high-resolution MRI images and histological sections from the same brains. These morphometric measurements were compared between anophthalmic and sighted ZRDBA mice obtained by breeding ZRDCT and DBA mice. Results from MRI analyses using the Multiple Automatically Generated Templates (MAGeT) method showed smaller volume for the primary visual cortex and superior colliculi in anophthalmic compared with sighted mice. Deformation-based morphometry revealed smaller volumes within the dorsal lateral geniculate nuclei and the lateral secondary visual cortex and larger volumes within olfactory areas, piriform cortex, orbital areas and the amygdala, in anophthalmic compared with sighted mice. Histological analyses revealed a larger volume for the amygdala and smaller volume for the superior colliculi, primary visual cortex and medial secondary visual cortex, in anophthalmic compared with sighted mice. The absence of superficial visual layers of the superior colliculus and the thinner cortical layer IV of the primary and secondary visual cortices may explain the smaller volume of these areas, although this was observed in a limited sample. The present study shows large-scale brain plasticity in a mouse model of congenital blindness. In addition, the congruence of MRI and histological findings support the use of MRI to investigate structural brain plasticity in the mouse.

Cortical interaction of bilateral inputs is similar for noxious and innocuous stimuli but leads to different perceptual effects.

The cerebral integration of somatosensory inputs from multiple sources is essential to produce adapted behaviors. Previous studies suggest that bilateral somatosensory inputs interact differently depending on stimulus characteristics, including their noxious nature. The aim of this study was to clarify how bilateral inputs evoked by noxious laser stimuli, noxious shocks, and innocuous shocks interact in terms of perception and brain responses. The experiment comprised two conditions (right-hand stimulation and concurrent stimulation of both hands) in which painful laser stimuli, painful shocks and non-painful shocks were delivered. Perception, somatosensory-evoked potentials (P45, N100, P260), laser-evoked potentials (N1, N2 and P2) and event-related spectral perturbations (delta to gamma oscillation power) were compared between conditions and stimulus modalities. The amplitude of negative vertex potentials (N2 or N100) and the power of delta/theta oscillations were increased in the bilateral compared with unilateral condition, regardless of the stimulus type (P < 0.01). However, gamma oscillation power increased for painful and non-painful shocks (P < 0.01), but not for painful laser stimuli (P = 0.08). Despite the similarities in terms of brain activity, bilateral inputs interacted differently for painful stimuli, for which perception remained unchanged, and non-painful stimuli, for which perception increased. This may reflect a ceiling effect for the attentional capture by noxious stimuli and warrants further investigations to examine the regulation of such interactions by bottom-up and top-down processes.

Spinal and Cerebral Integration of Noxious Inputs in Left-handed Individuals.

Some pain-related information is processed preferentially in the right cerebral hemisphere. Considering that functional lateralization can be affected by handedness, spinal and cerebral pain-related responses may be different between right- and left-handed individuals. Therefore, this study aimed to investigate the cortical and spinal mechanisms of nociceptive integration when nociceptive stimuli are applied to right -handed vs. left -handed individuals. The NFR, evoked potentials (ERP: P45, N100, P260), and event-related spectral perturbations (ERSP: theta, alpha, beta and gamma band oscillations) were compared between ten right-handed and ten left-handed participants. Pain was induced by transcutaneous electrical stimulation of the lower limbs and left upper limb. Stimulation intensity was adjusted individually in five counterbalanced conditions of 21 stimuli each: three unilateral (right lower limb, left lower limb, and left upper limb stimulation) and two bilateral conditions (right and left lower limbs, and the right lower limb and left upper limb stimulation). The amplitude of the NFR, ERP, ERSP, and pain ratings were compared between groups and conditions using a mixed ANOVA. A significant increase of responses was observed in bilateral compared with unilateral conditions for pain intensity, NFR amplitude, N100, theta oscillations, and gamma oscillations. However, these effects were not significantly different between right- and left-handed individuals. These results suggest that spinal and cerebral integration of bilateral nociceptive inputs is similar between right- and left-handed individuals. They also imply that pain-related responses measured in this study may be examined independently of handedness.

Distinct fMRI patterns colocalized in the cingulate cortex underlie the after-effects of cognitive control on pain.

Demanding tasks can influence following behaviors but the underlying mechanisms remain largely unclear. In the present functional magnetic resonance imaging (fMRI) study, we used multivariate pattern analyses (MVPA) to compare patterns of brain activity associated with pain in response to noxious stimuli administered after a task requiring cognitive control (Stroop) and evaluate their functional interaction based on a mediation analysis model. We found that performing a difficult cognitive task leads to subsequent increases in pain and pain-related multivariate responses across the brain and within the anterior mid-cingulate cortex (aMCC). Moreover, an aMCC pattern predictive of task performance was further reactivated during pain and predicted ensuing increases in pain-related brain responses. This suggests functional interactions between distinct but partly co-localized neural networks underlying executive control and pain. These findings offer a new perspective on the functional role of the cingulate cortex in pain and cognition and provide a promising framework to investigate dynamical interactions between partly overlapping brain networks.

Better Olfactory Performance and Larger Olfactory Bulbs in a Mouse Model of Congenital Blindness.

It is well established that early blindness results in enhancement of the remaining nonvisual sensory modalities accompanied by functional and anatomical brain plasticity. While auditory and tactile functions have been largely investigated, the results regarding olfactory functions remained less explored and less consistent. In the present study, we investigated olfactory function in blind mice using 3 tests: the buried food test, the olfactory threshold test, and the olfactory performance test. The results indicated better performance of blind mice in the buried food test and odor performance test while there was no difference in the olfactory threshold test. Using histological measurements, we also investigated if there was anatomical plasticity in the olfactory bulbs (OB), the most salient site for olfactory processing. The results indicated a larger volume of the OB driven by larger glomerular and granular layers in blind mice compared with sighted mice. Structural plasticity in the OB may underlie the enhanced olfactory performance in blind mice.

Paraspinal muscle function and pain sensitivity following exercise-induced delayed-onset muscle soreness.

PURPOSE: The aim of this study was to evaluate the effectiveness of an exercise protocol designed to induce delayed-onset muscle soreness (DOMS) in paraspinal muscles and its effects on low back functional capacities. METHODS: Twenty-four healthy participants were asked to perform four series of 25 trunk flexion-extension in a prone position (45° inclined Roman chair). The protocol was performed using loads corresponding to participant's trunk weight plus 10% of their trunk extension maximal voluntary contraction. Perceived soreness and pain were assessed using an 11-point numerical analogue scale three times a day during 5 day post-DOMS protocol. Pressure-pain thresholds (PPT) in paraspinal muscles (L2 and L4 bilaterally) and the vastus medialis (control site), and trunk extension maximal voluntary contraction were assessed 24-36 h post-protocol and compared to baseline (t tests). RESULTS: Muscle soreness (3.8/10) and pain (2.1/10) peak scores were observed 24-36 h post-protocol (mean of 28 h). A significant reduction in trunk extension maximal voluntary contraction was observed post-protocol (p = 0.005). Significant reductions in PPT were observed post-protocol for all trunk extensor sites (ps < 0.01), but not for the control site (p = 0.40). CONCLUSIONS: The exercise protocol efficiently led to low back muscle DOMS, reduced functional capacities, and increased pain sensitivity locally. Such protocol could be used as an efficient and safe experimental low back pain model.

Inhibitory effects of heterotopic noxious counter-stimulation on perception and brain activity related to Aß-fibre activation.

Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aß-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak-to-peak amplitude at Cz was significantly decreased by HNCS for non-nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aß-fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide-dynamic-range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.

Types of skin afferent fibers and spinal opioid receptors that contribute to touch-induced inhibition of heart rate changes evoked by noxious cutaneous heat stimulation.

BACKGROUND: In anesthetized rats and conscious humans, a gentle touch using a soft disc covered with microcones (with a texture similar to that of a finger), but not with a flat disc, inhibits nociceptive somatocardiac reflexes. Such an inhibitory effect is most reliably evoked when touch is applied to the skin ipsilateral and closest to nociceptive inputs. However, the mechanism of this inhibition is not completely elucidated. We aimed to clarify the types of cutaneous afferent fibers and spinal opioid receptors that contribute to antinociceptive effects of microcone touch. RESULTS: The present study comprised two experiments with urethane-anesthetized rats. In the first experiment, unitary activity of skin afferent fibers was recorded from the saphenous nerve, and responses to a 10-min touch using a microcone disc and a flat disc (control) were compared. Greater discharge rate during microcone touch was observed in low-threshold mechanoreceptive Aδ and C afferent units, whereas many Aß afferents responded similarly to the two types of touch. In the second experiment, the effect of an intrathecal injection of opioid receptor antagonists on the inhibitory effects of microcone touch on heart rate responses to noxious heat stimulation was examined. The magnitude of the heart rate response was significantly reduced by microcone touch in rats that received saline or naltrindole (δ-opioid receptor antagonist) injections. However, such an inhibition was not observed in rats that received naloxone (non-selective opioid receptor antagonist) or Phe-Cys-Tyr-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; µ-opioid receptor antagonist) injections. CONCLUSIONS: Microcone touch induced greater responses of low-threshold mechanoreceptive Aδ and C afferent units than control touch. The antinociceptive effect of microcone touch was abolished by intrathecal injection of µ-opioid receptor antagonist. These results suggest that excitation of low-threshold mechanoreceptive Aδ and C afferents produces the release of endogenous µ-opioid ligands in the spinal cord, resulting in the inhibition of nociceptive transmission that contributes to somatocardiac reflexes.

Efficacy of a Psychologically-Informed Physiotherapy Intervention in Patients with Chronic Low Back Pain at High Risk of Poor Prognosis: A Pilot and Feasibility Randomized Controlled Trial.

Purpose: To determine the feasibility of a randomized controlled trial (RCT) testing the efficacy of psychologically-informed physiotherapy (PIPT), which includes usual physiotherapy (UP) interventions, compared with UP, and to explore the preliminary effectiveness of the interventions. Method: People with chronic low back pain at high risk of poor prognosis (using the STarT Back screening tool) were recruited and allocated to PIPT or UP. Effectiveness of recruitment strategies, adherence to intervention, risk of contamination, and specific challenges were assessed. Functional capacity, pain, quality of life, kinesiophobia, catastrophization, central sensitization, and self-efficacy were measured at baseline, 6-, 12- and 24-week follow-ups. Results: Forty participants were recruited mainly by diffusing through Laval University's email list, and 10 physiotherapists treated the participants recruited. The retention rate of participants at 24 weeks was 72.5%. Adherence to treatment by participants and physiotherapists was very good. The risk of contamination was low, and the specific challenges identified were modifiable. Significant improvement over time in all clinical variables of interest, except self-efficacy, was observed with no difference between groups. Conclusions: As most success criteria were met, conducting an RCT evaluating PIPT and PU is feasible with modifications. PIPT and UP appear to be similarly effective.

Objectif: déterminer la faisabilité d'une étude randomisée et contrôlée (ÉRC) évaluant l'efficacité de la physiothérapie fondée sur la psychologie (PTFP), qui inclut les interventions de physiothérapie conventionelle (PC), par rapport à la PC, et explorer l'efficacité préliminaire des interventions. Méthodologie: les chercheurs ont recruté des personnes qui souffrent de douleurs lombaires chroniques, ayant une probabilité élevée de mauvais pronostic (au moyen de l'outil de dépistage STarT Back) et les ont réparties entre la PTFP et la PC. Ils ont évalué l'efficacité des stratégies de recrutement, l'adhésion à l'intervention, le risque de contamination et les difficultés particulières. Ils ont également mesuré la capacité fonctionnelle, la douleur, la qualité de vie, la kinésiophobie, la catastrophisation, la sensibilisation centrale et l'autoefficacité en début d'étude ainsi que lors des suivis à six, 12 et 24 semaines. Résultats: les chercheurs ont recruté 40 participants, principalement en diffusant le projet par courriel à la communauté de l'Université Laval, et dix physiothérapeutes les ont traités. Le taux de rétention des participants était de 72,5 % à 24 semaines. Les participants et les physiothérapeutes ont démontré une très bonne adhésion au traitement. Le risque de contamination était faible, et les difficultés particulières constatées pouvaient être modifiées. Les chercheurs ont observé une amélioration considérable au fil du temps pour toutes les variables cliniques d'intérêt, sauf l'autoefficacité, sans différence entre les groupes. Conclusions: puisque la plupart des critères de succès étaient respectés, il est faisable de réaliser une ÉRC pour évaluer la PTFP et la PU, sous réserve de modifications. La PTFP et la PC semblent avoir une efficacité similaire.

Reduction of Chronic Primary Low Back Pain by Spinal Manipulative Therapy is Accompanied by Decreases in Segmental Mechanical Hyperalgesia and Pain Catastrophizing: A Randomized Placebo-controlled Dual-blind Mixed Experimental Trial.

Chronic primary low back pain (CPLBP) refers to low back pain that persists over 3 months, that cannot be explained by another chronic condition, and that is associated with emotional distress and disability. Previous studies have shown that spinal manipulative therapy (SMT) is effective in relieving CPLBP, but the underlying mechanisms remain elusive. This randomized placebo-controlled dual-blind mixed experimental trial (NCT05162924) aimed to investigate the efficacy of SMT to improve CPLBP and its underlying mechanisms. Ninety-eight individuals with CPLBP and 49 controls were recruited. Individuals with CPLBP received SMT (n = 49) or a control intervention (n = 49), 12 times over 4 weeks. The primary outcomes were CPLBP intensity (0-100 on a numerical rating scale) and disability (Oswestry Disability Index). Secondary outcomes included pressure pain thresholds in 4 body regions, pain catastrophizing, Central Sensitization Inventory, depressive symptoms, and anxiety scores. Individuals with CPLBP showed widespread mechanical hyperalgesia (P < .001) and higher scores for all questionnaires (P < .001). SMT reduced pain intensity compared with the control intervention (mean difference: -11.7 [95% confidence interval, -11.0 to -12.5], P = .01), but not disability (P = .5). Similar mild to moderate adverse events were reported in both groups. Mechanical hyperalgesia at the manipulated segment was reduced after SMT compared with the control intervention (P < .05). Pain catastrophizing was reduced after SMT compared with the control intervention (P < .05), but this effect was not significant after accounting for changes in clinical pain. Although the reduction of segmental mechanical hyperalgesia likely contributes to the clinical benefits of SMT, the role of pain catastrophizing remains to be clarified. PERSPECTIVE: This randomized controlled trial found that 12 sessions of SMT yield greater relief of CPLBP than a control intervention. These clinical effects were independent of expectations, and accompanied by an attenuation of hyperalgesia in the targeted segment and a modulation of pain catastrophizing.

Mechanisms of chiropractic spinal manipulative therapy for patients with chronic primary low back pain: protocol for a mechanistic randomised placebo-controlled trial.

INTRODUCTION: Chronic low back pain (CLBP) is a highly prevalent and disabling condition. Identifying subgroups of patients afflicted with CLBP is a current research priority, for which a classification system based on pain mechanisms was proposed. Spinal manipulative therapy (SMT) is recommended for the management of CLBP. Yet, little data are available regarding its mechanisms of action, making it difficult to match this intervention to the patients who may benefit the most. It was suggested that SMT may influence mechanisms associated with central sensitisation. Therefore, classifying patients with CLBP according to central sensitisation mechanisms may help predict their response to SMT. METHODS AND ANALYSIS: This protocol describes a randomised placebo-controlled trial aiming to examine which variables linked to central sensitisation may help predict the clinical response to SMT in a cohort of patients with CLBP. One hundred patients with chronic primary low back pain will be randomised to receive 12 sessions of SMT or placebo SMT over a 4-week period. Pain intensity and disability will be assessed as primary outcomes after completing the 4-week treatment (primary endpoint), and at 4-week and 12-week follow-ups. Baseline values of two pain questionnaires, lumbar pressure pain thresholds, concentrations of an inflammatory cytokine and expectations of pain relief will be entered as predictors of the response to SMT in a multiple regression model. Changes in these variables after treatment will be used in a second multiple regression model. The reference values of these predictors will be measured from 50 age and sex-matched healthy controls to allow interpretation of values in patients. Mixed analyses of variance will also be conducted to compare the primary outcomes and the predictors between groups (SMT vs placebo) over time (baseline vs post-treatment). ETHICS AND DISSEMINATION: Ethical approval was granted by the Fundación Jiménez Díaz Clinical Research Ethics Committee. TRIAL REGISTRATION NUMBER: NCT05162924.

Spinal neurovascular coupling is preserved despite time-dependent alterations of spinal cord blood flow responses in a rat model of chronic back pain: implications for functional spinal cord imaging.

ABSTRACT: Functional magnetic resonance imaging has been used to investigate nociceptive processes in patients with chronic pain. However, the results may be confounded with changes in neurovascular coupling induced by chronic pain. The objective of this study was to examine spinal neurovascular coupling in a rat model of chronic back pain induced by muscle inflammation. Rats received 150 µL intramuscular injections of either complete Freund adjuvant (CFA: n = 18) or saline (control [CTL]: n = 18) in L5-L6 paravertebral muscles. Under 1.2% isoflurane anesthesia, spinal cord blood flow (SCBF) and local field potentials evoked by electrical stimulation of the sciatic nerve were recorded simultaneously in the lumbar enlargement of the spinal cord, 14 or 28 days after the injections. Mechanical hypersensitivity was observed in CFA rats compared with CTL rats for the back ( P < 0.001) and hind paws ( P < 0.01). Spinal cord blood flow response amplitude and local field potential amplitude were not significantly different between groups (day 14: P > 0.5; day 28: P > 0.6). However, the time course of SCBF responses was different between groups on day 14 ( P < 0.001) and day 28 ( P < 0.001). Nevertheless, neurovascular coupling was comparable between groups on days 14 and 28, whether neurovascular coupling was calculated with the amplitude or the area under the curve of SCBF responses (all P > 0.2). These results indicate that spinal hemodynamic changes reflect neuronal activity in this animal model, although the time course of SCBF responses is affected by chronic inflammatory back pain. This warrants a careful use of spinal functional magnetic resonance imaging in animal models and patients with chronic back pain.

Brain responses to the vicarious facilitation of pain by facial expressions of pain and fear.

Observing pain in others facilitates self-pain in the observer. Vicarious pain facilitation mechanisms are poorly understood. We scanned 21 subjects while they observed pain, fear and neutral dynamic facial expressions. In 33% of the trials, a noxious electrical stimulus was delivered. The nociceptive flexion reflex (NFR) and pain ratings were recorded. Both pain and fear expressions increased self-pain ratings (fear > pain) and the NFR amplitude. Enhanced response to self-pain following pain and fear observation involves brain regions including the insula (INS) (pain > fear in anterior part), amygdala, mid-cingulate cortex (MCC), paracentral lobule, precuneus, supplementary motor area and pre-central gyrus. These results are consistent with the motivational priming account where vicarious pain facilitation involves a global enhancement of pain-related responses by negatively valenced stimuli. However, a psychophysiological interaction analysis centered on the left INS revealed increased functional connectivity with the aMCC in response to the painful stimulus following pain observation compared to fear. The opposite connectivity pattern (fear > pain) was observed in the fusiform gyrus, cerebellum (I-IV), lingual gyrus and thalamus, suggesting that pain and fear expressions influence pain-evoked brain responses differentially. Distinctive connectivity patterns demonstrate a stronger effect of pain observation in the cingulo-insular network, which may reflect partly overlapping networks underlying the representation of pain in self and others.

Urinary TNF-α as a potential biomarker for chronic primary low back pain.

Introduction: Over two thirds of individuals with low back pain (LBP) may experience recurrent or persistent symptoms in the long term. Yet, current data do not allow to predict who will develop chronic low back pain and who will recover from an acute episode. Elevated serum levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) have been associated with poor recovery and persistent pain following an acute episode of LBP. Inflammatory cytokines may also mediate mechanisms involved in nociplastic pain, and thus, have significant implications in chronic primary low back pain (CPLBP). Methods: This study aimed to investigate the potential of urinary TNF-α levels for predicting outcomes and characterizing clinical features of CPLBP patients. Twenty-four patients with CPLBP and 24 sex- and age-matched asymptomatic controls were recruited. Urinary TNF-α concentrations were measured at baseline and after 4 weeks, during which CPLBP patients underwent spinal manipulative therapy (SMT). Results: Concentrations of TNF-α were found to be elevated in baseline urine samples of CPLBP patients compared to asymptomatic controls. Moreover, these values differed among patients depending on their pain trajectory. Patients with persistent pain showed higher levels of TNF-α, when compared to those with episodic CPLBP. Furthermore, baseline TNF-α concentrations and their changes after 4 weeks predicted alterations in pain intensity and disability following SMT in patients with CPLBP. Discussion: These findings warrant further research on the potential use of urinary TNF-α concentrations as a prognostic biomarker for CPLBP.

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.

Modulation of pain-induced neuromuscular trunk responses by pain expectations: a single group study.

PURPOSE: The purpose of this study was to investigate the alteration of pain-induced neuromuscular trunk responses by expectations in healthy volunteers. METHODS: Twenty-three asymptomatic participants performed series of flexion-extension movements in 3 different experimental conditions: innocuous heat stimulation (control) and noxious heat stimulation associated with expectations of low or high pain intensity. These stimuli were administered by a contact thermode placed over the lumbar region (L4 and L5) to assess the modulation of neuromuscular responses and kinematics during the flexion-extension task. Surface electromyography (EMG) of lumbar erector spinae at L2 and L3 and L4 and L5 as well as lumbopelvic kinematic variables were compared across conditions. RESULTS: Noxious stimulation significantly altered EMG responses but only in full trunk flexion. Interestingly, this alteration was significant only for muscles where noxious stimulation was applied (L4 and L5) and not for the other segment (L2 and L3). Conversely, expectations significantly altered EMG activity at L2 and L3 but not at the segment where noxious stimulation was applied. CONCLUSION: These results confirm previous findings and indicate that experimental pain can alter neuromuscular responses during a trunk flexion-extension task. Furthermore, this study suggests that expectations can alter some of these alterations. Future studies should determine whether neuromuscular changes induced by expectations may contribute to the transition from acute to chronic low-back pain.

Effects of spatial attention and limb position on the cortical interaction of bilateral noxious inputs.

Bilateral noxious inputs interact in the brain to provide a better representation of physical threat. In the present study, we investigated the effects of spatial attention and limb position on this interaction. Painful laser stimuli were applied randomly on the right hand or on both hands, while varying spatial attention (focal or overall) and limb position (hands near or far from each other). Pain perception and laser-evoked potentials (N1, N2, P2) were compared between conditions in 27 healthy volunteers. Compared with unilateral stimulation, bilateral stimulation increased pain (p = .004), the N2 (p = .0015) and P2 (p < .001) amplitude. The effects on pain and the P2 were greater when hands were in the near compared with the far position (p < .05). The effect on pain was also greater for overall compared with focal pain rating (p = .003). In addition, the N1 amplitude was greater for bilateral stimulation when hands were in the far compared with the near position (p = .01). These results show that increased brain responses and pain for bilateral compared with unilateral noxious stimulation are modulated differentially by spatial attention and limb position. This suggests that the integration of noxious inputs occurs through partially independent pain-related processes, that it is modulated by limb position, and that it is partially independent of pain perception. We propose that this is necessary to produce coordinated, flexible and adapted defensive responses.

Attenuation of widespread hypersensitivity to noxious mechanical stimuli by inhibition of GABAergic neurons of the right amygdala in a rat model of chronic back pain.

BACKGROUND: Chronic primary low back pain may be associated with hyperalgesia in uninjured tissues and with decreased pain inhibition. Previous studies have shown that the amygdala is involved in pain regulation and chronic pain, that neuronal activity in the amygdala is altered in models of persistent pain, and that the central nucleus of the right amygdala plays an active role in widespread hypersensitivity to noxious stimuli. METHODS: Behavioral, electrophysiological, biochemical, and chemogenetic methods were used to examine the role of the central nucleus of the right amygdala in hypersensitivity to noxious stimuli in a rat model of chronic back pain induced by a local injection of Complete Freund Adjuvant (CFA) in paraspinal muscles. RESULTS: CFA produced chronic inflammation limited to the injected area. CFA-treated rats showed increased pain-like (liking) behaviors during the formalin test compared with controls. They also showed widespread mechanical hypersensitivity compared with controls, which persisted for 2 months. This widespread hypersensitivity was accompanied by altered activity of different types of right amygdala neurons, as shown by extracellular recordings. Plasmatic levels of IL-1ß, IL-6, and TNF-α were not elevated after 1 or 2 months, indicating that persistent widespread hypersensitivity is not caused by persistent systemic inflammation. However, chemogenetic inhibition of GABAergic neurons in the right amygdala attenuated widespread mechanical hypersensitivity. CONCLUSIONS: These findings indicate that chronic widespread mechanical hypersensitivity in a model of chronic back pain can be attenuated by inhibiting GABAergic neurons of the right amygdala, and that widespread hypersensitivity is not maintained by chronic systemic inflammation. SIGNIFICANCE: The amygdala is a key structure involved in pain perception and modulation. The present results indicate that the GABAergic neurons of its central nucleus are involved in widespread hypersensitivity to noxious stimuli in a rat model of chronic back pain. The inhibition of amygdala GABAergic neurons may be a potential target for future interventions in patients with chronic back pain.

Disruption of working memory and contralateral delay activity by nociceptive stimuli is modulated by task demands.

ABSTRACT: Top-down processes allow the selection and prioritization of information by limiting attentional capture by distractors, and these mechanisms depend on task demands such as working memory (WM) load. However, bottom-up processes give salient stimuli a stronger neuronal representation and provoke attentional capture. The aim of this study was to examine the effect of salient nociceptive stimuli on WM while manipulating task demands. Twenty-one healthy participants performed a change detection task during which they had to determine whether 2 successive visual arrays were different or the same. Task demands were modulated by manipulating the WM load (set size included 2 or 4 objects to recall) and by the correspondence between the 2 successive visual arrays (change vs no change). Innocuous stimuli (control) or nociceptive stimuli (distractors) were delivered during the delay period between the 2 visual arrays. Contralateral delay activity and laser-evoked potentials were recorded to examine neural markers of visual WM and nociceptive processes. Nociceptive stimuli decreased WM performance depending on task demands (all P < 0.05). Moreover, compared with control stimuli, nociceptive stimuli abolished the increase in contralateral delay activity amplitude for set size 4 vs set size 2 (P = 0.04). Consistent with these results, laser-evoked potential amplitude was not decreased when task demands were high (P = 0.5). These findings indicate that WM may shield cognition from nociceptive stimuli, but nociceptive stimuli disrupt WM and alter task performance when cognitive resources become insufficient to process all task-relevant information.