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It is well established that early blindness results in brain plasticity and behavioral changes in both humans and animals. However, only a few studies have examined the effects of blindness on pain perception. In these studies, pain hypersensitivity was reported in early, but not late, blind humans. The underlying mechanisms remain unclear, but considering its key role in pain perception and modulation, the amygdala may contribute to this pain hypersensitivity. The first aim of this study was to develop an animal model of early blindness to examine the effects of blindness on pain perception. A mouse cross was therefore developed (ZRDBA mice), in which half of the animals are born sighted and half are born anophthalmic, allowing comparisons between blind and sighted mice with the same genetic background. The second aim of the present study was to examine mechanical and thermal pain thresholds as well as pain behaviors and pain-related c-Fos immunoreactivity induced by the formalin test in the amygdalas of blind and sighted mice. Group differences in amygdala volume were also assessed histologically. Blind mice exhibited lower mechanical and thermal pain thresholds and more pain behaviors during the acute phase of the formalin test, compared with sighted mice. Moreover, pain hypersensitivity during the formalin test was associated with increased c-Fos immunoreactivity in the amygdala. Furthermore, amygdala volume was larger bilaterally in blind compared with sighted mice. These results indicate that congenitally blind mice show pain hypersensitivity like early blind individuals and suggest that this is due in part to plasticity in the amygdala., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aim of the present study was to assess inhibition of pain and somatosensory-evoked potentials (SEPs) by heterotopic noxious counter-stimulation (HNCS) and by selective attention in patients with chronic non-specific LBP. Seventeen patients and age/sex-matched controls were recruited (10 men, 7 women; mean age ± SD: 43.3 ± 10.4 and 42.7 ± 11.1, respectively). On average, patients with LBP reported pain duration of 7.6 ± 6.5 years, light to moderate disability (19.3 ± 5.7/100) and low clinical pain intensity (21.8 ± 1.5/100), while pain catastrophizing, state and trait anxiety and depressive symptoms were not significantly different between groups (all p's >0.05). HNCS and selective attention had differential inhibitory effects on pain and SEP, but no difference was observed between groups. Across both groups, HNCS decreased pain (p = 0.06) as well as the N100 and the N150 components of SEP (p's <0.001), while selective attention only decreased pain (p < 0.01) and the N100 (p<0.001). In contrast, the P260 was decreased by HNCS only when attention was directed toward the HNCS stimulus (p<0.01). This indicates that patients with the characteristics described above do not show altered pain inhibitory mechanisms involved in HNCS and selective attention. Importantly, this experiment was carefully designed to control for non-specific effects associated with the repetition of the test stimulus and the effect of an innocuous counter-stimulation. It remains to be determined if these results hold for patients with severe LBP and psychological symptoms or whether symptom severity may be associated with pain inhibition deficits., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Locomotor networks after spinal cord injury (SCI) are shaped by training-activated proprioceptive and cutaneous inputs. Nociception from injured tissues may alter these changes but has largely been overlooked. The objective of the present study was to ascertain whether lumbar muscle inflammation hinders locomotion recovery in a mouse model of complete SCI. Lower limb kinematics during treadmill training was assessed before and after complete SCI at T8 (2, 7, 14, 21 and 28days post-injury). Locomotor recovery was compared in 4 groups of CD1 mice: control spinal mice; spinal mice with daily locomotor training; spinal mice with lumbar muscle inflammation (Complete Freund's Adjuvant (CFA) injection); and spinal mice with locomotor training and CFA. On day 28, H-reflex excitability and its inhibition at high-frequency stimulation (frequency-dependent depression: FDD) were compared between groups, all of which showed locomotor recovery. Recovery was enhanced by training, whereas lumbar muscle inflammation hindered these effects (knee angular excursion and paw drag: p's<0.05). In addition, lumbar muscle inflammation impaired hind limb coupling during locomotion (p<0.05) throughout recovery. Also, H-reflex disinhibition was prevented by training, with or without CFA injection (p's<0.05). Altogether, these results indicate that back muscle inflammation modulates spinally mediated locomotor recovery in mice with complete SCI, in part, by reducing adaptive changes induced by training., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Functional magnetic resonance imaging (fMRI) is based on neurovascular coupling, which allows inferring neuronal activity from hemodynamic changes. Spinal fMRI has been used to examine pain processes, although spinal neurovascular coupling has never been investigated. In addition, fluctuations in mean arterial pressure (MAP) occur during nociceptive stimulation and this may affect neurovascular coupling. The objective of this study was to examine neurovascular coupling in the rat spinal cord during nociceptive stimulation while MAP was manipulated by cervical spinal transection, which prevents nociception-related MAP increases. Six male Wistar rats were anesthetized with isoflurane (1.2-1.5%). Local field potentials (LFP) and spinal cord blood flow (SCBF) were recorded concurrently in the lumbar enlargement, where activity was evoked by electrical stimulation of the sciatic nerve. In intact conditions, stimulation of graded intensity produced proportional changes in SCBF and LFP that were paralleled by similar changes in MAP. However, spinal transection almost abolished MAP changes (p<0.001), while SCBF and LFP responses were not significantly affected (p>0.3) and remained similarly coupled before and after spinal transection. This indicates that spinal hemodynamic changes reflect neuronal activity even when large fluctuations in MAP occur. This contrasts with results from previous studies on cerebral neurovascular coupling and suggests that spinal autoregulation might allow better adaptation to sudden MAP changes than cerebral autoregulation. Although assessment of the coupling between spinal neuronal activity and BOLD signal remains to be investigated, this study supports the use of spinal fMRI, based on the tight coupling between SCBF and LFP., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p's<0.05) and T10 (p's<0.05), but less so at T10 compared with T2 (p's<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aim of the present study was to determine whether thoracic spinal manipulation (SM) decreases temporal summation of back pain. The study comprised two controlled experiments including 16 and 15 healthy participants, respectively. Each study included six sessions during which painful or non-painful electrical stimulations were delivered in three conditions: (1) control (2) light mechanical stimulus (MS) or (3) SM. Electrical stimulation was applied on the thoracic spine (T4), in the area where SM and MS were performed. In Experiment 1, electrical stimulation consisted in a single 1-ms pulse while a single or repeated train of ten 1-ms pulses was used in Experiment 2. SM involved articular cavitation while MS was a calibrated force of 25N applied manually for 2s. For the single pulse, changes in pain or tactile sensation in the SM or MS sessions compared with the CTL session were not significantly different (all p's>0.05). In contrast, temporal summation of pain was decreased in the SM session compared with the CTL session for both the single and repeated train (p's<0.05). Changes were not significant for the MS sessions (all p's>0.05) and no effect was observed for the tactile sensation (all p's>0.1). These results indicate that SM produces specific inhibitory effects on temporal summation of back pain, consistent with the involvement of a spinal anti-nociceptive mechanism in clinical pain relief by SM. This provides the first mechanistic evidence of back pain relief by spinal manipulation., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Inference on nociceptive and pain-related processes from functional magnetic resonance imaging is made with the assumption that the coupling of neuronal activity and cerebral hemodynamic changes is stable. However, since nociceptive stimulation is associated with increases in systemic arterial pressure, it is essential to determine whether this coupling remains the same during different levels of nociception and pain. The main objective of the present study was to compare the amplitude of local field potentials (LFP) and cerebral blood flow (CBF) changes in the primary somatosensory cortex during nociceptive electrical stimulation of the contralateral or ipsilateral forepaw in isoflurane-anesthetized rats, while manipulating mean arterial pressure (MAP). MAP changes induced by nociceptive stimulation were manipulated by transecting the spinal cord at the upper thoracic segments (T1-T2), which interrupts sympathetic pathways and prevents nociception-related MAP increases, while sensory pathways between the forepaws and the brain remain intact. Intensity-dependent increases in MAP and CBF were observed and these effects were abolished or significantly decreased after spinal transection (p<0.001 and p<0.05, respectively). In contrast, the intensity-dependent changes in LFP amplitude were decreased for the contralateral stimulation but increased for the ipsilateral stimulation after spinal transection (p<0.05). Thus, neurovascular coupling was altered differently by stimulus-induced MAP changes, depending on stimulus intensity and location. This demonstrates that CBF changes evoked by nociceptive processing do not always match neuronal activity, which may lead to inaccurate estimation of neuronal activity from hemodynamic changes. These results have important implications for neuroimaging of nociceptive and pain-related processes., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

It is well established that multisensory integration is a functional characteristic of the superior colliculus that disambiguates external stimuli and therefore reduces the reaction times toward simple audiovisual targets in space. However, in a condition where a complex audiovisual stimulus is used, such as the optical flow in the presence of modulated audio signals, little is known about the processing of the multisensory integration in the superior colliculus. Furthermore, since visual and auditory deficits constitute hallmark signs during aging, we sought to gain some insight on whether audiovisual processes in the superior colliculus are altered with age. Extracellular single-unit recordings were conducted in the superior colliculus of anesthetized Sprague-Dawley adult (10-12 months) and aged (21-22 months) rats. Looming circular concentric sinusoidal (CCS) gratings were presented alone and in the presence of sinusoidally amplitude modulated white noise. In both groups of rats, two different audiovisual response interactions were encountered in the spatial domain: superadditive, and suppressive. In contrast, additive audiovisual interactions were found only in adult rats. Hence, superior colliculus audiovisual interactions were more numerous in adult rats (38%) than in aged rats (8%). These results suggest that intersensory interactions in the superior colliculus play an essential role in space processing toward audiovisual moving objects during self-motion. Moreover, aging has a deleterious effect on complex audiovisual interactions., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

The voluntary control of respiration is used as a common means to regulate pain and emotions and is fundamental to various relaxation and meditation techniques. The aim of the present study was to examine how breathing frequency and phase affect pain perception, spinal nociceptive activity (RIII-reflex) and brain activity (scalp somatosensory-evoked potentials - SEP's). In 20 healthy volunteers, painful electric shocks individually adjusted to 120% of the RIII-reflex threshold were delivered to the sural nerve near the end of inspiration or expiration phases, during three cued-breathing conditions: (1) slow breathing (0.1 Hz) with slow (4s) inspiration (0.1Hz-SlowIns), (2) slow breathing (0.1 Hz) with fast (2s) inspiration (0.1 Hz-FastIns), and (3) normal breathing (0.2 Hz) with fast (2s) inspiration (0.2 Hz). Pain ratings were not affected by breathing patterns (p=0.3), but were significantly lower during inspiration compared with expiration (p=0.02). This phase effect was also observed on the N100 component of SEP's, but only in the 0.1-Hz-FastIns condition (p=0.03). In contrast, RIII-reflex amplitude was greater during inspiration compared with expiration (p=0.02). It was also decreased in the 0.1-Hz-SlowIns compared with the 0.2-Hz condition (p=0.01). Slow breathing also increased the amplitude of respiratory sinus arrhythmia (RSA), although these changes were not significantly associated with changes in pain responses. In conclusion, this study shows that pain and pain-related brain activity may be reduced during inspiration but these changes are dissociated from spinal nociceptive transmission. The small amplitude of these effects suggests that factors other than respiration contribute to the analgesic effects of relaxation and meditation techniques., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The cortical area located in the lateral portion of the posteromedial suprasylvian sulcus (PMLS) is considered a key area for motion processing. It receives major projections from areas 17 and 18 but also from the lateral posterior-pulvinar complex where neurons exhibit, for the most part, complex receptive fields (RF). Based on these inputs, complex-like RFs would be expected for PMLS neurons and results from hand-plot mapping support this idea. However, PMLS neurons' first-order spatiotemporal RF profiles and their role in shaping neuronal response characteristics is currently unknown. In this study, the first-order spatiotemporal characteristics of PMLS cells were revealed using reverse correlation analysis, based on responses elicited by coarse white noise stimuli. Experiments were carried out in adult anesthetized cats. Detailed RF profiles were obtained by analyzing bright and dark subfields separately. Results indicate that the average maximal spike probability is higher for dark subfields than for their paired bright subfields. Spatial RF analysis shows that neurons exhibit oval RF subfields and that their size is larger for dark subfields. The majority of cells have complex-like profiles, with spatially overlapping RF subfields. Temporal analysis showed that for the majority of cells, subfields are coincidentally activated; however, a subset of neurons exhibit time-dissociated subfield peak activity windows. Correlation analysis between spatial and temporal parameters of RF subfields and their neuron's response characteristics to gratings was also performed. The data show that the direction index is positively correlated with subfield size difference and negatively correlated with spatial subfield overlap. Modulation index is negatively correlated with the degree of temporal subfield activity overlap. We conclude that first-order RF structures are important functional factors that shape PMLS neurons response characteristics., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Biofeedback training is an efficient means to gain control over a physiological function typically considered involuntary. Accordingly, learning to self-regulate nociceptive physiological activity may improve pain control by activating endogenous modulatory processes. The aim of the present study was to assess whether trial-by-trial visual feedback of nociceptive flexion reflex (RIII-reflex) responses (an index of spinal nociception) evoked by brief painful shocks applied to the sural nerve could be beneficial to guide participants in adopting strategies aiming at modulating pain perception. In order to determine specific changes induced by biofeedback, the modulation of RIII-reflex amplitude and pain ratings was compared following instructions to increase or decrease RIII-reflex amplitude in three groups, including a biofeedback group receiving a visual signal corresponding to the RIII-reflex amplitude (valid feedback), a sham biofeedback group (similar but invalid feedback), and a control group receiving no feedback. Results indicate that participants in all three groups could gain control over RIII-reflex (p<0.001), resulting in the modulation of pain intensity (p<0.001) and pain unpleasantness (p<0.001). The biofeedback group was not significantly superior to the sham and the control groups in the modulation of RIII-reflex amplitude, pain intensity or unpleasantness. These results are consistent with the notion that RIII-reflex amplitude and pain perception can be modulated voluntarily by various cognitive strategies. However, immediate retrospective visual feedback of acute nociceptive responses presented iteratively in successive trials may not improve the efficacy of these self-regulation processes., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

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.