Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study

Complex Regional Pain Syndromes (CRPS) are characterized by a triad of sensory, motor and autonomic dysfunctions of still unknown origin. Pain and mechanical hyperalgesia are hallmarks of CRPS. There are several lines of evidence that central nervous system (CNS) changes are crucial for the development and maintenance of mechanical hyperalgesia. However, little is known about the cortical structures associated with the processing of hyperalgesia in pain patients. This study describes the use of functional magnetic resonance imaging (fMRI) to delineate brain activations during pin-prick hyperalgesia in CRPS. Twelve patients, in whom previous quantitative sensory testing revealed the presence of hyperalgesia to punctuate mechanical stimuli (i.e. pin-prick hyperalgesia), were included in the study. Pin-prick-hyperalgesia was elicited by von-Frey filaments at the affected limb. For control, the identical stimulation was performed on the unaffected limb. fMRI was used to explore the corresponding cortical activations. Mechanical stimulation at the unaffected limb was non-painful and mainly led to an activation of the contralateral primary somatosensory cortex (S1), insula and bilateral secondary somatosensory cortices (S2). The stimulation of the affected limb was painful (mechanical hyperalgesia) and led to a significantly increased activation of the S1 cortex (contralateral), S2 (bilateral), insula (bilateral), associative-somatosensory cortices (contralateral), frontal cortices and parts of the anterior cingulate cortex. The results of our study indicate a complex cortical network activated during pin-prick hyperalgesia in CRPS. The underlying neuronal matrix comprises areas not only involved in nociceptive, but also in cognitive and motor processing.     

Cortical Reorganization in Primary Somatosensory Cortex in Patients With Unilateral Chronic Pain

Bodily representations of the primary somatosensory (SI) cortex are constantly modified according to sensory input. Increased input due to training as well as loss of input due to deafferentation are reflected as changes in the extent of cortical representations. Recent studies in complex regional pain syndrome (CRPS) patients have indicated that the chronic pain itself is associated with cortical reorganization. However, it is unclear whether the observed reorganization is specific for CRPS or if it can be detected also in other types of chronic pain. We therefore searched for signs of cortical reorganization in a group of 8 patients who suffered from chronic pain associated with herpes simplex virus infections. The pain was widespread but restricted to unilateral side of the body and included the upper limb. We recorded neuromagnetic responses to tactile stimulation of fingers of both hands in patients and in a group of healthy, matched control subjects. In the patients, the distance between the thumb (D1) and little finger (D5) representations in SI cortex was statistically significantly smaller in the hemisphere contralateral to painful side than in the hemisphere contralateral to healthy side. In the control subjects, the D1–D5 distance was the same in both hemispheres.PerspectiveThe present results indicate that cortical reorganization occurs in chronic neuropathic pain patients even without peripheral nerve damage. It is possible that cortical reorganization is related to chronic pain, regardless of its etiology. Causality between reorganization and chronic pain should be examined further to develop therapeutic approaches for chronic pain.     

Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome

In the complex regional pain syndrome (CRPS), several theories proposed the existence of pathophysiological mechanisms of central origin. Recent studies highlighted a smaller representation of the CRPS-affected hand on the primary somatosensory cortex (SI) during non-painful stimulation of the affected side. We addressed the question whether reorganizational changes can also be found in the secondary somatosensory cortex (SII). Moreover, we investigated whether cortical changes might be accompanied by perceptual changes within associated skin territories. Seventeen patients with CRPS of one upper limb without the presence of peripheral nerve injuries (type I) were subjected to functional magnetic resonance imaging (fMRI) during electrical stimulation of both index fingers (IFs) in order to assess hemodynamic signals of the IF representation in SI and SII. As a marker of tactile perception, we tested 2-point discrimination thresholds on the tip of both IFs. Cortical signals within SI and SII were significantly reduced contralateral to the CRPS-affected IF as compared to the ipsilateral side and to the representation of age- and sex-matched healthy controls. In parallel, discrimination thresholds of the CRPS-affected IF were significantly higher, giving rise to an impairment of tactile perception within the corresponding skin territory. Mean sustained, but not current pain levels were correlated with the amount of sensory impairment and the reduction in signal strength. We conclude that patterns of cortical reorganization in SI and SII seem to parallel impaired tactile discrimination. Furthermore, the amount of reorganization and tactile impairment appeared to be linked to characteristics of CRPS pain.     

Temporo-spatial analysis of cortical activation by phasic innocuous and noxious cold stimuli--a magnetoencephalographic study

Clinical findings and recent non-invasive functional imaging studies pinpoint the insular cortex as the crucial brain area involved in cold sensation. By contrast, the role of primary (SI) and secondary (SII) somatosensory cortices in central processing of cold is controversial. So far, temporal activation patterns of cortical areas involved in cold processing have not been examined. Using magnetoencephalography, we studied, in seven healthy subjects, the temporo-spatial dynamics of brain processes evoked by innocuous and noxious cold stimulation as compared to tactile stimuli. For this purpose, a newly designed and magnetically silent cold-stimulator was employed. In separate runs, cold and painful cold stimuli were delivered to the dorsum of the right hand. Tactile afferents were stimulated by pneumatic tactile stimulation.

Following innocuous cold stimulation (ΔT=5±0.3°C in 50±2 ms), magnetic source imaging revealed an exclusive activation of the contra- and ipsilateral posterior insular cortex. The mean peak latencies were 194.3±38.1 and 241.0±31.7 ms for the response in the ipsi- and contralateral insular cortex, respectively. Based on the measurement of onset latencies, the estimated conduction velocity of peripheral nerve fibres mediating cold fell in the range of Aδ-fibres (7.4±0.8 m/s).

Noxious cold stimulation (ΔT=35±5°C in 70±12 ms) initially activated the contra- and ipsilateral insular cortices in the same latency ranges as innocuous cold stimuli. Additionally, we found an activation of the contra- and ipsilateral SII areas (peak latencies 304±22.7 and 310.1±19.4 ms, respectively) and a variable activation of the cingulate cortex. Notably, neither cold- nor painful cold stimulation produced an activation of SI. By contrast, the evoked cortical responses following tactile stimulation could be located to the contralateral SI cortex and bilateral SII.

In conclusion, this study strongly corroborates the posterior insular cortex as the primary somatosensory area for cortical processing of cold sensation. Furthermore, it supports the role of SII and the cingulate cortex in mediating freeze-pain. Therefore, these results suggest different processing of cold, freeze-pain and touch in the human brain.     

Altered Neurocognitive Processing of Tactile Stimuli in Patients with Complex Regional Pain Syndrome

Chronic pain in complex regional pain syndrome (CRPS) has been linked to tactile misperceptions and deficits in somatotopic representation of the affected limb. In this study, we identify altered cognitive processing of tactile stimuli in CRPS patients that we propose marks heterogeneity in tactile decision-making mechanisms. In a case-control design, we compared middle- and late-latency somatosensory evoked potentials in response to pseudorandomized mechanical stimulation of the digits of both hands (including CRPS-affected and nonaffected sides) between 13 CRPS patients and 13 matched healthy controls. During a task to discriminate the digit simulated, patients (compared with controls) had significantly lower accuracy and slowed response times but with high between-subject variability. At middle latencies (124–132?ms), tactile processing in patients relative to controls showed decrements in superior parietal lobe and precuneus (that were independent of task demands) but enhanced activity in superior frontal lobe (that were task-dependent). At late latencies, patients showed an augmented P300-like response under task demands that localized to the supplementary motor area. Source activity in the supplementary motor area correlated with slowed response times, although its scalp representation intriguingly correlated with better functioning of the affected limb, suggesting a compensatory mechanism. Future research should investigate the clinical utility of these putative markers of tactile decision-making mechanisms in CRPS.

Evidence for cortical hyperexcitability of the affected limb representation area in CRPS: a psychophysical and transcranial magnetic stimulation study

Functional alterations in noxious, sensory and motor circuits within the central nervous system may play an important role in the pathophysiology of complex regional pain syndrome (CRPS). The aim of the present study was to search for further evidence of hyperexcitability in the hemisphere contralateral to the affected limb in patients with CRPS by employing both psychophysical and transcranial magnetic stimulation (TMS) methods. Twelve patients with CRPS type I, confined to the distal part of a limb (six in an upper-limb and six in a lower-limb), were enrolled in the study. The quantitative thermal, mechanical and 'wind-up' like pain testing was performed at the most painful site in the affected limb and in the ipsilateral limb. Results were then compared to those found at mirror sites in the contralateral limbs. TMS was used to assess the inter-hemispheric difference in parameters of corticospinal excitability, intracortical inhibition, and intracortical facilitation. The quantitative thermal and mechanical testing showed significant differences in cold, heat and mechanical pain thresholds, as well as in the first and last 'wind-up' stimuli between the affected and the contralateral limbs of the CRPS patients. No significant differences between the ipsilateral unaffected limbs and their contralateral pair limbs were found. A significant reduction in the short intracortical inhibition associated with a significant increase of the I-wave facilitation was found in the hemisphere contralateral to the affected side in the upper-limb CRPS group. No significant inter-hemispheric asymmetry between the affected and the non-affected sides was revealed in the lower-limb CRPS group. Taken together, these results suggest that in patients with well-localized CRPS, there is evidence for sensory and motor CNS hyperexcitability, though it seems to involve only corresponding regions within the CNS rather than the entire hemisphere.     

Complex Regional Pain Syndrome Is Associated With Structural Abnormalities in Pain-Related Regions of the Human Brain

Complex regional pain syndrome (CRPS) is a chronic condition that involves significant hyperalgesia of the affected limb, typically accompanied by localized autonomic abnormalities and frequently by motor dysfunction. Although central brain systems are thought to play a role in the development and maintenance of CRPS, these systems have not been well characterized. In this study, we used structural magnetic resonance imaging to characterize differences in gray matter volume between patients with right upper extremity CRPS and matched controls. Analyses were carried out using a whole brain voxel-based morphometry approach. The CRPS group showed decreased gray matter volume in several pain-affect regions, including the dorsal insula, left orbitofrontal cortex, and several aspects of the cingulate cortex. Greater gray matter volume in CRPS patients was seen in the bilateral dorsal putamen and right hypothalamus. Correlation analyses with self-reported pain were then performed on the CRPS group. Pain duration was associated with decreased gray matter in the left dorsolateral prefrontal cortex. Pain intensity was positively correlated with volume in the left posterior hippocampus and left amygdala, and negatively correlated with the bilateral dorsolateral prefrontal cortex. Our findings demonstrate that CRPS is associated with abnormal brain system morphology, particularly pain-related sensory, affect, motor, and autonomic systems.PerspectiveThis paper presents structural changes in the brains of patients with CRPS, helping us differentiate CRPS from other chronic pain syndromes and furthering our understanding of this challenging disease.     

Pupillary Reflexes in Complex Regional Pain Syndrome: Asymmetry to Arousal Stimuli Suggests an Ipsilateral Locus Coeruleus Deficit

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain.PerspectiveThe locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.     

Oral structure representation in human somatosensory cortex

To clarify the topography of the areas representing whole intraoral structures and elucidate bilateral neuronal projection to those areas in the primary somatosensory (S1) cortex, we recorded somatosensory-evoked magnetic fields (SEFs), which reflect the earliest cortical responses to pure tactile stimulation, using magnetoencephalography and a piezo-driven tactile stimulation device. Subjects consisted of 10 healthy male adults. Following tactile stimulation of 6 sites on the oral mucosa (inferior/superior buccal mucosa, posterior/anterior tongue mucosa, and upper/lower lip mucosa), SEFs with a peak latency of 15 ms (1M) were identified bilaterally. In contrast, SEFs with a peak latency of 30 ms following right index finger tactile stimulation were identified only in the contralateral hemisphere. Equivalent current dipoles (ECDs) generating 15 ms components were found along the posterior wall of the central sulcus, bilaterally. The ECD locations for oral mucosa-representing areas were located inferiorly to those for the index finger, with the following pattern of organization from top to bottom along the central sulcus: index finger, upper or lower lip, anterior or posterior tongue and superior or inferior buccal mucosa, with a wide distribution, covering 30% of the S1 cortex. Source strength for 1M in the ipsilateral hemisphere was weaker than that in the contralateral hemisphere. These results clearly indicate that sensory afferents innervating the intraoral region project to both the contralateral and ipsilateral 3b areas via the trigeminothalamic tract, where contralateral projection is predominant. The results clarify the intraoral structure-representing areas in the S1 cortex, adding those areas to the classical "sensory homunculus".     

Touch or pain? Spatio-temporal patterns of cortical fMRI activity following brief mechanical stimuli

Most imaging studies on the human pain system have concentrated so far on the spatial distribution of pain-related activity. In the present study, we investigated similarities and differences between the spatial and temporal patterns of brain activity related to touch vs. pain perception. To this end, we adopted an event-related functional magnetic resonance imaging (fMRI) paradigm allowing us to separately assess the activity related to stimulus anticipation, perception, and coding. The fMRI signal increases following brief mechanical noxious or non-noxious stimulation of the hand dorsum were largely overlapping in the contralateral and ipsilateral hemispheres, including portions of the parietal, insular, frontal and cingulate cortices. Higher activity following noxious stimulation was found in the contralateral mid-anterior insular cortex, in the anterior mid-cingulate cortex (aMCC) and in the adjacent dorso-medial frontal cortex. Significant decreases in fMRI signals following both tactile and painful stimuli were found in perigenual cingulate (pACC)/medial prefrontal cortex (MPF) and in the posterior cingulate/precuneus/paracentral lobule; more intense decreases were found in the pACC/MPF following painful stimuli. fMRI signal increases in the contralateral insula and in aMCC, but not in the parietal cortex, were more prolonged following painful than tactile stimuli. Moreover, a second peak of signal increases (albeit of lower intensity) was found in anterior insula and aMCC during pain intensity rating. These results show specific spatio-temporal patterns of cortical activity related to processing noxious vs. non-noxious mechanical stimuli.     

Abnormal Brain Responses to Action Observation in Complex Regional Pain Syndrome

Patients with complex regional pain syndrome (CRPS) display various abnormalities in central motor function, and their pain is intensified when they perform or just observe motor actions. In this study, we examined the abnormalities of brain responses to action observation in CRPS. We analyzed 3-T functional magnetic resonance images from 13 upper limb CRPS patients (all female, ages 31–58 years) and 13 healthy, age- and sex-matched control subjects. The functional magnetic resonance imaging data were acquired while the subjects viewed brief videos of hand actions shown in the first-person perspective. A pattern-classification analysis was applied to characterize brain areas where the activation pattern differed between CRPS patients and healthy subjects. Brain areas with statistically significant group differences (q < .05, false discovery rate-corrected) included the hand representation area in the sensorimotor cortex, inferior frontal gyrus, secondary somatosensory cortex, inferior parietal lobule, orbitofrontal cortex, and thalamus. Our findings indicate that CRPS impairs action observation by affecting brain areas related to pain processing and motor control.

Cortical Alpha Rhythms Are Related to the Anticipation of Sensorimotor Interaction Between Painful Stimuli and Movements: A High-Resolution EEG Study

We tested whether cortical activation anticipating painful stimuli is reduced more by integrative processes on somatosensory painful and motor information relative to the same hand than when that information refers to different hands. In 3 conditions, visual warning stimuli were followed by visual target stimuli associated with an electrical painful stimulation at left index finger. In the Pain (control) condition, no task was required after the target stimuli. In the “Pain + ipsilateral movement” condition, the subjects had to perform a movement of the left index finger. In the “Pain + contralateral movement” condition, they had to perform a movement of the right index finger. Meanwhile, electroencephalographic data were recorded (n = 18) from 128 scalp electrodes. Off line, these data were spatially enhanced by surface Laplacian transformation. Sensorimotor cortical activation before the painful stimulation was probed by the percentage power reduction of alpha rhythms at approximately 8 to 12 Hz (event-related desynchronization, ERD). Results showed that the subjects perceived a lower stimulus intensity in both “Pain + ipsilateral” and “Pain + contralateral” conditions compared with the control “Pain” condition. Furthermore, wide anticipatory alpha ERD (approximately 10–12 Hz) was lower in amplitude in the “Pain + ipsilateral” than in the “Pain + contralateral” condition. These results suggest that modulation of alpha rhythms is a putative physiological mechanism underlying anticipatory processes preceding the integration of painful and motor information at cortical level. Furthermore, these processes show a marked interference (“gating”) when the sensorimotor integration refer to the same hand as opposed to both hands.PerspectiveWe showed that cortical alpha rhythms preceding painful stimulation are influenced by the preparation of contralateral and ipsilateral finger movements. These results motivate further investigation for testing the hypothesis that chronic pain patients might exaggerate the anticipatory activation of sensorimotor cortex to negligible pain stimuli.     

Illusion of pain: pre-existing knowledge determines brain activation of 'imagined allodynia'.

Allodynia means that innocuous tactile stimulation is felt as pain. Accordingly, cerebral activations during allodynia or touch should markedly differ. The aim of this study was to investigate whether the imagination of allodynia affects brain processing of touch in healthy subjects. Seventeen healthy subjects divided into 2 subgroups were investigated: The first group (n = 7) was familiar with allodynia, based on previous pain studies, whereas the second group (n = 10) had never knowingly experienced allodynia. Using functional magnetic resonance imaging, 2 experimental conditions were investigated. In one condition the subjects were simply touched at their left hand, whereas during the other condition they were asked to imagine pain (allodynia) during tactile stimulation of the right hand and to estimate the imagined pain on a numeric rating scale. Data processing and analysis were performed with the use of SPM5. The group analysis of all subjects revealed that tactile stimulation activated contralateral somatosensory cortices (S1 [primary] and S2 [secondary]), but the imagination of allodynia led to an additional activation of anterior cingulate cortex and bilateral activation of S2, insular cortex, and prefrontal cortices. Subgroup analysis using rating-weighted predictors revealed activation of the contralateral thalamus, anterior cingulate cortex, and amygdala and a bilateral activation of S1, S2, and insular cortex and prefrontal cortices in allodynia-experienced subjects. In contrast, allodynia-inexperienced subjects only activated contralateral S1 and bilateral S2. Just the imagination that touch is painful is able to partly activate the central pain system, but only when the subject has previous experience of this. According to our results, the medial pain system is involved in the encoding of imagined allodynia. PERSPECTIVE: This article reports that pain experience is able to alter central processing of sensory stimuli. Pain knowledge appears to be able to shift "normal" tactile processing to a different quality, resulting in modified brain activity. Therefore, our study may contribute to the current understanding of human pain and will promote future research on this field.     

Evoked magnetic fields following noxious laser stimulation of the thigh in humans

Primary somatosensory cortex (SI) and posterior parietal cortex (PPC) are activated by noxious stimulation. In neurophysiological studies using magnetoencephalography (MEG), however, it has been difficult to separate the activity in SI from that in PPC following stimulation of the upper limb, since the hand area of SI is very close to PPC. Therefore, we investigated human pain processing using MEG following the application of a thulium-YAG laser to the left thigh to separate the activation of SI and PPC, and to clarify the time course of the activities involved. The results indicated that cortical activities were recorded around SI, contralateral secondary somatosensory cortex (cSII), ipsilateral secondary somatosensory cortex (iSII), and PPC between 150-185 ms. The precise location of PPC was indicated to be the inferior parietal lobule (IPL), corresponding to Brodmann's area 40. The mean peak latencies of SI, cSII, iSII and IPL were 152, 170, 181, and 183 ms, respectively. This is the first study to clarify the time course of the activities of SI, SII, and PPC in human pain processing using MEG.     

Alteration in the response properties of primary somatosensory cortex related to differential aversive Pavlovian conditioning

The effects of differential aversive Pavlovian conditioning on the functional organization of primary somatosensory cortex (SI) were examined in 17 healthy participants. Neuroelectric source imaging from 60 electrodes was employed while nine subjects received an innocuous electric stimulus (conditioned stimulus, CS) to one finger (left or right) that was followed by painful electric shock to the lower back (unconditioned stimulus, US) and an innocuous stimulus to the other finger that was never followed by pain. Eight subjects received a presentation of the innocuous and painful stimuli with equal probability to both fingers (control group). The data included the electromyogram (EMG) from the left m. corrugator, and judgments of intensity, aversiveness, and CS-US contingency. Only the experimental group displayed EMG conditioning, differential contingency judgments, as well as a change of dipole orientation for the CS and an enhanced dipole moment for the US in the electroencephalogram. Intensity and unpleasantness ratings were altered in a more unspecific manner and did not differ between groups and stimulus conditions. The data suggest that SI contributes to memory processes in associative learning. Pavlovian conditioning of tactile responses might be important in the altered processing of painful stimuli in chronic pain patients where enhanced conditioning has been demonstrated.     

Die Gummihandillusion bei CRPS-Patienten

Next to neurogenic inflammation and pathological sympathetic-afferent coupling, functional imaging studies have shown the crucial role of maladaptive cortical reorgansation in the pathophysiology of CRPS. Bilateral neuroplastic alterations in the somatosensory cortex seem to play a substantial role in the dysfunctional sensory processing of stimuli. The aim was to investigate the multimodal integration of sensory and visual stimuli into the body scheme and the influence of higher cognitive body representation in the integration of multimodal schema, body relevant stimuli in patients with CRPS. The investigated sample included 24 patients suffering from CRPS of the upper extremities, 21 patients with chronic hand pain of other origins and 24 healthy probands. The rubber hand illusion was carried out for the first time in patients with complex regional pain syndrome (CRPS). The reprentations show that the patients can integrate a rubber hand in their body representation to the same degree as healthy patients. The intact experience of the rubber hand illusion by CRPS patients indicates that the integration of congruent visual and tactile stimuli in CRPS is intact.     

Temporomandibular Disorder Modifies Cortical Response to Tactile Stimulation

Individuals with temporomandibular disorder (TMD) suffer from persistent facial pain and exhibit abnormal sensitivity to tactile stimulation. To better understand the pathophysiological mechanisms underlying TMD, we investigated cortical correlates of this abnormal sensitivity to touch. Using functional magnetic resonance imaging (fMRI), we recorded cortical responses evoked by low-frequency vibration of the index finger in subjects with TMD and in healthy controls (HC). Distinct subregions of contralateral primary somatosensory cortex (SI), secondary somatosensory cortex (SII), and insular cortex responded maximally for each group. Although the stimulus was inaudible, primary auditory cortex was activated in TMDs. TMDs also showed greater activation bilaterally in anterior cingulate cortex and contralaterally in the amygdala. Differences between TMDs and HCs in responses evoked by innocuous vibrotactile stimulation within SI, SII, and the insula paralleled previously reported differences in responses evoked by noxious and innocuous stimulation, respectively, in healthy individuals. This unexpected result may reflect a disruption of the normal balance between central resources dedicated to processing innocuous and noxious input, manifesting itself as increased readiness of the pain matrix for activation by even innocuous input. Activation of the amygdala in our TMD group could reflect the establishment of aversive associations with tactile stimulation due to the persistence of pain.     

Somatotopic organization of human somatosensory cortices for pain: a single trial fMRI study

The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. To investigate the somatotopic organization of the nociceptive system, we applied Thulium-YAG-laser evoked pain stimuli, which have no concomitant tactile component, to the dorsum of the left hand and foot in randomized order. We used single-trial functional magnetic resonance imaging (fMRI) to assess differential hemodynamic responses to hand and foot stimulation for the group and in a single subject approach. The primary somatosensory cortex (SI) shows a clear somatotopic organization ipsi- and contralaterally to painful stimulation. Furthermore, a differential representation of hand and foot stimulation appeared within the contralateral opercular--insular region of the secondary somatosensory cortex (SII). This result provides evidence that both SI and SII encode spatial information of nociceptive stimuli without additional information from the tactile system and highlights the concept of a redundant representation of basic discriminative stimulus features in human somatosensory cortices, which seems adequate in view of the evolutionary importance of pain perception.     

Enhanced pain and autonomic responses to ambiguous visual stimuli in chronic Complex Regional Pain Syndrome (CRPS) type I

Cortical reorganisation of sensory, motor and autonomic systems can lead to dysfunctional central integrative control. This may contribute to signs and symptoms of Complex Regional Pain Syndrome (CRPS), including pain. It has been hypothesised that central neuroplastic changes may cause afferent sensory feedback conflicts and produce pain. We investigated autonomic responses produced by ambiguous visual stimuli (AVS) in CRPS, and their relationship to pain. Thirty CRPS patients with upper limb involvement and 30 age and sex matched healthy controls had sympathetic autonomic function assessed using laser Doppler flowmetry of the finger pulp at baseline and while viewing a control figure or AVS. Compared to controls, there were diminished vasoconstrictor responses and a significant difference in the ratio of response between affected and unaffected limbs (symmetry ratio) to a deep breath and viewing AVS. While viewing visual stimuli, 33.5% of patients had asymmetric vasomotor responses and all healthy controls had a homologous symmetric pattern of response. Nineteen (61%) CRPS patients had enhanced pain within seconds of viewing the AVS. All the asymmetric vasomotor responses were in this group, and were not predictable from baseline autonomic function. Ten patients had accompanying dystonic reactions in their affected limb: 50% were in the asymmetric sub‐group. In conclusion, there is a group of CRPS patients that demonstrate abnormal pain networks interacting with central somatomotor and autonomic integrational pathways.     

Area-specific representation of mechanical nociceptive stimuli within SI cortex of squirrel monkeys

While functional imaging studies in humans have consistently reported activation of primary somatosensory cortex (SI) with painful stimuli, the specific roles of subdivisions of areas 3a, 3b, and 1 within SI during pain perception are largely unknown, particularly in the representation of mechanical evoked pain. In this study, we investigated how modality, location, and intensity of nociceptive stimuli are represented within SI by using high-spatial resolution optical imaging of intrinsic signals in Pentothal-anesthetized squirrel monkeys. Perceptually comparable mechanical nociceptive and innocuous tactile stimuli were delivered by indenting the glabrous skin of the distal finger pads with 0.2 and 2 mm diameter probes, respectively. Within each of areas 3a, 3b, and 1, activations to mechanical nociceptive stimulation of individual distal finger pads were spatially distinct and somatotopically organized. We observed differential cortical activation patterns. Areas 3a, 3b, and 1 were all activated during mechanical nociceptive stimulation and were modulated by nociceptive stimulus intensity. However, with innocuous tactile stimulation, mainly areas 3b and 1 exhibited response modulation with different levels of stimulation. In summary, mechanical nociceptive inputs are area-specific and topographically represented within SI. We propose that all areas of SI are implicated in encoding the features of mechanical nociception, where areas 3a and 3b are distinctively involved in coding nociceptive and pressure sensation components of stimulation.