Altered C-tactile processing in human dynamic tactile allodynia

Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.     

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.     

Central pain in a hemispherectomized patient.

We have examined a hemispherectomized patient who complained of touch-evoked pricking and burning pain in her paretic hand, especially when the hand was cold. Psychophysical examination showed that for the paretic side she confused cool and warm temperatures, and confirmed that she had a robust allodynia to brush stroking that was enhanced at a cold ambient temperature. Functional magnetic resonance imaging (fMRI) showed that during brush-evoked allodynia, brain structures implicated in normal pain processing (viz. posterior part of the anterior cingulate cortex, secondary somatosensory cortex, and prefrontal cortices) were activated. The fMRI findings thus indicate that the central pain in this patient was served by brain structures implicated in normal pain processing. Possible pathophysiological mechanisms include plasticity as well as thalamic disinhibition.     

Cortical processing of noxious somatosensory stimuli in the persistent vegetative state

The persistent vegetative state (PVS) is a devastating medical condition characterized by preserved wakefulness contrasting with absent voluntary interaction with the environment. We used positron emission tomography to assess the central processing of noxious somatosensory stimuli in the PVS. Changes in regional cerebral blood flow were measured during high-intensity electrical stimulation of the median nerve compared with rest in 15 nonsedated patients and in 15 healthy controls. Evoked potentials were recorded simultaneously. The stimuli were experienced as highly unpleasant to painful in controls. Brain glucose metabolism was also studied with [(18)F]fluorodeoxyglucose in resting conditions. In PVS patients, overall cerebral metabolism was 40% of normal values. Nevertheless, noxious somatosensory stimulation-activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. Secondary somatosensory, bilateral insular, posterior parietal, and anterior cingulate cortices did not show activation in any patient. Moreover, in PVS patients, the activated primary somatosensory cortex was functionally disconnected from secondary somatosensory, bilateral posterior parietal, premotor, polysensory superior temporal, and prefrontal cortices. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices.     

A PET activation study of brush-evoked allodynia in patients with nerve injury pain

Acute experimental brush-evoked allodynia induces a cortical activation pattern that differs from that typically seen during experimental nociceptive pain. In this study, we used positron emission tomography to measure changes in regional cerebral blood flow (rCBF) in patients with clinical allodynia. Nine patients with peripheral nerve injury were scanned during rest, brush-evoked allodynia, and brushing of normal contralateral skin. PET data were analyzed for the whole group and for single subjects. Allodynic stimulation activated the contralateral orbitofrontal cortex (BA 11) in every patient. Whereas normal brushing activated most strongly the contralateral insular cortex, allodynic brushing produced an ipsilateral activation in this area. Another important difference between normal and allodynic brushing was the absence of a contralateral primary somatosensory cortex (SI) activation during allodynic brushing. No thalamic activation was observed during allodynic or control brushing. Although no anterior cingulate cortex (ACC) activation could be demonstrated in the group analysis, single subject analysis revealed that four patients activated this region during brush-evoked allodynia. A direct post hoc comparison of brush -and allodynia-induced rCBF changes showed that allodynia was associated with significantly stronger activations in orbitofrontal cortex and ipsilateral insula whereas non-painful brushing more strongly activated SI and BA 5/7. These findings indicate that activity in the cortical network involved in the sensory-discriminative processing of nociceptive pain is downregulated in neuropathic pain. Instead, there is an upregulation of activity in the orbitofrontal and insular cortices, which is probably due to the stronger emotional load of neuropathic pain and higher computational demands of processing a mixed sensation of brush and pain.     

Differential fMRI activation to noxious heat and tactile stimuli in parasylvian areas of new world monkeys

Emerging evidence supports an important role of posterior parasylvian areas in both pain and touch processing. Whether there are separate or shared networks for these sensations remains controversial. The present study compared spatial patterns of brain activation in response to unilateral nociceptive heat (47.5°C) or innocuous tactile stimulation (8-Hz vibration) to digits through high-resolution functional magnetic resonance imaging (fMRI) in squirrel monkeys. In addition, the temporal profile of heat-stimulus-evoked fMRI Blood Oxygenation Level Dependent (BOLD) signal changes was characterized. By examining high-resolution fMRI and histological measures at both the individual and the group levels, we found that both nociceptive heat and tactile stimuli elicited activation in bilateral secondary somatosensory and ventral parietal areas (S2/PV) and in ipsilateral ventral somatosensory areas (VS) and retroinsula (Ri). Bilateral posterior insular cortex (pIns) and area 7b responded preferentially to nociceptive heat stimulation. Single voxels within each activation cluster showed robust BOLD signal changes during each block of nociceptive stimulation. Across animals (n = 11), nociceptive response magnitudes of contralateral VS and pIns and ipsilateral Ri were significantly greater than corresponding areas in the opposite hemisphere. In sum, both distinct and shared areas in regions surrounding the posterior sylvian fissure were activated in response to nociceptive and tactile inputs in nonhuman primates.     

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.     

Gastric fundic distension activates fronto-limbic structures but not primary somatosensory cortex: a functional magnetic resonance imaging study

INTRODUCTION: The brain representation of visceral stimulation bears important similarities to that of somatic stimulation. However, the role of the primary (S1) and secondary (S2) somatosensory cortices in mediating gastric sensation is uncertain. MATERIALS AND METHODS: Eighteen healthy, right-handed volunteers (age 32 years+/-6.5 years; 14 men) underwent dynamic assessment of the relationship between sensation and fundic barostat distending pressure and volume, and then brain functional magnetic resonance imaging (fMRI) during noxious fundic distension. Cytoarchitectonic probability maps were used to examine in detail the null hypothesis that fundic distension did not produce significant activation of S1 or S2. RESULTS: Distending volume explained 74% of the variance in gastric sensation, compared to 64% with distending pressure. Incorporating distending volume into the regressor function for our fMRI analyses, we found that noxious fundic distension activated a widespread network of brain regions, including the pontine brainstem, thalami, cerebellum, insular cortex bilaterally, anterior and posterior cingulate cortex, right frontal lobe, and inferior parietal lobules. In detailed analyses, we found no evidence of activation of S1, but did find activation in one region of S2. DISCUSSION: Our findings suggest that an extensive, predominantly fronto-limbic network of brain regions, including the insular cortex, mediates perception of noxious gastric fundic distension in healthy humans, without significant participation by the primary somatosensory cortex. This and other recent studies lay the groundwork for investigations comparing brain processing of visceral stimuli between healthy volunteers and patients with functional dyspepsia.     

Acute opioid effects on human brain as revealed by functional magnetic resonance imaging

Functional magnetic resonance imaging has been widely used to study brain activation induced either by specific sensory stimulation or motor or cognitive task performance. We demonstrate that functional magnetic resonance imaging can provide information of brain regions involved in opioid-induced central nervous system effects. The reproducibility of the responses in the predefined regions of interest was confirmed by repeated boluses of ultra-short acting mu-opioid receptor agonist remifentanil and saline. We report spatially and temporally detailed information after remifentanil administration. Areas rich in mu-opioid receptors showed strong activations, whereas primary somatosensory cortex that has the lowest density of mu-opioid receptors showed negligible activation. The cingulate, orbitofrontal, posterior parietal and insular cortices, and amygdala showed activation, which was temporally closely related to most subjective sensations that were strongest at 80 to 90 s after drug administration. These areas belong to a circuitry that modulates the affective experience of sensory stimuli.     

Diffuse optical tomography of pain and tactile stimulation: activation in cortical sensory and emotional systems

Using diffuse optical tomography (DOT), we detected activation in the somatosensory cortex and frontal brain areas following tactile (brush) and noxious heat stimulation. Healthy volunteers received stimulation to the dorsum of the right hand. In the somatosensory cortex area, tactile stimulation produced a robust, contralateral to the stimulus, hemodynamic response with a weaker activation on the ipsilateral side. For the same region, noxious thermal stimuli produced bilateral activation of similar intensity that had a prolonged activation with a double peak similar to results that have been reported with functional MRI. Bilateral activation was observed in the frontal areas, oxyhemoglobin changes were positive for brush stimulation while they were initially negative (contralateral) for heat stimulation. These results suggest that based on the temporal and spatial characteristics of the response in the sensory cortex, it is possible to discern painful from mechanical stimulation using DOT. Such ability might have potential applications in a clinical setting in which pain needs to be assessed objectively (e.g., analgesic efficacy, pain responses during surgery).     

Altered central sensorimotor processing in patients with complex regional pain syndrome

Alterations in tactile sensitivity are common in patients with chronic pain. Recent brain imaging studies have indicated that brain areas activated by acute experimental pain partly overlap with areas processing innocuous tactile stimuli. However, the possible effect of chronic pain on central tactile processing has remained unclear. We have examined, both clinically and with whole-head magnetoencephalography, six patients suffering from complex regional pain syndrome (CRPS) of the upper limb. The cortical somatosensory responses were elicited by tactile stimuli applied to the fingertips and the reactivity of spontaneous brain oscillations was monitored as well. Tactile stimulation of the index finger elicited an initial activation at 65 ms in the contralateral SI cortex, followed by activation of the ipsi- and contralateral SII cortices at about 130 ms. The SI responses were 25-55% stronger to stimulation of the painful than the healthy side. The distance between SI representations of thumb and little finger was significantly shorter in the hemisphere contralateral than ipsilateral to the painful upper limb. In addition, reactivity of the 20-Hz motor cortex rhythm to tactile stimuli was altered in the CRPS patients, suggesting modified inhibition of the motor cortex. These results imply that chronic pain may alter central tactile and motor processing.     

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.     

Critical period for cross-modal plasticity in blind humans: a functional MRI study

The primary visual cortex (V1) in congenitally blind humans has been shown to be involved in tactile discrimination tasks, indicating that there is a shift in function of this area of cortex, but the age dependency of the reorganization is not fully known. To investigate the reorganized network, we measured the change of regional cerebral blood flow using 3.0 Tesla functional MRI during passive tactile tasks performed by 15 blind and 8 sighted subjects. There was increased activity in the postcentral gyrus to posterior parietal cortex and decreased activity in the secondary somatosensory area in blind compared with sighted subjects during a tactile discrimination task. This suggests that there is a greater demand for shape discrimination processing in blind subjects. Blind subjects, irrespective of the age at onset of blindness, exhibited higher activity in the visual association cortex than did sighted subjects. V1 was activated in blind subjects who lost their sight before 16 years of age, whereas it was suppressed in blind subjects who lost their sight after 16 years of age during a tactile discrimination task. This suggests that the first 16 years of life represent a critical period for a functional shift of V1 from processing visual stimuli to processing tactile stimuli. Because of the age-dependency, V1 is unlikely to be the "entry node" of the cortex for the redirection of tactile signals into visual cortices after blinding. Instead, the visual association cortex may mediate the circuitry by which V1 is activated during tactile stimulation.     

Differential opioid action on sensory and affective cerebral pain processing

Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly reduce the affective but not the sensory intensive dimension of pain. This suggests differential dose-response relationships of opioid analgesia on the sensory and affective components of pain. We investigated the effects of different alfentanil plasma concentration levels (0, 19.6+/-2.7, 47.2+/-7.6, and 76.6+/-11.3 ng/ml) on pain-related brain activation achieved by short pulses of gaseous CO(2) delivered to the nasal mucosa, using functional magnetic resonance imaging (fMRI) on a 3.0 T MRI scanner in 16 non-carriers and 9 homozygous carriers of the mu-opioid receptor gene variant OPRM1 118A>G. Increasing opioid concentrations had differential effects in brain regions processing the sensory and affective dimensions of pain. In brain regions associated with the processing of the sensory intensity of pain (primary and secondary somatosensory cortices, posterior insular cortex), activation decreased linearly in relation to alfentanil concentrations, which was significantly less pronounced in OPRM1 118G carriers. In contrast, in brain regions known to process the affective dimension of pain (parahippocampal gyrus, amygdala, anterior insula), pain-related activation disappeared at the lowest alfentanil dose, without genotype differences.     

Gender Difference in Premotor Activity during Active Tactile Discrimination

To investigate possible gender differences in tactile discrimination tasks, we measured cerebral blood flow of seven men and seven women using positron emission tomography and ¹⁵O water during tactile tasks performed with the right index finger. A nondiscrimination, somatosensory control task activated the left primary sensorimotor cortex and the left parietal operculum extending to the posterior insula without any gender difference. Compared with the control task, discrimination tasks activated the superior and inferior parietal lobules bilaterally, right dorsal premotor cortex, and dorsolateral prefrontal cortex in both genders, consistent with the notion of right hemisphere involvement during exploratory attentional movements. In both genders, symmetric activation of the superior and inferior parietal lobules and asymmetric activation of the right dorsolateral prefrontal cortex were confirmed. The former is consistent with the spatial representation of the tactile input and the latter with the spatial working memory. However, activation of the dorsal premotor cortex was asymmetric in men, whereas it was symmetric in women, the gender difference being statistically significant. This may suggest gender differences in motor programs for exploration in manipulospatial tasks such as tactile discrimination with active touch, possibly by greater interhemispheric interaction through the dorsal premotor cortices in women than in men.     

Cortical processing of mechanical hyperalgesia: A MEG study

Mechanical hyperalgesia may develop following tissue inflammation or nerve injury. Basically, peripheral sensitization leads to primary hyperalgesia at the site of injury, whereas secondary hyperalgesia occurs in the surrounding tissue and results from central sensitization. The present study focuses on the cerebral processing of secondary mechanical hyperalgesia. Primary (S1) and secondary (S2) somatosensory cortices and posterior parietal cortex (PPC) are thought to be involved in cerebral processing of noxious mechanical stimuli. However, their response pattern in the presence of mechanical hyperalgesia remains to be elucidated. Therefore, we investigated the cortical processing of secondary mechanical hyperalgesia using magnetoencephalography (MEG). In 12 healthy subjects mechanoinsensitive c‐nociceptors were repetitively stimulated using transcutaneously applied high‐current electrical stimulation. This procedure resulted in stable areas of secondary mechanical hyperalgesia. Pin‐prick stimuli were applied inside and outside the hyperalgesic area. The corresponding cortical activations were detected and quantified using MEG. We found pin‐prick‐induced sequential activation of contralateral S1, PPC and S2 as well as activation of ipsilateral S2 during both pin‐prick hyperalgesia and normal pin‐prick pain. During pin‐prick hyperalgesia significantly higher activation was detected in contralateral PPC and bilateral S2 but not in S1 compared to normal pin‐prick pain. In contrast to PPC, we found a significant correlation between increases of magnetic field strengths within bilateral S2 with the increase of pain ratings during pin‐prick hyperalgesia. We conclude that the S2 cortex may be involved for the processing of secondary mechanical hyperalgesia in the human brain. PPC activation may reflect higher attentional processing during mechanical hyperalgesia.     

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.     

fMRI reflects functional connectivity of human somatosensory cortex

Unilateral sensory stimulation reliably elicits contralateral somatotopic activation of primary (SI) and secondary (SII) somatosensory cortex. There is an ongoing debate about the occurrence and nature of concomitant ipsilateral SI and SII activation. Here we used functional magnetic resonance imaging (fMRI) in healthy human subjects with unilateral tactile stimulation of fingers and lips, to compare somatosensory activation patterns from distal and proximal body parts. We hypothesized that fMRI in humans should reflect the functional connectivity of somatosensory cortex as predicted by animal studies. We show that both unilateral finger and lip stimulations activate contra- and ipsilateral SI and SII cortices with high detection frequency. Correlations of BOLD-signals to the applied hemodynamic reference function were significantly higher in contralateral as compared to ipsilateral SI and SII cortices for both finger and lip stimulation, reflecting strong contribution of contralateral thalamocortical input. Furthermore, BOLD-signal correlations were higher in SI than in SII activations on the contralateral but not on the ipsilateral side. While these asymmetries within and across hemispheres were consistent for finger and lip stimulations, indicating analogous underlying organizing principles, they were less prominent for lip stimulation. Somatotopic organization was detected in SI but not in SII representations of fingers and lips. These results qualitatively and quantitatively support the prevalent concepts of anatomical and functional connectivity in the somatosensory system and therefore may allow interpretation of sensory evoked fMRI signals in terms of normal human brain function. Thus, the assessment of human somatosensory function with fMRI may permit in the future investigations of pathological conditions.     

Differential coding of hyperalgesia in the human brain: a functional MRI study

Neuropathic pain can be both ongoing or stimulus-induced. Stimulus-induced pain, also known as hyperalgesia, can be differentiated into primary and secondary hyperalgesia. The former results from sensitization of peripheral nociceptive structures, the latter involves sensitization processes within the central nervous system (CNS). Hypersensitivity towards heat stimuli, i.e. thermal hyperalgesia, is a key feature of primary hyperalgesia, whereas secondary hyperalgesia is characterized by hypersensitivity towards mechanical (e.g. pin-prick) stimulation. Using functional magnetic resonance imaging (fMRI), we investigated if brain activation patterns associated with primary and secondary hyperalgesia might differ. Thermal and pin-prick hyperalgesia were induced on the left forearm in 12 healthy subjects by topical capsaicin (2.5%, 30 min) application. Equal pain intensities of both hyperalgesia types were applied during fMRI experiments, based on previous quantitative sensory testing. Simultaneously, subjects had to rate the unpleasantness of stimulus-related pain. Pin-prick hyperalgesia (i.e. subtraction of brain activations during pin-prick stimulation before and after capsaicin exposure) led to activations of primary and secondary somatosensory cortices (S1 and S2), associative-somatosensory cortices, insula and superior and inferior frontal cortices (SFC, IFC). Brain areas activated during thermal hyperalgesia (i.e. subtraction of brain activations during thermal stimulation before and after capsaicin exposure) were S1 and S2, insula, associative-somatosensory cortices, cingulate cortex (GC), SFC, middle frontal cortex (MFC) and IFC. When compared to pin-prick hyperalgesia, thermal hyperalgesia led to an increased activation of bilateral anterior insular cortices, MFC, GC (Brodmann area 24' and 32') and contralateral SFC and IFC, despite equal pain intensities. Interestingly, stronger activations of GC, contralateral MFC and anterior insula significantly correlated to higher ratings of the stimulus-related unpleasantness. We conclude that thermal and mechanical hyperalgesia produce substantially different brain activation patterns. This is linked to different psychophysical properties.     

Trigeminal activation using chemical, electrical, and mechanical stimuli

Tactile, proprioceptive, and nociceptive information, including also chemosensory functions are expressed in the trigeminal nerve sensory response. To study differences in the processing of different stimulus qualities, we performed a study based on functional magnetic resonance imaging. The first trigeminal branch (ophthalmic nerve) was activated by (a) intranasal chemical stimulation with gaseous CO2 which produces stinging and burning sensations, but is virtually odorless, (b) painful, but not nociceptive specific cutaneous electrical stimulation, and (c) cutaneous mechanical stimulation using air puffs. Eighteen healthy subjects participated (eight men, 10 women, mean age 31 years). Painful stimuli produced patterns of activation similar to what has been reported for other noxious stimuli, namely activation in the primary and secondary somatosensory cortices, anterior cingulate cortex, insular cortex, and thalamus. In addition, analyses indicated intensity-related activation in the prefrontal cortex which was specifically involved in the evaluation of stimulus intensity. Importantly, the results also indicated similarities between activation patterns after intranasal chemosensory trigeminal stimulation and patterns usually found following intranasal odorous stimulation, indicating the intimate connection between these two systems in the processing of sensory information.