Coordinate-based meta-analysis of experimentally induced and chronic persistent neuropathic pain

Differences in brain activation in experimentally induced and chronic neuropathic pain conditions are useful for understanding central mechanisms leading to chronic neuropathic pain. Many mapping studies investigating both pain conditions are now available, and the latest tools for coordinate-based meta-analysis offer the possibility of random effects statistics. We performed a meta-analysis based on a literature search of published functional magnetic resonance imaging group studies to compare patterns of activity during experimentally induced and chronic neuropathic pain, for the later including four fibromyalgia studies. Stimulus-dependent activation in experimental pain was further divided into "thermal" and "non thermal" stimuli. A conjunction of experimentally induced and chronic neuropathic pain revealed activation of the bilateral secondary somatosensory cortex, right middle cingulate cortex, right inferior parietal lobe, supplementary motor area, right caudal anterior insula, and bilateral thalamus. Primary somatosensory activation was only observed during experimental non-thermal stimulation. Chronic neuropathic pain studies showed increased activation in the left secondary somatosensory cortex, anterior cingulate cortex, and right caudal anterior insula when compared to experimentally induced pain. Activation clusters in the anterior cingulate cortex and caudal anterior insula suggest a strong emotional contribution to the processing of chronic neuropathic pain.     

Activation of central sympathetic networks during innocuous and noxious somatosensory stimulation

Although pain is accompanied by autonomic nervous system responses, the cerebral circuits involved in the autonomic pain dimension remain elusive. Therefore, we used functional magnetic resonance imaging (fMRI) and investigated brain processing associated with cutaneous sympathetic vasoconstrictor reflexes during noxious stimulation. When a classical fMRI analysis based on the applied block design was performed, we were able to detect activations well known to be engaged in the central processing of touch and pain. A parametric fMRI analysis in which cutaneous vasoconstrictor activity was correlated with MRI signals revealed two distinct patterns of brain activity. During (i) noxious stimulation itself, brain activity correlated with sympathetic activity in the anterior insula, ventrolateral prefrontal cortex (VLPFC), anterior cingulate cortex (ACC), and secondary somatosensory cortex (S2). During (ii) baseline, brain activity correlated with sympathetic activity in the VMPFC, dorsolateral prefrontal cortex (DLPFC), OFC, PCC, cuneus, precuneus, occipital areas, and hypothalamus. Conjunction analysis revealed significant similar responses during periods of noxious stimulation and periods of sympathetic activation in the anterior insula, ACC and VLPFC (activation) and VMPFC, OFC, PCC, cuneus and precuneus (deactivation). Therefore, we here describe a cerebral network which may be engaged in the processing of the autonomic subdimension of the human pain experience.     

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.     

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.     

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.     

Neuronal specificity of acupuncture response: a fMRI study with electroacupuncture

Recently, neuronal correlates of acupuncture stimulation in human brain have been investigated by functional neuroimaging. The preliminary findings suggest that acupuncture at analgesic points involves the pain-related neuromatrix and may have acupoint-brain correlation. Although multiple models of control stimulations have been applied to address the specificity of the needling effect clinically, their impacts have not been evaluated by functional neuroimaging. With the advantage of objective parameter setting, electroacupuncture (EA) was used in this study to devise three distinct controls for real EA, i.e., mock EA (no stimulation), minimal EA (superficial and light stimulation), and sham EA (same stimulation as real EA) applied at nonmeridian points. Fifteen healthy volunteers received real EA at analgesic point Gallbladder 34 (Yanglinquan), sham EA, and one of either mock EA or minimal EA over the left leg in counter-balanced orders. Multisubject analysis showed that sham EA and real EA both activated the reported distributed pain neuromatrix. However, real EA elicited significantly higher activation than sham EA over the hypothalamus and primary somatosensory-motor cortex and deactivation over the rostral segment of anterior cingulate cortex. In the comparison of minimal EA versus mock EA, minimal EA elicited significantly higher activation over the medial occipital cortex. Single-subject analysis showed that superior temporal gyrus (encompassing the auditory cortex) and medial occipital cortex (encompassing the visual cortex) frequently respond to minimal EA, sham EA, or real EA. We concluded that the hypothalamus-limbic system was significantly modulated by EA at acupoints rather than at nonmeridian points, while visual and auditory cortical activation was not a specific effect of treatment-relevant acupoints and required further investigation of the underlying neurophysiological mechanisms.     

Disentangling linear and nonlinear brain responses to evoked deep tissue pain

Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional magnetic resonance imaging, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region's functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least 5 different, regionally specific activity profiles in the brain. Linearly increasing (eg, primary somatosensory/motor cortex, insulae) and intensity-independent (eg, secondary somatosensory cortex) activation was noted in traditional pain-processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (eg, posterior cingulate cortex), linearly decreasing (eg, contralateral inferior parietal lobule), and quadratic (U-shaped; eg, medial prefrontal cortex). The latter observation suggests that: (1) different DMN subregions exhibit functional heterogeneity and (2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.     

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).     

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.     

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.     

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

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

Different functions in the cingulate cortex, a meta-analytic connectivity modeling study

The cingulate cortex is a structurally heterogeneous brain region involved in emotional, cognitive and motor tasks. With the aim of identifying which behavioral domains are associated with the activation of the cingulate cortex, we performed a structure based-meta-analysis using the activation likelihood estimation (ALE), which assesses statistical significant convergence of neuroimaging studies using the BrainMap database. To map the meta-analytic coactivation maps of the cingulate cortex (MACM), we subdivided the parenchyma along the rostro-caudal axis in 12 bilateral equispaced ROIs. ROIs were not chosen according to previously suggested subdivisions, as to obtain a completely data-driven result. Studies were included with one or more activation coordinates in at least one of the 12 pre-defined ROIs. The meta-analytic connectivity profile and behavioral domains profiles were identified for each ROI. Cluster analysis was then performed on the MACM and behavioral domains to group together ROIs with similar profiles. The results showed that the cingulate cortex can be divided in three clusters according to the MACM parcellation and in four according to the behavioral domain-based parcellation. In addition, a behavioral-domain based meta-analysis was conducted and the spatial consistency of functional connectivity patterns across different domain-related ALE results was evaluated by computing probabilistic maps. These maps identified some portions of the cingulate cortex as involved in several tasks. Our results showed the existence of a more specific functional characterization of some portions of the cingulate cortex but also a great multifunctionality of others. By analyzing a large number of studies, structure based meta-analysis can greatly contribute to new insights in the functional significance of brain activations and in the role of specific brain areas in behavior.     

正常人体针灸效应功能性磁共振成像的研究

目的评价针刺体表穴位对脑部相应区域的功能性磁共振成像(fMRI)表现。方法17例健康志愿者，在1，5TMRI仪上进行针刺足三里(S36)、阳陵泉(G34)的实时动态fMRI检查，观察并分析针刺效果明显者的脑部功能变化情况，判断针刺效果及其意义。结果17例志愿者中13例检查成功，可见躯体感觉运动区(SMC)、运动前区(PMC)、副运动区(SMA)激活明显，额叶前部、扣带回、尾状核头部、豆状核及丘脑、岛叶、岛盖皮质大多有大面积明显激活，小脑和桥脑也可见有激活，在左侧丘脑、SMA、SMC、PMC激活区附近有信号减低的现象，但激活的像素数不多；信号减低区包括两侧额叶内侧面皮质，双侧扣带回前部皮质，两侧海马区，右侧眶回、基底节、尾状核头部等。结论针刺对脑部相关穴位的治疗效应显著，可产生广泛而复杂的脑功能变化，fMRI可清楚显示针刺效应引起的脑部功能变化，是针刺机制及效应良好且直观的评价途径。     

Acupuncture modulates resting state connectivity in default and sensorimotor brain networks

Previous studies have defined low-frequency, spatially consistent networks in resting fMRI data which may reflect functional connectivity. We sought to explore how a complex somatosensory stimulation, acupuncture, influences intrinsic connectivity in two of these networks: the default mode network (DMN) and sensorimotor network (SMN). We analyzed resting fMRI data taken before and after verum and sham acupuncture. Electrocardiography data were used to infer autonomic modulation through measures of heart rate variability (HRV). Probabilistic independent component analysis was used to separate resting fMRI data into DMN and SMN components. Following verum, but not sham, acupuncture there was increased DMN connectivity with pain (anterior cingulate cortex (ACC), periaqueductal gray), affective (amygdala, ACC), and memory (hippocampal formation, middle temporal gyrus) related brain regions. Furthermore, increased DMN connectivity with the hippocampal formation, a region known to support memory and interconnected with autonomic brain regions, was negatively correlated with acupuncture-induced increase in a sympathetic related HRV metric (LFu), and positively correlated with a parasympathetic related metric (HFu). Following verum, but not sham, acupuncture there was also increased SMN connectivity with pain-related brain regions (ACC, cerebellum). We attribute differences between verum and sham acupuncture to more varied and stronger sensations evoked by verum acupuncture. Our results demonstrate for the first time that acupuncture can enhance the post-stimulation spatial extent of resting brain networks to include anti-nociceptive, memory, and affective brain regions. This modulation and sympathovagal response may relate to acupuncture analgesia and other potential therapeutic effects.     

Hypothalamus and amygdala response to acupuncture stimuli in Carpal Tunnel Syndrome

Brain processing of acupuncture stimuli in chronic neuropathic pain patients may underlie its beneficial effects. We used fMRI to evaluate verum and sham acupuncture stimulation at acupoint LI-4 in Carpal Tunnel Syndrome (CTS) patients and healthy controls (HC). CTS patients were retested after 5 weeks of acupuncture therapy. Thus, we investigated both the short-term brain response to acupuncture stimulation, as well as the influence of longer-term acupuncture therapy effects on this short-term response. CTS patients responded to verum acupuncture with greater activation in the hypothalamus and deactivation in the amygdala as compared to HC, controlling for the non-specific effects of sham acupuncture. A similar difference was found between CTS patients at baseline and after acupuncture therapy. For baseline CTS patients responding to verum acupuncture, functional connectivity was found between the hypothalamus and amygdala – the less deactivation in the amygdala, the greater the activation in the hypothalamus, and vice versa. Furthermore, hypothalamic response correlated positively with the degree of maladaptive cortical plasticity in CTS patients (inter-digit separation distance). This is the first evidence suggesting that chronic pain patients respond to acupuncture differently than HC, through a coordinated limbic network including the hypothalamus and amygdala.     

A pilot study of functional magnetic resonance imaging of the brain during manual and electroacupuncture stimulation of acupuncture point (LI-4 Hegu) in normal subjects reveals differential brain activation between methods

OBJECTIVES: To characterize the brain activation patterns evoked by manual and electroacupuncture on normal human subjects. DESIGN: We used functional magnetic resonance imaging (fMRI) to investigate the brain regions involved in electroacupuncture and manual acupuncture needle stimulation. A block design was adopted for the study. Each functional run consists of 5 minutes, starting with 1-minute baseline and two 1-minute stimulation, the interval between the two stimuli was 1 minute. Four functional runs were performed on each subject, two runs for electroacupuncture and two runs for manual acupuncture. The order of the two modalities was randomized among subjects. During the experiment, acupuncture needle manipulation was performed at Large Intestine 4 (LI4, Hegu) on the left hand. For each subject, before scanning started, the needle was inserted perpendicular to the skin surface to a depth of approximately 1.0 cm. Electroacupuncture stimulation was delivered using a continuous rectangular wave form (pulse width 30 ms) at a frequency of 3 Hz. For manual acupuncture, the needle was rotated manually clockwise and counterclockwise at a rate of about 180 times per minute (3 Hz). SUBJECTS: Eleven right-handed, normal, healthy volunteer adults, 6 male and 5 female, ages 21-64 participated in the experiment. RESULTS: Results showed that electroacupuncture mainly produced fMRI signal increases in precentral gyrus, postcentral gyrus/inferior parietal lobule, and putamen/insula; in contrast, manual needle manipulation produced prominent decreases of fMRI signals in posterior cingulate, superior temporal gyrus, putamen/insula. CONCLUSION: These results indicate that different brain networks are involved during manual and electroacupuncture stimulation. It suggests that different brain mechanisms may be recruited during manual and electroacupuncture.     

Thermal and tactile sensory deficits and allodynia in a nerve-injured patient: a multimodal psychophysical and functional magnetic resonance imaging study

OBJECTIVE: A case study was conducted to examine a patient with chronic neuropathic pain of the right foot following peripheral nerve injury and characterize associated sensory abnormalities. METHODS: Multimodal psychophysical examination of the patient's affected and nonaffected foot included thermal sensibility, dynamic touch, and directional sensibility. In addition, we used functional magnetic resonance imaging to study cortical representation of brush-evoked allodynia. RESULTS: Detailed psychophysical examination revealed substantial deficits in warm, cool, and tactile perception on the injured foot. These findings indicated severe dysfunction of perceptual processes mediated by A beta, A delta, and C fibers. Despite reduced tactile perception, light touch evoked a deep burning pain in the foot. Functional magnetic resonance imaging during brushing of the patient's injured foot showed that tactile allodynia led to activation of several cortical regions including secondary somatosensory cortex, anterior and posterior insular cortex, and anterior cingulate cortex. Brushing of the patient's nonaffected foot led to fewer activated regions. DISCUSSION: The profound sensory disturbances suggest a possible deafferentation type of tactile allodynia mediated by changes within the central nervous system, such as a disruption of normal tactile or thermal inhibition of nociception. The functional magnetic resonance imaging data suggest that tactile allodynia is represented in similar brain regions as experimental pain.     

Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis

Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color-word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analogue scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain-related activation in multiple brain areas, particularly in the so-called 'medial pain system'. Distraction significantly increased the activation of the cingulo-frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo-frontal cortex may exert top-down influences on the PAG and posterior thalamus to gate pain modulation during distraction.     

The single-epoch fMRI design: validation of a simplified paradigm for the collection of subjective ratings

One of the goals of human functional imaging studies is to interpret brain activation in the context of an individual's subjective experience. However, functional magnetic resonance imaging (fMRI) studies usually employ a block design that consists of multiple epochs of stimulation; this strategy does not readily allow subjective responses to be assessed on a stimulus-by-stimulus basis. To address this issue, we developed a "single-epoch" design, consisting of a single stimulation period presented between two baseline periods. This allows subjective ratings to be acquired after each stimulus, while minimizing rating-induced confounds. To evaluate its sensitivity and utility, we obtained fMRI data using single-epoch and block designs (five stimuli between six baselines) and assessed regional brain activations evoked by both visual (a checkerboard pattern) and painful (noxious heat to right calf) stimuli. For both types of stimulation, data collected using the single-epoch design displayed activation patterns that were generally similar to those detected with the block design. Furthermore, only one single-epoch acquisition series was sufficient to detect bilateral activation in the visual cortex during visual stimulation and activation in the primary somatosensory cortex, the anterior cingulate cortex, and other regions during painful stimulation. In addition, analyses of a series of single-epoch data from a single individual revealed a stimulus-by-stimulus decrease in the activation in the anterior cingulate cortex that paralleled the decrease in the subject's psychophysical responses. These findings confirm that the single-epoch design is sensitive to regional signal changes and serves as a viable alternative to the block design when the collection of subjective responses is of critical importance.     

Activation of the cortical pain network by soft tactile stimulation after injection of sumatriptan

The anti-migraine drug sumatriptan often induces unpleasant somatosensory side effects, including a dislike of being touched. With a double-blind cross-over design, we studied the effects of sumatriptan and saline on perception (visual analogue scale) and cortical processing (functional magnetic resonance imaging) of tactile stimulation in healthy subjects. Soft brush stroking on the calf (n=6) was less pleasant (p<0.04) and evoked less activation of posterior insular cortex in the sumatriptan compared to the saline condition. Soft brushing activated pain processing regions (anterior insular, lateral orbitofrontal, and anterior cingulate cortices, and medial thalamus) only in the sumatriptan condition, whereas activation of somatosensory cortices was similar in both conditions. Soft brush stroking on the palm (n=6) was equally pleasant in both conditions. One possible mechanism for the activation of pain processing regions by brush stroking is sensitization of nociceptors by sumatriptan. Another possibility is inhibition of a recently discovered system of low-threshold unmyelinated tactile (CT) afferents that are present in hairy skin only, project to posterior insular cortex, and serve affective aspects of tactile sensation. An inhibition of impulse transmission in the CT system by sumatriptan could disinhibit nociceptive signalling and make light touch less pleasant. This latter alternative is consistent with the observed reduction in posterior insular cortex activation and the selective effects of stimulation on hairy compared to glabrous skin, which are not explained by the nociceptor sensitization account.