Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study.

OBJECTIVE: To investigate, using functional MRI (fMRI), the neural network that is activated by the pain component of capsaicin-induced secondary mechanical hyperalgesia. BACKGROUND: Mechanical hyperalgesia (i.e., pain to innocuous tactile stimuli) is a distressing symptom of neuropathic pain syndromes. Animal experiments suggest that alterations in central pain processing occur that render tactile stimuli capable of activating central pain-signaling neurons. A similar central sensitization can be produced experimentally with capsaicin. METHODS: In nine healthy individuals the cerebral activation pattern resulting from cutaneous nonpainful mechanical stimulation at the dominant forearm was imaged using fMRI. Capsaicin was injected adjacent to the stimulation site to induce secondary mechanical hyperalgesia. The identical mechanical stimulation was then perceived as painful without changing the stimulus intensity and location. Both activation patterns were compared to isolate the specific pain-related component of mechanical hyperalgesia from the tactile component. RESULTS: The pattern during nonpainful mechanical stimulation included contralateral primary sensory cortex (SI) and bilateral secondary sensory cortex (SII) activity. During hyperalgesia, significantly higher activation was found in the contralateral prefrontal cortex: the middle (Brodmann areas [BAs] 6, 8, and 9) and inferior frontal gyrus (BAs 44 and 45). No change was present within SI, SII, and the anterior cingulate cortex. CONCLUSIONS: Prefrontal activation is interpreted as a consequence of attention, cognitive evaluation, and planning of motor behavior in response to pain. The lack of activation of the anterior cingulate contrasts with physiologic pain after C-nociceptor stimulation. It might indicate differences in the processing of hyperalgesia and C-nociceptor pain or it might be due to habituation of affective sensations during hyperalgesia compared with acute capsaicin pain.     

脑卒中后中枢性疼痛

脑卒中后中枢性疼痛（CPSP）是脑卒中后与病灶有关的、在瘫痪躯体的一部分、持续或间断的及同时伴有感觉异常为主要特点的疼痛。由于临床医生对CPSP重视不足,导致患者长期处于疼痛状态,影响日常生活质量。为更好了解CPSP,本文就其流行病学、病理生理、临床特点及药物治疗做一综述。     

Dynamic EEG‐informed fMRI modeling of the pain matrix using 20‐ms root mean square segments

Previous studies on the spatio‐temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid‐cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain‐induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole‐brain coverage. In this study, we thought to investigate the spatio‐temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference‐free measure of event‐related EEG activity) in a time window 0–400 ms poststimulus were used to model trial‐to‐trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG‐derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG‐time windows suggests largely parallel signal processing in the bilateral operculo‐insular and mid‐cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Grey matter changes of the pain matrix in patients with burning mouth syndrome

Burning mouth syndrome (BMS) is characterized by a burning sensation in the mouth, usually in the absence of clinical and laboratory findings. Latest findings indicate that BMS could result from neuropathic trigeminal conditions. While many investigations have focused on the periphery, very few have examined possible central dysfunctions. To highlight changes of the central system of subjects with BMS, we analysed the grey matter concentration in 12 subjects using voxel‐based morphometry. Data were compared with a control group (Ct). To better understand the brain mechanisms underlying BMS, the grey matter concentration of patients was also compared with those of dysgeusic patients (Dys). Dysgeusia is another oral dysfunction condition, characterized by a distorted sense of taste and accompanied by a reduced taste function. We found that a major part of the ‘pain matrix’ presented modifications of the grey matter concentration in subjects with BMS. Six regions out of eight were affected [anterior and posterior cingulate gyrus, lobules of the cerebellum, insula/frontal operculum, inferior temporal area, primary motor cortex, dorsolateral pre‐frontal cortex (DLPFC)]. In the anterior cingulate gyrus, the lobules of the cerebellum, the inferior temporal lobe and the DLPFC, pain intensity correlated with grey matter concentration. Dys also presented changes in grey matter concentration but in different areas of the brain. Our results suggest that a deficiency in the control of pain could in part be a cause of BMS and that BMS and dysgeusia conditions are not linked to similar structural changes in the brain.     

Magnetoencephalographic study of event‐related fields and cortical oscillatory changes during cutaneous warmth processing

Thermoreception is an important cutaneous sense, which plays a role in the maintenance of our body temperature and in the detection of potential noxious heat stimulation. In this study, we investigated event‐related fields (ERFs) and neural oscillatory activities, which were modulated by warmth stimulation. We developed a warmth stimulator that could elicit a warmth sensation, without pain or tactile sensation, by using a deep‐penetrating 980‐nm diode laser. The index finger of each participant (n = 24) was irradiated with the laser warmth stimulus, and the cortical responses were measured using magnetoencephalography (MEG). The ERFs and oscillatory responses had late latencies (～1.3 s and 1.0–1.5 s for ERFs and oscillatory responses, respectively), which could be explained by a slow conduction velocity of warmth‐specific C‐fibers. Cortical sources of warmth‐related ERFs were seen in the bilateral primary and secondary somatosensory cortices (SI and SII), posterior part of the anterior cingulate cortex (pACC), ipsilateral primary motor, and premotor cortex. Thus, we suggested that SI, SII, and pACC play a role in processing the warmth sensation. Time–frequency analysis demonstrated the suppression of the alpha (8–13 Hz) and beta (18–23 Hz) band power in the bilateral sensorimotor cortex. We proposed that the suppressions in alpha and beta band power are involved in the automatic response to the input of warmth stimulation and sensorimotor interactions. The delta band power (1–4 Hz) increased in the frontal, temporal, and cingulate cortices. The power changes in delta band might be related with the attentional processes during the warmth stimulation.     

Migraine,allodynia, and implications for treatment

Allodynia – perception of pain from non‐noxious stimuli – is a common clinical feature in various pain syndromes. The significance for migraine has increasingly been recognized and the pathophysiology has been investigated in detail. Allodynia is a marker for sensitization of central trigeminal neurons. Intensity and persistence of allodynic symptoms are a function of duration of migraine attacks, frequency of attacks, and migraine history. It has been hypothesized that treatment success with triptans may be severely impaired in the presence of allodynia. However, randomized controlled trials did not confirm that. Treatment with cyclooxygenase inhibitors and dihydroergotamine does not seem to be limited by allodynia; these medications may be able to reverse allodynia. Data on the new class of calcitonin‐gene related‐peptide antagonists are not yet available. Additional and more refined randomized controlled trials, focusing on methodological issues pertaining to the determination of allodynia, are warranted to resolve the true relationship between allodynia and treatment response. Regardless – based on available randomized controlled trials – the recommendation prevails to initiate abortive treatment as soon as possible after attack onset when pain is still mild.     

Spinal p38 mitogen-activated protein kinase mediates allodynia induced by first-degree burn in the rat

Activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord has been implicated in the development and maintenance of pain states. In this study, we tested whether p38 MAPK is involved in the response to first-degree burn of the hind paw. This injury induces central sensitization leading to tactile allodynia and is mediated by activation of Ca(2+) permeable AMPA/kainate receptors through PKC and PKA. We demonstrate that p38 MAPK is rapidly and robustly activated in the superficial spinal dorsal horn after mild thermal injury to the hind paw. Activated p38 MAPK was localized primarily to microglia and to a lesser extent in oligodendrocytes and lamina II neurons. Astrocytes were not involved in the p38 MAPK response. Intrathecal pretreatment of pharmacological inhibitors of p38 MAPK (SB203580, SD-282) dose-dependently blocked development of tactile allodynia, a characteristic of the first-degree burn model. The effects of the inhibitors on tactile allodynia were lost when they were administered after injury. These studies identify p38 MAPK as a major mediator of tactile allodynia, most likely activated downstream of AMPA/kainate receptors.     

中枢性疼痛的神经外科治疗

目的 研究中枢性疼痛的神经外科治疗策略.方法 根据疼痛性质和部位的不同,行立体定向中脑毁损术1例、双侧扣带回前部毁损术2例、中脑加双侧扣带回联合毁损术9例、运动皮层电刺激术(MCS) 11例、脊髓电刺激术(SCS)3例和脊髓后根入髓区(DREZ)切开术79例次.结果 术后患者疼痛均不同程度减轻,1个月以内镇痛疗效满意,VAS评分较术前均显著降低(P＜0.01).随访12 -36个月,观察术后6个月以上的长期疗效,发现中脑加双侧扣带回联合毁损术好于单纯中脑或扣带回前部毁损术的效果;MCS和SCS治疗的多数患者疗效有波动;DREZ切开术的长期疗效满意,82.1％的臂丛神经撕脱后疼痛患者能够保持50％以上疼痛缓解率,88.9％的脊髓损伤后疼痛患者止痛疗效长期稳定.结论 神经外科止痛手术能够确实有效地治疗中枢性疼痛,脊髓损伤、脊神经根撕脱等脊髓水平的中枢性疼痛应该首选DREZ切开术治疗,对于脑梗死、脑出血等原因造成的中枢性疼痛,MCS是一种可供选择的治疗手段.     

Visceromotor roots of aesthetic evaluation of pain in art: an fMRI study

Empathy for pain involves sensory and visceromotor brain regions relevant also in the first-person pain experience. Focusing on brain activations associated with vicarious experiences of pain triggered by artistic or non-artistic images, the present study aims to investigate common and distinct brain activation patterns associated with these two vicarious experiences of pain and to assess whether empathy for pain brain regions contributes to the formation of an aesthetic judgement (AJ) in non-art expert observers. Artistic and non-artistic facial expressions (painful and neutral) were shown to participants inside the scanner and then aesthetically rated in a subsequent behavioural session. Results showed that empathy for pain brain regions (i.e. bilateral insular cortex, posterior sector of the anterior cingulate cortex and the anterior portion of the middle cingulate cortex) and bilateral inferior frontal gyrus are commonly activated by artistic and non-artistic painful facial expressions. For the artistic representation of pain, the activity recorded in these regions directly correlated with participants’ AJ. Results also showed the distinct activation of a large cluster located in the posterior cingulate cortex/precuneus for non-artistic stimuli. This study suggests that non-beauty-specific mechanisms such as empathy for pain are crucial components of the aesthetic experience of artworks.     

Cortical processing of brush-evoked allodynia

The cortical processing of allodynia (touch-evoked pain) resulting from neuralgia of the lateral cutaneous femoral nerve was investigated with a newly designed pneumatically driven brush by means of magnetoencephalography. Brushing the unaffected thigh produced subsequent activation of the contralateral primary somatosensory cortex (S1) with peak latencies of 37 and 56 ms. Brushing the affected side led to comparable activation of the contralateral S1 cortex. In addition, the magnetic fields were stronger, and the corresponding equivalent current dipoles were located more laterally, consistent with the presence of cortical reorganisation. Allodynia was also accompanied by an activation of the cingulate cortex, occurring only 92 ms. after stimulus onset, an observation suggesting an Abeta-fiber-mediated neuronal pathway involved in dynamic mechanical allodynia. This study corroborates the concept of cortical reorganisation underlying chronic pain. Furthermore, it demonstrates that a remarkable early activation of the cingulate cortex may be involved in the cortical processing of allodynia.     

fMRI and MEG analysis of visceral pain in healthy volunteers

Background Although many studies of painful rectal stimulation have found activation in the insula, cingulate, somatosensory, prefrontal cortices and thalamus, there is considerable variability when comparing functional magnetic resonance imaging (fMRI) results. Multiple factors may be responsible, including the model used in fMRI data analysis. Here, we assess the temporal response of activity to rectal barostat distension using novel fMRI and magnetoencephalography (MEG) analysis. Methods Liminal and painful rectal barostat balloon inflation thresholds were assessed in 14 female healthy volunteers. Subliminal, liminal and painful 40s periods of distension were applied in a pseudo‐randomized paradigm during fMRI and MEG neuroimaging. Functional MRI data analysis was performed comparing standard box‐car models of the full 40s of stimulus (Block) with models of the inflation (Ramp‐On) and deflation (Ramp‐Off) of the barostat. Similar models were used in MEG analysis of oscillatory activity. Key Results Modeling the data using a standard Block analysis failed to detect areas of interest found to be active using Ramp‐On and Ramp‐Off models. Ramp‐On generated activity in anterior insula and cingulate regions and other pain‐matrix associated areas. Ramp‐Off demonstrated activity of a network of posterior insula, SII and posterior cingulate. Active areas were consistent with those identified from MEG data. Conclusions & Inferences In studies of visceral pain, fMRI model design strongly influences the detected activity and must be accounted for to effectively explore the fMRI data in healthy subjects and within patient groups. In particular a strong cortical response is detected to inflation and deflation of the barostat, rather than to its absolute volume.     

Real time fMRI feedback of the anterior cingulate and posterior insular cortex in the processing of pain

Self‐regulation of brain activation using real‐time functional magnetic resonance imaging has been used to train subjects to modulate activation in various brain areas and has been associated with behavioral changes such as altered pain perception. The aim of this study was to assess the comparability of upregulation versus downregulation of activation in the rostral anterior cingulate cortex (rACC) and left posterior insula (pInsL) and its effect on pain intensity and unpleasantness. In a first study, we trained 10 healthy subjects to separately upregulate and downregulate the blood oxygenation level‐dependent response in the rACC or pInsL (six trials on 4 days) in response to painful electrical stimulation. The participants learned to significantly downregulate activation in pInsL and rACC and upregulate pInsL but not rACC. Success in the modulation of one region and direction of the modulation was not significantly correlated with success in another condition, indicating that the ability to control pain‐related brain activation is site‐specific. Less covariation between the areas in response to the nociceptive stimulus was positively correlated with learning success. Upregulation or downregulation of either region was unrelated to pain intensity or unpleasantness; however, our subjects did not learn rACC upregulation, which might be important for pain control. A significant increase in pain unpleasantness was found during upregulation of pInsL when covariation with the rACC was low. These initial results suggest that the state of the network involved in the processing of pain needs to be considered in the modulation of pain‐evoked activation and its behavioral effects. Hum Brain Mapp 35:5784–5798, 2014. © 2014 Wiley Periodicals, Inc.     

Neural activation during experimental allodynia: a functional magnetic resonance imaging study

Abstract Pain induced by gentle stroking, i.e. dynamic-mechanical allodynia, is one of the most distressing symptoms of neuropathic pain. The underlying neuronal pathways are still a matter of debate. Here, we investigated the cortical activations associated with dynamic-mechanical allodynia in an experimental human pain model by functional magnetic resonance imaging (fMRI). Large and stable areas of brush-evoked allodynia were induced in 11 healthy subjects by topical capsaicin (2.5%, 30 min) application following local heating (45 degrees C for 5 min), thus combining both physical and chemical sensitization. During the fMRI experiments, allodynia was rekindled by local heat application (40 degrees C for 5 min) immediately before the allodynia testing. Brushing the untreated forearm (control condition) led to activations of the contralateral primary somatosensory cortex (S1), contralateral parietal association cortex (PA), bilateral secondary somatosensory cortices (S2) and insula (contralateral). Brushing the allodynic skin was painful and the cortical responses were partially overlapping with those induced by the nonpainful brush stimulation. Additionally, the contralateral inferior frontal cortex (IFC) and the ipsilateral insula were activated. Direct comparison between nonpainful brushing and brush-evoked allodynia revealed significant increases in blood oxygenation level-dependent (BOLD) signals in contralateral S1, PA, IFC and bilateral S2/insula during allodynia. This study highlights the importance of a cortical network comprising S1, PA, S2/insula and IFC in the processing of dynamic-mechanical allodynia in the human brain. Furthermore, it demonstrates that the combined heat/capsaicin model can be used successfully in the exploration of brain processes underlying stimulus-evoked pain.     

Pain-related somatosensory evoked magnetic fields induced by controlled ballistic mechanical impacts.

The purpose of this study was to investigate cortical processing of painful compared with tactile mechanical stimulation by means of magnetoencephalography (MEG) using the novel technique of mechanical impact loading. A light, hard projectile is accelerated pneumatically in a guiding barrel and elicits a brief sensation of pain when hitting the skin in free flight. Controllable noxious and innocuous impact velocities facilitate the generation of different, predetermined stimulus intensities. The authors applied painful as well as tactile mechanical impacts to the dorsum of the second, third, and fourth digit of the nondominant hand. Pain-related somatosensory evoked magnetic fields (SSEFs) were compared with those following tactile stimulation in seven healthy volunteers. Contralateral primary sensory cortical area activation was observed within the first 70 msec after tactile as well as painful stimulus intensities. Only painful impacts elicited SSEF responses assigned to the bilateral secondary sensory cortical regions and to the middle part of the contralateral cingulate gyrus, which were active at latency ranges of 55 to 155 msec and 90 to 220 msec respectively. Additional long-latency responses occurred in these cortical areas as long as 280 msec after painful stimulation in three subjects. In contrast to tactile stimulation, painful mechanical impacts elicited SSEF responses in cortical areas demonstrated to be involved in central pain processing by previous MEG and neuroimaging studies. Because of its similarity to natural noxious stimuli and the possibility of adjustable painful and tactile impact velocities, the technique of mechanical impact loading provides a useful method for the neurophysiologic evaluation of cortical pain perception.     

Strength of prefrontal activation predicts intensity of suggestion‐induced pain

Suggestion, a powerful factor in everyday social interaction, is most effective during hypnosis. Subjective evaluations and brain‐imaging findings converge to propose that hypnotic suggestion strongly modulates sensory processing. To reveal the brain regions that mediate such a modulation, we analyzed data from a functional‐magnetic‐resonance‐imaging study on hypnotic‐suggestion‐induced pain on 14 suggestible subjects. Activation strengths in the right dorsolateral prefrontal cortex (DLPFC) during initiation of suggestion for pain correlated positively with the subjective intensity of the subsequent suggestion‐induced pain, as well as with the strengths of the maximum pain‐related activation in the in the secondary somatosensory (SII) cortex. Furthermore, activation of the insula and the anterior cingulate cortex predicted the pain‐related SII activation. The right DLPFC, as an area important for executive functions, likely contributes to functional modulation in the modality‐specific target areas of given suggestions. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Distinct and shared cerebral activations in processing innocuous versus noxious contact heat revealed by functional magnetic resonance imaging

Whether innocuous heat (IH)‐exclusive brain regions exist and whether patterns of cerebral responses to IH and noxious heat (NH) stimulations are similar remain elusive. We hypothesized that distinct and shared cerebral networks were evoked by each type of stimulus. Twelve normal subjects participated in a functional MRI study with rapidly ramped IH (38°C) and NH (44°C) applied to the foot. Group activation maps demonstrated three patterns of cerebral activation: (1) IH‐responsive only in the inferior parietal lobule (IPL); (2) NH‐responsive only in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), posterior insular cortex (IC), and premotor area (PMA); and (3) both IH‐ and NH‐responsive in the middle frontal gyrus, inferior frontal gyrus (IFG), anterior IC, cerebellum, superior frontal gyrus, supplementary motor area, thalamus, anterior cingulate cortex (ACC), lentiform nucleus (LN), and midbrain. According to the temporal analysis of regions of interest, the IPL exclusively responded to IH, and the S2, posterior IC, and PMA were exclusively activated by NH throughout the entire period of stimulation. The IFG, thalamus, ACC, and LN responded differently during different phases of IH versus NH stimulation, and the NH‐responsive‐only S1 responded transiently during the early phase of IH stimulation. BOLD signals in bilateral IPLs were specifically correlated with the ratings of IH sensation, while responses in the contralateral S1 and S2 were correlated with pain intensity. These results suggest that distinct and shared spatial and temporal patterns of cerebral networks are responsible for the perception of IH and NH. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Phantom limb pain in the human brain: unraveling neural circuitries of phantom limb sensations using positron emission tomography

Pain and other phantom limb (PL) sensations have been proposed to be generated in the brain and to be reflected in activation of specific neural circuits. To test this hypothesis, hypnosis was used as a cognitive tool to alternate between the sensation of PL movement and pain in 8 amputees. Brain activity was measured using positron emission tomography. PL movement and pain were represented by a propagation of neuronal activity within the corresponding sensorimotor and pain-processing networks. The sensation of movement was significantly (corrected for multiple comparisons) related to activity in the supplementary motor area and the primary sensorimotor cortex. The sensation of a painful PL posture activated the same brain areas but was weaker and less extended in the supplementary motor area. In contrast to the sensation of movement, pain was significantly related to activity in the thalamus, anterior cingulate, and lateral prefrontal cortex. Subjectively rated PL pain sensation correlated positively to activations in the anterior and posterior cingulate. These findings provide evidence that PL sensations are produced by the same central nervous processes that underlie the experience of the body when it is intact and that the corporeal awareness of PL pain is encoded in a thalamocortical network.     

fMRI evidence of degeneration‐induced neuropathic pain in diabetes: Enhanced limbic and striatal activations

Persistent neuropathic pain due to peripheral nerve degeneration in diabetes is a stressful symptom; however, the underlying neural substrates remain elusive. This study attempted to explore neuroanatomical substrates of thermal hyperalgesia and burning pain in a diabetic cohort due to pathologically proven cutaneous nerve degeneration (the painful group). By applying noxious 44°C heat stimuli to the right foot to provoke neuropathic pain symptoms, brain activation patterns were compared with those of healthy control subjects and patients with a similar degree of cutaneous nerve degeneration but without pain (the painless group). Psychophysical results showed enhanced affective pain ratings in the painful group. After eliminating the influence of different pain intensity ratings on cerebral responses, the painful group displayed augmented responses in the limbic and striatal structures, including the perigenual anterior cingulate cortex (ACC), superior frontal gyrus, medial thalamus, anterior insular cortex, lentiform nucleus (LN), and premotor area. Among these regions, blood oxygen level‐dependent (BOLD) signals in the ACC and LN were correlated with pain ratings to thermal stimulations in the painful group. Furthermore, activation maps of a simple regression analysis as well as a region of interest analysis revealed that responses in these limbic and striatal circuits paralleled the duration of neuropathic pain. However, in the painless group, BOLD signals in the primary somatosensory cortex and ACC were reduced. These results suggest that enhanced limbic and striatal activations underlie maladaptive responses after cutaneous nerve degeneration, which contributed to the development and maintenance of burning pain and thermal hyperalgesia in diabetes. Hum Brain Mapp 34:2733–2746, 2013. © 2012 Wiley Periodicals, Inc.     

Role of medial cortical networks for anticipatory processing in obsessive-compulsive disorder

Recurrent anticipation of ominous events is central to obsessions, the core symptom of obsessive-compulsive disorder (OCD), yet the neural basis of intrinsic anticipatory processing in OCD is unknown. We studied nonmedicated adults with OCD and case matched healthy controls in a visual-spatial working memory task with distractor. Magnetoencephalography was used to examine the medial cortex activity during anticipation of to-be-inhibited distractors and to-be-facilitated retrieval stimuli. In OCD anticipatory activation to distractors was abnormally reduced within the posterior cingulate and fusiform gyrus compared to prominent activation in controls. Conversely, OCD subjects displayed significantly increased activation to retrieval stimuli within the anterior cingulate and supplementary motor cortex. This previously unreported discordant pattern of medial anticipatory activation in OCD was accompanied by normal performance accuracy. While increased anterior cortex activation in OCD is commonly viewed as failure of inhibition, the current pattern of data implicates the operation of an anterior compensatory mechanism amending the posterior medial self-regulatory networks disrupted in OCD.