Neurophysiology and functional neuroanatomy of pain perception.

The traditional view that the cerebral cortex is not involved in pain processing has been abandoned during the past decades based on anatomic and physiologic investigations in animals, and lesion, functional neuroimaging, and neurophysiologic studies in humans. These studies have revealed an extensive central network associated with nociception that consistently includes the thalamus, the primary (SI) and secondary (SII) somatosensory cortices, the insula, and the anterior cingulate cortex (ACC). Anatomic and electrophysiologic data show that these cortical regions receive direct nociceptive thalamic input. From the results of human studies there is growing evidence that these different cortical structures contribute to different dimensions of pain experience. The SI cortex appears to be mainly involved in sensory-discriminative aspects of pain. The SII cortex seems to have an important role in recognition, learning, and memory of painful events. The insula has been proposed to be involved in autonomic reactions to noxious stimuli and in affective aspects of pain-related learning and memory. The ACC is closely related to pain unpleasantness and may subserve the integration of general affect, cognition, and response selection. The authors review the evidence on which the proposed relationship between cortical areas, pain-related neural activations, and components of pain perception is based.     

Brain generators of laser-evoked potentials: from dipoles to functional significance

In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior-posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a "lumped" activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.     

Corticofugal influences on thalamic neurons during nociceptive transmission in awake rats

Pain is a multidimensional phenomenon and processed in a neural network. The supraspinal, brain mechanisms are increasingly recognized in playing a major role in the representation and modulation of pain. The aim of the current study is to investigate the functional interactions between cortex and thalamus during nociceptive processing, by observing the pain-related information flow and neuronal correlations within thalamo-cortical pathways. Pain-evoked, single-neuron activity was recorded in awake Sprague-Dawley rats with a Magnet system. Eight-wire microarrays were implanted into four different brain regions, i.e., the primary somatosensory (SI) and anterior cingulate cortex (ACC), as well as ventral posterior (VP) and medial dorsal thalamus (MD). Noxious radiant heat was delivered to the rat hind paws on the side contralateral to the recording regions. A large number of responsive neurons were recorded in the four brain areas. Directed coherence analysis revealed that the amount of information flow was significantly increased from SI cortex to VP thalamus following noxious stimuli, suggesting that SI cortex has descending influence on thalamic neurons during pain processing. Moreover, more correlated neuronal activities indicated by crosscorrelation histograms were found between cortical and thalamic neurons, with cortical neurons firing ahead of thalamic units. On basis of the above findings, we propose that nociceptive responses are modulated by corticothalamic feedback during nociceptive transmission, which may be tight in the lateral pathway, while loose in the medial pathway.     

Fluvoxamine modulates pain sensation and affective processing of pain in human brain

To better understand the antinociceptive effect of fluvoxamine, we measured regional cerebral blood flow during laser-evoked pain and hot sensations using H(2)15O positron emission tomography and also subjective pain and hot sensations before and after fluvoxamine or placebo administration for 7 days to 12 healthy volunteers. The subjectively rated pain score was significantly reduced by fluvoxamine administration. Painful stimuli activated multiple brain regions. After fluvoxamine administration the ipsilateral anterior cingulate cortex (ACC), contralateral insular cortex (IC), and contralateral secondary somatosensory cortex (SII) activations were reduced. The bilateral IC activation was also reduced in the placebo group. These results suggest that fluvoxamine specifically reduced activation of the ACC and SII, which are areas concerned with the affective and integrative components of pain.     

Localization of pain‐related brain activation: A meta‐analysis of neuroimaging data

A meta‐analysis of 140 neuroimaging studies was performed using the activation‐likelihood‐estimate (ALE) method to explore the location and extent of activation in the brain in response to noxious stimuli in healthy volunteers. The first analysis involved the creation of a likelihood map illustrating brain activation common across studies using noxious stimuli. The left thalamus, right anterior cingulate cortex (ACC), bilateral anterior insulae, and left dorsal posterior insula had the highest likelihood of being activated. The second analysis contrasted noxious cold with noxious heat stimulation and revealed higher likelihood of activation to noxious cold in the subgenual ACC and the amygdala. The third analysis assessed the implications of using either a warm stimulus or a resting baseline as the control condition to reveal activation attributed to noxious heat. Comparing noxious heat to warm stimulation led to peak ALE values that were restricted to cortical regions with known nociceptive input. The fourth analysis tested for a hemispheric dominance in pain processing and showed the importance of the right hemisphere, with the strongest ALE peaks and clusters found in the right insula and ACC. The fifth analysis compared noxious muscle with cutaneous stimuli and the former type was more likely to evoke activation in the posterior and anterior cingulate cortices, precuneus, dorsolateral prefrontal cortex, and cerebellum. In general, results indicate that some brain regions such as the thalamus, insula and ACC have a significant likelihood of activation regardless of the type of noxious stimuli, while other brain regions show a stimulus‐specific likelihood of being activated. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

内、外侧痛觉系统——伤害性信息处理的并行通路

现代研究认为，完整的痛觉信号应该包括两种成分，即反映伤害性刺激参数(性质、定位、强度)的感觉辨别成分和反映情绪效应以及产生逃避行为的情感动机成分。相应地，在脑内存在两条平行上传的通路，分别传递痛的感觉和情绪信息。其中由脊髓背角深层广动力神经元发出，经过丘脑外侧核群投射到躯体感觉皮层的通路，可能传导伤害性刺激的感觉信息，称为外侧痛觉系统；由脊髓背角浅层痛觉特异性神经元发出，经由丘脑中线核群及板内核群投射到前扣带回和岛叶的通路，可能传递伤害性刺激的情绪成分，称为内侧痛觉系统。     

Pain Processing in Four Regions of Human Cingulate Cortex Localized with Co-registered PET and MR Imaging

Neurosurgical and positron emission tomography (PET) human studies and animal electrophysiological studies show that part of the anterior cingulate cortex (ACC) is nociceptive. Since the contribution of the ACC to pain processing is poorly understood, this study employed PET and magnetic resonance (MR) image co-registration in grouped and individual cases to locate regions of altered relative regional cerebral blood flow (rCBF). Seven right-handed, neurologically intact males were subjects; each received neuropsychological and pain threshold testing. Subjects were scanned during infusion of H₂[¹⁵O]: four randomized scans during innocuous heat stimulation to the back of the left hand and four scans during noxious but bearable heat to the same place. The averaged rCBF values during innocuous stimuli were subtracted from those during noxious stimuli and statistical parametric maps (SPMs) for the group were computed to identify regions of altered relative rCBF. Finally, single-subject PET images of elevated and reduced rCBF were co-registered with MR images and projected onto reconstructions of the medial surface of the hemisphere. The SPM analysis of the group showed one site with elevated rCBF in the midcingulate cortex and one in the perigenual cortex predominantly contralateral to the side of stimulation. There were bilateral sites of reduced rCBF in the cingulofrontal transitional cortex and in the posterior cingulate cortex (PCC). Co-registered PET and MR images for individuals showed that only one case had a single, large region of elevated rCBF, while the others had a number of smaller regions. Six cases had at least one significant elevation of rCBF in the right hemisphere that primarily involved area 24b'; five of these cases also had an elevation in area 32′, while the seventh case had elevated rCBF in these areas in the left hemisphere. The rostral site of elevated rCBF in the group was at the border of areas 24/24’and areas 32/32′, although most cases had a site of elevation more rostral in the perigenual cingulate cortex. The ACC site of reduced rCBF was in areas 8 and 32 and that in the PCC included much of areas 29/30 in the callosal sulcus, areas 23b and 31 on the cingulate gyral surface and parietal area 7m. The localization of relative rCBF changes suggests different roles for the cingulate cortex in pain processing: (i) elevated rCBF in area 24’may be involved in response selection like nocifensive reflex inhibition; (ii) activation of the perigenual cortex may participate in affective responses to noxious stimuli like suffering associated with pain; and (iii) reduced rCBF in areas 8 and 32 may enhance pain perception in the perigenual cortex, while that in the PCC may disengage visually guided processes.     

Pain processing within the primary somatosensory cortex in humans

To investigate the processing of noxious stimuli within the primary somatosensory cortex (SI), we recorded magnetoencephalography following noxious epidermal electrical stimulation (ES) and innocuous transcutaneous electrical stimulation (TS) applied to the dorsum of the left hand. TS activated two sources sequentially within SI: one in the posterior bank of the central sulcus and another in the crown of the postcentral gyrus, corresponding to Brodmann's areas 3b and 1, respectively. Activities from area 3b consisted of 20- and 30-ms responses. Activities from area 1 consisted of three components peaking at 26, 36 and 49 ms. ES activated one source within SI whose location and orientation were similar to those of the TS-activated area 1 source. Activities from this source consisted of three components peaking at 88, 98 and 109 ms, later by 60 ms than the corresponding TS responses. ES and TS subsequently activated a similar region in the upper bank of the sylvian fissure, corresponding to the secondary somatosensory cortex (SII). The onset latency of the SII activity following ES (109 ms) was later by 29 ms than that of the first SI response (80 ms). Likewise, the onset latency of SII activity following TS (52 ms) was later by 35 ms than that of area 1 of SI (17 ms). Therefore, our results showed that the processing of noxious and innocuous stimuli is similar with respect to the source locations and activation timings within SI and SII except that there were no detectable activations within area 3b following noxious stimulation.     

Mechanisms of intracerebral pain and itch perception in humans

Electrophysiological studies involving techniques such as magnetoencephalography (MEG) and hemodynamic studies involving techniques such as functional magnetic resonance imaging (fMRI) have recently been intensively used to elucidate the mechanisms underlying pain and itch perception in humans. The MEG results obtained after A-delta fiber (first pain) and C fiber (second pain) stimulation were similar, except for longer latency in the case of C fibers. Initially, the primary somatosensory cortex (SI) contralateral to the stimulation is activated, and the secondary somatosensory cortex (SII), insula, amygdala, and anterior cingulate cortex (ACC) in both hemispheres are then activated sequentially. The fMRI findings obtained after the stimulation of C fibers and those obtained after the stimulation of A-delta fibers both showed activation of the bilateral thalamus, bilateral SII, right (ipsilateral) middle insula, and bilateral Brodmann's area (BA) 24/32, with most of the activity being detected in the posterior region of the ACC. However, the magnitude of activity in the anterior insula on both sides and in BA 32/8/6, including the ACC and pre-supplementary motor area (pre-SMA), after the stimulation of C nociceptors was significantly stronger than that after the stimulation of A-delta nociceptors. We have recently developed a new stimulation electrode that causes an itching sensation via electrical stimulation applied to skin. The conduction velocity (CV) of the signals caused by this stimulation is approximately 1 m/sec in a range of CV of C fibers. The findings obtained after itch stimulation were similar to those obtained after pain stimulation, but the precuneus may be an itch-selective brain region. This unique finding was confirmed by both MEG and fMRI studies.     

Neural substrates underlying evaluation of pain in actions depicted in words

Previous research has shown that evaluation of pain shown in pictures is mediated by a cortical circuit consisting of the primary and secondary somatosensory cortex (SI and SII), the anterior cingulate cortex (ACC), and the insula. SI and SII subserve the sensory-discriminative component of pain processing whereas ACC and the insula mediate the affective-motivational aspect of pain processing. The current work investigated the neural correlates of evaluation of pain depicted in words. Subjects were scanned using functional magnetic resonance imaging (fMRI) while reading words or phrases depicting painful or neutral actions. Subjects were asked to rate pain intensity of the painful actions depicted in words or counting the number of Chinese characters in the words. Relative to the counting task, rating pain intensity induced activations in SII, the insula, the right middle frontal gyrus, the left superior temporal sulcus and the left middle occipital gyrus. Our results suggest that both the sensory-discriminative and affective-motivational components of the pain matrix are engaged in the processing of pain depicted in words.     

Positron emission tomography to study central pain integration

The study of pain integration, in vivo, within the human brain has been largely improved by the functional neuro-imaging techniques available for about 10 years. Positron Emission Tomography (PET), complemented by laser evoked potentials (LEP) and functional Magnetic Resonance Imaging (fMRI) can nowadays generate maps of physiological or neuropathic pain-related brain activity. LEP and fMRI complement PET by their better temporal resolution and the possibility of individual subject analyze. Recent advances in our knowledge of pain mechanisms concern physiological acute pain, neuropathic pain and investigation of analgesic mechanisms. The sixteen studies using PET have demonstrated pain-related activations in thalamus, insula/SII, anterior cingulate and posterior parietal cortices Activity in right pre-frontal and posterior parietal cortices, anterior cingulate and thalami can be modulated by attention (hypnosis, chronic pain, diversion, selective attention to pain) and probably subserve attentional processes rather than pain analysis. Responses in insula/SII cortex presumably subserve discriminative aspects of pain perception while SI cortex is particularly involved in particular aspects of pain discrimination (movement, contact.) In patients, neuropathic pain, angina and atypical facial pain result in PET abnormalities whose significance remain obscure but which are localized in thalamus and anterior cingulate cortices suggesting their distribution is not random while discriminative responses remain detectable in insula/SII. Drug or stimulation induced analgesia are associated with normalization of basal thalamic abnormalities associated with many chronic pains. The need to investigate the significance of these responses, their neuro-chemical correlates (PET), their time course, the individual strategies by which they have been generated by correlating PET data with LEP and fMRI results, are the challenges that remain to be addressed in the next few years by physicians and researchers. To advance our knowledge of the mechanisms generating both abnormal pain and analgesia (drugs and surgical techniques) in patients is the main motivation of such anexciting challenge.     

Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain

Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain‐like behaviors in sciatic nerve‐ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level‐dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve‐ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT‐3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve‐ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin‐2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain‐like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice. Synapse 68:235–247, 2014 . © 2014 Wiley Periodicals, Inc.     

Kortikale Repräsentation von Schmerz

Contrary to the traditional view that the cerebral cortex is not involved in pain perception an extensive cortical network associated with pain processing has been revealed during the past decades. This network consistently includes the primary (S1) and secondary somatosensory cortices (S2), the insular cortex, and the anterior cingulate cortex (ACC). These cortical areas are organized in parallel and contribute to different dimensions of pain experience. The S1 cortex is mainly involved in discriminative aspects of pain, while the S2 cortex seems to have an important role in cognitive aspects of pain perception. The insula has been proposed to be involved in autonomic reactions to noxious stimuli and in pain-related learning and memory. The ACC is closely related to pain affect and may subserve the integration of general affect, cognition, and response selection. Furthermore, first pain appears to be particularly related to activation of S1 whereas second pain is closely related to ACC activation.     

Primary and secondary somatosensory cortex responses to anticipation and pain: a magnetoencephalography study

Several brain regions, including the primary and secondary somatosensory cortices (SI and SII, respectively), are functionally active during the pain experience. Both of these regions are thought to be involved in the sensory-discriminative processing of pain and recent evidence suggests that SI in particular may also be involved in more affective processing. In this study we used MEG to investigate the hypothesis that frequency-specific oscillatory activity may be differentially associated with the sensory and affective components of pain. In eight healthy participants (four male), MEG was recorded during a visceral pain experiment comprising baseline, anticipation, pain and post-pain phases. Pain was delivered via intraluminal oesophageal balloon distension (four stimuli at 1 Hz). Significant bilateral but asymmetrical changes in neural activity occurred in the β-band within SI and SII. In SI, a continuous increase in neural activity occurred during the anticipation phase (20-30 Hz), which continued during the pain phase but at a lower frequency (10-15 Hz). In SII, oscillatory changes only occurred during the pain phase, predominantly in the 20-30 Hz β band, and were coincident with the stimulus. These data provide novel evidence of functional diversity within SI, indicating a role in attentional and sensory aspects of pain processing. In SII, oscillatory changes were predominantly stimulus-related, indicating a role in encoding the characteristics of the stimulus. We therefore provide objective evidence of functional heterogeneity within SI and functional segregation between SI and SII, and suggest that the temporal and frequency dynamics within cortical regions may offer valuable insights into pain processing.     

Altered somatosensory processing in trigeminal neuralgia

Trigeminal neuralgia (TN) is a pain state characterized by intermittent unilateral pain attacks in one or several facial areas innervated by the trigeminal nerve. The somatosensory cortex is heavily involved in the perception of sensory features of pain, but it is also the primary target for thalamic input of nonpainful somatosensory information. Thus, pain and somatosensory processing are accomplished in overlapping cortical structures raising the question whether pain states are associated with alteration of somatosensory function itself. To test this hypothesis, we used functional magnetic resonance imaging to assess activation of primary (SI) and secondary (SII) somatosensory cortices upon nonpainful tactile stimulation of lips and fingers in 18 patients with TN and 10 patients with TN relieved from pain after successful neurosurgical intervention in comparison with 13 healthy subjects. We found that SI and SII activations in patients did neither depend on the affected side of TN nor differ between operated and nonoperated patients. However, SI and SII activations, but not thalamic activations, were significantly reduced in patients as compared to controls. These differences were most prominent for finger stimulation, an area not associated with TN. For lip stimulation SI and SII activations were reduced in patients with TN on the contra‐ but not on the ipsilateral side to the stimulus. These findings suggest a general reduction of SI and SII processing in patients with TN, indicating a long‐term modulation of somatosensory function and pointing to an attempt of cortical adaptation to potentially painful stimuli. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Central representation of somatic sensations in the parietal operculum (SII) and insula

Four subjects with small restricted cerebral cortical infarcts have been examined. One had a lesion confined to the parietal operculum (SII), while in the second the SII lesion also encroached on the posterior insula; in the third subject, both banks of the sylvian fissure and the dorsal insula were involved, while in the fourth the lesion involved the upper bank of the sylvian fissure. In all cases, the postcentral gyrus (SI) was intact. Subjects 1 and 2 had mild spontaneous pain, but subjects 3 and 4 had never had spontaneous pain. In the affected areas, none could feel mechanical (skinfold pinch) pain. The 2 subjects with spontaneous pain could not discriminate sharpness (pinprick), but this was unimpaired in the third and fourth subjects. Warmth, cold, and heat pain were impaired in the 2 subjects with spontaneous pain, but not in those without; however warm-cold difference was greater in the affected regions of all subjects. The possibility must nevertheless be considered that the presence of central pain in some way alters the cortical mechanisms for the perception of thermal stimuli. Certainly, as we had earlier observed, spontaneous pain only occurs when there is interference with thermal sensation. Functional MRI (fMRI) studies following thermal stimulation in subjects 1 and 2 showed these areas, particularly SII, to be concerned with the reception of innocuous and noxious thermal stimuli, mechanical (skinfold pinch) pain and sharpness (pinprick), implying that SI is principally concerned with the reception of low-intensity mechanical stimuli, although it was activated in 1 of our fMRI-studied subjects by innocuous cooling.     

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.     

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.     

Dysfunctional pain modulation in somatoform pain disorder patients

To date, pain perception is thought to be a creative process of modulation carried out by an interplay of pro- and anti-nociceptive mechanisms. Recent research demonstrates that pain experience constitutes the result of top–down processes represented in cortical descending pain modulation. Cortical, mainly medial and frontal areas, as well as subcortical structures such as the brain stem, medulla and thalamus seem to be key players in pain modulation. An imbalance of pro- and anti-nociceptive mechanisms are assumed to cause chronic pain disorders, which are associated with spontaneous pain perception without physiologic scaffolding or exaggerated cortical activation in response to pain exposure. In contrast to recent investigations, the aim of the present study was to elucidate cortical activation of somatoform pain disorder patients during baseline condition. Scalp EEG, quantitative Fourier-spectral analyses and LORETA were employed to compare patient group (N = 15) to age- and sex-matched controls (N = 15) at rest. SI, SII, ACC, SMA, PFC, PPC, insular, amygdale and hippocampus displayed significant spectral power reductions within the beta band range (12–30 Hz). These results suggest decreased cortical baseline arousal in somatoform pain disorder patients. We finally conclude that obtained results may point to an altered baseline activity, maybe characteristic for chronic somatoform pain disorder.     

Dorsal raphe stimulation, 5-HT and morphine microiontophoresis effects on noxious and nonnoxious identified neurons in the medial thalamus of the rat

In single cell experiments, the characterization of the responses of medial thalamic neurons to noxious and nonnoxious stimulation was made to examine the effects of two substances involved in pain, morphine and 5-HT, and the action of one pain suppressor mechanism, dorsal raphe stimulation. Single cell activity was recorded in urethane anesthetized rats. Tail pinch and tail immersion in hot water were used as nociceptive stimuli. Skin strokes, air puffs and hair brushing were used as nonnociceptive stimuli. Morphine, 5-HT microiontophoresis and dorsal raphe stimulation were performed in all the recorded units. Fifty-eight percent from 61 medial thalamic recorded units responded both to noxious and nonnoxious stimulation; whereas only 18% and 24.6% of the units responded exclusively to noxious and nonnoxious stimulation, respectively. The noxious responding units were located in the most posterior portions of the medial thalamus. Dorsal raphe stimulation and 5-HT ejection prevented the excitation elicited by noxious input. Morphine ejection prevented both the noxious and nonnoxious input in medial thalamus, in a different population as compared to dorsal raphe stimulation or 5-HT ejection. These findings support the existence of a pain ascending mechanism mediated by an opioid-serotonergic interaction in the medial thalamus of the rat.