fMRI of thermal pain: effects of stimulus laterality and attention.

Brain activity was studied by fMRI in 18 healthy subjects during stimulation of the thenar eminence of the hand with either warm (non-painful, 40 degrees C) or hot (painful, 46-49 degrees C) stimuli using a contact thermode. Experiments were performed on the right and left hand independently and with two attentional contexts: subjects either attended to pain or attended to a visual global motion discrimination task (to distract them from pain). Group analysis demonstrated that attended warm stimulation of the right hand did not produce any significantly activated clusters. Painful thermal stimulation of either hand elicited significant activity over a large network of brain regions, including insula, inferior frontal gyrus, cingulate gyrus, secondary somatosensory cortex, cerebellum, and medial frontal gyrus (corrected P < 0.05). Insula activity was distributed along its anterior-posterior axis and depended on the hand stimulated and attentional context. In particular, activity within the posterior insula was contralateral to the site of stimulation, tested using regions of interest (ROI) analysis: significant side x site interaction (P = 0.001). With attention diverted from the painful stimulus bilateral anterior insula activity moved posteriorly to midinsula and decreased in extent (ROI analysis: significant main effect of attention (P = 0.03)). The role of the insula in thermosensation and attention is discussed.     

Temporal summation of heat pain in humans: Evidence supporting thalamocortical modulation

Noxious cutaneous contact heat stimuli (48 °C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10 s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20 s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20 s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.     

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

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

Cerebral responses to pain in patients suffering acute post-dental extraction pain measured by positron emission tomography (PET)

Previous studies with normal volunteers have demonstrated distributed cortical responses to experimental heat pain within a network of structures. The network includes the insula, anterior cingulate, prefrontal, inferior parietal and somatosensory cortices. Patients suffering from chronic nociceptive pain following rheumatoid arthritis (RA) have shown damped central responses to experimental heat pain applied to the back of the right hand. In this study of patients with acute, left-sided, post-molar-extraction (surgical) pain, we assessed the cortical responses to experimental heat pain, applied to the back of the right hand, using positron emission tomography (PET), and compared the responses with a previously reported control group and the RA group. In response to the experimental heat pain, the surgical group indicated significantly increased regional cerebral blood flow in the prefrontal cortex [Brodman's area (BA) 44] ipsilateral to the heat stimulus. Contralateral increases were detected in the putamen and transverse temporal gyrus (BA 40/41/42) with bilateral increases in the insular cortex. Compared to the control and RA group, there were significantly reduced responses in the anterior cingulate (BA 24), pre-frontal medial, and orbito-frontal (BA 9/10/32/47) cortices. These results suggest that relatively discrete regions of the cerebral cortex are responsible for acute nociceptive processing during an acute inflammatory episode. The reduced frontal and anterior cingulate responses to the experimental heat pain (applied to the right hand) during acute inflammatory pain (left jaw) illustrates cortical modulation of nociceptive processing that may be related to non-somatotopic, bilateral, nociceptive inputs to these areas.     

Sex differences in endogenous pain modulation by distracting and painful conditioning stimulation

Sex differences in endogenous pain modulation were tested in healthy volunteers (32 men, 30 women). Painful contact heat stimuli were delivered to the right leg alone, and then in combination with various electrical conditioning stimuli delivered to the left forearm. Four conditioning protocols were applied to each subject in separate sessions: mild, non-painful (control); distracting; stressful-yet-non-painful; strongly painful. Thermal stimuli were rated on visual analog scales for pain intensity (INT) and unpleasantness (UNP). Distracting and painful conditioning stimuli significantly reduced heat pain INT and UNP ratings for both sexes, with significantly larger distraction effects on INT ratings for men than women (p=0.004). No sex differences in pain-evoked hypoalgesia were detected (p>0.05). The stress protocol did not consistently reduce heat pain ratings, possibly because the protocol was not sufficiently stressful to activate endogenous modulatory systems. Regression analysis revealed that the magnitude of pain-evoked hypoalgesia was predicted by the perceived distraction (p=0.003) and stress (p=0.04) produced by the painful conditioning stimulation, providing evidence that distraction and stress contribute to pain-evoked hypoalgesia. However, the contribution of stress to pain-evoked hypoalgesia differed by sex (p=0.02), with greater perceived stress associated with greater hypoalgesia in men and the opposite trend in women, suggesting sex differences in the mechanisms underlying pain-evoked hypoalgesia. This study provides indirect evidence that multiple neural mechanisms are involved in endogenous pain modulation and suggests that sex-specific aspects of these systems may contribute to greater pain sensitivity and higher prevalence of many chronic pain conditions among women.     

The effect of trigeminal nociceptive stimulation on blink reflexes and pain evoked by stimulation of the supraorbital nerve

The aim of this study was to investigate the effect of painful conditioning stimuli on pain and blink reflexes to supraorbital nerve stimulation. Electromyograph activity was recorded bilaterally from the orbicularis oculi muscles in 13 normal participants in response to low (2.3 mA) and high-intensity (18.6 mA) electrical stimulation of the left supraorbital nerve before, during and after the application of ice to the left or right temple or immersion of the left hand in ice-water for 60 s. The pain evoked by the high-intensity electrical stimulus was greater during painful conditioning stimulation of the ipsilateral temple than during the recovery period afterwards, and was greater than during painful conditioning stimulation of the contralateral temple. These findings imply that spatial summation of nociceptive signals across different divisions of the trigeminal nerve can heighten pain. However, painful conditioning stimulation, particularly to the right temple, strongly suppressed the R2 component of the blink reflex to the low-intensity stimulus, and also suppressed R2 to the high-intensity stimulus. Thus, an inhibitory influence (e.g. diffuse noxious inhibitory controls) appeared to mask ipsilateral segmental facilitation of R2 during ice-induced headache. This finding contrasts with recent electrophysiological evidence of trigeminal sensitization in migraine.     

Spatial segregation of somato-sensory and pain activations in the human operculo-insular cortex

The role of operculo-insular region in the processing of somato-sensory inputs, painful or not, is now well established. However, available maps from previous literature show a substantial overlap of cortical areas activated by these stimuli, and the region referred to as the "secondary somatosensory area (SII)" is widely distributed in the parietal operculum. Differentiating SII from posterior insula cortex, which is anatomically contiguous, is not easy, explaining why the "operculo-insular" label has been introduced to describe activations by somatosensory stimuli in this cortical region. Based on the recent cyto-architectural parcellation of the human insular/SII cortices (Eickhoff et al., 2006, Kurth et al., 2010), the present study investigates with functional MRI (fMRI), whether these structural subdivisions could subserve distinct aspects of discriminative somato-sensory functions, including pain. Responses to five types of stimuli applied on the left hand of 25 healthy volunteers were considered: i) tactile stimuli; ii) passive movements; iii) innocuous cold stimuli; iv) non-noxious warm and v) heat pain. Our results show different patterns of activation depending on the type of somato-sensory stimulation. The posterior part of SII (OP1 area), contralateral to stimuli, was the only sub-region activated by all type of stimuli and might therefore be considered as a common cortical target for different types of somato-sensory inputs. Proprioceptive stimulation by passive finger movements activated the posterior part of SII (OP1 sub-region) bilaterally and the contralateral median part of insula (PreCG and MSG). Innocuous cooling activated the contralateral posterior part of SII (OP1) and the dorsal posterior and median part of insula (OP2, PostCG). Pain stimuli induced the most widespread and intense activation that was bilateral in SII (OP1, OP4) and distributed to all sub-regions of contralateral insula (except OP2) and to the anterior part of the ipsilateral insula (PreCG, MSG, ASG). However, the posterior granular part of insula contralateral to stimulus (Ig area) and the anterior part of SII bilaterally (OP4) were specifically activated during pain stimulation. This raises the question whether these latter areas could be the anatomical substrate of the sensory-discriminative processing of thermal pain.     

Does the insula tell our brain that we are in pain?

Current knowledge on pain-related cerebral networks has relied so far on stimulus-induced brain responses, but not on the analysis of brain activity during spontaneous pain attacks. In this case report, correlation between intracerebral field potentials and online sensations during spontaneously painful epileptic seizures suggests a crucial role of the insula in the development of subjective pain. Attacks originated from a very limited dysplasia located in the posterior third of the right insula and propagated to other areas of the pain matrix, including the parietal operculum and the midcingulate gyrus. Concomitant painful symptoms started on the left hand or the left foot and extended in a few seconds to the whole left side of the body, sparing the head. Continuous during the first seconds of the attack, the painful feeling evolved to throbbing and remained so until it progressively vanished, together with the spike discharge. Stimulation of the insula, but not of other pain matrix regions, induced pain identical to that of seizures. After thermocoagulation of the insular epileptic focus, a short, transient exacerbation of seizures with same painful features but different location was observed before a long-lasting and complete remission of the attacks. Although these preliminary data need to be confirmed, they strongly suggest that if the full pain experience involves the pain matrix network, the posterior insula seems to play a leading role in the triggering of this network and the resulting emergence of subjective pain experience.     

Cortical representation of experimental tooth pain in humans

Cortical processing of electrically induced pain from the tooth pulp was studied in healthy volunteers with fMRI. In a first experiment, cortical representation of tooth pain was compared with that of painful mechanical stimulation to the hand. The contralateral S1 cortex was activated during painful mechanical stimulation of the hand, whereas tooth pain lead to bilateral activation of S1. The S2 and insular region were bilaterally activated by both stimuli. In S2, the center of gravity of the activation during painful mechanical stimulation was more medial/posterior compared to tooth pain. In the insular region, tooth pain induced a stronger activation of the anterior and medial parts. The posterior part of the anterior cingulate gyrus was more strongly activated by painful stimulation of the hand. Differential activations were also found in motor and frontal areas including the orbital frontal cortex where tooth pain lead to greater activations. In a second experiment, we compared the effect of weak with strong tooth pain. A significantly greater activation by more painful tooth stimuli was found in most of those areas in which tooth pain had induced more activation than hand pain. In the medial frontal and right superior frontal gyri, we found an inverse relationship between pain intensity and BOLD contrast. We concluded that tooth pain activates a cortical network which is in several respects different from that activated by painful mechanical stimulation of the hand, not only in the somatotopically organized somatosensory areas but also in parts of the 'medial' pain projection system.     

Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: a single-trial fMRI study

The insula is involved in processing noxious information. It is consistently activated by acute noxious stimuli, can elicit pain on stimulation, and lesions encompassing the insula can alter pain perception. Anatomical tracing, electrophysiological and functional brain imaging investigations have suggested that the insula is somatotopically organized with respect to noxious cutaneous inputs. It has also recently been revealed that the anterior insula displays differential activation during cutaneous compared with muscle pain. Given this difference, it is important to determine if an insula somatotopy also exists for muscle pain. Using high-resolution functional magnetic resonance imaging (fMRI) we compared insula activation patterns in 23 subjects during muscle and cutaneous pain induced in the right leg and forearm. Group and frequency analyses revealed somatotopically organized signal increases in the posterior contralateral (left) and ipsilateral (right) anterior insula. Within the posterior contralateral insula, signal increases during both cutaneous and muscle forearm pain were located lateral and anterior to those evoked by leg pain, whereas in the ipsilateral anterior insula the pattern was reversed. Furthermore, within the ipsilateral anterior insula, muscle pain activated a region anterior to that activated by cutaneous pain. This somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on both stimulation site and type of tissue activated. This study reveals that the insula is organized somatopically with respect to muscle and cutaneous pain and that this organization is further separated according to the tissue in which the pain originates.     

Gastric distention activates satiety circuitry in the human brain

Gastric distention during meal ingestion activates vagal afferents, which send signals from the stomach to the brain and result in the perception of fullness and satiety. Distention is one of the mechanisms that modulates food intake. We measured regional brain activation during dynamic gastric balloon distention in 18 health subjects using functional magnetic resonance imaging and the blood oxygenation level-dependent (BOLD) responses. The BOLD signal was significantly changed by both inflow and outflow changes in the balloon's volume. For lower balloon volumes, water inflow was associated with activation of sensorimotor cortices and right insula. The larger volume condition additionally activated left posterior amygdala, left posterior insula and the left precuneus. The response in the left amygdala and insula was negatively associated with changes in self-reports of fullness and positively with changes in plasma ghrelin concentration, whereas those in the right amygdala and insula were negatively associated with the subject's body mass index. The widespread activation induced by gastric distention corroborates the influence of vagal afferents on cortical and subcortical brain activity. These findings provide evidence that the left amygdala and insula process interoceptive signals of fullness produced by gastric distention involved in the controls of food intake.     

PET study on central processing of pain in trigeminal neuropathy

Recent functional brain imaging studies with positron emission tomography (PET), in painful peripheral mononeuropathy and nitroglycerin-provoked cluster headache attacks, suggest a preference of the right hemisphere, especially the anterior cingulate cortex (ACC) and the medial prefrontal cortex (MPFC), in attributing emotional valence and attention to the pain suffering. We have investigated the central processing of painful trigeminal neuropathy (PTN) in patients treated with electric extradural precentral gyrus stimulation (PCGS). Increased regional cerebral blood flow (rCBF) was detected in the right caudal ACC [Brodmann area (BA) 24] and anterior limbic thalamus, while a decreased activity was observed in the right MPFC (BA 9/32) during the habitual-pain state, in comparison with the pain-alleviated state regardless of the inflicted side of PTN. The involvement of BA 9/32 and the anterior limbic thalamus spatially extended to the left hemisphere, but the local maxima and a significant negative correlation between the rCBF changes in the two structures were found only in the right hemisphere. The activation of the caudal BA24 further supports the theory that ACC is crucial for the suffering in chronic pain. Our study not only verifies the preferential role of the right hemisphere in the appreciation of pain suffering, but further supports that sustained chronic pain, being devoid of the motivational component of an escape response, targets the right hemisphere, particularly the BA24 of the ACC.     

Effect of subthalamic deep brain stimulation on pain in Parkinson’s disease

Painful sensations are common in Parkinson’s disease. In many patients, such sensations correspond to neuropathic pain and could be related to central alterations of pain processing. Subthalamic nuclei deep brain stimulation improves motor function in Parkinson’s disease. Several structures of the basal ganglia are involved in nociceptive function, and deep brain stimulation could thus also modify pain perception in Parkinson’s disease. To test this hypothesis, we compared subjective heat pain thresholds, in deep brain stimulation OFF and ON conditions in 2 groups of Parkinson’s disease patients with or without neuropathic pain. We also compared pain-induced cerebral activations during experimental nociceptive stimulations using H₂¹⁵O positron emission tomography in both deep brain stimulation OFF and ON conditions. Correlation analyses were performed between clinical and neuroimaging results. Deep brain stimulation significantly increased subjective heat pain threshold (from 40.3 ± 4.2 to 41.6 ± 4.3, P = .03) and reduced pain-induced cerebral activity in the somatosensory cortex (BA 40) in patients with pain, whereas it had no effect in pain-free patients. There was a significant negative correlation in the deep brain stimulation OFF condition between pain threshold and pain-induced activity in the insula of patients who were pain free but not in those who had pain. There was a significant positive correlation between deep brain stimulation-induced changes in pain threshold and in pain-induced cerebral activations in the primary somatosensory cortex and insula of painful patients only. These results suggest that subthalamic nuclei deep brain stimulation raised pain thresholds in Parkinson’s disease patients with pain and restored better functioning of the lateral discriminative pain system.     

The influence of simultaneous ratings on cortical BOLD effects during painful and non-painful stimulation

This fMRI study investigates the influence of a rating procedure on BOLD signals in common pain-activated cortical brain regions. Painful and non-painful mechanical impact stimuli were applied to the left hand of healthy volunteers. Subjects performed ratings of the perceived intensity during every second stimulation period by operating a visual analogue scale with the right hand. During every other stimulus period the subjects rested passively. Pain and touch stimuli were found to activate the same cortical areas previously defined as the "cortical pain matrix". General Linear Models were used to calculate contrasts between cortical activations during the "rating" and "non-rating" paradigm. In most brain regions activation following pain and touch was stronger during "rating" compared to "non-rating" conditions. Only the responses in the S1 projection field of the stimulated hand following pain were not influenced by the rating procedure. Furthermore, activations in the right and left posterior insular cortex and in the left superior frontal gyrus showed an opposite pattern, namely a stronger BOLD signal during "non-rating". We concluded: (1) Cortical areas regularly activated by painful stimuli may also be activated by touch stimulation. (2) Enhancement of the BOLD contrast by a rating procedure is probably an effect of closer stimulus evaluation and attention focussing. (3) In contrast to most other cortical regions, the posterior insular cortex, which is crucial for the integration of interoceptive afferent input, shows stronger responses in the absence of ratings, which points to a unique role of this region in the processing of somato-visceral information.     

Brainstem involvement in the initial response to pain

The autonomic responses to acute pain exposure usually habituate rapidly while the subjective ratings of pain remain high for more extended periods of time. Thus, systems involved in the autonomic response to painful stimulation, for example the hypothalamus and the brainstem, would be expected to attenuate the response to pain during prolonged stimulation. This suggestion is in line with the hypothesis that the brainstem is specifically involved in the initial response to pain. To probe this hypothesis, we performed a positron emission tomography (PET) study where we scanned subjects during the first and second minute of a prolonged tonic painful cold stimulation (cold pressor test) and nonpainful cold stimulation. Galvanic skin response (GSR) was recorded during the PET scanning as an index of autonomic sympathetic response. In the main effect of pain, we observed increased activity in the thalamus bilaterally, in the contralateral insula and in the contralateral anterior cingulate cortex but no significant increases in activity in the primary or secondary somatosensory cortex. The autonomic response (GSR) decreased with stimulus duration. Concomitant with the autonomic response, increased activity was observed in brainstem and hypothalamus areas during the initial vs. the late stimulation. This effect was significantly stronger for the painful than for the cold stimulation. Activity in the brainstem showed pain-specific covariation with areas involved in pain processing, indicating an interaction between the brainstem and cortical pain networks. The findings indicate that areas in the brainstem are involved in the initial response to noxious stimulation, which is also characterized by an increased sympathetic response.     

Single trial fMRI reveals significant contralateral bias in responses to laser pain within thalamus and somatosensory cortices

Pain is processed in multiple brain areas, indicating the complexity of pain perception. The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. We used single-trial functional magnetic resonance imaging (fMRI) to assess hemodynamic responses to right and left painful stimulation. Thulium-YAG-(yttrium-aluminium-granate)-laser-evoked pain stimuli, without concomitant tactile component, were applied to either hand in a randomized order. A contralateral bias of the BOLD response was investigated to determine areas involved in the coding of the side of stimulation, which we observed in primary (SI) and secondary (SII) somatosensory cortex, insula, and the thalamus. This suggests that these structures provide spatial information of selective nociceptive stimuli. More importantly, this contralateral bias of activation allowed functionally segregated activations within the SII complex, the insula, and the thalamus. Only distinct subregions of the SII complex, the posterior insula and the lateral thalamus, but not the remaining SII complex, the anterior insula and the medial thalamus, showed a contralaterally biased representation of painful stimuli. This result supports the hypothesis that sensory-discriminative attributes of painful stimuli, such as those related to body side, are topospecifically represented within the forebrain projections of the nociceptive system and highlights the concept of functional segregation and specialization within these structures.     

A positron emission tomography study of wind‐up pain in chronic postherniotomy pain

Many neuropathic pain conditions are characterized by abnormal responses to noxious or innocuous mechanical stimulation, including wind‐up pain. Whereas previous brain imaging studies have explored the cerebral correlates of hyperalgesia and allodynia, no studies are available on mechanical‐induced wind‐up pain in neuropathic pain patients. We therefore used positron emission tomography (PET) to investigate the cerebral response pattern of mechanical wind‐up pain in a homogenous group of 10 neuropathic pain patients with long‐standing postherniotomy pain in the groin area. Patients were scanned in the following conditions: (1) rest; (2) wind‐up pain, induced by 2 Hz von Frey stimulation in the painful area; (3) non‐painful 2 Hz von Frey stimulation in the homologous contralateral area and (4) tonic pressure pain in the homologous contralateral area. A direct comparison between wind‐up pain and non‐painful von Frey stimulation revealed that the former more strongly activated contralateral secondary somatosensory cortex, insula, anterior cingulate cortex, right dorsolateral prefrontal cortex, thalamus and cerebellum. In addition, wind‐up pain also activated the sublenticular extended amygdala (SLEA) and the brain stem. A direct comparison between wind‐up pain and pressure pain revealed that both activated a largely overlapping network. Since no de novo brain areas were activated by wind‐up pain, our data suggest that the processes specific to wind‐up pain do not occur at the cerebral level.     

Brain activation in response to bladder filling and simultaneous stimulation of the dorsal clitoral nerve--an fMRI study in healthy women

AIMS: Using functional magnetic resonance imaging (fMRI) we investigated the cortical and subcortical representations during bladder filling and the effect of simultaneous stimulation of the dorsal clitoral nerve on these cortical and subcortical structures. METHODS: After approval of the local ethics committee, 8 healthy females were included. Prior to scanning, subjects were catheterized and the bladder was filled until first desire to void occurred. In a block design protocol we performed repetitive manual bladder filling (FILLING) and emptying of additional 80 ml saline, alternating with rest conditions (REST) of constant bladder volume. The protocol was repeated with simultaneous stimulation of the dorsal clitoral nerve during the filling periods (COMBINED). Activation maps were calculated by means for 3 different contrasts: 1) FILLING>REST, 2) COMBINED>REST and 3) FILLING>COMBINED. RESULTS: A group analysis of contrast 1) showed activation of the right prefrontal and orbitofrontal cortices, the insula bilaterally, the left precuneus, the parietal operculum bilaterally, the cerebellum bilaterally (q(FDR)< or =0.001), the right anterior cingulate gyrus (q(FDR)< or =0.005) and the right anterior mid pons (q(FDR)< or =0.05). Contrast 2) showed activation in the right frontal area, the left insula, the parietal operculum bilaterally and the left cerebellum (q(FDR)< or =0.001). Deactivations were found in the middle frontal gyrus bilaterally and the post- and paracentral gyri bilaterally. Contrast 3) revealed stronger activation during FILLING in the bilateral frontal and prefrontal areas, the right anterior cingulated gyrus, and the right putamen (q(FDR)< or =0.05). Only the right insula showed stronger activation during the COMBINED condition. CONCLUSION: Simultaneous dorsal clitoral nerve stimulation during bladder filling reduced the activation of certain cortical areas suggesting a neuromodulatory effect of this stimulation on supraspinal centres involved in lower urinary tract control.     

A regression analysis study of the primary somatosensory cortex during pain

Several functional imaging studies of pain, using a number of different experimental paradigms and a variety of reference states, have failed to detect activations in the somatosensory cortices, while other imaging studies of pain have reported significant activations in these regions. The role of the somatosensory areas in pain processing has therefore been debated. In the present study the left hand was immersed in painfully cold water (standard cold pressor test) and in nonpainfully cold water during 2 min, and PET-scans were obtained either during the first or the second minute of stimulation. We observed no significant increase of activity in the somatosensory regions when the painful conditions were directly compared with the control conditions. In order to better understand the role of the primary somatosensory cortex (S1) in pain processing we used a regression analysis to study the relation between a ROI (region of interest) in the somatotopic S1-area for the stimulated hand and other regions known to be involved in pain processing. We hypothesized that although no increased activity was observed in the S1 during pain, this region would change its covariation pattern during noxious input as compared to the control stimulation if it is involved in or affected by the processing of pain. In the nonpainful cold conditions widespread regions of the ipsilateral and contralateral somatosensory cortex showed a positive covariation with the activity in the S1-ROI. However, during the first and second minute of pain this regression was significantly attenuated. During the second minute of painful stimulation there was a significant positive covariation between the activity in the S1-ROI and the other regions that are known to be involved in pain processing. Importantly, this relation was significantly stronger for the insula and the orbitofrontal cortex bilaterally when compared to the nonpainful state. The results indicate that the S1-cortex may be engaged in or affected by the processing of pain although no differential activity is observed when pain is compared with the reference condition.     

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

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