Electrical low‐frequency stimulation induces long‐term depression of sensory and affective components of pain in healthy man

Electrical low‐frequency stimulation (LFS) of nociceptive skin afferents reliably induces long‐term depression (LTD) of pain. Recent experiments have assessed the effects of LTD on pain perception by using a simple one‐dimensional rating scale. The psychophysical study investigated the impact of noxious LFS on the sensory and affective aspects of pain perception by multidimensional rating scales. In 20 healthy volunteers, nociceptive fibers of the left hand dorsum were electrically stimulated by a concentric electrode. Test stimulation series (15 stimuli each, 0.125Hz) were performed before (Pre) and after (Post) a conditioning LFS (1Hz, 20min) or no stimulation period (Control). Pain ratings concerning test stimulation and LFS were obtained by multidimensional assessment including Verbal rating scale of perceived stimulus intensity (VRS‐I) and unpleasantness (VRS‐U) and pain perception scale with sensory (SES‐S) and affective items (SES‐A). After the conditioning LFS, VRS‐I, VRS‐U, SES‐S, and SES‐A decreased as compared to Pre series and Control. During conditioning LFS, ratings decreased. Factor analysis of SES‐S revealed sole reduction of superficial sharp pain perception after conditioning LFS in contrast to Control experiment. Perception of deep rhythmic pain decreased over time. Deep constant pain and superficial heat pain were not affected. Electrical test stimulation via concentric electrode evokes sensory as well as affective pain perception. Both components decrease during noxious, conditioning LFS and remain depressed for at least one hour. Reduction of sharp pain points to Aδ fiber mediated LTD. These results stress the analgesic potency of LTD and its possible impact on future therapy in chronic pain.     

Electrical low‐frequency stimulation induces central neuroplastic changes of pain processing in man

Electrical low‐frequency stimulation (LFS) inhibits pain perception and nociceptive processing as shown by psychophysical and electrophysiological means (long‐term depression, LTD). Information regarding central mechanisms involved in LTD induction and maintenance are still missing. This study hypothesizes that electrical LFS induces changes in activation pattern of pain‐related brain areas. Thirty‐two electrophysiological and psychophysical experiments were performed in 16 healthy volunteers. Painful electrical test stimulation (0.125 Hz, 60 pulses) and conditioning LFS (1 Hz, 1200 pulses) were applied by a concentric electrode to the right hand. Test stimulation series were performed before (Pre) and after LFS (Post) or no stimulation period (Control). Volunteers rated pain perception according to a verbal rating scale (0–100). Somatosensory evoked cortical potentials were recorded with 64‐channel electroencephalography. Individual dipole source modeling using CURRY software (Compumedics, Hamburg, Germany) yielded information about dipole location and strength. The strongest decrease in LFS‐induced pain perception was shown after LFS (p < 0.01). Topographic distribution of cortical potentials revealed reproducible negative (N1, N2) and positive (P2) components. Dipole magnitude analysis showed a significant difference between Post LFS and Post Control for P2 (p < 0.01). P2 dipole location analysis yielded a significant posterior (p < 0.05) shift following LTD induction. Thus, data reveal central changes of pain processing after LTD induction. These experiments may help judging the potency of LTD as model for electrostimulation in future analgesic therapy.     

Opioidergic activation in the medial pain system after heat pain

Opioids modulate the affective component of pain and in vivo data indicate that opioids induce activation changes in the rostral ACC, insula and other brain areas. Hence, opioidergic release is to be expected in these brain regions following experimental pain stimulation. We examined healthy volunteers during heat pain and control subjects during rest using [18F]fluorodiprenorphine-PET. Pain stimulation led to significant reduction of diprenorphine binding in limbic and paralimbic brain areas including the rostral ACC and insula. The finding of altered opioidergic receptor availability in the rostral ACC after experimental nociceptive pain is novel and provides direct evidence for the involvement of this region in endogenous opioidergic inhibition of pain.     

A simultaneous EEG-fMRI study of painful electric stimulation

Together with a detailed behavioral analysis, simultaneous measurement of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) permits a better elucidation of cortical pain processing. We applied painful electrical stimulation to 6 healthy subjects and acquired fMRI simultaneously with an EEG measurement. The subjects rated various stimulus properties and the individual affective state. Stimulus-correlated BOLD effects were found in the primary and secondary somatosensory areas (SI and SII), the operculum, the insula, the supplementary motor area (SMA proper), the cerebellum, and posterior parts of the anterior cingulate gyrus (ACC). Perceived pain intensity was positively correlated with activation in these areas. Higher unpleasantness rating was associated with suppression of activity in areas known to be involved in stimulus categorization and representation (ventral premotor cortex, PCC, parietal operculum, insula) and enhanced activation in areas initiating, propagating, and executing motor reactions (ACC, SMA proper, cerebellum, primary motor cortex). Concordant dipole localizations in SI and ACC were modeled. Using the dipole strength in SI, the network was restricted to SI. The BOLD signal change in ACC was positively correlated to the individual dipole strength of the source in ACC thus revealing a close relationship of BOLD signal and possibly underlying neuronal electrical activity in SI and the ACC. The BOLD signal change decreased in SI over time. Dipole strength of the ACC source decreased over the experiment and increased during the stimulation block suggesting sensitization and habituation effects in these areas.     

Quality discrimination for noxious stimuli in secondary somatosensory cortex: A MEG‐study

A complex cortical network is believed to encode the multi‐dimensionality of the human pain experience. In the present study, we used magnetoencephalography (MEG) to examine whether the cortical processing of noxious stimuli with different psychophysical properties differs in primary (S1) and secondary (S2) somatosensory cortices. Noxious low (condition 1) and high (condition 2) current density stimulations of equal stimulus intensities were applied at the left forearm in 12 subjects in a randomised order. Concomitantly, subjects had to evaluate the corresponding sensory‐discriminative and affective‐motivational pain dimensions. MEG revealed an increased activation of bilateral secondary somatosensory cortices (S2) during condition 2 compared to condition 1. Higher activations of bilateral S2 were significantly correlated with higher scores for the sensory‐discriminative component during condition 2. In contrast, corresponding scores for the affective‐motivational pain dimension did not differ between both conditions. Therefore, concerning the sensory dimension of the human pain experience we conclude that the S2 cortex is involved in the encoding of quality discrimination.     

Activation of central sympathetic networks during innocuous and noxious somatosensory stimulation

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

Representation of somatosensory inputs within the cortical autonomic network

Regions of the cortical autonomic network (CAN) are activated during muscle contraction. However, it is not known to what extent CAN activation patterns reflect muscle sensory inputs, top-down signals from the motor cortex, and/or motor drive to cardiovascular structures. The present study explored the functional representation of somatosensory afferent input within the CAN with an a priori interest in the insula and ventral medial prefrontal cortex (vMPFC) (n=12). Heart rate (HR) and functional MRI data were acquired during 1) 30s periods of electrical stimulation of the wrist flexors at sub-motor (SUB; Type I,II afferents) and 2) motor thresholds (MOT; Type I,II,III afferents), 3) volitional wrist flexion at 5% maximal voluntary contraction (MVC) to match the MOT tension (VOL5%), and 4) volitional handgrip at 35% MVC to elicit tachycardia (VOL35%). Compared with rest, HR did not change during SUB, MOT, or VOL5% but increased during VOL35% (p<0.001). High frequency HR variability was 29.42±18.87 ms(2) (mean±S.D.) at rest and 39.85±27.60 ms(2) during SUB (p=0.06). High frequency HR variability was decreased during VOL35% compared to rest (p≤0.005). SUB increased activity in the bilateral posterior insula, vMPFC, subgenual anterior cingulate cortex (ACC), mid-cingulate cortex (MCC), and posterior cingulate cortex. MOT increased activity in the left posterior insula and MCC. During VOL5%, activity increased in the right anterior-mid insula. VOL35% was associated with activity in the bilateral insula as well as vMPFC and subgenual ACC deactivation. These data suggest that the left posterior insula processes sensory input from muscle during passive conditions and specifically that Type I and/or II muscle afferent stimulation during SUB impacts the vMPFC and/or subgenual ACC, regions believed to be involved in brain default mode and parasympathetic activity.     

The anterior cingulate cortex contains distinct areas dissociating external from self-administered painful stimulation: a parametric fMRI study

The anterior cingulate cortex (ACC) has a pivotal role in human pain processing by integrating sensory, executive, attentional, emotional, and motivational components of pain. Cognitive modulation of pain-related ACC activation has been shown by hypnosis, illusion and anticipation. The expectation of a potentially noxious stimulus may not only differ as to when but also how the stimulus is applied. These combined properties led to our hypothesis that ACC is capable of distinguishing external from self-administered noxious tactile stimulation. Thermal contact stimuli with noxious and non-noxious temperatures were self-administered or externally applied at the resting right hand in a randomized order. Two additional conditions without any stimulus-eliciting movements served as control conditions to account for the certainty and uncertainty of the impending stimulus. Calculating the differences in the activation pattern between self-administered and externally generated stimuli revealed three distinct areas of activation that graded with perceived stimulus intensity: (i) in the posterior ACC with a linear increase during external but hardly any modulation for the self-administered stimulation, (ii) in the midcingulate cortex with activation patterns independent of the mode of application and (iii) in the perigenual ACC with increasing activation during self-administered but decreasing activation during externally applied stimulation. These data support the functional segregation of the human ACC: the posterior ACC may be involved in the prediction of the sensory consequences of pain-related action, the midcingulate cortex in pain intensity coding and the perigenual ACC is related to the onset uncertainty of the impending stimuli.     

Functional brain imaging of trigeminal neuralgia

We used functional magnetic resonance imaging (fMRI) to analyze changes in brain activity associated with stimulation of the cutaneous trigger zone in patients with classic trigeminal neuralgia (CTN). Fifteen consecutive patients with CTN in the second or third division of the nerve, were included in this study. The fMRI paradigm consisted of light tactile stimuli of the trigger zone and the homologous contralateral area. Stimulation of the affected side induced pain in seven patients, but was not painful in eight patients on the day of the experiment. Painful stimuli were associated with significantly increased activity in the spinal trigeminal nucleus (SpV), thalamus, primary and secondary somatosensory cortices (S1, S2), anterior cingulate cortex (ACC), insula, premotor/motor cortex, prefrontal areas, putamen, hippocampus and brainstem. Nonpainful stimulation of the trigger zone activated all but three of these structures (SpV, brainstem and ACC). After a successful surgical treatment, activation induced by stimulation of the operated side was confined to S1 and S2. Our data demonstrate the pathological hyperexcitability of the trigeminal nociceptive system, including the second order trigeminal sensory neurons during evoked attacks of CTN. Such sensitization may depend on pain modulatory systems involving both the brainstem (i.e. periaqueductal gray and adjacent structures) and interconnected cortical structures (i.e. ACC). The fact that large portions of the classical ‘pain neuromatrix’ were also activated during nonpainful stimulation of the trigger zone, could reflect a state of maintained sensitization of the trigeminal nociceptive systems in CTN.     

Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case

Parietal, insular and anterior cingulate cortices are involved in the processing of noxious inputs and genesis of pain sensation. Parietal lesions may generate central pain by mechanisms generally assumed to involve the 'medial' pain system (i.e. medial thalamic nuclei and anterior cingulate cortex (ACC)). We report here PET and fMRI data in a patient who developed central pain and allodynia in her left side after a bifocal infarct involving both the right parietal cortex (SI and SII) and the right ACC (Brodmann areas 24 and 32), thus questioning the schematic representation of cortical pain processing. No rCBF increase was found in any part of the residual cingulate cortices, neither in the basal state (which included spontaneous pain and extended hypoperfusion around the infarct), nor during left allodynic pain. Thus, as previously observed in patients with lateral medullary infarct, neither spontaneous pain nor allodynia reproduce the cingulate activation observed after noxious pain in normal subjects. Conversely, both PET and fMRI data argue in favour of plastic changes in the 'lateral discriminative' pain system. Particularly, allodynia was associated with increased activity anteriorly to the infarct in the right insula/SII cortex. This response is likely to be responsible for the strange and very unpleasant allodynic sensation elicited on the left side by a non-noxious stimulation.     

Anatomical connections between brain areas activated during rectal distension in healthy volunteers: A visceral pain network

Diffusion Tensor Imaging (DTI) is a promising new imaging method allowing in vivo mapping of anatomical connections in the living human brain. We combined DTI with functional magnetic resonance imaging (fMRI) to investigate the anatomical relationships between areas involved in visceral sensations in humans. Non‐painful and moderately painful rectal distensions were performed in 11 healthy women (38.4 ± 3.1 years). fMRI was used to analyse the changes in brain activity during both types of distension. Then, DTI was applied for tracking fibers between the main activated regions. Non‐painful distension bilaterally activated the PreFrontal Cortex (PFC), the Anterior Cingulate Cortex (ACC) and the right insula. Painful distension bilaterally activated the primary (S1) and secondary (S2) somatosensory cortices, the motor cortex, the frontal inferior gyrus, the thalamus, the insula, the striatum and the cerebellum. DTI revealed direct connections between insula, and the four areas more frequently activated in this study, i.e. ACC, thalamus, S1, S2 and PFC. The combined use of fMRI and DTI in healthy subjects during rectal distension revealed a neural network of visceral sensory perception involving the insula, thalamus, somatosensory cortices, ACC and PFC.     

Multimodal therapeutic assessment of peripheral nerve stimulation in neuropathic pain: Five case reports with a 20‐year follow‐up

Neuropathic pain following peripheral nerve lesion is highly resistant to conventional pain treatments but may respond well to direct electrical peripheral nerve stimulation (PNS). In the 1980 s, we treated a series of 11 peripheral neuropathic pain patients with PNS. A first outcome assessment, conducted after a 52‐month follow‐up, revealed that the majority of the patients were significantly improved. Here, we present the results of a second and more comprehensive follow‐up, conducted after more than 20 years of PNS usage. Of the six patients still using PNS, five participated in a multimodality assessment of the long‐term efficacy of PNS. Home evaluations showed reduced pain ratings and improved quality‐of‐life during active periods of stimulation. Quantitative sensory testing confirmed the neuropathic character of the pain complaints. PNS had no significant overall effect on tactile detection, cool, warmth, cold pain and heat pain thresholds. Laser‐evoked potentials showed an enlarged N2–P2 complex during active PNS. Positron Emission Tomography revealed that PNS decreased activation in the pain matrix at rest and during thermal stimulation. PNS led to increased blood flow not only in primary somatosensory cortex, but also in anterior cingulate and insular cortices, suggesting that besides activation of the dorsal column lemniscal system, other mechanisms may play a role in its analgesic effects. These data show that PNS can provide truly long‐term pain relief in carefully selected patients and they provide some objective quantitative data in support of this. They encourage the planning of future prospective studies in a larger cohort of patients.     

Long-term depression of spinal nociception and pain in man: Influence of varying stimulation parameters

Electrical low-frequency stimulation (LFS) of spinal afferents induces long-term depression (LTD) of nociceptive processing in rodents. LTD and its parameters in man are largely unknown. This study addresses the hypothesis that LTD of spinal nociception and pain in man depends on LFS frequency (0.5, 1, 2 Hz), number of electrical pulses (300, 600, 1200), intensity (relating to pain threshold I_P: 1 × I_P, 2 × I_P, 4 × I_P), and on LFS repetition. One hundred and twenty electrophysiological and psychophysical experiments were performed in 29 healthy volunteers. Painful electrical test stimulation (0.125 Hz) and conditioning LFS were applied to right hand dorsum by a concentric electrode. Somatosensory evoked cortical potentials (SEP) were recorded and volunteers rated stimulus intensity. LFS with 0.5, 1, and 2 Hz induced significant reduction of SEP and pain ratings as compared to Control group. Effect on SEP amplitude after 1 Hz LFS preponderated that of 2 Hz stimulation. LTD of SEP and pain perception was induced by noxious LFS with 300–1200 pulses. SEP suppression augmented with increasing number of pulses. LFS with intensities 2 × I_P and 4 × I_P evoked sustained depression of SEP and pain perception in comparison to Control and 1 × I_P LFS. Established LTD after single LFS was amplified by an additional second LFS. Hence this study provides electrophysiological and psychophysical evidence for LTD of spinal nociceptive processing and pain perception in man and indicates appropriate LFS parameters 1 Hz, 1200 pulses and 4 × I_P for future studies on human LTD.     

Cerebral activation during anal and rectal stimulation.

While the rectum is innervated by visceral afferents, the anal canal is innervated by the somatosensory pudendal nerve. The representation of these two central domains of intestinal sensations in the human brain is largely unknown. Nonpainful pneumatic stimulation of the anal canal and the distal rectum using event-related functional magnetic resonance imaging (fMRI) was performed in eight healthy subjects. Subjective scaling of sensations revealed no differences in unpleasantness and pain during both stimuli. Both types of stimuli revealed fMRI activation in secondary somatosensory, insula, cingular gyrus, left inferior parietal, and right orbitofrontal cortex. Anal stimulation resulted in additional activation of primary sensory and motor cortex, supplementary motor area, and left cerebellum. We concluded that viscerorectal and somatosensory anal stimulation predominantly differ in their primary sensory activation and additional activation in motor areas. This motor response following aversive somatosensory stimuli may be caused by a reflexive avoidance reaction which is not observed after the more diffuse experienced visceral stimulation.     

Neural correlates of auditory sensory memory and automatic change detection

An auditory event-related potential component, the mismatch negativity (MMN), reflects automatic change detection and its prerequisite, sensory memory. This study examined the neural correlates of automatic change detection using BOLD fMRI and two rates of presentation previously shown to induce either a large or no MMN. A boxcar block design was employed in two functional scans, each performed twice. A block consisting of 1000-Hz standards (S) alternated with one consisting of 1000-Hz standards and 2000-Hz infrequent deviants (S + D). Presentation rate was either 150 or 2400 ms. Fourteen participants were instructed to ignore all auditory stimulation and concentrate on a film (no audio) by reading subtitles. Data analysis used SPM99 and random effects approach. Cluster statistics (P < 0.05, corrected) were employed at a height threshold of P < 0.001. At the short ISI, there was a significant BOLD response in the right superior temporal gyrus (STG), the left insula, and the left STG (including parts of primary auditory cortex). There were no suprathreshold clusters at the long rate, with S + D blocks inducing no greater activity than S blocks. These results support the hypothesis that the automatic detection of auditory change occurs in the STG bilaterally and relies on the maintenance of sensory memory traces.     

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.     

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

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

Brain activity related to temporal summation of C-fiber evoked pain

Temporal summation of "second pain" (TSSP) is considered to be the result of C-fiber-evoked responses of dorsal horn neurons, termed 'windup'. This phenomenon is dependent on stimulus frequency (0.33 Hz) and relevant for central sensitization and chronic pain. Previous brain imaging studies have only been used to characterize neural correlates of second pain but not its temporal summation. We utilized functional magnetic resonance imaging (fMRI) in healthy volunteers to measure brain responses associated with TSSP. Region of interest analysis was used to assess TSSP related brain activation. Eleven pain-free normal subjects underwent fMRI scanning during repetitive heat pulses to the right foot at 0.33 and 0.17 Hz. Stimulus intensities were adjusted to each individual's heat sensitivity to achieve comparable TSSP ratings of moderate pain in all subjects. As predicted, experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. fMRI statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including contralateral thalamus (THAL), S1, bilateral S2, anterior and posterior insula (INS), mid-anterior cingulate cortex (ACC), and supplemental motor areas (SMA). TSSP ratings were significantly correlated with brain activation in somatosensory areas (THAL, S1, left S2), anterior INS, and ACC. These results show that neural responses related to TSSP are evoked in somatosensory processing areas (THAL, S2), as well as in multiple areas that serve other functions related to pain, such as cognition (ACC, PFC), affect (INS, ACC, PAG), pre-motor activity (SMA, cerebellum), and pain modulation (rostral ACC).     

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

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

Effect of hypnotic pain modulation on brain activity in patients with temporomandibular disorder pain

Hypnosis modulates pain perception but the associated brain mechanisms in chronic pain conditions are poorly understood. Brain activity evoked by painful repetitive pin-prick stimulation of the left mental nerve region was investigated with use of fMRI in 19 patients with painful temporomandibular disorders (TMD) during hypnotic hypoalgesia and hyperalgesia and a control condition. Pain intensity and unpleasantness of the painful stimulation was scored on a 0-10 Numerical Rating Scale (NRS). NRS pain and unpleasantness scores during hypnotic hypoalgesia were significantly lower than in the control condition and significantly higher in the hypnotic hyperalgesia condition. In the control condition, painful stimulation caused significant activation of right posterior insula, primary somatosensory cortex (SI), BA21, and BA6, and left BA40 and BA4. Painful stimulation during hypnotic hyperalgesia was associated with increased activity in right posterior insula and BA6 and left BA40 whereas hypnotic hypoalgesia only was associated with activity in right posterior insula. Unexpectedly, direct contrasts between control and hypnotic hyperalgesia conditions revealed significant decreases in S1 during hyperalgesia. Direct contrasts between control and hypnotic hypoalgesia conditions demonstrated significant decreases in right posterior insula and BA21, as well as left BA40 during hypoalgesia. These findings are the first to describe hypnotic modulation of brain activity associated with nociceptive processing in chronic TMD pain patients and demonstrate that hypnotic hypoalgesia is associated with a pronounced suppression of cortical activity and a disconnection between patient-based scores and cortical activity in S1 during hypnotic hyperalgesia.