BACKGROUND:Migraine shows a cyclic pattern with an inter-ictal-, a pre-ictal, an ictal- and a post-ictal phase. We aimed to examine changes in psychophysical parameters during the migraine cycle.METHODS:The perception of nociceptive and non-nociceptive stimuli and an electrically induced axon-reflex-erythema were assessed in 20 healthy controls and 14 migraine patients on five consecutive days according to different phases of the migraine cycle. Pain was rated three times during a 10-second electrical stimulus. The size of the axon-reflex-erythema was determined using laser-Doppler-imaging. Intensity and hedonic estimates of odours presented by Sniffin' Sticks were rated.RESULTS:In healthy controls, no significant changes over the test days were observed. In migraine patients pain thresholds at the head decreased with an ictal minimum. Less habituation after five seconds of stimulation at the head was found pre-ictally, whereas reduced habituation to 10-second electrical stimulation was present in all phases. The axon-reflex-erythema size showed an inter-ictal-specific minimum at the head. odours were perceived ictally as more unpleasant and intense.CONCLUSIONS:Somatosensory functions, pain thresholds and habituation as predominantly central parameters, axon-reflex-erythema as a peripheral function of trigeminal neurons and odour perception as a predominantly extra-thalamic sensation change specifically over the migraine cycle indicating complex variations of neuronal signal processing.

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.

Sensory gain (i.e., hyperalgesia) and sensory loss (ie, hypoalgesia) are key features of neuropathic pain syndromes. Previously, we showed that conditioning electrical stimuli may provoke either sensory gain or decline in healthy subjects, depending on the stimulation frequencies applied. In the present study we sought to determine whether sensory decline induced by 20-Hz electrical stimulation preferentially of peptidergic C-nociceptors induces antihyperalgesic effects in a transdermal electrical pain model. Twelve healthy volunteers underwent 0.5-Hz noxious electrical stimulation of the right volar forearm for 35minutes, leading to secondary mechanical hyperalgesia. In 5 sessions the 0.5-Hz stimulus was applied either alone (Stim1) or with concurrent noxious 20-Hz stimulation at different sites (Stim2: ipsilateral 5 cm distance; Stim3: ipsilateral 10 cm distance; Stim4: contralateral arm; Stim5: contralateral dorsal foot). Close concurrent 20-Hz stimulation (Stim2) inhibited the development of hyperalgesia, as measured using the mechanical pain threshold, while remote and contralateral 20-Hz stimulation had no impact on mechanical pain threshold. However, after ipsilateral (stim2, stim3) and contralateral (stim4) forearm stimulation the area of hyperalgesia around the 0.5-Hz stimulation site was significantly reduced. Thus, antihyperalgesia was induced in a homotopic and in a heterotopic ipsisegmental manner. Underlying mechanisms may include neuroplastic changes of pro- and antinociceptive systems at the spinal or supraspinal level. We conclude that 20-Hz noxious electrical stimulation may represent a neurostimulatory paradigm with antihyperalgesic properties. These findings may thus be of relevance for the future therapy of neuropathic pain syndromes as well. Sensory decline induced by 20-Hz electrical stimulation of peptidergic C-nociceptors induces antihyperalgesic effects in a transdermal electrical pain model.

The insula plays a key role in brain processing of noxious and innocuous thermal stimuli. The anterior and the posterior portions of the insular cortex are involved in different ways in nociceptive and thermoceptive processing. Therefore, their stimulus-specific functional connectivity may also differ. Here we used functional magnetic resonance imaging (fMRI) to investigate the activity and functional connectivity of insular cortex subregions during noxious and innocuous thermal stimulation. In 11 healthy subjects, psychophysically controlled noxious and innocuous warm and cold stimuli were applied to the left forearm. To differentiate between the subregions of the insular cortex involved in pain processing and those involved in temperature processing, a 2×2 factorial fMRI analysis was performed. Pain processing insular areas (main effect of pain) were detected in bilateral aINS and contralateral pINS. Temperature processing insular areas (main effect of temperature) were also found in bilateral aINS and contralateral pINS. The individual signal time courses from the pain- and temperature processing insular activation clusters were used for calculation and comparison of stimulus-specific functional connectivity of aINS and pINS by means of a correlation analysis. As expected, both aINS and pINS were functionally connected to a large brain network — which predominantly includes areas involved in nociception and thermoception: primary (S1) and secondary (S2) somatosensory cortices, cingulate gyrus, prefrontal cortex (PFC) and parietal association cortices (PA). When statistically compared, during both noxious and innocuous stimulation, aINS was more strongly connected to PFC and to ACC than was pINS; pINS meanwhile was more strongly connected to S1 and to the primary motor cortex (M1). Interestingly, S2 was more strongly connected to aINS than to pINS during painful stimulation but not during innocuous thermal stimulation. We conclude that aINS is more strongly functionally connected to areas known for affective and cognitive processing, whereas pINS is more strongly connected with areas known for sensory-discriminative processing of noxious and somatosensory stimuli.

Endogenous pain modulation may provide facilitation or inhibition of nociceptive input by three main mechanisms. Firstly, modification of synaptic strength in the spinal dorsal horn may increase or decrease transmission of nociceptive signals to the brain. Secondly, local dorsal horn interneurons provide both feed-forward and feed-back modulation to spinothalamic and spinobulbar projection neurons. Thirdly, descending systems originating in the brainstem exert top-down modulation of nociceptive input at the spinal level. Not much is known on the activity of these systems in complex regional pain syndrome (CRPS). CRPS is a chronic pain condition characterized by burning pain and abnormalities in the sensory, motor and autonomous nervous system. In the present study, we tested changes in endogenous pain modulation in 27 CRPS patients compared with age-matched healthy controls. We applied repetitive noxious electrical stimuli (stimulation frequency 1 Hz) at the dorsal aspect of affected and unaffected hands in patients and to corresponding hands in controls. As known from previous studies this protocol simultaneously activates inhibitory and facilitatory pain modulating systems. This results in adaptation to the repetitive noxious stimulus, and simultaneously and at the same site, in development of an area of pinprick hyperalgesia. We measured (i) pain adaptation during the course of stimulation and (ii) the provoked area of pinprick hyperalgesia. These parameters were used as activity measures of pain inhibitory and pain facilitatory systems. As both measures result from gross inhibitory and gross facilitatory activity in pain modulatory systems, pain adaptation reflects net pain inhibition and area of pinprick hyperalgesia net pain facilitation. We found (i) decreased adaptation to painful electrical stimuli on both affected and unaffected hands of CRPS patients compared to healthy controls and (ii) increased areas of hyperalgesia on affected hands of CRPS patients compared to unaffected hands of CRPS patients and healthy controls. These findings imply a shift from inhibition towards facilitation of nociceptive input in CRPS patients, based on differential activation of subcomponents of the endogenous pain modulatory system. The differences were not correlated with duration of the disease, pain intensity, autonomic or motor function scores, presence or degree of evoked pain. However, significant correlation was found with the extent of adaptation and hyperalgesia on the unaffected hand. Thus, we hypothesize that differential activity in endogenous pain modulating systems may be not only a result of CRPS, but a potential risk factor for its development.

Recently, several functional imaging studies have shown that sensorimotor cortical representations may be changed in complex regional pain syndromes (CRPS). Therefore, we investigated tactile performance and tactile learning as indirect markers of cortical changes in patients with CRPS type I and controls. Patients had significant higher spatial discrimination thresholds at CRPS-affected extremities compared to both unaffected sides and control subjects. Furthermore, in order to improve tactile spatial acuity we used a Hebbian stimulation protocol of tactile coactivation. This consistently improved tactile acuity, both in controls and patients. However, the gain of performance was significantly lower on the CRPS-affected side implying an impaired perceptual learning ability. Therefore, we provide further support for an involvement of the CNS in CRPS, which may have implications to future neurorehabilitation strategies for this disease.

The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. In the present study we sought to characterize motor dysfunction in CRPS patients using kinematic analysis and functional imaging investigations on the cerebral representation of finger movements. Firstly, 10 patients and 12 healthy control subjects were investigated in a kinematic analysis assessing possible changes of movement patterns during target reaching and grasping. Compared to controls, CRPS patients particularly showed a significant prolongation of the target phase in this paradigm. The pattern of motor impairment was consistent with a disturbed integration of visual and proprioceptive inputs in the posterior parietal cortex. Secondly, we used functional MRI (fMRI) and investigated cortical activations during tapping movements of the CRPS-affected hand in 12 patients compared to healthy controls (n = 12). During finger tapping of the affected extremity, CRPS patients showed a significant reorganization of central motor circuits, with an increased activation of primary motor and supplementary motor cortices (SMA). Furthermore, the ipsilateral motor cortex showed a markedly increased activation. When the individual amount of motor impairment was introduced as regressor in the fMRI analysis, we were able to demonstrate that activations of the posterior parietal cortices (i.e. areas within the intraparietal sulcus), SMA and primary motor cortex were correlated with the extent of motor dysfunction. In summary, the results of this study suggest that substantial adaptive changes within the central nervous system may contribute to motor symptoms in CRPS.