Hermann O. Handwerker

Patterns of cortical reorganization in complex regional pain syndrome

Objective: To use magnetoencephalography to assess possible cortical reorganization in the primary somatosensory cortex (S1) of patients with complex regional pain syndrome (CRPS). Background: Patterns of pain and sensory symptoms in CRPS may indicate plastic changes of the CNS. Methods: Magnetic source imaging was used to explore changes in the cortical representation of digits (D) 1 and 5 in relation to the lower lip on the unaffected and affected CRPS side in 12 patients. Results: The authors found a significant shrinkage of the extension of the cortical hand representation for the CRPS affected side. The center of the hand was shifted toward the cortical representation of the lip. The cortical reorganization correlated with the amount of CRPS pain (r = 0.792), as measured by the McGill questionnaire, and the extent of mechanical hyperalgesia (r = 0.860). Using multiple regression analysis, the best predictor for the plastic changes was found to be mechanical hyperalgesia. Additionally, S1 sources following tactile stimulation were significantly increased on the CRPS side compared to the unaffected limb. Conclusions: This study showed reorganization of the S1 cortex contralateral to the CRPS affected side. The reorganization appeared to be linked to complaints of neuropathic pain.

Cortical reorganization during recovery from complex regional pain syndrome

Objective: To characterize reorganization of the primary somatosensory cortex (S1) during healing process in complex regional pain syndrome (CRPS). Background: Recently, the authors showed extensive reorganization of the S1 cortex contralateral to the CRPS affected side. Predictors for these plastic changes were CRPS pain and the extent of mechanical hyperalgesia. It is unclear how these S1 changes develop following successful therapy. Methods: The authors used magnetic source imaging to explore changes in the cortical representation of digits (D) 1 and 5 in relation to the lower lip on the unaffected and affected CRPS side in 10 patients during a year or more of follow-up. Results: Cortical reorganization reversed coincident with clinical improvement. A reduction of CRPS pain correlated with recovery from cortical reorganization. Conclusions: Changes of the somatotopic map within the S1 cortex may depend on CRPS pain and its recovery.

TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol.

The aim of this study was to evaluate the psychophysical effects of both TRPA1 and TRPM8 activation in humans by application of either cinnamaldehyde or menthol. We applied 10% cinnamaldehyde or 40% menthol solutions on the forearm in 10 study participants. Quantitative sensory testing and laser Doppler imaging was performed before and after exposure to the compounds. Cinnamaldehyde evoked significant spontaneous pain and induced heat and mechanical hyperalgesia, cold hypoalgesia and a neurogenic axon reflex erythema. In contrast, TRPM8 activation by menthol produced no axon reflex reaction and resulted in cold hyperalgesia. We conclude that agonists of TRPA1 and TRPM8 channels produce strikingly different psychophysical patterns.

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

&NA; 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.

Automatic classification and analysis of microneurographic spike data using a PC/AT

Using a standard PC-AT with a commercial analog data interface a system was designed which supports microneurographic experiments and which may also be used for other types of extracellular spike recordings. The signal is sampled on-line at 25 kHz and a spike is detected if the signal passes a certain threshold. The spikes are displayed on the screen and stored on disk. A second on-line mode records the responses of the examined unit to electrical stimulations, which are used to identify the type of fibre and to test the subsequent spike classification. The spikes are classified off-line using a template matching algorithm, which has unsupervised learning and discrimination phases. The results are displayed in a time-frequency plot and may be checked with the responses to electrical stimulations. Artifacts from EMG and other electrical fields are reliably sorted out. In recordings, which include more than one unit, their spikes are discriminated with a low error rate.

Functional imaging of allodynia in complex regional pain syndrome

Objective: To investigate cerebral activations underlying touch-evoked pain (dynamic–mechanical allodynia) in patients with neuropathic pain. Methods: fMRI was used in 12 patients with complex regional pain syndromes (CRPSs). Allodynia was elicited by gently brushing the affected CRPS hand. Elicited pain ratings were recorded online to obtain pain-weighted predictors. Both activations and deactivations of blood oxygenation level–dependent signals were investigated. Results: Nonpainful stimulation on the nonaffected hand activated contralateral primary somatosensory cortex (S1), bilateral insula, and secondary somatosensory cortices (S2). In contrast, allodynia led to widespread cerebral activations, including contralateral S1 and motor cortex (M1), parietal association cortices (PA), bilateral S2, insula, frontal cortices, and both anterior and posterior parts of the cingulate cortex (aACC and pACC). Deactivations were detected in the visual, vestibular, and temporal cortices. When rating-weighted predictors were implemented, only few activations remained (S1/PA cortex, bilateral S2/insular cortices, pACC). Conclusions: Allodynic stimulation recruits a complex cortical network. Activations include not only nociceptive but also motor and cognitive processing. Using a covariance approach (i.e., implementation of rating-weighted predictors) facilitates the detection of a neuronal matrix involved in the encoding of allodynia. The pattern of cortical deactivation during allodynia may hint at a shift of activation from tonically active sensory systems, like visual and vestibular cortices, into somatosensory-related brain areas.

Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography.

Abstract Regional cerebral blood flow was measured with positron emission tomography (PET) in six healthy volunteers at rest and during experimentally induced, sustained cutaneous pain on the dorsum of the right hand or on the dorsum of the right foot. Pain was inflicted by intracutaneous injection of capsaicin, providing a mainly C-fibre nociceptive stimulus. Statistical analysis showed significant activations along the central sulcus (SI) area when comparing pain in the hand to pain in the foot. Separate comparison of both pain states to a baseline revealed different locations along the central sulcus for hand pain and foot pain. The encountered differences are consistent with what is previously known about the somatotopics of non-painful stimuli. When comparing painful stimuli to baseline, the contralateral anterior cingulate gyrus, the ipsilateral anterior insular cortex and the ipsilateral prefrontal cortex were implicated. The results are consistent with an involvement of SI in the spatial discrimination of acute cutaneous pain.

Left vagus nerve stimulation suppresses experimentally induced pain

Objective: To test whether electric stimulation of the vagus nerve has an antinociceptive effect in humans. Background: In a variety of animal studies, vagus nerve stimulation was shown to inhibit nociceptive behavior as well as electric responses of spinal nociceptive neurons. In humans, chronic left vagus nerve stimulation is used to treat pharmacologically refractory epilepsy. Methods: The authors investigated experimental pain in 10 patients with seizures before and twice after implantation of a vagus nerve stimulator by using different controlled stimuli, including noxious heat, tonic pressure, and short impact. Pain was quantified on a visual analogue scale. Twelve nonepileptic age- and gender-matched individuals served as control subjects. Results: Vagus nerve stimulation reduced increasing pain associated with trains of five consecutive stimuli at 1.5-second intervals (“wind-up”; p < 0.001). In a similar manner, pain on tonic pressure was reduced by vagus nerve stimulation (p < 0.03). Pain associated with single-impact stimuli as well as heat pain thresholds were unaltered under vagus nerve stimulation. Thus, vagus nerve stimulation led to pain relief predominantly in experimental procedures in which pain magnitude was amplified by central processing. The antinociceptive effect was independent of the acute on-off cycles of vagus nerve stimulation. Conclusions: Vagus nerve stimulation is effective in reducing pain in humans. In humans, the antinociceptive effect might rely on central inhibition rather than alterations of peripheral nociceptive mechanisms. These results indicate a promising, potential future role of vagus nerve stimulation in pain treatment.

Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36–67 years old), and these were compared with 77 C-fibers from healthy controls (41–64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was ∼2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

Sudomotor function in sympathetic reflex dystrophy.

Abstract Sudomotor functions were studied in 27 patients suffering from reflex sympathetic dystrophy (RSD) according to the criteria established by Bonica (18 women, 9 men; mean age 50±12.3 years; median duration of disease 8 weeks, range 2–468 weeks). To measure local sweating rates, two small chambers (5 cm2) were affixed to corresponding areas of hairy skin on the affected and unaffected limbs. Dry nitrogen gas was passed through the chambers (270 ml/min) and evaporation was recorded at both devices with hygrometers. Thermoregulatory sweating (TST) was induced by raising body temperature (intake of 0.5 l hot tea and infra‐red irradiation). Local sweating was also induced through an axon reflex (QSART) by transcutaneous iontophoretic application of carbachol (5 min, 1 mA). In addition, skin temperature was measured on the affected and unaffected side by infra‐red thermography. Mean skin temperature was significantly higher on the affected side (P<0.003). In spite of the temperature differences, there was no difference in basal sweating on the affected and unaffected side. However, both methods of sudomotor stimulation lead to significantly greater sweating responses on the affected compared to the unaffected side (TST: P<0.05, QSART: P<0.004). Latency to onset of sweating was significantly shorter on the affected side under both test conditions (P<0.04 and P<0.003, respectively). Sweat responses were not correlated to absolute skin temperature but were probably related to the increased blood flow on the affected side. Our findings imply a differential disturbance of vasomotor and sudomotor mechanisms in affected skin. Whereas vasoconstrictor activity is apparently lowered, sudomotor output is either unaltered or may even be enhanced.