Tanja Schlereth

Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex.

Pain perception comprises sensory and emotional dimensions. While the emotional experience is thought to be represented in the right hemisphere, we here report a left-hemisphere dominance for the early sensory component of pain perception using brain electrical source analysis of laser-evoked potentials. Ten right-handed subjects underwent several series of laser radiant heat stimuli to pairs of parallel lines on the dorsum of the left or right hand. Stimulus location and intensity were randomised independently. The sensory-discriminative aspects of pain were emphasised by asking the subjects to perform either a spatial or an intensity discrimination task and were contrasted with active distraction by mental arithmetics. Pain ratings obtained after each of the laser stimulus series revealed an analgesic effect of distraction (27%, P < 0.001). Four equivalent dipole sources were active in the latency range of 100-200 ms (bilateral operculoinsular cortex, midcingulate gyrus, postcentral gyrus). The sources in the operculoinsular cortex exhibited (a) the shortest peak latency (155 +/- 6 ms), (b) the most pronounced enhancement during spatial and intensity discrimination tasks compared to active distraction (43%, P < 0.001), and (c) a significantly stronger source activity in the left hemisphere independent of stimulation side (23%, P < 0.05). The distribution of these sources extended into the dorsal insula. The postcentral source had the longest peak latency (180 +/- 7 ms); its source strength was task-dependent (25%, P = 0.051) but exhibited no hemisphere dominance. The midcingulate source had an intermediate peak latency (169 +/- 7 ms). Its source strength was modulated by tasks, but this modulation was significant only in the latency range >200 ms (46%, P < 0.001). These findings suggest a dominant role of the left frontal operculum and adjacent dorsal insula in the early sensory-discriminative dimensions of pain processing. This region has been proposed to be the cortical projection target of nociceptive pathways from the spinal cord to the ventroposteroinferior and ventromedial (its posterior part: VMpo) thalamic nuclei.

Differential nociceptive deficits in patients with borderline personality disorder and self-injurious behavior: laser-evoked potentials, spatial discrimination of noxious stimuli, and pain ratings

&NA; Approximately 70–80% of women meeting criteria for borderline personality disorder (BPD) report attenuated pain perception or analgesia during non‐suicidal, intentional self‐mutilation. The aim of this study was to use laser‐evoked potentials (LEPs) and psychophysical methods to differentiate the factors that may underlie this analgesic state. Ten unmedicated female patients with BPD (according to DSM‐IV) and 14 healthy female control subjects were investigated using brief radiant heat pulses generated by a thulium laser and five‐channel LEP recording. Heat pulses were applied as part of a spatial discrimination task (two levels of difficulty) and during a mental arithmetic task. BPD patients had significantly higher heat pain thresholds (23%) and lower pain ratings (67%) than control subjects. Nevertheless, LEP amplitudes were either normal (N1, P2, P3) or moderately enhanced in BPD patients (N2). LEP latencies and task performance did not differ between patients and control subjects. The P3 amplitudes, the vertex potential (N2–P2), and the N1, which is generated near the secondary somatosensory cortex, were significantly reduced during distraction by mental arithmetic in both groups. In addition, P3 amplitudes reflected task difficulty. This study confirms previous findings of attenuated pain perception in BPD. Normal nociceptive discrimination task performance, normal LEPs, and normal P3 potentials indicate that this attenuation is neither related to a general impairment of the sensory‐discriminative component of pain, nor to hyperactive descending inhibition, nor to attention deficits. These findings suggest that hypoalgesia in BPD may primarily be due to altered intracortical processing similar to certain meditative states.

Spatial discrimination thresholds for pain and touch in human hairy skin.

&NA; The traditional concept that pain is poorly localized has been challenged by recent studies, where subjects were able to point to the stimulated spot on the skin with an accuracy of 10–20 mm. Pointing movements themselves, however, have errors of about 15 mm. To determine the limits of sensory performance of the nociceptive system independent of motor performance, point localization of heat pain (540 mJ punctate laser stimuli, 5 mm diameter), mechanical pain (256 mN punctate probe, 200 &mgr;m diameter), and touch (16 mN von Frey probe, 1.1 mm diameter) were tested in a two‐alternative forced‐choice paradigm in 12 healthy subjects. Stimuli were applied in randomized order to two parallel lines on the back of the hand (4–32 mm distance). The cumulative distribution functions for correct localization were of similar sigmoid shape for all test stimuli, indicating logarithmic normal distributions. The 75% correct localization threshold for painful heat was 8.6 mm (3.1±0.1 log2 units) and did not differ significantly from that of non‐painful touch (9.0 mm, 3.2±0.2 log2 units). Localization of mechanically‐induced pain (5.1 mm, 2.4 ± 0.2 log2 units) was significantly more accurate than both heat pain and touch, possibly due to a synergism of two different sensory channels, the tactile channel and the nociceptive channel, which were activated simultaneously. For all three stimuli, discrimination was significantly better in radial–ulnar compared to proximal‐distal direction, which might be related to oval receptive field shapes. Sequential spatial discrimination for touch was significantly better than simultaneous spatial discrimination tested with a grating orientation task (18.9 mm), but both were one order of magnitude worse than at the finger tip (1.3 mm, 0.4±0.1 log2 units). In conclusion, pain evoked by radiant heat pulses and touch evoked by von Frey probes were localized with similar precision on the back of the hand. These findings indicate that outside the tactile fovea at finger tips or lips the spatial discrimination capacities of the nociceptive and tactile systems are about equal.

Development of a severity score for CRPS

&NA; The clinical diagnosis of Complex Regional Pain Syndrome (CRPS) is a dichotomous (yes/no) categorization necessary for clinical decision‐making. However, such dichotomous diagnostic categories do not convey an individuals subtle and temporal gradations in severity of the condition, and have poor statistical power when used as an outcome measure in research. This study evaluated the validity and potential utility of a continuous type score to index severity of CRPS. Psychometric and medical evaluations were conducted in 114 CRPS patients and 41 non‐CRPS neuropathic pain patients. Based on the presence/absence of 17 clinically‐assessed signs and symptoms of CRPS, an overall CRPS Severity Score (CSS) was derived. The CSS discriminated well between CRPS and non‐CRPS patients (p < .001), and displayed strong associations with dichotomous CRPS diagnoses using both IASP diagnostic criteria (Eta = 0.69) and proposed revised criteria (Eta = 0.77–0.88). Higher CSS was associated with significantly higher clinical pain intensity, distress, and functional impairments, as well as greater bilateral temperature asymmetry and thermal perception abnormalities (p’s < .05). In an archival prospective dataset, increases in anxiety and depression from pre‐surgical baseline to 4 weeks post‐knee arthroplasty were found to predict significantly higher CSS at 6‐ and 12‐month follow‐up (p’s < .05). Results indicate the CSS corresponds with and complements currently accepted dichotomous diagnostic criteria for CRPS, and support its validity as an index of CRPS severity. Its utility as an outcome measure in research studies is also suggested, with potential statistical advantages over dichotomous diagnostic criteria.

Peripheral amplification of sweating – a role for calcitonin gene‐related peptide

Neuropeptides are the mediators of neurogenic inflammation. Some pain disorders, e.g. complex regional pain syndromes, are characterized by increased neurogenic inflammation and by exaggerated sudomotor function. The aim of this study was to explore whether neuropeptides have a peripheral effect on human sweating. We investigated the effects of different concentrations of calcitonin gene‐related peptide (CGRP), vasoactive intestinal peptide (VIP) and substance P (SP) on acetylcholine‐induced axon reflex sweating in healthy subjects (total n= 18). All substances were applied via dermal microdialysis. The experiments were done in a parallel setting: ACh alone and ACh combined with CGRP, VIP or SP in various concentrations were applied. Acetylcholine (10−2m) always elicited a sweating response, neuropeptides alone did not. However, CGRP significantly enhanced ACh‐induced sweating (P < 0.01). Post hoc tests revealed that CGRP in physiological concentrations of 10−7–10−9m was most effective. VIP at any concentration had no significant effect on axon reflex sweating. The duration of the sweating response (P < 0.01), but not the amount of sweat, was reduced by SP. ACh‐induced skin blood flow was significantly increased by CGRP (P < 0.01), but unaltered by VIP and SP. The results indicate that CGRP amplifies axon reflex sweating in human skin.

The Sympathetic Nervous System and Pain

The sympathetic nervous system (SNS) and pain interact on many levels of the neuraxis. In healthy subjects, activation of the SNS in the brain usually suppresses pain mainly by descending inhibition of nociceptive transmission in the spinal cord. Furthermore, some experimental data even suggest that the SNS might control peripheral inflammation and nociceptive activation. However, even subtle changes in pathophysiology can dramatically change the effect of SNS on pain, and vice versa. In the periphery, inflammation or nociceptive activation is enhanced, spinal descending inhibition is reversed to spinal facilitation, and finally the awareness of all these changes will induce anxiety, which furthermore amplifies pain perception, affects pain behavior, and depresses mood. Unraveling the detailed molecular mechanisms of how this interaction of SNS and pain is established in health and disease will help us to treat pain more successfully in the future.

Activation of Cutaneous Immune Responses in Complex Regional Pain Syndrome

UNLABELLED The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are elevated in experimental skin blister fluid from CRPS-affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS, exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS, keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS, there was reduced keratinocyte proliferation, leading to epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS. PERSPECTIVE The results of this study support the hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain.

Complex regional pain syndrome An optimistic perspective

Complex regional pain syndrome (CRPS) presents with clinical symptoms that can no longer be explained by the initial trauma, including pain, sensory, motor, and trophic symptoms, and impairment of autonomic control of the limb. These symptoms spread distally and go beyond single nerve innervation territories. Typically, the symptoms change through the course of CRPS as a result of the varying pathophysiology. Diagnosis is made clinically after the rigorous elimination of other possible causes, and 3-phase bone scintigraphy can be a useful tool for confirming CRPS. In acute stages, inflammatory symptoms prevail and should be treated with anti-inflammatory agents (steroids), bisphosphonates, or topical application of dimethyl sulfoxide. In chronic stages, many symptoms are related to so-called central neuroplasticity; these include hyperalgesia, sensory loss, motor symptoms, body perception disturbance, autonomic symptoms, and learned incorrect behavior such as nonuse. At this stage, the only medical treatment that is effective against pain without improving the function is ketamine infusions, but this has side effects. Physical therapy, graded motor imagery, and pain exposure/graded exposure in vivo therapy can help to overcome central reorganization. If a relevant mental comorbidity is present, the patient should be referred for psychotherapeutic treatment. Invasive treatment should be restricted to special cases and only offered after psychosomatic assessment. If these recommendations are followed, CRPS prognosis is not as poor as commonly assumed. Whether the patients can return to their previous life depends on particular individual factors.

Hyperhidrosis--causes and treatment of enhanced sweating.

BACKGROUND Basically two types of sweating exist: thermoregulatory and emotional sweating. They are controlled by different centers: thermo regulatory sweating is regulated predominantly by the hypothalamus, emotional sweating predominantly by the limbic system. Enhanced sweating, called hyperhidrosis, can be generalized or focal. Primary focal hyperhidrosis is the most common type and affects the axillae, hands, feet, and face--areas principally involved in emotional sweating. Secondary hyperhidrosis develops due to dysfunction of the central or peripheral nervous system. METHODS Review based on a selective search of the literature via Medline and on the guidelines of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften [AWMF]). RESULTS Various conservative and surgical treatments exist for hyperhidrosis. Conservative treatment options are the local application of aluminum chloride, tap water iontophoresis, and the intracutaneous injection of botulinum toxin. Surgical approaches include endoscopic sympathectomy and axillary tumescent curettage and liposuction, removing the sweat glands. Systemic drugs (e.g. anticholinergic substances) can be used in the treatment of generalized hyperhidrosis. CONCLUSION A step-by-step approach is recommended for the treatment of hyperhidrosis. Local treatment options with few and minor side effects should be tried first.

In vivo release of non-neuronal acetylcholine from the human skin as measured by dermal microdialysis: effect of botulinum toxin.

Acetylcholine is synthesized in the majority of non‐neuronal cells, for example in human skin. In the present experiments, the in vivo release of acetylcholine was measured by dermal microdialysis. Two microdialysis membranes were inserted intradermally at the medial shank of volunteers. Physiological saline containing 1 μM neostigmine was perfused at a constant rate of 4 μl min−1 and the effluent was collected in six subsequent 20 min periods. Acetylcholine was measured by high‐pressure liquid chromatography (HPLC) combined with bioreactors and electrochemical detection. Analysis of the effluent by HPLC showed an acetylcholine peak that disappeared, when the analytical column was packed with acetylcholine‐specific esterase, confirming the presence of acetylcholine. In the absence of neostigmine, 71±51 pmol acetylcholine (n=4) was found during a 120 min period. The amount increased to 183±43 pmol (n=34), when the perfusion medium contained 1 μM neostigmine. Injection of 100 MU botulinum toxin subcutaneously blocked sweating completely, but the release of acetylcholine was not affected (botulinum toxin treated skin: 116±70 pmol acetylcholine/120 min; untreated skin: 50±20 pmol; n=4). Quinine (1 mM), inhibitor of organic cation transporters, and carnitine (0.1 mM), substrate of the Na+‐dependent carnitine transporter OCTN2, tended to reduce acetylcholine release (by 40%, not significant). Our experiments demonstrate, for the first time, the in vivo release of non‐neuronal acetylcholine in human skin. Organic cation transporters are not predominantly involved in the release of non‐neuronal acetylcholine from the human skin.