Comparison of T1-weighted landmark placement and ROI transfer onto diffusion-weighted EPI sequences for targeted tractography tasks in the optic nerve.

Diffusion-based tractography in the optic nerve requires sampling strategies assisted by anatomical landmark information (regions of interest [ROIs]). We aimed to investigate the feasibility of expert-placed, high-resolution T1-weighted ROI-data transfer onto lower spatial resolution diffusion-weighted images. Slab volumes from 20 volunteers were acquired and preprocessed including distortion bias correction and artifact reduction. Constrained spherical deconvolution was used to generate a directional diffusion information grid (fibre orientation distribution-model [FOD]). Three neuroradiologists marked landmarks on both diffusion imaging variants and structural datasets. Structural ROI information (volumetric interpolated breath-hold sequence [VIBE]) was respectively registered (linear with 6/12 degrees of freedom [DOF]) onto single-shot EPI (ss-EPI) and readout-segmented EPI (rs-EPI) volumes, respectively. All eight ROI/FOD-combinations were compared in a targeted tractography task of the optic nerve pathway. Inter-rater reliability for placed ROIs among experts was highest in VIBE images (lower confidence interval 0.84 to 0.97, mean 0.91) and lower in both ss-EPI (0.61 to 0.95, mean 0.79) and rs-EPI (0.59 to 0.86, mean 0.70). Tractography success rate based on streamline selection performance was highest in VIBE-drawn ROIs registered (6-DOF) onto rs-EPI FOD (70.0% over 5%-threshold, capped to failed ratio 39/16) followed by both 12-DOF-registered (67.5%; 41/16) and nonregistered VIBE (67.5%; 40/23). On ss-EPI FOD, VIBE-ROI-datasets obtained fewer streamlines overall with each at 55.0% above 5%-threshold and with lower capped to failed ratio (6-DOF: 35/36; 12-DOF: 34/34, nonregistered 33/36). The combination of VIBE-placed ROIs (highest inter-rater reliability) with 6-DOF registration onto rs-EPI targets (best streamline selection performance) is most suitable for white matter template generation required in group studies.

[Complex regional pain syndrome-An update]. / Komplexes regionales Schmerzsyndrom ­ ein Update.

Complex regional pain syndrome (CRPS) is a pain disorder that develops in the hands or feet after injury. Currently, two types are differentiated, CRPS I without and CRPS II with nerve lesions as well as with either an initially warm or an initially cold subtype, depending on the clinical symptoms. After trauma a certain amount of inflammatory reaction is considered physiological. In acute CRPS this inflammation persists for months and is maintained by diverse inflammatory mediators in peripheral tissue and in blood. This persisting inflammation leads to a sensitization of the nociceptive system, causes somatic cells to proliferate and gives rise to a disrupted endothelial function. The treatment concept aims to antagonize the pathophysiologic components and includes anti-inflammatory and analgetic treatment, mobilization and restoration of the sensorimotor function of the affected limb.

[Complex regional pain syndrome-An update]. / Komplexes regionales Schmerzsyndrom ­ ein Update.

Complex regional pain syndrome (CRPS) is a pain disorder that develops in the hands or feet after injury. Currently, two types are differentiated, CRPS I without and CRPS II with nerve lesions as well as with either an initially warm or an initially cold subtype, depending on the clinical symptoms. After trauma a certain amount of inflammatory reaction is considered physiological. In acute CRPS this inflammation persists for months and is maintained by diverse inflammatory mediators in peripheral tissue and in blood. This persisting inflammation leads to a sensitization of the nociceptive system, causes somatic cells to proliferate and gives rise to a disrupted endothelial function. The treatment concept aims to antagonize the pathophysiologic components and includes anti-inflammatory and analgetic treatment, mobilization and restoration of the sensorimotor function of the affected limb.

[Neurological or interdisciplinary outpatient pain treatment: comparison of treatment success and satisfaction]. / Neurologische oder interdisziplinäre Schmerzambulanz: Vergleich des Behandlungserfolges und der Zufriedenheit.

The aim of this study was to compare the satisfaction and success of treatment for pain patients who were interdisciplinary (anaesthesiological, psychosomatic, neurological, orthopedic) treated or underwent neurological care alone. Methods We selected 183 patients who were treated in our neurological clinic and in our interdisciplinary pain management center (IST). Of these, 142 patients having polyneuropathy, headache or muskuloskelettal pain were included in the final analysis. 39 patients (27.5 %) were treated in the IST and 103 patients were treated exclusively by a neurologist. These patients were asked to complete a questionnaire, and were queried about the satisfaction and pain parameters. Results The neurological and multidisciplinary pain treatment led to a similar improvement in pain (p < 0.001). This effect was independent of the underlying disease. The interdisciplinary outpatient treatment resulted not primarily in an increased patient satisfaction. Conclusions The reduction of pain and patient satisfaction of neurological outpatient pain treatment were comparable with those of a multidisciplinary outpatient therapy. The only significant advantage of the interdisciplinary treatment was lower hospitalization rate after therapy. This result cannot evaluate the efficiency of inpatient or day hospital pain management, but suggests that in many cases a neurological outpatient pain therapy is sufficient, so that neurological outpatient care should be promoted.

Brain connectivity networks underlying resting heart rate variability in acute ischemic stroke.

Acute strokes can affect heart rate variability (HRV), the mechanisms how are not well understood. We included 42 acute stroke patients (2-7 days after ischemic stroke, mean age 66 years, 16 women). For analysis of HRV, 20 matched controls (mean age 60.7, 10 women) were recruited. HRV was assessed at rest, in a supine position and individual breathing rhythmus for 5 min. The coefficient of variation (VC), the root mean square of successive differences (RMSSD), the powers of low (LF, 0.04-0.14 Hz) and high (HF, 0.15-0.50 Hz) frequency bands were extracted. HRV parameters were z-transformed related to age- and sex-matched normal subjects. Z-values < -1 indicate reduced HRV. Acute stroke lesions were marked on diffusion-weighted images employing MRIcroN and co-registered to a T1-weighted structural volume-dataset. Using independent component analysis (ICA), stroke lesions were related to HRV. Subsequently, we used the ICA-derived lesion pattern as a seed and estimated the connectivity between these brain regions and seven common functional networks, which were obtained from 50 age-matched healthy subjects (mean age 68.9, 27 women). Especially, LF and VC were frequently reduced in patients. ICA revealed one covarying lesion pattern for LF and one similar for VC, predominantly affecting the right hemisphere. Activity in brain areas corresponding to these lesions mainly impact on limbic (r = 0.55 ± 0.08) and salience ventral attention networks (0.61 ± 0.10) in the group with reduced LF power (z-score < -1), but on control and default mode networks in the group with physiological LF power (z-score > -1). No different connectivity could be found for the respective VC groups. Our results suggest that HRV alteration after acute stroke might be due to affecting resting-state brain networks.

Aberrant sensorimotor coupling and movement planning in complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) is characterized by inflammation and a failure of multimodal signal integration in the central nervous system (CNS). Central nervous system reorganization might account for sensory deficits, pain, and motor symptoms in CRPS, but it is not clear how motor control is affected by CNS mechanisms. The present study characterized the motor performance and related cortical activity of 16 CRPS patients and 16 control participants during the planning of visually guided unimanual grips, in patients with either the unaffected left or the affected right hand, and investigated resting-state sensorimotor coupling in MRI. Patients started isometric movements further in advance of the "go" cue and earlier than control participants. Even when accounting for this different timing, results showed side-independent overactivation in planning-related sensorimotor regions in CRPS during manual grips and increased functional coupling between those regions at rest. Fear of movement or individual pain scores contributed only marginally to the observed effects. The study suggests that changes in planning-related sensorimotor CNS regions may explain difficulties with force exertion and motor control in CRPS.Perspective : Functional changes in motor planning-related brain regions might indicate that feedback-enhanced functional motor training may be effective for CRPS rehabilitation.

Nociceptive two-point discrimination acuity and body representation failure in polyneuropathy.

OBJECTIVES: Although patients' complaints suggest polyneuropathy (PNP) and neuropathic pain, routine investigations do not always support the diagnosis. Assessing two-point-pain discrimination thresholds (2ptDT) and quantify body representation disturbances might be useful to close this diagnostic gap. METHODS: Pinprick pain and laser-heat pain perception thresholds and 2ptDT on hands, forearms, lower legs and feet were obtained in 20 PNP patients (mean age: 57.6 ± 13.9) and 20 healthy subjects (mean age: 50.6 ± 4.7 years). Body representation disturbances were assessed by self-estimating feet size and the Bath CRPS body perception disturbances questionnaire adapted for PNP. RESULTS: Pain perception thresholds and laser-heat pain 2ptDT were unaltered, but patients had higher pinprick pain 2ptDT then the healthy subjects. The 2ptDT for pinprick at the hands discriminate best between groups (U-test; p=0.001). Furthermore, patients estimated their feet longer than they are. In subsequent multivariate discriminant analyses, 2ptDT for pinprick pain at the hands, 2ptDT for laser-heat pain and the perception thresholds for laser-heat pain at the feet classified 85% of PNP vs. HC correctly. The combination of 2ptDT for pinprick pain at the hands, pinprick pain perception thresholds at the calves and foot length estimation differentiates painful vs. non-painful PNPs correctly in 90% of the cases. CONCLUSIONS: Testing 2ptDT for painful pinprick stimuli at the hands and asking for foot length estimation might add to diagnostic accuracy in painful PNP.

Local and Systemic Expression Pattern of MMP-2 and MMP-9 in Complex Regional Pain Syndrome.

Matrix metalloproteinases (MMP)-2 and MMP-9 play important roles in inflammation as well as in pain processes. For this reason, we compared the concentrations of these enzymes in skin and serum of patients with complex regional pain syndrome (CRPS), other pain diseases and healthy subjects. We analyzed ipsi- and contralateral skin biopsies of 18 CRPS patients, as well as in 10 pain controls and 9 healthy subjects. Serum samples were analyzed from 20 CRPS, 17 pain controls and 17 healthy subjects. All samples were analyzed with ELISA. Concentrations were then compared to clinical data as well as to quantitative sensory testing data.MMP-2 was increased in both ipsi- and contralateral skin biopsies of CRPS patients compared to healthy subjects. While low ipsilateral MMP-2 was associated with trophic changes, contralateral MMP-2 inversely correlated with the CRPS severity. MMP-9 was also locally increased in ipsilateral CRPS skin, and higher ipsi- and contralateral MMP-9 levels correlated with CRPS severity. We conclude that MMP-2 and MMP-9 are differently expressed depending on the clinical phenotype in CRPS. PERSPECTIVE: This article describes an upregulation of MMPs in CRPS and pain controls and shows different expression of MMP-2 and -9 depending on clinical phenotype in CRPS. These results provide evidence that MMP-2 and -9 play a key role in CRPS pathophysiology.

[Chronic postoperative pain. Epidemiology and psychological risk factors]. / Chronische Schmerzen nach Operationen. Epidemiologie unter besonderer Berücksichtigung psychologischer Risikofaktoren.

Acute postoperative pain is a still inevitable accompaniment of surgery. Up to 50% of the patients undergoing surgery--depending on its type--develop later on chronic postoperative pain. Psychological variables as minor depression, anxiety and pain-related catastrophizing as well as full-blown mental disorders are known risk factors. The relationship between such variables and postoperative pain is likely reciprocal.

Clinical phenotypes and classification algorithm for complex regional pain syndrome.

OBJECTIVE: We pursued the hypothesis that complex regional pain syndrome (CRPS) signs observed by neurologic examination display a structure allowing for alignment of patients to particular phenotype clusters. METHODS: Clinical examination data were obtained from 3 independent samples of 444, 391, and 202 patients with CRPS. The structure among CRPS signs was analyzed in sample 1 and validated with sample 2 using hierarchical clustering. For patients with CRPS in sample 3, an individual phenotype score was submitted to k-means clustering. Pain characteristics, quantitative sensory testing, and psychological data were tested in this sample as descriptors for phenotypes. RESULTS: A 2-cluster structure emerged in sample 1 and was replicated in sample 2. Cluster 1 comprised minor injury eliciting CRPS, motor signs, allodynia, and glove/stocking-like sensory deficits, resembling a CRPS phenotype most likely reflecting a CNS pathophysiology (the central phenotype). Cluster 2, which consisted of edema, skin color changes, skin temperature changes, sweating, and trophic changes, probably represents peripheral inflammation, the peripheral phenotype. In sample 3, individual phenotype scores were calculated as the sum of the mean values of signs from each cluster, where signs from cluster 1 were coded with 1 and from cluster 2 with -1. A k-means algorithm separated groups with 78, 36, and 88 members resembling the peripheral, central, and mixed phenotypes, respectively. The central phenotype was characterized by cold hyperalgesia at the affected limb. CONCLUSIONS: Statistically determined CRPS phenotypes may reflect major pathophysiologic mechanisms of peripheral inflammation and central reorganization.

The serum protease network-one key to understand complex regional pain syndrome pathophysiology.

Complex regional pain syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation, which is explained by local and systemic activation of a proinflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin-converting enzyme in patients treated for hypertension increases the odds to develop CRPS. This hint leads us to investigate the serum protease network activity in patients with CRPS vs respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate patients with CRPS, as well as healthy and pain (painful diabetic neuropathy [dPNP]) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in healthy control and dPNP is shifted to higher values for DBK1-8 and lower values for DBK1-5 at 1 hour of incubation in patients with CRPS. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators such as BK might be different in patients with CRPS; having a look at the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.

What is normal trauma healing and what is complex regional pain syndrome I? An analysis of clinical and experimental biomarkers.

Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison with healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patient-reported outcomes, and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FCs) not fulfilling the CRPS diagnostic criteria. We included upper-extremity FCs, acute CRPS I patients within 1 year after trauma, a second disease control group (painful diabetic polyneuropathy), and healthy controls. Fracture controls were not symptoms-free, but reported some pain, disability, anxiety, and cold pain hyperalgesia in quantitative sensory testing. Patients with CRPS had higher scores for pain, disability, and all patient-reported outcomes. In quantitative sensory testing, ipsilateral and contralateral sides differed significantly. However, on the affected side, patients with CRPS were more sensitive in only 3 parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors that distinguish CRPS and FC. Fracture control as a control group can assist to discover resolution factors after trauma.

Correlates and importance of neglect-like symptoms in complex regional pain syndrome.

Neglect-like symptoms (NLS) are frequently observed in complex regional pain syndrome (CRPS). The clinical meaning of NLS, however, is largely unknown. Therefore, this study sets out to assess the importance of NLS for patient outcome and to explore their clinical correlates. We assessed NLS in a group of 53 patients with CRPS and compared the results to 28 healthy volunteers. To define the origin of the NLS reports, we tested the subjective visual midline, performed a limb-laterality recognition test, and quantitative sensory testing. In addition, psychological and pain assessment scales were completed. Tests were analyzed with univariate and multivariate approaches. After 6 months, patients were reassessed and the influence of NLS on pain outcome was determined. Most patients reported NLS in the questionnaire, whereas subjective visual midline and limb-laterality recognition test in contrast to previous studies did not reveal perceptual disturbances. Neglect-like symptom scores were associated with pain and pain catastrophizing in acute CRPS and anxiety and thermal sensory loss in chronic CRPS. Furthermore, high NLS scores had a negative impact on pain outcome after 6 months. Our results indicate that NLS have a different meaning in acute and chronic CRPS and might be of prognostic value. Possibly, treatment should focus on reducing NLS.

Complex regional pain syndrome-up-to-date.

Complex regional pain syndrome (CRPS) was described for the first time in the 19th century by Silas Weir Mitchell. After the exclusion of other causes, CRPS is characterised by a typical clinical constellation of pain, sensory, autonomic, motor, or trophic symptoms which can no longer be explained by the initial trauma. These symptoms spread distally and are not limited to innervation territories. If CRPS is not improved in the acute phase and becomes chronic, the visible symptoms change throughout because of the changing pathophysiology; the pain, however, remains. The diagnosis is primarily clinical, although in complex cases further technical examination mainly for exclusion of alternative diagnoses is warranted. In the initial phase, the pathophysiology is dominated by a posttraumatic inflammatory reaction by the activation of the innate and adaptive immune system. In particular, without adequate treatment, central nociceptive sensitization, reorganisation, and implicit learning processes develop, whereas the inflammation moderates. The main symptoms then include movement disorders, alternating skin temperature, sensory loss, hyperalgesia, and body perception disturbances. Psychological factors such as posttraumatic stress or pain-related fear may impact the course and the treatability of CRPS. The treatment should be ideally adjusted to the pathophysiology. Pharmacological treatment maybe particularly effective in acute stages and includes steroids, bisphosphonates, and dimethylsulfoxide cream. Common anti-neuropathic pain drugs can be recommended empirically. Intravenous long-term ketamine administration has shown efficacy in randomised controlled trials, but its repeated application is demanding and has side effects. Important components of the treatment include physio- and occupational therapy including behavioural therapy (eg, graded exposure in vivo and graded motor imaging). If psychosocial comorbidities exist, patients should be appropriately treated and supported. Invasive methods should only be used in specialised centres and in carefully evaluated cases. Considering these fundamentals, CRPS often remains a chronic pain disorder but the devastating cases should become rare.

Using a Standardized Clinical Quantitative Sensory Testing Battery to Judge the Clinical Relevance of Sensory Differences Between Adjacent Body Areas.

BACKGROUND: Skin sensitivity to sensory stimuli varies among different body areas. A standardized clinical quantitative sensory testing (QST) battery, established for the diagnosis of neuropathic pain, was used to assess whether the magnitude of differences between test sites reaches clinical significance. METHODS: Ten different sensory QST measures derived from thermal and mechanical stimuli were obtained from 21 healthy volunteers (10 men) and used to create somatosensory profiles bilateral from the dorsum of the hands (the standard area for the assessment of normative values for the upper extremities as proposed by the German Research Network on Neuropathic Pain) and bilateral at volar forearms as a neighboring nonstandard area. The parameters obtained were statistically compared between test sites. RESULTS: Three of the 10 QST parameters differed significantly with respect to the "body area," that is, warmth detection, thermal sensory limen, and mechanical pain thresholds. After z-transformation and interpretation according to the QST battery's standard instructions, 22 abnormal values were obtained at the hand. Applying the same procedure to parameters assessed at the nonstandard site forearm, that is, z-transforming them to the reference values for the hand, 24 measurements values emerged as abnormal, which was not significantly different compared with the hand (P=0.4185). CONCLUSIONS: Sensory differences between neighboring body areas are statistically significant, reproducing prior knowledge. This has to be considered in scientific assessments where a small variation of the tested body areas may not be an option. However, the magnitude of these differences was below the difference in sensory parameters that is judged as abnormal, indicating a robustness of the QST instrument against protocol deviations with respect to the test area when using the method of comparison with a 95 % confidence interval of a reference dataset.

Psychological Predictors of Acute Postoperative Pain After Hysterectomy for Benign Causes.

OBJECTIVES: Psychological parameters have been shown to contribute significantly to the development of acute postoperative pain (APOP). For the prediction of APOP in chest malformation patients and cancer patients, we found pain-specific psychological predictors to be of higher relevance than general psychological predictors. The current study aims to further substantiate these findings. MATERIALS AND METHODS: In a sample of 73 middle-aged hysterectomy patients, 3 predictor sets were assessed 1 day before surgery: attentional biases (toward pain-related, social threat, and positive words in a dot-probe task), pain-related emotions and cognitions (pain anxiety, pain catastrophizing, and pain hypervigilance), and affective state variables (depression and somatization). APOP intensity rated 2 to 3 days after surgery and analgesic consumption during the first 48 postoperative hours were used as outcome measures. RESULTS: APOP intensity ratings were significantly explained by their best single predictors in a multiple regression analysis: social threat words of the dot-probe task, pain anxiety, and somatization (14.7% of explained variance). When comparing standardized ß coefficients, pain-specific psychological predictors appeared to be of higher explanatory relevance than general psychological predictors. In contrast, analgesic consumption could not be significantly predicted by the psychological variables. DISCUSSION: Hysterectomy patients at risk for high APOP intensity could be characterized by the psychological variables used, whereas their predictive value for analgesic consumption was limited. The high predictive potency of pain-specific psychological variables should be considered for further improvement of pain management and prevention, because pain-specific variables such as pain anxiety can be the target of focal psychological interventions when preparing for surgery.

Inverted Perceptual Judgment of Nociceptive Stimuli at Threshold Level following Inconsistent Cues.

OBJECTIVE: The perception of pain is susceptible to modulation by psychological and contextual factors. It has been shown that subjects judge noxious stimuli as more painful in a respective suggestive context, which disappears when the modifying context is resolved. However, a context in which subjects judge the painfulness of a nociceptive stimulus in exactly the opposite direction to that of the cues has never been shown so far. METHODS: Nociceptive stimuli (300 ms intranasal gaseous CO2) at the individual pain threshold level were applied after a visual cue announcing the stimulus as either "no pain", merely a "stimulus", or "pain". Among the stimuli at threshold level, other CO2 stimuli that were clearly below or above pain threshold were randomly interspersed. These were announced beforehand in 12 subjects randomly with correct or incorrect cues, i.e., clearly painful or clearly non-painful stimuli were announced equally often as not painful or painful. By contrast, in a subsequent group of another 12 subjects, the stimuli were always announced correctly with respect to the evoked pain. RESULTS: The random and often incorrect announcement of stimuli clearly below or above pain threshold caused the subjects to rate the stimuli at pain-threshold level in the opposite direction of the cue, i.e., when the stimuli were announced as "pain" significantly more often than as non-painful and vice versa (p < 10(-4)). By contrast, in the absence of incongruence between announcement and perception of the far-from-threshold stimuli, stimuli at pain threshold were rated in the cued direction. CONCLUSIONS: The present study revealed the induction of associations incongruent with a given message in the perception of pain. We created a context of unreliable cues whereby subjects perceived the stimulus opposite to that suggested by a prior cue, i.e., potentially nociceptive stimuli at pain threshold level that were announced as painful were judged as non-painful and vice versa. These findings are consistent with reported data on the effects of distrust on non-painful cognitive responses.

Multimodal distribution of human cold pain thresholds.

BACKGROUND: It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels. METHODS: Cold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 - 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit. RESULTS: CPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively. CONCLUSIONS: The localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 - 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.

Pattern of neuropathic pain induced by topical capsaicin application in healthy subjects.

Human experimental pain models are widely used to study drug effects under controlled conditions, but they require further optimization to better reflect clinical pain conditions. To this end, we measured experimentally induced pain in 110 (46 men) healthy volunteers. The quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain) was applied on untreated ("control") and topical capsaicin-hypersensitized ("test") skin. Z-transformed QST-parameter values obtained at the test site were compared with corresponding values published from 1236 patients with neuropathic pain using Bayesian statistics. Subjects were clustered for the resemblance of their QST pattern to neuropathic pain. Although QST parameter values from the untreated site agreed with reference values, several QST parameters acquired at the test site treated with topical capsaicin deviated from normal. These deviations resembled in 0 to 7 parameters of the QST pattern observed in patients with neuropathic pain. Higher degrees (50%-60%) of resemblance to neuropathic QST pattern were obtained in 18% of the subjects. Inclusion in the respective clusters was predictable at a cross-validated accuracy of 86.9% by a classification and regression tree comprising 3 QST parameters (mechanical pain sensitivity, wind-up ratio, and z-transformed thermal sensory limen) from the control sites. Thus, we found that topical capsaicin partly induced the desired clinical pattern of neuropathic pain in a preselectable subgroup of healthy subjects to a degree that fuels expectations that experimental pain models can be optimized toward mimicking clinical pain. The subjects, therefore, qualify for enrollment in analgesic drug studies that use highly selected cohorts to enhance predictivity for clinical analgesia.