Human REM sleep recalibrates neural activity in support of memory formation.

The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.

Noxious radiant heat evokes bi-component nociceptive withdrawal reflexes in spinal cord injured humans-A clinical tool to study neuroplastic changes of spinal neural circuits.

Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18-63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19-63] were included. The percentage of individuals with SCI responding to stimuli (70-77%; p < 0.001), their response rates (16-21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher's exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.

Stress-induced hyperalgesia instead of analgesia in patients with chronic musculoskeletal pain.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

Diabetic neuropathy is a generalized phenomenon with impact on hand functional performance and quality of life.

BACKGROUND AND PURPOSE: Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL-N), whereas the impact of upper limb neuropathy (UL-N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL-N and its functional and psychosocial consequences in type 2 diabetes. METHODS: Individuals with type 2 diabetes (n = 141) and an age- and sex-matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status. RESULTS: The prevalence of UL-N was 30.5% in patients with diabetes and that of LL-N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL-N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL-N had reduced estimates of psychosocial health including health-related QoL compared to control subjects and patients without UL-N. UL-N correlated with the severity of LL-N, but not with duration of diabetes, glycemia, age, or sex. CONCLUSIONS: This study points to a substantial prevalence of UL-N in type 2 diabetes. The sensory phenotype of patients with UL-N was similar to LL-N and was characterized by loss of sensory function. Our study demonstrated an association of UL-N with impaired manual dexterity and reduced health-related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes.

Pain thresholds and intensities of CRPS type I and neuropathic pain in respect to sex.

BACKGROUND AND AIMS: Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers. METHODS: QST data of 1,252 patients (669 female, 583 male) with PNI (n = 342), PNP (n = 571) or CRPS (n = 339), and average pain intensity reports from previously published studies were included. Absolute and z-values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects. RESULTS: Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p < .05). However, after z-transformation these differences disappeared except for PPT in CRPS (p = .001). DISCUSSION: Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes. SIGNIFICANCE: Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance.

Understanding Diabetic Neuropathy-From Subclinical Nerve Lesions to Severe Nerve Fiber Deficits: A Cross-Sectional Study in Patients With Type 2 Diabetes and Healthy Control Subjects.

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aß fibers) and mechanical pain (Aδ fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aß-, and Aδ-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN.

Technical and clinical performance of the thermo-test device "Q-Sense" to assess small fibre function: A head-to-head comparison with the "Thermal Sensory Analyzer" TSA in diabetic patients and healthy volunteers.

BACKGROUND: Thermo-test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device ("Q-Sense") was introduced, which is less expensive but has reduced cooling capacity (20°C). We assessed the reliability/validity of the "Q-Sense" by comparing it with the Thermal Sensory Analyzer (TSA). METHODS: Using a phantom-skin model, the physical characteristics of both devices were compared. The clinical performance was assessed in a multicentre study by performing Quantitative Sensory Testing (QST) in 121 healthy volunteers and 83 diabetic patients (Eudra-Med-No. CIV-12-05-006501). RESULTS: Both device types showed ~40% slower temperature ramps for heating/cooling than nominal data. Cold/warm detection thresholds (CDT, WDT) and heat pain thresholds (HPT) of healthy subjects did not differ between device types. Cold pain thresholds (CPT) were biased for Q-Sense by a floor effect (p < .001). According to intraclass correlation coefficients (ICC), agreement between TSA and Q-Sense was good/excellent for CDT (ICC = 0.894) and WDT (ICC = 0.898), moderate for HPT (ICC = 0.525) and poor for CPT (ICC = 0.305). In diabetic patients, the sensitivity of Q-Sense to detect cold hypoesthesia was reduced in males >60 years. Moderate correlations between thermal detection thresholds and morphological data from skin biopsies (n = 51) were similar for both devices. CONCLUSIONS: Physical characteristics of both thermo-test devices are similarly limited by the poor temperature conduction of the skin. The Q-Sense is useful for thermal detection thresholds but of limited use for pain thresholds. For full clinical use, the lower cut-off temperature should be set to ≤18°C. SIGNIFICANCE: High purchase costs prevent a widespread use of thermo-test devices for diagnosing small fibre neuropathy. The air-cooled "Q-Sense" could be a lower cost alternative, but its technical/clinical performance needs to be assessed because of its restricted cut-off for cooling (20°C). This study provides critical information on the physical characteristics and the clinical validity/reliability of the Q-Sense compared to the "Thermal Sensory Analyzer" (TSA). We recommend lowering the cut-off value of the Q-Sense to ≤18°C for its full clinical use.

Implementation of a Quality Index for Improvement of Quantification of Corneal Nerves in Corneal Confocal Microcopy Images: A Multicenter Study.

PURPOSE: Corneal confocal microscopy (CCM) is an imaging method to detect loss of nerve fibers in the cornea. The impact of image quality on the CCM parameters has not been investigated. We developed a quality index (QI) with 3 stages for CCM images and compared the influence of the image quality on the quantification of corneal nerve parameters using 2 modes of analysis in healthy volunteers and patients with known peripheral neuropathy. METHODS: Images of 75 participants were a posteriori analyzed, including 25 each in 3 image quality groups (QI 1-QI 3). Corneal nerve fiber length (CNFL) was analyzed using automated and semiautomated software, and corneal nerve fiber density and corneal nerve branch density were quantified using automated image analysis. Three masked raters assessed CCM image quality (QI) independently and categorized images into groups QI 1-QI 3. In addition, statistical analysis was used to compare interrater reliability. Analysis of variance was used for analysis between the groups. Interrater reliability analysis between the image ratings was performed by calculating Fleiss' kappa and its 95% confidence interval. RESULTS: CNFL, corneal nerve fiber density, and corneal nerve branch density increased significantly with QI (P < 0.001, all post hoc tests P < 0.05). CNFL was higher using semiautomated compared with automated nerve analysis, independent of QI. Fleiss kappa coefficient for interrater reliability of QI was 0.72. CONCLUSIONS: The quantification of corneal nerve parameters depends on image quality, and poorer quality images are associated with lower values for corneal nerve parameters. We propose the QI as a tool to reduce variability in quantification of corneal nerve parameters.

Deep phenotyping neuropathy: An underestimated complication in patients with pre-diabetes and type 2 diabetes associated with albuminuria.

AIMS: The aim of the study was to assess whether quantitative-sensory-testing could be used to evaluate prevalence and predictors of diabetic neuropathy (DPNP) in patients with pre-diabetes and type 2 diabetes. METHODS: Twenty-eight pre-diabetics and 108 patients with type 2 diabetes were evaluated using neuropathy-deficit-score (NDS), neuropathy-symptom-score (NSS), nerve-conduction-studies (NCS), short-QST-protocol to examine small fibers and the comprehensive QST-battery (long-QST) according to the German Research Network on Neuropathic Pain protocol. RESULTS: Long-QST revealed a DPNP-prevalence of 71% in pre-diabetics and 95% in patients with type 2 diabetes, while according to NDS it was only 11% and 63%, and NCS missed 58% of patients with DPNP. Small and medium fibers were similarly affected in both groups, while large fiber deficits were significantly more common in type 2 diabetes (p < 0.01). Complete loss of function in all fibers was significantly higher in patients with type 2 diabetes than in pre-diabetics (26% vs. 11%, p < 0.05). Hyperalgesia was slightly increased in pre-diabetes than in type 2 diabetes (57% vs. 43%, p = n.s.). However, NSS only showed significant associations with large fiber deficits. Logistic regression analyses revealed that age (OR 1.14[1.05/1.24]) and albuminuria (OR 12.8[1.52/107.3]) were independent predictors for the presence of DPNP. CONCLUSIONS: DPNP is much more prevalent in patients with pre-diabetes and type 2 diabetes and clinical routine tests may miss the majority of affected patients. Age and albuminuria, but not HbA1c, appear to be significantly associated with DPNP. CLINICAL TRIAL REGISTRATION: NCT03022721.

Spinal cord stimulation modulates descending pain inhibition and temporal summation of pricking pain in patients with neuropathic pain.

BACKGROUND: Spinal cord stimulation (SCS) is an established treatment option for patients with refractory chronic pain conditions. While effects of SCS on dorsal horn neuronal circuitries are intensively studied, current knowledge on the impact of SCS on descending pain pathways is scarce and relies on preclinical data. We aimed to address this topic and hypothesized a significant effect of SCS on descending pain modulation. In light of current efforts to determine the sensitivity of "static" versus "dynamic" somatosensory parameters to characterize pathophysiological pain conditions, all SCS patients were carefully investigated using both classes of somatosensory outcome parameters. METHODS: Descending pain pathways were investigated by using a "Cold Pressor Test." This test enables to evaluate the efficacy of conditioned pain modulation (CPM) at the individual level. CPM efficacy was assessed in eight neuropathic pain patients (age 55.5 ± 10.6) during the two conditions stimulator "ON" and "OFF." The impact of SCS on "static" and "dynamic" somatosensory parameters was explored by using a quantitative sensory testing (QST) battery. RESULTS: CPM efficacy on pressure pain sensitivity was nearly absent during "OFF" (- 1.2 ± 5.6% facilitation), but increased significantly to 16.3 ± 3.4% inhibition during "ON" (p = 0.03). While most "static" nociceptive QST parameters, represented by mechanical/thermal pain thresholds, exhibited only small effects of SCS (p > 0.05), the wind-up ratio was strongly reduced to within the normal range during "ON" (p = 0.04; Cohen's d = 1.0). Dynamic mechanical allodynia was abolished in six of seven patients. CONCLUSIONS: Our study provides first human evidence for an impact of SCS on descending pain pathways in the dorsolateral funiculus and emphasizes the significance of "dynamic" pain measures like "CPM"-efficacy and "temporal summation" to evaluate SCS treatment effects. Future prospective studies may use these measures of nociceptive processing to predict SCS therapy response.

Sleep Deprivation Related Changes of Plasma Oxytocin in Males and Female Contraceptive Users Depend on Sex and Correlate Differentially With Anxiety and Pain Hypersensitivity.

Disturbed sleep is known to substantially aggravate both the pain condition and the affective state of pain patients. The neurobiological mechanisms underlying these adverse effects are unknown. Oxytocin (OT), being largely involved in social and emotional behavior, is considered to also play a modulatory role in nociception. We hypothesized a pathophysiological role of OT for the hyperalgesic and anxiogenic effects of sleep loss. An established human model of one night of total sleep deprivation (TSD) was used to test this hypothesis. Twenty young healthy students (n = 10 male and n = 10 female) were investigated in a balanced cross-over design, contrasting TSD with a night of habitual sleep (HS). All females took monophasic oral contraceptives (OC) and were investigated during their 'pill-free' phase. Plasma OT concentrations were correlated with (1) pain thresholds, (2) descending pain inhibition, and (3) state-anxiety scores. Compared to the HS condition, the plasma OT concentration was significantly increased in sleep deprived females (p = 0.02) but not males (p = 0.69). TSD resulted in pain hypersensitivity to noxious cold (p = 0.05), noxious heat (p = 0.023), and pricking stimuli (p = 0.013) and significantly increased state-anxiety (p = 0.021). While, independent of sex, lower heat pain thresholds correlated with higher plasma OT (p = 0.036), no such associations were found for cold/mechanical pain. In sleep-deprived females, higher plasma OT showed a mild (but insignificant) association with lower pain inhibition (p = 0.093). We found a positive correlation between anxiety-scores and OT (p = 0.021), which was enhanced when respecting "sex" (p = 0.008) and "sleep" (p = 0.001) in a hierarchical regression analysis. Altogether, our study revealed a complex and partially sex-dependent correlation between plasma OT and TSD-induced changes of experimental pain and anxiety. The minor role of OT for TSD-induced changes of evoked pain, and its major involvement in anxiety, argues against a specific role of OT for linking the adverse effects of TSD on pain sensitivity and anxiety with each other. Future investigations are needed in order to dissect out the effect of OC on the sex-dependent effects of TSD observed in our study.

Pathophysiological mechanisms of neuropathic pain: comparison of sensory phenotypes in patients and human surrogate pain models.

As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.

The Role of Sex in Sleep Deprivation Related Changes of Nociception and Conditioned Pain Modulation.

Sex matters both in the clinical field of pain and sleep medicine. Sleep disturbances are highly prevalent in chronic pain patients and have been shown to deteriorate the pain condition. The pathomechanisms by which insomnia aggravates pain are currently unknown. Descending pain control may be compromised by disturbed sleep, but respective studies are few, inconsistent and largely imbalanced with respect to sex. We studied the role of sex on the effect of sleep deprivation on endogenous pain modulation and on nociceptive thresholds in a highly homogenous study population of 18 female (23.8 ±â€¯3.4 years) and 18 male (23.3 ±â€¯2.7) healthy students. One night of total sleep deprivation (TSD) was contrasted with one night of habitual sleep in a balanced cross-over design. A cold pressor test was used to explore the effect of TSD on supraspinal pain control. The effect of TSD on nociception was examined by Quantitative Sensory Testing (QST). RM-ANOVA was used for statistical analysis. We found a sex-dependent effect of TSD on descending pain pathways, since the endogenous capacity to inhibit pain was only reduced in sleep deprived females (interaction between 'sleep condition' and 'sex': p = 0.023). While TSD-induced cold and mechanical hyperalgesia were independent of sex, heat pain thresholds did only significantly decrease in sleep deprived females (p = 0.041). Our results point to a sex specific impact of TSD on descending pain inhibition. In the future, therapeutic strategies for pain patients with co-morbid insomnia may need to more explicitly respect the specific role of sex.

Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations.

In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5.

Subcutaneous Trigeminal Nerve Field Stimulation for Refractory Facial Pain.

Chronic or neuropathic trigeminal facial pain can be challenging to treat. Neurosurgical procedures should be applied when conservative treatment fails. Neuromodulation techniques for chronic facial pain include deep brain stimulation and motor cortex stimulation, which are complex to perform. Subcutaneous nerve field stimulation is certified for chronic back pain and is the least invasive form of neuromodulation. We applied this technique to treat chronic and neuropathic trigeminal pain as an individual therapy concept. First, trial stimulation is performed. Subcutaneous leads are placed in the painful trigeminal dermatome under local anesthesia. The leads are connected to an external neurostimulator that applies constant stimulation. Patients undergo a 12 day outpatient trial to assess the effect of the stimulation. Electrodes are removed after the trial. If the patient reports pain reduction of at least 50% in intensity and/or attack frequency, a reduction in medication or increase in quality of life, permanent implantation is scheduled. New electrodes are implanted under general anesthesia and are subcutaneously tunneled to an infraclavicular internal pulse generator. Patients are able to turn stimulation on and off and to increase or decrease the stimulation amplitude as needed. This technique represents a minimal invasive alternative to other more invasive means of neuromodulation for trigeminal pain such as motor cortex stimulation or deep brain stimulation.

Subcutaneous trigeminal nerve field stimulation for refractory trigeminal pain: a cohort analysis.

BACKGROUND: Neurosurgical pain management of drug-resistant trigeminal neuralgia (TN) is highly challenging. Microvascular decompression is a first-line neurosurgical approach for classical TN with neurovascular conflict, but can show clinical relapse despite proper decompression. Second-line destructive techniques like radiofrequency thermocoagulation have become reluctantly used due to their potential for irreversible side effects. Subcutaneous peripheral nerve field stimulation (sPNFS) is a minimally invasive neuromodulatory technique which has been shown to be effective for chronic localised pain conditions. Reports on sPNFS for the treatment of trigeminal pain (sTNFS) are still sparse and primarily focused on pain intensity as outcome measure. Detailed data on the impact of sTNFS on attack frequency are currently not available. METHODS: Patients were classified according to the International Headache Society classification (ICHD-3-beta). Three patients had classical TN without (n = 3) and another three TN with concomitant persistent facial pain (n = 3). Two patients suffered from post-herpetic trigeminal neuropathy (n = 2). All eight patients underwent a trial stimulation of at least 7 days with subcutaneous leads in the affected trigeminal area connected to an external neurostimulator. Of those, six patients received permanent implantation of a neurostimulator. During the follow-up (6-29 months, mean 15.2), VAS-scores, attack frequencies, oral drug intake, complications and side effects were documented. RESULTS: Seven out of eight patients responded to sTNFS (i.e. ≥50 % pain reduction) during the test trial. The pain intensity (according to VAS) was reduced by 83 ± 16 % (mean ± SD) and the number of attacks decreased by 73 ± 26 % (mean ± SD). Five out of six patients were able to reduce or stop pain medication. One patient developed device infection. Two patients developed stimulation-related side effects which could be resolved by reprogramming. CONCLUSIONS: Treatment by sTNFS is a beneficial option for patients with refractory trigeminal pain. Prospective randomised trials are required to systematically evaluate efficacy rates and safety of this low-invasive neurosurgical technique.

Two TRPV1 receptor antagonists are effective in two different experimental models of migraine.

BACKGROUND: The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine. METHODS: Male Sprague-Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene c-fos was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery. RESULTS: Inflammatory up-regulation of c-fos in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ-38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner. CONCLUSION: Our results describe two TRPV1 antagonists that are effective in two in vivo models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine.

One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain.

Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P<0.001) and resulted in higher scores of the State Anxiety Inventory (P<0.01). In addition to previously reported hyperalgesia to heat (P<0.05) and blunt pressure (P<0.05), study participants developed hyperalgesia to cold (P<0.01) and increased mechanical pain sensitivity to pinprick stimuli (P<0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.

IL-1ß stimulates COX-2 dependent PGE2 synthesis and CGRP release in rat trigeminal ganglia cells.

OBJECTIVE: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1ß) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. METHODS AND RESULTS: 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1ß can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1ß caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2)) release 4 hours after stimulation with IL-1ß, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2) and 24 hours after IL-1ß stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1ß induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. CONCLUSION: We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-ß leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2) (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine.