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We read with interest the article entitled “Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease” from Timothy Lawn et al. Their review summarized the current findings on pain processing as well as on pharmacotherapy of pain in both diseases. It further emphasizes the importance of mechanistic research for evidence-based pain medicine. We would like to comment on the experimental findings and on the importance of a mechanism-based approach in Parkinson disease (PD) after the correct diagnosis of PDrelated pain has been made because a mechanism-based approach has been already validated. Concerning experimental pain sensitivity, studies revealed increased pain sensitivity when tested in the medication defined off phase, whereas converse observations were made in the on phase. Increased pain sensitivity can be reversed by L-dopa or deep brain stimulation.

Pain is a frequent and disabling non-motor feature of Parkinson's disease (PD). The recently proposed PD Pain Classification System (PD-PCS) allows for an association of pain with PD to be determined before being allocated to the main pain mechanism (i.e. nociceptive, neuropathic, and nociplastic). In this article, previous studies on treatments for pain in PD are summarized according to the pain mechanisms. A mechanistic approach to treatment is discussed. We suggest that the first step should be optimizing dopaminergic therapy before other therapy is started. When these treatments remain unsuccessful, further causes of pain must be considered. The role of drugs, invasive treatments, and physiotherapeutic interventions are discussed with a focus on older PD patients and considering polypharmacy, altered pharmacokinetics, and comorbidities.

Swallowing and cough are crucial components of airway protection. In patients with neurogenic dysphagia (ND), there is a high prevalence of dystussia (impaired cough) and atussia (absence of cough). As a result, the ability to detect and remove aspirated material from the airway decreases, exacerbating the sequelae associated with ND, including aspiration pneumonia, a leading cause of mortality in ND. This controlled intervention study aimed to quantify the cough response to aerosolized capsaicin (AC) in patients with ND and assess the potential of AC as a therapeutic tool in treating ND-related dystussia and atussia. Furthermore, we propose a novel application method that enables AC treatment to be performed at home. Spirometry was used to measure peak cough flow (PCF) of voluntary cough (cough on command) and reflexive cough (cough secondary to pharyngeal exposure to AC) in 30 subjects with and 30 without ND. The capsaicin aerosol was generated by adding 1–10 drops of liquid cayenne extract (1.5–2% capsaicin) to 100 mL carbonated water (0.00075–0.001% to 0.0075–0.01% capsaicin). Voluntary PCF in the ND group was significantly lower than in the control group (p p = 0.225). Within the ND group, reflexive PCF was significantly higher than voluntary PCF (p = 0.001), while in healthy controls, reflexive PCF was significantly lower (p

Supplemental Digital Content is Available in the Text. An original tool to distinguish Parkinson disease-related from non-Parkinson disease-related pain and to classify it into 3 mechanistic pain descriptors., Pain is a common nonmotor symptom in patients with Parkinson disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into 3 groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory and McGill pain questionnaire [MPQ], PDQ-8 quality of life score, MDS-UPDRS scores, and nonmotor symptoms). 159 nondemented PD patients (disease duration 10.2 ± 7.6 years) and 37 healthy controls were recruited in 4 centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's Brief Pain Inventory and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression, and anxiety measures. Moderate intrarater and interrater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.

Summary Objectives Paired associative stimulation (PAS) can modulate motor excitability and consists of delivering repeated pairs of peripheral sensory stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor cortex. Our objective was to evaluate the effect of a PAS protocol using a painful stimulation. Methods Ten healthy volunteers underwent pain-PAS protocol consisting of 90 pairs of nociceptive stimulus over the right hand followed by an image-guided navigated TMS of the contralateral motor cortex, delivered at 0.1 Hz over 15 minutes. Four distinct inter-stimuli intervals (ISI) were assessed: −40 ms, +10 ms, +30 ms and +50 ms with respect to the individual pain-related evoked potential (N2 latency). The impact of pain-PAS was assessed by measuring motor evoked potentials (MEPs) amplitudes before and up to 30 minutes after the pain-PAS procedure. Results For the “N2 latency −40 ms” ISI condition, a significant decrease of MEP amplitude was observed in the immediate post-pain-PAS period. For longer ISIs, no significant changes were observed. Discussion A motor inhibition effect was produced by repetitive pairs of painful peripheral stimulation and TMS pulse delivered to the motor cortex before the afferent volley reaches the somatosensory cortex. This short ISI falls into a period of time corresponding to the cutaneous silent period, suggesting that the motor inhibition effect produced by pain-PAS could occur at spinal level. The repeated interaction of the nociceptive afferent input and the descending motor corticospinal volley could lead to reduced excitability of homonymous spinal motoneurons.

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The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson's disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.

Augmented spinal nociception during the "off" phase has been observed early in Parkinson's disease further increasing with disease duration. To find out whether increased spinal nociception represents a premotor feature, experimental pain sensitivity was assessed in idiopathic REM-sleep behavior disorder (IRBD) patients with or without signs of a neurodegenerative disorder compared to early Parkinson's disease (ePD) patients and healthy controls (HC). Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in 14 IRBD, 15 ePD patients in the medication-defined "off" state and 27 HC in an explorative cohort study. No significant differences between IRBD and HC were found with regard to spinal nociception (NFR) and experimental pain sensitivity. However, IRBD patient with anosmia and/or abnormal DaTSCAN tended to increased experimental pain sensitivity. In contrast, early PD patients exhibited increased NFR responses compared to HC, and a tendency for increased spinal nociception compared to IRBD patients. Increased spinal nociception may represent an early but not a premotor, non-motor feature of PD. Whether increased pain sensitivity already presents a premotor feature should be assessed in further studies.

Both anodal transcranial direct current stimulation (tDCS) of the left IFG and cathodal stimulation of the right IFG were shown to improve rehabilitation of stroke patients with Broca's aphasia. The study aimed at assessing the impact of a bihemispheric IFG stimulation compared to sham on postacute non-fluent aphasia. Twelve patients with non-fluent aphasia were included at least 4 weeks following cerebral stroke. Ten daily sessions of 2 mA bihemispheric verum or sham tDCS (anode on left IFG and cathode on right IFG) were performed concomitantly with individual language therapy in a double-blinded randomized controlled study with parallel group design. Language functions [i.e., communication (ANELT), picture naming and the Aachen aphasia test (AAT)] were assessed up to 1 month following tDCS. The picture naming task significantly improved (increased number of nouns) at the end of the tDCS procedure in the verum but not sham group. Improvements in the picture naming task and the communication task of the AAT at 4 weeks after tDCS procedure were only seen in the verum group. In patients with postacute cerebral stroke, repeated sessions of tDCS applied on both IFG concomitantly with language therapy were able to induce immediate effects on picture naming presumably due to an early left shift of language-associated function that maintained for 4 weeks. Effects on clinically relevant communicative abilities are likely.

Objectives Previous studies have shown that anodal transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) led to an improvement of various cognitive functions in patients with Alzheimer dementia, early affected by short-term memory deficits. Since this approach has not been evaluated in the context of vascular dementia, which rather affects the velocity of cognitive responses, we aimed at improving these functions by applying repetitive sessions of anodal tDCS. Methods Four 20-minute sessions of 2 mA anodal or sham at-home tDCS were applied to the left DLPFC in a single-blinded randomised study of 21 patients with mild vascular dementia, with parallel-group design. The effect of tDCS on cognitive testing was assessed up to two weeks beyond the stimulation time. Results A similar clinically meaningful improvement of various cognitive and behavioral dysfunction characteristics could be observed following either active or sham tDCS, whereas visual recall, and reaction times in the n-back task as well as in the go/no-go test improved only in the active tDCS group. Conclusions In patients with mild vascular dementia, anodal tDCS of the left DLPFC is able to produce additional effects to cognitive training on visual short-term memory, verbal working memory, and executive control.

Background Repetitive transcranial magnetic stimulation (rTMS) can relieve neuropathic pain when applied at high frequency (HF: 5–20 Hz) over the primary motor cortex (M1), contralateral to pain side. In most studies, rTMS is delivered over the hand motor hot spot (hMHS), whatever pain location. Navigation systems have been developed to guide rTMS targeting, but their value to improve rTMS efficacy remains to be demonstrated. Objective To compare the analgesic efficacy of HF-rTMS targeting the hMHS (non-navigated procedure) or the M1 representation of the pain region (navigated procedure). Methods The analgesic effect of a single session of 10 Hz-rTMS of M1 was assessed in 66 patients with neuropathic pain of various causes and locations, according to three conditions: sham or active non-navigated rTMS of the hMHS and active navigated rTMS of the pain region. Results Pain was relieved by both active rTMS conditions, and not by sham. Pain location influenced the results: upper or lower limb pain was significantly relieved, but not facial or hemibody pain. Pain relief lasted 1 week only after navigated rTMS, compared to sham. Conclusion Navigation may improve HF-rTMS efficacy in patients with limb pain, whereas targeting remains to be optimized for more diffuse or facial pain. What does this study add? To produce analgesic effects, HF-rTMS should be applied over the precentral cortex contralaterally to the painful side. Although the hMHS is the target normally chosen for stimulation, the optimal target has not been defined yet. Neuronavigational methods have been recently developed; they allow the integration of MRI data and are thought to improve rTMS efficacy.

Background Chronic spontaneous pain is a clinically relevant non-motor symptom in multiple system atrophy (MSA) and Parkinson's disease (PD). Experimental pain sensitivity, reflecting the mechanisms of nociception and pain perception leading to clinical pain, is known to be enhanced in both diseases at advanced stages. Also, this study aimed at investigating experimental pain sensitivity already at an early stage (i.e. symptom duration ≤5 years). Methods Experimental pain sensitivity was assessed by investigating the nociceptive flexion reflex (NFR, reflecting spinal nociception) and heat and electrical pain thresholds. ‘Off-drug’ MSA (n = 11) and PD (n = 14) patients selected at an early stage of the disease were compared to healthy controls (HC, n = 27). MSA patients had either parkinsonian (MSA-P, n = 5) or cerebellar (MSA-C, n = 6) subtypes. Results Compared to HC, MSA patients had lower heat pain sensitivity, whereas PD patients had reduced NFR threshold. MSA and PD patients did not differ from HC regarding other variables. MSA-P and MSA-C patients did not differ, either. Conclusions Impaired sensory discrimination and attention deficits could contribute to the reduced perception of heat pain in MSA, whereas in PD, local changes in spinal excitability or a diminished dopaminergic descending inhibition might impact on the motor efference of the NFR to reduce its threshold to nociceptive afferent information. What does this study add? This study investigated experimental pain sensitivity at an early stage in MSA and PD.

Background Pain is a significant burden for patients with Parkinson's disease (PD) with a high impact on quality of life. The present article aims at summarizing epidemiological, pathophysiological, clinical, and neurophysiological data regarding pain in PD. Methods In this domain, a procedure of systematic assessment is still lacking for the syndromic diagnosis and should take into account pain characteristics, effects of dopaminergic treatment, motor fluctuations, and non-PD-associated pain. Findings We propose an original questionnaire addressing an algorithm suitable for daily clinical practice. The questionnaire is based on a three-step approach addressing first the relationship between pain and PD (including temporal relationship with the course of the disease, association with motor fluctuations, and impact of antiparkinsonian treatment), before classifying pain into one of three main syndromes (i.e., musculoskeletal pain, psychomotor restlessness pain, and neuropathic pain). Conclusions The proposed questionnaire allows the characteristics of each pain type to be determined according to its relationship with the disease and its treatment. The validation of the clinical use of this questionnaire will be the goal of a forthcoming work.

A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson's disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer's disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Neuropathic pain is a very common burden of society. Although treatment options are various, their success is also limited. Cortical stimulation, which started with invasive epidural approach, first showed sufficient long-term analgesia in about half of the patients with chronic neuropathic pain, resistant to medication prior to implantation. More recently, noninvasive brain stimulation also proved to be effective in the treatment of these patients via rTMS delivered to the motor cortex. In addition, nTMS and nrTMS can be used to determine patient responsiveness and the most suitable site for subsequent electrode implantation.

Schmerzen zahlen zu den Symptomen, die Krebspatienten besonders belasten. Nicht zuletzt, weil sie haufig nicht ausreichend behandelt werden. Ein Grund fur die inadaquate Schmerzbehandlung sind fehlende Kenntnisse der komplexen Zusammenhange. Dies gilt insbesondere fur neuropathische Tumorschmerzen.

Image-guided navigation systems dedicated to transcranial magnetic stimulation (TMS) have been recently developed and offer the possibility to visualize directly the anatomical structure to be stimulated. Performing navigated TMS requires a perfect knowledge of cortical anatomy, which is very variable between subjects. This study aimed at providing a detailed description of sulcal and gyral anatomy of motor cortical regions with special interest to the inter-individual variability of sulci. We attempted to identify the most stable structures, which can serve as anatomical landmarks for motor cortex mapping in navigated TMS practice. We analyzed the 3D reconstruction of 50 consecutive healthy adult brains (100 hemispheres). Different variants were identified regarding sulcal morphology, but several anatomical structures were found to be remarkably stable (four on dorsoventral axis and five on rostrocaudal axis). These landmarks were used to define a grid of 12 squares, which covered motor cortical regions. This grid was used to perform motor cortical mapping with navigated TMS in 12 healthy subjects from our cohort. The stereotactic coordinates (x-y-z) of the center of each of the 12 squares of the mapping grid were expressed into the standard Talairach space to determine the corresponding functional areas. We found that the regions whose stimulation produced almost constantly motor evoked potentials mainly correspond to the primary motor cortex, with rostral extension to premotor cortex and caudal extension to posterior parietal cortex. Our anatomy-based approach should facilitate the expression and the comparison of the results obtained in motor mapping studies using navigated TMS.

Noninvasive cortical stimulation (NICS) can produce analgesic effects by means of repetitive transcranial magnetic stimulation or transcranial direct current stimulation (tDCS). Such effects have been demonstrated on chronic ongoing pain, as in acute provoked pain. The investigation of induced changes in the perception of experimental pain by NICS could help clinicians and researchers to better understand the mechanisms of action involved with these techniques and the role played by the cortex in the integration of nociceptive information. This review presents current literature data on the modulation of experimental pain perception by cortical stimulation. The observations found that NICS analgesic effects depend on the method used to provoke pain (referring to the type of nerve fibers and neural circuits that are recruited to mediate pain) and the parameters of cortical stimulation (especially the nature of the cortical target). The motor cortex (precentral cortical area) is the most widely used target for pain modulation. However, other targets, such as the dorsolateral prefrontal cortex, could be of particular interest to modulate various components of pain. Further developments in NICS techniques, such as image-guided navigated brain stimulation, might lead to improvement in the beneficial effects of NICS on pain. Finally, we discuss whether the results obtained in experimental pain can be transposed to the problem of chronic pain and whether they can be used to optimize cortical stimulation therapy for pain disorders.

Previous studies have shown that non-invasive stimulation of the dorsolateral prefrontal cortex (DLPFC) could modulate experimentally induced pain and working memory (WM) in healthy subjects. However, the two aspects have never been assessed concomitantly. The present study was set up to investigate the effects of transcranial direct current stimulation (tDCS) of the DLPFC on thermal pain and WM in the same population of healthy volunteers. In a randomized and balanced order of different sessions separated by 1 week, 20 min of 2 mA anodal, cathodal or sham tDCS were applied to the left or right DLPFC in two separate experiments. Twelve healthy volunteers were enrolled for each stimulated hemisphere. Warm and cold detection thresholds, heat and cold pain thresholds as well as heat pain tolerance thresholds were measured before, during and following tDCS. WM was assessed by a 2-back task applied once during cortical stimulation. Anodal tDCS of the right DLPFC led to an increase of tolerance to heat pain. The 2-back task revealed fewer outliers during cathodal tDCS of the left DLPFC. The present data show an involvement of the DLPFC in the processing of pain and WM. There was no correlation between these findings, suggesting that the analgesic effects of cortical stimulation are not associated with cognitive processing. However, this conclusion is difficult to affirm because of some limitations of the study regarding the parameters of stimulation or a ceiling effect of the 2-back task for instance.

Cluster headache (CH) is a rare headache disorder with severe unilateral headache bouts and autonomic symptoms. The pathophysiology of CH is not completely understood. Using a voxel-based morphometric paradigm or functional imaging, a key role of the hypothalamus and the pain matrix could be demonstrated during CH episodes. However, there are no diffusion tensor imaging (DTI) data investigating the white matter microstructure of the brain in patients with CH. Therefore, we used DTI to delineate microstructural changes in patients with CH in a headache-free state.Seven male patients with episodic CH and 7 healthy subjects were included and examined with a routine 1.5 T magnetic resonance imaging scanner. Whole-head DTI scans measuring fractional anisotropy were analyzed without a priori hypotheses using track-based spatial statistics.We found significant microstructural brain tissue changes bilaterally in the white matter of the brainstem, the frontal lobe, the temporal lobe, the occipital lobe, the internal capsule, and on the right side of thalamus and cerebellum. There were further lesions in the basal frontal lobe that were part of the olfactory system. Alterations of fractional anisotropy in the brainstem might indicate changes of the medial lemniscus and central sympathetic pathways.Patients with episodic CH have microstructural brain changes in regions that belong to the pain matrix. Furthermore, we were able to detect structural changes suggesting an involvement of the olfactory system as well as lesions in the brainstem indicating an involvement of trigeminal and sympathetic systems.

Pain sensitivity in Parkinson's disease is known to be altered in an L-dopa-dependent manner with increased spinal nociception and experimental pain perception in the medication-defined "off" state. As Parkinson's disease-related pain can be an early symptom in Parkinson's disease, the present study aimed to investigate experimental pain sensitivity and spinal nociception during clinical progression. The nociceptive flexion reflex as a marker of spinal nociception as well as electrical and heat pain thresholds were assessed during the medication-defined "off" state in 29 patients with Parkinson's disease divided into 3 severity groups (according to their Unified Parkinson's Disease Rating Scale motor score) and compared with 27 healthy elderly subjects. Parkinson's disease-related pain was also quantified. Data provided evidence that spinal nociception and pain sensitivity are preserved during the early phase of Parkinson's disease. Following increased spinal nociception (F(1,36) = 6.838, P = .013), experimental thermal and electrical pain sensitivity were augmented during the course of Parkinson's disease (F(1,34) = 5.397, P = .014; F(1,34) = 6.038, P = 0.053), whereas spinal nociception further increased (F(1,34) = 5.397, P < .001). Increased experimental pain sensitivity was observed in patients exhibiting Parkinson's disease-related pain. Spinal alterations either on the local level or induced by diminished dopaminergic descending inhibition probably led to increased pain sensitivity in later stages. Because Parkinson's disease-related pain is correlated with experimental pain sensitivity these 2 observations likely reflect a causal relation.

OBJECTIVE We investigated the influence of paired-pulse transcranial magnetic stimulation (ppTMS) of the motor cortex (M1) on perception of noxious electrical stimuli. The nociceptive flexion reflex response was assessed to determine spinal effects. METHODS In the first experiment, the effect of ppTMS of M1 on perception of noxious stimulation of the sural nerve was assessed by varying the stimulus onset asynchronies (SOAs) and the order of the stimulations (-400, -75, -25, 25, 125, 400 ms and control ppTMS, negative sign: ppTMS precedes the noxious stimulation). Effects of a preceding ppTMS on the RII and the RIII response of the nociceptive flexion reflex were investigated for SOAs of -400 and -75 ms. The effects of ppTMS of M1 and of the occipital cortex (Oz) on noxious stimulation of the radial nerve were investigated in a second experiment. Visual analogue scales were used to assess pain intensity and unpleasantness. RESULTS The results revealed increased pain unpleasantness scores for SOAs of -75, -25, 25, and 400 ms and decreased pain intensity scores for a SOA of -400 ms, when the sural nerve and M1 were stimulated. An increase of the area of the RII response was found for a SOA of -75 ms. For stimulation of the radial nerve, ppTMS of Oz but not of M1 increased the perceived pain at a SOA of 25 ms. DISCUSSION The facilitatory component of ppTMS led to increased pain perception when applied during the cortical process of Adelta fiber-mediated input, whereas the subsequent inhibitory component may lead to the opposite effect on the subsequent noxious stimulation.

Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (n = 37), FSHD (n = 17) or MG (n = 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG.

Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (n = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a "bottom-up" approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090-47,970) per patient in ALS, EUR 26,240 (95% CI 17,770-37,940) in FSHD and EUR 14,950 (95% CI 10,470-21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary.

Background.— The protein s100b indicates astrocytal damage as well as dysfunction of the blood-brain barrier (BBB), and neuron-specific enolase (NSE) is regarded as a marker for neuronal cell loss. Recently, s100b was shown to be a potentially useful marker for migraine in children. In this study, we investigated the levels of s100b and NSE in adult migraineurs during and after migraine attacks in order to gain some more insight into migraine pathophysiology. Methods.— Serum levels of s100b and NSE were measured in 21 migraineurs and compared with 21 healthy subjects matched by sex and age. In migraineurs, blood samples were taken during a migraine attack and following a pain-free period of 2-4 days. Results.— During migraine attacks elevated s100b levels could be observed. Maximal concentrations were detected in the pain-free period after 2-4 days. Regarding NSE, serum levels were decreased slightly during and after migraine bouts. Conclusions.— Our data suggest a prolonged disruption of BBB during and after migraine attacks. Other possible explanations concerning the detected serum levels of s100b and NSE will be discussed; however, neuronal cell death can be ruled out by the decreased serum concentrations of NSE. With regard to the results of the present study, further research is necessary to evaluate the role of s100b and NSE in migraine.

Background: Patients suffering from Parkinson’s disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. Objective: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. Method: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). Results: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. Conclusions: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

Objective: Old age has traditionally been viewed as being associated with a decline in emotional expressivity. Interestingly, empirical evidence based on analyses of facial expressions contradicts this traditionally view and points to absence of (or only very slight) age-related changes in emotional expressivity. However, this research on emotional expressivity in older persons has neglected one important emotionally colored state— expression of pain. In order to close this gap, we aimed to investigate the influence of age on the facial expression of pain. Methods: Forty young (mean age, 24.1 years) and 61 elderly (mean age, 72.3 years) subjects were investigated for their facial (Facial Action Coding System) and subjective responses to noxious mechanical and electrical stimuli of various intensities. Results: Young and elderly subjects did not differ with respect to the frequency of facial responses during noxious mechanical and electrical stimulations. Moreover, age had no significant impact on the pain specificity of these facial responses. Furthermore, we found no significant age differences in self-report ratings of pressure and electrical pain, thus indicating that both age groups experienced comparable amounts of pain intensities. Conclusion: These findings suggest that the facial expression of pain, like facial expressions of other affective states, remains unchanged in older persons. Consequently, elderly individuals seem to communicate pain through their facial expression as validly as younger individuals do.

Es ist bekannt, dass Demenzpatienten weniger Schmerzmittel erhalten und weniger uber Schmerzen klagen als kognitiv Gesunde. Hieraus ergibt sich die Frage, ob Demenzerkrankungen die Schmerzverarbeitung verandern. An 20 Patienten mit Demenz und 40 mit leichter kognitiver Beeintrachtigung (LKB) sowie 40 Kontrollpersonen wurden die verbalen (Kategorialskala), mimischen (FACS) und motorischen Schmerzreaktionen (R-III-Reflex) auf mechanische und elektrische Reize erfasst. Demenzpatienten schatzten die Starke der Schmerzreize nicht anders ein, waren jedoch seltener hierzu in der Lage. Bei gleich starken Reizen reagierten die Demenzpatienten mimisch starker; die Schwelle ihres R-III-Reflexes war vermindert. LKB-Patienten erwiesen sich in allen Schmerzparametern nur tendenziell verandert. Unsere Daten weisen daraufhin, dass die Verarbeitung akuter nozizeptiver Reize bei Demenzpatienten verstarkt ist. Vor dem Hintergrund der selteneren Analgetikaverordnung konnte dies auf eine schmerztherapeutische Unterversorgung von Demenzpatienten hindeuten.

Objective To determine the influence of different factors on test–retest reliability of frequently used transcranial magnetic stimulation (TMS) parameters while controlling for potential confounders in healthy subjects. Methods TMS was applied in 93 healthy volunteers (61% male) twice (mean retest interval of 34.0 ± 25.6 (SD) days) between 7 am and 2 pm by four investigators (sessions n investigator A = 47, investigator B = 95, investigator C = 28, investigator D = 16). Women were assessed in their follicular phase. Test stimulus (TS), resting motor threshold (RMT), short latency intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (SCP) were analyzed. Results Good test–retest reliabilities were observed for TS (r = .880) and RMT (r = .826), moderate for visual and automated analyzed CSP durations (resp. r = .466, r = .486), and poor for ICF (r = −.159). Reliable change indexes are reported. Gender (e.g. automated CSP women: r = .538 vs. men: r = .422), re-test interval and method of CSP-analysis did not influence reliabilities. Conclusions In a large sample of healthy volunteers we found good to moderate test–retest reliabilities in all but one TMS-parameter. Automated analysis of the CSP did not prove to be more reliable than visual determination. Significance This study contains analyses of re-test reliability in TMS considering several confounding factors. For the first time it presents reliable change indices for all frequently used TMS parameters.

Le cortex cerebral est la cible qui a ete la plus recemment evaluee pour le traitement des douleurs neuropathiques par neuromodulation. Au debut des annees 1990, les premiers succes de la stimulation epidurale du cortex moteur implantee chirurgicalement (EMCS) ont ete publies. Quelques annees plus tard a ete developpee la stimulation magnetique transcrânienne repetitive (rTMS), une technique de stimulation non invasive. Puis la stimulation electrique transcrânienne a courant continu (tDCS) a ete proposee. Pour toutes ces approches de neuromodulation corticale, invasives ou non-invasives, la principale cible etudiee et validee a ete le cortex moteur (gyrus precentral), mais d’autres cibles corticales sont en cours d’evaluation, comme le cortex prefrontal dorsolateral. Les mecanismes d’action de ces techniques presentent certaines similitudes, en particulier entre l’EMCS et la rTMS, mais aussi des differences qui pourraient justifier des indications et des applications specifiques, en particulier entre la rTMS et la tDCS. Il est donc important de connaitre les principes de ces techniques et de realiser une evaluation rigoureuse des resultats obtenus, afin d’eviter tout effet de mode. Differents types de syndromes douloureux, notamment la douleur neuropathique chronique refractaire, peuvent etre significativement ameliores par l’implantation d’un stimulateur cortical (EMCS) ou la repetition de seances quotidiennes de rTMS a haute frequence (5 a 20 Hz) ou de tDCS anodique, notamment pour des douleurs lateralisees, si la stimulation est appliquee sur le cortex moteur controlateral a la douleur. Cependant, les strategies therapeutiques de stimulation corticale restent a optimiser, notamment sur le plan de la conception des electrodes de stimulation epidurale, le ciblage de la rTMS ou le montage des electrodes de tDCS. Ceci devrait permettre de reduire le taux encore eleve de patients non-repondeurs, qui ne beneficient pas d’effets cliniquement pertinents de l’application de ces techniques.

Using pupillometry and sympathetic skin responses we compared the changes in local and systemic autonomic function within one week of a migraine attack. We investigated whether the measurement of the pupillary light reflex provides further information on the pathophysiology of migraine. Forty-two migraine patients and forty-two healthy age-matched controls were included. The parameters that were measured were the amplitude of the pupillary light reflex, the pupil size at the beginning of the measurement, the latency, the velocity of constriction and the velocity at the end of the dilatation. The average pupil size was 6.43 mm in the migraine group and 6.7 mm in the control group (p < 0.01). Reduced velocity of constriction and smaller amplitude of constriction in migraine patients within two days of an attack were signs of a parasympathetic dysfunction (p < 0.05). The sympathetic skin response did not differ significantly between migraine sufferers and controls. These findings indicate that both parasympathetic and sympathetic nerves supplying the eye are involved in migraine headache presumably due to effects on the pericarotid sympathetic fibers and involvement of trigeminal-parasympathetic reflexes.

Background and purpose High-dose steroid administration is the usual treatment of multiple sclerosis (MS) relapse, but it remains to determine whether this treatment may act by changing the excitability of cortical circuitry. Methods The functional cortical effects of high-dose steroids in 21 MS patients before and after 3 days of intravenous administration of methylprednisolone (1 g/day) for the treatment of MS relapse were studied. Investigations included various clinical scales [Kurtzke Functional System Scale (KFSS), Expanded Disability Status Scale and Fatigue Severity Scale, 10-m walk] and transcranial magnetic stimulation (TMS) tests of cortical excitability [resting motor threshold, recruitment curve of motor evoked potentials, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at various interstimuli intervals (ISIs), cortical silent period and interhemispheric inhibition]. Results Following steroid administration, clinical improvement was significant for the KFSS pyramidal (motor) and total scores, whilst TMS showed a reduction of SICI (mean and maximum values) and an increase of ICF at 10 ms ISI. Conclusions Very rapid functional changes in the excitability of cortical circuits involved in motor control can be induced by steroids, before any process of remyelination or axonal regeneration has time to occur. The net effect of steroids on the balance between intracortical GABAergic inhibition and glutamatergic facilitation was in favour of weaker inhibition or stronger facilitation, which could lead to improving the motor performance in MS patients.

ObjectiveSerum calcium (Ca2+) and parathyroid hormone (PTH), amongst others, modify cortical excitability. Alterations in cortical excitability were shown in patients with epilepsy as well as hyper- or hypoparathyroidism. In patients with primary hyperparathyroidism (pHPT), preoperative elevated serum calcium and parathyroidectomy (PTx) may affect mood and quality of life. We hypothesized that perioperative changes in Ca2+ and PTH in pHPT will affect cortical excitability and improve subjective health.Design and methodsTranscranial magnetic stimulation (TMS) was performed before and after surgery in 15 pHPT patients. We measured resting motor threshold, cortical silent period (CSP), short intracortical inhibition, and intracortical facilitation. Health questionnaires were administered before, 1 day and 6 months after PTx, along with the disease-specific Pasieka's parathyroid assessment of symptoms (PAS), which was, to our knowledge, its first use in German.ResultsSurgery was successful in all patients. TMS-measurements remained unchanged when analyzing all patients in this pilot study. Postoperatively, depression declined (P=0.05) and quality of life improved significantly (P=0.001) in the SF-36-subscales: vitality, social functioning, mental health and subjective health transition (post-hoc analysis). The PAS proved early relief of disease-specific symptoms (PConclusionsWe found unchanged cortical excitability comparing pre- and post-PTx in this pilot study. Mood and quality of life improved postoperatively. The German PAS is valuable in detecting disease-specific changes early after PTx.

Background and purpose: The prevalence of the heterozygous G2019S and R1441C/G/H mutations in LRRK2 in patients with Parkinson’s disease (PD) has shown a great variability depending on the sample population. Here we investigated the prevalence of these mutations in a large cohort of German PD patients (n = 1049). Results: We observed heterozygous G2019S mutations in five patients with apparently sporadic late-onset PD (LOPD; n = 3) and young-onset PD (YOPD) (one sporadic and one familial), respectively, resulting in an overall prevalence of 0.5%. No R1441C/G/H mutation was found in our sample. Discussion: In summary, the overall prevalence of the G2019S mutation in German PD patients is apparently somewhat lower than in patients from other nearby European countries. In contrast to previous reports, the G2019S mutation was also observed in apparently sporadic German LOPD patients.

Item does not contain fulltext OBJECTIVE: The purpose of this narrative review is to analyze the available literature concerning central sensitization and altered central pain processing in patients with chronic low back pain (LBP). METHODS: Literature was screened using several electronic search databases. Additional literature was obtained by reference tracking and expert consultation. Studies evaluating central pain processing in conservatively treated patients with chronic LBP were included. RESULTS: Results of studies examining the responsiveness to various stimuli in patients with chronic LBP are conflicting. Some studies in patients with chronic LBP have demonstrated exaggerated pain responses after sensory stimulation of locations outside the painful region, while other studies report no differences between patients and healthy subjects. Studies examining the integrity of the endogenous pain inhibitory systems report unaltered activity of this descending inhibitory system. In contrast, studies analyzing brain structure and function in relation to (experimentally induced) pain provide preliminary evidence for altered central nociceptive processing in patients with chronic LBP. Finally, also psychosocial characteristics, such as inappropriate beliefs about pain, pain catastrophizing, and/or depression may contribute to the mechanisms of central sensitization. CONCLUSIONS: It tempting to speculate that ongoing nociception is associated with cortical and subcortical reorganization and may play an important role in the process of the chronification of LBP. Future prospective research should explore to what extent these changes are reversible and if this reversibility is associated with improved functioning of patients.

Question To determine the influence of different factors on test-retest reliability of frequently used transcranial magnetic stimulation (TMS) parameters while controlling for potential confounders in healthy subjects. Methods TMS was applied in 93 healthy volunteers (61% male) twice (mean retest interval of 34.0 ± 25.6 (SD) days) between 7 am and 2 pm by four investigators (sessions n investigator A = 47, investigator B = 95, investigator C = 28, investigator D = 16). Women were assessed only in their follicular phase. Test stimulus (TS), resting motor threshold (RMT), short latency intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (SCP) were analyzed. CSP was analyzed visually and automatically. Results Good test-retest reliabilities were observed for TS (r = .880) and RMT (r = .826), moderate for visual and automated analyzed CSP durations (resp. r = .466, r = .486), and poor for ICF (r = −.159). Gender (eg. automated CSP women: r = .538 vs. men: r = .422), re-test interval and method of CSP-analysis did not influence reliabilities. Reliable change indices are reported. Conclusions In a large sample of healthy volunteers we found good to moderate test-retest reliabilities in all but one TMS-parameter. Automated analysis of the CSP did not prove to be more reliable than visual determination. For the first time it presents reliable change indices for all frequently used TMS parameters. These data can be helpful to determine the significance of observed changes in cortical excitability as well as for study design and sample size calculation in future research, in healthy populations.

Les douleurs sont tres communes dans la maladie de Parkinson (MP) et souvent associees a la maladie. La prevalence des douleurs augmente avec la progression clinique de la MP, de facon egalement parallele avec l’augmentation de la nociception spinale, qui est deja exageree au debut de la maladie. Pour savoir si l’augmentation de la nociception spinale et de la sensibilite a la douleur est un signe precoce precedant les signes moteurs dans la MP, nous avons explore des patients atteints de troubles comportementaux en sommeil paradoxal (TCSP ou REM Behavior Disorder [RBD]). En effet, les TCSP pourraient representer un stade preliminaire au developpement d’une maladie neurodegenerative comme la MP. Nous avons compare des patients TCSP avec des patients atteints de MP dans leurs 5 premieres annees. La nociception spinale etait mesuree au moyen de l’enregistrement du reflexe nociceptif de flexion (Nociceptive Flexion Reflex [NFR]) et la sensibilite a la douleur etait evaluee par un seuil electrique et un seuil thermique au chaud. Les patients atteints de TCSP ne presentaient pas d’anomalies quant aux mesures de nociception spinale et de sensibilite a la douleur, en dehors des patients presentant ouvertement des signes de maladie neurodegenerative (objectives au DATSCAN). Ce dernier groupe avait une sensibilite augmentee a la douleur experimentale provoquee, en comparaison avec un groupe temoin. A l’inverse, les patients atteints de MP montraient une elevation de la nociception spinale. L’augmentation de la sensibilite a la douleur pourrait etre un signe d’atteinte precedant l’atteinte motrice, alors que l’augmentation de la nociception spinale pourrait representer une atteinte non-motrice precoce de la MP.

The rehabilitation of neuropsychological sequels of cerebral stroke such as hemispatial neglect by noninvasive cortical stimulation (NICS) attracts increasing attention from the scientific community. The NICS techniques include primarily repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). They are based on the concept of either reactivating a hypoactive cortical region affected by the stroke (the right hemisphere in case of neglect) or reducing cortical hyperactivity of the corresponding cortical region in the contralateral hemisphere (the left hemisphere). In the studies published to date on the topic of neglect rehabilitation, rTMS was used to inhibit the left parietal cortex and tDCS to either activate the right or inhibit the left parietal cortex. Sham-controlled NICS studies assessed short-term effects, whereas long-term effects were only assessed in noncontrolled rTMS studies. Further controlled studies of large series of patients are necessary to determine the best parameters of stimulation (including the optimal cortical target location) according to each subtype of neglect presentation and to the time course of stroke recovery. To date, even if there are serious therapeutic perspectives based on imaging data and experimental studies, the evidence is not compelling enough to recommend any particular NICS protocol to treat this disabling condition in clinical practice.

Poststroke aphasia results from the lesion of cortical areas involved in the motor production of speech (Broca's aphasia) or in the semantic aspects of language comprehension (Wernicke's aphasia). Such lesions produce an important reorganization of speech/language-specific brain networks due to an imbalance between cortical facilitation and inhibition. In fact, functional recovery is associated with changes in the excitability of the damaged neural structures and their connections. Two main mechanisms are involved in poststroke aphasia recovery: the recruitment of perilesional regions of the left hemisphere in case of small lesion and the acquisition of language processing ability in homotopic areas of the nondominant right hemisphere when left hemispheric language abilities are permanently lost. There is some evidence that noninvasive cortical stimulation, especially when combined with language therapy or other therapeutic approaches, can promote aphasia recovery. Cortical stimulation was mainly used to either increase perilesional excitability or reduce contralesional activity based on the concept of reciprocal inhibition and maladaptive plasticity. However, recent studies also showed some positive effects of the reinforcement of neural activities in the contralateral right hemisphere, based on the potential compensatory role of the nondominant hemisphere in stroke recovery.

Noninvasive cortical stimulation (NICS) has been used during the acute, postacute and chronic poststroke phases to improve motor recovery in stroke patients having upper- and/or lower-limb paresis. This paper reviews the rationale for using the different NICS modalities to promote motor stroke rehabilitation. The changes in cortical excitability after stroke and the possible mechanisms of action of cortical stimulation in this context are outlined. A number of open and placebo-controlled trials have investigated the clinical effect of repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) of the primary motor cortex in patients with motor stroke. These studies attempted to improve motor performance by increasing cortical excitability in the stroke-affected hemisphere (via high-frequency rTMS or anodal tDCS) or by decreasing cortical excitability in the contralateral hemisphere (via low-frequency rTMS or cathodal tDCS). The goal of these studies was to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and to then restore a normal balance of interhemispheric inhibition. All these NICS techniques administered alone or in combination with various methods of neurorehabilitation were found to be safe and equally effective at the short term on various aspects of poststroke motor abilities. However, the long-term effect of NICS on motor stroke needs to be further evaluated before considering the use of such a technique in the daily routine management of stroke.

Objective We aimed to assess spinal nociception and experimental pain sensitivity in progressive supranuclear palsy-Richardson’s syndrome (PSP-R) compared to patients with Parkinson’s disease (PD) and healthy controls (HC). Methods Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in non-demented, non-depressed, probable PSP-R patients (N = 8), PD patients (N = 19) and 17 HC. Results PSP-R patients exhibited lower electrical pain thresholds and a tendency for lower NFR thresholds as compared to HC. No significant differences between PSP-R and PD patients were found with respect to experimentally-induced pain. However, significantly less PSP-R than PD patients reported disease-related pain. Conclusions Degeneration of the descending inhibitory control system within the brainstem in PSP-R might lead to increased experimental pain sensitivity while frontal cortical deterioration may alter self-estimation of pain.