[The new Parkinson's disease pain classification system (PD-PCS)]. / Die neue Parkinson-Schmerzklassifikation (PSK).

BACKGROUND: Chronic pain is a common non-motor symptom in patients with Parkinson's disease (PD). AIM: To facilitate the diagnosis of pain in PD, we developed a new classification system the Parkinson's disease pain classification system (PD-PCS) and translated the corresponding validated questionnaire into German. METHODS: A causal relationship of the respective pain syndrome with PD can be determined by four questions before assigning it hierarchically into one of three pain categories (neuropathic, nociceptive and nociplastic). RESULTS: In the initial validation study 77% of the patients (122/159) had PD-associated pain comprising 87 (55%) with nociceptive, 36 (22%) with nociplastic and 24 (16%) with neuropathic pain. The study revealed a high validity of the questionnaire and a moderate intrarater and interrater reliability. The questionnaire has been adapted into German and employed in 30 patients. DISCUSSION: The PD-PCS questionnaire is a valid and reliable tool to determine the relationship of a pain syndrome with PD before classifying it according to the underlying category, facilitating further diagnostics and treatment.

Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain.

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.

Test-retest reliability of single and paired pulse transcranial magnetic stimulation parameters in healthy subjects.

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.

Experimental pain sensitivity in multiple system atrophy and Parkinson's disease at an early stage.

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.

Relapses in multiple sclerosis: effects of high-dose steroids on cortical excitability.

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.

Perioperative changes in cortical excitability, mood, and quality of life in patients with primary hyperparathyroidism: a pilot study using transcranial magnetic stimulation.

OBJECTIVE: Serum calcium (Ca(2)(+)) 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 Ca(2)(+) and PTH in pHPT will affect cortical excitability and improve subjective health. DESIGN AND METHODS: Transcranial 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. RESULTS: SURGERY 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 (P<0.001). CONCLUSIONS: We 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.

Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age.

The optimization of the targeting of a defined cortical region is a challenge in the current practice of transcranial magnetic stimulation (TMS). The dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) are among the most usual TMS targets, particularly in its "therapeutic" application. This study describes a practical algorithm to determine the anatomical location of the DLPFC and M1 using a three-dimensional (3D) brain reconstruction provided by a TMS-dedicated navigation system from individual magnetic resonance imaging (MRI) data. The coordinates of the right and left DLPFC and M1 were determined in 50 normal brains (100 hemispheres) by five different investigators using a standardized procedure. Inter-rater reliability was good, with 95% limits of agreement ranging between 7 and 16 mm for the different coordinates. As expressed in the Talairach space and compared with anatomical or imaging data from the literature, the coordinates of the DLPFC defined by our algorithm corresponded to the junction between BA9 and BA46, while M1 coordinates corresponded to the posterior border of hand representation. Finally, we found an influence of gender and possibly of age on some coordinates on both rostrocaudal and dorsoventral axes. Our algorithm only requires a short training and can be used to provide a reliable targeting of DLPFC and M1 between various TMS investigators. This method, based on an image-guided navigation system using individual MRI data, should be helpful to a variety of TMS studies, especially to standardize the procedure of stimulation in multicenter "therapeutic" studies.

[Transcranial magnetic stimulation and motor cortex stimulation in neuropathic pain]. / Transkranielle Magnetstimulation und Motorkortexstimulation bei neuropathischen Schmerzen.

Non-invasive and invasive cortical stimulation allows the modulation of therapy-refractory neuropathic pain. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the contralateral motor cortex yields therapeutic effects at short-term and predicts the benefits of epidural motor cortex stimulation (MCS). The present article summarizes the findings on application, mechanisms and therapeutic effects of cortical stimulation in neuropathic pain.

Effects of transcranial direct current stimulation on pain perception and working memory.

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.

[French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. / Recommandations françaises sur l'utilisation de la stimulation magnétique transcrânienne répétitive (rTMS) : règles de sécurité et indications thérapeutiques.

During the past decade, a large amount of work on transcranial magnetic stimulation (TMS) has been performed, including the development of new paradigms of stimulation, the integration of imaging data, and the coupling of TMS techniques with electroencephalography or neuroimaging. These accumulating data being difficult to synthesize, several French scientific societies commissioned a group of experts to conduct a comprehensive review of the literature on TMS. This text contains all the consensual findings of the expert group on the mechanisms of action, safety rules and indications of TMS, including repetitive TMS (rTMS). TMS sessions have been conducted in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better assessment of risks associated with this technique. The number of reported side effects is extremely low, the most serious complication being the occurrence of seizures. In most reported seizures, the stimulation parameters did not follow the previously published recommendations (Wassermann, 1998) [430] and rTMS was associated to medication that could lower the seizure threshold. Recommendations on the safe use of TMS / rTMS were recently updated (Rossi et al., 2009) [348], establishing new limits for stimulation parameters and fixing the contraindications. The recommendations we propose regarding safety are largely based on this previous report with some modifications. By contrast, the issue of therapeutic indications of rTMS has never been addressed before, the present work being the first attempt of a synthesis and expert consensus on this topic. The use of TMS/rTMS is discussed in the context of chronic pain, movement disorders, stroke, epilepsy, tinnitus and psychiatric disorders. There is already a sufficient level of evidence of published data to retain a therapeutic indication of rTMS in clinical practice (grade A) in chronic neuropathic pain, major depressive episodes, and auditory hallucinations. The number of therapeutic indications of rTMS is expected to increase in coming years, in parallel with the optimisation of stimulation parameters.

No significance of the COMT val158met polymorphism in restless legs syndrome.

The catechol-O-methyltransferase (COMT) val(158)met polymorphism, which codes for the substitution of valine (val) by methionine (met) leading to a reduced COMT activity in homo- or heterozygous individuals, is associated with individual pain sensitivity and dopaminergic responses in Parkinson's disease as well as with various chronic painful diseases. Recent investigations support the notion of an alteration of the medial pain pathway as well as of the descending inhibitory control system in restless legs syndrome (RLS), that both involve dopaminergic transmission as well. Thus, the distribution of the COMT val(158)met polymorphism was assessed in 298 RLS patients and compared with 135 healthy controls in relation to sex, age of onset and family history. The data revealed no significant differences in the distribution of the COMT val(158)met polymorphism in RLS patients compared with the control group, also when the heterozygous and the homozygous group containing the (158)met allele were combined. In addition, sex, age of onset and family history were not associated with the COMT val(158)met polymorphism in this German population of RLS patients. The present study adds to previous mostly negative investigations on the genetic determination of dopaminergic transmission in RLS, which have - so far - only detected an association of the MAO-A activity and RLS in females in a French-Canadian population. Further investigations assessing the different COMT haplotypes and experimental and clinical parameters are nevertheless warranted.

Low-frequency rTMS of the vertex in the prophylactic treatment of migraine.

High-frequency repetitive transcranial magnetic stimulation (rTMS) increases and low-frequency rTMS decreases neural excitability. Clinically, rTMS shows beneficial effects in the treatment of neurological and psychiatric disorders. Furthermore, chronic and neuropathic pain has been shown to respond to rTMS treatment. A small pilot study revealed prophylactic effects of high-frequency rTMS in migraine. As there is evidence of neuronal hyperexcitability in migraine, we conducted a placebo-controlled, blinded study to evaluate the therapeutic effects of low-frequency rTMS in migraine. The primary end-point was defined as a reduction of migraine attacks compared with placebo, secondary outcomes were a reduction in the total number of days with headache, hours with headache, pain intensity and a decrease of analgesic intake for migraine. Twenty-seven migraineurs completed the study and were treated with rTMS on five consecutive days. For the verum group, two trains of 500 pulses with a frequency of 1 Hz were applied over vertex with a round coil. For the treatment of the placebo group, a figure-of-eight sham coil was used. A significant decrease of migraine attacks could be observed in the verum group. However, when comparing these effects with placebo, no significance was evident. The same was true concerning secondary outcome measures with regard to days with migraine and total hours with migraine. No effects were evident for pain intensity and use of analgesics. The rTMS treatment was tolerated well. rTMS stimulation over vertex with 1 Hz was not effective in migraine prophylaxis when compared with placebo. The positive effects regarding migraine attacks, days and total hours with migraine in the verum group are encouraging and indicate that further research on this topic is warranted.

Low-frequency rTMS of the premotor cortex reduces complex movement patterns in a patient with pantothenate kinase-associated neurodegenerative disease (PKAN).

INTRODUCTION: Pantothenate kinase-associated neurodegenerative disease (PKAN) is a secondary generalized dystonia associated with an accumulation of iron in the basal ganglia and increased motor cortex excitability. A pilot study in three patients with secondary generalized dystonia had reported a reduced frequency of painful axial spasms following inhibitory 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied over the premotor cortex. PATIENT AND METHODS: We compared the effects of real versus sham rTMS on the frequency of the complex movement pattern and the need for additional benzodiazepine medication in a 6-year-old male patient with PKAN. A 20-minute session of left premotor 1-Hz rTMS was performed daily on 5 consecutive days. RESULTS: The occurrence of the complex movement pattern was gradually reduced from three to two attacks daily to one attack daily by real rTMS while sham rTMS had no effect. This reduction was obtained concomitantly with a similar reduction of additional benzodiazepines for both real and sham rTMS sessions. CONCLUSION: Inhibitory rTMS of the premotor cortex may be used to temporarily control motor symptoms in PKAN.

Pain sensitivity and descending inhibition of pain in Parkinson's disease.

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.

The prevalence of the G2019S and R1441C/G/H mutations in LRRK2 in German patients with Parkinson's disease.

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.

[Multidimensional pain assessment in patients with dementia]. / Mehrdimensionale Schmerzmessung bei Demenzpatienten.

BACKGROUND: It is well known that patients with dementia complain less about pain and receive fewer analgesics than other patients. The question arises of whether disorders associated with dementia change the processing of pain. METHODS: A total of 20 patients with dementia and 40 patients with mild cognitive impairment (MCI) as well as 40 healthy control subjects were investigated for their subjective (category scale), facial (FACS) and motor (R-III reflex) pain responses to mechanical and electrical stimuli. RESULTS: Patients with dementia did not rate the intensity of the stimuli differently; however, they were less frequently capable of providing ratings. At equal levels of stimulus intensity, demented patients showed stronger facial responses. The R-III reflex thresholds were lowered in demented patients. MCI patients appeared only slightly changed. CONCLUSIONS: Our findings suggest that the processing of acute noxious stimuli is intensified in patients with dementia. Against the background of a reduced prescription of analgesics, an under-treatment of pain in patients with dementia might be the consequence.