Deep Brain Stimulation Improves Parkinson's Disease-Associated Pain by Decreasing Spinal Nociception.

Dopamine exerts antinociceptive effects on pain in PD at cortical and spinal levels, whereas only cortical effects have been described for DBS, so far. By assessing the nociceptive flexion reflex (NFR) threshold at medication on, and DBS ON and OFF in two patients, we showed that DBS additionally decreases spinal nociception.

Development and Validation of the Dystonia-Pain Classification System: A Multicenter Study.

BACKGROUND: Dystonia is associated with disabling nonmotor symptoms like chronic pain (CP), which is prevalent in dystonia and significantly impacts the quality of life (QoL). There is no validated tool for assessing CP in dystonia, which substantially hampers pain management. OBJECTIVE: The aim was to develop a CP classification and scoring system for dystonia. METHODS: A multidisciplinary group was established to develop the Dystonia-Pain Classification System (Dystonia-PCS). The classification of CP as related or unrelated to dystonia was followed by the assessment of pain severity score, encompassing pain intensity, frequency, and impact on daily living. Then, consecutive patients with inherited/idiopathic dystonia of different spatial distribution were recruited in a cross-sectional multicenter validation study. Dystonia-PCS was compared to validated pain, mood, QoL, and dystonia scales (Brief Pain Inventory, Douleur Neuropathique-4 questionnaire, European QoL-5 Dimensions-3 Level Version, and Burke-Fahn-Marsden Dystonia Rating Scale). RESULTS: CP was present in 81 of 123 recruited patients, being directly related to dystonia in 82.7%, aggravated by dystonia in 8.8%, and nonrelated to dystonia in 7.5%. Dystonia-PCS had excellent intra-rater (Intraclass Correlation Coefficient - ICC: 0.941) and inter-rater (ICC: 0.867) reliability. In addition, pain severity score correlated with European QoL-5 Dimensions-3 Level Version's pain subscore (r = 0.635, P < 0.001) and the Brief Pain Inventory's severity and interference scores (r = 0.553, P < 0.001 and r = 0.609, P < 0.001, respectively). CONCLUSIONS: Dystonia-PCS is a reliable tool to categorize and quantify CP impact in dystonia and will help improve clinical trial design and management of CP in patients affected by this disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A New Therapeutic Approach for Dystussia and Atussia in Neurogenic Dysphagia: Effect of Aerosolized Capsaicin on Peak Cough Flow.

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 < 0.001), while there was no significant difference in reflexive PCF (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 < 0.001). The data show that AC increased the tracheobronchial clearance efficacy in ND patients with dystussia and atussia, as it enabled subjects to access their individual cough potential, which is present, but inaccessible, due to neurological disorder.

Reappraisal of the anatomical landmarks of motor and premotor cortical regions for image-guided brain navigation in TMS practice.

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.

Pain in Parkinson disease: mechanistic substrates, main classification systems, and how to make sense out of them.

ABSTRACT: Parkinson disease (PD) affects up to 2% of the general population older than 65 years and is a major cause of functional loss. Chronic pain is a common nonmotor symptom that affects up to 80% of patients with (Pw) PD both in prodromal phases and during the subsequent stages of the disease, negatively affecting patient's quality of life and function. Pain in PwPD is rather heterogeneous and may occur because of different mechanisms. Targeting motor symptoms by dopamine replacement or with neuromodulatory approaches may only partially control PD-related pain. Pain in general has been classified in PwPD according to the motor signs, pain dimensions, or pain subtypes. Recently, a new classification framework focusing on chronic pain was introduced to group different types of PD pains according to mechanistic descriptors: nociceptive, neuropathic, or neither nociceptive nor neuropathic. This is also in line with the International Classification of Disease-11 , which acknowledges the possibility of chronic secondary musculoskeletal or nociceptive pain due to disease of the CNS. In this narrative review and opinion article, a group of basic and clinical scientists revise the mechanism of pain in PD and the challenges faced when classifying it as a stepping stone to discuss an integrative view of the current classification approaches and how clinical practice can be influenced by them. Knowledge gaps to be tackled by coming classification and therapeutic efforts are presented, as well as a potential framework to address them in a patient-oriented manner.

Diffusion tensor imaging in episodic cluster headache.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 and clinical progression in Parkinson's disease.

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.

Benign paroxysmal positional vertigo following diagnostic transcranial magnetic stimulation.

Benign paroxysmal positional vertigo is the most frequent cause of recurrent vertigo and according to the canalo- and cupulolithiasis theory it is caused by detached otoconia which accumulate in the semicircular canals. However, the mechanisms leading to detachment of otoconia from the matrix are still poorly understood. Head trauma, inner ear diseases, advanced age, migraine and bed rest are known predisposing factors. We report a case of a healthy 44-year-old female, who developed left sided benign paroxysmal positional vertigo 10 hours following standard bilateral diagnostic transcranial magnetic stimulation. As our patient did not innate any established predisposing factor and has a relatively young age, we conclude that diagnostic transcranial magnetic stimulation to elicit motor evoked potentials might be an iatrogenic cause of benign paroxysmal positional vertigo.

Diagnosis and Management of Pain in Parkinson's Disease: A New Approach.

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.

Dual-Task Treadmill Training for the Prevention of Falls in Parkinson's Disease: Rationale and Study Design.

Various factors, such as fear of falling, postural instability, and altered executive function, contribute to the high risk of falling in Parkinson's disease (PD). Dual-task training is an established method to reduce this risk. Motor-perceptual task combinations typically require a patient to walk while simultaneously engaging in a perceptual task. Motor-executive dual-tasking (DT) combines locomotion with executive function tasks. One augmented reality treadmill training (AR-TT) study revealed promising results of a perceptual dual-task training with a markedly reduced frequency of falls especially in patients with PD. We here propose to compare the effects of two types of concurrent tasks, perceptual and executive, on high-intensity TT). Patients will be trained with TT alone, in combination with an augmented reality perceptual DT (AR-TT) or with an executive DT (Random Number Generation; RNG-TT). The results are expected to inform research on therapeutic strategies for the training of balance in PD.

Consensus Statement on High-Intensity Focused Ultrasound for Functional Neurosurgery in Switzerland.

Background: Magnetic resonance-guided high-intensity focused ultrasound (MRgHiFUS) has evolved into a viable ablative treatment option for functional neurosurgery. However, it is not clear yet, how this new technology should be integrated into current and established clinical practice and a consensus should be found about recommended indications, stereotactic targets, patient selection, and outcome measurements. Objective: To sum up and unify current knowledge and clinical experience of Swiss neurological and neurosurgical communities regarding MRgHiFUS interventions for brain disorders to be published as a national consensus paper. Methods: Eighteen experienced neurosurgeons and neurologists practicing in Switzerland in the field of movement disorders and one health physicist representing 15 departments of 12 Swiss clinical centers and 5 medical societies participated in the workshop and contributed to the consensus paper. All experts have experience with current treatment modalities or with MRgHiFUS. They were invited to participate in two workshops and consensus meetings and one online meeting. As part of workshop preparations, a thorough literature review was undertaken and distributed among participants together with a list of relevant discussion topics. Special emphasis was put on current experience and practice, and areas of controversy regarding clinical application of MRgHiFUS for functional neurosurgery. Results: The recommendations addressed lesioning for treatment of brain disorders in general, and with respect to MRgHiFUS indications, stereotactic targets, treatment alternatives, patient selection and management, standardization of reporting and follow-up, and initialization of a national registry for interventional therapies of movement disorders. Good clinical evidence is presently only available for unilateral thalamic lesioning in treating essential tremor or tremor-dominant Parkinson's disease and, to a minor extent, for unilateral subthalamotomy for Parkinson's disease motor features. However, the workgroup unequivocally recommends further exploration and adaptation of MRgHiFUS-based functional lesioning interventions and confirms the need for outcome-based evaluation of these approaches based on a unified registry. MRgHiFUS and DBS should be evaluated by experts familiar with both methods, as they are mutually complementing therapy options to be appreciated for their distinct advantages and potential. Conclusion: This multidisciplinary consensus paper is a representative current recommendation for safe implementation and standardized practice of MRgHiFUS treatments for functional neurosurgery in Switzerland.

The Parkinson disease pain classification system: results from an international mechanism-based classification approach.

ABSTRACT: 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.

Lacosamide intoxication in attempted suicide.

The anticonvulsant drug lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and has been shown to be an effective add-on treatment for partial-onset seizures. Common adverse events (frequency 10%) of lacosamide doses up to 600 mg/day include nonspecific central nervous system effects (e.g., dizziness, ataxia, diplopia, and somnolence). There are no human data regarding the safety of very high dosages of lacosamide. We report the clinical course of a patient with bitemporal epilepsy who ingested 12 g of lacosamide, 56 g of gabapentin, 2g of topiramate, and 2.8 g of zonisamide during a suicide attempt. The patient was found comatose and experienced repeated generalized tonic-clonic seizures, aspiration with subsequent pneumonia, hypotension, and an increase in PR interval. Complete physical recovery occurred after several days of supportive treatment. We conclude that intoxication with lacosamide, in combination with overdoses of multiple AEDs, can be survived without sequelae, even after ingestion of 12 g lacosamide.

Serum concentrations of s100b and NSE in migraine.

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.

Effects of age and mild cognitive impairment on the pain response system.

BACKGROUND: Both age and dementia have been shown to have an effect on nociception and pain processing. The question arises whether mild cognitive impairment (MCI), which is thought to be a transitional stage between normal ageing and dementia, is also associated with alterations in pain processing. OBJECTIVE: The aim of the present study was to answer this question by investigating the impact of age and MCI on the pain response system. METHODS: Forty young subjects, 45 cognitively unimpaired elderly subjects and 42 subjects with MCI were investigated by use of an experimental multi-method approach. The subjects were tested for their subjective (pain ratings), motor (RIII reflex), facial (Facial Action Coding System) and their autonomic (sympathetic skin response and evoked heart rate response) responses to noxious electrical stimulation of the nervus suralis. RESULTS: We found significant group differences in the autonomic responses to noxious stimulation. The sympathetic skin response amplitude was significantly reduced in the cognitively unimpaired elderly subjects compared to younger subjects and to an even greater degree in subjects with MCI. The evoked heart rate response was reduced to a similar degree in both groups of aged subjects. Regression analyses within the two groups of the elderly subjects revealed that age and, in the MCI group, cognitive status were significant predictors of the decrease in autonomic responsiveness to noxious stimulation. Except for the autonomic parameters, no other pain parameter differed between the three groups. CONCLUSION: The pain response system appeared to be quite unaltered in MCI patients compared to cognitively unimpaired individuals of the same age. Only the sympathetic responsiveness qualified as an indicator of early aging effects as well as of pathophysiology associated with MCI, which both seemed to affect the pain system independently from each other.

Left Shifting of Language Related Activity Induced by Bihemispheric tDCS in Postacute Aphasia Following Stroke.

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.

Effects of ageing on spinal motor and autonomic pain responses.

The course of ageing leads to various changes in the nervous system, which can affect pain processing in the elderly. However, the affection of different components of the nociceptive system remains unclear. To investigate basic nocifensive responses, we compared age-related changes of autonomic and motor reflex responses to noxious electrical stimulation. In 39 healthy young subjects (mean +/- S.D.; 24.1 +/- 3.3 years) and 52 healthy elderly subjects (mean +/- S.D.; 71.9 +/- 5.3 years) the nociceptive flexion reflex (NFR) and the sympathetic skin response (SSR) were determined using noxious electrical stimulation of the sural nerve. Verbal pain ratings were assessed in addition. No ageing effects on the NFR and on verbal pain ratings were found, whereas the SSR amplitude declined significantly with ageing. Since both SSR and NFR share comparable primary afferent pathways and the motor as well as the subjective responses to noxious stimulation were preserved, our data seem to suggest that central or peripheral efferent sympathetic functions are altered by age.

Impact of age on the facial expression of pain.

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.

A reappraisal of pain-paired associative stimulation suggesting motor inhibition at spinal level.

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 0.1Hz over 15minutes. Four distinct inter-stimuli intervals (ISI) were assessed: -40ms, +10ms, +30ms and +50ms 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 30minutes after the pain-PAS procedure. RESULTS: For the "N2 latency -40ms" 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.