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.

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.

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.

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.

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.

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.

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.

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.

The treatment of fatigue by non-invasive brain stimulation.

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.

Is increased spinal nociception another hallmark for Parkinson's disease?

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.

Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS).

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.

At-home tDCS of the left dorsolateral prefrontal cortex improves visual short-term memory in mild vascular dementia.

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 2mA 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.

Loss in Executive Functioning Best Explains Changes in Pain Responsiveness in Patients with Dementia-Related Cognitive Decline.

There is ample evidence that dementia changes the processing of pain. However, it is not known whether this change in pain processing is related to the general decline in cognitive functioning or whether it may be related to specific domains of cognitive functioning. With the present study we tried to answer this question. We assessed different cognitive domains (orientation, memory, abstract thinking/executive function, aphasia and apraxia, and information processing speed) in 70 older patients with cognitive impairment (mild cognitive impairment up to moderate degrees of dementia). Pain responsiveness was assessed by measuring the nociceptive flexion reflex (NFR) threshold and facial responses to noxious electrical stimulation. Using regression analyses, we assessed which domain of cognitive functioning best predicted variance in pain responsiveness. Variance in pain responsiveness (NFR and facial expressions) was best explained by those items assessing executive functioning even when controlling for overall cognitive performance and memory functioning. The close association between executive functioning and pain responsiveness suggests that dementia-related neurodegeneration in prefrontal areas might result not only in reduced executive functioning but also in a loss of pain inhibitory potency, rendering the patient more vulnerable to pain. Our findings also suggest that pain assessment in dementia should be regularly completed by tests of cognitive functions.