HIGH FREQUENCY REPETITIVE SENSORY STIMULATION IN HEALTHY! SUBJECTS AND DYSTONIA

This thesis describes a series of studies involving both healthy subjects and patients with dystonia, in which the mechanisms of inhibitory plasticity have been explored with the use of a novel non-invasive brain stimulation technique, namely High-Frequency Repetitive Sensory Stimulation (HF-RSS), to understand how inhibitory mechanisms contribute to the pathogenesis of dystonia. To this aim, several “preliminary” and parallel experiments have been conducted to fully characterize the neurophysiological abnormalities in dystonia and the physiological changes induced by HF-RSS in healthy subjects. Thus, I have explored: 1. The neurophysiological correlates of abnormal somatosensory temporal discrimination in cervical dystonia, linking this behavioural abnormality with defective inhibitory mechanisms within the sensory cortex; 2. The behavioural consequences of HF-RSS in healthy subjects in terms of somatosensory temporal discrimination, showing that this technique can be in fact used as a novel non-invasive brain stimulation protocol in order to reversibly improve somatosensory temporal discrimination; 3. The neurophysiological mechanisms by which the observed behavioural improvement occurs after HF-RSS in healthy subjects. Thus, the improvement of somatosensory temporal discrimination is mostly driven by an enhancement of inhibitory processes occurring within the primary sensory cortex, a phenomenon known as inhibitory plasticity; 4. Whether HF-RSS could ameliorate inhibitory processes in cervical dystonia and, in turn, lead to an improvement of somatosensory temporal discrimination. It is here shown that patients showed a paradoxical response to such a stimulation protocol, suggestive of defective inhibitory plasticity as one of the main mechanisms contributing to the pathogenesis of dystonia. These results contribute to the understanding of the pathophysiology of dystonia, opening a novel window for future research and possibly novel treatments. Moreover, these results widened the understanding relative to this novel type of non-invasive brain stimulation that can be theoretically used for the study of other disorders where central inhibitory processes are thought to be defective

Proprioceptive drift is affected by the intermanual distance rather than the distance from the body's midline in the rubber hand illusion

In the rubber hand illusion (RHI), simultaneous brush stroking of a subject's hidden hand and a visible rubber hand induces a transient illusion of the latter to "feel like it's my hand" and a proprioceptive drift of the hidden own hand toward the rubber hand. Recent accounts of the RHI have suggested that the illusion would only occur if weighting of conflicting sensory information and their subsequent integration results in a statistically plausible compromise. In three different experiments, we investigated the role of distance between the two hands as well as their proximity to the body's midline in influencing the occurrence of the illusion. Overall, the results suggest that the illusion is abolished when placing the two hands apart, therefore increasing the mismatch between the visual and proprioceptive modality, whereas the proximity of the two hands to the body's midline plays only a minor role on the subjective report of the illusion. This might be driven by the response properties of visuotactile bimodal cells encoding the peripersonal space around the hand

Nonmotor symptoms in Parkinson's disease: classification and management

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Differentiating drug-induced parkinsonism from Parkinson's disease: An update on non-motor symptoms and investigations

Abstract Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease

A Pilot Study of Botulinum Toxin for Jerky, Position-Specific, Upper Limb Action Tremor

Background: We aimed to investigate the efficacy and safety of botulinum toxin (BT) injections for jerky action tremor of the upper limb. Methods: We performed an uncontrolled, prospective study of electromyography (EMG)-guided BT injections for jerky, position-specific, upper limb action tremor. The primary outcome was clinical global impression at 3–6 weeks after baseline. Results: Eight patients with jerky, position-specific action tremor involving the upper limb were consecutively recruited. After a median follow-up of 4.4 weeks (interquartile range [IQR] 3.6–6 weeks), four of them rated themselves as “improved” and two as “much improved.” Five of these six subjects reported improvements in specific activities of daily living (bringing liquids to mouth, feeding, shaving, and dressing). Upper limb subscore of the Fahn–Tolosa–Marin Tremor Rating Scale (FTM) significantly decreased from 4.5 (4–6) to 3 (2–5) (p = 0.01). Discussion: This pilot, prospective cohort study suggests that EMG-guided BT injections may improve jerky, position-specific, upper limb action tremor. Placebo-controlled studies evaluating larger samples of patients are warranted to confirm these findings

Development of the Digital Inclusion Questionnaire (DIQUEST) in Parkinson's Disease

Background No tool is currently able to measure digital inclusion in clinical populations suitable for telemedicine. We developed the "Digital Inclusion Questionnaire" (DIQUEST) to estimate access and skills in Parkinson's Disease (PD) patients and verified its properties with a pilot study.Methods Thirty PD patients completed the initial version of the DIQUEST along with the Mobile Device Proficiency Questionnaire (MDPQ) and a practical computer task. A Principal Components Analysis (PCA) was conducted to define the DIQUEST factor structure and remove less informative items. We used Cronbach's alpha to measure internal reliability and Spearman's correlation test to determine the convergent and predictive validity with the MDPQ and the practical task, respectively.Results The final version of the DIQUEST consisted of 20 items clustering in five components: "advanced skills," "navigation skills," "basic skills/knowledge," "physical access," and "economical access." All components showed high reliability (alpha > 0.75) as did the entire questionnaire (alpha = 0.94). Correlation analysis demonstrated high convergent (rho: 0.911; p<0.001) and predictive (rho: 0.807; p<0.001) validity.Conclusions We have here presented the development of the DIQUEST as a screening tool to assess the level of digital inclusion, particularly addressing the access and skills domains. Future studies are needed for its validation beyond PD

Shoulder-touch test to reveal incongruencies in persons with functional motor disorders

Clinical experience suggests that many patients with functional motor disorders (FMD), despite reporting severe balance problems, typically do not fall frequently. This discrepancy may hint towards a functional component. Here, we explored the role of the Shoulder-Touch test, which features a light touch on the patient's shoulders to reveal a possible functional etiology of postural instability

Psychometric properties of the Caregiver's inventory neuropsychological diagnosis dementia (CINDD) in mild cognitive impairment and dementia

Objectives: The Caregiver's Inventory Neuropsychological Diagnosis Dementia (CINDD) is an easy tool designed to quantify cognitive, behavioural and functional deficits of patients with cognitive impairment. Aim of the present study was to analyse the psychometric properties of the CINDD in Mild Cognitive Impairment (MCI) and Dementia (D). Design, setting and participants: The CINDD, composed by 9 sub-domains, was administered to fifty-six caregivers of patients with different types of dementia (D) and 44 caregivers of patients with MCI. All patients underwent an extensive neuropsychological assessment, the Neuropsychiatric Inventory (NPI) and functional autonomy scales. The reliability, convergent construct validity and possible cut-off of CINND were measured by Cronbach's alpha (α), Pearson's correlation and ROC analysis, respectively. Results: The D and MCI patients differed only for age (p=0.006). The internal consistency of CINDD was high (α= 0.969). The α-value for each CINDD domain was considered acceptable, except the mood domain (α=0.209). The CINDD total score correlated with cognitive screening tests; each domain of the CINDD correlated with the corresponding score from either tests or NPI (p<0.05), except for visuo-spatial perception skills and apathy. A screening cut-off equal to 59, can be used discriminate D from MCI (Sensitivity=0.70, Specificity=0.57). Conclusion: The CINDD is a feasible, accurate and reliable tool for the assessment of cognitive and behavioural difficulties in patients with different degree of cognitive impairment. It may be used to quantify and monitor caregiver-reported ecological data in both clinical and research settings

Anticipating Tomorrow: Tailoring Parkinson's Symptomatic Therapy Using Predictors of Outcome

Background: Although research into Parkinson's disease (PD) subtypes and outcome predictions has continued to advance, recommendations for using outcome prediction to guide current treatment decisions remain sparse. Objectives: To provide expert opinion‐based recommendations for individually tailored PD symptomatic treatment based on knowledge of risk prediction and subtypes. Methods: Using a modified Delphi approach, members of the Movement Disorders Society (MDS) Task Force on PD subtypes generated a series of general recommendations around the question: “Using what you know about genetic/biological/clinical subtypes (or any individual‐level predictors of outcome), what advice would you give for selecting symptomatic treatments for an individual patient now, based on what their subtype or individual characteristics predict about their future disease course?” After four iterations and revisions, those recommendations with over 75% endorsement were adopted. Results: A total of 19 recommendations were endorsed by a group of 13 panelists. The recommendations primarily centered around two themes: (1) incorporating future risk of cognitive impairment into current treatment plans; and (2) identifying future symptom clusters that might be forestalled with a single medication. Conclusions: These recommendations provide clinicians with a framework for integrating future outcomes into patient‐specific treatment choices. They are not prescriptive guidelines, but adaptable suggestions, which should be tailored to each individual. They are to be considered as a first step of a process that will continue to evolve as additional stakeholders provide new insights and as new information becomes available. As individualized risk prediction advances, the path to better tailored treatment regimens will become clearer

The Pain in Dystonia Scale (PIDS)—Development and Validation in Cervical Dystonia

BACKGROUND: A better understanding of pain in adult-onset idiopathic dystonia (AOID) is needed to implement effective therapeutic strategies. OBJECTIVE: To develop a new rating instrument for pain in AOID and validate it in cervical dystonia (CD). METHODS: Development and validation of the Pain in Dystonia Scale (PIDS) comprised three phases. In phase 1, international experts and participants with AOID generated and evaluated the preliminary items for content validity. In phase 2, the PIDS was drafted and revised by the experts, followed by cognitive interviews to ensure self-administration suitability. In phase 3, the PIDS psychometric properties were assessed in 85 participants with CD and retested in 40 participants. RESULTS: The final version of PIDS evaluates pain severity (by body-part), functional impact, and external modulating factors. Test-retest reliability showed a high-correlation coefficient for the total score (0.9, P < 0.001), and intraclass correlation coefficients were 0.7 or higher for all items in all body-parts subscores. The overall PIDS severity score showed high internal consistency (Cronbach's α, 0.9). Convergent validity analysis revealed a strong correlation between the PIDS severity score and the Toronto Western Spasmodic Torticollis Rating Scale pain subscale (0.8, P < 0.001) and the Brief Pain Inventory-short form items related to pain at time of the assessment (0.7, P < 0.001) and impact of pain on daily functioning (0.7, P < 0.001). CONCLUSION: The PIDS is the first specific questionnaire developed to evaluate pain in all patients with AOID, here, demonstrating high-level psychometric properties in people with CD. Future work will validate PIDS in other forms of AOID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society