Machine Learning in Tremor Analysis: Critique and Directions.

Tremor is the most frequent human movement disorder, and its diagnosis is based on clinical assessment. Yet finding the accurate clinical diagnosis is not always straightforward. Fine-tuning of clinical diagnostic criteria over the past few decades, as well as device-based qualitative analysis, has resulted in incremental improvements to diagnostic accuracy. Accelerometric assessments are commonplace, enabling clinicians to capture high-resolution oscillatory properties of tremor, which recently have been the focus of various machine-learning (ML) studies. In this context, the application of ML models to accelerometric recordings provides the potential for less-biased classification and quantification of tremor disorders. However, if implemented incorrectly, ML can result in spurious or nongeneralizable results and misguided conclusions. This work summarizes and highlights recent developments in ML tools for tremor research, with a focus on supervised ML. We aim to highlight the opportunities and limitations of such approaches and provide future directions while simultaneously guiding the reader through the process of applying ML to analyze tremor data. We identify the need for the movement disorder community to take a more proactive role in the application of these novel analytical technologies, which so far have been predominantly pursued by the engineering and data analysis field. Ultimately, big-data approaches offer the possibility to identify generalizable patterns but warrant meaningful translation into clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroimaging advances in Parkinson's disease.

PURPOSE OF REVIEW: Neuroimaging in Parkinson's disease is an evolving field, providing in-vivo insights into the structural and biochemical changes of the condition, although its diagnosis remains clinical. Here, we aim to summarize the most relevant recent advances in neuroimaging in Parkinson's disease to assess the underlying disease process, identify a biomarker of disease progression and guide or monitor therapeutic interventions. RECENT FINDINGS: The clinical applications of imaging technology increasingly allow to quantify pigments (iron, neuromelanin) on MRI, proteins (tau), cell markers (phosphodiesterases, microglia) and neurotransmitter receptors (dopamine, serotonin, noradrenalin, cholin) via PET protocols, activity maps by resting-state and task-dependent functional MRI, as well as microstructural changes (free water) through diffusion-based assessments. Their application provides increasing insight on the temporal and spatial dynamics of dopaminergic and other neurotransmitter systems as well as anatomical structures and circuits in Parkinson's disease. An expanding list of PET tracers increases the yield of functional studies. SUMMARY: This review summarizes the most recent, relevant advances in neuroimaging technology in Parkinson's disease. In particular, the combination of different imaging techniques seems promising to maximize the scope of future work, which should, among others, aim at identifying the best imaging marker of disease progression.

Functional lesional neurosurgery for tremor: a systematic review and meta-analysis.

BACKGROUND: This work evaluates the consistency, effect size and incidence of persistent side effects of lesional neurosurgical interventions in the treatment of tremor due to Parkinson's disease (PD), essential tremor (ET), multiple sclerosis (MS) and midbrain lesions. METHODS: Systematic review and meta-analysis according to PRISMA-P guidelines. Random effects meta-analysis of standardised mean difference based on a peer-reviewed protocol (PROSPERO no. CRD42016048049). RESULTS: From 1249 abstracts screened, 86 peer-reviewed studies reporting 102 cohorts homogeneous for tremor aetiology, surgical target and technique were included.Effect on PD tremor was better when targeted at the ventral intermediate nucleus (V.im.) by radiofrequency ablation (RF) (Hedge's g: -4.15;) over V.im. by Gamma Knife (GK) (-2.2), subthalamic nucleus (STN) by RF (-1.12) and globus pallidus internus (GPi) by RF (-0.89). For ET MRI-guided focused ultrasound (MRIgFUS) ablation of the cerebellothalamic tract (CTT) (-2.35) and V.im. (-2.08) showed similar mean tremor reductions to V.im. ablation by RF (-2.42) or GK (-2.13). In MS V.im. ablation by GK (-1.96) and RF (-1.63) were similarly effective.Mean rates of persistent side effects after unilateral lesions in PD were 12.8% (RF V.im.), 13.6% (RF STN), 9.2% (RF GPi), 0.7% (GK V.im.) and 7.0% (MRIgFUS V.im.). For ET, rates were 9.3% (RF V.im.), 1.8% (GK V.im.), 18.7% (MRIgFUS V.im.) and 0.0% (MRIgFUS CTT), for MS 37.7% (RF V.im.) and for rubral tremor 30.3% (RF V.im.). CONCLUSION: This meta-analysis quantifies safety, consistency and efficacy of lesional neurosurgical interventions for tremor by target, technique and aetiology.

Functional lesional neurosurgery for tremor: back to the future?

For nearly a century, functional neurosurgery has been applied in the treatment of tremor. While deep brain stimulation has been in the focus of academic interest in recent years, the establishment of incisionless technology, such as MRI-guided high-intensity focused ultrasound, has again stirred interest in lesional approaches.In this article, we will discuss the historical development of surgical technique and targets, as well as the technological state-of-the-art of conventional and incisionless interventions for tremor due to Parkinson's disease, essential and dystonic tremor and tremor related to multiple sclerosis (MS) and midbrain lesions. We will also summarise technique-inherent advantages of each technology and compare their lesion characteristics. From this, we identify gaps in the current literature and derive future directions for functional lesional neurosurgery, in particularly potential trial designs, alternative targets and the unsolved problem of bilateral lesional treatment. The results of a systematic review and meta-analysis of the consistency, efficacy and side effect rate of lesional treatments for tremor are presented separately alongside this article.

Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum.

BACKGROUND: Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE: The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS: In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS: Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION: This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult-onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society.

[Focused ultrasound ablation as tremor treatment]. / Fokussierter Ultraschall in der Behandlung von Tremor.

BACKGROUND: The development of high-intensity magnetic resonance imaging (MRI)-guided focused ultrasound (MRIgFUS) ablation has widened the spectrum of interventional techniques for stereotactic functional neurosurgery of lesions. This has resulted in novel incisionless intervention approaches for the therapy of tremor disorders. The safety and efficacy is documented by recent study data. OBJECTIVES: This article encompasses a description of the technological basis and typical course of MRIgFUS interventions, a comparison to alternative open or incisionless surgical techniques as well as a review of the current evidence base for MRIgFUS ablation in the context of lesional interventions to treat tremor. MATERIAL AND METHODS: Narrative literature review and comparison. RESULTS: Depending on the surgical target and tremor etiology published trials of MRIgFUS ablation report a reduction of tremor intensity of up to 80% after 6-12 months follow-up without the disadvantages of open brain surgery. CONCLUSION: The MRIgFUS functional neurosurgery is conducted only at a limited number of treatment sites. First data on lesions of the thalamic ventral intermediary nucleus (V.im.) as well as subthalamic fiber tracts have been published. These results indicate an effective and safe treatment of tremor disorders by MRIgFUS ablation. Incisionless lesional surgery using MRIgFUS is a significant addition to the interventional armamentarium for functional stereotactic neurosurgery and a potentially valuable alternative to established interventional therapy options for tremor disorders.

Pain modulation is affected differently in medication-overuse headache and chronic myofascial pain - A multimodal MRI study.

Background Neuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders. Methods In this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH ( N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16). Results In a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula. Conclusions Hyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.

Head movement dynamics in dystonia: a multi-centre retrospective study using visual perceptive deep learning.

Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clinical management and limiting understanding of the underlying neurobiology. To address this, we developed a visual perceptive deep learning framework that utilizes standard clinical videos to comprehensively evaluate and quantify disease states and the impact of therapeutic interventions, specifically deep brain stimulation. This framework overcomes the limitations of traditional rating scales and offers an efficient and accurate method that is rater-independent for evaluating and monitoring dystonia patients. To evaluate the framework, we leveraged semi-standardized clinical video data collected in three retrospective, longitudinal cohort studies across seven academic centres. We extracted static head angle excursions for clinical validation and derived kinematic variables reflecting naturalistic head dynamics to predict dystonia severity, subtype, and neuromodulation effects. The framework was also applied to a fully independent cohort of generalised dystonia patients for comparison between dystonia sub-types. Computer vision-derived measurements of head angle excursions showed a strong correlation with clinically assigned scores. Across comparisons, we identified consistent kinematic features from full video assessments encoding information critical to disease severity, subtype, and effects of neural circuit interventions, independent of static head angle deviations used in scoring. Our visual perceptive machine learning framework reveals kinematic pathosignatures of dystonia, potentially augmenting clinical management, facilitating scientific translation, and informing personalized precision neurology approaches.

Age-related telomere attrition in the human putamen.

Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known phenomenon and epidemiologically correlated with age-related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post-mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross-sectional cortical brain samples so far indicated no attrition with age. Hence, age-related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte-rich spleen samples from 98 post-mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region-specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region- and age-dependent expression pattern corresponded with region-dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age-related vulnerability of the nigro-striatal network.

Non-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence.

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained shortly after the end of the stimulation and can be phenomenologically predicted. Finally, we use feature-based statistical-learning and neurophysiological-modelling to show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop, thus establishing its causal role. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may in the future represent a powerful neuromodulatory strategy to treat brain disorders.

Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients.

A prodromal phase of Parkinson's disease (PD) may precede motor manifestations by decades. PD patients' siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings' risk is not elevated.

The CloudUPDRS smartphone software in Parkinson's study: cross-validation against blinded human raters.

Digital assessments of motor severity could improve the sensitivity of clinical trials and personalise treatment in Parkinson's disease (PD) but have yet to be widely adopted. Their ability to capture individual change across the heterogeneous motor presentations typical of PD remains inadequately tested against current clinical reference standards. We conducted a prospective, dual-site, crossover-randomised study to determine the ability of a 16-item smartphone-based assessment (the index test) to predict subitems from the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) as assessed by three blinded clinical raters (the reference-standard). We analysed data from 60 subjects (990 smartphone tests, 2628 blinded video MDS-UPDRS III subitem ratings). Subject-level predictive performance was quantified as the leave-one-subject-out cross-validation (LOSO-CV) accuracy. A pre-specified analysis classified 70.3% (SEM 5.9%) of subjects into a similar category to any of three blinded clinical raters and was better than random (36.7%; SEM 4.3%) classification. Post hoc optimisation of classifier and feature selection improved performance further (78.7%, SEM 5.1%), although individual subtests were variable (range 53.2-97.0%). Smartphone-based measures of motor severity have predictive value at the subject level. Future studies should similarly mitigate against subjective and feature selection biases and assess performance across a range of motor features as part of a broader strategy to avoid overly optimistic performance estimates.

Oligomer-prone E57K-mutant alpha-synuclein exacerbates integration deficit of adult hippocampal newborn neurons in transgenic mice.

In the adult mammalian hippocampus, new neurons are constantly added to the dentate gyrus. Adult neurogenesis is impaired in several neurodegenerative mouse models including α-synuclein (a-syn) transgenic mice. Among different a-syn species, a-syn oligomers were reported to be the most toxic species for neurons. Here, we studied the impact of wild-type vs. oligomer-prone a-syn on neurogenesis. We compared the wild-type a-syn transgenic mouse model (Thy1-WTS) to its equivalent transgenic for oligomer-prone E57K-mutant a-syn (Thy1-E57K). Transgenic a-syn was highly expressed within the hippocampus of both models, but was not present within adult neural stem cells and neuroblasts. Proliferation and survival of newly generated neurons were unchanged in both transgenic models. Thy1-WTS showed a minor integration deficit regarding mushroom spine density of newborn neurons, whereas Thy1-E57K exhibited a severe reduction of all spines. We conclude that cell-extrinsic a-syn impairs mushroom spine formation of adult newborn neurons and that oligomer-prone a-syn exacerbates this integration deficit. Moreover, our data suggest that a-syn reduces the survival of newborn neurons by a cell-intrinsic mechanism during the early neuroblast development. The finding of increased spine pathology in Thy1-E57K is a new pathogenic function of oligomeric a-syn and precedes overt neurodegeneration. Thus, it may constitute a readout for therapeutic approaches.

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury.

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition. We assessed sleep-wake behavior by means of standard electrophysiological recordings before and 1, 7, and 28 days after sham or traumatic brain injury procedures. Sleep-wake findings were then correlated to immunohistochemically labeled and stereologically quantified neuronal arousal systems. Compared with control animals, we found that closed diffuse traumatic brain injury caused increased sleep need one month after trauma, and sleep was more consolidated. As histological correlate, we found a reduced number of histamine immunoreactive cells in the tuberomammillary nucleus, potentially related to increased neuroinflammation. Monoaminergic and hypocretinergic neurotransmitter systems in the hypothalamus and rostral brainstem were not affected, however. These results suggest that our rat traumatic brain injury model reflects human post-traumatic sleep-wake disturbances and associated histopathological findings very accurately, thus providing a study platform for novel treatment strategies for affected patients.

Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial.

Importance: Sleep-wake disorders are a common and debilitating nonmotor manifestation of Parkinson disease (PD), but treatment options are scarce. Objective: To determine whether nocturnal administration of sodium oxybate, a first-line treatment in narcolepsy, is effective and safe for excessive daytime sleepiness (EDS) and disturbed nighttime sleep in patients with PD. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover phase 2a study carried out between January 9, 2015, and February 24, 2017. In a single-center study in the sleep laboratory at the University Hospital Zurich, Zurich, Switzerland, 18 patients with PD and EDS (Epworth Sleepiness Scale [ESS] score >10) were screened in the sleep laboratory. Five patients were excluded owing to the polysomnographic diagnosis of sleep apnea and 1 patient withdrew consent. Thus, 12 patients were randomized to a treatment sequence (sodium oxybate followed by placebo or placebo followed by sodium oxybate, ratio 1:1) and, after dropout of 1 patient owing to an unrelated adverse event during the washout period, 11 patients completed the study. Two patients developed obstructive sleep apnea during sodium oxybate treatment (1 was the dropout) and were excluded from the per-protocol analysis (n = 10) but included in the intention-to-treat analysis (n = 12). Interventions: Nocturnal sodium oxybate and placebo taken at bedtime and 2.5 to 4.0 hours later with an individually titrated dose between 3.0 and 9.0 g per night for 6 weeks with a 2- to 4-week washout period interposed. Main Outcomes and Measures: Primary outcome measure was change of objective EDS as electrophysiologically measured by mean sleep latency in the Multiple Sleep Latency Test. Secondary outcome measures included change of subjective EDS (ESS), sleep quality (Parkinson Disease Sleep Scale-2), and objective variables of nighttime sleep (polysomnography). Results: Among 12 patients in the intention-to-treat population (10 men, 2 women; mean [SD] age, 62 [11.1] years; disease duration, 8.4 [4.6] years), sodium oxybate substantially improved EDS as measured objectively (mean sleep latency, +2.9 minutes; 95% CI, 2.1 to 3.8 minutes; P = .002) and subjectively (ESS score, -4.2 points ; 95% CI, -5.3 to -3.0 points; P = .001). Thereby, 8 (67%) patients exhibited an electrophysiologically defined positive treatment response. Moreover, sodium oxybate significantly enhanced subjective sleep quality and objectively measured slow-wave sleep duration (+72.7 minutes; 95% CI, 55.7 to 89.7 minutes; P < .001). Differences were more pronounced in the per-protocol analysis. Sodium oxybate was generally well tolerated under dose adjustments (no treatment-related dropouts), but it induced de novo obstructive sleep apnea in 2 patients and parasomnia in 1 patient, as detected by polysomnography, all of whom did not benefit from sodium oxybate treatment. Conclusions and Relevance: This study provides class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patients with PD. Special monitoring with follow-up polysomnography is necessary to rule out treatment-related complications and larger follow-up trials with longer treatment durations are warranted for validation. Trial Registration: clinicaltrials.gov Identifier: NCT02111122.