A window into the mind-brain-body interplay: Development of diagnostic, prognostic biomarkers, and rehabilitation strategies in functional motor disorders.

BACKGROUND AND AIMS: Functional motor disorders (FMD) present a prevalent, yet misunderstood spectrum of neurological conditions characterized by abnormal movements (i.e., functional limb weakness, tremor, dystonia, gait impairments), leading to substantial disability and diminished quality of life. Despite their high prevalence, FMD often face delayed diagnosis and inadequate treatment, resulting in significant social and economic burdens. The old concept of psychological factors as the primary cause (conversion disorder) has been abandoned due to the need for more evidence about their causal role. According to a predictive coding account, the emerging idea is that symptoms and disability may depend on dysfunctions of a specific neural system integrating interoception, exteroception, and motor control. Consequently, symptoms are construed as perceptions of the body's state. Besides the main pathophysiological features (abnormal attentional focus, beliefs/expectations, and sense of agency), the lived experience of symptoms and their resulting disability may depend on an altered integration at the neural level of interoception, exteroception, and motor control. METHODS AND MATERIALS: Our proposal aims to elucidate the pathophysiological mechanisms of FMD through a three-stage research approach. Initially, a large cohort study will collect behavioral, neurophysiological, and MRI biomarkers from patients with FMD and healthy controls, employing eXplainable Artificial Intelligence (XAI) to develop a diagnostic algorithm. Subsequently, validation will occur using patients with organic motor disorders. Finally, the algorithm's prognostic value will be explored post-rehabilitation in one subgroup of patients with FMD. RESULTS: Data collection for the present study started in May 2023, and by May 2025, data collection will conclude. DISCUSSION: Our approach seeks to enhance early diagnosis and prognostication, improve FMD management, and reduce associated disability and socio-economic costs by identifying disease-specific biomarkers. TRIAL REGISTRATION: This trial was registered in clinicaltrials.gov (NCT06328790).

Movement disorders of the stomatognathic system: A blind spot between dentistry and medicine.

Movement disorders of the stomatognathic system include oromandibular dystonia (OMD), oral dyskinesia, sleep/awake bruxism, functional (psychogenic) stomatognathic movement disorders (FSMDs), tremors, and hemimasticatory spasm (HMS). Most patients first consult dentists or oral surgeons. The differential diagnoses of these involuntary movements require both neurological and dental knowledge and experience, and some of these movement disorders are likely to be diagnosed as bruxism or temporomandibular disorders (TMDs) by dental professionals. However, excepting movement disorder specialists, neurologists may find it difficult to differentially diagnose these disorders. Patients may visit numerous medical and dental specialties for several years until a diagnosis is made. Therefore, movement disorders of the oral region may represent a blind spot between dentistry and medicine.The present narrative review aimed to describe the clinical characteristics and differential diagnoses of some movement disorders, as well as the problems bridging dentistry and medicine. Movement disorders have the following characteristic clinical features: OMD - task specificity, sensory tricks and the morning benefit; FSMDs - inconsistent and incongruous symptoms, spreading to multiple sites and the lack of sensory tricks; and HMS - the paroxysmal contraction of unilateral jaw-closing muscles, the persistence of symptoms during sleep and the loss of a silent period. A careful differential diagnosis is essential for the adequate and effective treatment of each involuntary movement. Refining the latest definition of bruxism may be necessary to prevent the misdiagnosis of involuntary movements as bruxism.Both dental and medical professionals should take an interest in the movement disorders of the stomatognathic system, and these disorders should be diagnosed and treated by a multidisciplinary team.

Juvenile-onset Huntington's disease - Spectrum and evolution of presenting movement disorders.

Juvenile-onset Huntington's disease (HD) is a rare subset of HD with symptom-onset before the age of 18. In contrast to the adult population, children present early-on with behavioral, psychiatric, and cognitive symptoms, in addition to a diverse spectrum of movement disorders. This poses a distinct challenge in diagnosis and management. We here describe the spectrum of movement disorders, accompanied with detailed video recordings, in seven cases of juvenile-onset HD. Our findings highlight early cognitive and behavioral symptoms, preceding motor symptoms. The diverse movement disorder phenotypes included dystonia, Parkinsonism, myoclonus, and chorea, findings which underscore the heterogeneity of presenting symptoms.

Movement Disorders in Brain Sagging Syndrome Due To Spontaneous Intracranial Hypotension: A Review.

Background: Spontaneous intracranial hypotension (SIH), a treatable condition that stems from spinal leakage of cerebrospinal fluid, usually presents with orthostatic headache, nausea, vomiting, dizziness, and tinnitus. A subset of patients, especially those with sagging of brain structures ("brain sagging syndrome"), develop several movement abnormalities. As SIH is treatable with epidural blood patch (EBP), movement disorders neurologists should be familiar with this syndrome. Method: The authors performed a literature search in PubMed in July 2024 using the Boolean phrase- (("Brain sagging")OR("Intracranial hypotension"))AND(((((((((("Movement disorders")OR("Involuntary movements"))OR("Tremor"))OR("Dystonia"))OR("Chorea"))OR("Ballismus"))OR("Myorhythmia"))OR ("Tic"))OR("Ataxia"))OR("Parkinsonism")). Result: We tabulated 21 case reports/series that highlighted the presence of movement disorders. The most reported phenomenology is gait unsteadiness. While it usually emerges in the background of the classic SIH symptoms, rarely, patients may present with isolated gait dysfunction. Tremor is the second most reported phenomenology with postural and kinetic tremor being the common subtypes. Holmes tremor has also been reported in SIH. Other reported phenomenologies are parkinsonism, chorea, and dystonia. One study reported a unique phenomenology i.e. compulsive repetitive flexion and breath holding in 35.3% of the patients. In majority of the patients, EBP resulted in substantial clinical and radiological improvement. Discussion: Brain sagging syndrome due to SIH may present with a wide range of movement disorders. Mechanical distortion of the posterior fossa and subcortical structures result in the emergence of such movement abnormality. SIH adds to the list of conditions that result in "treatable movement disorders." Therefore, movement disorders neurologists should be versed with the diagnosis and clinical features of this condition.

Impact of motor dysfunction on neuropsychiatric symptom profile in patients with autopsy-confirmed Alzheimer's disease.

Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer's Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer's Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Automatic two-dimensional & three-dimensional video analysis with deep learning for movement disorders: A systematic review.

The advent of computer vision technology and increased usage of video cameras in clinical settings have facilitated advancements in movement disorder analysis. This review investigated these advancements in terms of providing practical, low-cost solutions for the diagnosis and analysis of movement disorders, such as Parkinson's disease, ataxia, dyskinesia, and Tourette syndrome. Traditional diagnostic methods for movement disorders are typically reliant on the subjective assessment of motor symptoms, which poses inherent challenges. Furthermore, early symptoms are often overlooked, and overlapping symptoms across diseases can complicate early diagnosis. Consequently, deep learning has been used for the objective video-based analysis of movement disorders. This study systematically reviewed the latest advancements in automatic two-dimensional & three-dimensional video analysis using deep learning for movement disorders. We comprehensively analyzed the literature published until September 2023 by searching the Web of Science, PubMed, Scopus, and Embase databases. We identified 68 relevant studies and extracted information on their objectives, datasets, modalities, and methodologies. The study aimed to identify, catalogue, and present the most significant advancements, offering a consolidated knowledge base on the role of video analysis and deep learning in movement disorder analysis. First, the objectives, including specific PD symptom quantification, ataxia assessment, cerebral palsy assessment, gait disorder analysis, tremor assessment, tic detection (in the context of Tourette syndrome), dystonia assessment, and abnormal movement recognition were discussed. Thereafter, the datasets used in the study were examined. Subsequently, video modalities and deep learning methodologies related to the topic were investigated. Finally, the challenges and opportunities in terms of datasets, interpretability, evaluation methods, and home/remote monitoring were discussed.

Paroxysmal movement disorders.

Paroxysmal movement disorders include two groups of intermittent neurologic disorders: paroxysmal dyskinesia, in which episodes of involuntary hyperkinetic movements (mainly chorea and/or dystonia) occur with preserved consciousness, and episodic ataxias, which are characterized by discrete attacks of cerebellar dysfunction, sometimes associated with progressive ataxia. Since episodic ataxias are individually discussed in Chapter 8 of this volume, we herein provide a deep overview of phenotypic, genetic, pathophysiologic, diagnostic, and treatment aspects of paroxysmal dyskinesia, following the trigger-based nomenclature which distinguishes paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-induced dyskinesia. Emerging paroxysmal dyskinesia not fulfilling the criteria for the above-mentioned subtypes will also be discussed. Phenotypic and genotypic overlap among paroxysmal movement disorders, epilepsy, and migraine have progressively emerged, thus shedding light on a shared pathophysiologic framework. Advances in our understanding of the pathomechanisms underlying paroxysmal movement disorders, which involve dysfunctions of ion channels, proteins associated with the vesical synaptic cycle machinery, and proteins involved in neuronal energy metabolism, point toward a discrete number of converging pathophysiologic pathways and may lay foundations for developing target-specific therapies.

Development of a Tremor Detection Algorithm for Use in an Academic Movement Disorders Center.

Tremor, defined as an "involuntary, rhythmic, oscillatory movement of a body part", is a key feature of many neurological conditions including Parkinson's disease and essential tremor. Clinical assessment continues to be performed by visual observation with quantification on clinical scales. Methodologies for objectively quantifying tremor are promising but remain non-standardized across centers. Our center performs full-body behavioral testing with 3D motion capture for clinical and research purposes in patients with Parkinson's disease, essential tremor, and other conditions. The objective of this study was to assess the ability of several candidate processing pipelines to identify the presence or absence of tremor in kinematic data from patients with confirmed movement disorders and compare them to expert ratings from movement disorders specialists. We curated a database of 2272 separate kinematic data recordings from our center, each of which was contemporaneously annotated as tremor present or absent by a movement physician. We compared the ability of six separate processing pipelines to recreate clinician ratings based on F1 score, in addition to accuracy, precision, and recall. The performance across algorithms was generally comparable. The average F1 score was 0.84±0.02 (mean ± SD; range 0.81-0.87). The second highest performing algorithm (cross-validated F1=0.87) was a hybrid that used engineered features adapted from an algorithm in longstanding clinical use with a modern Support Vector Machine classifier. Taken together, our results suggest the potential to update legacy clinical decision support systems to incorporate modern machine learning classifiers to create better-performing tools.

Cocaine-induced Movement Disorder: A Literature Review.

This study aims to describe movement disorders secondary to cocaine use. To our knowledge, while these presentations have been previously reported in the literature, a comprehensive review has not been published yet. We searched six databases from 1986 to 2022 without language restriction. Case reports, case series, and literature reviews have been analysed to find associations between cocaine use and movement disorders. The present study encompasses epidemiology, clinical manifestations, pathophysiology, and diagnostic challenges of abnormal movements associated with cocaine use. This review highlights the importance of proper initial evaluation and investigation taking into account the broad spectrum of differential diagnoses and exclusion of primary movement disorders. The role of the dopaminergic system in movement disorders is reviewed. Cocaine use is associated with movement disorders such as dystonia, parkinsonism, akathisia, and tics. The complex interaction of multiple factors, including other neurological conditions, such as Tourette syndrome, and additional substances of abuse is discussed. The presentation of these manifestations is often heterogeneous and does not follow a specific pattern. In this way, future research is needed to improve our understanding of the pathophysiological mechanisms and develop novel drug targets for these disorders. Increased awareness among the general public and policymakers could translate into reduced stigma and improved care.

Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.

INTRODUCTION: CTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype. METHODS: patients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings. RESULTS: 13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients. CONCLUSIONS: CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.

Research on Monitoring Assistive Devices for Rehabilitation of Movement Disorders through Multi-Sensor Analysis Combined with Deep Learning.

This study aims to integrate a convolutional neural network (CNN) and the Random Forest Model into a rehabilitation assessment device to provide a comprehensive gait analysis in the evaluation of movement disorders to help physicians evaluate rehabilitation progress by distinguishing gait characteristics under different walking modes. Equipped with accelerometers and six-axis force sensors, the device monitors body symmetry and upper limb strength during rehabilitation. Data were collected from normal and abnormal walking groups. A knee joint limiter was applied to subjects to simulate different levels of movement disorders. Features were extracted from the collected data and analyzed using a CNN. The overall performance was scored with Random Forest Model weights. Significant differences in average acceleration values between the moderately abnormal (MA) and severely abnormal (SA) groups (without vehicle assistance) were observed (p < 0.05), whereas no significant differences were found between the MA with vehicle assistance (MA-V) and SA with vehicle assistance (SA-V) groups (p > 0.05). Force sensor data showed good concentration in the normal walking group and more scatter in the SA-V group. The CNN and Random Forest Model accurately recognized gait conditions, achieving average accuracies of 88.4% and 92.3%, respectively, proving that the method mentioned above provides more accurate gait evaluations for patients with movement disorders.

HABIT training in unilateral spastic cerebral palsy children having mirror movement disorder.

The single-arm feasibility study was planned to evaluate the therapeutic effect of hand arm bimanual intensive training in improving the fine and gross motor functions of hand, and in the reduction of intensity with respect to mirror movement disorder. The sample comprised unilateral spastic cerebral palsy children aged 6-16 years who were having mirror movement disorder and were able to make a gross grip. The hand arm bimanual intensive training was provided to the participants for 6 hours per day for 15 days for a total of 90 hours. Comparison of baseline and post-intervention showed that the functional independence level of children had improved, with improvement in unimanual and bimanual hand performance (p˂0.05). However, there was no improvement seen in the severity of mirror movements (p>0.05). Hence, hand arm bimanual intensive training was found to be effective in increasing the functional independence of cerebral palsy children by improving the hand function, but there was no effect on mirror movement disorder.

Individualized Physiotherapy of Upper Body Functional Movement Disorder - Two Illustrative Cases.

Background: Information on specialist physiotherapeutic treatment for functional movement disorders is scarce. Previous studies focussed on functional gait disorders and availability of descriptions of the practical application especially for other body regions is very limited. Cases: We present two illustrative cases, demonstrating the key elements of physiotherapy for the treatment of functional movement disorders beyond gait difficulties. The individual applicability of the specific core elements of physiotherapy, adapted to the individual needs of each patient, are described. We also explain, how different sensory stimuli can be used to shift attention away from symptoms and thus reduce them. Moreover, we discuss how patients' agency can be encouraged and how this results in therapy key moments, contributing to a sustained improvement of symptoms. Conclusion: Thus, our case series are intended to guide clinicians and therapists alike, to promote disease-specific physiotherapy for this common and treatable neuropsychiatric disorder.

A randomized cross-over study protocol to evaluate long-term gait training with a pediatric robotic exoskeleton outside the clinical setting in children with movement disorders.

Individuals with neuromuscular disorders display a combination of motor control deficits and lower limb weakness contributing to knee extension deficiency characterized by exaggerated stance phase knee flexion. There is a lack of evidence for long-term improvement of knee extension deficiency with currently available clinical treatment programs. Our previous work testing a wearable robotic exoskeleton with precisely timed assistive torque applied at the knee showed immediate increases in knee extension during walking for children with cerebral palsy, which continued to improve over an acute practice period. When we applied interleaved assistance and resistance to knee extension, we observed improvements in knee extension and increased muscle activation indicating the potential for muscle strengthening when used over time. There is a need for additional, high-quality trials to assess the impact of dosage, intensity and volume of training necessary to see persistent improvement in lower limb function for these patient populations. This randomized crossover study (ClinicalTrials.gov: NCT05726591) was designed to determine whether 12 weeks of overground gait training with a robotic exoskeleton outside of the clinical setting, following an initial in clinic accommodation period, has a beneficial effect on walking ability, muscle activity and overall motor function. Participants will be randomized to either complete the exoskeleton intervention or continue their standard therapy for 12 weeks first, followed by a crossover to the other study component. The primary outcome measure is change in peak knee extension angle during walking; secondary outcome measures include gait speed, strength, and validated clinical scales of motor function and mobility. Assessments will be completed before and after the intervention and at 6 weeks post-intervention, and safety and compliance will be monitored throughout. We hypothesize that the 12-week exoskeleton intervention outside the clinical setting will show greater improvements in study outcome measures than the standard therapy.

Clinical neurophysiology in the treatment of movement disorders: IFCN handbook chapter.

In this review, different aspects of the use of clinical neurophysiology techniques for the treatment of movement disorders are addressed. First of all, these techniques can be used to guide neuromodulation techniques or to perform therapeutic neuromodulation as such. Neuromodulation includes invasive techniques based on the surgical implantation of electrodes and a pulse generator, such as deep brain stimulation (DBS) or spinal cord stimulation (SCS) on the one hand, and non-invasive techniques aimed at modulating or even lesioning neural structures by transcranial application. Movement disorders are one of the main areas of indication for the various neuromodulation techniques. This review focuses on the following techniques: DBS, repetitive transcranial magnetic stimulation (rTMS), low-intensity transcranial electrical stimulation, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), and focused ultrasound (FUS), including high-intensity magnetic resonance-guided FUS (MRgFUS), and pulsed mode low-intensity transcranial FUS stimulation (TUS). The main clinical conditions in which neuromodulation has proven its efficacy are Parkinson's disease, dystonia, and essential tremor, mainly using DBS or MRgFUS. There is also some evidence for Tourette syndrome (DBS), Huntington's disease (DBS), cerebellar ataxia (tDCS), and axial signs (SCS) and depression (rTMS) in PD. The development of non-invasive transcranial neuromodulation techniques is limited by the short-term clinical impact of these techniques, especially rTMS, in the context of very chronic diseases. However, at-home use (tDCS) or current advances in the design of closed-loop stimulation (tACS) may open new perspectives for the application of these techniques in patients, favored by their easier use and lower rate of adverse effects compared to invasive or lesioning methods. Finally, this review summarizes the evidence for keeping the use of electromyography to optimize the identification of muscles to be treated with botulinum toxin injection, which is indicated and widely performed for the treatment of various movement disorders.

Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins?

Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.