Involuntary Abnormal Movements Research Articles

Rodent Models of Huntington's Disease: An Overview.

Huntington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by a genetic mutation in the IT15 gene. This neurodegenerative disorder is caused by a polyglutamine repeat expansion mutation in the widely expressed huntingtin (HTT) protein. HD is characterized by the degeneration of basal ganglia neurons and progressive cell death in intrinsic neurons of the striatum, accompanied by dementia and involuntary abnormal choreiform movements. Animal models have been extensively studied and have proven to be extremely valuable for therapeutic target evaluations. They reveal the hallmark of the age-dependent formation of aggregates or inclusions consisting of misfolded proteins. Animal models of HD have provided a therapeutic strategy to treat HD by suppressing mutant HTT (mHTT). Transgenic animal models have significantly increased our understanding of the molecular processes and pathophysiological mechanisms underlying the HD behavioral phenotype. Since effective therapies to cure or interrupt the course of the disease are not yet available, clinical research will have to make use of reliable animal models. This paper reviews the main studies of rodents as HD animal models, highlighting the neurological and behavioral differences between them. The choice of an animal model depends on the specific aspect of the disease to be investigated. Toxin-based models can still be useful, but most experimental hypotheses depend on success in a genetic model, whose choice is determined by the experimental question. There are many animal models showing similar HD symptoms or pathologies. They include chemical-induced HDs and genetic HDs, where cell-free and cell culture, lower organisms (such as yeast, Drosophila, C. elegans, zebrafish), rodents (mice, rats), and non-human primates are involved. These models provide accessible systems to study molecular pathogenesis and test potential treatments. For developing more effective pharmacological treatments, better animal models must be available and used to evaluate the efficacy of drugs.

Bobble Head Doll Syndrome

Introduction. Bobble head doll syndrome is a neurological syndrome characterized by abnormal involuntary movements of the head combining repetitive or episodic movements of 2 to 3 Hz back and forth in the anterior-posterior direction that can be assimilated to approval movements (yes-yes) and occasionally lateral rotations that can be assimilated to disapproval signs (no-no). It is a rare entity first described by Benton[1]. We describe three cases managed at the Yalgado Ouédraogo University Hospital in Burkina Faso.
 Observations. Three children, one girl and two boys, aged respectively 5, 9 and 14 years were seen for involuntary abnormal head movements associating lateral rotations assimilated to signs of disapproval (no-no) in two cases, and back and forth movements of the head in one case. In the 14-year-old adolescent, there was also a picture of intracranial hypertension. Clinical examination revealed ataxia and macrocrania in both cases and a syndrome in 1 case. Imaging revealed triventricular hydrocephalus on aqueductal stenosis in all cases with an associated supra sellar cyst in 2 cases. The treatment consisted of endoscopic treatment in 2 cases and ventriculoperitoneal shunt in 1 case. Surgery allowed a considerable regression of involuntary movements of the head in the immediate postoperative period and a complete recovery in the long term.
 Conclusion. The bobble head doll syndrome is a rare entity related to the consequences of chronic hydrocephalus responsible for abnormal movements whose management done well and early leads to favourable results.

Gut Microbiome Composition in Dystonia Patients.

Dystonia is a movement disorder in which patients have involuntary abnormal movements or postures. Non-motor symptoms, such as psychiatric symptoms, sleep problems and fatigue, are common. We hypothesise that the gut microbiome might play a role in the pathophysiology of the (non-)motor symptoms in dystonia via the gut-brain axis. This exploratory study investigates the composition of the gut microbiome in dystonia patients compared to healthy controls. Furthermore, the abundance of neuro-active metabolic pathways, which might be implicated in the (non-)motor symptoms, was investigated. We performed both metagenomic and 16S rRNA sequencing on the stool samples of three subtypes of dystonia (27 cervical dystonia, 20 dopa-responsive dystonia and 24 myoclonus-dystonia patients) and 25 controls. While microbiome alpha and beta diversity was not different between dystonia patients and controls, dystonia patients had higher abundances of Ruminococcus torques and Dorea formicigenerans, and a lower abundance of Butyrivibrio crossotus compared to controls. For those with dystonia, non-motor symptoms and the levels of neurotransmitters in plasma explained the variance in the gut microbiome composition. Several neuro-active metabolic pathways, especially tryptophan degradation, were less abundant in the dystonia patients compared to controls. This suggest that the gut-brain axis might be involved in the pathophysiology of dystonia. Further studies are necessary to confirm our preliminary findings.

Neuroacanthocytosis Syndromes: The Clinical Perspective

The two very rare neurodegenerative diseases historically known as the “neuroacanthocytosis syndromes” are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.

Clinical Presentation and Management of Peripheral-induced Oromandibular Dystonia in Nigeria: A Case Report and Literature Update

Oromandibular dystonia (OMD) is a rare focal neurological disorder associated with impaired masticatory function, dysphagia, dysphonia, and involuntary abnormal movements of the mandible of varying severity. The peripheral-induced variant among other factors is a common aetiological factor of secondary dystonias, associated with constellations of clinical features and presents with differing responses to various treatment therapies. To report a case of oromandibular dystonia and to add to the body of literature. The case report is of a 33-year-old male who presented with complaints pain on speaking and from the temporomandibular joint area for 8 months which adversely affected patient’s work, social life and psychological well-being. Examination revealed retraction and repetitive but uncoordinated pattern of labial, cheek and masticatory muscular movement on mouth opening and closing. Diagnosis of oromandibular dystonia was made on clinical grounds. Patient was managed with a combination of medications by the oral physician, and physical therapy, which led to a significant improvement in the control of muscle contractions within 5 weeks. OMD though a rare neuromuscular condition can present to the dentist, and effective assessment, diagnosis and collaboration with relevant specialities are key to improved outcome.

Hyperkinetic Rat Model Induced by Optogenetic Parafascicular Nucleus Stimulation.

The parafascicular nucleus (PF) plays important roles in controlling the basal ganglia. It is not well known whether the PF affects the development of abnormal involuntary movements (AIMs). This study was aimed to find a role of the PF in development of AIMs using optogenetic methods in an animal model. Fourteen rats were underwent stereotactic operation, in which they were injected with an adeno-associated virus with channelrhodopsin (AAV2-hSyn-ChR2-mCherry) to the lateral one third of the PF. Behavior test was performed with and without optical stimulation 14 days after the injection of the virus. AIM of rat was examined using AIM score. After the behavior test, rat's brain was carefully extracted and the section was examined using a fluorescence microscope to confirm transfection of the PF. Of the 14 rats, seven rats displayed evident involuntary abnormal movements. AIM scores were increased significantly after the stimulation compared to those at baseline. In rats with AIMs, mCherry expression was prominent in the PF, while the rats without AIM lacked with the mCherry expression. AIMs could be reversibly induced by stimulating the PF through an optogenetic method.

Blind Person Smart Helmet

Abstract: Blind people and other visually impaired, physically disabled people in our society face difficulties in moving in daily life. Due to poor visibility, they often fail to detect surrounding obstacles and injure themselves. Due to blindness, involuntary abnormal movements, and lack of a timely rescue system, the degree of injury and other adverse effects are aggravated. One possible way to alleviate the suffering of blind and visually impaired person could be to design an assistive device capable of taking corrective action based on location, proximity and fall event information (if applicable). The goal of this research was to develop a costeffective, comfortable and easy to manufacture smart helmet for safe and smooth mobility for the blind person.

When Agitation, Hallucination, and Paranoia Mean More Than Psychosis.

When Agitation, Hallucination, and Paranoia Mean More Than Psychosis.

Multi-Exergames to Set Targets and Supplement the Intensified Conventional Balance Training in Patients With Stroke: A Randomized Pilot Trial

People who survive a stroke usually suffer movement disorders resulting in involuntary abnormal movements. Intensive and repetitive physiotherapy is often a key to functional restoration of movements. Rehabilitation centers have recently offered balance training supported by exergames in addition to conventional therapy. The primary objective was to investigate different types of balance training (multi-exergaming and conventional) in addition to a conventional 6-week physiotherapy program. Furthermore, we examined the choice of an appropriate exergame to target balance training. We designed a randomized pilot trial. Hospital inpatients with stroke aged 33–65 were recruited and randomized into 2 groups by drawing lots; a control group receiving 1 week of conventional balance training and an exergaming group 1 week of multiple-game exergaming, comprising single leg exercises, weight shifting, balancing and standing up. Center of pressure was monitored for the exergaming group and clinical data were collected (non-blinded assessment) using Four Square Step Test, Timed Up and Go, 10 m Walk Test, Romberg, Sharpened Romberg, Clinical Test for Sensory Interaction in Balance in both groups. Statistical tests were used to find significant (p < 0.05) differences and Cohen’s U3 for effect sizes. Recruited participants (20/30) met the inclusion criteria and were randomized; 10 per group. 1 participant of the exergaming group was excluded from center of pressure analysis. Both groups demonstrated substantively and statistically significant improvements of functional balance, in particular the exergaming group (FSST p = 0.009, U3 = 0.9 and 10 MWT p = 0.008, U3 = 0.9). However, significant differences between the groups were found in tests with eyes closed, Sharpened Romberg test (p = 0.05) and standing on the right leg (p = 0.035). The center of pressure area decreased up to 20% for the exergaming group. Both types of additional balance training demonstrated comparable outcomes, however, the multi-exergaming could target specific motor control disorders by the selection of exergames according to Gentile’s taxonomy. We may not prioritize exergaming due to the low statistical power of clinical outcomes. However, exergaming enables independent balance training, which is feasible without strenuous physiotherapy and may thus be crucial for future home or telerehabilitation services.Clinical Trial Registration: www.clinicaltrials.gov/, identifier NCT03282968.

Soft Material-Enabled, Active Wireless, Thin-Film Bioelectronics for Quantitative Diagnostics of Cervical Dystonia.

Recent advances in flexible materials, nanomanufacturing, and system integration have provided a great opportunity to develop wearable flexible hybrid electronics for human healthcare, diagnostics, and therapeutics. However, existing medical devices still rely on rigid electronics with many wires and separate components, which hinders wireless, comfortable, continuous monitoring of health-related human motions. Here, we introduce advanced materials and system integration technologies that enable a soft, active wireless, thin-film bioelectronics. The low-modulus, highly flexible wearable electronic system incorporates a nanomembrane wireless circuit and functional chip components, enclosed by a soft elastomeric membrane. The bioelectronic system offers a gentle, seamless mounting on the skin, while offering a comfortable, highly sensitive and accurate detection of head movements. We utilize the wireless wearable hybrid system for quantitative diagnostics of cervical dystonia (CD) that is characterized by involuntary abnormal head postures and repetitive head movements, sometimes with neck muscle pain. A set of analytical and experimental studies shows a soft system packaging, hard-soft materials integration, and quantitative assessment of physiological signals detected by the SKINTRONICS. In vivo demonstration, involving ten human subjects, captures the device feasibility for use in CD measurement.

Chorea-ballism as a dominant clinical manifestation in heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation in mitochondrial genome: a case report

BackgroundMitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, the most common maternally inherited mitochondrial disease, can present with a wide range of neurological manifestations including both central and peripheral nervous system involvement. The most frequent genetic mutation reported in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome is A3243G in MT-TL1 gene. Stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature constitute the known presentations in this syndrome. Among the abnormal involuntary movements in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome, myoclonus is the commonest. Other movement disorders, including chorea, are rarely reported in this disorder.Case presentationA 14-year-old South Asian boy from rural Bengal (India), born of a second degree consanguineous marriage, with normal birth and development history, presented with abnormal brief jerky movements involving his trunk and limbs, with recurrent falls for 10 months. We present here a case of heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation, in which the clinical picture was dominated by a host of involuntary abnormal movements including chorea-ballism, myoclonus, and oromandibular dystonia in a backdrop of cognitive decline, seizure, and stroke-like episode. A final diagnosis was established by muscle biopsy and genetic study. Haloperidol was administered to control the involuntary movements along with introduction of co-enzyme Q, besides symptomatic management for his focal seizures. Six months into follow-up his seizures and abnormal movements were controlled significantly with slight improvement of cognitive abilities.ConclusionThe dominance of hyperkinetic movements in the clinical scenario and the finding of a point mutation A3251G in MT-TL1 gene make this a rare presentation.

The use of clozapine and clonazepam co-administration in the treatment of a severe tardive dyskinesia: A case report

This is a case report of a patient who was treated with clozapine and clonazepam after he developed neuroleptic-induced tardive dyskinesia following treatment for schizophrenia. There are reports of clozapine treatment itself causing tardive dyskinesia; however, more reports have shown clozapine’s benefit for patients with neuroleptic-induced tardive dyskinesia. This is a case report of a patient with neuroleptic-induced tardive dyskinesia who benefitted from clozapine treatment with adjuvant use of clonazepam – the first such case report from Ethiopia. A 43-year-old male patient developed severe involuntary abnormal body movements mainly involving the trunk after he received chlorpromazine for 8 years for the diagnosis of schizophrenia. When the movement disorder became intolerable and disabling, the diagnosis of severe neuroleptic-induced tardive dyskinesia was established and the patient was started on clozapine with adjuvant clonazepam treatment. Following such management, the patient responded well and the dyskinetic movements were fully controlled, and the patient was able to work. Patients with severe and disabling neuroleptic-induced tardive dyskinesia can be treated and be productive if they receive treatment with clozapine, with adjuvant use of clonazepam.

Tardive Dyskinesia Revisited-A Clinical Management Priority Perspective: A Voyage into High Dose Buspirone Part B

We discuss several major related and integrated issues in this two-part series of papers on tardive dyskinesia (TD). In this, the second paper, Part B, the management and mechanisms are emphasized; in Part A the diagnosis and assessment of tardive dyskinesia was discussed. In this Part B series of articles we examine several special important priorities in this condition associated with sometimes permanent involuntary abnormal movements associated with the neuroleptic drugs. We particularly examine the management of this enormously important condition. After the diagnosis and assessment of TD, comes the clinical approach to management and the options and theories behind that approach. There remain no approved medications for the management of tardive dyskinesia. Therefore, all treatments are “out of labeling”. The purpose of this paper is to shed light on high dose buspirone treatment, originally described by the author in 1989 [1], and which after more than a quarter century requires re-evaluation as it still appears, in the author’s opinion, to be the logical and most appropriate management for TD. A major issue focuses, on the updated experience of more than a quarter century with generally almost completely positive effects of high-dose buspirone (HDB) treatment of tardive dyskinesia (TD) and the next issue provides an important, major theoretical demonstration of the mechanism of tardive dyskinesia. The dopamine 2 or 2-3 supersensitivity hypothesis as a cause of TD is strongly supported by HDB. In Part B, the issue of choice of medication for psychosis and related medical conditions becomes pertinent. The choices relate to the newer second generation atypical neuroleptics (SGAs) compared with the older typical, first generation neuroleptics (FGAs). The generally more expensive SGA drugs have become far the most used anti-psychotic agents in wealthy countries such as the United States, because of their efficacy and ostensible safety. Certain maxims are mentioned.

ID 347 – Facial myokymia in devic disease

Introduction Neuromyelitis optica, also known as Devic disease,is one of the inflammatory idiopathic demyelinating diseases of the central nervous system. Involuntary abnormal movements have been described in this disease. Patient We describe a 49 y/o woman, diagnosed of neuromyelitis optica, with positive immunoglobulin G, NMO Ig G, targeting aquaporin 4 water channel, and presenting for the last five years with involuntary, rippling, wavelike, continuos left facial movements. Results Needle EMG demostrated many myokymic discharges in orbicularis oculi y oris muscles on the left. The discharges ranged form doublets to triplets recurring several times per second. Motor units within bursts fired between 25 and 100 Hz. Discussion The involunary fine movements of left facial muscles here described, associated with myokimic discharges on the needle EMG, can be the expression of a change in the microenvironment of the axon membrane with a hiperexcitable ectopic generator, caused by demyelination of the root of facial nerve in the brainstem.

A patient with unilateral periodic leg movements associated with pontine infarction.

A patient with unilateral periodic leg movements associated with pontine infarction.

Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson's disease.

Parkinson's disease (PD) is the most common motor neurodegenerative disorder affecting approximately 4 million people worldwide. Although PD presents primarily with motor dysfunction, non-motor symptoms including cognitive decline, mood disorders, reduced olfaction and constipation are also often present, with some of these non-motor symptoms even presenting prior to the onset of motor symptoms. It is well known that PD is largely caused by the gradual degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNc), along with the presence of protein aggregates called Lewy bodies, which consist primarily of α-synuclein and are found in the cytoplasm of surviving neurons. This ongoing cell loss and Lewy body pathology is not confined to the SNc, but is also seen in other brain regions implicated in PD pathogenesis such as the locus ceruleus. Nonetheless, the cause of cell death in PD still remains somewhat elusive. Numerous secondary cell injury cascades have been linked to this progressive dopaminergic cell death, including inflammation, blood brain barrier (BBB) dysfunction, oxidative stress, glutamate excitotoxicity and mitochondrial dysfunction. Despite this, current PD treatment does not protect dopaminergic neurons but rather provides symptomatic benefit by replacing lost striatal dopamine (DA) either directly or by preventing its breakdown. The “gold-standard” treatment for PD is L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor to DA, combined with a peripheral dopa decarboxylase inhibitor such as benseraside. Since its inception as a PD therapeutic over 50 years ago, L-DOPA has primarily been administered in a pulsatile manner. This type of L-DOPA delivery results in maladaptive changes to brain signaling pathways and expression of L-DOPA induced dyskinesia (LID), or involuntary abnormal movements. Unfortunately, all patients will develop LID at some stage throughout their treatment, which they often find much more debilitating than the motor symptoms they presented with at diagnosis. Current research is thus focused on developing novel neuroprotective therapies that aim to treat the underlying cause of the disease, as well discovering possible adjunct therapies to L-DOPA that inhibit the expression of LID without interfering with L-DOPA motor improvement. Our recent studies have identified the neuropeptide substance P (SP) and its tachykinin NK1 receptor (NK1-R) as novel neuroprotective targets for both ongoing dopaminergic degeneration and mild to moderate LID. Thus treatment with an NK1-R antagonist may provide a new PD therapeutic that shows particular efficacy in the early stages of PD and LID (Thornton and Vink, 2012; Thornton et al., 2014).

Motor function-related maladaptive plasticity in stroke: A review

Brain plasticity can be classified as adaptive and maladaptive. Maladaptive plasticity indicates hindered functional recovery or the development of an unwanted symptom. Although a considerable amount is known about adaptive plasticity in stroke, relatively little is known of maladaptive plasticity. In the current study, previous studies on motor function-related maladaptive plasticity in stroke are reviewed in terms of compensatory movement pattern (CMP), delayed-onset involuntary abnormal movements (IAMs), and the ipsilateral motor pathway as a motor recovery mechanism. For successful stroke rehabilitation, it is important that the characteristics of maladaptive plasticity are accurately recognized. However, there is a lack of definitive evidence regarding the recognition of motor function-related maladaptive plasticity, although it seems that each of the three above-mentioned topics are involved. As for CMP, patients with a good neurological state as much as having a normal movement pattern, should be considered to have maladaptive plasticity, and in terms of the ipsilateral motor pathway, patients with bilateral innervations can be considered to have maladaptive plasticity. On the other hand, IAMs due to delayed neuronal degeneration should be ruled out in patients with delayed-onset IAMs. Therefore, for the accurate recognition of motor function-related maladaptive plasticity in stroke, a thorough evaluation of neurological state using brain mapping techniques is necessary, and subsequently, the prevention or intensive management of maladaptive plasticity is needed.

Beneficial Effects of Fluvoxamine for Chorea in a Patient With Huntington’s Disease

Beneficial Effects of Fluvoxamine for Chorea in a Patient With Huntington’s Disease

Post-stroke Movement Disorders: Clinical Manifestations and Pharmacological Management.

Involuntary abnormal movements have been reported after ischaemic and haemorrhagic stroke. Post stroke movement disorders can appear as acute or delayed sequel. At the moment, for many of these disorders the knowledge of pharmacological treatment is still inadequate. Dopaminergic and GABAergic systems may be mainly involved in post-stroke movement disorders. This article provides a review on drugs commonly used in post-stroke movement disorders, given that some post-stroke movement disorders have shown a partial benefit with pharmacological approach.

MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson's Disease

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 (Fig.1). A 12 μm thin tissue section is covered with a MALDI matrix, which facilitates desorption and ionization of intact peptides and proteins that can be detected with a mass analyzer, typically using a MALDI TOF/TOF mass spectrometer. Generally hundreds of peaks can be assessed in a single rat brain tissue section. In contrast to commonly used imaging techniques, this approach does not require prior knowledge of the molecules of interest and allows for unsupervised and comprehensive analysis of multiple molecular species while maintaining high molecular specificity and sensitivity2. Here we describe a MALDI IMS based approach for elucidating region-specific distribution profiles of neuropeptides in the rat brain of an animal model Parkinson's disease (PD). PD is a common neurodegenerative disease with a prevalence of 1% for people over 65 of age3,4. The most common symptomatic treatment is based on dopamine replacement using L-DOPA5. However this is accompanied by severe side effects including involuntary abnormal movements, termed L-DOPA-induced dyskinesias (LID)1,3,6. One of the most prominent molecular change in LID is an upregulation of the opioid precursor prodynorphin mRNA7. The dynorphin peptides modulate neurotransmission in brain areas that are essentially involved in movement control7,8. However, to date the exact opioid peptides that originate from processing of the neuropeptide precursor have not been characterized. Therefore, we utilized MALDI IMS in an animal model of experimental Parkinson's disease and L-DOPA induced dyskinesia. MALDI imaging mass spectrometry proved to be particularly advantageous with respect to neuropeptide characterization, since commonly used antibody based approaches targets known peptide sequences and previously observed post-translational modifications. By contrast MALDI IMS can unravel novel peptide processing products and thus reveal new molecular mechanisms of neuropeptide modulation of neuronal transmission. While the absolute amount of neuropeptides cannot be determined by MALDI IMS, the relative abundance of peptide ions can be delineated from the mass spectra, giving insights about changing levels in health and disease. In the examples presented here, the peak intensities of dynorphin B, alpha-neoendorphin and substance P were found to be significantly increased in the dorsolateral, but not the dorsomedial, striatum of animals with severe dyskinesia involving facial, trunk and orolingual muscles (Fig. 5). Furthermore, MALDI IMS revealed a correlation between dyskinesia severity and levels of des-tyrosine alpha-neoendorphin, representing a previously unknown mechanism of functional inactivation of dynorphins in the striatum as the removal of N-terminal tyrosine reduces the dynorphin's opioid-receptor binding capacity9. This is the first study on neuropeptide characterization in LID using MALDI IMS and the results highlight the potential of the technique for application in all fields of biomedical research.