The transcription regulator Lmo3 is required for the development of medial ganglionic eminence derived neurons in the external globus pallidus.

The external globus pallidus (GPe) is an essential component of the basal ganglia, a group of subcortical nuclei that are involved in control of action. Changes in the firing of GPe neurons are associated with both passive and active body movements. Aberrant activity of GPe neurons has been linked to motor symptoms of a variety of movement disorders, such as Parkinson's Disease, Huntington's disease and dystonia. Recent studies have helped delineate functionally distinct subtypes of GABAergic GPe projection neurons. However, not much is known about specific molecular mechanisms underlying the development of GPe neuronal subtypes. We show that the transcriptional regulator Lmo3 is required for the development of medial ganglionic eminence derived Nkx2.1+ and PV+ GPe neurons, but not lateral ganglionic eminence derived FoxP2+ neurons. As a consequence of the reduction in PV+ neurons, Lmo3-null mice have a reduced GPe input to the subthalamic nucleus.

GNAO1-related movement disorder: An update on phenomenology, clinical course, and response to treatments.

AIM: To evaluate clinical phenotype and molecular findings of 157 cases with GNAO1 pathogenic or likely pathogenic variants delineating the clinical spectrum, course, and response to treatments. METHOD: Clinical phenotype, genetic data, and pharmacological and surgical treatment history of 11 novel cases and 146 previously published patients were analyzed. RESULTS: Complex hyperkinetic movement disorder (MD) characterizes 88% of GNAO1 patients. Severe hypotonia and prominent disturbance of postural control seem to be hallmarks in the early stages preceding the hyperkinetic MD. In a subgroup of patients, paroxysmal exacerbations became so severe as to require admission to intensive care units (ICU). Almost all patients had a good response to deep brain stimulation (DBS). Milder phenotypes with late-onset focal/segmental dystonia, mild to moderate intellectual disability, and other minor neurological signs (i.e., parkinsonism and myoclonus) are emerging. MRI, previously considered noncontributory to a diagnosis, can show recurrent findings (i.e., cerebral atrophy, myelination and/or basal ganglia abnormalities). Fifty-eight GNAO1 pathogenic variants, including missense changes and a few recurrent splice site defects, have been reported. Substitutions at residues Gly203, Arg209 and Glu246, together with the intronic c.724-8G > A change, account for more than 50% of cases. INTERPRETATION: Infantile or childhood-onset complex hyperkinetic MD (chorea and/or dystonia) with or without paroxysmal exacerbations, associated hypotonia, and developmental disorders should prompt research for GNAO1 mutations. DBS effectively controls and prevents severe exacerbations and should be considered early in patients with specific GNAO1 variants and refractory MD. Prospective and natural history studies are necessary to define genotype-phenotype correlations further and clarify neurological outcomes.

Cerebral creatine deficiency disorders - A clinical, genetic and follow up study from India.

INTRODUCTION: Cerebral creatine deficiency syndromes (CCDS) are a group of potentially treatable neurometabolic disorders. The clinical, genetic profile and follow up outcome of Indian CCDS patients is presented. MATERIALS AND METHODS: This was a retrospective cohort of CCDS patients seen over six-years. Diagnosis was based either on low creatine peak on proton magnetic resonance spectroscopy (MRS) and/or genetic evaluation. RESULTS: Thirteen patients were eligible [8 creatine transporter deficiency (CTD), 4 guanidinoacetate methyltransferase (GAMT) deficiency and 1 could not be classified]. The mean (±SD) age at diagnosis was 7.2(±5.0) years. Clinical manifestations included intellectual disability (ID) with significant expressive speech delay in all. Most had significant behavior issues (8/13) and/or autism (8/13). All had history of convulsive seizures (11/13 had epilepsy; 2 patients only had febrile seizures) and 2/13 had movement disorder. Constipation was the commonest non-neurological manifestation (5/13 patients). Cranial MRI was normal in all CTD patients but showed globus pallidus hyperintensity in all four with GAMT deficiency. MRS performed in 11/13 patients, revealed abnormally low creatine peak. A causative genetic variant (novel mutation in nine) was identified in 12 patients. Three GAMT deficiency and one CTD patient reported neurodevelopmental improvement and good seizure control after creatine supplementation. CONCLUSION: Intellectual disability, disproportionate speech delay, autism, and epilepsy, were common in our CCDS patients. A normal structural neuroimaging with easily controlled febrile and/or afebrile seizures differentiated CTD from GAMT deficiency patients who had abnormal neuroimaging and often difficult to control epilepsy and movement disorder.

Central nervous system physiology.

This is the second chapter of the series on the use of clinical neurophysiology for the study of movement disorders. It focusses on methods that can be used to probe neural circuits in brain and spinal cord. These include use of spinal and supraspinal reflexes to probe the integrity of transmission in specific pathways; transcranial methods of brain stimulation such as transcranial magnetic stimulation and transcranial direct current stimulation, which activate or modulate (respectively) the activity of populations of central neurones; EEG methods, both in conjunction with brain stimulation or with behavioural measures that record the activity of populations of central neurones; and pure behavioural measures that allow us to build conceptual models of motor control. The methods are discussed mainly in relation to work on healthy individuals. Later chapters will focus specifically on changes caused by pathology.

The critical balance between dopamine D2 receptor and RGS for the sensitive detection of a transient decay in dopamine signal.

In behavioral learning, reward-related events are encoded into phasic dopamine (DA) signals in the brain. In particular, unexpected reward omission leads to a phasic decrease in DA (DA dip) in the striatum, which triggers long-term potentiation (LTP) in DA D2 receptor (D2R)-expressing spiny-projection neurons (D2 SPNs). While this LTP is required for reward discrimination, it is unclear how such a short DA-dip signal (0.5-2 s) is transferred through intracellular signaling to the coincidence detector, adenylate cyclase (AC). In the present study, we built a computational model of D2 signaling to determine conditions for the DA-dip detection. The DA dip can be detected only if the basal DA signal sufficiently inhibits AC, and the DA-dip signal sufficiently disinhibits AC. We found that those two requirements were simultaneously satisfied only if two key molecules, D2R and regulators of G protein signaling (RGS) were balanced within a certain range; this balance has indeed been observed in experimental studies. We also found that high level of RGS was required for the detection of a 0.5-s short DA dip, and the analytical solutions for these requirements confirmed their universality. The imbalance between D2R and RGS is associated with schizophrenia and DYT1 dystonia, both of which are accompanied by abnormal striatal LTP. Our simulations suggest that D2 SPNs in patients with schizophrenia and DYT1 dystonia cannot detect short DA dips. We finally discussed that such psychiatric and movement disorders can be understood in terms of the imbalance between D2R and RGS.

Feature selection to classify lameness using a smartphone-based inertial measurement unit.

BACKGROUND AND OBJECTIVES: Gait can be severely affected by pain, muscle weakness, and aging resulting in lameness. Despite the high incidence of lameness, there are no studies on the features that are useful for classifying lameness patterns. Therefore, we aimed to identify features of high importance for classifying population differences in lameness patterns using an inertial measurement unit mounted above the sacral region. METHODS: Features computed exhaustively for multidimensional time series consisting of three-axis angular velocities and three-axis acceleration were carefully selected using the Benjamini-Yekutieli procedure, and multiclass classification was performed using LightGBM (Microsoft Corp., Redmond, WA, USA). We calculated the relative importance of the features that contributed to the classification task in machine learning. RESULTS: The most important feature was found to be the absolute value of the Fourier coefficients of the second frequency calculated by the one-dimensional discrete Fourier transform for real input. This was determined by the fast Fourier transformation algorithm using data of a single gait cycle of the yaw angular velocity of the pelvic region. CONCLUSIONS: Using an inertial measurement unit worn over the sacral region, we determined a set of features of high importance for classifying differences in lameness patterns based on different factors. This completely new set of indicators can be used to advance the understanding of lameness.

Evaluation of movement and brain activity.

Clinical neurophysiology studies can contribute important information about the physiology of human movement and the pathophysiology and diagnosis of different movement disorders. Some techniques can be accomplished in a routine clinical neurophysiology laboratory and others require some special equipment. This review, initiating a series of articles on this topic, focuses on the methods and techniques. The methods reviewed include EMG, EEG, MEG, evoked potentials, coherence, accelerometry, posturography (balance), gait, and sleep studies. Functional MRI (fMRI) is also reviewed as a physiological method that can be used independently or together with other methods. A few applications to patients with movement disorders are discussed as examples, but the detailed applications will be the subject of other articles.

Diagnostic usefulness of 10-step tandem gait test for the patient with degenerative cervical myelopathy.

Tandem gait is considered one of the most useful screening tools for gait impairment. The aim of this study is to evaluate diagnostic usefulness of 10-step tandem gait test for the patients with degenerative cervical myelopathy (DCM). Sixty-two DCM patients were compared to 55 persons without gait abnormalities as control. We counted the number of consecutive steps and graded into five according the number of steps and stability. Five grades of tandem gait were investigated for association with clinical parameters including qualitative Japanese orthopedic association (JOA) sub-score for lower extremities and Nurick scale and quantitative balance and gait assessments. The number of tandem steps were reduced and the grades of tandem gait were differently distributed in the DCM patients compared to controls (steps, 7.1 ± 3.6 versus 9.9 ± 0.4, p < 0.001; grades of 0/1/2/3/4/5, 1/13/14/15/19 versus 0/0/2/15/38, p < 0.001 in patients with DCM and control respectively). Patients with DCM showed more unstable balance and abnormal gait features including slower velocity, shorter strides, wider bases with increased stance phase of a gait cycle compared to the control group. The grades of tandem gait were correlated with JOA sub-score (r = 0.553, p < 0.001) and the Nurick scale (r = - 0.652, p < 0.001) as well as both balance and gait parameters. In DCM patients, tandem gait was impaired and correlated with severity of gait abnormality. The authors believe that 10-step tandem gait test is an objective and useful screening test for evaluating gait disturbance in patients with DCM.

A novel non-human primate model of Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases.

White matter degeneration in remote brain areas of stroke patients with motor impairment due to basal ganglia lesions.

Diffusion tensor imaging (DTI) studies have revealed distinct white matter (WM) characteristics of the brain following diseases. Beyond the lesion-symptom maps, stroke is characterized by extensive structural and functional alterations of brain areas remote to local lesions. Here, we further investigated the structural changes over a global level by using DTI data of 10 ischemic stroke patients showing motor impairment due to basal ganglia lesions and 11 healthy controls. DTI data were processed to obtain fractional anisotropy (FA) maps, and multivariate pattern analysis was used to explore brain regions that play an important role in classification based on FA maps. The WM structural network was constructed by the deterministic fiber-tracking approach. In comparison with the controls, the stroke patients showed FA reductions in the perilesional basal ganglia, brainstem, and bilateral frontal lobes. Using network-based statistics, we found a significant reduction in the WM subnetwork in stroke patients. We identified the patterns of WM degeneration affecting brain areas remote to the lesions, revealing the abnormal organization of the structural network in stroke patients, which may be helpful in understanding of the neural mechanisms underlying hemiplegia.

Towards real-world generalizability of a circuit for action-stopping.

Two decades of cross-species neuroscience research on rapid action-stopping in the laboratory has provided motivation for an underlying prefrontal-basal ganglia circuit. Here we provide an update of key studies from the past few years. We conclude that this basic neural circuit is on increasingly firm ground, and we move on to consider whether the action-stopping function implemented by this circuit applies beyond the simple laboratory stop signal task. We advance through a series of studies of increasing 'real-worldness', starting with laboratory tests of stopping of speech, gait and bodily functions, and then going beyond the laboratory to consider neural recordings and stimulation during moments of control presumably required in everyday activities such as walking and driving. We end by asking whether stopping research has clinical relevance, focusing on movement disorders such as stuttering, tics and freezing of gait. Overall, we conclude there are hints that the prefrontal-basal ganglia action-stopping circuit that is engaged by the basic stop signal task is recruited in myriad scenarios; however, truly proving this for real-world scenarios requires a new generation of studies that will need to overcome substantial technical and inferential challenges.

Corticomuscular coupling analysis based on improved LSTM and transfer entropy.

The study of functional corticomuscular coupling can reflect the interaction between the cerebral cortex and muscle tissue, thereby helping to understand how the brain controls muscle tissue and the effect of muscle movement on brain function. This study proposes a detection model of the coupling strength between the cortex and muscles. The detection model uses an adaptive selector to choose the optimal long short-term memory network, uses this network to extract the features of electroencephalography and electromyography, and finally transforms time characteristics into the frequency domain. The transfer entropy is used to represent the interaction intensity of signals in different frequency bands. Using this model, we analyze the coupling relationship between the cortex and muscles in the three movements of wrist flexion, wrist extension, and clench fist, and compare the model with traditional wavelet coherence analysis and deep canonical correlation analysis. The experimental results show that our model can not only express the bidirectional coupling relationship between different frequency bands but also suppress the possible false coupling that traditional methods may detect. Our research shows that the proposed model has great potential in medical rehabilitation, movement decoding, and other fields.

Movement disorders in systemic autoimmune diseases: Clinical spectrum, ancillary investigations, pathophysiological considerations.

With the advances in neuroimmunology especially due to the discovery of new neuronal antibodies, the recognition of treatable antibody-related movement disorders has recently received much attention. In contrast, the identification and characterisation of movement disorders associated with systemic autoimmune diseases remains a substantially unexplored area. Beyond the classic few associations such as chorea and antiphospholipid syndrome, or ataxia and coeliac disease, movement disorders have been reported in association with several systemic autoimmune diseases, however a clear image of clinical phenotypes, investigations, and treatment outcomes in these conditions has never been drawn. In this review, we analyse data from approximately 300 cases and summarise the epidemiological, clinical and diagnostic features of movement disorders associated with systemic autoimmune diseases, and the available knowledge about treatment and outcomes. We highlight that movement disorders in systemic autoimmune conditions are frequently the only or among a few presenting manifestations and are mostly treatable disorders responding to immunotherapy or dietary modifications. We point out the pertinent combination of clinical features and investigations which can suggest the underlying autoimmune nature of these movement disorders, and thus address the most appropriate treatment.

Progress in sensorimotor neuroscience of schizophrenia spectrum disorders: Lessons learned and future directions.

The number of neuroimaging studies on movement disorders, sensorimotor, and psychomotor functioning in schizophrenia spectrum disorders (SSD) has steadily increased over the last two decades. Accelerated by the addition of the "sensorimotor domain" to the Research Domain Criteria (RDoC) framework in January 2019, neuroscience research on the role of sensorimotor dysfunction in SSD has gained greater scientific and clinical relevance. To draw attention to recent rapid progress in the field, we performed a triennial systematic review (PubMed search from January 1st, 2018 through December 31st, 2020), in which we highlight recent neuroimaging findings and discuss methodological pitfalls as well as challenges for future research. The identified magnetic resonance imaging (MRI) studies suggest that sensorimotor abnormalities in SSD are related to cerebello-thalamo-cortico-cerebellar network dysfunction. Longitudinal and interventional studies highlight the translational potential of the sensorimotor domain as putative biomarkers for treatment response and as targets for non-invasive neurostimulation techniques in SSD.

Effect of Acupuncture on Neuroplasticity of Stroke Patients with Motor Dysfunction: A Meta-Analysis of fMRI Studies.

Objective: To analyze the pattern of intrinsic brain activity variability that is altered by acupuncture compared with conventional treatment in stroke patients with motor dysfunction, thus providing the mechanism of stroke treatment by acupuncture. Methods: Chinese and English articles published up to May 2020 were searched in the PubMed, Web of Science, EMBASE, and Cochrane Library databases, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Database. We only included randomized controlled trials (RCTs) using resting-state fMRI to observe the effect of acupuncture on stroke patients with motor dysfunction. R software was used to analyze the continuous variables, and Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) was used to perform an analysis of fMRI data. Findings. A total of 7 studies comprising 143 patients in the treatment group and 138 in the control group were included in the meta-analysis. The results suggest that acupuncture treatment helps the healing process of motor dysfunction in stroke patients and exhibits hyperactivation in the bilateral basal ganglia and insula and hypoactivation in motor-related areas (especially bilateral BA6 and left BA4). Conclusion: Acupuncture plays a role in promoting neuroplasticity in subcortical regions that are commonly affected by stroke and cortical motor areas that may compensate for motor deficits, which may provide a possible mechanism underlying the therapeutic effect of acupuncture.

Results of the First GNAO1-Related Neurodevelopmental Disorders Caregiver Survey.

BACKGROUND: We sought to expand our knowledge of the clinical spectrum of GNAO1-related neurodevelopmental disorders through a caregiver survey reviewing medical and developmental history and development of epilepsy and movement disorders. METHODS: An online survey was administered to caregivers of individuals diagnosed with GNAO1 pathogenic variants. RESULTS: Eighty-two surveys were completed. Nearly all (99%) reported the first symptom of concern by age one year with the most frequently identified concerns as hypotonia (68%), developmental delay (67%), seizures (29%), difficulty feeding (23%), and abnormal movements (20%). All caregivers reported developmental delays with a spectrum of severity. Movement disorders (76%) were more common than epilepsy (52%), although 33% reported both. The onset of seizures tended to be earlier than abnormal movements. Nearly half (48%) of those with any seizures, reported they were no longer having recurrent seizures. No single most effective medication for movement disorders or epilepsy was noted. Ten participants have had deep brain stimulator for their movement disorder, and all indicated positive effects. CONCLUSIONS: GNAO1-related neurodevelopmental disorders most often present within the first year of life with nonspecific symptoms of hypotonia or developmental delay. Although associated epilepsy and movement disorders can be severe, GNAO1-associated epilepsy may not always be medically refractory or lifelong.

Implicit motor imagery using laterality recognition in functional movement disorders.

Functional movement disorder (FMD) presents as disabling motor symptoms that cannot be explained by organic processes. Despite the lack of lesion or known central nervous system dysfunction, distortion in sensorimotor processing in movement generation and execution is often observed. A person's capacity to judge laterality of a body part requires processing of sensorimotor information. This prospective observational study compared reaction time (RT) and accuracy (ACC) of hand laterality recognition between 30 people diagnosed with FMD and 30 age-matched healthy control participants. The association of RT and ACC with severity of FMD as measured by the Simplified Functional Movement Disorders Rating Scale (SFMDRS) was also explored. RT was on average 0.6 s slower (95% CI 0.4 - 0.8 s, p < 0.001) in patients with FMD (mean 2.2 s, standard deviation (SD) 0.5) than controls (mean 1.7 s, SD 0.3). ACC was on average 8.9% lower (95% CI -15.7 - -2.2, p = 0.01) in patients with FMD (mean 79.6%, SD 16.6) than controls (mean 88.5%, SD 8.1). When adjusted for SFMDRS using robust regression, RT was 0.3 s slower (95% CI 0.01 - 0.5, p = 0.04) in cases than in controls, but ACC was no longer different between groups. There was a moderate negative correlation between RT and ACC in FMD patients (ρ -0.58, p < 0.001 but not in controls (ρ -0.26, p = 0.17). People with FMD had significantly slower RT and lower ACC compared to the control group. These results provide new insights into underlying sensorimotor processing deficits in those with FMD.

Spinal Inhibitory Interneurons: Gatekeepers of Sensorimotor Pathways.

The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level.

Sensorimotor, Attentional, and Neuroanatomical Predictors of Upper Limb Motor Deficits and Rehabilitation Outcome after Stroke.

The rehabilitation of motor deficits following stroke relies on both sensorimotor and cognitive abilities, thereby involving large-scale brain networks. However, few studies have investigated the integration between motor and cognitive domains, as well as its neuroanatomical basis. In this retrospective study, upper limb motor responsiveness to technology-based rehabilitation was examined in a sample of 29 stroke patients (18 with right and 11 with left brain damage). Pretreatment sensorimotor and attentional abilities were found to influence motor recovery. Training responsiveness increased as a function of the severity of motor deficits, whereas spared attentional abilities, especially visuospatial attention, supported motor improvements. Neuroanatomical analysis of structural lesions and white matter disconnections showed that the poststroke motor performance was associated with putamen, insula, corticospinal tract, and frontoparietal connectivity. Motor rehabilitation outcome was mainly associated with the superior longitudinal fasciculus and partial involvement of the corpus callosum. The latter findings support the hypothesis that motor recovery engages large-scale brain networks that involve cognitive abilities and provides insight into stroke rehabilitation strategies.

Movement perception of the tonic vibration reflex is abnormal in functional limb weakness.

INTRODUCTION: We tested the hypothesis that functional limb weakness is associated with possible dysfunction of the central processing of proprioceptive information, by evaluating the amount of tonic vibration reflex (TVR) and the perception of the TVR movement. METHODS: The study sample was 20 patients with functional weakness of the lower and/or the upper limbs and 25 healthy controls; delivery of 92-Hz transcutaneous vibration of the biceps brachii tendon of the unrestrained arm stimulated predominantly the muscle spindle afferent and elicited elbow flexion (tonic vibration reflex, TVR). Blindfolded participants had to match the final position of the vibrated arm with their contralateral tracking arm. The TVR and perception of the TVR movement were measured as angle movements of the vibrated arm and the tracking arm, respectively. RESULTS: The magnitude of the TVR of the vibrated arm and movement perception of the TVR of the tracking arm were significantly reduced in the patients compared to the controls. No correlation was found between magnitude of the TVR and perception of the TVR movement, suggesting that the abnormalities were independent of each other. Moreover, the abnormalities did not differ between the patients with/without bilateral upper limb involvement or between the affected and the unaffected side in patients with unilateral impairment, suggesting that the observed deficits are independent of motor impairment. CONCLUSIONS: Proprioceptive dysfunction may underlie alterations in body movement and in sense of agency in such patients and may play a role in the pathophysiology of functional limb weakness.