Functional Movement Disorders: Updates and Clinical Overview.

Functional movement disorder(FMD) is a type of functional neurological disorder(FND) that is common, but often difficult to diagnose or manage. FMD can present as various phenotypes including tremor, dystonia, myoclonus, gait disorders and Parkinsonism. Conducting a clinical examination appropriate for the assessment of a patient with suspected FMD is important, and various diagnostic testing maneuvers may also be helpful. Treatment involving a multi-disciplinary team, either outpatient or inpatient, has been found to be most effective. Examples of such treatment protocols are also discussed in this review. While recognition and understanding of the disorder appears to have improved over the past few decades, as well as development of treatments, it is not uncommon for patients and physicians to continue to experience various difficulties when dealing with this disorder. In this review, I provide a practical overview of FMD and discuss how the clinical encounter itself can play a role in patients' acceptance of the diagnosis. Updates on recent neuroimaging studies that aid in the understanding of the pathophysiology are also discussed.

Biological Mechanism of Sex Difference in Stroke Manifestation and Outcomes.

BACKGROUND AND OBJECTIVES: Female patients tend to have greater disability and worse long-term outcomes after stroke than male patients. To date, the biological basis of sex difference in ischemic stroke remains unclear. We aimed to (1) assess sex differences in clinical manifestation and outcomes of acute ischemic stroke and (2) investigate whether the sex disparity is due to different infarct locations or different impacts of infarct in the same location. METHODS: This MRI-based multicenter study included 6,464 consecutive patients with acute ischemic stroke (<7 days) from 11 centers in South Korea (May 2011-January 2013). Multivariable statistical and brain mapping methods were used to analyze clinical and imaging data collected prospectively: admission NIH Stroke Scale (NIHSS) score, early neurologic deterioration (END) within 3 weeks, modified Rankin Scale (mRS) score at 3 months, and culprit cerebrovascular lesion (symptomatic large artery steno-occlusion and cerebral infarction) locations. RESULTS: The mean (SD) age was 67.5 (12.6) years, and 2,641 (40.9%) were female patients. Percentage infarct volumes on diffusion-weighted MRI did not differ between female patients and male patients (median 0.14% vs 0.14%, p = 0.35). However, female patients showed higher stroke severity (NIHSS score, median 4 vs 3, p < 0.001) and had more frequent END (adjusted difference 3.5%; p = 0.002) than male patients. Female patients had more frequent striatocapsular lesions (43.6% vs 39.8%, p = 0.001) and less frequent cerebrocortical (48.2% vs. 50.7% in patients older than 52 years, p = 0.06) and cerebellar (9.1% vs. 11.1%, p = 0.009) lesions than male patients, which aligned with angiographic findings: female patients had more prevalent symptomatic steno-occlusion of the middle cerebral artery (MCA) (31.1% vs 25.3%; p < 0.001) compared with male patients, who had more frequent symptomatic steno-occlusion of the extracranial internal carotid artery (14.2% vs 9.3%; p < 0.001) and vertebral artery (6.5% vs 4.7%; p = 0.001). Cortical infarcts in female patients, specifically left-sided parieto-occipital regions, were associated with higher NIHSS scores than expected for similar infarct volumes in male patients. Consequently, female patients had a higher likelihood of unfavorable functional outcome (mRS score >2) than male patients (adjusted absolute difference 4.5%; 95% CI 2.0-7.0; p < 0.001). DISCUSSION: Female patients have more frequent MCA disease and striatocapsular motor pathway involvement with acute ischemic stroke, along with left parieto-occipital cortical infarcts showing greater severity for equivalent infarct volumes than in male patients. This leads to more severe initial neurologic symptoms, higher susceptibility to neurologic worsening, and less 3-month functional independence, when compared with male patients.

Investigation of the posterior parietal cortex to ventral premotor connection in writer's cramp using transcranial magnetic stimulation.

The posterior parietal, premotor and motor cortices are brain regions relevant in the planning of movement. Previous transcranial magnetic stimulation (TMS) studies have shown ipsilateral premotor-to-motor inhibition in healthy subjects at rest. This premotor-to-motor inhibition has been found to be altered in patients with writer's cramp (WC), a common type of focal hand dystonia. We aimed to investigate the influence of the posterior parietal cortex on the ipsilateral ventral premotor cortex using a three single-pulse TMS paradigm. Nineteen right-handed subjects (eleven healthy volunteers and eight WC patients) completed the study. A three single-pulse TMS paradigm (preconditioning, conditioning, and test stimuli) was used to sequentially stimulate the left posterior parietal, ventral premotor, and primary motor cortices. We found that in both healthy subjects and patients, stimulating the ipsilateral posterior parietal cortex resulted in reversal of the resting premotor-to-motor inhibition. Resting premotor-to-motor inhibition was also found, with no statistically significant group difference. Furthermore, a facilitatory effect of the posterior parietal cortex on the primary motor cortex was found in both groups. Our results suggest that in the resting state, the inhibitory effect of the left posterior parietal cortex on the ipsilateral ventral premotor cortex found in healthy subjects is also intact in WC patients. While we are unable to identify any parietal-to-premotor connectivity abnormality in the resting state, an abnormality during a specific task cannot be excluded. Previously reported conductivity abnormalities in resting fMRI do not appear to translate into a TMS physiological abnormality.

Effects of anodal stimulation and motor practice on limb-kinetic apraxia in Parkinson's disease.

Limb-kinetic apraxia, the loss of the ability to make precise, independent but coordinated finger and hand movements affects quality of life in patients with Parkinson's disease. We aimed to examine the effects of anodal transcranial direct current stimulation of the left posterior parietal cortex and upper extremity motor practice on limb-kinetic apraxia in Parkinson's disease. This study was conducted in a randomized, double-blind, sham-controlled fashion. Patients confirmed to have Parkinson's disease were recruited. Twenty-eight participants completed the study and were randomized to two groups: anodal or sham stimulation. For participants assigned to active stimulation, anodal stimulation of the left posterior parietal cortex was performed using 2 mA current for 20 min. Patients received anodal or sham stimulation, followed by motor practice in both groups. The primary outcome measure was time-performing sequential buttoning and unbuttoning, and several secondary outcome measures were obtained. A statistically significant interaction between stimulation type and timepoint on time taken to perform buttoning and unbuttoning was found. Patients who received anodal stimulation were found to have a significant decrease in sequential buttoning and unbuttoning time immediately following stimulation and at 24 h in the medication-ON state, compared to the medication-OFF state (31% and 29% decrease, respectively). Anodal stimulation of the left posterior parietal cortex prior to motor practice appears to be effective for limb-kinetic apraxia in Parkinson's disease. Future long-term, multi-session studies looking at the long-term effects of anodal stimulation and motor practice on limb-kinetic apraxia in Parkinson's disease may be worthwhile.

Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study.

BACKGROUND: Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke. METHODS AND FINDINGS: In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules. CONCLUSIONS: Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

Effects of Onabotulinum Toxin A on Gait in Parkinson's Disease Patients with Foot Dystonia.

We investigated the effects of botulinum toxin on gait in Parkinson's disease (PD) patients with foot dystonia. Six patients underwent onabotulinum toxin A injection and were assessed by Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), visual analog scale (VAS) of pain, Timed Up and Go (TUG), Berg Balance Test (BBT), and 3D gait analysis at baseline, 1 month, and 3 months. BFMDRS (p = 0.002), VAS (p = 0.024), TUG (p = 0.028), and BBT (p = 0.034) were improved. Foot pressures at Toe 1 (p = 0.028) and Midfoot (p = 0.018) were reduced, indicating botulinum toxin's effects in alleviating the dystonia severity and pain and improving foot pressures during walking in PD.

Transcranial Direct Current Stimulation and Yoga for Functional Movement Disorders.

BACKGROUND: Functional movement disorder (FMD), a conversion disorder characterized by involuntary movements, is difficult to treat. METHODS: We aimed to assess the effects of anodal transcranial direct current stimulation (tDCS) and yoga in FMD patients (n=5). TDCS of the right temporoparietal junction, a brain region relevant in the sense of self-agency, was conducted. Subjects underwent both sham and anodal tDCS with a washout period of 3 weeks. Yoga was used as a mode of exercise, as well as in conjunction with stimulation to sustain potential changes in neural plasticity. RESULTS: A total of 5 subjects completed the study [mean age: 52 (SE: 4) y, disease duration: 5 (SE: 1.6) y], undergoing both sham and anodal tDCS. Anodal tDCS does not appear to be superior to sham tDCS in alleviating symptoms and disability, but combining tDCS and yoga appears to lead to mild improvement noted on clinical observation, based on the change in the efficacy index of Clinical Global Impression found in 4 subjects. CONCLUSION: Our study results suggest that anodal tDCS is not superior to sham tDCS in alleviating subjective symptoms and disability in FMD. However, interpretation of these results is limited due to the small number of stimulation sessions and number of subjects. Future studies using more frequent stimulation sessions are needed to further determine whether anodal tDCS may have a therapeutic effect in this patient group compared with sham tDCS.

Botulinum toxin and occupational therapy for Writer's cramp.

BACKGROUND: Writer's cramp (WC) is a form of focal hand dystonia, for which focal botulinum neurotoxin (BoNT) injections are the current best therapy. Past studies have shown that some types of rehabilitative therapy can be useful. We hypothesized that BoNT together with a specific type of occupational therapy would be better than BoNT alone for treating WC patients comparing the effects with a patient-rated subjective scale. METHODS: Twelve WC patients were randomized to two groups. Six received only BoNT therapy and 6 received BoNT & occupational therapy. The occupational therapy involved specific exercises of finger movements in the direction opposite to the dystonic movements during writing. BoNT was injected by movement disorders neurologists in the affected muscles under electromyography-guidance. The primary outcome was the patient-rated subjective scale at 20 weeks. Secondary exploratory outcomes included the writer's cramp rating scale (WCRS), writer's cramp impairment scale (WCIS), the writer's cramp disability scale (WCDS), handgrip strength and kinetic parameters. RESULTS: The patient-rated subjective scale scores at 20 weeks were not significantly different between the two groups. Significant objective improvement was noted in the BoNT & occupational therapy group, as noted by the decrease (28%) in WCIS scores. CONCLUSIONS: Improvement of the primary outcome measure, the patient-rated subjective scale, was not achieved. However, significant improvement was found in the BoNT & occupational therapy group in a secondary measure of impairment. Our hypothesis-driven study results are likely limited by small sample size, and further large-scale studies of occupational therapy methods to improve the efficacy of BoNT seems worthwhile.

Mapping the Supratentorial Cerebral Arterial Territories Using 1160 Large Artery Infarcts.

Importance: Cerebral vascular territories are of key clinical importance in patients with stroke, but available maps are highly variable and based on prior studies with small sample sizes. Objective: To update and improve the state of knowledge on the supratentorial vascular supply to the brain by using the natural experiment of large artery infarcts and to map out the variable anatomy of the anterior, middle, and posterior cerebral artery (ACA, MCA, and PCA) territories. Design, Setting, and Participants: In this cross-sectional study, digital maps of supratentorial infarcts were generated using diffusion-weighted magnetic resonance imaging (MRI) of 1160 patients with acute (<1-week) stroke recruited (May 2011 to February 2013) consecutively from 11 Korean stroke centers. All had supratentorial infarction associated with significant stenosis or occlusion of 1 of 3 large supratentorial cerebral arteries but with patent intracranial or extracranial carotid arteries. Data were analyzed between February 2016 and August 2017. Main Outcomes and Measures: The 3 vascular territories were mapped individually by affected vessel, generating 3 data sets for which infarct frequency is defined for each voxel in the data set. By mapping these 3 vascular territories collectively, we generated data sets showing the Certainty Index (CI) to reflect the likelihood of a voxel being a member of a specific vascular territory, calculated as either ACA, MCA, or PCA infarct frequency divided by total infarct frequency in that voxel. Results: Of the 1160 patients (mean [SD] age, 67.0 [13.3] years old), 623 were men (53.7%). When the cutoff CI was set as 90%, the volume of the MCA territory (approximately 54% of the supratentorial parenchymal brain volume) was about 4-fold bigger than the volumes of the ACA and PCA territories (each approximately 13%). Quantitative studies showed that the medial frontal gyrus, superior frontal gyrus, and anterior cingulate were involved mostly in ACA infarcts, whereas the middle frontal gyrus and caudate were involved mostly by MCA infarcts. The PCA infarct territory was smaller and narrower than traditionally shown. Border-zone maps could be defined by using either relative infarct frequencies or CI differences. Conclusions and Relevance: We have generated statistically rigorous maps to delineate territorial border zones and lines. The new topographic brain atlas can be used in clinical care and in research to objectively define the supratentorial arterial territories and their borders.

Clinical Characteristics of Functional Movement Disorders: A Clinic-based Study.

Background: Functional movement disorders are recognized as a "crisis" in neurology. We aimed to determine the rate of incidence of functional movement disorder patients at a university outpatient neurology clinic in South Korea, and highlight the clinical and phenomenological characteristics. Methods: Patients who were assessed by a movement disorders neurologist at a university hospital between March 2016 and May 2017 were screened for functional movement disorders. Demographic and clinical data were reviewed, and the phenomenology of movements was studied. Results: Of 321 patients evaluated for the chief complaint of a movement abnormality, approximately 10% (31 patients) were diagnosed with a functional movement disorder. The female to male ratio was 7:1 (27 females to four males). The mean age at presentation was 53 years (standard error 3.6 years), and the mean disease duration was 5 years (standard error 1.4 years). Sixty-one percent (19 out of 31 patients) had a past medical history of depression, anxiety, or other psychiatric illnesses. Tremor and speech abnormalities were most prevalent (19 and 12 patients, respectively). Onset was reported to be abrupt in 14 patients (45%). Thirteen (42%) patients were found to have improvement at a follow-up visit, 10 (32%) had no improvement, and eight (26%) were lost to follow-up. Discussion: Functional movement disorders are not uncommon in the outpatient neurology clinic. Our results confirm that tremor is the most frequent movement occurring in functional movement disorders, and the most commonly affected body parts were found to be the upper and lower extremities. Speech was also found to be frequently involved (39%). Patients with no improvement at follow-up had longer mean disease duration (6.2 years), consistent with previous observations that prolonged symptom duration is associated with poor clinical outcome. Our study results obtained from a Korean population suggest that previous observations on functional movement disorders from other regions hold true in Eastern Asia.

Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation.

Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi-lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re-arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome-wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub-fractionation into triton-extracted membrane proteins and luminal samples (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin-1/2 and ß-Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)-based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes.

Apraxia: Review and Update.

Praxis, the ability to perform skilled or learned movements is essential for daily living. Inability to perform such praxis movements is defined as apraxia. Apraxia can be further classified into subtypes such as ideomotor, ideational and limb-kinetic apraxia. Relevant brain regions have been found to include the motor, premotor, temporal and parietal cortices. Apraxia is found in a variety of highly prevalent neurological disorders including dementia, stroke and Parkinsonism. Furthermore, apraxia has been shown to negatively affect quality of life. Therefore, recognition and treatment of this disorder is critical. This article provides an overview of apraxia and highlights studies dealing with the neurophysiology of this disorder, opening up novel perspectives for the use of motor training and noninvasive brain stimulation as treatment.

Contribution of transcranial magnetic stimulation to assessment of brain connectivity and networks.

The goal of this review is to show how transcranial magnetic stimulation (TMS) techniques can make a contribution to the study of brain networks. Brain networks are fundamental in understanding how the brain operates. Effects on remote areas can be directly observed or identified after a period of stimulation, and each section of this review will discuss one method. EEG analyzed following TMS is called TMS-evoked potentials (TEPs). A conditioning TMS can influence the effect of a test TMS given over the motor cortex. A disynaptic connection can be tested also by assessing the effect of a pre-conditioning stimulus on the conditioning-test pair. Basal ganglia-cortical relationships can be assessed using electrodes placed in the process of deep brain stimulation therapy. Cerebellar-cortical relationships can be determined using TMS over the cerebellum. Remote effects of TMS on the brain can be found as well using neuroimaging, including both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). The methods complement each other since they give different views of brain networks, and it is often valuable to use more than one technique to achieve converging evidence. The final product of this type of work is to show how information is processed and transmitted in the brain.