Assessment Of Motor Behaviour Research Articles

Characterizing the journey of Rett syndrome among females in the United States: a real-world evidence study using the Rett syndrome natural history study database

BackgroundWith the advent of the first targeted therapy for Rett Syndrome (RTT), a comprehensive assessment of the journey of RTT is needed to elucidate on present unmet needs in this population. This study characterized females with RTT in the United States and their disease journey with respect to longitudinal treatment patterns, RTT-related outcomes, and changes in disease severity.MethodsThis retrospective cohort study used registry data of females with RTT from the 5211 RTT Natural History Study (RNHS) (November 2015–July 2021). Pharmacological and supportive therapy use, RTT-related outcomes, and RTT severity, as measured by the Clinical Severity Scale and Motor Behavioral Assessment scale, were evaluated following the first RNHS visit. Analyses were conducted overall and in subgroups by RTT type (classic and atypical RTT) and age at first visit (pediatric and adult).ResultsA total of 455 females with RTT were included in the study, of whom 90.5% had classic RTT and 79.8% were pediatric individuals. Over a median follow-up of 4 years, use of pharmacological therapies, including prokinetic agents (42.7% vs. 28.3%), and supportive therapies, including physical therapy (87.3% vs. 40.2%) and speech-language therapy (86.8% vs. 23.9%), were more common in pediatric than adult individuals (all p < 0.05). Nearly half (44.6%) of all individuals had a hospital or emergency room visit, with a higher proportion of visits in individuals with classic RTT than atypical RTT and pediatric than adult individuals (both p = 0.001). An increasing trend in clinical severity was observed in pediatric individuals (mean change per year: 0.24; 95% confidence interval [CI]: 0.03, 0.44), while an increasing trend in motor-behavioral dysfunction was observed in pediatric individuals (mean change per year: 1.12; 95% CI: 0.63, 1.60) and those with classic RTT (mean change per year: 0.97; 95% CI: 0.53, 1.41).ConclusionsFindings from this study highlight the considerable burden of RTT across disease subtype and age. Despite reliance on supportive therapies and healthcare encounters, individuals with RTT experience increasing disease severity and motor-behavioral dysfunction in childhood and adolescence, underscoring the unmet needs of this population and the value of early intervention to manage RTT in the long-term.

Is trofinetide a future treatment for Rett syndrome? A comprehensive systematic review and meta-analysis of randomized controlled trials

BackgroundRett syndrome (RTT) is a rare, life-threatening, genetic neurodevelopmental disorder. Treatment in RTT encounters many challenges. Trofinetide, a modified amino-terminal tripeptide of insulin-like growth factor 1, has demonstrated clinically promising results in RTT. In this study, trofinetide efficacy and safety in RTT are systematically reviewed and meta-analyzed.MethodsA systematic search of five electronic databases was conducted until January 2024. Review Manager 5.4 software was used for the analysis. The analysis was based on a weighted mean difference and standard error with a confidence interval (CI) of 95%, and a statistically significant P-value was considered if it was < 0.05. The study was registered on PROSPERO with registration number CRD42024499849. Quality of evidence was assessed using GRADE.ResultsThree randomized controlled trials (RCTs) with 276 patients were included in the analysis. Trofinetide improved both caregiver outcomes and clinical scales by improving the Rett Syndrome Behavior Questionnaire (RSBQ) (mean difference (MD): − 3.46 points, 95% CI: − 5.63 to − 1.27, P = 0.0002) and Clinical Global Impression Scale–Improvement (CGI-I) (MD: − 0.35, 95% CI: − 0.51 to − 0.18, P < 0.0001), respectively. However, trofinetide neither improved the Caregiver Top 3 Concerns Visual Analog Scale nor the Rett Motor Behavioral Assessment. Regarding safety, trofinetide was significantly associated with vomiting compared to placebo (odds ratio (OR): 3.17, 95% CI: 1.57 to 6.43, P = 0.001). After solving heterogeneity, results showed a statistically significant incidence of diarrhea in the trofinetide (200 mg) group compared to placebo (OR: 18.51, 95% CI: 9.30 to 36.84, P ≤ 0.00001).ConclusionsTrofinetide demonstrated statistically significant improvements in CGI-I and RSBQ in pediatrics and adult patients with Rett. Side effects are limited to vomiting and diarrhea. Although diarrhea yielded an insignificant result in our analysis, it emerged as a cause for treatment discontinuation in the participating trials, and a statistically significant risk for diarrhea emerged when excluding the study using a lower dose of the drug, hence causing heterogeneity, in the meta-analysis. Given the diverse genetic landscape of RTT, future RCTs investigating correlations between RTT genotype and phenotypic improvements by trofinetide will be beneficial. RCTs encompassing male patients with larger and longer cohorts are recommended.Graphical

Safety and efficacy of trofinetide in Rett syndrome: a systematic review and meta-analysis of randomized controlled trials

IntroductionRett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and stereotypic hand movements. Given the limited treatment options for Rett syndrome, there is a dire need for effective interventions.ObjectiveTo evaluate the safety and efficacy of trofinetide in Randomized Controlled Trials (RCTs) that report on Rett syndrome patients.MethodsWe identified 109 articles from four databases (Scopus, PubMed, Web of Science, and Cochrane CENTRAL). After removing the duplicates, we narrowed them down to 59 articles for further assessment. We included RCTs that evaluated the efficacy and safety of trofinetide in patients with Rett syndrome. Three studies were eligible for inclusion. Two independent reviewers evaluated the identified studies’ titles, abstracts, and full texts, extracting pertinent data. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) 2.0 tool. We then conducted a meta-analysis using the fixed effects model in the case of insignificant heterogeneity; otherwise, we used the random effects model. Based on the nature of the outcome, we analyzed the mean difference or the odds ratio. Analysis was conducted using RevMan version 5.3.ResultsAmong the analyzed outcomes in 181 patients in the trofinetide group and 134 patients in the placebo group, significant improvement in Rett Syndrome Behavior Questionnaire (RSBQ) scores was observed at 200 mg dosage (overall mean difference: -3.53, p = 0.001). Clinical Global Impression-Improvement (CGI-I) scores improved considerably at 200 mg dosage (overall mean difference: -0.34, p < 0.0001). No substantial changes were observed in Motor Behavioral Assessment (MBA) or Top 3 Caregiver Concerns. We evaluated Treatment Emergent Adverse Events (TEAEs) across the various dosages and noted significant associations with diarrhea (200 mg), vomiting (200 mg), and irritability (200 mg). However, we did not find a significant association between any of the dosages and the incidence of decreased appetite.ConclusionTrofinetide demonstrated potential in improving RSBQ and CGI-I scores at 200 mg dosage. Although no substantial changes were found in MBA and top 3 caregiver concerns. Adverse events were linked to specific dosages.

Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS).

Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed.

Circadian aspects of mobility-related behavior in patients with dementia: An exploratory analysis in acute geriatric psychiatry.

Analyzing patients' mobility-related behavior may improve the assessment of motor behavior in dementia, however, few studies addressed circadian aspects of mobility. This cross-sectional explorative study analyzed the timing of peak mobility-related behavior, the prevalence of mobility-related sundowning and nocturnal mobility-related behavior and associated clinical characteristics in acute geriatric psychiatry. Mobility-related behavior of 73 patients (M: 81years) was measured over 48h using lower-back worn hybrid motion sensors. We derived the start of the 30-min period with peak gait activity (highest number of steps) for each day and the number of nocturnal steps taken from 10PM to 7AM. Professional caregiver ratings of the patients' motor behavior were conducted within the Neuropsychiatric Inventory (NPI). The mean start time of peak gait activity was 2:37PM, but large variations in timing were found (range: 3:25AM-9:30PM). Twenty-five patients (34%) were identified as "sundowners". Nocturnal mobility-related behavior was measured in 35 patients (53%), whereas professional caregivers assessed night-time disorders in only 19 patients (26%). Clinical characteristics of "sundowners" were not significantly different from other patients, except for lower doses of antipsychotics as compared to non-sundowners (M:1.6mg/day; p=0.015). The number of nocturnal steps was significantly associated to corresponding NPI ratings (Spearman's rho=0.4; p<0.001). Analyzing the timing of peak gait activity and nocturnal step-count seem to provide clinical applicable information on the circadian aspects of mobility-related behavior in acute geriatric psychiatry. Even though the clinical validity needs to be evaluated, objective information on the individual circadian aspects of mobility-related behavior could help to personalize treatment with benefits for patients and caregivers.

Wearable accelerometers for measuring and monitoring the motor behaviour of infants with brain damage during CareToy-Revised training

BackgroundNowadays, wearable sensors are widely used to quantify physical and motor activity during daily life, and they also represent innovative solutions for healthcare. In the clinical framework, the assessment of motor behaviour is entrusted to clinical scales, but they are dependent on operator experience. Thanks to their intrinsic objectivity, sensor data are extremely useful to provide support to clinicians. Moreover, wearable sensors are user-friendly and compliant to be used in an ecological environment (i.e., at home). This paper aims to propose an innovative approach useful to predict clinical assessment scores of infants’ motor activity.Materials and methodsStarting from data acquired by accelerometers placed on infants’ wrists and trunk during playtime, we exploit the method of functional data analysis to implement new models combining quantitative data and clinical scales. In particular, acceleration data, transformed into activity indexes and combined with baseline clinical data, represent the input dataset for functional linear models.ConclusionsDespite the small number of data samples available, results show correlation between clinical outcome and quantitative predictors, indicating that functional linear models could be able to predict the clinical evaluation. Future works will focus on a more refined and robust application of the proposed method, based on the acquisition of more data for validating the presented models.Trial registration number: ClincalTrials.gov; NCT03211533. Registered: July, 7th 2017. ClincalTrials.gov; NCT03234959. Registered: August, 1st 2017.

Anthropometric Measures Correspond with Functional Motor Outcomes in Females with Rett Syndrome

To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

Multifactorial Assessment of Motor Behavior in Rats after Unilateral Sciatic Nerve Crush Injury.

The induction of a peripheral nerve injury is a widely used method in neuroscience for the assessment of repair and pain mechanisms among others. In addition, in the research field of movement disorders, sciatic crush injury has been employed to trigger a dystonia-like phenotype in genetically predisposed DYT-TOR1A rodent models of dystonia. To achieve consistent, reproducible and comparable results after a sciatic nerve crush injury, a standardized method for inducing the nerve crush is essential, in addition to a standardized phenotypical characterization. Attention must be paid not only to the specific assortment of behavioral tests, but also to the technical requirements, the correct execution and consecutive data analysis. This protocol describes in detail how to perform a sciatic nerve crush injury and provides a behavioral test battery for the assessment of motor deficits in rats that includes the open field test, the CatWalk XT gait analysis, the beam walking task, and the ladder rung walking task.

Multifactorial Assessment of Motor Behavior in Rats after Unilateral Sciatic Nerve Crush Injury

The induction of a peripheral nerve injury is a widely used method in neuroscience for the assessment of repair and pain mechanisms among others. In addition, in the research field of movement disorders, sciatic crush injury has been employed to trigger a dystonia-like phenotype in genetically predisposed DYT-TOR1A rodent models of dystonia. To achieve consistent, reproducible and comparable results after a sciatic nerve crush injury, a standardized method for inducing the nerve crush is essential, in addition to a standardized phenotypical characterization. Attention must be paid not only to the specific assortment of behavioral tests, but also to the technical requirements, the correct execution and consecutive data analysis. This protocol describes in detail how to perform a sciatic nerve crush injury and provides a behavioral test battery for the assessment of motor deficits in rats that includes the open field test, the CatWalk XT gait analysis, the beam walking task, and the ladder rung walking task.

EFFECTS OF INFUSION OF DENTAL PULP-DERIVED MESENCHYMAL STEM CELLS INDUCED AND NOT INDUCED TO NEURONAL DIFFERENTIATION IN AN ANIMAL MODEL OF PARKINSON‘S DISEASE

<h3>Background</h3> Parkinson‘s disease (PD) is a chronic neurodegenerative disease that typically affects dopaminergic neurons in the substantia nigra pars compacta (SNpc). Current therapy has several adverse effects, reinforcing the search for adjuvant therapeutic protocols such as stem cells. The use of mesenchymal stem cells (MSC) can promote a neuroprotective effect. However, information regarding their effectiveness and mechanisms of action in PD are lacking. Dental pulp stem cells (DPSC) have the potential to differentiate into neurons, expressing the genes of this cell type. This study aimed to evaluate the effects of infusion of induced and non-induced DPSC on neuronal differentiation in an animal model of PD induced by 6-hydroxydopamine (6-OHDA). <h3>Methods</h3> Third molars were collected, and DPSC were isolated and characterized according to the International Society for Cellular Therapy (ISCT). DPSC were induced to neuronal differentiation for 21 days. The differentiation potential was evaluated by immunofluorescence and immunophenotyping. For the animal model of PD, 6-OHDA (3µ in saline with 0.2% ascorbic acid) or saline with 0.2% ascorbic acid (1uL) was infused in the medial prosencephalic bundle of male Wistar rats (280-330g) to generate a retrograde lesion in the SNpc. The following groups were performed: SHAM, 6-OHDA+saline, 6-OHDA+DPSC, and 6-OHDA+DPSC induced to neuronal differentiation. After seven days, 100,000 cells were transplanted into the SNpc. An open field test was performed for the motor behavioral assessment. <h3>Results</h3> DPSC showed MSC characteristics according to an ISCT. The DPSC showed an immunophenotypic profile like neural stem cells regarding neuronal markers. After differentiation, there was an increase in the expression of βIII-tubulin (<i>p</i><0.0001) and Nestin (<i>p</i>=0.0188) when compared to the control. The motor behavioral evaluation showed a statistically significant reduction in the animals‘ total locomotor activity time after the 6-OHDA infusion (<i>p</i><0.05). After infusion of differentiated and non-differentiated DPSC in SNpc, it was possible to observe an improvement in locomotor activity time compared to OHDA+saline group. <h3>Conclusion</h3> The animal model used showed significant motor impairment, which is characteristic of PD, and the infusion of induced and non-induced DPSC to neuronal differentiation proved to be efficient in reversing this impairment, demonstrating to be a promising strategy for the treatment of PD.

Associations between worse executive control and greater fall risk in Geriatric Major Depressive Disorder

<h3>Introduction</h3> Psychomotor disturbances (e.g. psychomotor retardation/agitation) are a core feature of major depressive disorder (MDD) and when present, predict poor treatment outcomes. Psychomotor impairment in late life MDD (LLD) reflect deficits in motor and sensorimotor function, which impair balance control in older adults (OAs). When compared to healthy OAs, those with LLD are ∼35% more likely to fall, develop a fear of falling, and avoid physical activity, all of which predict early mortality. OAs who fall lose their independence and have a worse quality of life, and the rate of deaths from falls is rising. The association between LLD and fall-risk is complicated by pharmacologic treatments that intensify fall-risk; anti-depressants decrease walking speed and increase fall-risk equivalent to antipsychotic and benzodiazepine medications. A poor understanding of <i>when, why, and how</i>falls occur in LLD has led to a knowledge gap regarding relationships between psychomotor disturbance, LLD and fall-risk. Complicating matters, roughly 40% of patients with LLD suffer from cognitive difficulty called cognitive control deficits (CCD) that predispose them to poor clinical outcomes like disability, SSRI treatment resistance, relapse, and suicide. Converging evidence suggests a common neurobiological etiology underlie LLD, CCD and fall-risk. OAs with CCD are three times more likely to fall than their healthy peers and are more susceptible to recurrent falls. OAs with CCD are more likely to exhibit worse health outcomes and mobility deficits suggesting greater fall-risk. The co-occurrence and clinical relevance of these phenomena provides a unique opportunity for investigation. The purpose of this study was to quantify associations between CCD and fall-risk in treatment resistant LLD. Our hypothesis was LLD patients who fail to respond to treatment with SSRI/SNRI would be more likely to exhibit CCD, which would be negatively associated with fall history. <h3>Methods</h3> Participants were aged ≥ 65 years and met DSM-IV-TR/Research Diagnostic criteria for unipolar MDD (Hamilton Depression Rating Scale (HDRS)>19) in an interview with a licensed clinician (SM) despite treatment with SSRI/SNRI antidepressants for ≥8 weeks. Data collection was part of screening for a larger intervention study at Weill Cornell Medical College. Exclusion criteria included: No diagnosis or evidence of dementing disorder (Mini-Mental State Examination (MMSE) score <25), reporting psychotic features/disorders or acute suicidal ideation, severe medical illness, or neurological disorders. Fall history was determined with a brief survey. Participants completed a neuropsychological battery including the Trail Making Test; a test of cognitive flexibility that is associated with fall risk in OA. Participants who reported a fall one or more times in the preceding year were classified as a ‘faller', those that had not fallen were ‘non-fallers'. Group differences (fallers, non-fallers) in CCD were compared with independent t-tests. Logistic regression predicted fall status with CCD performance outcomes, while controlling for gender. <h3>Results</h3> A total of 30 OA participants with MDD were included in the analysis. Approximately 1/3 of our OA participants with MDD reported falling within the last year (<i>n</i> = 9). Fallers exhibited significantly poorer cognitive control as determined by TMT B and D TMT (both <i>p <</i> 0.001). Logistic regression including gender as a covariate showed D TMT significantly predicted fall status, Gender ß = -0.014, <i>p</i> = 0.918, and Faller status: ß = 0.746, <i>p</i> < 0.001. <h3>Conclusions</h3> The purpose of this study was to estimate the risk of falling in treatment resistant LLD and examine the relationship between CCD and fall risk in depressed OA. Our results demonstrate that in treatment resistant LLD, patients on adequate dosages of SSRI/SNRI antidepressants, roughly one third of patients have fallen within the last year, and that CCD may have a strong independent influence on rates of falling. This rate of falls is consistent with existing reports of fall-risk in community dwelling OAs and OAs with MDD. Our preliminary results suggest that CCD is an important factor that catalyzes fall-risk in LLD, and highlight yet another vulnerability of treatment resistant LLD patients. Though this is a preliminary retrospective study, our results suggest that clinicians may improve prediction of fall risk in LLD patients by assessing CCD, with a short, paper-pencil test that can be administered bedside. Given the new NIMH mandate to quantify features of sensorimotor function across psychiatric conditions, we propose that future investigations of LLD include objective, dimensional, large-scale assessment of motor behavior that can be integrated with other objective assessments (e.g. cognitive, functional, affective). If the associations between CCD and falls prove robust in LLD patients, CCD could serve as an intervention target to reduce fall-risk, depression, and other related negative clinical sequalae. <h3>Funding</h3> Morimoto: K 23 MH 095830, UL1TR000457 Alexopolous: R01 MH065653, P50 MH113838

Variability of the Motor Behavior during Continued Practice of the Same Motor Game: A Preliminary Study

Motor behavior assessment during games could help physical education teachers and team coaches to design effective and efficient motor interventions. This study aimed to assess the variability of the physical and behavioral responses during continued practice of the game tail tag with a ball. Sixteen Spanish youth soccer players from an under-14 team played tail tag, with a ball, during four sessions (5 repetitions of 1 min per session). Physical (i.e., Total Distance (TD) and PlayerLoad (PL)) and behavioral (i.e., Surface Area (SA) and change in the Geometrical Centre position (cGCp)) dimensions were assessed with a local positioning system. The mean of the five series of each session was considered for further statistical analysis. The main finding was that the external load decreased (d = small − large) and the use of space varied during the continued practice of tail tag. Initially, SA increased substantially (d = large) and cGCp decreased slightly (d = small), and then both variables tended to stabilize. This suggests that after several repetitions of the same motor game, physical education teachers and team sports coaches should use this again later, modifying this or proposing new motor games where players respond to these activities that consist in greater uncertainty than to well-known motor games.

A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials.

Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females. Recent work indicates the potential for disease modifying therapies. However, there remains a need to develop outcome measures for use in clinical trials. Using data from a natural history study (n = 1,075), we examined the factor structure, internal consistency, and validity of the clinician-reported Motor Behavior Assessment scale (MBA). The analysis resulted in a five-factor model: (1) motor dysfunction, (2) functional skills, (3) social skills, (4) aberrant behavior, and (5) respiratory behaviors. Item Response Theory (IRT) analyses demonstrated that all items had acceptable discrimination. The revised MBA subscales showed a positive relationship with parent reported items, age, and a commonly used measure of clinical severity in RTT, and mutation type. Further work is needed to evaluate this measure longitudinally and to add items related to the RTT phenotype.

Protective role of mirtazapine in adult female Mecp2+/\u2212 mice and patients with Rett syndrome

BackgroundRett syndrome (RTT), an X-linked neurodevelopmental rare disease mainly caused by MECP2-gene mutations, is a prototypic intellectual disability disorder. Reversibility of RTT-like phenotypes in an adult mouse model lacking the Mecp2-gene has given hope of treating the disease at any age. However, adult RTT patients still urge for new treatments. Given the relationship between RTT and monoamine deficiency, we investigated mirtazapine (MTZ), a noradrenergic and specific-serotonergic antidepressant, as a potential treatment.MethodsAdult heterozygous-Mecp2 (HET) female mice (6-months old) were treated for 30 days with 10 mg/kg MTZ and assessed for general health, motor skills, motor learning, and anxiety. Motor cortex, somatosensory cortex, and amygdala were analyzed for parvalbumin expression. Eighty RTT adult female patients harboring a pathogenic MECP2 mutation were randomly assigned to treatment to MTZ for insomnia and mood disorders (mean age = 23.1 ± 7.5 years, range = 16–47 years; mean MTZ-treatment duration = 1.64 ± 1.0 years, range = 0.08–5.0 years). Rett clinical severity scale (RCSS) and motor behavior assessment scale (MBAS) were retrospectively analyzed.ResultsIn HET mice, MTZ preserved motor learning from deterioration and normalized parvalbumin levels in the primary motor cortex. Moreover, MTZ rescued the aberrant open-arm preference behavior observed in HET mice in the elevated plus-maze (EPM) and normalized parvalbumin expression in the barrel cortex. Since whisker clipping also abolished the EPM-related phenotype, we propose it is due to sensory hypersensitivity. In patients, MTZ slowed disease progression or induced significant improvements for 10/16 MBAS-items of the M1 social behavior area: 4/7 items of the M2 oro-facial/respiratory area and 8/14 items of the M3 motor/physical signs area.ConclusionsThis study provides the first evidence that long-term treatment of adult female heterozygous Mecp2tm1.1Bird mice and adult Rett patients with the antidepressant mirtazapine is well tolerated and that it protects from disease progression and improves motor, sensory, and behavioral symptoms.

Discovery of Novel Procaine‐Imidazole Derivative as Inhibitor of Monoamine Oxidase‐B for Potential Benefit in Parkinson's Disease

AbstractThe clinically utility of selective monoamine oxidase (MAO)‐B inhibitors in Parkinson disease is widely recognized due to significant improvement in altered motor function and long‐term benefit. Therefore, in the present study, a series of procaine‐imidazole was synthesized and subsequently evaluated for MAO‐A and MAO‐B inhibitory activity in an enzymatic assay. Comparative inhibitory activity suggest that, target compounds selectively inhibit MAO‐B, as compared to MAO‐A. Among the tested derivatives, compound 8 i (2‐(diethylamino)ethyl4‐(4‐(4‐fluorophenyl)‐2‐(4‐hydroxyphenyl)‐1H‐imidazol‐1‐yl)benzoate) selectively inhibited MAO‐B with IC50 of 0.032±0.002 (selectivity index over MAO‐A=475). The anti‐Parkinson effect of compound 8 i was further evaluated in MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) induced animal model of PD. It has been found that, compound 8 i causes significant improvement in motor function of mice as revealed by motor behavioral assessment using the footprint and horizontal wire test. Compound 8 i also improved the level of anti‐oxidant enzymes in the striatum of animal brains. Our study demonstrated the development of procaine‐imidazole derivatives as potent and selective MAO‐B inhibitor as potential agent against PD.

Brain tissue volumes at term-equivalent age are associated with early motor behavior in very preterm infants.

Preterm birth is associated with a wide range of adverse developmental outcomes, including sensory, motor, cognitive and language impairments, and behavioral or attention problems. Subtle motor deficits that might emerge in premature infants with no evident or with mild brain injury encompass qualitative and quantitative aspects of motor behavior. This prospective cohort study provided an evaluation of the relationship between brain tissue volumes revealed by magnetic resonance imaging (MRI) at term-equivalent age and motor behavior in infancy in very preterm infants (total number=40; mean gestational age=28weeks+4days; mean birth weight=1190g) without evident or with mild brain injury. Infants were recruited at birth and assessed at 12months corrected age using the tool for qualitative and quantitative assessment of motor behavior, infant motor profile. The brain tissue was segmented first using advanced segmentation techniques and the volumes were measured by summing the volumes of all voxels belonging to a particular tissue class. The associations between volumetric brain MRI measures with motor behavior were explored using linear regression analyses. Results showed that larger total brain volumes were associated with higher motor score. Similar relationships were documented for parietal lobe, deep gray matter, and cerebellum volumes. Volumetric quantitative data of brain structures may serve as biomarkers for subtle motor deficits described in very preterm born infants without or with mild brain lesions apparent on MRI.

Assessment of bilateral motor skills and visuospatial attention in children with perinatal stroke using a robotic object hitting task

BackgroundWhile motor deficits are the hallmark of hemiparetic cerebral palsy, children may also experience impairments in visuospatial attention that interfere with participation in complex activities, including sports or driving. In this study, we used a robotic object hitting task to assess bilateral sensorimotor control and visuospatial skills in children with hemiparesis due to perinatal arterial ischemic stroke (AIS) or periventricular venous infarct (PVI). We hypothesized that performance would be impaired bilaterally and be related to motor behavior and clinical assessment of visuospatial attention.MethodsForty-nine children with perinatal stroke and hemiparetic cerebral palsy and 155 typically developing (TD) children participated in the study. Participants performed a bilateral object hitting task using the KINARM Exoskeleton Robot, in which they used virtual paddles at their fingertips to hit balls that fell from the top of the screen with increasing speed and frequency over 2.3 min. We quantified performance across 13 parameters including number of balls hit with each hand, movement speed and area, biases between hands, and spatial biases. We determined normative ranges of performance accounting for age by fitting 95% prediction bands to the TD children. We compared parameters between TD, AIS, and PVI groups using ANCOVAs accounting for age effects. Lastly, we performed regression analysis between robotic and clinical measures.ResultsThe majority of children with perinatal stroke hit fewer balls with their affected arm compared to their typically developing peers. We also found deficits with the ipsilesional (“unaffected”) arm. Children with AIS had greater impairments than PVI. Despite hitting fewer balls, we only identified 18% of children as impaired in hand speed or movement area. Performance on the Behavioral Inattention Test accounted for 21–32% of the variance in number of balls hit with the unaffected hand.ConclusionsChildren with perinatal stroke-induced hemiparetic cerebral palsy may have complex bilateral deficits reflecting a combination of impairments in motor skill and visuospatial attention. Clinical assessments and interventions should address the interplay between motor and visuospatial skills.

Multifactorial motor behavior assessment for real-time evaluation of emerging therapeutics to treat neurologic impairments

Integrating multiple assessment parameters of motor behavior is critical for understanding neural activity dynamics during motor control in both intact and dysfunctional nervous systems. Here, we described a novel approach (termed Multifactorial Behavioral Assessment (MfBA)) to integrate, in real-time, electrophysiological and biomechanical properties of rodent spinal sensorimotor network activity with behavioral aspects of motor task performance. Specifically, the MfBA simultaneously records limb kinematics, multi-directional forces and electrophysiological metrics, such as high-fidelity chronic intramuscular electromyography synchronized in time to spinal stimulation in order to characterize spinal cord functional motor evoked potentials (fMEPs). Additionally, we designed the MfBA to incorporate a body weight support system to allow bipedal and quadrupedal stepping on a treadmill and in an open field environment to assess function in rodent models of neurologic disorders that impact motor activity. This novel approach was validated using, a neurologically intact cohort, a cohort with unilateral Parkinsonian motor deficits due to midbrain lesioning, and a cohort with complete hind limb paralysis due to T8 spinal cord transection. In the SCI cohort, lumbosacral epidural electrical stimulation (EES) was applied, with and without administration of the serotonergic agonist Quipazine, to enable hind limb motor functions following paralysis. The results presented herein demonstrate the MfBA is capable of integrating multiple metrics of motor activity in order to characterize relationships between EES inputs that modulate mono- and polysynaptic outputs from spinal circuitry which in turn, can be used to elucidate underlying electrophysiologic mechanisms of motor behavior. These results also demonstrate that proposed MfBA is an effective tool to integrate biomechanical and electrophysiology metrics, synchronized to therapeutic inputs such as EES or pharmacology, during body weight supported treadmill or open field motor activities, to target a high range of variations in motor behavior as a result of neurological deficit at the different levels of CNS.

Target-Specific Action Classification for Automated Assessment of Human Motor Behavior from Video.

Objective monitoring and assessment of human motor behavior can improve the diagnosis and management of several medical conditions. Over the past decade, significant advances have been made in the use of wearable technology for continuously monitoring human motor behavior in free-living conditions. However, wearable technology remains ill-suited for applications which require monitoring and interpretation of complex motor behaviors (e.g., involving interactions with the environment). Recent advances in computer vision and deep learning have opened up new possibilities for extracting information from video recordings. In this paper, we present a hierarchical vision-based behavior phenotyping method for classification of basic human actions in video recordings performed using a single RGB camera. Our method addresses challenges associated with tracking multiple human actors and classification of actions in videos recorded in changing environments with different fields of view. We implement a cascaded pose tracker that uses temporal relationships between detections for short-term tracking and appearance based tracklet fusion for long-term tracking. Furthermore, for action classification, we use pose evolution maps derived from the cascaded pose tracker as low-dimensional and interpretable representations of the movement sequences for training a convolutional neural network. The cascaded pose tracker achieves an average accuracy of 88% in tracking the target human actor in our video recordings, and overall system achieves average test accuracy of 84% for target-specific action classification in untrimmed video recordings.

Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome.

Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2. We additionally compare the phenotype of this cohort (n = 48) to other reported cohorts with MDS. Utilizing existing indices of clinical severity in Rett syndrome, we found that larger duplication size correlates with higher severity in total clinical severity scores (r = 0.36; P = 0.02), and in total motor behavioral assessment inventory scores (r = 0.31; P = 0.05). Greater severity was associated with having the RAB39B gene duplicated, although most of these participants also had large duplications. Results suggest that developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism are common in MDS. This is the first study to show that duplication size is related to clinical severity. Future studies should examine whether large duplications which do not encompass RAB39B also contribute to clinical severity. Results also suggest the need for creating an MDS specific severity scale.