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Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22–1·10]; d=0·46 [0·16–0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Background Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost‐effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. Methods A trial‐based cost–utility analysis over a 9‐month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality‐adjusted life years (QALYs) were computed using health utilities generated from the EQ‐5D‐5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. Results Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ‐5D‐5L were not statistically significantly different between the two arms. The incremental cost‐effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life‐Revised (MQOL‐R) questionnaire. The intervention was cost‐effective in a subgroup experiencing medium deterioration in motor neuron symptoms. Conclusions Despite the intervention being cost‐ineffective in the primary analysis, the significant difference in the effects measured by MQOL‐R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

BackgroundChildren with developmental coordination disorder (DCD) show improved motor function after Cognitive Orientation to Occupational Performance (CO-OP) intervention; however, the neural basis for these improvements is unknown.MethodsIn this randomized waitlist-controlled trial, 78 children with DCD (with/without ADHD) were randomly assigned to either a treatment or waitlist group and underwent three resting-state MRI scans over six months. The treatment group received intervention between the first and second scan; the waitlist group received intervention between the second and third scan.ResultsAfter CO-OP intervention, children with DCD [13 male, 8 female; mean (SD) age: 10.0 (1.7) years] showed increased functional connectivity between the default mode network and right anterior cingulate gyrus (p < 0.01). Additional gains were noted at follow-up three months after the intervention, with greater functional connectivity between the dorsal attention network and precentral gyrus (p < 0.02). However, children with DCD + ADHD [18 male, 1 female; mean (SD) age: 10.0 (1.14) years] did not show brain changes following CO-OP.ConclusionFor children with DCD, increased functional connectivity in networks associated with self-, emotion-, and attention-regulation may underlie motor skill improvements observed after CO-OP intervention. Modifications to the CO-OP protocol may be required to induce similar brain changes in children with DCD + ADHD.ImpactThis study provides neuroscientific evidence for the Cognitive Orientation to Occupational Performance (CO-OP) approach as an effective rehabilitation intervention to induce brain and behavioral changes in children with DCD.While children with DCD ± ADHD showed improved motor function after CO-OP, only children with DCD showed brain changes after intervention.Children with DCD showed increased functional connectivity in networks associated with self-, emotion-, and attention-regulation after the intervention.Treatment modifications may be required to induce similar brain changes in children with DCD + ADHD.Pediatricians are encouraged to refer children with DCD  with and without ADHD for CO-OP intervention to improve their motor skills.

Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder with limited treatment options. Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. The Motor Neuron Disease–Systematic Multi-Arm Randomised Adaptive Trial (MND–SMART) seeks to identify effective disease modifying drugs. This study investigates person-specific factors affecting recruitment and retention. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. Participants with MND completed questionnaires and this was supplemented with clinical data. 12 months after completing the questionnaires we used MND–SMART recruitment data to establish if members of our cohort engaged with the trial. 120 people with MND completed questionnaires for this study. Mean age at participation was 66 (SD = 9), 14% ( n =  17) were categorised as long survivors, with 68% ( n =  81) of participants male and 60% ( n =  73) had the ALS sub-type. Of the 120 study participants, 50% ( n =  60) were randomised into MND–SMART and 78% ( n =  94) expressed interest an in participating. After the 1-year follow-up period 65% ( n =  39) of the 60 randomised participants remained in MND–SMART. Older age was significantly associated with reduced likelihood of participation (OR = 0.92, 95% CI = 0.88–0.96, p =  0.000488). The findings show that people with MND are highly motivated to engage in research, but older individuals remain significantly less likely to participate. We recommend the inclusion of studies to explore characteristics of prospective and current participants alongside trials.

Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease. Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease. We did an investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 clinical trial at four tertiary motor neuron disease centres in Italy. Eligible patients were aged 18–80 years; had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria, or primary lateral sclerosis according to Pringle's criteria; had spasticity symptoms due to motor neuron disease for at least 3 months; had spasticity scores of 1 or greater in at least two muscle groups on the Modified Ashworth Scale; and were taking an antispasticity regimen that was maintained at a stable dose for 30 days before enrolment. Participants were assigned (1:1) by an independent statistician via a computer-generated randomisation sequence to a standardised oromucosal spray (nabiximols) containing a defined combination of delta-9-tetrahydrocannabinol and cannabidiol (each 100 μL actuation contained 2·7 mg delta-9-tetrahydrocannabinol and 2·5 mg cannabidiol) or to placebo for 6 weeks. Participants self-titrated during the first 14 treatment days according to a predefined escalation scheme (maximum 12 actuations per 24 h), then maintained that dose for 4 weeks. The primary endpoint was the change in the score on the Modified Ashworth Scale, which was assessed at baseline and after 6 weeks. Safety and tolerability were also monitored. Participants, investigators, site personnel, and the study statistician were masked to treatment allocation. All randomised participants who received at least one dose of study drug were included in the analysis. This trial is registered with ClinicalTrials.gov, number NCT01776970. The trial is closed to new participants with follow-up completed. Between Jan 19, 2013, and Dec 15, 2014, 60 participants were randomly assigned, and 59 participants were included in the final analysis (29 in the nabiximols group and 30 in the placebo group). Modified Ashworth Scale scores improved by a mean of 0·11 (SD 0·48) in the nabiximols group and deteriorated by a mean of 0·16 (0·47) in the placebo group (adjusted effect estimate −0·32 [95% CI −0·57 to −0·069]; p=0·013). Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred. In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile. These findings should be investigated further in larger clinical trials. Italian Research Foundation for Amyotrophic Lateral Sclerosis.

Background We are undertaking a multicentre randomised controlled trial to determine the effectiveness of including a sleep study (polysomnography (PSG)) to assist the commencement of non-invasive ventilation (NIV) in people with motor neurone disease (MND): the Polysomnographic titration of non-invasive ventilation in motor neurone disease (PSG4NIVinMND; 3-three letter acronym ; 3TLA ) trial. A process evaluation will be conducted alongside the clinical trial to understand: (1) the implementation of the 3TLA intervention in the trial sites, including barriers and enablers, and (2) the mechanisms through which the 3TLA intervention produces change. This protocol paper describes the rationale, aims and methods of the 3TLA process evaluation. Methods To guide the design of the process evaluation, a logic model representing the 3TLA intervention, the likely mechanisms of impact, potential external contextual factors and assumptions, and the anticipated outcomes was developed by the researchers in collaboration with the 3TLA Trial Steering Committee. From this, five key process evaluation research questions were identified, a priori. The mixed-methods design is guided by three implementation frameworks: the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework, the Theoretical Domains Framework (TDF), and the Theoretical Framework of Acceptability (TFA). We will conduct semi-structured interviews with approximately 20–30 clinical trial participants (people with MND) and their carers, and focus groups and surveys with approximately 60 health professionals involved in delivering the intervention at each site. Quantitative process data will also be collected from the main clinical trial. Qualitative and quantitative data will be analysed iteratively throughout the trial, independent of the main trial outcome analyses. Process evaluation findings will be triangulated with the results of the clinical trial. Discussion This process evaluation incorporates a mixed-methods design and is informed by three theoretical frameworks. It will provide insights into how the 3TLA intervention was implemented, for whom and how the 3TLA intervention was (and was not) effective, and what adaptations may be needed to facilitate future implementation into routine clinical practice. Trial registration ClinicalTrials.gov NCT05136222. Registered on November 25, 2021.

Background: Deficiencies in oral motor function and feeding skills are common in children with cerebral palsy (CP). Oral motor therapy is a useful method to improve oral motor function and feeding skills. Oral motor facilitation technique (OMFT) is a newly designed comprehensive oral motor therapy, including postural control, sensory adaptation, breathing control, sensorimotor facilitation, and direct feeding. Methods: This study was performed to identify the effect of OMFT on oral motor function and feeding skills in children with CP. A total of 21 children with CP (3–10 years, GMFCS III–V) participated in 16 weeks (16 sessions) of OMFT. The effects on oral motor function and feeding skills were assessed using the Oral Motor Assessment Scale (OMAS) before the treatment, 8 and 16 weeks after OMFT. Data were analyzed using the Friedman test and post-hoc analysis. Results: Significant improvement was found in oral motor function and feeding skills including mouth closure, lip closure on the utensil, lip closure during deglutition, control of the food during swallowing, mastication, straw suction, and control of liquid during deglutition after OMFT. Mouth closure was the most effective and mastication was the least effective item. Sixteen weeks is more effective than 8 weeks of OMFT. Conclusion: OMFT could be an effective and useful oral motor therapy protocol to improve oral motor function and feeding skills in children with CP.

Sensory organisation of balance control is compromised in children with developmental coordination disorder (DCD). A randomised controlled trial involving 88 children with DCD was conducted to evaluate the efficacy of a task-specific balance training (functional-movement training, FMT) programme in improving balance deficits in a DCD population. The DCD participants were randomly assigned to either a FMT group or a control group. The FMT group received two training sessions/ week for 3 months. Measurements of the participants’ sensory organisation (somatosensory, vestibular and visual ratios), balance and motor proficiency (Movement Assessment Battery for Children, MABC scores) and center of pressure sway velocity (Unilateral Stance Test, UST scores) were taken at baseline, immediately after FMT and 3 months after FMT. The FMT group showed greater improvements than the controls in somatosensory ratio at 3 and 6 months (all P < 0.001), but the within-group changes were not significant (P > 0.05). The results of both the MABC and the UST also indicated that the balance performance of the FMT group was significantly better than that of the control group at 3 and 6 months (all P < 0.05). Task-specific balance training was found to marginally improve the somatosensory function and somewhat improve the balance performance of children with DCD.

The aim of this study was to integrate a gaze training intervention (i.e., quiet eye training; QET) that has been shown to improve the throwing and catching skill of children with Developmental Coordination Disorder (DCD), within an approach (i.e., group therapy) that might alleviate the negative psychosocial impact of these motor skill deficits. Twenty-one children with DCD were split into either QET (8 male 3 female, mean age of 8.6 years (SD = 1.04) or technical training (TT) groups (7 male 3 female, mean age of 8.6 years (SD = 1.84). The TT group were given movement-related instructions via video, relating to the throw and catch phases, while the QET group were also taught to fixate a target location on the wall prior to the throw (QE1) and to track the ball prior to the catch (QE2). Each group partook in a 4-week, group therapy intervention and measurements of QE duration and catching performance were taken before and after training, and at a 6-week delayed retention test. Parental feedback on psychosocial and motor skill outcomes was provided at delayed retention. Children improved their gaze control and catching coordination following QET, compared to TT. Mediation analysis showed that a longer QE aiming duration (QE1) predicted an earlier onset of tracking the ball prior to catching (QE2) which predicted catching success. Parents reported enhanced perceptions of their child's catching ability and general coordination in the QET group compared to the TT group. All parents reported improvements in their child's confidence, social skills and predilection for physical activity following the trial. The findings offer initial support for an intervention that practitioners could apply to address deficits in the motor and psychosocial skills of children with DCD. ClinicalTrials.gov NCT02904980.