High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

Actual and imagined music-cued gait training for people with multiple sclerosis: a multicentre qualitative study.

OBJECTIVES: To explore the experiences and acceptability of music-cued motor imagery (MCMI), music-cued gait training (MCGT), and combined MCMI and MCGT (MCMI-MCGT) in people with multiple sclerosis (pwMS). We also aimed to explore participants' self-rated health status postintervention and gather recommendations for further programme development. DESIGN: Qualitative study alongside the double-blind randomised controlled real and imagined gait training with music-cueing (RIGMUC) multicentre trial of MCMI, MCGT and MCMI-MCGT. SETTING: PwMS recruited for the RIGMUC trial from Departments of Neurology at Medical Universities of Innsbruck and Graz and Clinic for Rehabilitation Muenster, Austria. PARTICIPANTS: All 132 pwMS with mild to moderate disability randomised into the trial were included in the analysis. METHODS: Participants practised home-based MCMI, MCGT or MCMI-MCGT for 30 min, 4×/week, for 4 weeks. Three trained researchers conducted weekly semistructured telephone interviews during the intervention period, supporting adherence, addressing problems, sharing experiences and assessing intervention acceptability. Follow-up interviews at 4-week postintervention aimed to understand participants' self-rated changes in walking, fatigue and overall health compared with their prestudy condition. Investigator triangulation was employed among the researchers to enhance trustworthiness and credibility. RESULTS: Using thematic analysis, we identified five themes: (1) empowerment, (2) remaining in sync, (3) interconnection between imagined and actual walking, (4) sustaining focus and (5) real-world transfer. Participants appreciated and found the imagined and actual MCGT innovative. Problems included concentration issues, early fatigue in advanced disability and difficulty synchronising with music cues. Positive changes in walking, fatigue and overall health postinterventions were reported offering valuable insights for programme development. CONCLUSIONS: A participatory study to codevelop a music-cued exercise programme for pwMS seems appropriate as participants appreciated the innovation and effectiveness of both imagined and actual MCGT. Future studies should also investigate pwMS' potential and limitations in enhancing their MCMI abilities with intensive therapist-supported practice. TRIAL REGISTRATION NUMBER: DRKS00023978.

Evaluation of the T25FW in minimally disabled people with multiple sclerosis.

BACKGROUND: Walking impairment is one of the most prevalent symptoms in people with multiple sclerosis (pwMS). In this study, we aimed to explore the usefulness of a simple walking test, the Timed 25 Foot Walk (T25FW), in detecting subtle differences in "fully ambulatory" pwMS compared to HC. METHODS: We therefore investigated retrospective data from a clinical real-life cohort of 650 pwMS. We first analyzed the amount of patients showing clinically relevant impairment in the T25FW (T25FW > 6 s) within different levels of disability according to the Expanded Disability Status Scale (EDSS). For detailed analysis in "fully ambulatory" pwMS, we formed four groups according to the respective levels of disability (EDSS 0, EDSS 1, EDSS 1.5-2, EDSS 2.5-3), and compared their walking speed to age- and sex-matched healthy controls (HC). RESULTS: In our cohort, the number of patients showing clinically relevant slowing in the T25FW ranged from 15% in "fully ambulatory" patients (EDSS 0-3) to 69% in patients with moderate (EDSS 3.5-5.5) and 100% in patients with severe impairment (EDSS ≥6). Further analyses in "fully ambulatory" patients revealed that all EDSS-subgroups showed significant slowing compared to HC. The mean difference to walking speed of HC became gradually more pronounced from 0.15 m/s in asymptomatic patients (EDSS 0) to 0.5 m/s in patients with EDSS 2.5-3. CONCLUSION: These findings underline the ability of the T25FW to detect slowing even in patients with minimal disability. While the difference to HC was slightly below clinical relevance in asymptomatic patients (EDSS 0), slowing gradually worsened from EDSS 1 onwards and exceeded published thresholds for clinical meaningfulness.

Actual and Imagined Music-Cued Gait Training in People with Multiple Sclerosis: A Double-Blind Randomized Parallel Multicenter Trial.

BACKGROUND: Actual and imagined cued gait trainings have not been compared in people with multiple sclerosis (MS). OBJECTIVE: To analyze the effects of cued motor imagery (CMI), cued gait training (CGT), and combined CMI and cued gait training (CMI-CGT) on motor, cognitive, and emotional functioning, and health-related quality of life in people with MS. METHODS: In this double-blind randomized parallel-group multicenter trial, people with MS were randomized (1:1:1) to CMI, CMI-CGT, or CGT for 30 minutes, 4×/week for 4 weeks. Patients practiced at home, using recorded instructions, and supported by ≥6 phone calls. Data were collected at weeks 0, 4, and 13. Co-primary outcomes were walking speed and distance, analyzed by intention-to-treat. Secondary outcomes were global cognitive impairment, anxiety, depression, suicidality, fatigue, HRQoL, motor imagery ability, music-induced motivation, pleasure and arousal, self-efficacy, and cognitive function. Adverse events and falls were continuously monitored. RESULTS: Of 1559 screened patients, 132 were randomized: 44 to CMI, 44 to CMI-CGT, and 44 to CGT. None of the interventions demonstrated superiority in influencing walking speed or distance, with negligible effects on walking speed (η2 = 0.019) and distance (η2 = 0.005) observed in the between-group comparison. Improvements in walking speed and walking distance over time corresponded to large effects for CMI, CMI-CGT, and CGT (η2 = 0.348 and η2 = 0.454 respectively). No severe study-related adverse events were reported. CONCLUSIONS: CMI-GT did not lead to improved walking speed and distance compared with CMI and CGT alone in people with MS. Lack of a true control group represents a study limitation. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00023978.

Evaluation of a self-administered iPad®-based processing speed assessment for people with multiple sclerosis in a clinical routine setting.

BACKGROUND: Limited resources often hinder regular cognitive assessment of people with multiple sclerosis (pwMS) in standard clinical care. A self-administered iPad®-based cognitive screening-tool (Processing Speed Test; PST) might mitigate this problem. OBJECTIVE: To evaluate the PST in clinical routine. METHODS: We investigated the feasibility of the PST in both a quiet and a waiting room setting. We assessed the validity of the PST in comparison with the established Symbol Digit Modalities Test (SDMT). We explored associations between processing speed assessments and the Brief International Cognitive Assessment for MS (BICAMS), magnetic resonance imaging (MRI) parameters, and psychological factors. Additionally, we explored the ability of the PST to detect impairment in processing speed compared to the SDMT. RESULTS: The PST was feasible in the waiting room setting. PST and SDMT correlated comparably with the BICAMS, MRI parameters, and psychological variables. Of 172 pwMS, 50 (30.8%) showed cognitive impairment according to the BICAMS; respective values were 47 (27.3%) for the SDMT and 9 (5.2%) for the PST. CONCLUSIONS: The PST performed in a waiting room setting correlates strongly with established cognitive tests. It thus may be used to assess processing speed in a resource-efficient manner and complement cognitive assessment in clinical routine. Despite comparable validity of the PST and SDMT, we identified more pwMS with impaired processing speed using normative data of the SDMT compared to the PST and advise caution, that the common cut-off score of - 1.5 SD from the current PST is not appropriate in Europe.

Psychological factors and brain magnetic resonance imaging metrics associated with fatigue in persons with multiple sclerosis.

BACKGROUND: Besides demographics and clinical factors, psychological variables and brain-tissue changes have been associated with fatigue in persons with multiple sclerosis (pwMS). Identifying predictors of fatigue could help to improve therapeutic approaches for pwMS. Therefore, we investigated predictors of fatigue using a multifactorial approach. METHODS: 136 pwMS and 49 normal controls (NC) underwent clinical, neuropsychological, and magnetic resonance imaging examinations. We assessed fatigue using the "Fatigue Scale for Motor and Cognitive Functions", yielding a total, motor, and cognitive fatigue score. We further analyzed global and subcortical brain volumes, white matter lesions and microstructural changes (examining fractional anisotropy; FA) along the cortico striatal thalamo cortical (CSTC) loop. Potential demographic, clinical, psychological, and magnetic resonance imaging predictors of total, motor, and cognitive fatigue were explored using multifactorial linear regression models. RESULTS: 53% of pwMS and 20% of NC demonstrated fatigue. Besides demographics and clinical data, total fatigue in pwMS was predicted by higher levels of depression and reduced microstructural tissue integrity in the CSTC loop (adjusted R2 = 0.52, p < 0.001). More specifically, motor fatigue was predicted by lower education, female sex, higher physical disability, higher levels of depression, and self-efficacy (adjusted R2 = 0.54, p < 0.001). Cognitive fatigue was also predicted by higher levels of depression and lower self-efficacy, but in addition by FA reductions in the CSTC loop (adjusted R2 = 0.45, p < 0.001). CONCLUSIONS: Our results indicate that depression and self-efficacy strongly predict fatigue in MS. Incremental variance in total and cognitive fatigue was explained by microstructural changes along the CSTC loop, beyond demographics, clinical, and psychological variables.

No common factor for illusory percepts, but a link between pareidolia and delusion tendency: A test of predictive coding theory.

Predictive coding theory is an influential view of perception and cognition. It proposes that subjective experience of the sensory information results from a comparison between the sensory input and the top-down prediction about this input, the latter being critical for shaping the final perceptual outcome. The theory is able to explain a wide range of phenomena extending from sensory experiences such as visual illusions to complex pathological states such as hallucinations and psychosis. In the current study we aimed at testing the proposed connection between different phenomena explained by the predictive coding theory by measuring the manifestation of top-down predictions at progressing levels of complexity, starting from bistable visual illusions (alternating subjective experience of the same sensory input) and pareidolias (alternative meaningful interpretation of the sensory input) to self-reports of hallucinations and delusional ideations in everyday life. Examining the correlation structure of these measures in 82 adult healthy subjects revealed a positive association between pareidolia proneness and a tendency for delusional ideations, yet without any relationship to bistable illusions. These results show that only a subset of the phenomena that are explained by the predictive coding theory can be attributed to one common underlying factor. Our findings thus support the hierarchical view of predictive processing with independent top-down effects at the sensory and cognitive levels.

Information processing speed as a prognostic marker of physical impairment and progression in patients with multiple sclerosis.

BACKGROUND: Prediction of disability progression in patients with MS (pwMS) is challenging. So far, scarce evidence exists suggesting knowledge about how cognitive performance may potentially improve prediction of physical impairment and disability progression in MS. Therefore, we wanted to assess the prognostic value of cognitive performance regarding physical impairment and disability progression in pwMS. METHODS: 85 patients (64% female; 60% relapse-remitting MS; mean age=36.78 ± 9.63 years) underwent clinical, neuropsychological (Brief Repeatable Battery for Neuropsychological Test (BRB-N)) and brain MRI (T1-weighted and T2-weighted FLAIR images) assessment at baseline and after an average of 7 years (SD=3.75) at follow-up. We assessed physical impairment and annualized disability progression (disability progression divided by follow-up duration) using the Expanded Disability Status Scale (EDSS). To compare patients with no or mild physical impairment (EDSS≤2.5) and patients with moderate to severe physical impairment (EDSS≥3.0), we used an EDSS score ≥3.0 as cut-off. Silent progression was defined by an EDSS worsening of at least 0.5 in the absence of relapses and inflammation in relapsing-remitting MS. RESULTS: In hierarchical regression models (method "STEPWISE", forward) performance in information processing speed was a significant and independent predictor of physical impairment (EDSS≥3.0) at follow-up (model R²=0.671, b=-1.46, OR=0.23, p=0.001) and annualized disability progression (adjusted model R²=0.257, ß=-0.26, 95% CI: -0.066, -0.008, p=0.012), in addition to demographics (age, education, individual follow-up time), clinical (EDSS, disease duration, clinical phenotype, annualized-relapse-rate) and MRI measures (brain volumes and T2-lesion load). In a MANCOVA controlled for age, disease duration and individual follow-up time, worse baseline performance in information processing speed was found in patients with higher EDSS at follow-up (m=-1.91, SD=1.18, p<0.001) and silent progression (m=-2.19, SD=1.01, p=0.038). CONCLUSION: Performance in information processing speed might help to identify patients at risk for physical impairment. Therefore, neuropsychological assessment should be integrated in clinical standard care to support disease management in pwMS.

Effects of actual and imagined music-cued gait training on motor functioning and brain activity in people with multiple sclerosis: protocol of a randomised parallel multicentre trial.

INTRODUCTION: Motor imagery (MI) refers to the mental rehearsal of a physical action without muscular activity. Our previous studies showed that MI combined with rhythmic-auditory cues improved walking, fatigue and quality of life (QoL) in people with multiple sclerosis (pwMS). Largest improvements were seen after music and verbally cued MI. It is unclear whether actual cued gait training achieves similar effects on walking as cued MI in pwMS. Furthermore, in pwMS it is unknown whether any of these interventions leads to changes in brain activation. The purpose of this study is therefore to compare the effects of imagined and actual cued gait training and a combination thereof on walking, brain activation patterns, fatigue, cognitive and emotional functioning in pwMS. METHODS AND ANALYSIS: A prospective double-blind randomised parallel multicentre trial will be conducted in 132 pwMS with mild to moderate disability. Randomised into three groups, participants will receive music, metronome and verbal cueing, plus MI of walking (1), MI combined with actual gait training (2) or actual gait training (3) for 30 min, 4× per week for 4 weeks. Supported by weekly phone calls, participants will practise at home, guided by recorded instructions. Primary endpoints will be walking speed (Timed 25-Foot Walk) and distance (2 min Walk Test). Secondary endpoints will be brain activation patterns, fatigue, QoL, MI ability, anxiety, depression, cognitive functioning, music-induced motivation-to-move, pleasure, arousal and self-efficacy. Data will be collected at baseline, postintervention and 3-month follow-up. MRI reference values will be generated using 15 matched healthy controls. ETHICS AND DISSEMINATION: This study follows the Standard Protocol Items: Recommendations for Interventional Trials-PRO Extension. Ethical approval was received from the Ethics Committees of the Medical Universities of Innsbruck (1347/2020) and Graz (33-056 ex 20/21), Austria. Results will be disseminated via national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS00023978.

Programming experience associated with neural efficiency during figural reasoning.

In the present study, we investigated neural processes underlying programming experience. Individuals with high programming experience might develop a form of computational thinking, which they can apply on complex problem-solving tasks such as reasoning tests. Therefore, N = 20 healthy young participants with previous programming experience and N = 21 participants without any programming experience performed three reasoning tests: Figural Inductive Reasoning (FIR), Numerical Inductive Reasoning (NIR), Verbal Deductive Reasoning (VDR). Using multi-channel EEG measurements, task-related changes in alpha and theta power as well as brain connectivity were investigated. Group differences were only observed in the FIR task. Programmers showed an improved performance in the FIR task as compared to non-programmers. Additionally, programmers exhibited a more efficient neural processing when solving FIR tasks, as indicated by lower brain activation and brain connectivity especially in easy tasks. Hence, behavioral and neural measures differed between groups only in tasks that are similar to mental processes required during programming, such as pattern recognition and algorithmic thinking by applying complex rules (FIR), rather than in tasks that require more the application of mathematical operations (NIR) or verbal tasks (VDR). Our results provide new evidence for neural efficiency in individuals with higher programming experience in problem-solving tasks.