Cerebellar Contributions to Motor and Cognitive Control in Multiple Sclerosis✰✰✰.

OBJECTIVE: To evaluate relationships between specific cerebellar regions and common clinical measures of motor and cognitive function in persons with multiple sclerosis (PwMS). DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Twenty-nine PwMS and 28 age- and sex-matched controls without multiple sclerosis (MS) (N=57). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Both diffusion and lobule magnetic resonance imaging analyses and common clinical measures of motor and cognitive function were used to examine structure-function relationships in the cerebellum. RESULTS: PwMS demonstrate significantly worse motor and cognitive function than controls, including weaker strength, slower walking, and poorer performance on the Symbol Digit Modalities Test, but demonstrate no differences in cerebellar volume. However, PwMS demonstrate significantly worse diffusivity (mean diffusivity: P=.0003; axial diffusivity: P=.0015; radial diffusivity: P=.0005; fractional anisotropy: P=.016) of the superior cerebellar peduncle, the primary output of the cerebellum. Increased volume of the motor lobules (I-V, VIII) was significantly related to better motor (P<.022) and cognitive (P=.046) performance, and increased volume of the cognitive lobules (VI-VII) was also related to better motor (P<.032) and cognitive (P=.008) performance, supporting the role of the cerebellum in both motor and cognitive functioning. CONCLUSIONS: These data highlight the contributions of the cerebellum to both motor and cognitive function in PwMS. Using novel neuroimaging techniques to examine structure-function relationships in PwMS improves our understanding of individualized differences in this heterogeneous group and may provide an avenue for targeted, individualized rehabilitation aimed at improving cerebellar dysfunction in MS.

Measurement Properties of Backward Walking and Its Sensitivity and Feasibility in Predicting Falls in People With Multiple Sclerosis.

BACKGROUND: People with multiple sclerosis (MS) experience mobility impairments that elevate fall risk, increasing the need to identify clinical measures that accurately predict falls. Backward walking (BW) better differentiates fallers from nonfallers in MS. However, no studies have reported the measurement properties of the backward walking Timed 25-Foot Walk (B-T25-FW) and BW metrics, like BW velocity. Additionally, it is unknown whether BW can predict future falls in MS or its link to activity levels. This study assessed the reliability and responsiveness of B-T25-FW and BW metrics, including BW velocity. It also examined whether BW could predict falls at 3 and 6 months and its association with activity levels. METHODS: During 2 separate visits, 23 people with MS completed the forward walking Timed 25-Foot Walk (F-T25-FW) and B-T25-FW, as well as forward walking and BW assessments in which spatiotemporal measures were recorded. Test-retest reliability was determined with intraclass correlation coefficients, and minimum detectable changes were calculated. Correlation analyses explored the relationship between BW velocity, B-T25-FW, prospective falls, and activity levels. RESULTS: B-T25-FW and BW velocity exhibited excellent test-retest reliability. Large effect sizes to interpret clinically meaningful change in the B-T25-FW and BW velocity were also found. Both metrics demonstrated modest negative correlations with falls at 3 and 6 months and correlated strongly with very active minutes at 3- and 6-months post study. CONCLUSIONS: The B-T25-FW and BW velocity are effective and reliable in clinical use for evaluating functional mobility in people with MS, are sensitive enough to detect subtle changes, and may be a meaningful marker for tracking disease progression and treatment efficacy.

Cerebellar volume measures may differentiate multiple sclerosis fallers from non-fallers.

Introduction: The cerebellum is a common lesion site in persons with multiple sclerosis (PwMS). Physiologic and anatomic studies have identified a topographic organization of the cerebellum including functionally distinct motor and cognitive areas. This study implemented a recent parcellation algorithm developed by Han et al., 2020 to a sample of PwMS and healthy controls to examine relationships among specific cerebellar regions, fall status, and common clinical measures of motor and cognitive functions. Methods: Thirty-one PwMS and 29 age and sex-matched controls underwent an MRI scan and motor and cognitive testing. The parcellation algorithm was applied to all images and divided the cerebellum into 28 regions. Mann-Whitney U tests were used to compare cerebellar volumes among PwMS and controls, and MS fallers and MS non-fallers. Relationships between cerebellar volumes and motor and cognitive function was evaluated using Spearman correlations. Results: PwMS performed significantly worse on functional measures compared to controls. We found significant differences in volumetric measures between PwMS and controls in the corpus medullare, lobules I-III, and lobule V. Volumetric differences seen between PwMS and controls were primarily driven by the MS fallers. Finally, functional performance on motor and cognitive tasks was associated with cerebellar volumes. Conclusions: Using the parcellation tool, our results showed that volumes of motor and cognitive lobules impact both motor and cognitive performance, and that functional performance and cerebellar volumes distinguishes MS fallers from non-fallers. Future studies should explore the potential of cerebellar imaging to predict falls in PwMS.

Examining the Influence of Cognition on the Relationship Between Backward Walking and Falls in Persons With Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) causes motor, cognitive, and sensory impairments that result in injurious falls. Current fall risk measures in MS (ie, forward walking [FW] speed and balance) are limited in their sensitivity. Backward walking (BW) velocity is a sensitive marker of fall risk and correlates with information processing speed (IPS) and visuospatial memory (VSM) in persons with MS. Backward walking is a complex motor task that requires increased cognitive demands, which are negatively affected by MS; however, whether cognitive function modifies the sensitivity of BW as a fall risk assessment in MS remains unknown. This study examines the influence of cognition on the relationship between BW and falls in persons with MS. METHODS: Measures of BW, FW, IPS, VSM, and retrospective falls were collected. Hierarchical regression tested moderation and included an interaction term predicting number of falls. Covariates for all analyses included age and disease severity. RESULTS: Thirty-eight persons with MS participated. Although BW, IPS, and covariates significantly predicted the number of falls (R 2 = 0.301; P = .016), there was no evidence of moderation. Backward walking, VSM, and covariates also significantly predicted number of falls (R 2 = 0.332, P = .008), but there was no evidence of moderation. The FW models generated comparable results. CONCLUSIONS: The relationship between BW velocity and falls was not conditional on IPS or VSM in this sample. Larger-scale studies examining additional cognitive domains commonly affected by MS and prospective falls are needed to characterize neurobiological processes relevant to BW and its clinical application in the assessment of fall risk.

Associations between myelin water imaging and measures of fall risk and functional mobility in multiple sclerosis.

BACKGROUND AND PURPOSE: Myelin water fraction (MWF) deficits as measured by myelin water imaging (MWI) have been related to worse motor function in persons with multiple sclerosis (PwMS). However, it is unknown if measures from MWI metrics in motor areas relate to fall risk measures in PwMS. The objective of this study was to examine the relationship between MWI measures in motor areas to performance on clinical measures of fall risk and disability in PwMS. METHODS: Sixteen individuals with relapsing-remitting MS participated (1 male, 15 female; age 47.1 years [12.3]; Expanded Disability Status Scale 4.0 [range 0-6.5]) and completed measures of walking and fall risk (Timed 25 Foot Walk [T25FW] and Timed Up and Go). MWF and the geometric mean of the intra-/extracellular water T2 (geomT2IEW ) values reflecting myelin content and contribution of large-diameter axons/density, respectively, were assessed in three motor-related regions. RESULTS: The geomT2IEW of the corticospinal tract (r = -.599; p = .018) and superior cerebellar peduncles (r = -.613; p = .015) demonstrated significant inverse relationships with T25FW, suggesting that decreased geomT2IEW was related to slower walking. Though not significant, MWF in the corticospinal tract and superior cerebellar peduncles also demonstrated fair relationships with the T25FW, suggesting that worse performance on the T25FW was associated with lower MWF values. CONCLUSIONS: MWI of key motor regions was associated with walking performance in PwMS. Further MWI studies are needed to identify relationships between pathology and clinical function in PwMS to guide targeted rehabilitation therapies aimed at preventing falls.

Using myelin water imaging to link underlying pathology to clinical function in multiple sclerosis: A scoping review.

BACKGROUND: Multiple sclerosis (MS) symptoms and pathology are heterogenous and complex. Identifying links between MS-related pathology (i.e., myelin damage) and associated clinical symptoms is critical for developing targeted therapeutics. Conventional MRI, commonly used for MS diagnosis and disease monitoring, lacks specificity with functional performance. Myelin water imaging (MWI) demonstrates increased specificity to myelin and is viewed as the gold standard for imaging myelin content in vivo. Yet, there is a paucity of MWI studies in MS and only a limited number also examine clinical function. Thus, it remains unknown whether MWI corresponds to functional performance in MS. This scoping review aimed to examine relations between MWI and functional domains relevant to MS to inform and guide future research. METHODS: Seven databases were searched from their inception to September 1, 2021. Studies of adults with MS that included both brain MWI and either a measure of physical function, a measure of cognitive function, or a measure of disease severity were included. Thirteen studies (11 observational, 2 intervention) met the inclusion criteria. RESULTS: The most commonly investigated MWI metric is the myelin water fraction (MWF). Persons with MS demonstrated markedly decreased MWF compared to healthy controls globally and across brain regions of interest (ROIs). Decreased MWF was associated with higher disability, worse motor and cognitive performance and decreased intervention response. Only five studies examined structure-function relationships in brain areas related to walking and cognitive function and only six studies extracted MWI metrics from explicit brain ROIs. CONCLUSIONS: MWI is a neuroimaging technique with increased specificity to myelin and offers greater insight to MS-driven pathology and its clinical manifestations, including motor and cognitive dysfunction and rehabilitation response. This scoping review identified critical gaps in MWI research in MS to offer future perspectives including ROI-based studies, inclusion of multi-domain functional assessment and examining MWI to provide evidence of neuroplasticity following training.

Cerebellar Dysfunction in Multiple Sclerosis: Considerations for Research and Rehabilitation Therapy.

Introduction. Cerebellar pathology is common among persons with multiple sclerosis (PwMS). The cerebellum is well recognized for its role in motor control and motor learning and cerebellar pathology in multiple sclerosis is associated with enhanced motor impairment and disability progression. The Problem. To mitigate motor disability progression, PwMS are commonly prescribed exercise and task-specific rehabilitation training. Yet, whether cerebellar dysfunction differentially affects rehabilitation outcomes in this population remains unknown. Furthermore, we lack rehabilitation interventions targeting cerebellar dysfunction. The Solution. Here, we summarize the current understanding of the impact of cerebellar dysfunction on motor control, motor training, and rehabilitation in persons with multiple sclerosis. Recommendations. Additionally, we highlight critical knowledge gaps and propose that these guide future research studying cerebellar dysfunction in persons with multiple sclerosis.

COVID-19 Pandemic and Impact on Patients with Autism Spectrum Disorder.

The COVID-19 infectious disease pandemic has caused significant fear and uncertainty around the world and had significant adverse psychological impact. Children, adolescents and adults with autism spectrum disorder (ASD) are a particularly vulnerable population, impacted by stay-at-home orders, closures at nonessential services, and social distancing standards. This commentary describes various challenges faced by individuals with ASD in the United States including disruptions caused by educational and vocational changes, challenges to home and leisure routines, limited access to behavioral health services and changes in health services delivery due to the pandemic. We highlight the need for ongoing skills development for individuals and development within systems to better respond to needs of the ASD population in future emergencies.

Validating the walking while talking test to measure motor, cognitive, and dual-task performance in ambulatory individuals with multiple sclerosis.

INTRODUCTION: Multiple Sclerosis (MS) is associated with demyelination of the central nervous system that negatively impacts both motor and cognitive function, resulting in difficulty performing simultaneous motor and cognitive tasks, or dual-tasks. Declines in dual-tasking have been linked with falls in MS; thus, dual-task assessment with the Walking While Talking Test (WWTT) is commonly utilized in the clinical setting. However, the validity and minimal detectable change (MDC) of the WWTT has not been established for persons with MS. The primary objective of the study was to establish the WWTT as a valid measure of dual-task function by examining concurrent validity with other motor, cognitive and dual-task measures, and to establish the MDC for both the simple and complex conditions of the WWTT. METHODS: In a single visit, 38 adults (34 female, mean (SD) age 49.8(±9.1), Patient Determined Disease Steps (PDDS) mean 3, range 1-6) completed the WWTT simple (walk while reciting the alphabet) and complex (walk while reciting every other letter of the alphabet) conditions as well as a battery of cognitive and motor tests. Spearman correlations were used to examine concurrent validity. The sample was divided into low and high disability groups to determine the impact of disability severity on relationships among WWTT and cognitive and motor function. RESULTS: Excellent concurrent validity (r ≥ 0.79; p < 0.001) was observed for the WWTT simple and complex with both motor (Timed Up-and-Go, Timed 25-Foot Walk, forward and backward walking velocity, Six-Spot Step Test) and dual-task measures (Timed Up-and-Go Cognitive). The WWTT-simple demonstrated moderate concurrent validity with measures of processing speed (Symbol Digit Modalities Test, p = 0.041) and was related to all motor and dual-task measures across disability levels. The WWTT complex was only related to complex motor tasks in the low disability group. Within the low disability group, WWTT was associated with processing speed (p = 0.045) and working memory (California Verbal Learning Test, p = 0.012). The MDC values were established for WWTT simple (6.9 s) and complex (8 s) conditions. DISCUSSION: The WWTT is a quick, easy-to-administer clinical measure that captures both motor and cognitive aspects of performance for persons with MS. Clinicians should consider adding the WWTT to the evaluation of persons with MS to examine dual-task performance.

Backward walking sensitively detects fallers in persons with multiple sclerosis.

BACKGROUND: Individuals with multiple sclerosis experience deficits in mobility resulting in injurious falls. Fall detection has proved challenging; the majority of clinical measures rely on forward walking and balance measures, yet these measures have poor sensitivity and predictive value for differentiating between fallers and non-fallers. Backward walking better differentiates fallers from non-fallers in the elderly and other neurodegenerative diseases; therefore, the objective of this study was to examine both forward and backward walking to determine the strongest, unique contributor that differentiates fallers from non-fallers in persons with multiple sclerosis. METHODS: In a single session, spatiotemporal measures of forward and backward walking and fall history were collected. For the subsequent six months, individuals recorded falls in a fall diary. Discriminant function analysis was used to determine what variables most strongly and uniquely differentiate multiple sclerosis fallers from non-fallers. RESULTS: Thirty-eight individuals with multiple sclerosis participated. Forward and backward velocity, stride length, and double support time as well as age, disease severity, and symptom duration were included in the models. Together, the variables differentiated between fallers and non-fallers (Wilk's lambda χ2 (8, N = 36) = 0.497, p<0.001) and in rank order, backward walking velocity was the strongest unique predictor. Repeating the analysis with a stepwise approach yielded that backward walking velocity in the first step (χ2 (1, 34) = 0.68, F = 15.96, p<0.001) and symptom duration in the second step (χ2 = 0.59, F (2, 33) = 11.46; p<0.001) most strongly differentiated retrospective fallers and non-fallers. This stepwise model with backward walking velocity and symptom duration accurately classified 76.3% of cases. Addition of forward walking measures did not significantly improve the models, and indeed the accuracy of classification was reduced to 71.1%. Exploratory analysis showed that backward walking velocity was the best predictor of prospectively reported fallers and non-fallers (χ2 (1, 7) = 0.43, F = 9.20, p = 0.02). CONCLUSION: Backward walking velocity exhibits the highest effect magnitude and specificity in differentiating fallers from non-fallers in individuals with MS and demonstrates potential as clinically feasible and efficient fall detection tool.

Backward Walking and Dual-Task Assessment Improve Identification of Gait Impairments and Fall Risk in Individuals with MS.

BACKGROUND: Individuals with multiple sclerosis (MS) experience deficits in motor and cognitive domains, resulting in impairment in dual-task walking ability. The goal of this study was to compare performance of forward walking and backward walking in single- and dual-task conditions in persons with MS to age- and sex-matched healthy controls. We also examined relationships between forward and backward walking to cognitive function, balance, and retrospective fall reports. METHODS: All measures were collected in a single session. A 2 × 2 × 2 mixed model ANOVA was used to compare differences in forward and backward walking in single- and dual-task conditions between MS and healthy controls. Spearman correlations were used to examine relationships between gait and cognitive function, falls, and balance. RESULTS: Eighteen individuals with relapsing-remitting MS and 14 age- and sex-matched healthy controls participated. Backward walking velocity revealed significant differences between groups for both single-task (p = 0.015) and dual-task (p = 0.014) conditions. Persons with MS demonstrated significant differences between single- and dual-task forward and backward walking velocities (p = 0.023; p = 0.004), whereas this difference was only apparent in the backward walking condition for healthy controls (p = 0.004). In persons with MS, there were significant differences in double support time between single- and dual-task conditions in both backward (p < 0.001) and forward (p = 0.001) directions. More falls at six months were significantly associated with shorter backward dual-task stride length (r = -0.490; p = 0.046) and slower velocity (r = -0.483; p = 0.050). CONCLUSION: Differences in MS and age- and sex-matched healthy controls are more pronounced during backward compared to forward walking under single- and dual-task conditions. Future work with a larger sample size is needed to validate the clinical utility of backward walking and dual-task assessments and mitigate the limited sensitivity of the current dual-task assessments that primarily rely upon forward walking.

Combining Magnetization Transfer Ratio MRI and Quantitative Measures of Walking Improves the Identification of Fallers in MS.

Multiple sclerosis (MS) impacts balance and walking function, resulting in accidental falls. History of falls and clinical assessment are commonly used for fall prediction, yet these measures have limited predictive validity. Falls are multifactorial; consideration of disease-specific pathology may be critical for improving fall prediction in MS. The objective of this study was to examine the predictive value of clinical measures (i.e., walking, strength, sensation) and corticospinal tract (CST) MRI measures, both discretely and combined, to fall status in MS. Twenty-nine individuals with relapsing-remitting MS (mean ± SD age: 48.7 ± 11.5 years; 17 females; Expanded Disability Status Scale (EDSS): 4.0 (range 1-6.5); symptom duration: 11.9 ± 8.7 years; 14 fallers) participated in a 3T brain MRI including diffusion tensor imaging and magnetization transfer ratio (MTR) and clinical tests of walking, strength, sensation and falls history. Clinical measures of walking were significantly associated with CST fractional anisotropy and MTR. A model including CST MTR, walk velocity and vibration sensation explained >31% of the variance in fall status (R2 = 0.3181) and accurately distinguished 73.8% fallers, which was superior to stand-alone models that included only MRI or clinical measures. This study advances the field by combining clinical and MRI measures to improve fall prediction accuracy in MS.

Satiety-responsive neurons in the medial orbitofrontal cortex of the macaque.

Feeding-related gustatory, olfactory, and visual activation of the orbitofrontal cortex (OFC) decreases following satiety. Previous neurophysiological studies have concentrated on the caudolateral OFC (clOFC). We describe satiety-induced modulation of 23 gustatory, 5 water, and 15 control neurons in the medial OFC (mOFC), where gustatory neurons represent a much larger percentage of the population. For 15 of the 23 gustatory neurons (65%), every significant taste response evoked during pre-satiety testing decreased following satiety (X=70%). Responses evoked by the ineffective taste stimuli during pre-satiety testing were unchanged following satiety. The graded response decrements of the mOFC gustatory neurons stand in marked contrast to the clOFC responses, which are almost completely suppressed by satiety. Two other novel findings are reported here. First, all significant pre-satiety taste responses of four gustatory neurons increased following satiety (X=51%). Second, post-satiety emergent taste responses were observed in 7 of 15 neurons (47%) classified as non-responsive during pre-satiety testing. The presence of increased responsiveness and emergent gustatory neurons in the mOFC suggests that meal termination may require active processes as well as the passive loss of hedonic value.

Gustatory neural responses in the medial orbitofrontal cortex of the old world monkey.

The primary taste cortex has widespread and occasionally dense projections to the orbitofrontal cortex (OFC) in the macaque. Nonetheless, electrophysiological studies have revealed that only 2-8% of the cells in the OFC are activated by taste stimuli on the tongue. We describe an area centered in Brodmann's area 13m of the medial OFC (mOFC) where taste neurons are more concentrated. It consists of a 12 mm2 core, where gustatory neurons constituted 20% of the population, and a 1 mm perimeter in which 8% of the cells responded to taste. Data were collected from three awake cynomolgus monkeys (Macaca fascicularis) prepared for chronic recording. Single neurons were isolated with epoxylite-coated tungsten microelectrodes and tested for responsiveness to 1.0 m glucose, 0.3 m NaCl, 0.03 m HCl, and 0.001 m QHCl. These stimuli elicited responses that were 96% excitatory and ranged from 5.2 to 5.9 spikes/s. Cells were broadly tuned (H = 0.79), similar to those in the anterior insula (H = 0.70), and decidedly unlike the narrowly tuned taste neurons in the caudolateral OFC (clOFC; H = 0.39). Whereas 82% of the taste cells in the clOFC respond to glucose, in the mOFC, HCl-responsive (56%), glucose-responsive (50%), NaCl-responsive (43%), and QHCl-responsive (40%) cells were almost evenly represented. The mOFC taste area appears to comprise a major gustatory relay that lies anatomically and functionally between the anterior insula and the clOFC.