Backward Walking: A Novel Marker Of Fall Risk, Cognitive Dysfunction, And Myelin Damage In Persons With Multiple Sclerosis

Multiple sclerosis (MS) is a progressive, neurologic disease of the central nervous system that causes debilitating motor, sensory and cognitive impairments. As a result, persons with MS are at an increased risk for falls and falls represent a serious public health concern for the MS population. The current clinical measures used to assess fall risk in MS patients lack sensitivity and predictive validity for falls and are limited in their ability to capture to multiple functional domains (i.e., motor, sensory, cognitive and pathological domains) that are impaired by MS. Backward walking sensitively detects falls in the elderly and other neurologic diseases. However, backward walking and falls has never been explored in the MS population and the underlying reasons as to why backward walking sensitively detects falls remains unknown. Identification of a quick, simply and clinically feasible fall risk measures related to multiple functions impacted by MS and related to fall risk, which can detect falls before they occur is critical for fall prevention and timely and targeted intervention. Therefore, this dissertation examines backward walking as a novel marker of fall risk and its cognitive and pathological underpinnings to support its clinical utility. Our results indicate that backward walking is a sensitive marker of fall risk in the MS population, regardless of co-morbid cognitive deficits, and that examining underlying brain regions likely to contribute to backward walking performance including the corticospinal tract, corpus callosum and cerebellum, with neuroimaging tools sensitive to myelin (i.e., Myelin Water Imaging) demonstrate potential to identify underlying mechanisms of backward walking performance in the MS population. This work is the critical first step in establishing backward walking as a sensitive marker of fall risk for the MS population and leads the way to more personalized fall prevention therapies and interventions to improve clinical outcomes and decrease fall rates in the MS population

Psychological Resilience as a Protective Factor for the Motor System in Multiple Sclerosis

Multiple Sclerosis (MS) is a lifelong progressive neurologic disease of the central nervous system (CNS) that interrupts the flow of information within the brain and between the brain and the body, resulting in a variety of symptoms across the visual, sensory, motor, and autonomic functions. The concept of psychological resilience is emerging in clinical research, including research on MS, as a productive way to view the outcomes and experiences of living with a chronic disease and identify potential protective factors. The purpose of this dissertation was to examine the protective and predictive quality of psychological resilience in various domains of motor functioning. A sample of 130 patients underwent neuropsychological testing along with neurological examination at two distinct time points (baseline and 3-year follow-up). As part of each evaluation, patients were administered various tasks of motor functioning: the two-minute walk test (2MWT; a measure of gait endurance and stamina), timed 25-foot walk (T25FW; a measure of gait speed), nine-hole peg test (NHPT; a measure of upper extremity speed and coordination), grooved pegboard (G-Pegs; a measure of fine motor speed and dexterity), grip strength (Grip; a measure of upper body strength), and finger tapping test (FTT; a measure of simple motor speed), which served as this study’s outcomes. Psychological resilience, the primary predictor of interest, was operationalized as the self-reported ability of adapting well in the face of substantial adversity and significant sources of stress and was estimated using a validated self-report measure the Connor-Davidson Resilience Scale, 10 item version (CD-RISC-10). Additional predictors included mood, fatigue, demographic variables, disease variables, and magnetic resonance imaging (MRI) estimates. In contrast to our hypothesis, psychological resilience and functional outcomes were not correlated. Psychological resilience did not predict change in motor functioning over time and did not serve as a moderator between disease burden and motor functioning. As such, the present study does not provide support for psychological resilience as a protective factor for the motor system in MS or for resilience in predicting differential decline in motor functioning

Effects of Two High-Frequency Physical Therapy Programs on Balance, Gait, Fatigue, and Quality of Life in People with Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease involving the inflammation and demyelination in both brain and spinal cord. MS typically affects people in early adulthood in the range of 20-40 years old, and most patients with MS experience symptoms on a daily basis, such as walking difficulties, balance impairment, and fatigue, which can be disabling and impact the Quality of Life (QOL). The main purpose of this investigation is to determine if our novel, adaptive, high-frequency physical therapy protocol, compared with the conventional therapeutic exercise protocol, has the potential to improve participants’ dynamic balance, gait, fatigue, and overall QOL based on clinical measurement scales. After the completion of this investigation, we found that both types of protocols with the same high dosage improved the balance, gait, fatigue, and QOL in people with MS similarly in a clinically relevant manner. Our results provide evidence that a high-frequency physical therapy intervention consisting of twice per day and five days per week sessions may be an important parameter for improving balance, gait, fatigue, and QOL in people with MS

Automatic assessment of the 2-minute walk distance for remote monitoring of people with multiple sclerosis

The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes

Automatic Assessment of the 2-Minute Walk Distance for Remote Monitoring of People with Multiple Sclerosis

The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes

Neurorehabilitation in Multiple Sclerosis: insights into fatigue and motor function

About this work This doctoral project aims to improve the overall knowledge on the effects of neurorehabilitation in People with Multiple Sclerosis (PwMS), by providing more insights on fatigue and the relationship between fatigue and motor functional aspects. The general introduction provides background information on the main topics of this doctoral project. In the first part, the specific disease characteristics of Multiple Sclerosis are described. In the second part, the current status of fatigue and motor impairment and a focus on the management are presented. Finally, the aims and outline thesis are reported. Four studies were conducted and reported in 4 different chapters. The first study provides information about the cardiac autonomic function during rest, postural changes and exercise and the relationship between autonomic modulation of heart rate and the perceived fatigue. The second study investigates the effect of an experimental rehabilitation protocol which combines aerobic training and task oriented exercises aimed to reduce fatigue and improve upper limb impairments and function. The third study provides information about preliminary effects of a high-intensity rehabilitative multimodal training protocol carried out on a treadmill aimed at improving mobility and balance. The fourth study shows the effectiveness of functional electrical stimulation on reducing falls, improving gait kinematics and promoting energy recovery. Lastly, general conclusions, including main findings and clinical implications, are provided at the end of the doctoral thesis

Cognitive-motor interference in people with multiple sclerosis: a kinematic approach to clarify the effect of cognitive load on walking performance

The simultaneous performance of cognitive tasks during locomotion (or cognitive-motor dual-task) is known to cause performance deficits in either one of, or both tasks. Furthermore, these performance decrements are exacerbated by the presence of motor impairments and cognitive dysfunctions characteristic of numerous neurological diseases, such as multiple sclerosis (MS). In this regard the assessment of walking while performing a cognitive task may represent a relevant outcome measure, because it allows measuring, in a laboratory setting, individual’s ability to cope with walking challenging situations similar to everyday living. The first aim of this thesis is to provide an experimental setup, based on the use of optoelectronic stereophotogrammetry, for obtaining quantitative evaluation of walking biomechanics and motor strategies during dual-task performance in both healthy adults and people with MS (pwMS). Then, this experimental methodology is tested as suitable method not only for detecting, measuring and characterizing disability, but also for testing intervention effectiveness in clinical practice. Specifically, the study is focused on the assessment of spatiotemporal parameters and lower limb kinematics during single- (normal pace walking) and dual-task (walking while performing a discrimination and decision-making). This thesis is composed of four experiments. The first two aimed to measure the effect of cognitive-motor interference on walking biomechanics in terms of spatiotemporal parameters and lower limb joint kinematics. In this regard, a sample of pwMS stratified by disability level (low disability, EDSS 1.0-2.5, n=37; mild to moderate disability, EDSS 3.0-6.0, n=44) and a sample of age- and gender-matched healthy adults (n=41) underwent a 3D kinematic evaluation of single- and dual-task performance using a motion capture system. Differences between conditions and groups were investigated using a two-way repeated ANOVA. The results reported that gait speed and stride length were sensitive motor variables in detecting differences from single- to dual-task condition in both pwMS and unaffected individuals, whereas spatiotemporal parameters closely related to balance control (e.g. step width, double support phase duration) were sensitive to changes only in pwMS with moderate disability. Moreover, those patients showed significant changes in the kinematics of distal joint (shank-foot) and proximal joint (hip), including a reduction in ankle plantarflexion and hip extension peak at the terminal stance phase. These observed changes in more impaired patients are compensatory mechanism to stabilize body posture and allow safe locomotion during complicate dual-task activities. Finally, the other two experiments were designed to provide a clinical application of this methodology, as a tool for quantitatively assessing biomechanics changes after an innovative therapeutic intervention. In this regard, a sample of pwMS (n=34) with mild to moderate disability participated in a bicentric clinical trial. As per protocol, pwMS completed an intervention consisting of either active or sham multiple sessions of transcranial direct current stimulation (tDCS) combined with physical activity, aimed to improve walking performance. Following repeated application of active tDCS, the results obtained from the quantitative gait analysis showed greater improvements in gait velocity, step length and walking endurance. This improvement measured in walking had corresponding effects on walking dual-task performance. In fact, the dual-task cost of gait parameters was significantly reduced after the active tDCS intervention. In conclusion, the quantitative assessment of walking impairments during the execution of functional task in pwMS can support a deep learning of both movement features and motor strategies, which should have implications for the design and validation of clinical intervention aimed at improving functional walking

FOOT DROP AND FATIGABILITY IN PEOPLE WITH MULTIPLE SCLEROSIS

People with Multiple Sclerosis (pwMS) often experience walking impairments such as foot drop which can lead to trip and falls. Foot drop can be either transient and is often induced by exercise (fatigability) in pwMS whose walking ability is not affected and can become more fixed with disease progression. The overall aim of this PhD was to explore foot drop, its presence in pwMS with different disability levels and the psychometric properties of outcomes used to evaluate walking impairments. The first study in this thesis was a systematic review into the level of evidence for the psychometric properties of walking measures that have been used to evaluate the effect of assistive technology such as FES for foot drop in MS. Moderate to strong psychometric evidence was found for the Multiple Sclerosis Walking Scale, Timed 25 Foot Walk, 6 minute and 10 meter walk tests. There were no psychometric studies for three-dimensional (3D) gait kinematics in pwMS even though it was one of the most frequently used outcome measures. The second study assessed the test-retest reliability of 3D ankle kinematics and spatiotemporal parameters in pwMS, with low Expanded Disability Status Scale (EDSS < 3.5) and in those with moderate to high EDSS (EDSS: 4-6). Reliability was excellent for ankle kinematics and spatiotemporal parameters in both groups, with lower minimal detectable change (MDC95%) values in the low EDSS group compared to the higher EDSS group. The third study investigated transient exercise induced foot drop in highly physically active pwMS (EDSS < 3.5) and health controls using 3D kinematics. It was found that 6 out of 15 pwMS and none of the healthy controls presented this phenomenon. The fourth study examined the direct orthotic effect of FES during dual-tasking (i.e. walking combined with a cognitive task) and after inducing fatigability. Low to moderate effect sizes indicated that the direct orthotic effect was higher under dual-task and fatiguing conditions but this needs to be confirmed in appropriately powered studies. In conclusion, the studies in this thesis have contributed to the psychometric evidence of gait kinematics in pwMS, have objectively documented the presence of transient foot drop in highly physically active pwMS and orthotic effect of FES under a variety of conditions simulating the perceived benefits in ‘real life’ reported by FES users. Key words: multiple sclerosis, foot drop, fatigability, FES, psychometric properties, 3D gait kinematic

Kinematic Analysis of Lower Limb Joint Asymmetry during Gait in People with Multiple Sclerosis

The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunc- tions, which may relevantly affect postural control, gait and a wide range of activities of daily living. While it is quite common to observe a different impact of the disease on the two limbs (i.e., one of them is more affected), less clear are the effects of such asymmetry on gait performance. The present retrospective cross-sectional study aimed to characterize the magnitude of interlimb asymmetry in pwMS, particularly as regards the joint kinematics, using parameters derived from angle-angle di- agrams. To this end, we analyzed gait patterns of 101 pwMS (55 women, 46 men, mean age 46.3, average Expanded Disability Status Scale (EDSS) score 3.5, range 1–6.5) and 81 unaffected individ- uals age- and sex-matched who underwent 3D computerized gait analysis carried out using an eight-camera motion capture system. Spatio-temporal parameters and kinematics in the sagittal plane at hip, knee and ankle joints were considered for the analysis. The angular trends of left and right sides were processed to build synchronized angle–angle diagrams (cyclograms) for each joint, and symmetry was assessed by computing several geometrical features such as area, orientation and Trend Symmetry. Based on cyclogram orientation and Trend Symmetry, the results show that pwMS exhibit significantly greater asymmetry in all three joints with respect to unaffected individ- uals. In particular, orientation values were as follows: 5.1 of pwMS vs. 1.6 of unaffected individuals at hip joint, 7.0 vs. 1.5 at knee and 6.4 vs. 3.0 at ankle (p &lt; 0.001 in all cases), while for Trend Sym- metry we obtained at hip 1.7 of pwMS vs. 0.3 of unaffected individuals, 4.2 vs. 0.5 at knee and 8.5 vs. 1.5 at ankle (p &lt; 0.001 in all cases). Moreover, the same parameters were sensitive enough to discriminate individuals of different disability levels. With few exceptions, all the calculated sym- metry parameters were found significantly correlated with the main spatio-temporal parameters of gait and the EDSS score. In particular, large correlations were detected between Trend Symmetry and gait speed (with rho values in the range of –0.58 to –0.63 depending on the considered joint, p &lt; 0.001) and between Trend Symmetry and EDSS score (rho = 0.62 to 0.69, p &lt; 0.001). Such results suggest not only that MS is associated with significantly marked interlimb asymmetry during gait but also that such asymmetry worsens as the disease progresses and that it has a relevant impact on gait performances