Fatigue in Spinal Muscular Atrophy: a fundamental open issue.

Hereditary proximal 5q Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder with onset mainly in infancy or childhood. The underlying pathogenic mechanism is the loss of alpha motor neurons in the anterior horns of spine, due to deficiency of the survival motor neuron (SMN) protein as a consequence of the deletion of the SMN1 gene. Clinically, SMA is characterized by progressive loss of muscle strength and motor function ranging from the extremely severe, the neonatal onset type 1, to the mild type 4 arising in the adult life. All the clinical variants share the same molecular defect, the difference being driven mainly by the copy number of SMN2 gene, a centromeric gene nearly identical to SMN1 with a unique C to T transition in Exon 7 that results in exclusion of Exon 7 during post-transcriptional processing. In all the types of SMA the clinical picture is characterized by hypotonia, weakness and areflexia. Clinical severity can vary a lot between the four main recognized types of SMA. As for the most of patients affected by different neuromuscular disorders, also in SMA fatigability is a major complaint as it is frequently reported in common daily activities and negatively impacts on the overall quality of life. The increasing awareness of fatigability as an important dimension of impairment in Neuromuscular Disorders and particularly in SMA, is making it both a relevant subject of study and identifies it as a fundamental therapeutic target. In this review, we aimed to overview the current literature articles concerning this problem, in order to highlight what is known and what deserves further research.

An 8-month adapted motor activity program in a young CMT1A male patient.

Background: It is unclear whether prolonged periods of training can be well tolerated. In Charcot-Marie Tooth disease (CMT). We report the effects of an 8-month, adapted motor activity (AMA) program in a 16-years-old CMT1A male patient. The program included strength, mobility, and balance training (two sessions per week, 1 h per session). Measures: Walking ability and walking velocity (Six-Minute Walking Test-6MWT, Ten Meters Walking Test-10 mW T), balance (Y-Balance Test-YBT, Berg Balance Scale-BBS), functional mobility (Short Physical Performance Battery-Short physical performance battery), fatigue (Checklist Individual strength questionnaire - CIS20R), health and quality of life (Short Form Health Survey 36 questionnaire-SF-36) were evaluated in three moments: before (T0), after 5 (T1) and 8 (T2) months of adapted motor activity. Dorsal and plantar foot flexion strength (Maximal Voluntary Contraction-maximum voluntary contraction) and neuromuscular functions (Electromyography-sEMG, interpolated twitch technique-ITT) were measured at T1 and T2. Results: Relative to T0, an amelioration of walking ability (6MWT, +9,3%) and balance (with improvements on Y-balance composite normalized mean reach of the right and left limb of 15,3% and 8,5%, respectively) was appreciable. Relative to T1, an increase in foot strength in three out of four movements (right plantar flexion, +39,3%, left plantar flexion, +22,7%, left dorsal flexion, 11,5%) was observed. Concerning voluntary muscle activation, a greater recruitment in the left, unlike right, medial gastrocnemius was observed. Conclusion: Results suggest the safety of an 8-month AMA program in a young patient affected by CMT1A.

Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy.

BACKGROUND: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). METHODS: People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. RESULTS: 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73-0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51-0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). CONCLUSIONS: PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.

Type 1 diabetes management in a competitive athlete: A five-year case report.

Type I diabetes has an incidence of 15 per 100,000 people. Though it is a metabolic disorder, it can be seen in top, even professional athletes. Physical activity is recommended to manage diabetes, but there is a lack of specific knowledge on diabetes management and exercise from dedicated medical staff. This bias leads to suboptimal diabetes management, causing frequent hyper and hypoglycemia, a dysregulation of glycated hemoglobin, blood glucose out of control, and consequent needs to often intervene with extra insulin or carbohydrates. For 5 years, we followed a highly competitive male Caucasian athlete Vovinam Viet Vo Dao, with type I diabetes, aged 17. We monitored his glycated hemoglobin, the insulin drug administered, and glycemia blood level averages. We obtained, over time, a decrease in glycated hemoglobin by almost -22% and insulin administered by -37.33%, and average blood glycemia levels diminished by almost -27%. In addition, we carried out bioimpedance analysis and stratigraphy on the abdomen. Federation trainers supervised all physical training; we recorded an improvement in the general condition, underlined in particular by an increase in phase angle (from bioimpedance) of +17%.

Case report: Personalized adapted motor activity in a COVID-19 patient complicated by critical illness polyneuropathy and myopathy.

Background: COVID-19 may require hospitalization in an intensive care unit (ICU) and is often associated with the onset of critical illness polyneuropathy (CIP) and critical illness myopathy (CIM). Due to the spread of the disease around the world, the identification of new rehabilitation strategies for patients facing this sequence of events is of increasing importance. Case presentation: We report the clinical presentation and the beneficial effects of a prolonged, supervised adapted motor activity (AMA) program in a highly deconditioned 61-year-old male COVID-19 patient discharged from the ICU and complicated by residual CIP and CIM. The program included aerobic, strength, gait, and balance training (1 h, 2 sessions per week). Measures: Pulmonary (spirometry), metabolic (indirect calorimetry and bioimpedance), and neuromuscular functions (electromyography) were evaluated at baseline and after 1 year of training. Results: Relative to baseline, an amelioration of several spirometric parameters such as vital capacity (VC, +40%), total lung capacity (TLC, +25%), and forced expiratory volume in 1 s (FEV1, +28%) was appreciable. Metabolic parameters such as body water (60%-46%), phase angle (3.6°-5.9°), and respiratory quotient (0.92-0.8) returned to the physiological range. Electromyographic parameters were substantially unchanged. The overall amelioration in clinical parameters resulted in a significant improvement of patient autonomy and the quality of life. Conclusion: Our results highlight the importance of AMA for counteracting respiratory, metabolic, and functional but not neuromuscular impairments in COVID-19 patients with residual CIM and CIP.

Dual task gait deteriorates gait performance in cervical dystonia patients: a pilot study.

Day-to-day walking-related activities frequently involve the simultaneous performance of two or more tasks (i.e., dual task). Dual task ability is influenced by higher order cognitive and cortical control mechanisms. Recently, it has been shown that the concomitant execution of an attention-demanding task affected postural control in subject with cervical dystonia (CD). However, no study has investigated whether dual tasking might deteriorate gait performance in CD patients. To investigate whether adding a concomitant motor and cognitive tasks could affect walking performance in CD subjects.17 CD patients and 19 healthy subjects (HS) participated in this pilot case-control study. Gait performance was evaluated during four walking tasks: usual, fast, cognitive dual task and obstacle negotiation. Spatiotemporal parameters, dual-task cost and coefficients of variability (CV%) were measured by GaitRite® and were used to detect differences between groups. Balance performance was also assessed with Mini-BEST and Four Step Square tests. In CD participants, correlation analysis was computed between gait parameters and clinical data. Significant differences in complex gait and balance performance were found between groups. CD patients showed lower speed, longer stance time and higher CV% and dual-task cost compared to HS. In CD, altered gait parameters correlated with balance performance and were not associated with clinical features of CD. Our findings suggest that complex walking performance is impaired in patients with CD and that balance and gait deficits might be related.

Ghost spasticity in multiple sclerosis.

Spasticity is the velocity-dependent hypertonia frequently encountered in patients affected by Upper Motor Neuron Syndrome. It is due to a tonic stretch reflex, which is evoked in patients at rest. The aim of this study, performed using surface electromyography (EMG), was to investigate stretch reflex excitability in the hamstrings muscles of patients affected by progressive Multiple Sclerosis (MS) and to correlate EMG results with clinical findings. Thirty patients and 20 age-matched healthy controls were investigated. EMG activity was recorded from biceps femoris muscle with the patient at rest. To stretch hamstrings muscles, the patient's leg was manually moved from maximal flexion to maximal extension at 3 different velocities to investigate both phasic and tonic stretch reflex. Only 7 patients were affected by hypertonia of the hamstrings; 4 of them showed muscle contracture. A tonic stretch reflex was present in the vast majority of the recruited patients, whether they presented hypertonia of the hamstrings or not. Tonic stretch reflex is often present in the hamstrings muscles of progressive MS patients without producing increased muscle tone. This "ghost spasticity" is likely to be, for its intrinsic features, an important risk factor for the development of contractures in the hamstrings muscles.

Tactile and proprioceptive dysfunction differentiates cervical dystonia with and without tremor.

OBJECTIVE: To determine whether different phenotypes of cervical dystonia (CD) express different types and levels of somatosensory impairment. METHODS: We assessed somatosensory function in patients with CD with and without tremor (n = 12 each) and in healthy age-matched controls (n = 22) by measuring tactile temporal discrimination thresholds of the nondystonic forearm and proprioceptive acuity in both the dystonic (head/neck) and nondystonic body segments (forearm/hand) using a joint position-matching task. The head or the wrist was passively displaced along different axes to distinct joint positions by the experimenter or through a robotic exoskeleton. Participants actively reproduced the experienced joint position, and the absolute joint position-matching error between the target and the reproduced positions served as a marker of proprioceptive acuity. RESULTS: Tactile temporal discrimination thresholds were significantly elevated in both CD subgroups compared to controls. Proprioceptive acuity of both the dystonic and nondystonic body segments was elevated in patients with CD and tremor with respect to both healthy controls and patients with CD without tremor. That is, tactile abnormalities were a shared dysfunction of both CD phenotypes, while proprioceptive dysfunction was observed in patients with CD with tremor. CONCLUSIONS: Our findings suggest that the pathophysiology in CD can be characterized by 2 abnormal neural processes: a dysfunctional somatosensory gating mechanism involving the basal ganglia that triggers involuntary muscle spasms and abnormal processing of proprioceptive information within a defective corticocerebellar loop, likely affecting the feedback and feedforward control of head positioning. This dysfunction is expressed mainly in CD with tremor.

Podokinetic After-Rotation Is Transiently Enhanced or Reversed by Unilateral Axial Muscle Proprioceptive Stimulation.

Unilateral axial muscle vibration, eliciting a proprioceptive volley, is known to incite steering behavior. Whole-body rotation while stepping in place also occurs as an after-effect of stepping on a circular treadmill (podokinetic after-rotation, PKAR). Here, we tested the hypothesis that PKAR is modulated by axial muscle vibration. If both phenomena operate through a common pathway, enhancement or cancellation of body rotation would occur depending on the stimulated side when vibration is administered concurrently with PKAR. Seventeen subjects participated in the study. In one session, subjects stepped in place eyes open on the center of a platform that rotated counterclockwise 60°/s for 10 min. When the platform stopped, subjects continued stepping in place blindfolded. In other session, a vibratory stimulus (100 Hz, 2 min) was administered to right or left paravertebral muscles at lumbar level at two intervals during the PKAR. We computed angular body velocity and foot step angles from markers fixed to shoulders and feet. During PKAR, all subjects rotated clockwise. Decreased angular velocity was induced by right vibration. Conversely, when vibration was administered to the left, clockwise rotation velocity increased. The combined effect on body rotation depended on the time at which vibration was administered during PKAR. Under all conditions, foot step angle was coherent with shoulder angular velocity. PKAR results from continuous asymmetric input from the muscles producing leg rotation, while axial muscle vibration elicits a proprioceptive asymmetric input. Both conditioning procedures appear to produce their effects through a common mechanism. We suggest that both stimulations would affect our straight ahead by combining their effects in an algebraic mode.

Balance in Blind Subjects: Cane and Fingertip Touch Induce Similar Extent and Promptness of Stance Stabilization.

Subjects with low vision often use a cane when standing and walking autonomously in everyday life. One aim of this study was to assess differences in the body stabilizing effect produced by the contact of the cane with the ground or by the fingertip touch of a firm surface. Another aim was to estimate the promptness of balance stabilization (or destabilization) on adding (or withdrawing) the haptic input from cane or fingertip. Twelve blind subjects and two subjects with severe visual impairment participated in two experimental protocols while maintaining the tandem Romberg posture on a force platform. In one protocol, subjects lowered the cane to a second platform on the ground and lifted it in sequence at their own pace. In the other protocol, they touched an instrumented pad with the index finger and withdrew the finger from the pad in sequence. In both protocols, subjects were asked to exert a force not granting mechanical stabilization. Under steady-state condition, the finger touch or the contact of the cane with the ground significantly reduced (to ∼78% and ∼86%, respectively) the amplitude of medio-lateral oscillation of the centre of foot pressure (CoP). Oscillation then increased when haptic information was removed. The delay to the change in body oscillation after the haptic shift was longer for addition than withdrawal of the haptic information (∼1.4 s and ∼0.7 s, respectively; p < 0.001), but was not different between the two haptic conditions (finger and cane). Similar stabilizing effects of input from cane on the ground and from fingertip touch, and similar latencies to integrate haptic cue from both sources, suggest that the process of integration of the input for balance control is initiated by the haptic stimulus at the interface cane-hand. Use of a tool is as helpful as the fingertip input, and does not produce different stabilization. Further, the latencies to haptic cue integration (from fingertip or cane) are similar to those previously found in a group of sighted subjects, suggesting that integration delays for automatic balance stabilization are not modified by visual impairment. Haptic input from a tool is easily exploited by the neural circuits subserving automatic balance stabilization in blind people, and its use should be enforced by sensory-enhancing devices and appropriate training.

Postural Stabilization Strategies to Motor Contagion Induced by Action Observation Are Impaired in Parkinson's Disease.

Postural reactions can be influenced by concomitant tasks or different contexts and are modulated by a higher order motor control. Recent studies investigated postural changes determined by motor contagion induced by action observation (chameleon effect) showing that observing a model in postural disequilibrium induces an increase in healthy subjects' body sway. Parkinson's disease (PD) is associated with postural instability and impairments in cognitively controlled balance tasks. However, no studies investigated if viewing postural imbalance might influence postural stability in PD and if patients are able to inhibit a visual postural perturbation. In this study, an action observation paradigm for assessing postural reaction to motor contagion in PD subjects and healthy older adults was used. Postural stability changes were measured during the observation of a static stimulus (control condition) and during a point-light display of a gymnast balancing on a rope (biological stimulus). Our results showed that, during the observation of the biological stimulus, sway area and antero-posterior and medio-lateral displacements of center of pressure significantly increased only in PD participants, whereas correct stabilization reactions were present in elderly subjects. These results demonstrate that PD leads to a decreased capacity to control automatic imitative tendencies induced by motor contagion. This behavior could be the consequence either of an inability to inhibit automatic imitative tendencies or of the cognitive load requested by the task. Whatever the case, the issue about the ability to inhibit automatic imitative tendencies could be crucial for PD patients since it might increase falls risk and injuries.

Haptic Cues for Balance: Use of a Cane Provides Immediate Body Stabilization.

Haptic cues are important for balance. Knowledge of the temporal features of their effect may be crucial for the design of neural prostheses. Touching a stable surface with a fingertip reduces body sway in standing subjects eyes closed (EC), and removal of haptic cue reinstates a large sway pattern. Changes in sway occur rapidly on changing haptic conditions. Here, we describe the effects and time-course of stabilization produced by a haptic cue derived from a walking cane. We intended to confirm that cane use reduces body sway, to evaluate the effect of vision on stabilization by a cane, and to estimate the delay of the changes in body sway after addition and withdrawal of haptic input. Seventeen healthy young subjects stood in tandem position on a force platform, with eyes closed or open (EO). They gently lowered the cane onto and lifted it from a second force platform. Sixty trials per direction of haptic shift (Touch → NoTouch, T-NT; NoTouch → Touch, NT-T) and visual condition (EC-EO) were acquired. Traces of Center of foot Pressure (CoP) and the force exerted by cane were filtered, rectified, and averaged. The position in space of a reflective marker positioned on the cane tip was also acquired by an optoelectronic device. Cross-correlation (CC) analysis was performed between traces of cane tip and CoP displacement. Latencies of changes in CoP oscillation in the frontal plane EC following the T-NT and NT-T haptic shift were statistically estimated. The CoP oscillations were larger in EC than EO under both T and NT (p < 0.001) and larger during NT than T conditions (p < 0.001). Haptic-induced effect under EC (Romberg quotient NT/T ~ 1.2) was less effective than that of vision under NT condition (EC/EO ~ 1.5) (p < 0.001). With EO cane had little effect. Cane displacement lagged CoP displacement under both EC and EO. Latencies to changes in CoP oscillations were longer after addition (NT-T, about 1.6 s) than withdrawal (T-NT, about 0.9 s) of haptic input (p < 0.001). These latencies were similar to those occurring on fingertip touch, as previously shown. Overall, data speak in favor of substantial equivalence of the haptic information derived from both "direct" fingertip contact and "indirect" contact with the floor mediated by the cane. Cane, finger and visual inputs would be similarly integrated in the same neural centers for balance control. Haptic input from a walking aid and its processing time should be considered when designing prostheses for locomotion.

Body sway adaptation to addition but not withdrawal of stabilizing visual information is delayed by a concurrent cognitive task.

The aim of this study was to test the effects of a concurrent cognitive task on the promptness of the sensorimotor integration and reweighting processes following addition and withdrawal of vision. Fourteen subjects stood in tandem while vision was passively added and removed. Subjects performed a cognitive task, consisting of counting backward in steps of three, or were "mentally idle." We estimated the time intervals following addition and withdrawal of vision at which body sway began to change. We also estimated the time constant of the exponential change in body oscillation until the new level of sway was reached, consistent with the current visual state. Under the mentally idle condition, mean latency was 0.67 and 0.46 s and the mean time constant was 1.27 and 0.59 s for vision addition and withdrawal, respectively. Following addition of vision, counting backward delayed the latency by about 300 ms, without affecting the time constant. Following withdrawal, counting backward had no significant effect on either latency or time constant. The extension by counting backward of the time interval to stabilization onset on addition of vision suggests a competition for allocation of cortical resources. Conversely, the absence of cognitive task effect on the rapid onset of destabilization on vision withdrawal, and on the relevant reweighting time course, advocates the intervention of a subcortical process. Diverting attention from a challenging standing task discloses a cortical supervision on the process of sensorimotor integration of new balance-stabilizing information. A subcortical process would instead organize the response to removal of the stabilizing sensory input.NEW & NOTEWORTHY This study is the first to test the effect of an arithmetic task on the time course of balance readjustment following visual withdrawal or addition. Performing such a cognitive task increases the time delay following addition of vision but has no effect on withdrawal dynamics. This suggests that sensorimotor integration following addition of a stabilizing signal is performed at a cortical level, whereas the response to its withdrawal is "automatic" and accomplished at a subcortical level.

The Neuro-Mechanical Processes That Underlie Goal-Directed Medio-Lateral APA during Gait Initiation.

Gait initiation (GI) involves passing from bipedal to unipedal stance. It requires a rapid movement of the center of foot pressure (CoP) towards the future swing foot and of the center of mass (CoM) in the direction of the stance foot prior to the incoming step. This anticipatory postural adjustment (APA) allows disengaging the swing leg from the ground and establishing favorable conditions for stepping. This study aimed to describe the neuro-mechanical process that underlies the goal-directed medio-lateral (ML) APA. We hypothesized that controlled knee flexion of the stance leg contributes to the initial ML displacement of the CoP and to the calibration of the first step. Fourteen subjects initiated gait starting from three different initial stance widths of 15 cm (Small), 30 cm (Medium), and 45 cm (Large). Optoelectronic, force platform and electromyogram (EMG) measurements were performed. During APA, soleus activity diminished bilaterally, while tibialis anterior (TA) activity increased, more so in the stance leg than in the swing leg, and to a larger extent with increasing initial stance width. Knee flexion of the stance leg was observed during APA and correlated with the ML CoP displacement towards the swing leg. ML CoP and CoM displacements during APA increased with increasing stance width. The activity of stance-leg TA was correlated with the degree of knee flexion. Swing-leg tensor fasciae latae (TFL) was also active during APA. Across subjects, when stance-leg tibialis activity was low, TFL activity was large and vice versa. The modulation of the ML CoP position during APA allowed the gravity-driven torque to place the CoM just lateral to the stance foot during step execution. Accordingly, the gravity-driven torque, the ML CoM velocity during step execution, and the step width at foot contact (FC) were lower in the Small and greater in the Large condition. Consequently, the position of the stepping foot at FC remained close to the sagittal plane in all three conditions. Conclusively, coordinated activation of hip abductors and ankle dorsiflexors during APA displaces the CoP towards the swing leg, and sets the contact position for the swing foot.

Processing time of addition or withdrawal of single or combined balance-stabilizing haptic and visual information.

We investigated the integration time of haptic and visual input and their interaction during stance stabilization. Eleven subjects performed four tandem-stance conditions (60 trials each). Vision, touch, and both vision and touch were added and withdrawn. Furthermore, vision was replaced with touch and vice versa. Body sway, tibialis anterior, and peroneus longus activity were measured. Following addition or withdrawal of vision or touch, an integration time period elapsed before the earliest changes in sway were observed. Thereafter, sway varied exponentially to a new steady-state while reweighting occurred. Latencies of sway changes on sensory addition ranged from 0.6 to 1.5 s across subjects, consistently longer for touch than vision, and were regularly preceded by changes in muscle activity. Addition of vision and touch simultaneously shortened the latencies with respect to vision or touch separately, suggesting cooperation between sensory modalities. Latencies following withdrawal of vision or touch or both simultaneously were shorter than following addition. When vision was replaced with touch or vice versa, adding one modality did not interfere with the effect of withdrawal of the other, suggesting that integration of withdrawal and addition were performed in parallel. The time course of the reweighting process to reach the new steady-state was also shorter on withdrawal than addition. The effects of different sensory inputs on posture stabilization illustrate the operation of a time-consuming, possibly supraspinal process that integrates and fuses modalities for accurate balance control. This study also shows the facilitatory interaction of visual and haptic inputs in integration and reweighting of stance-stabilizing inputs.