Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.

Closing the Loop: From Motor Neuroscience to Neurorehabilitation.

The fields of human motor control, motor learning, and neurorehabilitation have long been linked by the intuition that understanding how we move (and learn to move) leads to better rehabilitation. In reality, these fields have remained largely separate. Our knowledge of the neural control of movement has expanded, but principles that can directly impact rehabilitation efficacy remain somewhat sparse. This raises two important questions: What can basic studies of motor learning really tell us about rehabilitation, and are we asking the right questions to improve the lives of patients? This review aims to contextualize recent advances in computational and behavioral studies of human motor learning within the framework of neurorehabilitation. We also discuss our views of the current challenges facing rehabilitation and outline potential clinical applications from recent theoretical and basic studies of motor learning and control.

Supraspinal contributions to defective antagonistic inhibition and freezing of gait in Parkinson's disease.

The neuromuscular circuit mechanisms of freezing of gait in Parkinson's disease have received little study. Technological progress enables researchers chronically to sense local field potential activity of the basal ganglia in patients while walking. To study subthalamic activity and the circuit processes of supraspinal contributions to spinal motor integration, we recorded local field potentials, surface EMG of antagonistic leg muscles and gait kinematics in patients while walking and freezing. To evaluate the specificity of our findings, we controlled our findings to internally generated volitional stops. We found specific activation-deactivation abnormalities of oscillatory activity of the subthalamic nucleus both before and during a freeze. Furthermore, we were able to show with synchronization analyses that subthalamo-spinal circuits entrain the spinal motor neurons to a defective timing and activation pattern. The main neuromuscular correlates when turning into freezing were as follows: (i) disturbed reciprocity between antagonistic muscles; (ii) increased co-contraction of the antagonists; (iii) defective activation and time pattern of the gastrocnemius muscle; and (iv) increased subthalamo-muscular coherence with the gastrocnemius muscles before the freeze. Beyond the pathophysiological insights into the supraspinal mechanisms contributing to freezing of gait, our findings have potential to inform the conceptualization of future neurorestorative therapies.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Vertebral level specific modulation of paraspinal muscle activity based on vestibular signals during walking.

Evoking muscle responses by electrical vestibular stimulation (EVS) may help to understand the contribution of the vestibular system to postural control. Although paraspinal muscles play a role in postural stability, the vestibulo-muscular coupling of these muscles during walking has rarely been studied. This study aimed to investigate how vestibular signals affect paraspinal muscle activity at different vertebral levels during walking with preferred and narrow step width. Sixteen healthy participants were recruited. Participants walked on a treadmill for 8 min at 78 steps/min and 2.8 km/h, at two different step width, either with or without EVS. Bipolar electromyography was recorded bilaterally from the paraspinal muscles at eight vertebral levels from cervical to lumbar. Coherence, gain, and delay of EVS and EMG responses were determined. Significant EVS-EMG coupling (P < 0.01) was found at ipsilateral and/or contralateral heel strikes. This coupling was mirrored between left and right relative to the midline of the trunk and between the higher and lower vertebral levels, i.e. a peak occurred at ipsilateral heel strike at lower levels, whereas it occurred at contralateral heel strike at higher levels. EVS-EMG coupling only partially coincided with peak muscle activity. EVS-EMG coherence slightly, but not significantly, increased when walking with narrow steps. No significant differences were found in gain and phase between the vertebral levels or step width conditions. In summary, vertebral level specific modulation of paraspinal muscle activity based on vestibular signals might allow a fast, synchronized, and spatially co-ordinated response along the trunk during walking. KEY POINTS: Mediolateral stabilization of gait requires an estimate of the state of the body, which is affected by vestibular afference. During gait, the heavy trunk segment is controlled by phasic paraspinal muscle activity and in rodents the medial and lateral vestibulospinal tracts activate these muscles. To gain insight in vestibulospinal connections in humans and their role in gait, we recorded paraspinal surface EMG of cervical to lumbar paraspinal muscles, and characterized coherence, gain and delay between EMG and electrical vestibular stimulation, during slow walking. Vestibular stimulation caused phasic, vertebral level specific modulation of paraspinal muscle activity at delays of around 40 ms, which was mirrored between left, lower and right, upper vertebral levels. Our results indicate that vestibular afference causes fast, synchronized, and spatially co-ordinated responses of the paraspinal muscles along the trunk, that simultaneously contribute to stabilizing the centre of mass trajectory and to keeping the head upright.

Polypharmacy Is Associated With Slow Gait Speed and Recurrent Falls in Older People With HIV.

BACKGROUND: Older people with human immunodeficiency virus (HIV, PWH) are prone to using multiple medications due to higher rates of medical comorbidities and the use of antiretroviral therapy (ART). We assessed the prevalence and clinical impact of polypharmacy among PWH. METHODS: We leveraged clinical data from the AIDS Clinical Trials Group A5322 study "Long-Term Follow-up of Older HIV-infected Adults: Addressing Issues of Aging, HIV Infection and Inflammation" (HAILO). We included PWH aged ≥40 years with plasma HIV RNA levels <200 copies/µL. We assessed the relationship between polypharmacy (defined as the use of 5 or more prescription medications, excluding ART) and hyperpolypharmacy (defined as the use of 10 or more prescription medications, excluding ART) with slow gait speed (less than 1 meter/second) and falls, including recurrent falls. RESULTS: Excluding ART, 24% of study participants had polypharmacy and 4% had hyperpolypharmacy. Polypharmacy was more common in women (30%) than men (23%). Participants with polypharmacy had a higher risk of slow gait speed (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.27-2.50) and increased risk of recurrent falls (OR = 2.12; 95% CI = 1.06-4.23). The risk for recurrent falls was further increased in those with hyperpolypharmacy compared with those without polypharmacy (OR = 3.46; 95% CI = 1.32-9.12). CONCLUSIONS: In this large, mixed-sex cohort of PWH aged ≥40 years, polypharmacy was associated with slow gait speed and recurrent falls, even after accounting for medical comorbidities, alcohol use, substance use, and other factors. These results highlight the need for increased focus on identifying and managing polypharmacy and hyperpolypharmacy in PWH.

Developing a novel dual-injection FDG-PET imaging methodology to study the functional neuroanatomy of gait.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

Kinematic and neuromuscular characterization of cognitive involvement in gait control in healthy young adults.

The signature of cognitive involvement in gait control has rarely been studied using both kinematic and neuromuscular features. The present study aimed to address this gap. Twenty-four healthy young adults walked on an instrumented treadmill in a virtual environment under two optic flow conditions: normal (NOF) and perturbed (POF, continuous mediolateral pseudorandom oscillations). Each condition was performed under single-task and dual-task conditions of increasing difficulty (1-, 2-, 3-back). Subjective mental workload (raw NASA-TLX), cognitive performance (mean reaction time and d-prime), kinematic (steadiness, variability, and complexity in the mediolateral and anteroposterior directions), and neuromuscular (duration and variability of motor primitives) control of gait were assessed. The cognitive performance and the number and composition of motor modules were unaffected by simultaneous walking, regardless of the optic flow condition. Kinematic and neuromuscular variability was greater under POF compared with NOF conditions. Young adults sought to counteract POF by rapidly correcting task-relevant gait fluctuations. The depletion of cognitive resources through dual-tasking led to reduced kinematic and neuromuscular variability and this occurred to the same extent regardless of simultaneous working memory (WM) load. Increasing WM load led to a prioritization of gait control in the mediolateral direction over the anteroposterior direction. The impact of POF on kinematic variability (step velocity) was reduced when a cognitive task was performed simultaneously, but this phenomenon was not modulated by WM load. Collectively, these results shed important light on how young adults adjust the processes involved in goal-directed locomotion when exposed to varying levels of task and environmental constraints.NEW & NOTEWORTHY The kinematic and neuromuscular signatures of cognitive involvement in gait control have rarely been studied jointly. We sought to address this issue using gait perturbation and dual-task paradigms. The protocol consisted of a fixed-speed treadmill walk to which visual and cognitive constraints were applied separately and together. The results revealed that young adults optimally regulated their gait to cope with these constraints by maintaining relatively stable muscle synergies and flexibly allocating attentional resources.

Ballet practice improves neuromuscular and biomechanical responses to an unexpected standing-slip in older adults.

Falls and fall-induced injuries are common and consequential in older adults. Ballet emphasizes full-body coordination, leg strength, and postural control. However, it remains unknown whether ballet can indeed reduce falls in older adults. This study examined biomechanical and neuromuscular responses of older recreational ballet dancers to an unexpected standing-slip. Twenty older ballet dancers (17 females, 3 males) and 23 age- and sex-matched nondancers (19 females, 4 males) were exposed to an unexpected slip during treadmill standing. The slip-faller rate was the primary outcome. The secondary outcomes were kinematic measurements, including dynamic gait stability, slip distance, and recovery stepping performance (step latency, duration, length, and speed). The tertiary outcome was the electromyography latency of leg muscles (bilateral tibialis anterior, medial gastrocnemius, rectus femoris, and biceps femoris). Fewer dancers fell than nondancers after the standing-slip (45% vs. 83%, P = 0.005, d = 0.970). Dancers displayed better stability at recovery foot liftoff (P = 0.006) and touchdown (P = 0.012), a shorter step latency (P = 0.020), shorter step duration (P = 0.011), faster step speed (P = 0.032), and shorter slip distance (P = 0.015) than nondancers. They also exhibited shorter latencies than nondancers for the standing leg rectus femoris (P = 0.028) and tibialis anterior (P = 0.002), and the stepping leg biceps femoris (P = 0.031), tibialis anterior (P = 0.017), and medial gastrocnemius (P = 0.030). The results suggest that older ballet dancers experience a lower fall risk and are more stable than nondancers following an unexpected standing-slip. The greater stability among dancers could be attributed to more biomechanically effective recovery stepping, possibly associated with the ballet-induced neuromuscular benefit-an earlier leg muscle activation.NEW & NOTEWORTHY This is the first study to examine how older ballet dancers respond to an unexpected external slip perturbation while standing. The results suggest that older ballet dancers experience a reduced fall risk after the slip than their nondancer counterparts. The lower fall risk can be accounted for by dancers' quicker neuromuscular reactions to the slip that result in a more effective recovery step and thus higher stability against backward falls due to the slip.

Task difficulty of visually guided gait modifications involves differences in central drive to spinal motor neurons.

Walking in natural environments requires visually guided modifications, which can be more challenging when involving sideways steps rather than longer steps. This exploratory study investigated whether these two types of modifications involve different changes in the central drive to spinal motor neurons of leg muscles. Fifteen adults [age: 36 ± 6 (SD) years] walked on a treadmill (4 km/h) while observing a screen displaying the real-time position of their toes. At the beginning of the swing phase, a visual target appeared in front (forward) or medial-lateral (sideways) of the ground contact in random step cycles (approximately every third step). We measured three-dimensional kinematics and electromyographic activity from leg muscles bilaterally. Intermuscular coherence was calculated in the alpha (5-15 Hz), beta (15-30 Hz), and gamma bands (30-45 Hz) approximately 230 ms before and after ground contact in control and target steps. Results showed that adjustments toward sideways targets were associated with significantly higher error, lower foot lift, and higher cocontraction between antagonist ankle muscles. Movements toward sideways targets were associated with larger beta-band soleus (SOL): medial gastrocnemius (MG) coherence and a more narrow and larger peak of synchronization in the cumulant density before ground contact. In contrast, movements toward forward targets showed no significant differences in coherence or synchronization compared with control steps. Larger SOL:MG beta-band coherence and short-term synchronization were observed during sideways, but not forward, gait modifications. This suggests that visually guided gait modifications may involve differences in the central drive to spinal ankle motor neurons dependent on the level of task difficulty.NEW & NOTEWORTHY This exploratory study suggests a specific and temporally restricted increase of central (likely corticospinal) drive to ankle muscles in relation to visually guided gait modifications. The findings indicate that a high level of visual attention to control the position of the ankle joint precisely before ground contact may involve increased central drive to ankle muscles. These findings are important for understanding the neural mechanisms underlying visually guided gait and may help develop rehabilitation interventions.

Impact of visual rotations on heading direction and center of mass control during steady-state gait.

Visual information is essential to navigate the environment and maintain postural stability during gait. Visual field rotations alter the perceived heading direction, resulting in gait trajectory deviations, known as visual coupling. It is unclear how center of mass (CoM) control relative to a continuously changing base of support (BoS) is adapted to facilitate visual coupling. This study aimed to characterize mediolateral (ML) balance control during visual coupling in steady-state gait. Sixteen healthy participants walked on an instrumented treadmill, naive to sinusoidal low-frequency (0.1 Hz) rotations of the virtual environment around the vertical axis. Rotations were continuous with 1) high or 2) low amplitude or were 3) periodic with 10-s intervals. Visual coupling was characterized with cross-correlations between CoM trajectory and visual rotations. Balance control was characterized with the ML margin of stability (MoSML) and by quantifying foot placement control as the relation between CoM dynamics and lateral foot placement. Visual coupling was strong on a group level (continuous low: 0.88, continuous high: 0.91, periodic: 0.95) and moderate to strong on an individual level. Higher rotation amplitudes induced stronger gait trajectory deviations. The MoSML decreased toward the deviation direction and increased at the opposite side. Foot placement control was similar compared with regular gait. Furthermore, pelvis and foot reorientation toward the rotation direction was observed. We concluded that visual coupling was facilitated by reorientating the body and shifting the extrapolated CoMML closer to the lateral BoS boundary toward the adjusted heading direction while preserving CoM excursion and foot placement control.NEW & NOTEWORTHY Healthy, naive participants were unaware of subtle, low-frequency rotations of the visual field but still coupled their gait trajectory to a rotating virtual environment. In response, participants decreased their margin of stability toward the new heading direction, without changing the center of mass excursion magnitude and foot placement strategy.

The effects of P2 segment of posterior cerebral artery to thalamus blood supply pattern on gait in cerebral small vessel disease: A 7 T MRI based study.

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.

Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study.

OBJECTIVE: Freezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. METHOD: Low-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. RESULTS: Regarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. CONCLUSION: This study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

Motor interference on lateral pelvis shifting towards the paretic leg during walking and its cortical mechanisms in persons with stroke.

Motor interference, where new skill acquisition disrupts the performance of a previously learned skill, is a critical yet underexplored factor in gait rehabilitation post-stroke. This study investigates the interference effects of two different practice schedules, applying interleaved (ABA condition) and intermittent (A-A condition) pulling force to the pelvis during treadmill walking, on lateral pelvis shifting towards the paretic leg in individuals with stroke. Task A involved applying resistive pelvis force (pulling towards the non-paretic side), and Task B applied assistive force (pulling towards the paretic side) at the stance phase of the paretic leg during walking. Sixteen individuals with chronic stroke were tested for gait pattern changes, including lateral pelvis shifting and spatiotemporal gait parameters, and neurophysiological changes, including muscle activity in the paretic leg and beta band absolute power in the lesioned cortical areas. A-A condition demonstrated increased lateral pelvis shifting towards the paretic side, extended paretic stance time and longer non-paretic step length after force release while ABA condition did not show any changes. These changes in gait pattern after A-A condition were accompanied by increased muscle activities of the ankle plantarflexors, and hip adductors/abductors. A-A condition demonstrated greater changes in beta band power in the sensorimotor regions compared to ABA condition. These findings suggest that while walking practice with external force to the pelvis can improve lateral pelvis shifting towards the paretic leg post-stroke, practicing a new pelvis shifting task in close succession may hinder the performance of a previously obtained lateral pelvis shifting pattern during walking.

Biochemical, biomechanical and imaging biomarkers of ischemic stroke: Time for integrative thinking.

Stroke is one of the leading causes of adult disability affecting millions of people worldwide. Post-stroke cognitive and motor impairments diminish quality of life and functional independence. There is an increased risk of having a second stroke and developing secondary conditions with long-term social and economic impacts. With increasing number of stroke incidents, shortage of medical professionals and limited budgets, health services are struggling to provide a care that can break the vicious cycle of stroke. Effective post-stroke recovery hinges on holistic, integrative and personalized care starting from improved diagnosis and treatment in clinics to continuous rehabilitation and support in the community. To improve stroke care pathways, there have been growing efforts in discovering biomarkers that can provide valuable insights into the neural, physiological and biomechanical consequences of stroke and how patients respond to new interventions. In this review paper, we aim to summarize recent biomarker discovery research focusing on three modalities (brain imaging, blood sampling and gait assessments), look at some established and forthcoming biomarkers, and discuss their usefulness and complementarity within the context of comprehensive stroke care. We also emphasize the importance of biomarker guided personalized interventions to enhance stroke treatment and post-stroke recovery.

Functional connectivity compensation in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a disabling motor symptom prevalent in patients with Parkinson's disease (PD); however, its pathophysiological mechanisms are poorly understood. This study aimed to investigate whole-brain functional connectivity (FC) pattern alterations in PD patients with FOG. A total of 18 PD patients, 10 with FOG (PD-FOG) and 8 without FOG (PD-nFOG), and 10 healthy controls were enrolled. High-resolution 3D T1-weighted and resting-state functional MRI (rs-fMRI) data were obtained from all participants. The groups' internetwork connectivity differences were explored with rs-fMRI FC using seed-based analysis and graph theory. Multiple linear regression analysis estimated the relationship between FC changes and clinical measurements. Rs-fMRI analysis demonstrated alterations in FC in various brain regions between the three groups. Freezing of Gait Questionnaire severity was correlated with decreased brain functional connection between Vermis12 and the left temporal occipital fusiform cortex (r = -0.82, P < .001). Graph theory topological metrics indicated a decreased clustering coefficient in the right superior temporal gyrus in the PD-nFOG group. PD-FOG patients exhibited a compensatory increase in connectivity between the left inferior frontal gyrus language network and the postcentral gyrus compared to PD-nFOG patients. Further, the decreased connection between Vermis 12 and the left temporal occipital fusiform cortex may serve as a potential neuroimaging biomarker for tracking PD-FOG and distinguishing between PD subtypes.

Functional assessment in patients with castration-resistant prostate cancer treated with darolutamide: results from the DaroAcT study.

BACKGROUND: Androgen receptor inhibitors (ARIs) are approved for the treatment of advanced prostate cancer; however, some patients may experience symptoms and side effects that hinder their physical functioning. The Timed Up and Go (TUG) and Short Physical Performance Battery (SPPB) tests are used to assess physical functioning in older adults and are recommended assessments for patients with prostate cancer, despite lacking validation in this setting. METHODS: DaroAct (NCT04157088) was an open-label, multicenter, phase 2b study designed to evaluate the effects of the ARI darolutamide (lead-in phase) and darolutamide vs enzalutamide (randomized phase) on physical functioning in men with castration-resistant prostate cancer (CRPC). Only the lead-in phase, in which participants received darolutamide 600 mg twice daily, was completed. The TUG and SPPB tests were used to assess physical functioning. RESULTS: The lead-in phase enrolled 30 participants. During 24 weeks of treatment, 8 (32.0%) of 25 evaluable participants exhibited clinically meaningful worsening in TUG from baseline (primary endpoint). At the week 24 visit, 5 (21.7%) of 23 participants had worsening in TUG time, and 8 (33.3%) of 24 participants had worsening in SPPB score. Because only 48% of participants had the same outcome on the TUG and SPPB tests, the study was terminated without initiating the randomized comparison. CONCLUSION: Most participants showed no clinically meaningful worsening in physical functioning after 24 weeks of darolutamide treatment, but poor agreement between tests was observed. Tools to accurately and consistently measure the impact of ARIs on physical functioning in patients with CRPC are needed.

Distributional data analysis via quantile functions and its application to modeling digital biomarkers of gait in Alzheimer's Disease.

With the advent of continuous health monitoring with wearable devices, users now generate their unique streams of continuous data such as minute-level step counts or heartbeats. Summarizing these streams via scalar summaries often ignores the distributional nature of wearable data and almost unavoidably leads to the loss of critical information. We propose to capture the distributional nature of wearable data via user-specific quantile functions (QF) and use these QFs as predictors in scalar-on-quantile-function-regression (SOQFR). As an alternative approach, we also propose to represent QFs via user-specific L-moments, robust rank-based analogs of traditional moments, and use L-moments as predictors in SOQFR (SOQFR-L). These two approaches provide two mutually consistent interpretations: in terms of quantile levels by SOQFR and in terms of L-moments by SOQFR-L. We also demonstrate how to deal with multi-modal distributional data via Joint and Individual Variation Explained using L-moments. The proposed methods are illustrated in a study of association of digital gait biomarkers with cognitive function in Alzheimers disease. Our analysis shows that the proposed methods demonstrate higher predictive performance and attain much stronger associations with clinical cognitive scales compared to simple distributional summaries.

A Plantar Pressure Detection and Gait Analysis System Based on Flexible Triboelectric Pressure Sensor Array and Deep Learning.

Gait detection is essential for the assessment of human health status and early diagnosis of diseases. The current gait analysis systems are bulky, limited in the scope of use, and cause interference with the movement of the measured person. Hence, it is necessary to develop a wearable gait detection system that is soft, breathable, lightweight, and self-powered. Here, a plantar pressure sensor array and gait analysis system based on a flexible triboelectric pressure sensor (FTPS) array is developed. Soft, breathable, and wearable electrospinning nanofiber film with excellent triboelectric properties is used as the plantar pressure sensor, achieving a high sensitivity of 45.1 mV kPa-1 in the range of 40-200 kPa and 19.4 mV kPa-1 in the range of 200-400 kpa. 32 FTPSs are integrated into an intelligent insole, which has the characteristics of soft, easy production, good air permeability, long-time stability, no external power supply, and etc. Based on the long short-term memory artificial neural network deep learning model, the accuracy of gait judgment can reach 94.23%. This work provides a feasible solution for real-time gait detection, which will have potential applications in human health assessment and early diagnosis of disease.