Neurorehabilitation and Neural Repair

Introduction: High-intensity locomotor training (HIT) is recommended for improving walking capacity, but treatment responses are variable. Understanding the brain changes underlying responsiveness to training could provide insight into this variability. Emerging evidence suggests upregulation of the contralesional cortico-reticulospinal tract (CRST) may contribute to walking function after stroke. However, it is unclear whether CRST upregulation is supportive or maladaptive, and no studies have examined CRST changes after HIT. This study investigated how CRST and corticospinal tract (CST) strength and laterality reorganize, and their relationship with walking capacity after locomotor HIT. Methods: Ten participants with chronic stroke completed a 4-week no-intervention control phase then 4-weeks of HIT. Diffusion MRI and 6-minute walk distance were obtained at weeks 0, 4, and 8. Analysis tested changes in ipsilesional and contralesional CRST and CST strength and laterality. Associations between changes in tract laterality and walking capacity were examined. Results: During the treatment phase (vs. the control phase), there were significantly greater increases in contralesional CRST strength (1.02 SD [95% CI: 0.25, 1.79]), contralesional CRST laterality (4.44 [2.15, 6.72]), and 6-minute walk distance (33 meters [17, 50]). Walking capacity improvements were associated with changes in CRST laterality (r = 0.77, p = 0.01), but not CST laterality (r = -0.01, p = 0.98). Discussion: Following HIT, increases in contralesional CRST strength and laterality were observed. CRST laterality changes were strongly associated with walking improvements, suggesting a possible supportive role of contralesional CRST in mediating training-related improvements in walking function after stroke.

Recovery of hand and arm function is critical for improving quality of life in individuals with tetraplegia due to spinal cord injury (SCI). Nerve transfer procedures can restore meaningful hand and arm function in chronic SCI, yet postoperative outcomes vary widely. We conducted a prospective, single-arm, open-label trial to assess the impact of intensive, robot-assisted rehabilitation training on functional recovery and cortical reorganization following nerve transfer. The primary endpoint was assessment of hand and arm function measured by the Box and Blocks Test. We report the results from three participants, AIS A at enrollment, who completed six weeks of intensive robotic training at least 1 year after nerve transfer surgery (NCT04041063). All participants demonstrated minimally important difference improvements in at least one secondary clinical outcome. These improvements were accompanied by cortical reorganization measured by transcranial magnetic stimulation motor mapping, indicating integration of the newly established peripheral motor pathways. No serious adverse events related to surgery or rehabilitation occurred. Although recruitment was limited by the COVID-19 pandemic and precludes definitive conclusions regarding efficacy, these findings suggest that standardized, intensive robotic rehabilitation may enhance functional outcomes after nerve transfer surgery for chronic tetraplegia.

BACKGROUNDDamage to the early visual cortex after an occipital stroke typically results in the loss of conscious vision in the contralateral hemifield. Nonetheless, extensive perceptual training can restore visual motion discrimination in the blind-field. Here, we assessed, in a cohort study, whether improvements transferred to an untrained Gabor detection task and whether awareness within the blind field increased. We then explored the neural underpinnings of these changes. METHODSEighteen participants (6 female; aged 24-74 years; >6 months post-stroke) completed at least six months of visual rehabilitation in their blind field. Rehabilitation consisted of participants practicing a two-alternative, forced-choice, motion discrimination task using random dot stimuli, five days/week, at home, at one or two non-overlapping, locations in their blind-field. Each participant also completed two in-lab visits: one pre- and one post-training. A subset returned to the lab for a follow-up visit three months later to assess persistence of recovery. In addition to the trained task, an untrained, drifting-Gabor detection task was used to measure transfer of learning and changes in visual awareness at the trained locations. To investigate neural mechanisms underlying generalisation of improvements, participants completed MRI scanning at each lab visit. Magnetic resonance spectroscopy (MRS) was used to quantify GABA and glutamate concentrations in the ipsilesional motion sensitive area, hMT+, and a control voxel in the sensorimotor cortex. Functional MRI was conducted to assess BOLD signal changes in hMT+ and across the rest of the brain during passive viewing of high contrast Gabor stimuli in the blind field. RESULTSParticipants showed significant improvements in motion direction discrimination (trained task) between pre- and post-training in-lab visits, which generalised to improvements in Gabor detection and awareness (untrained task). Reduced GABA and glutamate in ipsilesional hMT+ was linked to improved Gabor detection, but not awareness. Increased BOLD signals in hMT+ and dorsolateral prefrontal cortex also correlated with improved Gabor detection, while awareness changes were linked to higher-level areas associated with visual attention in the contralesional prefrontal cortex (area 46) and inferior parietal lobule. CONCLUSIONSLong-term visual rehabilitation using a global motion discrimination task generalised to enhance both detection and awareness of moving Gabors within the blind field of occipital stroke survivors. Improvements were supported by selective changes in brain regions known to be involved in motion perception and attention respectively, suggesting that a broad network supports recovery, which could be targeted to enhance outcomes.

Importance: Severe stroke is a leading cause of death and disability worldwide. Survivors and their families face long-term unmet needs, including care that does not reflect patients' values, fragmented care, and high rates of psychological distress among caregivers. Objective: To describe the conceptual framework of the longitudinal transdisciplinary neuropalliative care support (LOTUS) intervention and assess its fidelity in a pilot feasibility study. Design: Pilot feasibility randomized study; fidelity was assessed using weekly checklists completed by the LOTUS nurse and qualitative analysis of weekly LOTUS team meeting transcripts. Setting: Single comprehensive stroke center in Western New York. Participants: Patients hospitalized with severe stroke and their caregivers. Dyads were randomized to usual care or intervention. Intervention: The LOTUS intervention is implemented in a stepped-care fashion using 5 strategies: Awareness, Assistance, Adjustment, Acceptance and Alignment (5As). Led by a specially trained nurse with a chaplain, social worker, psychologist, and neuropalliative care physician, the LOTUS team follows dyads from early in the hospital course through 6 months. Main Outcomes and Measures: Fidelity, the degree to which the intervention was delivered as intended, assessed via (1) utilization of 5A activities from weekly LOTUS checklists; (2) thematic analysis of weekly LOTUS team meeting transcripts. Results: Of 26 patients in the trial, 13 were randomized to intervention. The LOTUS nurse completed 108 checklists, with an average of 619 minutes of direct contact per participant over 6 months. Each component of the 5A's was utilized. Awareness and Assistance predominated early after enrollment and revolved around personhood, support, and self-efficacy. Adjustment was especially relevant during care transitions and was typically supported by the LOTUS social worker. Acceptance and Alignment were more prevalent during later meetings, with the LOTUS psychologist supporting identification and modeling of coping skills and the LOTUS physician guiding prognosis and goals-of-care conversations. The LOTUS nurse served as primary point of contact, providing continuity and a trusting relationship, while other team members functioned in a predominantly advisory role. Conclusions: The LOTUS intervention was delivered with fidelity to the 5A-framework, supporting a future randomized clinical trial to evaluate its efficacy in patients with severe stroke and their caregivers.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

Background: Post-stroke apathy (PSA) is a common, disabling syndrome with few evidence-based treatment options. We evaluated the safety, feasibility, acceptability, and evidence of effects of a three-day accelerated intermittent theta burst stimulation-repetitive transcranial magnetic stimulation (iTBS-rTMS) protocol targeting the left dorsomedial prefrontal cortex (dmPFC) in chronic stroke survivors with apathy. Methods: Stroke survivors with symptomatic apathy received open-label iTBS-rTMS at the left dmPFC (21,600 pulses across 36 sessions; 3 treatment days; 12 sessions/day within one week). Safety endpoints included adverse events, neuroradiological findings, and objective cognitive performance. Secondary outcomes included measures of apathy and other neuropsychiatric symptoms as well as psychosocial functioning, including quality of life and caregiver burden. Participants were followed up for one month. Results: Fourteen participants (mean age = 61.8 {+/-} 14.0 years; mean time since stroke = 55.6 {+/-} 31.6 months) completed the iTBS-rTMS treatment course. No serious adverse events occurred. Participants rated the treatment as highly acceptable, and cognitive performance was stable from pre- to post-rTMS with no treatment-related changes on structural MRI. Regarding apathy, participants had significant improvements with moderate to large effect sizes on the Lille Apathy Rating Scale (LARS), on both self (d = 0.78) and caregiver-rated versions (d = 1.28), p<0.05 pretreatment-to-one-month follow-up. In addition, secondary measures of psychosocial function also showed improvement with moderate to large effect sizes (Stroke Specific Quality of Life Scale: d = 0.62; Zarit Burden Interview: d = 0.72), and the Brief Inventory of Psychosocial Function: d = 0.89). Conclusions: In chronic stroke survivors with PSA, accelerated iTBS-rTMS targeting the left dmPFC appears to be safe, feasible, tolerable, and highly acceptable, with preliminary evidence suggesting a potential role in reducing apathy and secondarily promoting improvements in quality of life, caregiver burden, and broader psychosocial function.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is provoked by turning, doorways and dual-task walking. We evaluated WALK, a cadence-linked vibration neuromodulation combined with motor-learning training. Methods: Single-centre, sham-controlled pilot randomised trial. Adults with PD (Hoehn and Yahr 2 to 4) and neurologist-verified FOG were randomised 1:1 to intervention (WALK; vibration enabled) or sham (WALK; vibration disabled), alongside identical supervised home-based training for 6 weeks (3 sessions per week). OFF-medication assessments were performed at S0, S8 and S16. At S8 and S16, assessments were completed without a device and then with a device (fixed order). The primary endpoint was the mZ-FOG total (0 to 36). Results: Forty participants completed follow-up assessments (intervention n=24; sham n=16) with 100% session adherence and no serious device-related adverse events. In the intervention group, mZ-FOG total improved when assessed with the device at S8 ({Delta}=8.08) and S16 ({Delta}=9.21) relative to S0, with partial retention when assessed without the device at S16 ({Delta}=5.54). Conclusions: Cadence-linked, localised vibration neuromodulation plus motor-learning training was feasible and was associated with clinically meaningful within-intervention-group reductions in FOG. Taken together, the effect sizes and task-specific pattern support progression to a multicentre, assessor-blinded trial with an active sham, powered for between-group comparisons and durability and/or adherence endpoints.

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

Background: Occupational therapists can improve stroke survivors hand and arm movement and participation in daily activities through action observation (AO). AO involves watching another persons hand or arm complete a movement or task. While research generally supports the use of AO with stroke survivors, there are limited AO videos are available to occupational therapists which makes applying AO challenging. Objective: The purpose of this work is to develop structured and widely accessible tool to support access to AO for stroke survivors, occupational therapists, and researchers. Methods: To develop an AO video library for stroke rehabilitation, functional and non-functional upper limb task deficits were first identified through clinical observations and clinician interviews to establish a prioritized list of daily activities. In collaboration with media production specialists, healthy adult volunteers were recruited and filmed performing these tasks from both first- and third-person perspectives. The recorded videos were then systematically edited, enhanced with instructional title slides, and distributed via a public YouTube channel for clinical application and a categorized digital repository for research purposes. Results: Initial assessments revealed a complete lack of familiarity, awareness, and utilization of AO resources among local occupational therapists, despite high perceived clinical utility. To address this gap, a final library of 150 tasks was established, resulting in the production of 419 finalized, standardized videos featuring six healthy volunteers. For clinical application, these videos were hosted on a free, public YouTube channel organized into 18 functional playlists, while a parallel set was structured into distinct movement categories for research repository storage. Conclusion: By providing a structured and highly accessible tool, this repository enables clinicians, researchers, and caregivers to readily implement evidence-based action observation interventions in both clinical and home settings.

Freezing of gait is a disabling episodic symptom of Parkinson's disease, typically emerging during complex locomotor tasks such as turning, obstacle negotiation, and gait initiation. These tasks require effective motor planning and proactive visual search of the intended walking route. Current evidence suggests that people with Parkinson's disease and freezing of gait show different patterns of visual search compared to those without freezing of gait and healthy older adults. However, existing reports are based on relatively simple tasks that lack common triggers for freezing of gait and do not adequately control for other factors likely to influence visual search, such as motor symptom severity and balance ability. This study examined visual search behaviour in 24 healthy older adults and 37 people with Parkinson's disease (21 with freezing of gait, 16 without) during a complex walking task requiring repeated turning and navigation through narrow spaces. Visual search characteristics were compared between people with Parkinson's disease and healthy controls, and relationships between visual search, freezing of gait, motor symptom severity, and balance ability were explored within the Parkinson's disease group. Compared with healthy controls, people with Parkinson's disease showed significantly fewer fixations toward areas outside the walking path, longer average fixation durations, and reduced saccade amplitudes, with no differences in proactive visual planning of the intended route. No relationship was found between visual search outcomes and freezing of gait. Reduced fixations to outside-path areas were associated with poorer functional balance independently of motor symptom severity. These findings indicate that restricted visual sampling in Parkinson's disease is primarily associated with balance impairment rather than freezing of gait or motor symptom severity.

Introduction Functional neurological disorder (FND) is a common cause of neurological disability and is associated with substantial healthcare utilisation and cost. Most available treatments target specific symptom subtypes, and prospective evidence regarding the effect of treatment on health-system costs remains limited. We evaluated the real-world clinical and economic outcomes of a transdiagnostic outpatient intervention, attention-based rehabilitation (ABR). Methods We conducted a pragmatic waitlist-controlled study in 54 consecutively referred patients with neurologist-diagnosed FND attending a specialist outpatient service. Clinical outcomes--including quality of life (Short Form-36), social and occupational participation (Work and Social Adjustment Scale), symptom severity, and mental health (Hospital Anxiety and Depression Scale)--were assessed at waitlist entry, treatment commencement, treatment completion, and 6 and 12 months post-treatment. Healthcare utilisation and costs were obtained prospectively from health-service financial records for the 6 months preceding treatment, the treatment period, and two consecutive 6-month post-treatment periods. Longitudinal clinical outcomes and healthcare costs were analysed using Bayesian mixed-effects and mixture models, respectively. Results All clinical measures remained stable or worsened during the waitlist control period. Across treatment, six of eight SF-36 domains, WSAS, employment status, and both HADS subdomains improved, with maintenance through 12 months. Patient-reported symptom improvement persisted post-treatment. Expected monthly health system costs approximately halved post-treatment, with net cost savings by approximately 50 days. Conclusion A fixed-duration, symptom-agnostic outpatient ABR programme was associated with durable improvements in functioning and quality of life, alongside substantial reductions in healthcare utilisation and cost, supporting scalable symptom-agnostic treatment models for FND.

Stroke is a leading cause of long-term disability, often resulting in persistent motor impairments reflecting disruptions in large-scale brain networks. While electroencephalography (EEG) has long been used to monitor neurophysiological changes following stroke, an integrated framework capturing spatiotemporal dynamics would help understand changes over time. In this study, we analysed resting-state EEG from stroke patients at one week (Session 1) and three months (Session 2) post-stroke to investigate electrophysiological biomarkers of motor recovery, indexed by changes in the Fugl-Meyer scale ({Delta}FM ). We quantified spectral properties, focusing on the relative alpha band power, microstate metrics such as mean duration, complexity, and transition probabilities, and measures of metastability and synchrony derived from the Kuramoto Order Parameter. Among all the EEG measures, the longitudinal change in relative alpha power emerged as the strongest single correlate of motor improvement, accounting for the largest proportion of variance among the examined EEG measures. Although metastability and synchrony alone did not reach statistical significance, they showed moderate positive correlations with {Delta}FM, particularly in the alpha and theta ranges, and once combined with alpha power, added 26% in explaining the variance in {Delta}FM . Microstate parameters did not explain additional variance in recovery once alpha power and network-level dynamics were considered. A hierarchical model combining alpha power, metastability/synchrony, and microstates explained over 78% of the variance in {Delta}FM, indicating that stroke recovery involves restoring balanced alpha oscillations and flexible large-scale brain coordination. Future research with larger samples and more frequent longitudinal assessments is required to confirm the prognostic utility of integrated EEG biomarkers for guiding personalised stroke rehabilitation strategies.

Background: Huntington ' s disease (HD) causes progressive postural control deficits, but how sensory reweighting mechanisms degrade across disease stages remains poorly understood. Objective: To determine whether objective markers of postural sway track disease severity and altered sensory reweighting across the HD spectrum. Methods: Ninety-seven adults (46 {+/-} 14 yrs) were categorized into four groups: 29 with HD, 27 pre-manifest (PM), 28 not at risk (AR-), and 13 age-matched healthy controls (HC). Participants performed three trials of quiet standing with eyes open and eyes closed on a force plate. Results: Manifest HD individuals exhibited greater AP, ML, and total COP sway displacement compared with the PM, AR-, and HC groups. HD and PM groups demonstrated greater instability with eyes closed. COP wavelet power was concentrated below 1 Hz across all groups. The eyes-open to eyes-closed change in 0-1 Hz power predicted total COP sway in HC (68%), AR- (45%), and PM (46%), but this relation was substantially weaker in HD. Conclusions: Progressive weakening of oscillatory-sway coupling distinguishes manifest HD from premanifest stages. PM individuals demonstrate early sensory reweighting deficits that manifest only when vision is removed, while HD individuals show decoupled oscillatory activity that fails to support stable postural regulation. This progressive decoupling may serve as a candidate marker of disease conversion prior to overt motor diagnosis.

Ankle clonus is a sustained, involuntary, rhythmic muscle contraction frequently observed in humans with spinal cord injury (SCI). Although its pathophysiology remains incompletely understood, converging evidence suggests a role for brainstem systems in its generation. Following SCI, brainstem neuromodulatory inputs partially compensate for the loss of descending motor pathways by regulating motoneuron excitability during involuntary contractions, suggesting their involvement in the generation of clonus. To test this hypothesis, motoneuron excitability in response to Ia synaptic input was quantified using the soleus H reflex and maximal motor response (H/M ratio), and brainstem involvement was probed using the long lasting component of the cutaneous reflex (LLR) in the tibialis anterior and soleus muscles, as well as the StartReact response-an involuntary release of a movement triggered by a startling stimulus thought to engage the reticulospinal tract. We studied individuals with chronic SCI, both with and without ankle clonus, using standardized clinical tests across two days. Participants with clonus showed elevated H/M ratios, indicating increased motoneuron excitability, whereas those without clonus exhibited lower values than controls. Additionally, individuals with clonus exhibited longer LLR duration and greater LLR magnitude in both muscles, along with shorter reaction times to startle stimuli, consistent with enhanced monoaminergic and reticulospinal contributions. Notably, LLR duration was positively correlated with both StartReact response and H/M ratio. Together, these findings support a role for descending brainstem systems-particularly monoaminergic and reticulospinal pathways-in the maintenance of clonus in chronic SCI.

BackgroundtPA is used for the acute treatment of ischaemic stroke because it converts plasminogen to active plasmin, which breaks down clots. Previous studies show that tPA-activated plasminogen impairs brain endothelial barrier function. However, it is unclear whether the plasmin product of this reaction directly contributes to brain endothelial barrier deterioration. ObjectiveDetermine whether plasmin directly influences the human brain endothelial barrier. MethodsWe developed a new serum-free hCMEC/D3 culture model with ECIS real-time monitoring to establish how plasmin in isolation influences the brain endothelial barrier. ResultsECIS monitoring demonstrated that plasmin caused a concentration-dependent decline in hCMEC/D3 barrier integrity, which was primarily mediated by a reduction in endothelial cell-to-cell interactions. Whilst a decrease in membrane capacitance and increase in basolateral adhesion were also observed, these changes were less marked. The inclusion of 2-antiplasmin ameliorated the changes in hCMEC/D3 barrier properties, suggesting this response is mediated by plasmins proteolytic activity. Quantitative immunocytochemistry confirmed that plasmin stimulated a decline in the key junctional molecules, Claudin-5, VE-Cadherin (CD144), {beta}-Catenin, ZO-1 and PECAM-1 (CD31), which likely contributed to the deterioration of paracellular cell-to-cell interactions. Interestingly, using this serum-free model, tPA alone didnt influence hCMEC/D3 barrier properties, whilst tPA with plasminogen did, implicating plasmins involvement. ConclusionPlasmin directly impaired the barrier function of hCMEC/D3 brain endothelial cell monolayers by stimulating a decline in key junctional molecules. This plasmin-mediated brain endothelial barrier deterioration has important implications for tPA use and should be considered whilst designing safer thrombolytic treatment options for patients experiencing acute ischemic stroke.

PurposeParkinsons disease (PD) is a neurodegenerative disease that affects motor control but can also influence sensory perception. Changes in vision and proprioception are well-documented but less is known about how PD alters auditory perception, particularly perception of speech acoustic properties. The current study examined perception of speech rate and intensity in PD and the relationship of auditory perception to disease severity. MethodPeople with PD were compared to age- and hearing-matched controls using perceptual tasks focused on discrimination and learning of speech rate and intensity. For rate discrimination, speech, non-speech, and visual stimuli were included to determine whether performance differences for PD participants and controls were specific to speech. Disease severity was assessed using the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and the relationship to performance on perceptual discrimination and learning tasks was evaluated. ResultsPeople with PD performed significantly worse than controls in the rate discrimination task for all types of stimuli. There were no significant group differences for intensity discrimination. However, participants with greater PD disease severity demonstrated significantly poorer intensity discrimination accuracy. Performance on learning tasks utilizing rate and intensity manipulations did not differ between PD and control participants and was unrelated to PD disease severity. ConclusionsPeople with PD had difficulty discriminating rate differences across speech, non-speech, and visual stimuli, indicating that challenges with rate perception are not limited to speech. The relationship between intensity discrimination and disease severity suggests common dopaminergic networks between motor symptoms and auditory perception in PD.

BACKGROUND: Dual task walking requires simultaneous management of cognitive and motor demands and is associated with changes in gait and cortical activation. However, the relationship between task related cortical recruitment and dual task related gait adjustments in healthy young adults remains unclear. This study aimed to investigate the effects of dual tasking on gait performance and cortical activation, and to examine the association between changes in cortical activity and dual-task costs. METHODS: This cross sectional study included 33 healthy young adults. Participants performed three conditions: single task walking, cognitive single task (verbal fluency), and dual task walking. Each condition was repeated 10 times using a repeated short block design with randomized trial presentation. Gait performance was assessed using an instrumented walkway, and cortical activation was measured using functional near infrared spectroscopy. Dual task costs were calculated for gait and cognitive outcomes. Statistical analysis included repeated measures analysis of variance (ANOVA) and Wilcoxon signed rank tests, with false discovery rate correction for multiple comparisons. Associations between changes in cortical activation and dual task costs were examined using correlation analyses. RESULTS: Dual task walking resulted in significant changes in gait, including reduced speed, step and stride length, and increased base of support, stance, and double support (all p < 0.05), while cognitive performance remained unchanged. Dual tasking was associated with increased cortical activation in left prefrontal and motor related regions. Greater increases in cortical activation were associated with lower dual task costs across most gait parameters, with significant correlations observed in the left dorsolateral prefrontal cortex (r {approx} 0.42 to 0.47 for speed and stride length; p < 0.05). Double support showed a distinct pattern, suggesting a specific temporal adjustment within the gait cycle. CONCLUSIONS: Dual task walking in young adults is associated with coordinated behavioral and cortical adaptations. Increased cortical recruitment is linked to reduced motor interference, suggesting that broader engagement of cortical networks may contribute to performance under cognitive motor load.

Impaired reading, i.e., alexia, is common after left hemisphere stroke. The most common deficit in alexia is a difficulty reading aloud pronounceable novel words, also called pseudowords. While semantic and phonological processes both subserve reading real words, pseudoword reading deficits in alexia are typically ascribed to phonological deficits alone. Some theories, however, suggest that pseudoword reading relies in part on lexical-semantic knowledge, such that semantic deficits could also contribute to poor pseudoword reading in alexia. Leveraging a large sample of left-hemisphere stroke survivors, we examine the cognitive and neural substrates of pseudoword reading accuracy and two error types: lexicalization errors, where a pseudoword is incorrectly read as a real word, and nonword errors, where a pseudoword is read as an incorrect nonword. 76 left-hemisphere stroke survivors read 60 pseudowords aloud, and performed two pseudoword repetition tasks to assess phonological processing and two picture naming tasks to assess mappings between lexical semantics and phonology. Regression models assessed how pseudoword repetition and naming related to overall accuracy and rates of lexicalization and nonword errors in pseudoword reading. Voxel-based and connectome lesion-symptom mapping localized the neural territory responsible for these errors. Both pseudoword repetition and naming independently related to pseudoword reading accuracy. Pseudoword repetition but not naming deficits predicted higher rates of lexicalization errors, while naming but not pseudoword repetition deficits predicted higher rates of nonword errors. Greater nonword error rate also predicted smaller imageability effects in real word reading (t(71)=-3.2, p=0.002). Lexicalization errors were associated with lesions to and disconnections of the left putamen and basal ganglia. Nonword errors were associated with lesions to the superior and middle temporal gyri, as well as broad temporo-parietal disconnections, overlapping with previous lesion-mapping results implicating these regions in semantic contributions to word reading. These results suggest that lexicalization errors result from impaired planning and execution of novel motor plans, causing a reliance on the well-learned motor plans associated with lexical items. In contrast, greater rates of nonword errors, relative to lexicalization errors, occur when semantic contributions to reading are impaired. Overall, these findings demonstrate that semantic processes are involved in reading pseudowords, at least in stroke alexia. These findings support connectionist accounts of reading in which damage in the direct orthography to phonology route for reading leads to reliance on semantic representations, even for pseudowords, suggesting a reinterpretation of pseudoword reading as a pure measure of phonological reading deficits.

The Disconnection Symptom Discoverer (DSD) model proposes to predict long-term performance on neuropsychological tests from stroke lesion disconnection profiles. The model requires external validation to determine reproducibility and generalizability to new and different patients. Here, we investigated whether the DSD supports accurate multi-domain cognitive outcome predictions at three different timepoints post stroke, in a clinically representative independent cohort. In this study, the DSD was used to predict visuospatial attention, verbal memory, and language scores in an independent cohort of 74 stroke survivors (mean age = 69.2, 39% female) with 3 repeated cognitive assessments. DSD-predicted scores were compared to observed neuropsychological scores collected at <2 weeks, six months, and > 2 years post-stroke. DSD-predicted language outcomes were significantly correlated with observed behaviour at the <2 weeks timepoint, but no other significant correlations between DSD-predicted scores were identified. Importantly, DSD-predicted verbal memory and visuospatial domain scores were not significantly correlated with observed behaviour at any of the considered timepoints (minimum p-value = 0.33). Across all tests and timepoints, DSD-predicted scores had an average Mean Absolute Error (MAE) of 0.21 (SD = 0.13, range = 0.04-0.43), with the highest errors occurring between predicted and observed memory scores. Larger stroke lesions were associated with higher MAE, indicating that the DSD performance was modulated by stroke severity. Overall, these results indicate that the DSD did not yield informative predictions of long-term cognitive outcomes in this external dataset. This finding provides an important illustration of potential overfitting issues within cognitive outcome prediction models, highlighting the need for caution when aiming to predict long-term post-stroke cognitive outcomes and further external validation of proposed models.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss, muscle atrophy and paralysis. Although traditionally considered a MN-specific disease, accumulating evidence supports a crucial contribution of skeletal muscle pathology to disease onset and progression. Except for specific mutations, to date there is no effective treatment for ALS. FOXO transcription factors regulate programs of atrophy, metabolism and stress response in skeletal muscle, and their inhibition has shown beneficial effects in cellular and Drosophila models of ALS. MethodsIn this study, we investigated whether pharmacological FOXO inhibition (iFOXO) could modify disease progression and muscle pathology in female hSOD1G93A mice. Mice received daily oral administration of iFOXO starting at presymptomatic (P50; n=5 per group) or symptomatic (P90; n=9 mice per group) stages until end-stage. Body weight was monitored longitudinally, and motor performance was evaluated using grip strength and hanging-wire tests. Tibialis anterior and soleus muscles, representing fast- and slow-twitch muscles respectively, were analyzed by histology and immunofluorescence to assess fiber atrophy, fibrosis, lipid accumulation, satellite cell pool and fiber type composition. Quadriceps muscles (n=3 per group) were used for RNA-seq analysis. ResultsWhile histological analyses revealed severe fiber atrophy and increased fibrosis in hSOD1G93A mice, satellite cell numbers were preserved or mildly increased in a muscle and treatment onset dependent manner. iFOXO treatment did not improve motor performance, survival or attenuate muscle atrophy. Transcriptomic profiling indicated that genotype was the predominant driver of gene expression changes, while iFOXO produced only subtle, treatment onset dependent effects on pathways related to oxidative stress responses, mitochondrial function and adaptive metabolism. ConclusionOverall, FOXO inhibition alone showed limited therapeutic benefit in the hSOD1G93A ALS mouse model. These findings highlight the dominant influence of ALS driven molecular alterations over pharmacological modulation and emphasize the need for combinatorial therapeutic strategies targeting multiple disease mechanisms, including those preserving nerve health.