SpinalTRAQ: A novel volumetric cervical spinal cord atlas identifies the corticospinal tract synaptic projectome in healthy and post-stroke mice.

Descending corticospinal tract (CST) connections to the neurons of the cervical spinal cord are vital for performance of forelimb-specific fine motor skills. In rodents, CST axons are almost entirely crossed at the level of the medullary decussation. While specific contralateral axon projections have been well-characterized using anatomic and molecular approaches, the field currently lacks a cohesive imaging modality allowing rapid quantitative assessment of the entire, bilateral cervical cord projectome at the level of individual laminae and cervical levels. This is potentially important as the CST is known to undergo marked structural remodeling in development, injury, and disease. We developed SpinalTRAQ (Spinal cord Tomographic Registration and Automated Quantification), a novel volumetric cervical spinal cord atlas and machine learning-driven microscopy acquisition and analysis pipeline that uses serial two-photon tomography- images to generate unbiased, region-specific quantification of the fluorescent pixels of anterograde AAV-labeled CST pre-synaptic terminals. In adult mice, the CST synaptic projectome densely innervates the contralateral hemicord, particularly in laminae 5 and 7, with sparse, monosynaptic input to motoneurons in lamina 9. Motor pools supplying axial musculature in the upper cervical cord are bilaterally innervated. The remainder of the ipsilateral cord has sparse labeling in a distinct distribution compared to the contralateral side. Following a focal stroke of the motor cortex, there is a complete loss of descending corticospinal axons from the injured side. Consistent with prior reports of axon collateralization, the CST spinal projectome increases at four weeks post-stroke and continues to elevate by six weeks post stroke. At six weeks post-stroke, we observed striking synapse formation in the denervated hemicord from the uninjured CST in a homotopic distribution. Additionally, CST synaptic reinnervation increases in the denervated lamina 9 in nearly all motoneuron pools, exhibiting novel patterns of connectivity. Detailed level- and lamina-specific quantification of the bilateral cervical spinal cord synaptic projectome reveals previously undescribed patterns of CST connectivity in health and injury-related plasticity.

Investigating premotor corticospinal excitability in fast and slow voluntary contractions of the elbow flexors.

Corticospinal excitability (CSE) increases prior to a voluntary contraction; however, the relative contributions of premotor cortical and spinal mechanisms are poorly understood. It is unknown whether the intended voluntary contractile rate affects CSE. Eighteen young, healthy participants (nine females) completed isometric elbow flexion contractions targeting 50% maximal voluntary contraction (MVC) torque, at either fast (fast as possible) or slow (25% MVC/s) contractile rates. Participants were cued to contract with warning (red) and "GO" (green) visual signals. Magnetic and electric stimulations were applied to elicit motor evoked potentials (MEPs), cervicomedullary evoked potentials (CMEPs), and M-waves, in the surface electromyogram (EMG) recorded over the biceps brachii. MEPs and CMEPs were collected at 0, 25, 50 and 75% premotor reaction time (RT - defined as the time between the "GO" cue and onset of biceps brachii EMG) and compared to a resting baseline. MEP amplitude was greater than baseline at 75% RT (p=0.009), and CMEP amplitude was significantly increased at all RT points relative to baseline (p≤0.001). However, there were no differences in MEP and CMEP amplitudes when compared between fast and slow conditions (p≥0.097). Normalized to the CMEP, there was no difference in MEP amplitude from baseline in either contractile condition (p≥0.264). These results indicate that increased premotor CSE is a spinally-mediated response. Furthermore, premotor CSE is not influenced by the intended voluntary contractile rate. CMEP amplitudes were larger for females than males within the premotor RT period (p=0.038), demonstrating that premotor spinal excitability responses may be influenced by sex.

Explainable artificial intelligence on safe balance and its major determinants in stroke patients.

This study develops explainable artificial intelligence for predicting safe balance using hospital data, including clinical, neurophysiological, and diffusion tensor imaging properties. Retrospective data from 92 first-time stroke patients from January 2016 to June 2023 was analysed. The dependent variables were independent mobility scores, i.e., Berg Balance Scales with 0 (45 or below) vs. 1 (above 45) measured after three and six months, respectively. Twenty-nine predictors were included. Random forest variable importance was employed for identifying significant predictors of the Berg Balance Scale and testing its associations with the predictors, including Berg Balance Scale after one month and corticospinal tract diffusion tensor imaging properties. Shapley Additive Explanation values were calculated to analyse the directions of these associations. The random forest registered a higher or similar area under the curve compared to logistic regression, i.e., 91% vs. 87% (Berg Balance Scale after three months), 92% vs. 92% (Berg Balance Scale after six months). Based on random forest variable importance values and rankings: (1) Berg Balance Scale after three months has strong associations with Berg Balance Scale after one month, Fugl-Meyer assessment scale, ipsilesional corticospinal tract fractional anisotropy, fractional anisotropy laterality index and age; (2) Berg Balance Scale after six months has strong relationships with Fugl-Meyer assessment scale, Berg Balance Scale after one month, ankle plantar flexion muscle strength, knee extension muscle strength and hip flexion muscle strength. These associations were positive in the SHAP summary plots. Including Berg Balance Scale after one month, Fugl-Meyer assessment scale or ipsilesional corticospinal tract fractional anisotropy in the random forest will increase the probability of Berg Balance Scale after three months being above 45 by 0.11, 0.08, or 0.08. In conclusion, safe balance after stroke strongly correlates with its initial motor function, Fugl-Meyer assessment scale, and ipsilesional corticospinal tract fractional anisotropy. Diffusion tensor imaging information aids in developing explainable artificial intelligence for predicting safe balance after stroke.

Advanced tractography-guided laser ablation of a perirolandic long-term epilepsy-associated tumor: illustrative case.

BACKGROUND: Microsurgical resection of drug-resistant epilepsy-associated perirolandic lesions can lead to postoperative motor impairment. Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (MRgLITT) has emerged as a less invasive alternative, offering reduced surgical risks and improved neurological outcomes. Electrophysiological tools routinely used for motor mapping in resective microsurgery are incompatible with intraoperative MRI. The utilization of advanced neuroimaging adjuncts for eloquent brain mapping during MRgLITT is imperative. The authors present the case of a 17-year-old athlete who underwent MRgLITT for a perirolandic long-term epilepsy-associated tumor (LEAT). They performed probabilistic multi-tissue constrained spherical deconvolution (MT-CSD) tractography to delineate the corticospinal tract (CST) for presurgical planning and intraoperative image guidance. The CST tractography was integrated into neuronavigation and MRgLITT workstation software to guide the ablation while monitoring the CST throughout the procedure. OBSERVATIONS: The integration of CST tractography into neuronavigation workstation planning and laser ablation workstation thermoablation is feasible and practical, facilitating complete ablation of a deep-seated perirolandic LEAT while preserving motor function. LESSONS: Probabilistic MT-CSD tractography enhanced MRgLITT planning as well as intraprocedural CST visualization and preservation, leading to a favorable functional outcome. The limitations of tractography and the predictability of thermal output distribution compared to the gold standard of microsurgical resection merit further discussion. https://thejns.org/doi/10.3171/CASE24139.

Neuromuscular characteristics of eccentric, concentric and isometric contractions of the knee extensors.

PURPOSE: We compared voluntary drive and corticospinal responses during eccentric (ECC), isometric (ISOM) and concentric (CON) muscle contractions to shed light on neurophysiological mechanisms underpinning the lower voluntary drive in a greater force production in ECC than other contractions. METHODS: Sixteen participants (20-33 years) performed ISOM and isokinetic (30°/s) CON and ECC knee extensor contractions (110°-40° knee flexion) in which electromyographic activity (EMG) was recorded from vastus lateralis. Voluntary activation (VA) was measured during ISOM, CON and ECC maximal voluntary contractions (MVCs). Transcranial magnetic stimulation elicited motor-evoked potentials (MEPs) and corticospinal silent periods (CSP) during MVCs and submaximal (30%) contractions, and short-interval intracortical inhibition (SICI) in submaximal contractions. RESULTS: MVC torque was greater (P < 0.01) during ECC (302.6 ± 90.0 Nm) than ISOM (269.8 ± 81.5 Nm) and CON (235.4 ± 78.6 Nm), but VA was lower (P < 0.01) for ECC (68.4 ± 14.9%) than ISOM (78.3 ± 13.1%) and CON (80.7 ± 15.4%). In addition, EMG/torque was lower (P < 0.02) for ECC (1.9 ± 1.1 µV.Nm-1) than ISOM (2.2 ± 1.2 µV.Nm-1) and CON (2.7 ± 1.6 µV.Nm-1), CSP was shorter (p < 0.04) for ECC (0.097 ± 0.03 s) than ISOM (0.109 ± 0.02 s) and CON (0.109 ± 0.03 s), and MEP amplitude was lower (P < 0.01) for ECC (3.46 ± 1.67 mV) than ISOM (4.21 ± 2.33 mV) and CON (4.01 ± 2.06 mV). Similar results were found for EMG/torque and CSP during 30% contractions, but MEP and SICI showed no differences among contractions (p > 0.05). CONCLUSIONS: The lower voluntary drive indicated by reduced VA during ECC may be partly explained by lower corticospinal excitability, while the shorter CSP may reflect extra muscle spindle excitation of the motoneurons from vastus lateralis muscle lengthening.

Central motor conduction time predicts new pyramidal MRI lesion and stroke-in-evolution in acute ischemic stroke.

Stroke is one of the leading causes of disability worldwide. Stroke-in-evolution is an essential issue as it is often associated with a worse outcome. Central motor conduction time (CMCT) is the time required for neural impulses to travel through the central nervous system to the target muscles. CMCT prolongation indicates dysfunction of the corticospinal tract. This study aims to investigate the impact of CMCT on clinical features and MRI characteristics in patients with acute ischemic stroke. A total of 94 patients with suspected acute ischemic stroke, with an average age of 67.13 ± 10.73 years old and 69.15 % being male, were enrolled in this study. All patients underwent evaluation for stroke risk factors, medical record review, CMCT examination (with CMCT (+) indicating CMCT prolongation), cranial MRI examinations, and data analysis. Compared to CMCT (-), the number of CMCT (+) subjects was significantly higher in all groups except the "Ever Stroke" group. The CMCT (+) group exhibited significantly higher values of "NIHSS" and "mRS" compared to the CMCT (-) group. After ANCOVA adjustment, the number of CMCT (+) subjects remained significantly higher only in the radiologically classified "New Pyramidal Lesion on MRI" and clinically classified "Stroke-In-Evolution" groups. In conclusion, CMCT serves as both a diagnostic indicator of acute ischemic stroke with weakness accompanied by new pyramidal lesions on brain MRI, rather than weakness associated with old lesions on brain MRI, and as a predictive marker for stroke progression during hospitalization.

METTL5-mediated 18S rRNA m6A modification promotes corticospinal tract sprouting after unilateral traumatic brain injury.

The key to improving function of an impaired limb after unilateral brain injury is promotion of corticospinal tract (CST) sprouting across the midline into the denervated hemicord. Previous studies have unveiled specific genes that regulate CST sprouting. CST sprouting may also be regulated by RNA modification. We examined METTL5, the methyltransferase for 18S rRNA m6A modification, as a regulator of CST sprouting in mice. Overexpression of METTL5 in contralesional corticospinal neurons promoted CST sprouting after unilateral traumatic brain injury. Mechanically, METTL5-mediated 18S rRNA m6A modification promoted the translation efficiency (TE) of various genes. Notably, the upregulation of TE in the gene Cfl1, which encodes cofilin, led to an increase in its expression. Additionally, the upregulation of TE in the gene Inpp5k led to the activation of cofilin. Active cofilin stimulates actin polymerization and facilitates protrusion and bundling of microtubules, thus promoting axon outgrowth. These findings offer valuable insights for developing novel strategies to promote CST sprouting.

Magnetic resonance imaging and tractography of sensorimotor tracts in fetuses with intraventricular hemorrhage: feasibility and added prognostic value.

OBJECTIVES: To assess the feasibility, characteristics and prognostic value of prenatal visualization of the corticospinal tracts (CSTs) using diffusion-weighted magnetic resonance imaging (MRI)-based tractography in fetuses with intraventricular hemorrhage (IVH). METHODS: This was a retrospective single-center cohort study of singleton fetuses diagnosed with IVH on MRI from January 2011 to December 2018. The left and right CSTs were reconstructed according to an in-utero diffusion tensor imaging sequence using a multi-region of interest (ROI) deterministic tractography approach. The CSTs were segmented by two polygonal ROI: at the level of the posterior limb of the internal capsule and the crus cerebri. The morphology and integrity of the CSTs were assessed visually. Internal capsule and crus cerebri apparent diffusion coefficient and fractional anisotropy values were measured. Postnatal motor function data were obtained from the parents using the functional status scale. RESULTS: A total of 35 fetuses with IVH (mean ± SD gestational age, 29.1 ± 5.1 (range, 19.9-38.9) weeks) were included in the analysis. Parenchymal involvement on T2-weighted sequences was demonstrated in 19 (54%) of the cohort. CST involvement correlated significantly with the presence of parenchymal damage on T2-weighted imaging (P = 0.02). Among liveborn cases, the rate of motor impairment was 14% (1/7) in children with intact CSTs compared with 100% (5/5) in cases in which the CSTs were impaired (P = 0.015). CONCLUSIONS: Fetal corticospinal tractography is feasible technically and offers valuable prognostic information. It enhances parental counseling by providing insights into potential motor outcome, underscoring its utility in complementing fetal neurosonography in cases of prenatal IVH. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The corticospinal tract in multiple sclerosis: correlation between cortical excitability and magnetic resonance imaging measures.

Multiple sclerosis (MS) is a central nervous system disease involving gray and white matters. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) could help identify potential markers of disease evolution, disability, and treatment response. This work evaluates the relationship between intracortical inhibition and facilitation, motor cortex lesions, and corticospinal tract (CST) integrity. Consecutive adult patients with progressive MS were included. Sociodemographic and clinical data were collected. MRI was acquired to assess primary motor cortex lesions (double inversion and phase-sensitive inversion recovery) and CST integrity (diffusion tensor imaging). TMS outcomes were obtained: motor evoked potentials (MEP) latency, resting motor threshold, short-interval intracortical facilitation (ICF) and inhibition. Correlation analysis was performed. Twenty-five patients completed the study (13 females, age: 55.60 ± 11.49 years, Expanded Disability Status Score: 6.00 ± 1.25). Inverse correlations were found between ICF mean and each of CST radial diffusivity (RD) (ρ =-0.56; p < 0.01), CST apparent diffusion coefficient (ADC) (ρ=-0.44; p = 0.03), and disease duration (ρ=-0.46; p = 0.02). MEP latencies were directly correlated with disability scores (ρ = 0.55; p < 0.01). High ADC/RD and low ICF have been previously reported in patients with MS. While the former could reflect structural damage of the CST, the latter could hint towards an aberrant synaptic transmission as well as a depletion of facilitatory compensatory mechanisms that helps overcoming functional decline. The findings suggest concomitant structural and functional abnormalities at later disease stages that would be accompanied with a heightened disability. The results should be interpreted with caution mainly because of the small sample size that precludes further comparisons (e.g., treated vs. untreated patients, primary vs. secondary progressive MS). The role of these outcomes as potential MS biomarkers merit to be further explored.

A perfect recipe for a corticospinal neuron.

A tailored cocktail of genes can reprogram a subset of progenitors to no longer produce glial cells and instead develop into neurons involved in motor control.

Combined biomaterial scaffold and neuromodulation strategy to promote tissue repair and corticospinal connectivity after spinal cord injury in a rodent model.

Spinal cord injury (SCI) damages the trauma site, leading to progressive and secondary structural defects rostral and caudal to the injury. Interruption of ascending and descending pathways produce motor, sensory, and autonomic impairments, driving the need for effective therapies. In this study, we address lesion site repair and promoting descending projections using a combined biomaterial-neuromodulation strategy in a rat model of cervical contusion SCI. To promote tissue repair, we used Chitosan fragmented physical hydrogel suspension (Cfphs), a biomaterial formulation optimized to mitigate inflammation and support tissue remodeling. To promote descending projections, we targeted the corticospinal motor system with dual motor cortex-trans-spinal direct current neuromodulation to promote spared corticospinal tract (CST) axon sprouting rostral and caudal to SCI. Cfphs, injected into the lesion site acutely, was followed by 10 days of daily neuromodulation. Analysis was made at the chronic phase, 8-weeks post-SCI. Compared with SCI only, Cfphs alone or in combination with neuromodulation prevented cavity formation, by promoting tissue remodeling at the injury site, abrogated astrogliosis surrounding the newly formed tissue, and enabled limited CST axon growth into the remodeled injury site. Cfphs alone significantly reduced CST axon dieback and was accompanied by preserving more CST axon gray matter projections rostral to SCI. Cfphs + neuromodulation produced sprouting rostral and caudal to injury. Our findings show that our novel biomaterial-neuromodulation combinatorial strategy achieves significant injury site tissue remodeling and promoted CST projections rostral and caudal to SCI.

Areal specializations in the morpho-electric and transcriptomic properties of primate layer 5 extratelencephalic projection neurons.

Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas. Additionally, while infragranular ET and non-ET neurons retain distinct neuronal properties across multiple regions, there are regional morpho-electric and gene expression specializations in the L5 ET subclass, providing mechanistic insights into the specialized functional architecture of the primate neocortex.

Modulation of motor cortex inhibition during manual dexterity tasks: an adaptive threshold hunting study.

The ability to perform intricate movements is crucial for human motor function. The neural mechanisms underlying precision and power grips are incompletely understood. Corticospinal output from M1 is thought to be modulated by GABAA-ergic intracortical networks within M1. The objective of our study was to investigate the contribution of M1 intracortical inhibition to fine motor control using adaptive threshold hunting (ATH) with paired-pulse TMS during pinch and grasp. We hypothesized that short-interval intracortical inhibition (SICI) could be assessed during voluntary activation and that corticomotor excitability and SICI modulation would be greater during pinch than grasp, reflecting corticospinal control. Seventeen healthy participants performed gradual pinch and grasp tasks. Using ATH, paired-pulse TMS was applied in the anterior-posterior current direction to measure MEP latencies, corticomotor excitability, and SICI. MEP latencies indicated that the procedure preferentially targeted late I-waves. In terms of corticomotor excitability, there was no difference in the TMS intensity required to reach the MEP target during pinch and grasp. Greater inhibition was found during pinch than during grasp. ATH with paired-pulse TMS permits investigation of intracortical inhibitory networks and their modulation during the performance of dexterous motor tasks revealing a greater modulation of GABAA-ergic inhibition contributing to SICI during pinch compared with grasp. NEW & NOTEWORTHY Primary motor cortex intracortical inhibition was investigated during dexterous manual task performance using adaptive threshold hunting. Motor cortex intracortical inhibition was uniquely modulated during pinching versus grasping tasks.

Central and peripheral neuromuscular fatigue following ramp and rapid maximal voluntary isometric contractions.

Introduction: Maximal voluntary isometric contractions (MVICs) as a fatiguing modality have been widely studied, but little attention has been given to the influence of the rate of torque development. Given the established differences in motor command and neuromuscular activation between ramp and rapid MIVCs, it is likely performance fatigue differs as well as the underlying physiological mechanisms. Purpose: To compare responses for rapid and maximal torque following ramp and rapid MVICs, and the corresponding neuromuscular and corticospinal alterations. Methods: On separate visits, twelve healthy males (22.8 ± 2.5 years) performed fatiguing intermittent MVICs of the knee extensors with either 2 s (RAMP) or explosive (RAPID) ramp-ups until a 50% reduction in peak torque was achieved. Before and after each condition, maximal and rapid torque measures were determined from an MVIC. Additionally, peripheral (twitch parameters) and central (voluntary activation) fatigue, as well as rapid muscle activation, and cortical-evoked twitch and electromyographic responses were recorded. Results: Maximal and late-phase rapid torque measures (p ≤ 0.001; η p 2 = 0.635-0.904) were reduced similarly, but early rapid torque capacity (0-50 ms) (p = 0.003; d = 1.11 vs. p = 0.054; d = 0.62) and rapid muscle activation (p = 0.008; d = 1.07 vs. p = 0.875; d = 0.06) decreased more after RAMP. Changes in peripheral fatigue, as indicated by singlet and doublet contractile parameters (p < 0.001 for all; η p 2 = 0.752-0.859), and nerve-evoked voluntary activation (p < 0.001; η p 2 = 0.660) were similar between conditions. Corticospinal inhibition (via silent period) was only increased after RAPID (p = 0.007; d = 0.94 vs. p = 0.753; d = 0.09), whereas corticospinal voluntary activation and excitability were unchanged. Conclusion: Ramp, fatiguing MVICs impaired early rapid torque capacity more than rapid MVICs, and this was accompanied by decrements in rapid muscle activation. Responses for peripheral and central fatigue (nerve and cortical stimulation) were largely similar between conditions, except that rapid MVICs increased corticospinal inhibition.

The relationship between corticospinal excitability and structural integrity in stroke patients.

BACKGROUND: Evaluation of the structural integrity and functional excitability of the corticospinal tract (CST) is likely to be important in predicting motor recovery after stroke. Previous reports are inconsistent regarding a possible link between CST structure and CST function in this setting. This study aims to investigate the structure‒function relationship of the CST at the acute phase of stroke (<7 days). METHODS: We enrolled 70 patients who had an acute ischaemic stroke with unilateral upper extremity (UE) weakness. They underwent a multimodal assessment including clinical severity (UE Fugl Meyer at day 7 and 3 months), MRI to evaluate the CST lesion load and transcranial magnetic stimulation to measure the maximum amplitude of motor evoked potential (MEP). RESULTS: A cross-sectional lesion load above 87% predicted the absence of MEPs with an accuracy of 80.4%. In MEP-positive patients, the CST structure/function relationship was bimodal with a switch from a linear relationship (rho=-0.600, 95% CI -0.873; -0.039, p<0.03) for small MEP amplitudes (<0.703 mV) to a non-linear relationship for higher MEP amplitudes (p=0.72). In MEP-positive patients, recovery correlated with initial severity. In patients with a positive MEP <0.703 mV but not in patients with an MEP ≥0.703 mV, MEP amplitude was an additional independent predictor of recovery. In MEP-negative patients, we failed to identify any factor predicting recovery. CONCLUSION: This large multimodal study on the structure/function of the CST and stroke recovery proposes a paradigm change for the MEP-positive patients phenotypes and refines the nature of the link between structural integrity and neurophysiological function, with implications for study design and prognostic information.

The Effects of the StartReact on Reaction Time, Rate of Force Development, and Muscle Activity in Biceps Brachii.

The StartReact test, increasingly popular for assessing cortico-reticular functioning, is a valid method to influence the firing of reticulospinal tract neurons noninvasively. However, there remains limited evidence on how different stimuli employed in the StartReact test impact motor output in humans. The present study tested elbow flexor responses of 33 adults (aged 26-48 years) to visual stimuli only (LED light), audio-visual (80 dB) stimuli, and startle-inducing audio-visual (120 dB) stimuli sitting with the arm supinated in an electromechanical dynamometer. Surface electromyogram (EMG) recorded muscle activity from the right biceps brachii muscle. Participants were presented with 20 stimuli for each of the three conditions in pseudorandom order with interstimulus intervals of ~8 s. Reaction times were calculated from the stimulus trigger to the initial rise in the EMG signal above 7 × SD from baseline. Rate of torque development (RTD) and EMG signals were recorded throughout and analyzed over their initial 50 ms and 100 ms time-windows. Reaction times were reduced from visual (169 ± 23) to audio-visual (140 ± 23) and further reduced to startle-inducing audio-visual stimuli (108 ± 19, p < 0.001). While RTD and EMG were consistently greatest following startle-inducing stimuli (p < 0.001), they were also enhanced following all audio-visual stimuli over 100 ms (p < 0.05). It appears that startle-inducing audio-visual stimuli result in shorter reaction times, increased RTD, and enhanced muscle activity within the initial 50 ms, likely from subcortical upregulation. However, the 100 ms time-window suggests cortical upregulation following all audio-visual stimuli considering the longer transmission times.

Synaptotagmin 4 Supports Spontaneous Axon Sprouting after Spinal Cord Injury.

Injuries to the central nervous system (CNS) can cause severe neurological deficits. Axonal regrowth is a fundamental process for the reconstruction of compensatory neuronal networks after injury; however, it is extremely limited in the adult mammalian CNS. In this study, we conducted a loss-of-function genetic screen in cortical neurons, combined with a Web resource-based phenotypic screen, and identified synaptotagmin 4 (Syt4) as a novel regulator of axon elongation. Silencing Syt4 in primary cultured cortical neurons inhibits neurite elongation, with changes in gene expression involved in signaling pathways related to neuronal development. In a spinal cord injury model, inhibition of Syt4 expression in cortical neurons prevented axonal sprouting of the corticospinal tract, as well as neurological recovery after injury. These results provide a novel therapeutic approach to CNS injury by modulating Syt4 function.

Brain-Hand Function Relationships Based on Level of Grasp Function in Chronic Left-Hemisphere Stroke.

BACKGROUND AND OBJECTIVE: The biomarkers of hand function may differ based on level of motor impairment after stroke. The objective of this study was to determine the relationship between resting state functional connectivity (RsFC) and unimanual contralesional hand function after stroke and whether brain-behavior relationships differ based on level of grasp function. METHODS: Sixty-two individuals with chronic, left-hemisphere stroke were separated into three functional levels based on Box and Blocks Test performance with the contralesional hand: Low (moved 0 blocks), Moderate (moved >0% but <90% of blocks relative to the ipsilesional hand), and High (moved ≥90% of blocks relative to the ipsilesional hand). RESULTS: RsFC in the ipsilesional and interhemispheric motor networks was reduced in the Low group compared to the Moderate and High groups. While interhemispheric RsFC correlated with hand function (grip strength and Stroke Impact Scale Hand) across the sample, contralesional RsFC correlated with hand function in the Low group and no measures of connectivity correlated with hand function in the Moderate and High groups. Linear regression modeling found that contralesional RsFC significantly predicted hand function in the Low group, while no measure correlated with hand function in the High group. Corticospinal tract integrity was the only predictor of hand function for the Moderate group and in an analysis across the entire sample. CONCLUSIONS: Differences in brain-hand function relationships based on level of motor impairment may have implications for predictive models of treatment response and the development of intervention protocols aimed at improving hand function after stroke.

Alpha and beta/low-gamma frequency bands may have distinct neural origin and function during post-stroke walking.

Plantarflexors provide propulsion during walking and receive input from both corticospinal and corticoreticulospinal tracts, which exhibit some frequency-specificity that allows potential differentiation of each tract's descending drive. Given that stroke may differentially affect each tract and impair the function of plantarflexors during walking; here, we examined this frequency-specificity and its relation to walking-specific measures during post-stroke walking. Fourteen individuals with chronic stroke walked on an instrumented treadmill at self-selected and fast walking speed (SSWS and FWS, respectively) while surface electromyography (sEMG) from soleus (SOL), lateral gastrocnemius (LG), and medial gastrocnemius (MG) and ground reaction forces (GRF) were collected. We calculated the intermuscular coherences (IMC; alpha, beta, and low-gamma bands between SOL-LG, SOL-MG, LG-MG) and propulsive impulse using sEMG and GRF, respectively. We examined the interlimb and intralimb IMC comparisons and their relationships with propulsive impulse and walking speed. Interlimb IMC comparisons revealed that beta LG-MG (SSWS) and low-gamma SOL-LG (FWS) IMCs were degraded on the paretic side. Intralimb IMC comparisons revealed that only alpha IMCs (both speeds) exhibited a statistically significant difference to random coherence. Further, alpha LG-MG IMC was positively correlated with propulsive impulse in the paretic limb (SSWS). Alpha and beta/low-gamma bands may have a differential functional role, which may be related to the frequency-specificity of the underlying descending drives. The persistence of alpha band in plantarflexors and its strong positive relationship with propulsive impulse suggests relative alteration of corticoreticulospinal tract after stroke. These findings imply the presence of frequency-specific descending drives to walking-specific muscles in chronic stroke.

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.