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Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.

Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that EphA7 and EfnA5 are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, EphA7 and EfnA5 forward and reverse inhibitory signals direct collateral extension such that EphA7-positive frontal and occipital cortical areas extend their axon collaterals into the EfnA5-negative rostral part of the basilar pons, whereas EfnA5-positive parietal cortical areas extend their collaterals into the EphA7- negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets. [ABSTRACT FROM AUTHOR]

Human corticospinal transmission is commonly studied using brain stimulation. However, this approach is biased to activity in the fastest conducting axons. It is unclear whether conclusions obtained in this context are representative of volitional activity in mild-to-moderate contractions. An alternative to overcome this limitation may be to study the corticospinal transmission of endogenously generated brain activity. Here, we investigate in humans (N=19; of either sex), the transmission speeds of cortical β rhythms (~20 Hz) traveling to arm (first dorsal interosseous) and leg (tibialis anterior; TA) muscles during tonic mild contractions. For this purpose, we propose two improvements for the estimation of corticomuscular β transmission delays. First, we show that the cumulant density (cross-covariance) is more accurate than the commonly-used directed coherence to estimate transmission delays in bidirectional systems transmitting band-limited signals. Second, we show that when spiking motor unit activity is used instead of interference electromyography, corticomuscular transmission delay estimates are unaffected by the shapes of the motor unit action potentials (MUAPs). Applying these improvements, we show that descending corticomuscular β transmission is only 1-2 ms slower than expected from the fastest corticospinal pathways. In the last part of our work, we show results from simulations using estimated distributions of the conduction velocities for descending axons projecting to lower motoneurons (from macaque histologic measurements) to suggest two scenarios that can explain fast corticomuscular transmission: either only the fastest corticospinal axons selectively transmit β activity, or else the entire pool does. The implications of these two scenarios for our understanding of corticomuscular interactions are discussed. [ABSTRACT FROM AUTHOR]

Penfield's motor homunculus describes a caricaturised yet useful representation of the map of various body parts on the pre-central cortex. We propose a supplemental map of the clinically represented areas of human body in pre-central cortex and a novel subcortical corticospinal tract map. We believe this knowledge is essential for safe surgery in patients with eloquent brain lesions. A single-institution retrospective cohort study of patients who underwent craniotomy for motor eloquent lesions with intraoperative motor neuromonitoring (cortical and subcortical) between 2015 and 2020 was performed. All positive cortical and subcortical stimulation points were taken into account and cartographic maps were produced to demonstrate cortical and subcortical areas of motor representation and their configuration. A literature review in PubMed was performed. One hundred and eighty consecutive patients (58.4% male, 41.6% female) were included in the study with 81.6% asleep and 18.4% awake craniotomies for motor eloquent lesions (gliomas 80.7%, metastases 13.8%) with intraoperative cortical and subcortical motor mapping. Based on the data, we propose a supplemental clinical cortical and a novel subcortical motor map to the original Penfield's motor homunculus, including demonstration of localisation of intercostal muscles both in the cortex and subcortex which has not been previously described. The supplementary clinical cortical and novel subcortical motor maps of the homunculus presented here have been derived from a large cohort of patients undergoing direct cortical and subcortical brain mapping. The information will have direct relevance for improving the safety and outcome of patients undergoing resection of motor eloquent brain lesions. [ABSTRACT FROM AUTHOR]

Although adverse early experiences prime individuals to be at increased risk for chronic pain, little research has examined the trauma-pain relationship in early life or the underlying mechanisms that drive pathology over time. Given that early experiences can potentiate the nociceptive response, this study aimed to examine the effects of a high-fat, high-sugar (HFHS) diet and early life stress (maternal separation [MS]) on pain outcomes in male and female adolescent rats. Half of the rats also underwent a plantar-incision surgery to investigate how the pain system responded to a mildly painful stimuli in adolescence. Compared with controls, animals that were on the HFHS diet, experienced MS, or had exposure to both, exhibited increased anxiety-like behavior and altered thermal and mechanical nociception at baseline and following the surgery. Advanced magnetic resonance imaging demonstrated that the HFHS diet and MS altered the maturation of the brain, leading to changes in brain volume and diffusivity within the anterior cingulate, amygdala, corpus callosum, nucleus accumbens, and thalamus, while also modifying the integrity of the corticospinal tracts. The effects of MS and HFHS diet were often cumulative, producing exacerbated pain sensitivity and increased neurobiological change. As early experiences are modifiable, understanding their role in pain may provide targets for early intervention/prevention. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate relationship between the diffusion indexes of corticospinal tract (CST) and the neurological motor outcomes in chronic pontine stroke patients. METHODS: Diffusion tensor imaging (DTI) is performed in 27 patients with chronic pontine stroke. Fractional anisotropy (FA) values along the CST area, the track number, and the CST length are measured. Neurological and motor outcomes are evaluated based on Fugl-meyer (FM), National Institutes of Health Stroke Scale (NIHSS), Barthel index (BI), and modified Rankin scale (mRS) scores. The relationships between FA ratios (rFAs) in the CST of stroke subjects and their clinical motor scores are analyzed through Spearman's correlation analysis. Then, diffusion tensor tractography (DTT) is performed to show the injury degree of CST. RESULTS: First, FA values are decreased in the infarct area, cerebral peduncle, posterior limb of the internal capsule, and precentral gyrus compared with those in the contralateral side. The number of CST is decreased in the ipsilateral side of the infarct. Second, rFAs in the cerebral peduncle, posterior limb of the internal capsule, and CST rnum correlate positively with FM scores (r = 0.824, 0.672, 0.651, p < 0.001) and negatively with mRS scores (r = –0.835, –0.604, –0.645, p≤0.001). Third, the injury degree of CST correlates negatively with FM scores (r = –0.627, p < 0.001). CONCLUSIONS: The study demonstrates that rFAs in the cerebral peduncle, posterior limb of the internal capsule, and CST rnum associate with motor outcome, suggesting that DTI may be applicable for outcome evaluation. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of long-term disability in young adults. An evidence-based treatment for TBI recovery, especially in the chronic phase, is not yet available. Using a severe TBI mouse model, we demonstrate that the neurorestorative efficacy of repeated treatments with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF + G-CSF) in the chronic phase is superior to SCF + G-CSF single treatment. SCF + G-CSF treatment initiated at 3 months post-TBI enhances contralesional corticospinal tract sprouting into the denervated side of the cervical spinal cord and re-balances the TBI-induced overgrown synapses in the hippocampus by enhancing microglial function of synaptic pruning. These neurorestorative changes are associated with SCF + G-CSF-improved somatosensory-motor function and spatial learning. In the chronic phase of TBI, severe TBI-caused microglial degeneration in the cortex and hippocampus is ameliorated by SCF + G-CSF treatment. These findings reveal the therapeutic potential and possible mechanism of SCF + G-CSF treatment in brain repair during the chronic phase of severe TBI. [ABSTRACT FROM AUTHOR]

Motor output maps within primary motor cortex are widely distributed and modified by motor skill learning and neurological injury. Functions that these maps represent after spinal cord injury remain debatable. Moreover, the pattern of reorganization and whether it supports recovery of compromised motor function is not well understood. A deeper understanding of the pathophysiological mechanisms of motor dysfunction after spinal cord injury is necessary to develop and optimize repair strategies. There are three purposes for this review. The first is to synthesize available research on spontaneous reorganization with primary motor cortex following spinal cord injury. The second is to draw on existing evidence from the motor skill learning and brain injury literature to interpret the form and purpose of motor maps. The third purpose is to account for the existing research on intervention-induced reorganization of primary motor cortex following spinal cord injury. We conclude with directions for future work, emphasizing the need for multi-modal investigations that construct maps with both neuroimaging and non-invasive stimulation methods to derive a cohesive understanding of the effects of spinal cord injury on reorganization within primary motor cortex.

Spinal cord injury is a devastating condition that is followed by long and often unsuccessful recovery after trauma. The state of the art approach to manage paralysis and concomitant impairments is rehabilitation, which is the only strategy that has proven to be effective and beneficial for the patients over the last decades. How rehabilitation influences the remodeling of spinal axonal connections in patients is important to understand, in order to better target these changes and define the optimal timing and onset of training. While clinically the answers to these questions remain difficult to obtain, rodent models of rehabilitation like bicycling, treadmill training, swimming, enriched environments or wheel running that mimic clinical rehabilitation can be helpful to reveal the axonal changes underlying motor recovery. This review will focus on the different animal models of spinal cord injury rehabilitation and the underlying changes in neuronal networks that are improved by exercise and rehabilitation.

Spinal cord injury is associated with chronic sensorimotor deficits due to the interruption of ascending and descending tracts between the brain and spinal cord. Functional recovery after anatomically complete spinal cord injury is limited due to the lack of long-distance axonal regeneration of severed fibers in the adult central nervous system. Most spinal cord injuries in humans, however, are anatomically incomplete. Although restorative treatment options for spinal cord injury remain currently limited, research from experimental models of spinal cord injury have revealed a tremendous capability for both spontaneous and treatment-induced plasticity of the corticospinal system that supports functional recovery. We review recent advances in the understanding of corticospinal circuit plasticity after spinal cord injury and concentrate mainly on the hindlimb motor cortex, its corticospinal projections, and the role of spinal mechanisms that support locomotor recovery. First, we discuss plasticity that occurs at the level of motor cortex and the reorganization of cortical movement representations. Next, we explore downstream plasticity in corticospinal projections. We then review the role of spinal mechanisms in locomotor recovery. We conclude with a perspective on harnessing neuroplasticity with therapeutic interventions to promote functional recovery.

This study examined the prognosis of the ipsilesional corticospinal tracts (CSTs) with preserved integrities at the early stage of cerebral infarction using follow-up diffusion tensor tractography (DTT). Thirty-one patients with a supratentorial infarction were recruited. DTT, Motricity Index (MI), modified Brunnstrom classification (MBC), and functional ambulation category (FAC) were performed twice at the early and chronic stages. The patients were classified into two groups based on the integrity of the ipsilesional CST on the second DTT: Group A (24 patients; 77.4%)—preserved integrity and Group B (7 patients; 22.6%)—disrupted integrity. No significant differences in MI, MBC, and FAC were observed between groups A and B at the first and second evaluations, except for FAC at the first evaluation (p > 0.05). MI, MBC, and FAC at the second evaluation were significantly higher than at the first evaluation in both groups A and B (p < 0.05). On the second DTT, one patient (4.2%) in group A showed a false-positive result, whereas five patients (71.4%) in group B had false-negative results. Approximately 20% of patients showed disruption of the ipsilesional CST at the chronic stage. However, the clinical outcomes in hand and gait functions were generally good. Careful interpretation considering the somatotopy of the ipsilesional CST is needed because of the high false-negative results on DTT at the chronic stage.

Many chronic stroke patients suffer from worsened hand function, and functional recovery of the hand does not occur well after six months of stroke. Therefore, predicting final hand function after stroke through acute phase imaging would be an important issue in counseling with the patients or their family. Thus, we investigated the remaining white matter integrity in the corticospinal tract (CST) and cortico-ponto-cerebellar tract (CPCT) at the acute stage of stroke and chronic hand function after stroke, and present the cut-off value of fiber number (FN) and fractional anisotropy (FA) of CST and CPCT at the acute stage for predicting final hand function after the recovery period. This retrospective case-control study included 18 stroke patients who were classified into two groups: poor hand function with stroke (n = 11) and good hand function with stroke (n = 7). DTI was done within two months ± 15 days after onset, and the Jebson’s Hand Function test was conducted 6–12 months after onset. The investigation of white matter was focused on the values of FN and FA for CST and CPCT, which were measured separately. The normalized (affected/non-affected) FA and FN values in the CPCT in the good hand function group were higher than those in the poor hand function group. The normalized FN and FA values in the CST were not significantly different between the poor hand function group and the good hand function group. The normalized cut-off value that distinguished the good hand function group from the poor hand function group was 0.8889 for FA in the CPCT. The integrity of the CPCT in the acute stage was associated with hand function in the chronic stage after a stroke. Ultimately, the integrity of the CPCT in the early stage after onset can be used to predict chronic hand function. Based on these results, cerebellar afferent fiber measurements may be a useful addition to predict hand function and plan specific rehabilitation strategies in stroke patients.

This study investigated the relationship of the nigrostriatal tract (NST) with motor function and the corticospinal tract (CST) using diffusion tensor tractography in chronic hemiparetic stroke patients. Forty-three consecutive patients with putaminal hemorrhage in the chronic stage were recruited. The Motricity Index was used to evaluate the motor function of affected hemiparetic extremities. The fractional anisotropy and the tract volume of ipsilesional NST and ipsilesional CST were acquired. The tract volume (Rho = 0.824) of ipsilesional NST and fractional anisotropy (r = 0.682) and the tract volume (Rho = 0.886) of ipsilesional CST showed a strong positive correlation with the Motricity Index score. The fractional anisotropy of ipsilesional NST showed moderate positive correlations with the fractional anisotropy (r = 0.449) and tract volume (Rho = 0.353) of ipsilesional CST. The tract volume of ipsilesional NST showed strong positive correlations with the fractional anisotropy (Rho = 0.716) and the tract volume (Rho = 0.799) of ipsilesional CST. The regression model showed that the tract volumes of ipsilesional NST and ipsilesional CST were positively associated with the Motricity Index score (Adjusted R2 = 0.763, F = 45.998). Mediation analysis showed that the tract volume of ipsilesional CST partially mediated the effects of the tract volume of ipsilesional NST on the Motricity Index score (z = 3.34). A close relationship was found between ipsilesional NST and the motor function of affected extremities in chronic hemiparetic patients with putaminal hemorrhage. Moreover, ipsilesional NST influenced the motor function of affected extremities indirectly through ipsilesional CST.

Purpose: Despite the important role of manual dexterity in child development, the neurobiological mechanisms associated with manual dexterity in childhood remain unclear. We leveraged fixel-based analysis (FBA) to examine the longitudinal association between manual dexterity and the development of white matter structural properties in the corticospinal tract (CST). Methods: High angular diffusion weighted imaging (HARDI) data were acquired for 44 right-handed typically developing children (22 female) aged 9-13 across two timepoints (timepoint 1: mean age 10.5 years ± 0.5 years, timepoint 2: 11.8 ± 0.5 years). Manual dexterity was assessed using the Grooved Pegboard Test, a widely used measure of manual dexterity. FBA-derived measures of fiber density and morphology were generated for the CST at each timepoint. Connectivity-based fixel enhancement and mixed linear modelling were used to examine the longitudinal association between manual dexterity and white matter structural properties of the CST. Results: Longitudinal mixed effects models showed that greater manual dexterity of the dominant hand was associated with increased fiber cross-section in the contralateral CST. Analyses further demonstrated that the rate of improvement in manual dexterity was associated with the rate of increase in fiber cross-section in the contralateral CST between the two timepoints. Conclusion: Our longitudinal data suggest that the development of manual dexterity in late childhood is associated with maturation of the CST. These findings significantly enhance our understanding of the neurobiological systems that subserve fine motor development and provide an important step toward mapping normative trajectories of fine motor function against microstructural and morphological development in childhood.

Repetitive peripheral magnetic stimulation (rPMS) may improve motor function following central nervous system lesions, but the optimal parameters of rPMS to induce neural plasticity and mechanisms underlying its action remain unclear. We examined the effects of rPMS over wrist extensor muscles on neural plasticity and motor performance in 26 healthy volunteers. In separate experiments, the effects of rPMS on motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), direct motor response (M-wave), Hoffmann-reflex, and ballistic wrist extension movements were assessed before and after rPMS. First, to examine the effects of stimulus frequency, rPMS was applied at 50, 25, and 10 Hz by setting a fixed total number of stimuli. A significant increase in MEPs of wrist extensors was observed following 50 and 25 Hz rPMS, but not 10 Hz rPMS. Next, we examined the time required to induce plasticity by increasing the number of stimuli, and found that at least 15 min of 50 and 25 Hz rPMS was required. Based on these parameters, lasting effects were evaluated following 15 min of 50 or 25 Hz rPMS. A significant increase in MEP was observed up to 60 min following 50 and 25 Hz rPMS; similarly, an attenuation of SICI and enhancement of ICF were also observed. The maximal M-wave and Hoffmann-reflex did not change, suggesting that the increase in MEP was due to plastic changes at the motor cortex. This was accompanied by increasing force and electromyograms during wrist ballistic extension movements following 50 and 25 Hz rPMS. These findings suggest that 15 min of rPMS with 25 Hz or more induces an increase in cortical excitability of the relevant area rather than altering the excitability of spinal circuits, and has the potential to improve motor output.

Purpose: The purpose of this study was to measure the diffusion spectrum imaging (DSI) parameters of corticospinal tracts (CSTs) and evaluate diffusional changes in CSTs in patients with idiopathic normal pressure hydrocephalus (iNPH) by DSI.Methods: Twenty-three iNPH patients and twenty-one healthy controls (HCs) were involved in this study. Brain DSI data for all participants were collected through the same MR scanning procedure. The diffusion parameters measured and analyzed included quantitative anisotropy (QA), the isotropic diffusion component (ISO), general fractional anisotropy (GFA), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of corticospinal tracts.Results: The QA and ISO values of corticospinal tracts in iNPH patients were significantly lower than those in HCs (PLQA = 0.008, PRQA = 0.016, PLISO = 0.024, PRISO = 0.016). The mean MD, AD, and RD values in iNPH patients were significantly higher than those in HCs (PMD = 0.032, PAD = 0.032, PRD = 0.048,). No significant differences in GFA and FA values were noted between iNPH patients and HCs.Conclusion: Decreased QA and ISO values of corticospinal tracts were found in iNPH patients. Quantitative CST evaluation using DSI may lead to information that can improve the present understanding of the disease mechanism.

Tumors infiltrating the motor system lead to significant disability, often caused by corticospinal tract injury. The delineation of the healthy-pathological white matter (WM) interface area, for which diffusion magnetic resonance imaging (dMRI) has shown promising potential, may improve treatment outcome. However, up to 90% of white matter (WM) voxels include multiple fiber populations, which cannot be correctly described with traditional metrics such as fractional anisotropy (FA) or apparent diffusion coefficient (ADC). Here, we used a novel fixel-based along-tract analysis consisting of constrained spherical deconvolution (CSD)-based probabilistic tractography and fixel-based apparent fiber density (FD), capable of identifying fiber orientation specific microstructural metrics. We addressed this novel methodology’s capability to detect corticospinal tract impairment. We measured and compared tractogram-related FD and traditional microstructural metrics bihemispherically in 65 patients with WHO grade III and IV gliomas infiltrating the motor system. The cortical tractogram seeds were based on motor maps derived by transcranial magnetic stimulation. We extracted 100 equally distributed cross-sections along each streamline of corticospinal tract (CST) for along-tract statistical analysis. Cross-sections were then analyzed to detect differences between healthy and pathological hemispheres. All metrics showed significant differences between healthy and pathologic hemispheres over the entire tract and between peritumoral segments. Peritumoral values were lower for FA and FD, but higher for ADC within the entire cohort. FD was more specific to tumor-induced changes in CST than ADC or FA, whereas ADC and FA showed higher sensitivity. The bihemispheric along-tract analysis provides an approach to detect subject-specific structural changes in healthy and pathological WM. In the current clinical dataset, the more complex FD metrics did not outperform FA and ADC in terms of describing corticospinal tract impairment.

Background: White matter (WM) impairment is a hallmark of amyotrophic lateral sclerosis (ALS). This study evaluated the capacity of mean apparent propagator magnetic resonance imaging (MAP-MRI) for detecting ALS-related WM alterations. Methods: Diffusion images were obtained from 52 ALS patients and 51 controls. MAP-derived indices [return-to-origin/-axis/-plane probability (RTOP/RTAP/RTPP) and non-Gaussianity (NG)/perpendicular/parallel NG (NG⊥/NG||)] were computed. Measures from diffusion tensor/kurtosis imaging (DTI/DKI) and neurite orientation dispersion and density imaging (NODDI) were also obtained. Voxel-wise analysis (VBA) was performed to determine differences in these parameters. Relationship between MAP parameters and disease severity (assessed by the revised ALS Functional Rating Scale (ALSFRS-R)) was evaluated by Pearson’s correlation analysis in a voxel-wise way. ALS patients were further divided into two subgroups: 29 with limb-only involvement and 23 with both bulbar and limb involvement. Subgroup analysis was then conducted to investigate diffusion parameter differences related to bulbar impairment. Results: The VBA (with threshold of P

Congenital heart disease (CHD) patients are at risk for neurodevelopmental impairments, including altered motor function. However, little is known about the neuroanatomical correlates of persistent motor deficits in CHD. Thus, we examined the link between corticospinal tract (CST) microstructure and motor function in adolescent and adult CHD patients compared to healthy controls.This study investigated 89 CHD patients (N(adolescents) = 47, N(adults) = 42, mean age = 19.9 years) and 97 age-matched healthy controls (N(adolescents) = 44, N(adults) = 53, mean age = 20.6 years). Diffusion tensor imaging was conducted and fractional anisotropy (FA) of the left and right CST was extracted for each participant. Fine (pegboard) and pure motor (repeated finger, hand and foot movements) performance was evaluated with a standardized test battery. FA and motor performance were correlated and the effect of CHD complexity was tested using multivariate linear regression.Clinically relevant motor impairments (>2SD below normative mean) were evident in 24% of patients and 9% of controls. On average, motor performance was lower in CHD patients compared to controls, particularly in those with more complex CHD (fine motor: p = 0.023; pure motor: p

We describe the clinical features of two sisters with Parkinson's disease (PD) of Indian descent living in Malaysia. Both were homozygous for the known PINK1 mutation p.Leu489Pro (c.1466T>C). The proband, who has been followed up by us over a span of 35 years, had a fairly "classic" clinical presentation for PARK-PINK1, including young onset, a clear response to dopamine replacement therapy, and development of troublesome motor fluctuations and dyskinesias. Her dyskinesias improved substantially with clozapine treatment, which to our knowledge has not specifically been reported for PARK-PINK1; this treatment has been sustained for nearly a decade. The clinical phenotype of the older sister was more akin to later-onset "idiopathic" PD; however, her brain MRI showed abnormal signal in the posterior limb of the internal capsules and the hypothalamus. Our report contributes to the scarce literature on monogenic PD in the Malaysian / Indian population, and further supports the pathogenicity of the PINK1 p.Leu489Pro variant. [ABSTRACT FROM AUTHOR]

RTL1 (also termed paternal expressed 11 (PEG11)) is considered the major imprinted gene responsible for the placental and fetal/neonatal muscle defects that occur in the Kagami–Ogata and Temple syndromes (KOS14 and TS14, respectively). However, it remains elusive whether RTL1 is also involved in their neurological symptoms, such as behavioral and developmental delay/intellectual disability, feeding difficulties, motor delay, and delayed speech. Here, we demonstrate that the mouse RTL1 protein is widely expressed in the central nervous system (CNS), including the limbic system. Importantly, two disease model mice with over‐ and under‐expression of Rtl1 exhibited reduced locomotor activity, increased anxiety, and impaired amygdala‐dependent cued fear, demonstrating that Rtl1 also plays an important role in the CNS. These results indicate that the KOS14 and TS14 are neuromuscular as well as neuropsychiatric diseases caused by irregular CNS RTL1 expression, presumably leading to impaired innervation of motor neurons to skeletal muscles as well as malfunction of the hippocampus‐amygdala complex. It is of considerable interest that eutherian‐specific RTL1 is expressed in mammalian‐ and eutherian‐specific brain structures, that is, the corticospinal tract and corpus callosum, respectively, suggesting that RTL1 might have contributed to the acquisition of both these structures themselves and fine motor skill in eutherian brain evolution. [ABSTRACT FROM AUTHOR]

Modulatory actions of inputs from the visual system to cervical interneurons (IN) for arm muscle control are poorly understood in humans. In the present study, we examined whether visual stimulation modulates the excitation of cervical IN systems mediating corticospinal tract (CST) inputs to biceps brachii (BB). Twenty-eight healthy volunteers were seated, and electromyogram recordings from the BB were performed across six experiments, each with discrete objectives. A flash stimulator for visual stimulation (50-μs duration) was placed 60 cm from the participant’s eye. The CST was stimulated with transcranial magnetic/electrical stimulation (TMS/TES, respectively) contralateral to the recording site. Visual stimulation with TMS/TES was randomly delivered during weak tonic BB contractions. Single TMS/TES-induced motor-evoked potentials (MEPs) were markedly enhanced from 60–100 ms after visual stimulation compared with the control condition. The MEPs were significantly increased by combining the electrical stimulation of the ulnar nerve at the wrist [7.5–12 ms of nerve stimulation (NERVE)/TMS interval] with and without visual stimulation compared with the algebraic summation of responses obtained with either TMS or NERVE. Interestingly, the combined stimulation-induced MEP facilitation was significantly increased after visual stimulation compared with the control. Single motor unit (MU) recording also revealed the further enhancement of combined stimulation effects on the firing probabilities of MU during visual stimulation, which was observed in the peaks of the peristimulus time histogram, 1–2 ms later than the onset latency. The present findings suggest that visual stimulation facilitates the oligosynaptic CST excitation of arm motoneurons mediated by the cervical IN system. NEW & NOTEWORTHY To date, little is known about how visual information modulates the human cervical motor systems, including the presumed interneuron (IN) circuitry. This study demonstrates that photic visual stimulation influences presumed oligosynaptic corticospinal transmission to arm motoneurons, which are mediated by cervical INs. In animals, these systems are known to be crucial for visually guided switching movements, and similar visual input systems to INs may exist in humans. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to measure the diffusion spectrum imaging (DSI) parameters of corticospinal tracts (CSTs) and evaluate diffusional changes in CSTs in patients with idiopathic normal pressure hydrocephalus (iNPH) by DSI. Methods: Twenty-three iNPH patients and twenty-one healthy controls (HCs) were involved in this study. Brain DSI data for all participants were collected through the same MR scanning procedure. The diffusion parameters measured and analyzed included quantitative anisotropy (QA), the isotropic diffusion component (ISO), general fractional anisotropy (GFA), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of corticospinal tracts. Results: The QA and ISO values of corticospinal tracts in iNPH patients were significantly lower than those in HCs (PLQA = 0.008, PRQA = 0.016, PLISO = 0.024, PRISO = 0.016). The mean MD, AD, and RD values in iNPH patients were significantly higher than those in HCs (PMD = 0.032, PAD = 0.032, PRD = 0.048,). No significant differences in GFA and FA values were noted between iNPH patients and HCs. Conclusion: Decreased QA and ISO values of corticospinal tracts were found in iNPH patients. Quantitative CST evaluation using DSI may lead to information that can improve the present understanding of the disease mechanism. [ABSTRACT FROM AUTHOR]

Repetitive peripheral magnetic stimulation (rPMS) may improve motor function following central nervous system lesions, but the optimal parameters of rPMS to induce neural plasticity and mechanisms underlying its action remain unclear. We examined the effects of rPMS over wrist extensor muscles on neural plasticity and motor performance in 26 healthy volunteers. In separate experiments, the effects of rPMS on motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), direct motor response (M-wave), Hoffmann-reflex, and ballistic wrist extension movements were assessed before and after rPMS. First, to examine the effects of stimulus frequency, rPMS was applied at 50, 25, and 10 Hz by setting a fixed total number of stimuli. A significant increase in MEPs of wrist extensors was observed following 50 and 25 Hz rPMS, but not 10 Hz rPMS. Next, we examined the time required to induce plasticity by increasing the number of stimuli, and found that at least 15 min of 50 and 25 Hz rPMS was required. Based on these parameters, lasting effects were evaluated following 15 min of 50 or 25 Hz rPMS. A significant increase in MEP was observed up to 60 min following 50 and 25 Hz rPMS; similarly, an attenuation of SICI and enhancement of ICF were also observed. The maximal M-wave and Hoffmann-reflex did not change, suggesting that the increase in MEP was due to plastic changes at the motor cortex. This was accompanied by increasing force and electromyograms during wrist ballistic extension movements following 50 and 25 Hz rPMS. These findings suggest that 15 min of rPMS with 25 Hz or more induces an increase in cortical excitability of the relevant area rather than altering the excitability of spinal circuits, and has the potential to improve motor output. [ABSTRACT FROM AUTHOR]

Background: This study involves analysis of the relationship between variables obtained using diffusion tensor imaging (DTI) and motor outcome in gliomas adjacent to the corticospinal tract (CST). Methods: Histologically confirmed glioma patients who were to undergo surgery between January 2018 and December 2019 were prospectively enrolled. All patients had a preoperative magnetic resonance imaging (MRI) study that included DTI, a tumor 2 cm or less from the CST, and postsurgical control within 48 h. Patients with MRI that was performed at other center, tumors with primary and premotor cortex invasion, postsurgical complications directly affecting motor outcome and tumor progression <6 months were excluded in the study. In pre- and post-surgical MRI, we measured the following DTI-derived metrics: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity of the entire CST and peritumoral CST regions and in the contralateral hemisphere. The motor outcome was assessed at 1, 3, and 6 months using the Medical Research Council scale. Results: Eleven patients were analyzed, and six corresponded to high-grade gliomas and five to low-grade gliomas. Four patients had previous motor impairment and seven patients had postsurgical motor deficits (four transient and three permanent). An FA ratio of 0.8 between peritumoral CST regions and the contralateral hemisphere was found to be the cutoff, and lower values were obtained in patients with permanent motor deficits. Conclusion: Quantitative analysis of DTI that was performed in the immediate postsurgery period can provide valuable information about the motor prognosis after surgery for gliomas near the CST. [ABSTRACT FROM AUTHOR]

The development and persistence of laterality is a key feature of human motor behavior, with the asymmetry of hand use being the most prominent. The idea that asymmetrical functions of the hands reflect asymmetries in terms of structural and functional brain organization has been tested many times. However, despite advances in laterality research and increased understanding of this population-level bias, the neural basis of handedness remains elusive. Recent developments in diffusion magnetic resonance imaging enabled the exploration of lateralized motor behavior also in terms of white matter and connectional neuroanatomy. Despite incomplete and partly inconsistent evidence, structural connectivity of both intrahemispheric and interhemispheric white matter seems to differ between left and right-handers. Handedness was related to asymmetry of intrahemispheric pathways important for visuomotor and visuospatial processing (superior longitudinal fasciculus), but not to projection tracts supporting motor execution (corticospinal tract). Moreover, the interindividual variability of the main commissural pathway corpus callosum seems to be associated with handedness. The review highlights the importance of exploring new avenues for the study of handedness and presents the latest state of knowledge that can be used to guide future neuroscientific and genetic research. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the integrity of the corticospinal tracts (CST) in patients with SCA3 and age- and gender-matched healthy control subjects using diffusion tensor imaging (DTI). We also looked at the clinical correlates of such diffusivity abnormalities. Methods: We assessed 2 cohorts from different Brazilian centers: cohort 1 (n = 29) scanned in a 1.5 T magnet and cohort 2 (n = 91) scanned in a 3.0 T magnet. We used Pearson's coefficients to assess the correlation of CST DTI parameters and ataxia severity (expressed by SARA scores). Results: Two different results were obtained. Cohort 1 showed no significant between-group differences in DTI parameters. Cohort 2 showed significant between-group differences in the FA values in the bilateral precentral gyri (p < 0.001), bilateral superior corona radiata (p < 0.001), bilateral posterior limb of the internal capsule (p < 0.001), bilateral cerebral peduncle (p < 0.001), and bilateral basis pontis (p < 0.001). There was moderate correlation between CST diffusivity parameters and SARA scores in cohort 2 (Pearson correlation coefficient: 0.40–0.59). Conclusion: DTI particularly at 3 T is able to uncover and quantify CST damage in SCA3. Moreover, CST microstructural damage may contribute with ataxia severity in the disease. [ABSTRACT FROM AUTHOR]

Tumors infiltrating the motor system lead to significant disability, often caused by corticospinal tract injury. The delineation of the healthy-pathological white matter (WM) interface area, for which diffusion magnetic resonance imaging (dMRI) has shown promising potential, may improve treatment outcome. However, up to 90% of white matter (WM) voxels include multiple fiber populations, which cannot be correctly described with traditional metrics such as fractional anisotropy (FA) or apparent diffusion coefficient (ADC). Here, we used a novel fixel-based along-tract analysis consisting of constrained spherical deconvolution (CSD)-based probabilistic tractography and fixel-based apparent fiber density (FD), capable of identifying fiber orientation specific microstructural metrics. We addressed this novel methodology's capability to detect corticospinal tract impairment. We measured and compared tractogram-related FD and traditional microstructural metrics bihemispherically in 65 patients with WHO grade III and IV gliomas infiltrating the motor system. The cortical tractogram seeds were based on motor maps derived by transcranial magnetic stimulation. We extracted 100 equally distributed cross-sections along each streamline of corticospinal tract (CST) for along-tract statistical analysis. Cross-sections were then analyzed to detect differences between healthy and pathological hemispheres. All metrics showed significant differences between healthy and pathologic hemispheres over the entire tract and between peritumoral segments. Peritumoral values were lower for FA and FD, but higher for ADC within the entire cohort. FD was more specific to tumor-induced changes in CST than ADC or FA, whereas ADC and FA showed higher sensitivity. The bihemispheric along-tract analysis provides an approach to detect subject-specific structural changes in healthy and pathological WM. In the current clinical dataset, the more complex FD metrics did not outperform FA and ADC in terms of describing corticospinal tract impairment. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. This study reports a case of motor and sensory function recovery after massive left cerebral infarction in a young man, along with preserved function of the injured hemisphere. He received early rehabilitation therapy in a nerval care unit within 1 wk of surgery, and the rehabilitation lasted for more than 3 yrs. When he gradually recovered from coma, his motor, sensory, and speech functions improved significantly. Two years later, he was able to live independently and returned to work. The findings of functional magnetic resonance imaging, diffusion tensor imaging, somatosensory evoked potential, and motor evoked potential confirmed that there was a strong connection between his right brain and the right limbs. Thus, early rehabilitation is a promising approach for restoring motor and sensory function after massive brain injury or extensive brain tissue damage. [ABSTRACT FROM AUTHOR]

Our previous studies demonstrated that axonal remodeling of the corticospinal tract (CST) contributes to neurological recovery after stroke in rodents. The present study employed a novel non-invasive peripheral approach, to over-express tPA in denervated spinal motor neurons via recombinant adeno-associated virus (AAV) intramuscular injection in transgenic mice subjected to permanent middle cerebral artery occlusion (MCAo), in which the CST axons are specifically and completely labeled with yellow fluorescent protein (YFP). One day after surgery, mice were randomly selected to receive saline, AAV5-RFP, or tPA (1 × 1010 viral particles) injected into the stroke-impaired forelimb muscles (n = 10/group). Functional deficits and recovery were monitored with foot-fault and single pellet reaching tests. At day 28 after MCAo, mice received intramuscular injection of PRV-614-mRFP (1.52 × 107 pfu) as above, and were euthanized four days later. Compared with saline or AAV-RFP-treated mice, AAV-tPA significantly enhanced behavioral recovery (p < 0.01, both tests), as well as increased CST axonal density in the denervated gray matter of the cervical cord (p < 0.001), and RFP-positive pyramidal neurons in both ipsilesional and contralesional cortices (p < 0.001). Behavioral outcomes were significantly correlated to neural remodeling (p < 0.05). Our results provide a fundamental basis for the development of therapeutic approaches aimed at promoting corticospinal innervation for stroke treatment. [ABSTRACT FROM AUTHOR]

Aim of the Study To predict motor recovery after stroke by detection of diffusion tensor imaging (DTI) fractional anisotropy (FA) changes of corticospinal tract (CST) and correlate findings with clinical scores to provide more effective treatment and rehabilitation. Subjects and Methods Thirty patients with cerebral stroke were enrolled and underwent conventional magnetic resonance imaging and DTI at admission and 1 month after stroke. Mean diffusivity (MD), FA, FA ratio (rFA), and fiber number (FN) values of CST were calculated at the pons at admission and after 1 month of stroke. Three-dimensional reconstruction of bilateral CST and the structural changes of fibrous bands were observed. Severity of limb weakness was assessed by using the motor sub-index scores of the National Institutes of Health Stroke Scale (NIHSS) at admission, and after 1, 6, and 9 months for severity of limb weakness. Results The mean age of our patients was 61.32 ± 4.34 years, 17/30 (56.6%) were females, and 13/30 (43.4%) were males. In our study, 18/30 (60%) were hypertensive, 19/30 (63.3%) were diabetic, and 12/30 (40%) were smokers. A significant negative correlation was found between rFA and FN in the ipsilateral CST of the cerebral infarction at the rostral part of pons after 1 month of infarction and NIHSS score at 6 months (r = 0.377, p = 0.04 and r = 0.237, p = 0.02, respectively). However, a positive insignificant correlation was found between MD and NIHSS (r = 0.345, p = 0.635). The initial NIHSS score at the time of injury was 19.2 ± 4.3, which changed to 7.9 ± 2.4, 4.6 ± 1.9, and 3.3 ± 1.4 at 1, 6, and 9 months, respectively. Conclusion DTI is a sensitive tool for early detection of Wallerian degeneration in the CST after stroke, and can predict motor performance to provide effective treatment and rehabilitation to improve quality of life. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) is the imaging technique used in vivo to visualise white matter pathways. The cortico-spinal tract (CST) belongs to one of the most often delineated tracts preoperatively, although the optimal DTI method has not been established yet. Considering that various regions of interests (ROIs) could be selected, the reproducibility of CST tracking among different centres is low. We aimed to select the most reliable tractography method for outlining the CST for neurosurgeons.Materials and Methods: Our prospective study consisted of 32 patients (11 males, 21 females) with a brain tumour of various locations. DTI and T1-weighed image series were acquired prior to the surgery. To draw the CST, the posterior limb of the internal capsule (PLIC) and the cerebral peduncle (CP) were defined as two main ROIs. Together with these main ROIs, another four cortical endpoints were selected: the frontal lobe (FL), the supplementary motor area (SMA), the precentral gyrus (PCG) and the postcentral gyrus (POCG). Based on these ROIs, we composed ten virtual CSTs in DSI Studio. The fractional anisotropy, the mean diffusivity, the tracts' volume, the length and the number were compared between all the CSTs. The degree of the CST infiltration, tumour size, the patients' sex and age were examined.Results: Significant differences in the number of tracts and their volume were observed when the PLIC or the CP stood as a single ROI comparing with the two- ROI method (all p < 0.05). The mean CST volume was 40054U (SD ± 12874) and the number of fibres was 259.3 (SD ± 87.3) when the PLIC was a single ROI. When the CP was a single ROI, almost a half of fibres (147.6; SD ± 64.0) and half of the CST volume (26664U; SD ± 10059U) was obtained (all p < 0.05). There were no differences between the various CSTs in terms of fractional anisotropy, mean diffusivity, the apparent diffusion coefficient, radial diffusivity and the tract length (p > 0.05). The CST was infiltrated by a growing tumour or oedema in 17 of 32 patients; in these cases, the mean and apparent diffusion of the infiltrated CST was significantly higher than in uncompromised CSTs (p = 0.04). CST infiltration did not alter the other analysed parameters (all p > 0.05).Conclusions: A universal method of DTI of the CST was not developed. However, we found that the CP or the PLIC (with or without FL as the second ROI) should be used to outline the CST. [ABSTRACT FROM AUTHOR]

Humans learn motor skills (MSs) through practice and experience and may then retain them for recruitment, which is effective as a rapid response for novel contexts. For an MS to be recruited for novel contexts, its recruitment range must be extended. In addressing this issue, we hypothesized that an MS is dynamically modulated according to the feedback context to expand its recruitment range into novel contexts, which do not involve the learning of an MS. The following two sub-issues are considered. We previously demonstrated that the learned MS could be recruited in novel contexts through its modulation, which is driven by dynamically regulating the synergistic redundancy between muscles according to the feedback context. However, this modulation is trained in the dynamics under the MS learning context. Learning an MS in a specific condition naturally causes movement deviation from the desired state when the MS is executed in a novel context. We hypothesized that this deviation can be reduced with the additional modulation of an MS, which tunes the MS-produced muscle activities by using the feedback gain signals driven by the deviation from the desired state. Based on this hypothesis, we propose a feedback gain signal-driven tuning model of a learned MS for its robust recruitment. This model is based on the neurophysiological architecture in the cortico-basal ganglia circuit, in which an MS is plausibly retained as it was learned and is then recruited by tuning its muscle control signals according to the feedback context. In this study, through computational simulation, we show that the proposed model may be used to neurophysiologically describe the recruitment of a learned MS in novel contexts.

BackgroundCorticospinal tract impairment is no longer an absolute exclusion in the updated Movement Disorder Society Parkinson’s disease criteria. Triple stimulation technique (TST) is an accurate method to quantitatively assess the integrity and impairment of corticospinal pathway in a variety of neurological diseases. This study aims to evaluate the corticospinal tract impairment in Parkinson’s disease (PD) patients using TST.MethodsTen PD patients, 19 multiple-system atrophy parkinsonian variant (MSA-P) patients, and 12 healthy controls (HC) were sequentially recruited in this study. Information of age, disease duration, pyramidal signs, and Hoehn and Yahr (H&Y) stage was obtained from all patients. The TST was assessed at right abductor digiti minimi for HCs and both sides for patients. The Chi-square test was used for categorical variables, and variance analysis was performed for continuous variables in comparing the difference among PD, MSA-P, and HC, plus the post hoc tests for pairwise comparisons.ResultsAll subjects were age and gender matched. There was no significant difference in disease duration (p = 0.855), H-Y stage (p = 0.067), and the percentage of pyramidal signs present (p = 0.581) between MSA-P and PD patients. The mean TST ratio was 55.5 ± 32.2%, 81.7 ± 19.8%, and 96.8 ± 3.0% for PD, MSA-P, and HCs, correspondingly. PD patients had a significant lower TST amplitude ratio than MSA-P and HCs. The TST ratio of MSA-P was lower than HCs, but there was no significant difference (p = 0.160). Additionally, it was significantly higher in percentage of abnormal TST ratio between PD patients and MSA-P (p = 0.010).ConclusionCorticospinal tract impairment is not a rare manifestation in PD and can be quantitatively evaluated with TST. The result needs to be verified in amplified sample.

To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed “the self-regulation clock” and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the “clock” circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates.

INTRODUCTION: Diffusion MRI tractography has been increasingly used to delineate white matter pathways in vivo for which the leading clinical application is presurgical mapping of eloquent regions. However, there is rare opportunity to quantify the accuracy or sensitivity of these approaches to delineate white matter fiber pathways in vivo due to the lack of a gold standard. Intraoperative electrical stimulation (IES) provides a gold standard for the location and existence of functional motor pathways that can be used to determine the accuracy and sensitivity of fiber tracking algorithms. In this study we used intraoperative stimulation from brain tumor patients as a gold standard to estimate the sensitivity and accuracy of diffusion tensor MRI (DTI) and q-ball models of diffusion with deterministic and probabilistic fiber tracking algorithms for delineation of motor pathways. METHODS: We used preoperative high angular resolution diffusion MRI (HARDI) data (55 directions, b = 2000 s/mm(2)) acquired in a clinically feasible time frame from 12 patients who underwent a craniotomy for resection of a cerebral glioma. The corticospinal fiber tracts were delineated with DTI and q-ball models using deterministic and probabilistic algorithms. We used cortical and white matter IES sites as a gold standard for the presence and location of functional motor pathways. Sensitivity was defined as the true positive rate of delineating fiber pathways based on cortical IES stimulation sites. For accuracy and precision of the course of the fiber tracts, we measured the distance between the subcortical stimulation sites and the tractography result. Positive predictive rate of the delineated tracts was assessed by comparison of subcortical IES motor function (upper extremity, lower extremity, face) with the connection of the tractography pathway in the motor cortex. RESULTS: We obtained 21 cortical and 8 subcortical IES sites from intraoperative mapping of motor pathways. Probabilistic q-ball had the best sensitivity (79%) as determined from cortical IES compared to deterministic q-ball (50%), probabilistic DTI (36%), and deterministic DTI (10%). The sensitivity using the q-ball algorithm (65%) was significantly higher than using DTI (23%) (p

Stroke can cause Wallerian degeneration in regions outside of the brain, particularly in the corticospinal tract. To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract following stroke, we induced photochemical infarction of the sensorimotor cortex leading to Wallerian degeneration along the full extent of the corticospinal tract. We first used a routine, sensitive marker of axonal injury, amyloid precursor protein, to examine Wallerian degeneration of the corticospinal tract. An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the ischemic cortex, with no positive signal in distal parts of the corticospinal tract, at all time points. To improve visualization of Wallerian degeneration, we next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent protein-expressing axons. Using this approach, we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke. In addition, microglia mobilized and activated early, from day 7 after stroke, but did not maintain a phagocytic state over time. Meanwhile, astrocytes showed relatively delayed mobilization and a moderate response to Wallerian degeneration. Moreover, no anterograde degeneration of spinal anterior horn cells was observed in response to Wallerian degeneration of the corticospinal tract. In conclusion, our data provide evidence for dynamic, pathogenic spatiotemporal changes in major cellular components of the corticospinal tract during Wallerian degeneration., Competing Interests: None

Introduction: Single-pulse transcranial magnetic stimulation (TMS) has many applications for pediatric clinical populations, including infants with perinatal brain injury. As a noninvasive neuromodulation tool, single-pulse TMS has been used safely in infants and children to assess corticospinal integrity and circuitry patterns. TMS may have important applications in early detection of atypical motor development or cerebral palsy., Areas Covered: The authors identified and summarized relevant studies incorporating TMS in infants, including findings related to corticospinal development and circuitry, motor cortex localization and mapping, and safety. This special report also describes methodologies and safety considerations related to TMS assessment in infants, and discusses potential applications related to diagnosis of cerebral palsy and early intervention., Expert Opinion: Single-pulse TMS has demonstrated safety and feasibility in infants with perinatal brain injury and may provide insight into neuromotor development and potential cerebral palsy diagnosis. Additional research in larger sample sizes will more fully evaluate the utility of TMS biomarkers in early diagnosis and intervention. Methodological challenges to performing TMS in infants and technical/equipment limitations require additional consideration and innovation toward clinical implementation. Future research may explore use of noninvasive neuromodulation techniques as an intervention in younger children with perinatal brain injury to improve motor outcomes.

Aims: Control of finger forces underlies our capacity for skilled hand movements acquired during development and reacquired after neurological injury. Learning force control by the digits, therefore, predicates our functional independence. Noninvasive neuromodulation targeting synapses that link corticospinal neurons onto the final common pathway via spike-timing-dependent mechanisms can alter distal limb motor output on a transient basis, yet these effects appear subject to individual differences. Here, we investigated how this form of noninvasive neuromodulation interacts with task repetition to influence early learning of force control during precision grip., Methods: The unique effects of neuromodulation, task repetition, and neuromodulation coinciding with task repetition were tested in three separate conditions using a within-subject, cross-over design (n = 23)., Results: We found that synchronizing depolarization events within milliseconds of stabilizing precision grip accelerated learning but only after accounting for individual differences through inclusion of subjects who showed upregulated corticospinal excitability at 2 of 3 time points following conditioning stimulation (n = 19)., Conclusions: Our findings provide insights into how the state of the corticospinal system can be leveraged to drive early motor skill learning, further emphasizing individual differences in the response to noninvasive neuromodulation. We interpret these findings in the context of biological mechanisms underlying the observed effects and implications for emerging therapeutic applications., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Stroke is the third leading cause of death and disability worldwide. Post-stroke spasticity (PSS) is the most common complication of stroke but represents only one of the many manifestations of upper motor neuron syndrome. As an upper motor neuron, the corticospinal tract (CST) is the only direct descending motor pathway that innervates the spinal motor neurons and is closely related to the recovery of limb function in patients with PSS. Therefore, promoting axonal remodeling in the CST may help identify new therapeutic strategies for PSS. In this review, we outline the pathological mechanisms of PSS, specifically their relationship with CST, and therapeutic strategies for axonal regeneration of the CST after stroke. We found it to be closely associated with astroglial scarring produced by astrocyte activation and its secretion of neurotrophic factors, mainly after the onset of cerebral ischemia. We hope that this review offers insight into the relationship between CST and PSS and provides a basis for further studies., (© 2023. The Author(s).)