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BACKGROUND: The recovery of function after spinal cord injury depends on the functional remodeling of the motor cortex. However, the anatomical evidence underlying the functional remodeling of the motor cortex is still illusive. Analyzing the anatomical changes in the motor cortex after spinal cord injury can provide new ideas and research directions for regulating functional recovery and rehabilitation after spinal cord injury. OBJECTIVE: To analyze the neural circuit structural basis of functional remodeling of the primary motor cortex after spinal cord injury. METHODS: C57BL/6J mice were randomly divided into a sham operation group and a spinal cord injury group. The adeno-associated virus vectors expressing the fusion protein of Cre recombinase were injected into C4 of mice of both groups. The adeno-associated virus vectors with Cre recombinase-inducible expression of avian sarcoma/leukosis envelope glycoprotein receptor TVA and rabies glycoprotein were injected into the primary motor cortex. Fourteen days later, a C6 dorsal hemisection mice model was established in the spinal cord injury group. The pseudotyped rabies virus was injected into the primary motor cortex of mice of both groups. After 7 days, brain samples were collected and frozen sections were made. The distribution of input neurons innervating corticospinal motor neurons in the brain was observed and analyzed quantitatively. RESULTS AND CONCLUSION: Fluorescence microscopy observation and quantitative analysis found that input neurons innervating corticospinal motor neurons of the primary motor cortex in mice of both groups were distributed in the cerebral cortex, thalamus and midbrain. Among them, in the sham operation group, the number of input neurons in the mouse cerebral cortex accounted for (84.0±3.6)% of total brain input neurons; that in the thalamus accounted for (10.6±2.3)%, and that in the midbrain accounted for (0.7±0.4)%. Direct synaptic input neurons in the spinal cord injury group accounted for (81.7±1.0)%, (13.1±0.5)%, and (1.6±0.8)% in the cerebral cortex, thalamus and midbrain, respectively. The proportion and number of primary motor cortex input neurons in the three regions of the spinal cord injury group did not differ significantly from that of the sham operation group. After spinal cord injury, the number of input neurons innervating corticospinal pyramidal motor neurons in various brain regions did not change significantly, suggesting that functional remodeling of the motor cortex after spinal cord injury may not only depend on changes in synaptic input related to injured corticospinal motor neurons, but also on transcriptional regulation changes within the injured neurons themselves. [ABSTRACT FROM AUTHOR]

Background. There is as yet no uniform view as to the effectiveness of fluorescence microscopy (FM) in patients with tumors located near functionally important areas of the brain (FAB), where the surgeon can elect to terminate resection because of a high risk of increasing neurological deficit. Task. To evaluate the effectiveness of FM in removing gliomas near the motor cortex (MC) and corticospinal tract (CST). Methods. A total of 108 adult patients with gliomas near the MC and CST who underwent surgery with neurophysiological monitoring were divided into two groups depending on the use of FM: a control group (34 patients without FM) and a study group (62 patients with FM). Results. The extent of resection and the frequency of neurological deficits in the postoperative period were not significantly different in the groups studied. Conclusions. Despite the absence of any statistically significant between-group difference, FM may be of value as a component of intraoperative monitoring in this group of patients. [ABSTRACT FROM AUTHOR]

This article presents a unique case of ipsilateral hemiparesis in a 66-year-old individual, contrary to the conventional understanding of supratentorial strokes causing contralateral neurological deficits. The patient exhibited persistent weakness and sensory abnormalities on the left side of the body following a left occipital infarct. Neuroimaging revealed a chronic stroke in the left occipital lobe, with diffusion tensor imaging demonstrating uncrossed pyramidal tracts at the level of the medulla. The discussion encompasses the anatomical basis of corticospinal tract crossing, historical perspectives, and previous documented cases of ipsilateral strokes. The rarity of complete uncrossed corticospinal tracts without underlying congenital abnormalities or genetic disorders is highlighted. The study underscores the importance of considering such atypical presentations in stroke evaluations and the role of advanced imaging techniques in confirming diagnosis and understanding underlying mechanisms.

Brown-Séquard Syndrome (BSS) is a rare neurological condition caused by a unilateral spinal cord injury (SCI). Upon initial ipsilesional hemiplegia, patients with BSS typically show substantial functional recovery over time. Preclinical studies on experimental BSS demonstrated that spontaneous neuroplasticity in descending motor systems is a key mechanism promoting functional recovery. The reticulospinal (RS) system is one of the main descending motor systems showing a remarkably high ability for neuroplastic adaptations after incomplete SCI. In humans, little is known about the contribution of RS plasticity to functional restoration after SCI. Here, we investigated RS motor drive to different muscles in a subject with Brown-Séquard-plus Syndrome (BSPS) five months post-injury using the StartReact paradigm. RS drive was compared between ipsi-and contralesional muscles, and associated with measures of functional recovery. Additionally, corticospinal (CS) drive was investigated using transcranial magnetic stimulation (TMS) in a subset of muscles. The biceps brachii showed a substantial enhancement of RS drive on the ipsi- vs. contralesional side, whereas no signs of CS plasticity were found ipsilesionally. This finding implies that motor recovery of ipsilesional elbow flexion is primarily driven by the RS system. Results were inversed for the ipsilesional tibialis anterior, where RS drive was not augmented, but motor-evoked potentials recovered over six months post-injury, suggesting that CS plasticity contributed to improvements in ankle dorsiflexion. Our findings indicate that the role of RS and CS plasticity in motor recovery differs between muscles, with CS plasticity being essential for the restoration of distal extremity motor function, and RS plasticity being important for the functional recovery of proximal flexor muscles after SCI in humans. [ABSTRACT FROM AUTHOR]

Stroke patients commonly face challenges during magnetic resonance imaging (MRI) examinations due to involuntary movements. This study aims to overcome these challenges by utilizing multiple overlapping-echo detachment (MOLED) quantitative technology. Through this technology, we also seek to detect microstructural changes of the normal-appearing corticospinal tract (NA-CST) in subacute-chronic stroke patients. 79 patients underwent 3.0 T MRI scans, including routine scans and MOLED technique. A deep learning network was utilized for image reconstruction, and the accuracy, reliability, and resistance to motion of the MOLED technique were validated on phantoms and volunteers. Subsequently, we assessed motor dysfunction severity, ischemic lesion volume, T 2 values of the bilateral NA-CST, and the T 2 ratio (rT 2) between the ipsilesional and contralesional NA-CST in patients. The MOLED technique showed high accuracy (P < 0.001) and excellent repeatability, with a mean coefficient of variation (CoV) of 1.11%. It provided reliable quantitative results even under head movement, with a mean difference (Mean diff) = 0.28% and a standard deviation difference (SD diff) = 1.34%. Additionally, the T 2 value of the ipsilesional NA-CST was significantly higher than contralesional side (P < 0.001), and a positive correlation was observed between rT 2 and the severity of motor dysfunction (r s = 0.575, P < 0.001). Furthermore, rT 2 successfully predicted post-stroke motor impairment, with an area under the curve (AUC) was 0.883. The MOLED technique offers significant advantages for quantitatively imaging stroke patients with involuntary movements. Additionally, T 2 mapping from MOLED can detect microstructural changes in the NA-CST, potentially aiding in monitoring stroke-induced motor impairment. [ABSTRACT FROM AUTHOR]

Gliomas adjacent to the corticospinal tract (CST) should be carefully resected to preserve motor function while achieving maximal surgical resection. Modern high-field intraoperative magnetic resonance imaging (iMRI) enables precise visualization of the residual tumor and intraoperative tractography. We prospectively evaluated the extent of resection and distance between the tumor resection cavity and CST using 3-T iMRI combined with motor evoked potentials (MEP) in glioma surgery. Participants comprised patients who underwent surgery for solitary supratentorial glioma located within 10 mm of the CST. All cases underwent surgery using neuronavigation with overlaid CST under MEP monitoring. The correlation between distance from CST and transcortical MEP amplitude was calculated using Spearman rank correlation. Among the 63 patients who underwent surgery, 27 patients were enrolled in the study. Gross total resections were achieved in 26 of the 27 cases. Volumetric analysis showed the extent of resection was 98.6%. Motor function was stable or improved in 24 patients (Stable/Improved group) and deteriorated in 3 patients (Deteriorated group). All patients in the Deteriorated group showed motor deficit before surgery. Mean intraoperative minimal distance was significantly longer in the Stable/Improved group (7.3 mm) than in the Deteriorated group (1.1 mm; P < 0.05). MEP amplitude correlated with minimal distance between the resection cavity and CST (R = 0.64). Resection of gliomas adjacent to CST with a navigation system using 3-T iMRI could result in an ultimate EOR >98%. The combination of intraoperative tractography and MEP contributes to maximal removal of motor-eloquent gliomas. [ABSTRACT FROM AUTHOR]

[Display omitted] • Our findings do not support the use of rTMS as a standalone treatment for CLBP. • Top-down and bottom-up interventions might trigger a distinct priming mechanism. • Our study contributed to optimizing treatment strategies for CLBP. The study aims to explore the effects of combining repetitive transcranial magnetic stimulation (rTMS) with sling exercise (SE) intervention in patients with chronic low back pain (CLBP). This approach aims to directly stimulate brain circuits and indirectly activate trunk muscles to influence motor cortex plasticity. However, the impact of this combined intervention on motor cortex organization and clinical symptom improvement is still unclear, as well as whether it is more effective than either intervention alone. To investigate this, patients with CLBP were randomly assigned to three groups: SE/rTMS, rTMS alone, and SE alone. Motor cortical organization, numerical pain rating scale (NPRS), Oswestry Disability Index (ODI), and postural balance stability were measured before and after a 2-week intervention. The results showed statistically significant differences in the representative location of multifidus on the left hemispheres, as well as in NPRS and ODI scores, in the combined SE/rTMS group after the intervention. When compared to the other two groups, the combined SE/rTMS group demonstrated significantly different motor cortical organization, sway area, and path range from the rTMS alone group, but not from the SE alone group. These findings highlight the potential benefits of a combined SE/rTMS intervention in terms of clinical outcomes and neuroadaptive changes compared to rTMS alone. However, there was no significant difference between the combined intervention and SE alone. Therefore, our research does not support the use of rTMS as a standalone treatment for CLBP. Our study contributed to optimizing treatment strategies for individuals suffering from CLBP. [ABSTRACT FROM AUTHOR]

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.

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. 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. 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. Single pulse transcranial magnetic stimulation (TMS) is a safe and noninvasive way to study brain activity in infants and children who have experienced brain injuries around the time of birth. Infants who have had an early brain injury may develop cerebral palsy, a developmental disability that affects movement. TMS uses a device that gives single pulses of energy to activate specific areas of the brain. This can be used to study how the brain connects to the muscles in the body through paths or 'tracts.' TMS helps researchers understand the development of the tracts and the potential need for therapy. This article reviews research studies that used TMS in infants and explains how TMS can be used to assess brain development. It also reviews safety considerations and challenges related to using TMS in infants. TMS could be a valuable tool for early diagnosis of cerebral palsy and could also help guide treatments for infants with brain injuries. However, more research is needed, using larger groups of infants, to potentially expand the use of TMS in clinical practice. Future directions include developing infant-specific research tools and using noninvasive brain stimulation to improve recovery for infants with brain injuries. [ABSTRACT FROM AUTHOR]

Background: Lower capacity to generate knee extension maximal voluntary force (MVF) has been observed in individuals affected with patellar tendinopathy (PT) compared to asymptomatic controls. This MVF deficit is hypothesized to emanate from alterations in corticospinal excitability (CSE). The modulation of CSE is intricately linked to the excitability levels at multiple sites, encompassing neurones within the corticospinal tract (CST), intracortical neurones within the primary motor cortex (M1), and the alpha motoneurone. The aim of this investigation was to examine the excitability of intracortical neurones, CST neurones, and the alpha motoneurone, and compare these between volleyball and basketball athletes with PT and matched asymptomatic controls. Method: Nineteen athletes with PT and 18 asymptomatic controls participated in this cross‐sectional study. Transcranial magnetic stimulation was utilized to assess CST excitability, corticospinal inhibition (silent period, and short‐interval cortical inhibition). Peripheral nerve stimulation was used to evaluate lumbar spine and alpha motoneurone excitability, including the evocation of lumbar‐evoked potentials and maximal compound muscle action potential (MMAX), and CSE with central activation ratio (CAR). Knee extension MVF was also assessed. Results: Athletes with PT exhibited longer silent period duration and greater electrical stimulator output for MMAX, as well as lower MVF, compared to asymptomatic controls (p < 0.05). Conclusion: These findings indicate volleyball and basketball athletes with PT exhibit reduced excitability of the alpha motoneurone or the neuromuscular junction, which may be linked to lower MVF. Subtle alterations at specific sites may represent compensatory changes to excitability aiming to maintain efferent drive to the knee extensors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Most in vivo SCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures. Here, we followed animals into the chronic phase following SCI, to address this gap. Male macaques received targeted deafferentation, affecting three digits of one hand, and were divided into short (4-6 months) or long-term (11-12 months) groups, based on post-injury survival times. Monkeys were assessed behaviorally, where possible, and all exhibited an initial post-injury deficit in manual dexterity, with gradual functional recovery over 2 months. We previously reported extensive sprouting of somatosensory corticospinal (S1 CST) fibers in the dorsal horn in the first five post-injury months. Here, we show that by 1 year, the S1 CST sprouting is pruned, with the terminal territory resembling control animals. This was reflected in the number of putatively "functional" synapses observed, which increased over the first 4-5 months, and then returned to baseline by 1 year. Microglia density also increased in the affected dorsal horn at 4-6 months and then decreased, but did not return to baseline by 1 year, suggesting refinement continues beyond this time. Overall, there is a long period of reorganization and consolidation of adaptive circuitry in the dorsal horn, extending well beyond the initial behavioral recovery. This provides a potential window to target therapeutic opportunities during the chronic phase. [ABSTRACT FROM AUTHOR]

Brown-Séquard Syndrome (BSS) is a rare neurological condition caused by a unilateral spinal cord injury (SCI). Upon initial ipsilesional hemiplegia, patients with BSS typically show substantial functional recovery over time. Preclinical studies on experimental BSS demonstrated that spontaneous neuroplasticity in descending motor systems is a key mechanism promoting functional recovery. The reticulospinal (RS) system is one of the main descending motor systems showing a remarkably high ability for neuroplastic adaptations after incomplete SCI. In humans, little is known about the contribution of RS plasticity to functional restoration after SCI. Here, we investigated RS motor drive to different muscles in a subject with Brown-Séquard-plus Syndrome (BSPS) five months post-injury using the StartReact paradigm. RS drive was compared between ipsi- and contralesional muscles, and associated with measures of functional recovery. Additionally, corticospinal (CS) drive was investigated using transcranial magnetic stimulation (TMS) in a subset of muscles. The biceps brachii showed a substantial enhancement of RS drive on the ipsi- vs. contralesional side, whereas no signs of CS plasticity were found ipsilesionally. This finding implies that motor recovery of ipsilesional elbow flexion is primarily driven by the RS system. Results were inversed for the ipsilesional tibialis anterior, where RS drive was not augmented, but motor-evoked potentials recovered over six months post-injury, suggesting that CS plasticity contributed to improvements in ankle dorsiflexion. Our findings indicate that the role of RS and CS plasticity in motor recovery differs between muscles, with CS plasticity being essential for the restoration of distal extremity motor function, and RS plasticity being important for the functional recovery of proximal flexor muscles after SCI in humans.

We present clinical observation of a 3-year-old child during recovery after acute hypoxic brain injury (freshwater drowning). Using diagnostic transcranial magnetic stimulation and magnetic resonance tractography with reconstruction of the corticospinal tract (CST) originated from the primary motor cortex and supplementary motor area (SMA), we determined that hypoxic brain injury induced activation of CST from the SMA. The period of reorganization was associated with the development of epileptiform patterns, that confirms the transient hyperexcitability of cortical neurons. Our findings indicate no recovery of motor function after acute hypoxic brain injury when CST originated only from SMA.

This paper explores the potential of rAAV2-retro to deliver gene modifying cargoes to the cells of origin of multiple pathways that are interrupted by spinal cord injury (SCI), summarizing data from previous studies and new data from additional experiments. rAAV-retro exhibits uniquely robust and reliable long-distance retrograde transport from pre-terminal axons and synapses back to neuronal bodies. Previous studies have documented that various AAV-based genetic modifications can enable axon regeneration after SCI, but these have targeted the cells of origin of one pathway at a time. In contrast, rAAV-retro can simultaneously transduce large numbers of neurons of origin of multiple spinal pathways with single injections into the spinal cord. Our initial studies use RosatdTomato and double transgenic PTENf/f; RosatdTomato mice in which transfection with rAAV-retro/Cre deletes PTEN and activates tdT expression in the same neurons. Injections of rAAV-retro/Cre into the cervical, thoracic and lumbar spinal cord led to topographically specific retrograde transduction in cortical motoneurons and neurons in subcortical regions that give rise to different spinal pathways. Our results confirm and extend previous studies indicating selective transduction of neurons that terminate at the level of the injection with minimal retrograde transduction of axons in transit to lower levels. We document feasibility of using rAAV-retro expressing shRNA against PTEN along with a GFP reporter (rAAV-retro-shPTEN/GFP) to effectively knock down PTEN in multiple populations of neurons, which can be used in any species. Some limitations and caveats of currently available rAAV-retros are discussed. Together, our results support the potential applications of rAAV-retro for AAV-based gene-modifications for SCI.

The corticospinal tract (CST) is a critically important white matter fiber tract in the human brain that enables control of voluntary movements of the body. The CST exhibits a somatotopic organization, which means that the motor neurons that control specific body parts are arranged in order within the CST. Diffusion magnetic resonance imaging (MRI) tractography is increasingly used to study the anatomy of the CST. However, despite many advances in tractography algorithms over the past decade, modern, state‐of‐the‐art methods still face challenges. In this study, we compare the performance of six widely used tractography methods for reconstructing the CST and its somatotopic organization. These methods include constrained spherical deconvolution (CSD) based probabilistic (iFOD1) and deterministic (SD‐Stream) methods, unscented Kalman filter (UKF) tractography methods including multi‐fiber (UKF2T) and single‐fiber (UKF1T) models, the generalized q‐sampling imaging (GQI) based deterministic tractography method, and the TractSeg method. We investigate CST somatotopy by dividing the CST into four subdivisions per hemisphere that originate in the leg, trunk, hand, and face areas of the primary motor cortex. A quantitative and visual comparison is performed using diffusion MRI data (N = 100 subjects) from the Human Connectome Project. Quantitative evaluations include the reconstruction rate of the eight anatomical subdivisions, the percentage of streamlines in each subdivision, and the coverage of the white matter–gray matter (WM–GM) interface. CST somatotopy is further evaluated by comparing the percentage of streamlines in each subdivision to the cortical volumes for the leg, trunk, hand, and face areas. Overall, UKF2T has the highest reconstruction rate and cortical coverage. It is the only method with a significant positive correlation between the percentage of streamlines in each subdivision and the volume of the corresponding motor cortex. However, our experimental results show that all compared tractography methods are biased toward generating many trunk streamlines (ranging from 35.10% to 71.66% of total streamlines across methods). Furthermore, the coverage of the WM–GM interface in the largest motor area (face) is generally low (under 40%) for all compared tractography methods. Different tractography methods give conflicting results regarding the percentage of streamlines in each subdivision and the volume of the corresponding motor cortex, indicating that there is generally no clear relationship, and that reconstruction of CST somatotopy is still a large challenge. Overall, we conclude that while current tractography methods have made progress toward the well‐known challenge of improving the reconstruction of the lateral projections of the CST, the overall problem of performing a comprehensive CST reconstruction, including clinically important projections in the lateral (hand and face areas) and medial portions (leg area), remains an important challenge for diffusion MRI tractography. [ABSTRACT FROM AUTHOR]

Background: Gliomas have infiltrative nature and tumor volume has direct prognostic value. Optimal resection limits delineated by high-frequency monopolar stimulation with multipulse short train technique is still a matter of debate for safe surgery without (or with acceptable) neurological deficits. It is also an enigma whether the same cut-off values are valid for high and low grades. We aimed to analyze the value of motor mapping/monitoring findings on postoperative motor outcome in diffuse glioma surgery. Methods: Patients who were operated on due to glioma with intraoperative neuromonitorization at our institution between 2017 and 2021 were analyzed. Demographic information, pre- and post-operative neurological deficit, magnetic resonance images, resection rates, and motor evoked potential (MEP) findings were analyzed. Results: Eighty-seven patients of whom 55 had high-grade tumors were included in the study. Total/near-total resection was achieved in 85%. Subcortical motor threshold (ScMTh) from resection cavity to the corticospinal tract was ≤ 2mA in 17; 3 mA in 14; 4 mA in 6; 5 mA in 7, and ≥5mA in 50 patients. On the 6th month examination, six patients (5 with high-grade tumor) had motor deficits. These patients had changes in MEP that exceeded critical threshold during monitoring. Receiver operating characteristic analysis revealed 2.5 mA ScMTh as the cut-off point for limb paresis after awakening and 6 months for the groups. Conclusions: Subcortical mapping with MEP monitoring helps to achieve safe wider resection. The optimal safe limit for SCMTh was determined as 2.5 mA. Provided that safe threshold values are maintained in MEP, surgeon may force the functional limits by lowering the SCMTh to 1 mA, especially in low-grade gliomas. [ABSTRACT FROM AUTHOR]

The corticospinal tract (CST) forms a central part of the voluntary motor apparatus in all mammals. Thus, injury, disease, and subsequent degeneration within this pathway result in chronic irreversible functional deficits. Current strategies to repair the damaged CST are suboptimal in part because of underexplored molecular heterogeneity within the adult tract. Here, we combine spinal retrograde CST tracing with single-cell RNA sequencing (scRNAseq) in adult male and female mice to index corticospinal neuron (CSN) subtypes that differentially innervate the forelimb and hindlimb. We exploit publicly available datasets to confer anatomic specialization among CSNs and show that CSNs segregate not only along the forelimb and hindlimb axis but also by supraspinal axon collateralization. These anatomically defined transcriptional data allow us to use machine learning tools to build classifiers that discriminate between CSNs and cortical layer 2/3 and nonspinally terminating layer 5 neurons in M1 and separately identify limb-specific CSNs. Using these tools, CSN subtypes can be differentially identified to study postnatal patterning of the CST in vivo, leveraged to screen for novel limb-specific axon growth survival and growth activators in vitro, and ultimately exploited to repair the damaged CST after injury and disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • Axon guidance molecules (AGM) regulate neuronal development. • AGMs play a crucial role in directing axons to their final destinations. • After CNS traumas, defects in these processes affect neuronal circuit rebuilding. • AGMs expression in spinal cord circuits can help find novel therapeutic targets. Axon guidance molecules (AGM) are critical regulators of neural development and play a vital role in guiding axons to their target regions during spinal cord development. The correct wiring of neural circuits depends on these molecules' precise expression and function. Defects in axonal pathfinding, growth cone navigation, axonal branching, and synapse formation have far-reaching implications for neuronal circuit construction and function after CNS traumas, such as spinal cord injury (SCI), which affect the expression or activity of AGM. Ascending and descending paths in the spinal cord have been found to include many AGM, including Netrins, Slits, Semaphorins (Sema), Ephrins, and their receptors. In contrast to the repulsive signals like Slits and Semaphorins, which restrict axonal growth and guide axons away from unsuitable locations, Netrins are appealing guidance cues that encourage axonal growth and guidance. Defects in motor function and sensory processing can result from changes in the expression or activity of Ephrins or their receptors, which play an essential role in axonal guidance and synaptic plasticity in the spinal cord. Herein, we highlighted the expressions, functions, and mechanisms of AGM in ascending and descending spinal cord tracts, which can help us identify novel therapeutic targets to improve axonal regeneration and functional recovery after SCI. [ABSTRACT FROM AUTHOR]

It is well documented that attention‐deficit hyperactivity disorder (ADHD) often presents with co‐occurring motor difficulties. However, little is known about the biological mechanisms that explain compromised motor skills in approximately half of those with ADHD. To provide insight into the neurobiological basis of poor motor outcomes in ADHD, this study profiled the development of white matter organization within the cortico‐spinal tract (CST) in adolescents with ADHD with and without co‐occurring motor problems, as well as non‐ADHD control children with and without motor problems. Participants were 60 children aged 9–14 years, 27 with a history of ADHD and 33 controls. All underwent high‐angular resolution diffusion MRI data at up to three time points (115 in scans total). We screened for motor impairment in all participants at the third time point (≈14 years) using the Developmental Coordination Disorder Questionnaire (DCD‐Q). Following pre‐processing of diffusion MRI scans, fixel‐based analysis was performed, and the bilateral CST was delineated using TractSeg. Mean fiber density (FD) and fiber cross‐section (FC) were extracted for each tract at each time‐point. To investigate longitudinal trajectories of fiber development, linear mixed models were performed separately for the left and right CST, controlling for nuisance variables. To examine possible variations in fiber development between groups, we tested whether the inclusion of group and the interaction between age and group improved model fit. At ≈10 years, those with ADHD presented with lower FD within the bilateral CST relative to controls, irrespective of their prospective motor status. While these microstructural abnormalities persisted into adolescence for individuals with ADHD and co‐occurring motor problems, they resolved for those with ADHD alone. Divergent maturational pathways of motor networks (i.e., the CST) may, at least partly, explain motor problems individuals with ADHD. [ABSTRACT FROM AUTHOR]

Introduction: Central post-stroke pain (CPSP), seen in the aftermath of a stroke, is an underdiagnosed entity but quite a disabling complication. All the postulated theories regarding the pathogenesis of CPSP point to its origin in the central pain pathways. However, this study attempts to demonstrate the role of other contributing areas in the generation of CPSP. Materials and Methods: In this single-center tertiary care hospital-based study, 24 patients with both ischemic and hemorrhagic strokes of variable durations were recruited, and Magnetic Resonance Imaging (MRI) imaging with diffusion tensor imaging (DTI) acquisition was done. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of the spinothalamic tract (STT), corticospinal tract (CST), superior thalamic radiation (STR), basal ganglia (BG), and primary somatosensory cortex (SSC) were compared between normal and abnormal sides and also in extrathalamic lesions separately. Results: Significant differences with lower FA were noted in STT, CST, STR, and SSC and higher ADC values in BG, STR, CST, and SSC on comparison between the normal and lesion sides. On individual sub-analysis, ischemic stroke had significant changes in the FA value of CST and the ADC value of STR and CST, while hemorrhagic stroke had significant changes in the FA and ADC values of STR and SSC, as well as the FA value of STT. In the analysis of the extrathalamic strokes, significance persisted in all the studied parameters except the BG. The CST abnormalities were evident even in patients with clinical motor improvement. On multivariate analysis, visual analogue scale score severity was correlated with thalamic lesions. Conclusion: Contrary to the belief that STT is solely responsible for CPSP, the role of CST, STR, BG, and SSC as contributing areas is evident from this study and may be more well established if studied in a larger population. [ABSTRACT FROM AUTHOR]

Aims: To investigate microstructural impairments of corticospinal tracts (CSTs) with different origins in amyotrophic lateral sclerosis (ALS) using neurite orientation dispersion and density imaging (NODDI). Methods: Diffusion‐weighted imaging data acquired from 39 patients with ALS and 50 controls were used to estimate NODDI and diffusion tensor imaging (DTI) models. Fine maps of CST subfibers originating from the primary motor area (M1), premotor cortex, primary sensory area, and supplementary motor area (SMA) were segmented. NODDI metrics (neurite density index [NDI] and orientation dispersion index [ODI]) and DTI metrics (fractional anisotropy [FA] and mean/axial/radial diffusivity [MD/AD/RD]) were computed. Results: The patients with ALS showed microstructural impairments (reflected by NDI, ODI, and FA reductions and MD, AD, and RD increases) in CST subfibers, especially in M1 fibers, which correlated with disease severity. Compared with other diffusion metrics, NDI yielded a higher effect size and detected the greatest extent of CST subfibers damage. Logistic regression analyses based on NDI in M1 subfiber yielded the best diagnostic performance compared with other subfibers and the whole CST. Conclusions: Microstructural impairment of CST subfibers (especially those originating from M1) is the key feature of ALS. The combination of NODDI and CST subfibers analysis may improve diagnosing performance for ALS. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) causes severe sequelae and significant social loss, depending on the extent of the damage. Most previous studies have focused on the pathology of the spinal cord to develop treatments for SCI. However, it is now known that the brain, which is not directly damaged, also undergoes morphological changes after spinal cord injury, which could affect natural recovery and treatment. In recent years, magnetic resonance imaging (MRI) has been developed to analyze functional changes in the brain. Resting- state functional MRI (rsfMRI), which captures brain activity at rest, can calculate functional connections between brain areas and identify central hubs by network analysis. Purpose: We aim to investigate functional connectivity in the brain using rsfMRI after SCI and to determine how brain-network main hubs change over time. Methods: We evaluated rsfMRI in 10 mice of the contusional SCI model and calculated connectivity using graph theory. We evaluated "centrality," a representative parameter of network analysis. The subtype of centrality was degree centrality, which indicates the hub function of a single area. The five times of rsfMRI were performed in each individual mouse: before injury and at 1, 3, 7, and 14 weeks post-injury. Results: Before the injury, the degree centralities of the primary and secondary motor cortex were high, suggesting that these motor cortices served as main hubs for motor function. After SCI, the hub function of the motor cortices decreased by 14 weeks. In contrast, hub function in the external capsule and the putamen comparatively increased with time after injury, suggesting that the extrapyramidal/subcortical system, which runs the ventral side of the spinal cord and remains after injury in this model, becomes dominant. Conclusion: We demonstrated the shift of the brain network hub after SCI. The results of this study provide basic information for understanding brain network changes after SCI and would be useful for treatment selection and evaluation of its efficacy in SCI patients. [ABSTRACT FROM AUTHOR]

Abstract Background Methods Results Conclusion There is limited information on brain perfusion single-photon emission computed tomography (SPECT) findings related to motor outcomes in patients with stroke. We aimed to investigate whether brain SPECT can be used to determine motor outcomes after corona radiata infarction.Eighty-nine patients were recruited in this study. Brain SPECT and diffusion tensor tractography (DTT) were conducted to evaluate the state of the corticospinal tract (CST) within 7–30 days of corona radiata infarct. Motor outcome was measured 6 months after infarct onset and was evaluated using the modified Brunnstrom classification (MBC) and functional ambulation category (FAC) for motor function of the upper and lower extremities, respectively. The presence of hypoperfusion on brain SPECT was evaluated in the frontal lobe, temporal lobe, parietal lobe, basal ganglia, thalamus, and cerebellum on both the ipsilesional and contralesional sides. Statistical analysis was performed using multivariate logistic regression, comparing patients in which CST was spared versus interrupted.Hypoperfusion in the contralesional cerebellum was indicative of poor recovery in both the upper and lower extremities after corona radiata infarction when the CST was interrupted. Additionally, when the CST was preserved, hypoperfusion in the ipsilesional thalamus was indicative of poor recovery of the lower extremities.Brain SPECT evaluation was shown to be a useful tool for predicting motor outcomes in patients with corona radiata infarcts. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS. [ABSTRACT FROM AUTHOR]

Expression of CD40 and CD192 markers in different monocyte subpopulations has been reported to be altered in people with MS (pwMS). Also, functional connectivity of the corticospinal motor system pathway alterations has been proved by transcranial magnetic stimulation (TMS). The study objective was to investigate the expression of CD40 and CD192 in classical (CD14++CD16−), intermediate CD14++CD16+ and non-classical (CD14+CD16++) blood monocyte subpopulations in pwMS, undergoing neurophysiological TMS assessment of the corticospinal tract integrity by recording motor-evoked potentials (MEPs). Radiological examination on lesion detection with MRI was performed for 23 patients with relapsing–remitting MS treated with teriflunomide. Then, immunological analysis was conducted on peripheral blood samples collected from the patients and 10 healthy controls (HC). The blood samples were incubated with anti-human CD14, CD16, CD40 and CD192 antibodies. Next, pwMS underwent neurological testing of functional disability (EDSS) and TMS assessment with recording MEPs from upper and lower extremity muscles. The results show that in comparison to HC subjects, both pwMS with normal and altered MEP findings (prolonged MEP latency or absent MEP response) had significantly decreased surface receptor expression measured (MFIs) of CD192 and increased CD40 MFI in classical monocytes, and significantly increased percentages of classical and total monocytes positive for CD40. Knowing CD40's pro-inflammatory action, and CD192 as a molecule that enables the passing of monocytes into the brain, decreased CD192 in classical monocytes could represent a beneficial anti-inflammatory parameter. [ABSTRACT FROM AUTHOR]

Lesion load of the corticospinal tract (CST-LL), a measure of overlap between a stroke lesion and the CST, is one of the strongest predictors of motor outcomes following stroke. CST-LL is typically calculated by using a probabilistic map of the CST originating from the primary motor cortex (M1). However, higher order motor areas also have projections that contribute to the CST and motor control. In this retrospective study, we examined whether evaluating CST-LL from additional motor origins is more strongly associated with post-stroke motor severity than using CST-LL originating from M1 only. We found that lesion load to both the ventral premotor (PMv) cortex and M1 were more strongly related to stroke motor severity indexed by Fugl-Meyer Assessment cut-off scores than CST-LL of M1 alone, suggesting that higher order motor regions add clinical relevance to motor impairment.

Bromethalin toxicosis is an increasingly common clinical presentation in dogs that may be fatal depending on the extent of intoxication. Antemortem diagnosis of bromethalin toxicosis was achieved in three dogs by demonstration of the active metabolite desmethylbromethalin in fat or serum. Magnetic resonance imaging (MRI) findings were consistent with a diffuse leukoencephalopathy with restricted diffusion and prominent involvement of the corticospinal motor tracts on T2-weighted and diffusion-weighted sequences. Imaging findings were confirmed in one non-surviving dog at necropsy. Resolution of MRI abnormalities was demonstrated in one surviving dog that was consistent with the associated resolution of clinical signs. Initial findings in these dogs support further investigation of specific MRI patterns in cases of leukoencephalopathy to aid differential diagnosis. While antemortem detection of bromethalin and its metabolites confirms exposure, quantitation may be informative as a prognostic biomarker.

Background: Neural activity helps construct neural circuits during development and this function is leveraged by neuromodulation protocols to promote connectivity and repair in maturity. Neuromodulation targeting the motor cortex (MCX) strengthens connections for evoking muscle contraction (MEPs). Mechanisms include promoting local MCX and corticospinal tract (CST) synaptic efficacy and also axon terminal structural changes. Objective: In this study, we address the question of potential causality between neuronal activation and the neuronal structural response. Methods: We used patterned optogenetic activation (ChR2-EYFP), daily for 10-days, to deliver intermittent theta burst stimulation (iTBS) to activate MCX neurons within the forelimb representation in healthy rats, while differentiating them from neurons in the same population that were not activated. We used chemogenetic DREADD activation to produce a daily period of non-patterned neuronal activation. Results: We found a significant increase in CST axon length, axon branching, contacts targeted to a class of premotor interneuron (Chx10), as well as projections into the motor pools in the ventral horn in optically activated but not neighboring non-activated neurons. A period of 2-h of continuous activation daily for 10 days using DREADD chemogenetic activation with systemic clozapine N-oxide (CNO) administration also increased CST axon length and branching, but not the ventral horn and Chx10 targeting effects. Both patterned optical and chemogenetic activation reduced MCX MEP thresholds. Conclusion: Our findings show that targeting of CST axon sprouting is dependent on patterned activation, but that CST spinal axon outgrowth and branching are not. Our optogenetic findings, by distinguishing optically activated and non-activated CST axons, suggests that the switch for activity-dependent axonal outgrowth is neuron-intrinsic.

Objective To explore the characteristics of white matter degeneration in amyotrophic lateral sclerosis(ALS)patients with different onset and spreading patterns by using diffusion tensor imaging(DTI). Methods We enrolled 86 ALS patients and 44 healthy controls. The patients were divided into bulbar- and spinal-onset subgroups according to their onset site, as well as horizon, vertical, interpose/skip, and caudal-rostral subgroups based on the spreading direction of the involved regions. The white matter fiber tracts corresponding to the motor network were set as the region of interest. We used tract-based spatial statistics to evaluate differences between the above groups and the normal controls, with family-wise error(FWE)correction and P<0.05 as statistical significance. Results The white matter degeneration of ALS patients with bulbar onset was mainly limited to the corona radiation part of the corticospinal tract, while those with spinal onset showed extensive degeneration of corticospinal tract and corpus callosum Ⅲ area(FWE correction, P<0.05). In patients with horizontal and vertical dissemination, decreased integrity of the entire corticospinal tract was found, with patients in the latter group showed extra degeneration in the Ⅲ part of the corpus callosum. Restricted degeneration of the corticospinal tract within bilateral corona radiata was detected in patients with caudal-rostral and interposed/skip spreading pattens(FWE correction, P<0.05). Conclusion Different onset and disease spread patterns of ALS patients correspond to divergent brain degeneration patterns. The diagnosis, treatment, and management of ALS should fully consider the heterogeneity of the disease. [ABSTRACT FROM AUTHOR]

Unilateral spastic cerebral palsy (USCP) is caused by damage to the developing brain and affects motor function, mainly lateralized to one side of the body. Children with USCP have difficulties grasping objects, which can affect their ability to perform daily activities. Although cerebral palsy is typically classified according to motor function, sensory abnormalities are often present as well and may contribute to motor impairments, including grasping. In this review, we show that the integrity and connectivity pattern of the corticospinal tract (CST) is related to execution and anticipatory control of grasping. However, as this may not explain all the variance of impairments in grasping function, we also describe the potential roles of sensory and sensorimotor integration deficits that contribute to grasp impairments. We highlight studies measuring fingertip forces during object manipulation tasks, as this approach allows for the dissection of the close association of sensory and motor function and can detect the discriminant use of sensory information during a complex, functional task (i.e., grasping). In addition, we discuss the importance of examining the interactions of the sensory and motor systems together, rather than in isolation. Finally, we suggest future directions for research to understand the underlying mechanisms of grasp impairments. [ABSTRACT FROM AUTHOR]

Background: To evaluate the degeneration of the corticospinal tract (CST) and corpus callosum (CC) in patients with motor neuron disease and upper motor neuron (UMN) dysfunction using diffusion kurtosis imaging (DKI). Methods: Twenty‐seven patients and 33 healthy controls underwent magnetic resonance imaging along with clinical and neuropsychological testing. Tractography of diffusion tensor images was performed to extract tracts of the bilateral CST and CC. Group mean differences both across the entire averaged tract and along each tract were assessed, including correlations between diffusion metrics and clinical measures. Tract‐based spatial statistics (TBSS) was performed to evaluate the spatial distribution of whole‐brain microstructural abnormalities in patients. Results: In comparison to controls, patients had significantly higher mean and radial diffusivity and lower fractional anisotropy (FA), kurtosis anisotropy, mean kurtosis (MK), and radial kurtosis (RK) in the CST and CC (p <.017). Along‐the‐tract analysis revealed changes concentrated in the posterior limb of the internal capsule, corona radiata, and primary motor cortex (false‐discovery rate p <.05). FA of the left CST correlated with disease progression rate, whereas MK of the bilateral CST correlated with UMN burden (p <.01). TBSS results corroborated along‐tract analysis findings and additionally revealed reduced RK and MK in the fornix, where diffusion tensor imaging (DTI) changes were absent. Conclusion: DKI abnormalities in the CST and CC are present in patients with UMN dysfunction, potentially revealing complementary information to DTI regarding the pathology and microstructural alterations occurring in such patients. DKI shows promise as a potential in vivo biomarker for cerebral degeneration in amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Subcortical stroke may cause widespread structural changes to the cerebral cortex in multiple domains; however, the details of this process remain unclear. In this prospective observational study, we acquired two datasets to investigate the effect of lesion location on cortical structure. One was cross-sectional, comprising 269 patients with chronic stroke, either capsular stroke (CS) or pontine stroke (PS), and the other was longitudinal, comprising 119 patients with CS or PS. In the chronic-stage data, both CS and PS exhibited reduced cortical thickness in the precentral gyrus and increased cortical thickness and area in the frontal, temporal, occipital and insular cortices. Cortical thicknesses were correlated with motor outcomes in the precentral and lingual gyri, and early impairment of the corticospinal tract was associated with cortical thickness in the middle frontal gyrus. In the longitudinal dataset, CS showed gradually decreasing cortical thickness in the precentral gyrus, and both CS and PS showed gradually increasing cortical thickness and area in regions with significant structural reorganization. Subcortical stroke can therefore cause complex cortical structural changes in multi-domain regions involved in motor, primary and higher cognitive areas and have different evolution patterns depending on the subcortical level of the lesion affecting the motor pathways. [ABSTRACT FROM AUTHOR]

Introduction: Central post-stroke pain (CPSP), seen in the aftermath of a stroke, is an underdiagnosed entity but quite a disabling complication. All the postulated theories regarding the pathogenesis of CPSP point to its origin in the central pain pathways. However, this study attempts to demonstrate the role of other contributing areas in the generation of CPSP. Materials and Methods: In this single-center tertiary care hospital-based study, 24 patients with both ischemic and hemorrhagic strokes of variable durations were recruited, and Magnetic Resonance Imaging (MRI) imaging with diffusion tensor imaging (DTI) acquisition was done. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of the spinothalamic tract (STT), corticospinal tract (CST), superior thalamic radiation (STR), basal ganglia (BG), and primary somatosensory cortex (SSC) were compared between normal and abnormal sides and also in extrathalamic lesions separately. Results: Significant differences with lower FA were noted in STT, CST, STR, and SSC and higher ADC values in BG, STR, CST, and SSC on comparison between the normal and lesion sides. On individual sub-analysis, ischemic stroke had significant changes in the FA value of CST and the ADC value of STR and CST, while hemorrhagic stroke had significant changes in the FA and ADC values of STR and SSC, as well as the FA value of STT. In the analysis of the extrathalamic strokes, significance persisted in all the studied parameters except the BG. The CST abnormalities were evident even in patients with clinical motor improvement. On multivariate analysis, visual analogue scale score severity was correlated with thalamic lesions. Conclusion: Contrary to the belief that STT is solely responsible for CPSP, the role of CST, STR, BG, and SSC as contributing areas is evident from this study and may be more well established if studied in a larger population.

Therapeutic intervention for spinal cord injury is limited, with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training. As compared with learning novel compensatory strategies, rehabilitation focuses on restoring movements lost to injury. Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning, or if it engages previously trained motor circuits without requiring novel learning remains an open question. In this study, mice were randomly assigned to receive intraperitoneal injection with the pan-nicotinic, non-competitive antagonist mecamylamine and the nicotinic α7 subunit selective antagonist methyllycaconitine citrate salt or vehicle (normal saline) prior to motor learning assays, then randomly reassigned after motor learning for rehabilitation study post-injury. Cervical spinal cord dorsal column lesion was used as a model of incomplete injury. Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury. Our findings indicate that critical differences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.

The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

ObjectiveWhen a stroke damages the corticospinal tract (CST), it has been hypothesized that the motor system switches to using the corticoreticulospinal tract (CRST) resulting in abnormal arm synergies. Is use of these tracts mutually exclusive, or can the motor system spontaneously switch between them depending on the type of movement it wants to make? If the motor system can share control at will, then people with a rudimentary ability to make dexterous movements should be able to perform synergistic arm movements as well.MethodsWe analyzed clinical assessments of 319 persons' abilities to perform "out-of-synergy" and "in-synergy" arm movements after chronic stroke using the Upper Extremity Fugl-Meyer (UEFM) scale.ResultsWe identified a moderate range of arm impairment (UEFM = ~30-40) where subjects had a rudimentary ability to make out-of-synergy (~23%-50% on the out-of-synergy score) and dexterous hand movements (~3-10 blocks on Box and Blocks Test). Below this range persons could perform in-synergy but not out-of-synergy or dexterous movements. In the moderate range, however, scoring better on out-of-synergy movements correlated with scoring worse on in-synergy movements (P = .001, r ≈ -0.6).ConclusionRudimentary dexterity corresponded with reduced ability to move the arm in-synergy. This finding supports the idea that CST and CRST compete and has implications for rehabilitation therapy.

Abstract Background To evaluate the degeneration of the corticospinal tract (CST) and corpus callosum (CC) in patients with motor neuron disease and upper motor neuron (UMN) dysfunction using diffusion kurtosis imaging (DKI). Methods Twenty‐seven patients and 33 healthy controls underwent magnetic resonance imaging along with clinical and neuropsychological testing. Tractography of diffusion tensor images was performed to extract tracts of the bilateral CST and CC. Group mean differences both across the entire averaged tract and along each tract were assessed, including correlations between diffusion metrics and clinical measures. Tract‐based spatial statistics (TBSS) was performed to evaluate the spatial distribution of whole‐brain microstructural abnormalities in patients. Results In comparison to controls, patients had significantly higher mean and radial diffusivity and lower fractional anisotropy (FA), kurtosis anisotropy, mean kurtosis (MK), and radial kurtosis (RK) in the CST and CC (p

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes—and their microstructural underpinnings—remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

The cerebral cortex innervates motor neurons in the anterior horn of the spinal cord by regulating of interneurons. At present, nerve tracing, immunohistochemistry, and immunoelectron microscopy are used to explore and confirm the characteristics of synaptic connections between the corticospinal tract (CST) and cervical spinal calretinin (Cr) interneurons. Our morphological results revealed that (1) biotinylated dextran amine labeled (BDA+) fibers from the cerebral cortex primarily presented a contralateral spinal distribution, with a denser distribution in the ventral horn (VH) than in the dorsal horn (DH). An electron microscope (EM) showed that BDA+ terminals formed asymmetric synapses with spinal neurons, and their mean labeling rate was not different between the DH and VH. (2) Cr-immunoreactive (Cr+) neurons were unevenly distributed throughout the spinal gray matter, and were denser and larger in the VH than in the DH. At the single labeling electron microscope (EM) level, the labeling rate of Cr+ dendrites was higher in the VH than in the DH, in which Cr+ dendrites mainly received asymmetric synaptic inputs, and between the VH and DH. (3) Immunofluorescence triple labeling showed obvious apposition points among BDA+ terminals, synaptophysin and Cr+ dendrites, with a higher density in the VH than in the DH. (4) Double labeling in EM, BDA+ terminals and Cr+ dendrites presented the same pattern, BDA+ terminals formed asymmetric synapses either with Cr+ dendrites or Cr negative (Cr-) dendrites, and Cr+ dendrites received either BDA+ terminals or BDA- synaptic inputs. The average percentage of BDA+ terminals targeting Cr+ dendrites was higher in the VH than in the DH, but the percentage of BDA+ terminals targeting Crdendrites was prominently higher than that targeting Cr+ dendrites. There was no difference in BDA+ terminal size. The percentage rate for Cr+ dendrites receiving BDA+ terminal inputs was lower than that receiving BDA- terminal inputs, and the BDA+ terminal size was larger than the BDA- terminal size received by Cr+ dendrites. The present morphological results suggested that spinal Cr+ interneurons are involved in the regulatory process of the cortico-spinal pathway. [ABSTRACT FROM AUTHOR]

Background and purpose: This study sought to evaluate the relationship of progressive corticospinal tract (CST) degeneration with survival in patients with amyotrophic lateral sclerosis (ALS). Methods: Forty‐one ALS patients and 42 healthy controls were prospectively recruited from the Canadian ALS Neuroimaging Consortium. Magnetic resonance imaging scanning and clinical evaluations were performed on participants at three serial visits with 4‐month intervals. Texture analysis was performed on T1‐weighted magnetic resonance imaging scans and the texture feature 'autocorrelation' was quantified. Whole‐brain group‐level comparisons were performed between patient subgroups. Linear mixed models were used to evaluate longitudinal progression. Region‐of‐interest and 3D voxel‐wise Cox proportional‐hazards regression models were constructed for survival prediction. For all survival analyses, a second independent cohort was used for model validation. Results: Autocorrelation of the bilateral CST was increased at baseline and progressively increased over time at a faster rate in ALS short survivors. Cox proportional‐hazards regression analyses revealed autocorrelation of the CST as a significant predictor of survival at 5 years follow‐up (hazard ratio 1.28, p = 0.005). Similarly, voxel‐wise whole‐brain survival analyses revealed that increased autocorrelation of the CST was associated with shorter survival. ALS patients stratified by median autocorrelation in the CST had significantly different survival times using the Kaplan–Meier curve and log‐rank tests (χ2 = 7.402, p = 0.007). Conclusions: Severity of cerebral degeneration is associated with survival in ALS. CST degeneration progresses faster in subgroups of patients with shorter survival. Neuroimaging holds promise as a tool to improve patient management and facilitation of clinical trials. [ABSTRACT FROM AUTHOR]

Chronic and severe upper-limb motor deficits can result from damage to the corticospinal tract. However, it remains unclear what their characteristics are and whether only corticospinal tract damage determines their characteristics. This study aimed to investigate the clinical characteristics and neural bases of chronic and severe upper-limb motor deficits. Motor deficits, including spasticity, of 45 patients with brain lesions were assessed using clinical scales. Regarding their scores, we conducted a principal component analysis that statistically extracted the clinical characteristics as two principal components. Using these principal components, we investigated the neural bases underlying their characteristics through lesion analyses of lesion volume, lesion sites, corticospinal tract, or other regional white-matter integrity. Principal component analysis showed that the clinical characteristics of chronic and severe upper-limb motor deficits could be described as a comprehensive severity and a trade-off relationship between proximal motor functions and wrist/finger spasticity. Lesion analyses revealed that the comprehensive severity was correlated with corticospinal tract integrity, and the trade-off relationship was associated with the integrity of other regional white matter located anterior to the posterior internal capsule, such as the anterior internal capsule. This study indicates that the severity of chronic and severe upper-limb motor deficits can be determined according to the corticospinal tract integrity, and such motor deficits may be further characterized by the integrity of other white matter, where the corticoreticular pathway can pass through, by forming a trade-off relationship where patients have higher proximal motor functions but more severe wrist/finger spasticity, and vice versa. [ABSTRACT FROM AUTHOR]

Neural activity helps construct neural circuits during development and this function is leveraged by neuromodulation protocols to promote connectivity and repair in maturity. Neuromodulation targeting the motor cortex (MCX) strengthens connections for evoking muscle contraction (MEPs). Mechanisms include promoting local MCX and corticospinal tract (CST) synaptic efficacy and also axon terminal structural changes. In this study, we address the question of potential causality between neuronal activation and the neuronal structural response. We used patterned optogenetic activation (ChR2-EYFP), daily for 10-days, to deliver intermittent theta burst stimulation (iTBS) to activate MCX neurons within the forelimb representation in healthy rats, while differentiating them from neurons in the same population that were not activated. We used chemogenetic DREADD activation to produce a daily period of non-patterned neuronal activation. We found a significant increase in CST axon length, axon branching, contacts targeted to a class of premotor interneuron (Chx10), as well as projections into the motor pools in the ventral horn in optically activated but not neighboring non-activated neurons. A period of 2-h of continuous activation daily for 10 days using DREADD chemogenetic activation with systemic clozapine N-oxide (CNO) administration also increased CST axon length and branching, but not the ventral horn and Chx10 targeting effects. Both patterned optical and chemogenetic activation reduced MCX MEP thresholds. Our findings show that targeting of CST axon sprouting is dependent on patterned activation, but that CST spinal axon outgrowth and branching are not. Our optogenetic findings, by distinguishing optically activated and non-activated CST axons, suggests that the switch for activity-dependent axonal outgrowth is neuron-intrinsic. • Daily patterned optical activation produced CST axon sprouting and enhanced branching. • Non-stimulated neighboring neurons did not express the growth response. • Imaging shows causality between optical activation and axon structural changes. • Chemogenetic activation produced enhanced activity also resulting in axon growth response. • Patterned optical, but not chemogenetic, activation targeted sprouting to premotor interneurons and to motor pools. [ABSTRACT FROM AUTHOR]

Objectives: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. Methods: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. Results: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST's homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. Conclusions: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms. [ABSTRACT FROM AUTHOR]