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Cell replacement therapy is expected as a new and more radical treatment against brain damage. We previously reported that transplanted human cerebral organoids extend their axons along the corticospinal tract in rodent brains. The axons reached the spinal cord but were still sparse. Therefore, this study optimized the host brain environment by the adeno-associated virus (AAV)-mediated expression of axon guidance proteins in mouse brain. Among netrin-1, SEMA3, and L1CAM, only L1CAM significantly promoted the axonal extension of mouse embryonic brain tissue-derived grafts. L1CAM was also expressed by donor neurons, and this promotion was exerted in a haptotactic manner by their homophilic binding. Primary cortical neurons cocultured on L1CAM-expressing HEK-293 cells supported this mechanism. These results suggest that optimizing the host environment by the AAV-mediated expression of axon guidance molecules enhances the effect of cell replacement therapy., 遺伝子治療によるホスト脳の環境最適化が細胞移植効果を高める --ホスト脳へのL1CAMの強制発現によるマウス胎仔脳移植片の軸索伸長促進効果--. 京都大学プレスリリース. 2023-03-24., Combining cell transplantation and gene therapy to enhance axonal outgrowth in the central nervous system. 京都大学プレスリリース. 2023-04-06.

The premotor (PM) and primary motor (M1) cortical areas broadcast voluntary motor commands through multiple neuronal pathways, including the corticorubral projection that reaches the red nucleus (RN). However, the respective contribution of M1 and PM to corticorubral projections as well as changes induced by motor disorders or injuries are not known in nonhuman primates. Here, we quantified the density and topography of axonal endings of the corticorubral pathway in RN in intact monkeys, as well as in monkeys subjected to either cervical spinal cord injury (SCI), Parkinson's disease (PD)-like symptoms or primary motor cortex injury (MCI). Twenty adult macaque monkeys of either sex were injected with the biotinylated dextran amine anterograde tracer either in PM or in M1. We developed a semiautomated algorithm to reliably detect and count axonal boutons within the magnocellular and parvocellular (pRN) subdivisions of RN. In intact monkeys, PM and M1 preferentially target the medial part of the ipsilateral pRN, reflecting its somatotopic organization. Projection of PM to the ipsilateral pRN is denser than that of M1, matching previous observations for the corticotectal, corticoreticular, and corticosubthalamic projections (Fregosi et al., 2018, 2019; Borgognon et al., 2020). In all three types of motor disorders, there was a uniform and strong decrease (near loss) of the corticorubral projections from PM and M1. The RN may contribute to functional recovery after SCI, PD, and MCI, by reducing direct cortical influence. This reduction possibly privileges direct access to the final output motor system, via emphasis on the direct corticospinal projection.SIGNIFICANCE STATEMENTWe measured the corticorubral projection density arising from the PM or the M1 cortices in adult macaques. The premotor cortex sent denser corticorubral projections than the primary motor cortex, as previously observed for the corticotectal, corticoreticular, and corticosubthalamic projections. The premotor cortex may thus exert more influence than primary motor cortex onto subcortical structures. We next asked whether the corticorubral motor projections undergo lesion-dependent plasticity after either cervical spinal cord injury, Parkinson's disease-like symptoms, or primary motor cortex lesion. In all three types of pathology, there was a strong decrease of the corticorubral motor projection density, suggesting that the red nucleus may contribute to functional recovery after such motor system disorders based on a reduced direct cortical influence.

Background Hemorrhagic stroke is one of the leading causes of morbidity and mortality worldwide. Medical management has been the mainstay of treatment for patients with intracerebral hemorrhage (ICH). However, with the advent of advanced imaging and minimally invasive surgery (MIS) techniques for hematoma evacuation, patients with large ICH could potentially benefit from surgical intervention. Herein, we report a case with a large ICH that was evacuated using a novel DTT-guided parafascicular Brain Path/Myriad technique. Methods Chart review including clinical data and imaging results were performed as well as literature search. Results In this case presented, a 55-year-old woman presented with acute onset of left facial droop, dysarthria, and left hemiparesis. Brain MRI showed a large right basal ganglia hematoma which had displaced the ipsilateral corticospinal tract (CST) medially on DTT imaging. A right anterior parafascicular approach was utilized for an MIS evacuation of the hematoma using Brain Path/Myriad. Post-operative CT head showed excellent evacuation of the hematoma and the patient recovered with stable neurological functions. Conclusion Surgical evacuation of ICH using DTT-guided Brain parafascicular Path/Myriad is an excellent method to rapidly decrease the hematoma burden in patients with ICH to protect the CST.

Background Cavernous malformations are clusters of abnormal and hyalinized capillaries without interfering brain tissue. Here, we present a cavernous malformation operated under awake conditions, due to location, in an eloquent area and using intraoperative magnetic resonance imaging due to patient’s movement upon the awake phase. Case presentation We present the pre-, per-, and postoperative course of an inferior parietal cavernous malformation, located in eloquent area, in a 27-year-old right-handed Caucasian male, presenting with intralesional hemorrhage and epilepsy. Preoperative diffusion tensor imaging has shown the cavernous malformation at the interface between the arcuate fasciculus and the inferior fronto-occipital fasciculus. We describe the microsurgical approach, combining preoperative diffusion tensor imaging, neuronavigation, awake microsurgical resection, and intraoperative magnetic resonance imaging. Conclusion Complete microsurgical en bloc resection has been performed and is feasible even in eloquent locations. Intraoperative magnetic resonance imaging was considered an important adjunct, particularly used in this case as the patient moved during the “awake" phase of the surgery and thus neuronavigation was not accurate anymore. Postoperative course was marked by a unique, generalized seizure without any adverse event. Immediate and 3 months postoperative magnetic resonance imaging confirmed the absence of any residue. Pre- and postoperative neuropsychological exams were unremarkable.

OBJECTIVE In some cases of incomplete cervical spinal cord injury (iSCI) there is marked paresis and dysfunction of upper-extremity movement but not lower-extremity movement. A continued explanation of such symptoms is a somatotopic organization of corticospinal tract (CST) fibers passing through the decussation at the craniovertebral junction (CVJ) and lateral CST (LCST). In central cord syndrome, it has been suggested that injury to the core of the cervical cord may include selective damage to medially located arm/hand LCST fibers, without compromising laterally located leg fibers. Because such somatotopic organization in the primate CST might contribute to the disproportionate motor deficits after some forms of iSCI, the authors made a systematic investigation of CST organization in the CVJ and LCST using modern neuroanatomical techniques. METHODS High-resolution anterograde tracers were used in 11 rhesus macaque monkeys to define the course of the corticospinal projection (CSP) through the CVJ and LCST from the arm/hand, shoulder, and leg areas of the primary motor cortex (M1). This approach labels CST fibers of all sizes, large and small, arising in these areas. The CSP from the dorsolateral and ventrolateral premotor cortex and supplementary motor area were also studied. A stereological approach was adapted to quantify labeled fiber distribution in 8 cases. RESULTS There was no evidence for somatotopic organization of CST fibers passing through the CVJ or contralateral LCST. Fiber labeling from each cortical representation was widespread throughout the CST at the CVJ and LCST and overlapped extensively with fibers from other representations. This study demonstrated no significant difference between medial versus lateral subsectors of the LCST in terms of number of fibers labeled from the M1 arm/hand area. CONCLUSIONS This investigation firmly rejects the concept of somatotopy among CST fibers passing through the CVJ and LCST, in contrast with the somatotopy in the cortex, corona radiata, and internal capsule. All CST fibers in the CVJ and LCST would thus appear to be equally susceptible to focal or diffuse injury, regardless of their cortical origin. The disproportionate impairment of arm/hand movement after iSCI must therefore be due to other factors, including greater dependence of hand/arm movements on the CST compared with the lower limb. The dispersed and intermingled nature of frontomotor fibers may be important in motor recovery after cervical iSCI.

The corticospinal tract (CST) is the preeminent voluntary motor pathway that controls human movements. Consequently, long-standing interest has focused on CST location and function in order to understand both loss and recovery of neurological function after incomplete cervical spinal cord injury, such as traumatic central cord syndrome. The hallmark clinical finding is paresis of the hands and upper-extremity function with retention of lower-extremity movements, which has been attributed to injury and the sparing of specific CST fibers. In contrast to historical concepts that proposed somatotopic (laminar) CST organization, the current narrative summarizes the accumulated evidence that 1) there is no somatotopic organization of the corticospinal tract within the spinal cord in humans and 2) the CST is critically important for hand function. The evidence includes data from 1) tract-tracing studies of the central nervous system and in vivo MRI studies of both humans and nonhuman primates, 2) selective ablative studies of the CST in primates, 3) evolutionary assessments of the CST in mammals, and 4) neuropathological examinations of patients after incomplete cervical spinal cord injury involving the CST and prominent arm and hand dysfunction. Acute traumatic central cord syndrome is characterized by prominent upper-extremity dysfunction, which has been falsely predicated on pinpoint injury to an assumed CST layer that specifically innervates the hand muscles. Given the evidence surveyed herein, the pathophysiological mechanism is most likely related to diffuse injury to the CST that plays a critically important role in hand function.

Failure of CNS neurons to mount a significant growth response after trauma contributes to chronic functional deficits after spinal cord injury. Activator and repressor screening of embryonic cortical neurons and retinal ganglion cellsin vitroand transcriptional profiling of developing CNS neurons harvestedin vivohave identified several candidates that stimulate robust axon growthin vitroandin vivo. Building on these studies, we sought to identify novel axon growth activators induced in the complex adult CNS environmentin vivo. We transcriptionally profiled intact sprouting adult corticospinal neurons (CSNs) after contralateral pyramidotomy (PyX) in nogo receptor-1 knock-out mice and found that intact CSNs were enriched in genes in the 3-phosphoinositide degradation pathway, including six 5-phosphatases. We explored whether inositol polyphosphate-5-phosphatase K (Inpp5k) could enhance corticospinal tract (CST) axon growth in preclinical models of acute and chronic CNS trauma. Overexpression ofInpp5kin intact adult CSNs in male and female mice enhanced the sprouting of intact CST terminals after PyX and cortical stroke and sprouting of CST axons after acute and chronic severe thoracic spinal contusion. We show thatInpp5kstimulates axon growth in part by elevating the density of active cofilin in labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. We identifyInpp5kas a novel CST growth activator capable of driving compensatory axon growth in multiple complex CNS injury environments and underscores the veracity of usingin vivotranscriptional screening to identify the next generation of cell-autonomous factors capable of repairing the damaged CNS.SIGNIFICANCE STATEMENTNeurologic recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post-trauma.In vitroscreening strategies exploit the intrinsically high growth capacity of embryonic CNS neurons to identify novel axon growth activators. While promising candidates have been shown to stimulate axon growthin vivo, concomitant functional recovery remains incomplete. We identifiedInpp5kas a novel axon growth activator using transcriptional profiling of intact adult corticospinal tract (CST) neurons that had initiated a growth response after pyramidotomy in plasticity sensitized nogo receptor-1-null mice. Here, we show thatInpp5koverexpression can stimulate CST axon growth after pyramidotomy, stroke, and acute and chronic contusion injuries. These data supportin vivoscreening approaches to identify novel axon growth activators.

BACKGROUND: To compare the microstructural integrity of the corticospinal tract (CST) between glioma patients with motor epilepsy and without epilepsy using mean apparent propagator magnetic resonance imaging (MAP-MRI). METHODS: A total of 26 patients with glioma adjacent to the CST pathway (10 with motor epilepsy and 16 without epilepsy) and 13 matched healthy controls underwent brain structural and diffusion MRI. The morphological characteristics of the CST (tract volume, tract number, and average length) were extracted, and diffusion parameter values including mean squared displacement (MSD), q-space inverse variance (QIV), return-to-origin probability (RTOP), return-to-axis probabilities (RTAP), return-to-plane probabilities (RTPP), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) along the CST were evaluated. The CST features were compared between healthy and affected sides and the relative CST features were compared across the three groups of participants. A receiver operating characteristic (ROC) curve was plotted to assess the performance of each relative CST characteristic for glioma-induced CST changes. RESULTS: For patients without epilepsy, the tract number, tract volume, FA, RD, MSD, QIV, and RTAP changed significantly on the affected CST side compared with those on the healthy CST side (P=0.002, 0.002, 0.030 0.017, 0.039, 0.044, and 0.002, respectively). In contrast, for patients with motor epilepsy, no significant difference was found between the affected and healthy side in almost all CST features except RTPP (P=0.028). Compared with patients with motor epilepsy, the relative tract number, tract volume, AD, and RTAP were significantly lower (P=0.027, 0.018, 0.040, and 0.027, respectively) in patients without epilepsy, and their areas under the curve (AUCs) were 0.763, 0.781, 0.744, and 0.763, respectively. No significant difference was found between patients with motor epilepsy and matched healthy controls. CONCLUSIONS: The MAP-MRI is a promising approach for evaluating CST changes. It provides additional information reflecting the microstructural complexity of the CST and demonstrates the preserved microstructural integrity of the CST in glioma patients with motor epilepsy.

Supplemental Digital Content is available in the text., Background and Purpose: We investigated the relation between the ipsilesional corticospinal tract (CST) state and activity of daily living independence in patients with chronic intracerebral hemorrhage. Methods: Fifty-six consecutive patients with unilateral intracerebral hemorrhage and 38 healthy control subjects were recruited for this study. The Motricity index and the modified Barthel index were used to evaluate motor function of the affected extremities and activity of daily living independence, respectively. The diffusion tensor imaging parameter values for fractional anisotropy (FA) and voxel number (VN) of the CST were determined. Ratios of the ipsilesional to the contralesional CST measures were calculated and are presented as the CST-ratio (FA value and VN). Results: The FA value and VN of the ipsilesional CST and the CST-ratio in the patient group were lower than those of the control group (P

Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press. Studying white matter connections with tractography is a promising approach to understand the development of different brain processes, such as proprioception. An emerging method is to use functional brain imaging to select the cortical seed points for tractography, which is considered to improve the functional relevance and validity of the studied connections. However, it is unknown whether different functional seeding methods affect the spatial and microstructural properties of the given white matter connection. Here, we compared functional magnetic resonance imaging, magnetoencephalography, and manual seeding of thalamocortical proprioceptive tracts for finger and ankle joints separately. We showed that all three seeding approaches resulted in robust thalamocortical tracts, even though there were significant differences in localization of the respective proprioceptive seed areas in the sensorimotor cortex, and in the microstructural properties of the obtained tracts. Our study shows that the selected functional or manual seeding approach might cause systematic biases to the studied thalamocortical tracts. This result may indicate that the obtained tracts represent different portions and features of the somatosensory system. Our findings highlight the challenges of studying proprioception in the developing brain and illustrate the need for using multimodal imaging to obtain a comprehensive view of the studied brain process.

Objective To develop an asleep motor mapping paradigm for accurate detection of the corticospinal tract during glioma surgery and compare outcomes with awake patients undergoing glioma resection. Methods A consecutive cohort of adult patients undergoing craniotomy for suspected diffuse glioma with tumor in a perirolandic location who had awake or asleep cortical and subcortical motor mapping with positive areas of motor stimulation were assessed for postoperative extent of resection (EOR), permanent neurological deficit, and proximity of stimulation to diffusion tensor imaging–based corticospinal tract depiction on preoperative magnetic resonance imaging. Outcome data were compared between asleep and awake groups. Results In the asleep group, all 16 patients had improved or no change in motor function at last follow-up (minimum 3 months of follow-up). In the awake group, all 23 patients had improved function or no change at last follow-up. EOR was greater in the asleep group (mean [SD] EOR 88.71% [17.56%]) versus the awake group (mean [SD] EOR 80.62% [24.44%]), although this difference was not statistically significant (P = 0.3802). Linear regression comparing distance from stimulation to corticospinal tract in asleep (n = 14) and awake (n = 4) patients was r = −0.3759, R2 = 0.1413, P = 0.1853, and 95% confidence interval = −0.4453 to 0.09611 and r = 0.7326, R2 = 0.5367, P = 0.2674, and 95% confidence interval = −7.042 to 14.75, respectively. Conclusion In this small patient series, asleep motor mapping using commonly available motor evoked potential hardware appears to be safe and efficacious in regard to EOR and functional outcomes.

We previously observed in rodents that during the 2nd postnatal week corticospinal axons make monosynaptic connections with motoneurons. Prior to that finding, it had been believed that such contacts only occur in higher primates. Although an in vitro electrophysiological study is prerequisite for studying the developmental time course of synaptic connections, the technical difficulty of reliably recording synaptic responses from spinal motoneurons in animals over 2 weeks old hampered the study. Instead, we used retrograde transsynaptic labeling with a genetically modified rabies virus to confirm the presence of direct corticomotoneuronal connections at an early developmental stage and to show that these connections were subsequently eliminated. However, determination of an accurate elimination time course and quantitative evaluation of synaptic connectivity cannot be achieved through viral-tracing experiments. For the present study, we improved the slice preparation procedure and maintenance of slice viability, which enabled us to record postsynaptic responses using the whole cell patch-clamp technique from retrogradely labeled forearm motoneurons up until postnatal week 7. We examined the extent of corticomotoneuronal monosynaptic connections and studied the time course of their accumulation and loss. Positive ratios of monosynaptic corticomotoneuronal EPSCs increased from P6 to P8 and then plateaued (P8–P13: 65%). Thereafter, the monosynaptic connections declined until P21, at which time they were no longer detected. The time course of the falling phase and elimination was confirmed by experiments using optogenetic stimulation. The timing of the elimination fell within the same range (P18-22) estimated in our earlier study using retrograde transsynaptic labeling.

Background. Structural integrity of the ipsilesional corticospinal tract (CST) is important for upper limb motor recovery after stroke. However, additional neuromechanisms associated with motor function poststroke are less well understood, especially regarding the lower limb. Objective. To investigate the neural basis of upper/lower limb motor deficits poststroke by correlating measures of motor function with diffusion tensor imaging-derived indices of white matter integrity (fractional anisotropy (FA), mean diffusivity (MD)) in primary and secondary motor tracts/structures. Methods. Forty-three individuals with chronic stroke (time poststroke, 64.4 ± 58.8 months) underwent a comprehensive motor assessment and MRI scanning. Correlation and multiple regression analyses were performed to examine relationships between FA/MD in a priori motor tracts/structures and motor function. Results. FA in the ipsilesional CST and red nucleus (RN) was positively correlated with motor function of both the affected upper and lower limb ( r = 0.36 ‐ 0.55 , p ≤ 0.01 ), while only ipsilesional RN FA was associated with gait speed ( r = 0.50 ). Ipsilesional CST FA explained 37.3% of the variance in grip strength ( p < 0.001 ) and 31.5% of the variance in Arm Motricity Index ( p = 0.004 ). Measures of MD were not predictors of motor performance. Conclusions. Microstructural integrity of the ipsilesional CST is associated with both upper and lower limb motor function poststroke, but appears less important for gait speed. Integrity of the ipsilesional RN was also associated with motor performance, suggesting increased contributions from secondary motor areas may play a role in supporting chronic motor function and could become a target for interventions.

Axon regeneration after spinal cord injury (SCI) is limited by both a decreased intrinsic ability of neurons to grow axons and the growth-hindering effects of extrinsic inhibitory molecules expressed around the lesion. Deletion ofphosphatase and tensin homolog(Pten) augments mechanistic target of rapamycin (mTOR) signaling and enhances the intrinsic regenerative response of injured corticospinal neurons after SCI. Because of the variety of growth-restrictive extrinsic molecules, it remains unclear how inhibition of conserved inhibitory signaling elements would affect axon regeneration and rewiring after SCI. Moreover, it remains unknown how a combinatorial approach to modulate both extrinsic and intrinsic mechanisms can enhance regeneration and rewiring after SCI. In the present study, we deletedRhoAandRhoC, which encode small GTPases that mediate growth inhibition signals of a variety of extrinsic molecules, to remove global extrinsic pathways.RhoA/RhoCdouble deletion in mice suppressed retraction or dieback of corticospinal axons after SCI. In contrast,Ptendeletion increased regrowth of corticospinal axons into the lesion core. Although deletion of bothRhoAandPtendid not promote axon regrowth across the lesion or motor recovery, it additively promoted rewiring of corticospinal circuits connecting the cerebral cortex, spinal cord, and hindlimb muscles. Our genetic findings, therefore, reveal that a combinatorial approach to modulate both intrinsic and extrinsic factors can additively promote neural circuit rewiring after SCI.SIGNIFICANCE STATEMENTSCI often causes severe motor deficits because of damage to the corticospinal tract (CST), the major neural pathway for voluntary movements. Regeneration of CST axons is required to reconstruct motor circuits and restore functions; however, a lower intrinsic ability to grow axons and extrinsic inhibitory molecules severely limit axon regeneration in the CNS. Here, we investigated whether suppression of extrinsic inhibitory cues by genetic deletion ofRhoas well as enhancement of the intrinsic pathway by deletion ofPtencould enable axon regrowth and rewiring of the CST after SCI. We show that simultaneous elimination of extrinsic and intrinsic signaling pathways can additively promote axon sprouting and rewiring of the corticospinal circuits. Our data demonstrate a potential molecular approach to reconstruct motor pathways after SCI.

Purpose To clarify brain abnormalities on magnetic resonance imaging (MRI) and its clinical implications in lissencephaly/subcortical band heterotopia (LIS/SBH) spectrum patients. Methods The clinical severity and classification according to Di Donato were retrospectively reviewed in 23 LIS/SBH spectrum patients. The morphological and signal abnormalities of the brainstem, corpus callosum, and basal ganglia were also assessed. The brainstem distribution pattern of the corticospinal tract (CST) was analyzed by diffusion tensor imaging (DTI) and categorized into two types: normal pattern, in which the CST and medial lemniscus (ML) are separated by the dorsal portion of the transverse pontine fiber, and the abnormal pattern, in which the CST and ML are juxtaposed on the dorsal portion of a single transverse pontine fiber. Correlations between MR grading score and potential additional malformative findings of the brain and clinical symptoms were investigated. Results All patients with grade 3 (n = 5) showed brainstem deformities, signal abnormalities of pontine surface and had a tendency of basal ganglia deformity and callosal hypoplasia whereas those abnormalities were rarely seen in patients with grade 1 and 2 (n = 18). For DTI analysis, the patients with grade 3 LIS/SBH had typically abnormal CST, whereas the patients with grade 1 and 2 LIS/SBH had normal CST. The classification was well correlated with CST and brainstem abnormalities and clinical severity. Conclusion MR assessment including DTI analysis may be useful in assessing the clinical severity in LIS/BH spectrum and may provide insight into its developmental pathology.

Background: Slits and Robos were associated with the generation of axons of corticospinal tract during the corticospinal tract (CST) remodeling after the cerebral ischemic stroke (CIS). However, little is known about the mechanism of CST remodeling. In this study, we detected the expression of Slits and Robos in middle cerebral artery occlusion (MCAO) rats to investigate the roles of Slits and Robos in the CIS. Methods: MCAO model was established using modified Zea Longa method. Beam walking test (BWT) was conducted to evaluate the motor function. The images of the track of cortical spinal cord beam on day 7, 14 and 21 were observed by anterograde CST tracing. Biopinylated dextan amine (BDA) was used to mark CST anterogradely. Expression of GAP-43 mRNA and GAP-43 protein in cervical spinal cord was detected by Real-Time PCR and Western blot analysis, respectively. The expression of Slit1, Slit2 and Robo1 in cervical spinal cord was detected by immunofluorescence staining.Results: The scores in the model group were significantly reduced compared to sham-operation group on day 7 (PPPP>0.05). In contrast, significant increase was noticed in the scores in model group, presenting a time-dependent manner. More CST staining fibers could be observed at the degenerative side in the model group compared with that of the sham-operation group on day 21. GAP-43 mRNA expression in the model group showed significant increase compared to that of sham-operation group on day 14 (P=0.015) and 21 days (P=0.002). The expression of GAP-43 protein in model group showed significant increase compared to that of sham-operation group on day 14 (P=0.022) and day 21 (P=0.008), respectively. The expression of Slit1 and Slit2 showed increase on day 14 and day 21, while the expression of Robo1 showed significant decrease in MCAO rats.Conclusion: Up-regulation of Slit1 and Slit2 and the downregulation of Robo1 may be related to the axons of CST midline crossing in spinal cord of MCAO rat during the spontaneous recovery of impaired motor function.

The nuclear erythroid 2-related-factor (Nrf2) transcription factor/hemoxygenase 1 (HO-1) is a key regulator of an important neuroprotection response by driving the interpretation of various cytoprotective gene to encode for anti-inflammatory, antioxidant, and detoxifying proteins. Various studies investigated that the upregulation of Nrf2/HO-1 has become the potential therapeutic approach in amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis is a motor neuron disease in which there is a progressive loss of upper motor neuron and lower motor neurons of the motor cortex, brain stem, and corticospinal tract. A result of this upregulation of Nrf2/HO-1 indicates that in the brain, anti-oxidant capacity is reinforced. Further, this shows a cytoprotective effect against oxidative stress in amyotrophic lateral sclerosis. A study reported functions associated with the Nrf2/HO-1 in the neuronal cell, oligodendrocytes, microglia, and astrocytes. Although ALS's pathogenesis is not yet clear, but it is compelling. The evidence shows any dysfunction in the brain such as mitochondrial dysfunction, protein aggregation, glial cell activation, excitotoxicity, and apoptosis which gives ALS-like symptoms. In this review, we have mainly focused on detailing the downregulation of Nrf2/HO-1, which may be the prime reason and may further serve as a pathological hallmark for ALS development. As surveyed, there are limited targetbased interventions that only provide symptomatic relief but do not cure the disease completely. Dysregulation of the Nrf2/HO-1 signaling pathway leads to many physiological changes contributing to neurological conditions, including ALS. Based on the above view, we summarized the combined role of Nrf2/HO-1 signaling in ALS and explored potential therapeutic strategies for disease improvement through pathway modulators.

This study aimed to explore the value of magnetic resonance imaging (MRI) features based on deep learning super-resolution algorithms in evaluating the value of propofol anesthesia for brain protection of patients undergoing craniotomy evacuation of the hematoma. An optimized super-resolution algorithm was obtained through the multiscale network reconstruction model based on the traditional algorithm. A total of 100 patients undergoing craniotomy evacuation of hematoma were recruited and rolled into sevoflurane control group and propofol experimental group. Both were evaluated using diffusion tensor imaging (DTI) images based on deep learning super-resolution algorithms. The results showed that the fractional anisotropic image (FA) value of the hind limb corticospinal tract of the affected side of the internal capsule of the experimental group after the operation was 0.67 ± 0.28. The National Institute of Health Stroke Scale (NIHSS) score was 6.14 ± 3.29. The oxygen saturation in jugular venous (SjvO2) at T4 and T5 was 61.93 ± 6.58% and 59.38 ± 6.2%, respectively, and cerebral oxygen uptake rate (CO2ER) was 31.12 ± 6.07% and 35.83 ± 7.91%, respectively. The difference in jugular venous oxygen (Da-jvO2) at T3, T4, and T5 was 63.28 ± 10.15 mL/dL, 64.89 ± 13.11 mL/dL, and 66.03 ± 11.78 mL/dL, respectively. The neuron-specific enolase (NSE) and central-nerve-specific protein (S100β) levels at T5 were 53.85 ± 12.31 ng/mL and 7.49 ± 3.16 ng/mL, respectively. In terms of the number of postoperative complications, the patients in the experimental group were better than the control group under sevoflurane anesthesia, and the differences were substantial ( P

BACKGROUND AND PURPOSE: Selective voluntary motor control is an important factor influencing gross motor function, interjoint coordination, and the outcome of hamstring-lengthening surgery in spastic cerebral palsy. Using DTI, we investigated whether selective voluntary motor control would show strong correlations with WM motor tract microstructure and whether selective voluntary motor control is more sensitive to global WM impairment than gross motor function. MATERIALS AND METHODS: Children with spastic bilateral cerebral palsy born preterm and typically developing children were recruited. The Selective Control Assessment of the Lower Extremity (SCALE) and Gross Motor Function Measure (GMFM) were assessed in participants with cerebral palsy. Participants underwent brain MR imaging to collect DWI data. Tract-Based Spatial Statistics was used to analyze the WM for between-group differences and correlations with SCALE and GMFM. ROI analyses compared motor regions. RESULTS: Twelve children with cerebral palsy (mean age, 11.5 years) and 12 typically developing children (mean age, 10.3 years) participated. Altered DTI outcomes were found throughout the whole brain for the cerebral palsy group. SCALE, developed to evaluate selective voluntary motor control in cerebral palsy, showed significant positive correlations with fractional anisotropy in more WM voxels throughout the whole brain and for motor regions, including the corticospinal tract and corpus callosum, compared with GMFM. A significant negative correlation between radial diffusivity and SCALE, but not GMFM, was found within the corpus callosum. CONCLUSIONS: SCALE was a more sensitive clinical correlate of motor and whole-brain WM tract impairment in children with spastic bilateral cerebral palsy, suggesting greater anisotropy and myelination in these regions for those with higher selective voluntary motor control.

Background. Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. Objective. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. Methods. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. Results. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Conclusions. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.

Introduction Corticospinal tract injury caused by direct hematoma compression and secondary damage induced from blood toxic substances might influence the outcomes in patients with intracerebral hemorrhage (ICH). This study aimed to evaluate the safety and efficacy of hematoma evacuation via image-guided para-corticospinal tract approach based on the protection of compressed or residual corticospinal tract. Methods Seventy-five patients with ICH who underwent the image-guided para-corticospinal tract approach were retrospectively collected into the surgery group. Diffusion tensor imaging or computed tomography angiography was performed to identify the relationship between important white matter tracts and hematoma. The neuronavigation system for the preoperative imaging data loaded was used to identify the location of the burr hole, insertion trajectory, and depth of insertion. Cortical entry points and insertion trajectories were kept parallel to the corticospinal tract route into the hematoma based on the protection of compressed or residual corticospinal tract. Hematoma was removed under the image-guided para-corticospinal tract approach. Seventy-five age-, sex-, hematoma site-, and volume-matched patients with ICH who underwent conservative treatment were selected as controls. Demographical, clinical, radiological, and treatment-related data were retrospectively analyzed. Functional outcome was evaluated by modified Rankin scale on day 90. Results A total of 150 patients with ICH were retrospectively enrolled. The median Glasgow coma scale (GCS) score on admission was 11 (IQR 8–13). Deep hematoma (thalamus and basal ganglion) was present in 86.7% (130 patients). The mean hematoma volume on admission was 47 ± 19 mL, and the postoperative hematoma volume was 11 ± 10 mL. A higher proportion of favorable outcome was observed in the surgery group than in conservative treatment group (32.0% versus 17.4%; p = 0.037). Conclusion Hematoma evacuation via image-guided para-corticospinal tract approach based on the protection of compressed or residual corticospinal tract seems to be safer in patients with ICH with a relatively higher functional independence.

BACKGROUND Corticospinal tract (CST) injury has been shown to exert a major influence on functional recovery after ischemic stroke. PURPOSE To evaluate the prognostic value of CST injury estimated using a recent developed tractometry-based method. STUDY TYPE Prospective. POPULATION Forty-eight patients with CST damage induced by stroke lesion who underwent brain magnetic resonance imaging within 7 days from onset. SEQUENCE Diffusion-weighted imaging (b = 1000 seconds/mm2 ) and diffusion kurtosis imaging (DKI) spin-echo echo-planar sequence with three b-values (0, 1250, and 2500 seconds/mm2 ) at 3.0 T. ASSESSMENT A recently developed approach that combines tract segmentation and orientation mapping was used for CST-specific tractography and tractometry. CST injury was estimated using the proposed method with diffusion metrics extracted from DKI sequence and with the first principal component (PC1) of the metrics. We also calculated the weighted lesion load (wLL) for comparison. Clinical evaluation included the National Institutes of Health Stroke Score in the acute phase and the modified Rankin scale at 3 months post-stroke. The correlations between CST injury and initial motor impairment, as well as the prognostic values of CST injury for functional outcomes were evaluated. STATISTICAL TESTS Pearson correlation and logistic regression. Area under the receiver operating characteristic curve. P

The specific role of white matter (WM) microstructure in parkinsonism among patients with schizophrenia spectrum disorders (SSD) is largely unknown. To determine whether topographical alterations of WM microstructure contribute to parkinsonism in SSD patients, we examined healthy controls (HC, n=16) and SSD patients with and without parkinsonism, as defined by Simpson-Angus Scale total score of ≥4 (SSD-P, n=33) or

Objective Corticospinal tract (CST) injury may lead to motor disorders in children with Cerebral Palsy (CP). However, the precise underlying mechanisms are still ambiguous. We aimed to characterize the CST structure and function in children with CP and determine their contributions to balance and gait impairments. Method Twenty-six children with spastic CP participated. Transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) were utilized to characterize CST structure and function. Common clinical measures were used to assess gait speed, endurance and balance, and mobility. Results CST structure and function were significantly altered in children with CP. Different abnormal patterns of CST structure were identified as either abnormal appearance of brain hemispheres (Group-1) or semi-normal CST appearance (Group-2). We found significant correlations between the DTI parameters of the more affected CST and gait features only in Group-1. Conclusion CST structure and function are abnormal in children with CP and these abnormalities may contribute to balance and gait impairment in some children with CP. Significance Our findings may lead to the development of further investigations on the mechanisms underlying gait impairment in children with CP and on decision-making for more effective rehabilitation.

Injury to long axonal projections is a central pathological feature at the early phase of intracerebral hemorrhage (ICH). It has been reported to contribute to persistent functional disability following ICH. However, the molecular mechanisms that drive axonal degeneration remain unclear. Autologous blood was injected into the striatum to mimic the pathology of ICH. Observed significant swollen axons with characteristic retraction bulbs were found around the striatal hematoma at 24 h after ICH. Electronic microscopic examination revealed highly disorganized microtubule and swollen mitochondria in the retraction bulbs. MEC17 is a specific α-tubulin acetyltransferase, ablation of acetylated α-tubulin in MEC17-/- mice aggravated axonal injury, axonal transport mitochondria dysfunction, and motor dysfunction. In contrast, treatment with tubastatin A (TubA), which promotes microtubule acetylation, significantly alleviated axonal injury and protected the integrity of the corticospinal tract and fine motor function after ICH. Moreover, results showed that 41% mitochondria were preferentially bundled to the acetylated α-tubulin in identifiable axons and dendrites in primary neurons. This impaired axonal transport of mitochondria in primary neurons of MEC17-/- mice. Given that opening of mitochondrial permeability transition pore (mPTP) induces mitochondrial dysfunction and impairs ATP supply thereby promoting axonal injury, we enhanced the availability of acetylated α-tubulin using TubA and inhibited mPTP opening with cyclosporin A. The results indicated that this combined treatment synergistically protected corticospinal tract integrity and promoted fine motor control recovery. These findings reveal key intracellular mechanisms that drive axonal degeneration after ICH and highlight the need to target multiple factors and respective regulatory mechanisms as an effective approach to prevent axonal degeneration and motor dysfunction after ICH.

Neural oscillations may contain important information pertaining to stroke rehabilitation. This study examined the predictive performance of electroencephalography‐derived neural oscillations following stroke using a data‐driven approach. Individuals with stroke admitted to an inpatient rehabilitation facility completed a resting‐state electroencephalography recording and structural neuroimaging around the time of admission and motor testing at admission and discharge. Using a lasso regression model with cross‐validation, we determined the extent of motor recovery (admission to discharge change in Functional Independence Measurement motor subscale score) prediction from electroencephalography, baseline motor status, and corticospinal tract injury. In 27 participants, coherence in a 1–30 Hz band between leads overlying ipsilesional primary motor cortex and 16 leads over bilateral hemispheres predicted 61.8% of the variance in motor recovery. High beta (20–30 Hz) and alpha (8–12 Hz) frequencies contributed most to the model demonstrating both positive and negative associations with motor recovery, including high beta leads in supplementary motor areas and ipsilesional ventral premotor and parietal regions and alpha leads overlying contralesional temporal–parietal and ipsilesional parietal regions. Electroencephalography power, baseline motor status, and corticospinal tract injury did not significantly predict motor recovery during hospitalization (R 2 = 0–6.2%). Findings underscore the relevance of oscillatory synchronization in early stroke rehabilitation while highlighting contributions from beta and alpha frequency bands and frontal, parietal, and temporal–parietal regions overlooked by traditional hypothesis‐driven prediction models., This study examined the predictive performance of electroencephalography‐derived neural oscillations following stroke using a data‐driven approach. In 27 participants, EEG coherence in a 1–30 Hz band between leads overlying ipsilesional primary motor cortex and 16 leads over bilateral hemispheres predicted 61.8% of the variance in motor recovery.

White matter abnormalities represent early neuropathological events in neurodegenerative diseases such as Alzheimer's disease (AD), investigating these white matter alterations would likely provide valuable insights into pathological changes over the course of AD. Using a novel mathematical framework called “Director Field Analysis” (DFA), we investigated the geometric microstructural properties (i.e., splay, bend, twist, and total distortion) in the orientation of white matter fibers in AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database. Results revealed that AD patients had extensive orientational changes in the bilateral anterior thalamic radiation, corticospinal tract, inferior and superior longitudinal fasciculus, inferior fronto‐occipital fasciculus, and uncinate fasciculus in comparison with CN. We postulate that these orientational changes of white matter fibers may be partially caused by the expansion of lateral ventricle, white matter atrophy, and gray matter atrophy in AD. In contrast, aMCI individuals showed subtle orientational changes in the left inferior longitudinal fasciculus and right uncinate fasciculus, which showed a significant association with the cognitive performance, suggesting that these regions may be preferential vulnerable to breakdown by neurodegenerative brain disorders, thereby resulting in the patients' cognitive impairment. To our knowledge, this article is the first to examine geometric microstructural changes in the orientation of white matter fibers in AD and aMCI. Our findings demonstrate that the orientational information of white matter fibers could provide novel insight into the underlying biological and pathological changes in AD and aMCI., Orientational changes may be partially caused by the expansion of lateral ventricle, white matter atrophy and gray matter atrophy in Alzheimer's disease. The inferior longitudinal fasciculus and uncinate fasciculus may be more vulnerable to breakdown by neurodegenerative brain disorders, thereby resulting in the patients' cognitive impairment in amnestic mild cognitive impairment.

Depression is a common occurrence in patients with Parkinson's disease (PD); however, its pathophysiology is still unclear. This study assessed the association between the integrity of white matter and depressive symptoms in patients with PD. 67 patients with PD were divided into a non-depressed PD group (ndPD, n = 30) and a depressed PD group (dPD, n = 37). The dPD group was further subdivided into a mild-moderately depressed PD (mdPD, n = 22) and a severely depressed PD group (sdPD, n = 15). Tract-Based Spatial Statistics was used to compare fractional anisotropy (FA) between groups. Region-of-interest analysis was used to explore changes in diffusivity indices in the regions showing FA abnormalities. The sdPD patients exhibited significantly reduced FA in the left superior longitudinal fasciculus, uncinate fasciculus, anterior corona radiata, corticospinal tract, and bilateral inferior fronto-occipital fasciculus when compared with the ndPD patients, but the decreased FA was within a smaller area when compared with the mdPD patients. No significant difference in FA was found between the mdPD and ndPD groups. Among the dPD patients, FA values in the left superior longitudinal fasciculus negatively correlated with BDI scores. Impaired white matter integrity in the prefronto-limbic/temporal circuitry, mainly in the left hemisphere, is associated with severe, but not mild-moderate depressive symptoms in patients with PD.

Key points: Suppression of corticospinal excitability is reliably observed during preparation for a range of motor actions, leading to the belief that this preparatory inhibition is a physiologically obligatory component of motor preparation. The neurophysiological function of this suppression is uncertain. We restricted the time available for participants to engage in preparation and found no evidence for preparatory inhibition. The function of preparatory inhibition can be inferred from our findings that sensory stimulation can disrupt motor output in the absence of preparatory inhibition, but enhance motor output when inhibition is present. These findings suggest preparatory inhibition may be a strategic process which acts to protect prepared actions from external interference. Our findings have significant theoretical implications for preparatory processes. Findings may also have a pragmatic benefit in that acoustic stimulation could be used therapeutically to facilitate movement, but only if the action can be prepared well in advance. Abstract: Shortly before movement initiation, the corticospinal system undergoes a transient suppression. This phenomenon has been observed across a range of motor tasks, suggesting that it may be an obligatory component of movement preparation. We probed whether this was also the case when the urgency to perform a motor action was high, in a situation where little time was available to engage in preparatory processes. We controlled the urgency of an impending motor action by increasing or decreasing the foreperiod duration in an anticipatory timing task. Transcranial magnetic stimulation (TMS; experiment 1) or a loud acoustic stimulus (LAS; experiment 2) were used to examine how corticospinal and subcortical excitability were modulated during motor preparation. Preparatory inhibition of the corticospinal tract was absent when movement urgency was high, though motor actions were initiated on time. In contrast, subcortical circuits were progressively inhibited as the time to prepare increased. Interestingly, movement force and vigour were reduced by both TMS and the LAS when movement urgency was high, and enhanced when movement urgency was low. These findings indicate that preparatory inhibition may not be an obligatory component of motor preparation. The behavioural effects we observed in the absence of preparatory inhibition were induced by both TMS and the LAS, suggesting that accessory sensory stimulation may disrupt motor output when such stimulation is presented in the absence of preparatory inhibition. We conclude that preparatory inhibition may be an adaptive strategy which can serve to protect the prepared motor action from external interference.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age, which include impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity, and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% of the patients live for more than 10 years. The limited intervention of pharmacologically active compounds, that are used clinically, is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models, where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB, is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, this current review specially targeted the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with the up-regulation of intracellular adenyl cyclase/cAMP/ CREB and activation of mitochondrial-ETC coenzyme-Q10 as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

This study examined the effect of temporal changes in corticospinal excitability in motor imagery (MI) and the effect of real-time guides for MI on excitability changes. The MI task involved wrist flexion and motor evoked potentials using transcranial magnetic stimulation were recorded and examined from the flexor carpi radialis. Ballistic (momentary MI) and tonic (continuous MI) conditions were used, and the duration of each MI was different. In Experiment 1, each MI task was performed using an acoustic trigger. In Experiment 2, a real-time guide was presented on a computer screen, which provided a visual indication of the onset and duration of the MI task through via moving dots on the screen. The results indicate that the corticospinal excitability changed differently, depending on the duration of MI. Additionally, with real-time guides, the change in corticospinal excitability became clearer. Thus, corticospinal excitability changes due to the temporal specificities of MI, as well as with actual motor output. Moreover, if MI is actively performed without a guide, it is likely to show an unintended change in corticospinal excitability. It is suggested that when MI is performed with visual guide, the excitatory changes of the corticospinal tract might be different from the actual motor output. Therefore, when using MI for mental practices, it is possible to improve the effect of a guide for MI, such as a visual indicator for motor output. Additionally, when examining neural activities in MI, it may be necessary to consider the characteristics of motion performed by MI.

Neurological soft signs (NSS) are related to grey matter and functional brain abnormalities in schizophrenia. Studies in healthy subjects suggest, that NSS are also linked to white matter. However, the association between NSS and white matter abnormalities in schizophrenia remains to be elucidated. The present study investigated, if NSS are related to white matter alterations in patients with schizophrenia. The total sample included 42 healthy controls and 41 patients with schizophrenia. We used the Neurological Evaluation Scale (NES), and we acquired diffusion weighted magnetic resonance imaging to assess white matter on a voxel-wise between subject statistic. In patients with schizophrenia, linear associations between NES with fractional anisotropy (FA), radial, axial, and mean diffusivity were analyzed with tract-based spatial statistics while controlling for age, medication dose, the severity of the disease, and motion. The main pattern of results in patients showed a positive association of NES with all diffusion measures except FA in important motor pathways: the corticospinal tract, internal capsule, superior longitudinal fascicle, thalamocortical radiations and corpus callosum. In addition, exploratory tractography analysis revealed an association of the right aslant with NES in patients. These results suggest that specific white matter alterations, that is, increased diffusivity might contribute to NSS in patients with schizophrenia.

Key points The corticoreticulospinal tract (CReST) is a descending motor pathway that reorganizes after corticospinal tract (CST) injury in animals. In humans, the pattern of CReST innervation to upper limb muscles has not been carefully examined in healthy individuals or individuals with CST injury. In this study we assessed CReST projections to an arm and hand muscle on the same side of the body in healthy and chronic stoke subjects using transcranial magnetic stimulation. We show that CReST connection strength to the muscles differs between healthy and stroke subjects, with stronger connections to hand than arm in healthy subjects, and stronger connections to the arm than hand in stroke subjects. These results help us better understand CReST innervation patterns in the upper limb, and may point to its role in normal motor function and motor recovery in humans. Abstract The corticoreticulospinal tract (CReST) is a major descending motor pathway in many animals, but little is known about its innervation patterns in proximal and distal upper extremity (UE) muscles in humans. The contralesional CReST furthermore reorganizes after corticospinal tract (CST) injury in animals, but it is less clear whether CReST innervation changes after stroke in humans. We thus examined CReST functional connectivity, connection strength, and modulation in an arm and hand muscle of healthy (n = 15) and chronic stroke (n = 16) subjects. We delivered transcranial magnetic stimulation to the contralesional hemisphere (assigned in healthy subjects) to elicit ipsilateral motor evoked potentials (iMEPs) from the paretic biceps (BIC) and first dorsal interosseous (FDI) muscle. We operationalized CReST functional connectivity as iMEP presence/absence, CReST projection strength as iMEP size, and CReST modulation as change in iMEP size by head rotation. We found comparable CReST functional connectivity to the BICs and FDIs in both subject groups. However, the pattern of CReST connection strength to the muscles diverged between groups, with stronger connections to FDIs than BICs in healthy subjects and stronger connections to BICs than FDIs in stroke subjects. Head rotation modulated only FDI iMEPs of healthy subjects. Our findings indicate that the healthy CReST does not have a proximal innervation bias, and its strong FDI connections may have functional relevance to finger individuation. The reversed CReST innervation pattern in stroke subjects confirms its reorganization after CST injury, and its strong BIC connections may indicate upregulation for particular UE muscles or their functional actions. This article is protected by copyright. All rights reserved.

We report a case series of children with childhood apraxia of speech, by describing behavioral and white matter microstructural changes following 2 different treatment approaches. Five children with childhood apraxia of speech were assigned to a motor speech treatment (PROMPT) and 5 to a language, nonspeech oral motor treatment. Speech assessment and brain MRI were performed pre- and post-treatment. The ventral (tongue/larynx) and dorsal (lips) corticobulbar tracts were reconstructed in each subject. Mean fractional anisotropy and mean diffusivity were extracted. The hand corticospinal tract was assessed as a control pathway. In both groups speech improvements paralleled changes in the left ventral corticobulbar tract fractional anisotropy. The PROMPT treated group also showed fractional anisotropy increase and mean diffusivity decrease in the left dorsal corticobulbar tract. No changes were detected in the hand tract. Our results may provide preliminary support to the possible neurobiologic effect of a multimodal speech motor treatment in childhood apraxia of speech.

The hot cross bun (HCB) sign encompasses a cross-shaped hyperintensity area in the pons on axial T2-weighted magnetic resonance imaging (MRI). The HCB sign is characteristic of multiple system atrophy (MSA) and has occasionally been observed in other neurological disorders. Here, we report an autopsied case of corticobasal degeneration (CBD) that showed the HCB sign. A female patient presented with progressive gait disturbance and cognitive impairment at the age of 60 years. A neurological examination revealed dysarthria, muscle rigidity of the limbs, akinesia, truncal ataxia, urinary incontinence, and dementia. The HCB sign was observed on a brain MRI at the age of 65 years, and a clinical diagnosis of possible MSA was made. She died of pneumonia at the age of 67 years. A postmortem observation, provided neuropathological findings characteristic of CBD, including the presence of astrocytic plaques, pretangles, neuropil threads, and ballooned neurons in association with four-repeat-tau aggregation. Interestingly, the pons displayed severe neuronal loss and astrogliosis that were prominent in the pontine and raphe nuclei. Myelin sheath depletion was prominent in the transverse fibers of the pontine base and the myelinated fibers of the pontine tegmentum in contrast to relative sparing of the pontine corticospinal tract and medial lemniscus. The cerebellar dentate nucleus exhibited neuronal loss and grumose degeneration. Western blot analysis of sarkosyl-insoluble fractions from brain tissue lysates using an anti-phosphorylated tau antibody identified immunoreactive signal bands in approximately 37-40, 43, 64, and 68 kDa, consistent with CBD. Genetic analysis did not reveal any known pathogenic mutations in the microtubule-associated protein tau gene (MAPT). Our case was characterized by the HCB sign and concordant neuropathological changes in the pons. CBD should be considered an underlying pathology of the HCB sign, even though the pontocerebellar changes would be unusual in CBD cases.

The insula is a lobe located deep in each hemisphere of the brain and is surrounded by eloquent cortical, white matter, and basal ganglia structures. The aim of this study was to provide an anatomical description of the insula and white matter tracts related to surgical treatment of gliomas through a transcortical approach. The study also discusses surgical implications in terms of intraoperative brain mapping. Five adult brains were prepared according to the Klingler technique. Cortical anatomy was evaluated with the naked eye, whereas white matter dissection was performed with the use of a microscope. The widest exposure of the insular surface was noted through the temporal operculum, mainly in zones III and IV according to the Berger-Sanai classification. By going through the pars triangularis in all cases, the anterior insular point and most of zone I were exposed. The narrowest and deepest operating field was observed by going through the parietal operculum. This method provided a suitable approach to zone II, where the corticospinal tract is not covered by the basal ganglia and is exposed just under the superior limiting sulcus. At the subcortical level, the identification of the inferior frontoocipital fasciculus at the level of the limen insulae is critical in terms of preserving the lenticulostriate arteries. Detailed knowledge of the anatomy of the insula and subcortical white matter that is exposed through each operculum is essential in preoperative planning as well as in the intraoperative decision-making process in terms of intraoperative brain mapping.

BACKGROUND AND PURPOSE The corticospinal tract (CST) is a crucial brain pathway for distal arm and hand motor control. We aimed to determine whether a diffusion tensor imaging (DTI)-derived CST metric predicts distal upper extremity (UE) motor improvements in chronic stroke survivors. METHODS We analyzed clinical and neuroimaging data from a randomized controlled rehabilitation trial. Participants completed clinical assessments and neuroimaging at baseline and clinical assessments 4 months later, postintervention. Using univariate linear regression analysis, we determined the linear relationship between the DTI-derived CST fractional anisotropy asymmetry (FAasym) and the percentage of baseline change in log-transformed average Wolf Motor Function Test time for distal items (ΔlnWMFT-distal_%). The least absolute shrinkage and selection operator (LASSO) linear regressions with cross-validation and bootstrapping were used to determine the relative weighting of CST FAasym, other brain metrics, clinical outcomes, and demographics on distal motor improvement. Logistic regression analyses were performed to test whether the CST FAasym can predict clinically significant UE motor improvement. RESULTS lnWMFT-distal significantly improved at the group level. Baseline CST FAasym explained 26% of the variance in ΔlnWMFT-distal_%. A multivariate LASSO model including baseline CST FAasym, age, and UE Fugl-Meyer explained 39% of the variance in ΔlnWMFT-distal_%. Further, CST FAasym explained more variance in ΔlnWMFT-distal_% than the other significant predictors in the LASSO model. DISCUSSION AND CONCLUSIONS CST microstructure is a significant predictor of improvement in distal UE motor function in the context of an UE rehabilitation trial in chronic stroke survivors with mild-to-moderate motor impairment.Video Abstract available for more insight from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A350).

In animal experiments, the indirect corticospinal tract (CST) system via cervical interneurons has been shown to mediate motor commands for online adjustment of visuomotor behaviors, such as target-reaching. However, it is still unclear whether the similar CST system functions to perform similar motor behaviors in humans. To clarify this, we investigated changes in motor-evoked potentials (MEPs) in the elbow muscles following transcranial magnetic stimulation, transcranial electrical stimulation, or cervicomedullary stimulation while participants executed target-reaching and switching movements. We found that the MEP, whether elicited cortically or subcortically, was modulated depending on the direction of the switching movements. MEP facilitation began around the onset of the switching activities in an agonist muscle. Furthermore, ulnar nerve-induced MEP facilitation, which could be mediated by presumed cervical interneuronal systems, also increased at the onset of MEP facilitation. In a patient with cortical hemianopsia who showed switching movements in the scotoma, the MEPs were facilitated just before the switching activities. Our findings suggested that CST excitation was flexibly tuned with the switching movement initiation, which could partly take place in the subcortical networks, including the presumed cervical interneuronal systems.

Background The effect of infarct pattern on functional outcome in acute ischemic stroke is incompletely understood. Purpose To investigate the association of qualitative and quantitative infarct variables at 24-hour follow-up noncontrast CT and diffusion-weighted MRI with 90-day clinical outcome. Materials and Methods The Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke, or ESCAPE-NA1, randomized controlled trial enrolled patients with large-vessel-occlusion stroke undergoing mechanical thrombectomy from March 1, 2017, to August 12, 2019. In this post hoc analysis of the trial, qualitative infarct variables (predominantly gray [vs gray and white] matter involvement, corticospinal tract involvement, infarct structure [scattered vs territorial]) and total infarct volume were assessed at 24-hour follow-up noncontrast CT or diffusion-weighted MRI. White and gray matter infarct volumes were assessed in patients by using follow-up diffusion-weighted MRI. Infarct variables were compared between patients with and those without good outcome, defined as a modified Rankin Scale score of 0-2 at 90 days. The association of infarct variables with good outcome was determined with use of multivariable logistic regression. Separate regression models were used to report effect size estimates with adjustment for total infarct volume. Results Qualitative infarct variables were assessed in 1026 patients (mean age ± standard deviation, 69 years ± 13; 522 men) and quantitative infarct variables were assessed in a subgroup of 358 of 1026 patients (mean age, 67 years ± 13; 190 women). Patients with gray and white matter involvement (odds ratio [OR] after multivariable adjustment, 0.19; 95% CI: 0.14, 0.25; P < .001), corticospinal tract involvement (OR after multivariable adjustment, 0.06; 95% CI: 0.04, 0.10; P < .001), and territorial infarcts (OR after multivariable adjustment, 0.22; 95% CI: 0.14, 0.32; P < .001) were less likely to achieve good outcome, independent of total infarct volume. Conclusion Infarct confinement to the gray matter, corticospinal tract sparing, and scattered infarct structure at 24-hour noncontrast CT and diffusion-weighted MRI were highly predictive of good 90-day clinical outcome, independent of total infarct volume. Clinical trial registration no. NCT02930018 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mossa-Basha in this issue.

To study if spinal motor evoked potentials (SpMEPs), muscle responses after electrical stimulation of the spinal cord, can monitor the corticospinal tract. Study 1 comprised 10 consecutive cervical or thoracic myelopathic patients. We recorded three types of muscle responses intraoperatively: (1) transcranial motor evoked potentials (TcMEPs), (2) SpMEPs and (3) SpMEPs + TcMEPs from the abductor hallucis (AH) using train stimulation. Study 2 dealt with 5 patients, who underwent paired train stimulation to the spinal cord with intertrain interval of 50-60 ms for recording AH SpMEPs. We will also describe two illustrative cases to demonstrate the clinical value of AH SpMEPs for monitoring the motor pathway. In Study 1, SpMEPs and SpMEPs + TcMEPs recorded from AH measured nearly the same, suggesting the collision of the cranially evoked volleys with the antidromic signals induced by spinal cord stimulation via the corticospinal tracts. In Study 2, the first and second train stimuli elicited almost identical SpMEPs, indicating a quick return of transmission after 50-60 ms considered characteristic of the corticospinal tract rather than the dorsal column, which would have recovered much more slowly. Of the two patients presented, one had no post-operative neurological deteriorations as anticipated by stable SpMEPs, despite otherwise insufficient IONM, and the other developed post-operative motor deficits as predicted by simultaneous reduction of TcMEPs and SpMEPs in the face of normal SEPs. Electrical stimulation of the spinal cord primarily activates the corticospinal tract to mediate SpMEPs.

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder characterized by progressive demyelination ranging from mild myelopathic forms (adrenomyeloneuropathy [AMN]) to severe cerebral variants (adult cerebral adrenoleukodystrophy [ACALD]). The aim of this study was to compare cognitive function in adult-onset X-ALD phenotypes.Cognitive function in various domains (intelligence, attention, memory, executive function, and processing speed) was assessed in 172 adults (117 with AMN, 30 with arrested ACALD, and 25 with acute ACALD) using comprehensive neuropsychological batteries. Phenotype differences were examined by analyses of variance.X-ALD phenotypes significantly differed in nonverbal intelligence, sustained attention, verbal encoding, nonverbal recognition, and processing speed (ps 0.050). No group differences emerged regarding verbal intelligence, verbal retrieval and recognition, and executive function (ps 0.050). Specifically, patients with acute ACALD showed severe cognitive deficits compared to AMN and normal data, with largest effects on processing speed. Contrary, cognition was overall intact in patients with AMN, independent of sex and corticospinal tract involvement, and those with arrested ACALD showed mild cognitive dysfunction, particularly in verbal encoding and processing speed.Cerebral demyelination in patients with X-ALD causes white matter dementia, mainly characterized by an extreme slowdown in processing speed associated with deficits in attention and learning. Most patients with AMN show intact cognitive function. Future prospective, longitudinal studies with more sensitive imaging techniques are required to clarify whether early mild cognitive dysfunction found in some patients with AMN may be associated with subtle myelin abnormalities that do not yet appear as white matter lesions on cerebral MRI (cMRI) but have the potential to serve as early predictors of later cerebral progression. ANN NEUROL 2021;90:266-273.

OBJECTIVE: Evaluate longitudinal changes in brain microstructure and volumes in very preterm during the first year of life with and without intervention. DESIGN: Descriptive pilot study METHODS: Five preterm infants in a three-arm clinical trial, one SPEEDI Early, two SPEEDI Late, and two usual care. Brain structural and diffusion MRI’s were acquired within 72 hours after neonatal intensive care unit discharge (n=5), three months post-baseline (n=5), and six months post-baseline (n=3). Fractional anisotropy (FA), Mean diffusivity (MD), and volume metrics were computed for five brain regions. RESULTS: More than 60% of eligible participants completed 100% of the scheduled MRIs. FA and volume increased from baseline to six months across all brain regions. Rate of white matter volume change from baseline to six months was highest in SPEEDI Early. CONCLUSIONS: Non-sedated longitudinal MRI is feasible in very preterm infants and appears to demonstrate longitudinal changes in brain structure and connectivity.

Stroke remains the leading source of long-term disability. As the only direct descending motor pathway, the corticospinal tract (CST) is the primary pathway to innervate spinal motor neurons and one of the most well studied tracts in human neuroanatomy. Its clinical significance can be demonstrated in many distinguished traumatic situations and diseases such as stroke. Along‐tract statistics analysis enables the extraction of quantitative diffusion metrics along specific white matter fiber tracts. Besides quantitative metrics derived from classical diffusion tensor imaging (DTI), such as fractional anisotropy and diffusivities. In this study, we extracted DTI derived quantitative microstructural diffusion metrics along the CST tract in patients with moderate to severe subacute stroke. Respectively DTI metric of individual patient's fiber tract was then plotted. This approach may be useful for future studies that may compare in two different time (acute and chronic). The contribution of this work presents a totally computerized method of DTI image recognition based on conventional neural network (CNN) in order to supply quantitative appraisal of clinical characteristics. The obtained results have achieved an important classification (Accuracy=94.12%) when applying the CNN. The proposed methodology enables us to assess the classification of the used DTI images database within a reduced processing time. Experimental results prove the success of the proposed rating system for a suitable analysis of microstructural diffusion when compared to previous work.

A library of single-slice images of commonly derived white matter fibre pathways for public use

Background: The role played by the non-dominant parietal lobe in motor cognition, attention and spatial awareness networks has potentiated the use of awake surgery. When this is not feasible, asleep monitoring and mapping techniques should be used to achieve an onco-functional balance. Objective: This study aims to assess the feasibility of a dual-strip method to obtain direct cortical stimulation for continuous real-time cortical monitoring and subcortical mapping of motor and visual pathways simultaneously in parietal lobe tumour surgery. Methods: Single-centre prospective study between May’19-November’20 of patients with intrinsic non-dominant parietal-lobe tumours. Two subdural strips were used to simultaneously map and monitor motor and visual pathways. Results: Fifteen patients were included. With regards to motor function, a large proportion of patients had abnormal interhemispheric resting motor threshold ratio (iRMTr) (71.4%), abnormal Cortical Excitability Score (CES) (85.7%), close distance to the corticospinal tract – Lesion-To-Tract Distance (LTD) – 4.2mm, Cavity-To-Tract Distance (CTD) – 7mm and intraoperative subcortical distance - 6.4mm. Concerning visual function, the LTD and CTD for optic radiations (OR) were 0.5mm and 3.4mm, respectively; the mean intensity for positive subcortical stimulation of OR was 12mA±2.3mA and 5/6 patients with deterioration of VEPs>50% had persistent hemianopia and transgression of ORs. 12 patients remained stable, one patient had a de-novo transitory hemiparesis, and two showed improvements in motor symptoms. A higher iRMTr for lower limbs was related with a worse motor outcome (p=0.013) and a longer CTD to OR was directly related with a better visual outcome (p=0.041). At 2 weeks after hospital discharge, all patients were ambulatory at home and all proceeded to have oncological treatment. Conclusion: We propose motor and visual function boundaries for asleep surgery of intrinsic non-dominant parietal tumours. Pre-operative abnormal cortical excitability of the motor cortex, deterioration of the VEP recordings and CTD

Background: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a disorder of GABA degradation with use-dependent downregulation of postsynaptic GABAA/B receptors. We aim to measure the resulting cortical excitation: inhibition ratio using transcranial magnetic stimulation. Methods: In this single-center observational study, 18 subjects with SSADHD and 8 healthy controls underwent transcranial magnetic stimulation. Resting motor threshold, cortical silent period, and long-interval intracortical inhibition were measured in both groups. Resting motor threshold in focal epilepsy patients from an institutional transcranial magnetic stimulation database were also included. Results: SSADHD subjects had higher resting motor threshold than healthy controls but lower relative to focal epilepsy patients. Resting motor threshold decreased with age in all groups. Cortical silent period was longer in SSADHD subjects than in healthy controls. No difference was detected in long-interval intracortical inhibition between the 2 groups. Conclusion: Findings suggest abnormal corticospinal tract physiology in SSADHD, but with preserved developmental trajectory for corticospinal tract maturation. Defining features of these transcranial magnetic stimulation metrics in SSADHD will be better elucidated through this ongoing longitudinal study.

Purpose: Microsurgical anatomy of the corticospinal tract, its functional role and crucial points in differential diagnosis were evaluated. There is no consensus about its differences and cerebral origin of the corticospinal tract. Tractography and cadaver dissection can help to investigate the characteristics of the corticospinal tract. Also, amyotrophic lateral sclerosis is hard to diagnose as it has common symptoms and signs with other disorders. Methods: Three formalin-fixed human brains (six sides) were dissected by the Klingler technique in a stepwise manner from the lateral to medial and superior to inferior under 6x–40x magnification using a surgical microscope. All stages of the dissection were photographed using three-dimensional method. Lastly, we present a patient with the sign of drop foot who underwent electromyographical and radiological examination, diagnosed as atypic amyotrophic lateral sclerosis. Results: The connections of the corticospinal tract, in particular the travel in the in trajectories of stepwise in manner cerebral origin. We demonstrated a case report with anatomic correlation to define the damage of corticospinal tract in variable levels. Crucial landmarks, connections, eloquent brain areas that related to the corticospinal tract were emphasized. Conclusion: So that pointing the importance of such disorders to keep in mind as not to move forward with incorrect operation decision. Trajectory of one of the largest desending pathway, corticospinal tract and the relationship with different diagnosis should be considered.

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

After spinal cord injury (SCI) in mammals, there is only limited repair and, consequently, only moderate recovery. One mechanism frequently discussed to be involved in this recovery is plasticity (i.e., adaptations in spared neuronal circuitries). In the current study, we tested the effect of an intrathecal application of the TrkB agonist antibody, 29D7, on plasticity after cervical SCI in adult rats. Treatment with 29D7 for 4 weeks resulted in an ∼50% increase in collateral sprouting of severed corticospinal tract fibers above the lesion compared to the control group and enhanced branching in the gray matter rostral to the injury. Growth-associated protein 43 immunoreactivity in the spinal cord rostral to the level of the injury as well as contralateral to the lesion was also increased. These indications of enhanced plasticity by 29D7 were paralleled by improved performances of the mildly affected paw, as assessed by Montoya and tray reaching tasks. The reaching behaviors of the paw ipsilateral to the side of severe injury to the cortico- and rubrospinal tract were not altered by the treatment. The present study suggests that 29D7 may be a potential candidate to promote plasticity and functional recovery, especially after moderate SCI. Future studies confirming these results, along with a potential combinatory therapy including rehabilitative training, will be needed to evaluate the clinical value of such a treatment.

OBJECTIVE This prospective case-control study was conducted to examine whether spherical deconvolution (SD) can unveil microstructural abnormalities in the corticospinal tract (CST) caused by IDH-mutant gliomas. To determine the significance of abnormal microstructure, the authors investigated the correlation between diffusion parameters and neurophysiological data collected with navigated transcranial magnetic stimulation (nTMS). METHODS Twenty participants (10 patients and 10 healthy controls) were recruited. Diffusion-weighted images were acquired on a 3-T MRI scanner using a cardiac-gated single-shot spin echo echo-planar imaging multiband sequence (TE 80 msec, TR 4000 msec) along 90 diffusion directions with a b-value of 2500 sec/mm2 (FOV 256 × 256 mm). Diffusion tensor imaging tractography and SD tractography were performed with deterministic tracking. The anterior portion of the ipsilateral superior peduncle and the precentral gyrus were used as regions of interest to delineate the CST. Diffusion indices were extracted and analyzed for significant differences between hemispheres in patients and between patient and control groups. A navigated brain stimulation system was used to deliver TMS pulses at hotspots at which motor evoked potentials (MEPs) for the abductor pollicis brevis, first digital interosseous, and abductor digiti minimi muscles are best elicited in patients and healthy controls. Functional measurements such as resting motor threshold (rMT), amplitude of MEPs, and latency of MEPs were noted. Significant differences between hemispheres in patients and between patients and controls were statistically analyzed. The Spearman rank correlation was used to investigate correlations between diffusion indices and functional measurements. RESULTS The hindrance modulated orientational anisotropy (HMOA), measured with SD tractography, is lower in the hemisphere ipsilateral to glioma (p = 0.028). The rMT in the hemisphere ipsilateral to a glioma is significantly greater than that in the contralateral hemisphere (p = 0.038). All measurements contralateral to the glioma, except for the mean amplitude of MEPs (p = 0.001), are similar to those of healthy controls. Mean diffusivity and axial diffusivity from SD tractography are positively correlated with rMT in the hemisphere ipsilateral to glioma (p = 0.02 and 0.006, respectively). The interhemispheric difference in HMOA and rMT is correlated in glioma patients (p = 0.007). CONCLUSIONS SD tractography can demonstrate microstructural abnormality within the CST of patients with IDH1-mutant gliomas that correlates to the functional abnormality measured with nTMS.