Injured Corticospinal Tract Research Articles

Accuracy of Measurements of the Structural Reserve for Upper Limb Function in Patients With Moderate-to-Severe Stroke.

The structural integrity of the corticospinal tract (CST) is an important biomarker of poststroke upper limb recovery. Injured CST undergoes Wallerian degeneration rostrocaudally during the first few months. However, there is no standardized measurement of the structural integrity of the CST. This study aimed to determine the measurement accuracy of the structural integrity of the CST. This cross-sectional study included 50 consecutive patients with middle cerebral artery stroke who underwent diffusion tensor imaging upon transfer from the acute stroke unit to the inpatient rehabilitation facility (2018-2022). We evaluated hemiplegic upper limb function using Shoulder Abduction and Finger Extension (SAFE) scores. Fractional anisotropy values representing the structural integrity of the CST were evaluated using 4 region of interest-based and 2 tract-based measurements, including the posterior limb of internal capsule, cerebral peduncle, pons, pontomedullary junction, entire CST, and CST in the brainstem. Multivariate linear regression models and the area under the curve (AUC) were used to determine measurement accuracy for hemiplegic upper limb function. The structural integrity of the CST at the pontomedullary junction showed the highest explanatory power, followed by the entire CST, in the multivariate linear regression models (adjusted R2=0.459 and 0.425, respectively). The structural integrity of the CST at the pontomedullary junction also showed the highest AUC, followed by the entire CST, in discriminating patients with a SAFE score of <8 or 5 from those with SAFE ≥8 or 5 (SAFE <8: AUC, 0.90 [95% CI, 0.80-1.00]; AUC, 0.83 [0.66-0.99]; SAFE <5: AUC, 0.87 [0.77-0.96]; AUC, 0.83, [0.72-0.95], respectively). The structural integrity of the CST measured at the pontomedullary junction or entire CST demonstrated the highest accuracy for hemiplegic upper limb function in the subacute phase of stroke.

Delayed activation of leg somatotopic fibers of an injured corticospinal tract in a patient with cerebral infarction.

Delayed activation of leg somatotopic fibers of an injured corticospinal tract in a patient with cerebral infarction.

Transneuronal delivery of designer cytokines: perspectives for spinal cord injury.

Transneuronal delivery of designer cytokines: perspectives for spinal cord injury.

Axotomy Induces Drp1-Dependent Fragmentation of Axonal Mitochondria

It is well established that CNS axons fail to regenerate, undergo retrograde dieback, and form dystrophic growth cones due to both intrinsic and extrinsic factors. We sought to investigate the role of axonal mitochondria in the axonal response to injury. A viral vector (AAV) containing a mitochondrially targeted fluorescent protein (mitoDsRed) as well as fluorescently tagged LC3 (GFP-LC3), an autophagosomal marker, was injected into the primary motor cortex, to label the corticospinal tract (CST), of adult rats. The axons of the CST were then injured by dorsal column lesion at C4-C5. We found that mitochondria in injured CST axons near the injury site are fragmented and fragmentation of mitochondria persists for 2 weeks before returning to pre-injury lengths. Fragmented mitochondria have consistently been shown to be dysfunctional and detrimental to cellular health. Inhibition of Drp1, the GTPase responsible for mitochondrial fission, using a specific pharmacological inhibitor (mDivi-1) blocked fragmentation. Additionally, it was determined that there is increased mitophagy in CST axons following Spinal cord injury (SCI) based on increased colocalization of mitochondria and LC3. In vitro models revealed that mitochondrial divalent ion uptake is necessary for injury-induced mitochondrial fission, as inhibiting the mitochondrial calcium uniporter (MCU) using RU360 prevented injury-induced fission. This phenomenon was also observed in vivo. These studies indicate that following the injury, both in vivo and in vitro, axonal mitochondria undergo increased fission, which may contribute to the lack of regeneration seen in CNS neurons.

Peri-infarct reorganization of an injured corticospinal tract in a patient with cerebral infarction.

Peri-infarct reorganization of an injured corticospinal tract in a patient with cerebral infarction.

Single-session cortical electrical stimulation enhances the efficacy of rehabilitative motor training after spinal cord injury in rats

Low neuronal cAMP levels in adults and a further decline following traumatic central nervous system (CNS) injury has been associated with the limited ability of neurons to regenerate. An approach to increase neuronal cAMP levels post injury is electrical stimulation. Stimulation as a tool to promote neuronal growth has largely been studied in the peripheral nervous system or in spared fibers of the CNS and this research suggests that a single session of electrical stimulation is sufficient to initiate a long-lasting axonal growth program. Here, we sought to promote plasticity and growth of the injured corticospinal tract with electrical cortical stimulation immediately after its spinal injury. Moreover, given the importance of rehabilitative motor training in the clinical setting and in translating plasticity into functional recovery, we applied training as a standard treatment to all rats (i.e., with or without electrical stimulation). Our findings show that electrical cortical stimulation did improve recovery in forelimb function compared to the recovery in unstimulated animals. This recovery is likely linked to increased corticospinal tract plasticity as evidenced by a significant increase in sprouting of collaterals above the lesion site, but not to increased regenerative growth through the lesion itself.

Cortical electrical stimulation in female rats with a cervical spinal cord injury to promote axonal outgrowth.

Electrical stimulation (ES) to promote corticospinal tract (CST) repair after spinal cord injury (SCI) is underinvestigated. This study is the first to detail intracortical ES of the injured CST. We hypothesize that cortical ES will promote CST collateralization and regeneration, prevent dieback, and improve recovery in an SCI rat model. The CST was transected at the the fourth cervical level in adult female Lewis rats trained in a stairwell grasping task. Animal groups included (a) ES333 (n = 14; 333 Hz, biphasic pulse for 0.2-ms duration every 500 ms, 30 pulses per train); (b) ES20 (n = 14; 20 Hz, biphasic pulse for 0.2-ms duration every 1 s, 60 pulses per train); (c) SCI only (n = 10); and (d) sham (n = 10). ES of the injured forelimb's motor cortex was performed for 30 min immediately prior to SCI. Comparisons between histological data were performed with a 1-way ANOVA or Kruskal-Wallis test, and grasping scores were compared using repeated-measures 2-way ANOVA. Significantly more axonal collateralization was found in ES333 animals compared with controls (p < .01). Axonal dieback analysis revealed ES20 rats to have consistently more dieback than the other groups at all points measured (p < .05). No difference in axonal regeneration was found between groups, nor was there any difference in functional recovery. Cortical ES of the injured CST results in increased collateral sprouting and influences neuroplasticity depending on the ES parameters used. Further investigation regarding optimal parameters and its functional effects is required.

C.04: Motor cortex electrical stimulation to promote spinal cord injury repair in an animal model

Background: Electrical stimulation (ES) to promote corticospinal tract (CST) repair has been recently examined, though remains under investigated. We examine the role of motor cortex ES on axonal re-growth and functional recovery in a spinal cord injury (SCI) rat model. Methods: A partial transection was performed at C4 in 48 rats. Animal groups included: ES333 rats (n=14; 333Hz, biphasic pulse, 0.2ms every 500ms), ES20 (n=14; 20Hz, biphasic pulse, 0.2ms every 1ms), SCI only (n=10), and sham (n=10; electrode insertion without ES). Rats were trained in stairwell-grasping with subsequent SCI and ES. Post-injury reaching scores were recorded weekly, and histology completed quantifying axonal re-growth. Results: Post-SCI grasping (p&lt;0.01, ANOVA) and well reached were lower than baseline values (p&lt;0.01, ANOVA) for all groups. ES20 animals had lower grasping scores (p=0.03, ANOVA) and farthest well reached scores post-SCI than controls (p=0.03, ANOVA). ES333 rats had more axonal collaterals (axonal sprouts rostral to lesion) compared to control animals (p&lt;0.01, M-W). No difference was found between groups with respect to axonal regeneration into the lesion (p=0.13, ANOVA). Conclusions: Cortical ES of the injured CST results in greater axonal outgrowth, and influences functional outcomes depending on ES parameters. ES is a potentially promising SCI therapy, but further investigation is required.

Recovery of an injured corticospinal tract by subcortical peri-lesional reorganization in a patient with intracerebral hemorrhage.

The corticospinal tract (CST) is a neural tract responsible for motor function in the human brain. It is mainly related to hand movements (Jang, 2014). Therefore, recovery of an injured CST contributes to good recovery in stroke patients and a thorough knowledge of the recovery mechanism regarding an injured CST is required for successful brain rehabilitation.

Recovery of an injured corticospinal tract during the early stage of rehabilitation following pontine infarction.

Motor weakness is a common and important sequela of stroke, and motor recovery is mostly achieved within 3 months following stroke (Jorgensen et al., 1995; Fujii and Nakada, 2003), suggesting the importance of active rehabilitation during the early stage of stroke. Many studies have reported on neurological recovery during this period, however, little is known about pontine infarction (Jang et al., 2007; Kwon and Jang, 2012; Kwon et al., 2013; Yeo and Jang, 2013; Chang et al., 2014; Jang and Yeo, 2014; Seo and Jang, 2015). In this study, we attempted to demonstrate the recovery of an injured corticospinal tract (CST) using diffusion tensor tractography (DTT) and transcranial magnetic stimulation (TMS) during the early stage of rehabilitation following pontine infarction.

Recovery of corticospinal tract injured by traumatic axonal injury at the subcortical white matter: a case report.

The corticospinal tract (CST) is a major neural tract for motor function in the human brain. In addition, CST is mainly concerned with execution of movement of the hand (Jang, 2014). However, few studies are reported on the mechanism underlying CST recovery after traumatic brain injury (Seo and Jang, 2015). In this study, we report on a case that showed recovery of an injured CST by traumatic axonal injury (TAI) at subcortical white matter, as detected on follow-up diffusion tensor tractography (DTT).

Recovery of an Injured Corticospinal Tract in a Patient With Infarction on the Corona Radiata

Recovery of an Injured Corticospinal Tract in a Patient With Infarction on the Corona Radiata

Recovery of an Injured Corticospinal Tract in a Patient With Infarction on the Corona Radiata

Purpose: Many studies have attempted to elucidate the motor recovery mechanisms of stroke. In the current study, we report on a patient with infarction who showed recovery of an injured corticospinal tract (CST), using diffusion tensor imaging (DTI). Methods: A 20-year-old male presented with severe paralysis of the left extremities following an infarction in the right corona radiate and basal ganglia. The patient showed good motor recovery as much as being able to manipulate object using his left hand and could walk independently on stairs at 9 months after onset. Results: At 1 month after onset, the right CST showed decreased fiber volume due to the partial injury at the level of the corona radiate, and no (motor evoked potential) MEP was evoked from the right hemisphere. By contrast, the results at 9 months showed increased fiber volume of the right CST and the amplitude of MEP had improved to normal range on TMS. Conclusion: These results suggest that the severely injured right CST and MEP amplitude had been recovered during 9 months. Therefore, this result has important implications for brain plasticity and brain rehabilitation in patients with infarction.

Recovery of a degenerated corticospinal tract after injury in a patient with intracerebral hemorrhage: confirmed by diffusion tensor tractography imaging.

Recovery of a degenerated corticospinal tract after injury in a patient with intracerebral hemorrhage: confirmed by diffusion tensor tractography imaging.

Motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment: a diffusion tensor imaging study.

Previous diffusion tensor imaging (DTI) studies regarding pediatric patients with motor dysfunction have confirmed the correlation between DTI parameters of the injured corticospinal tract and the severity of motor dysfunction. There is also evidence that DTI parameters can help predict the prognosis of motor function of patients with cerebral palsy. But few studies are reported on the DTI parameters that can reflect the motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment. In the present study, 36 pediatric patients with hemiplegic cerebral palsy were included. Before and after rehabilitation treatment, DTI was used to measure the fiber number (FN), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of bilateral corticospinal tracts. Functional Level of Hemiplegia scale (FxL) was used to assess the therapeutic effect of rehabilitative therapy on clinical hemiplegia. Correlation analysis was performed to assess the statistical interrelationship between the change amount of DTI parameters and FxL. DTI findings obtained at the initial and follow-up evaluations demonstrated that more affected corticospinal tract yielded significantly decreased FN and FA values and significantly increased ADC value compared to the less affected corticospinal tract. Correlation analysis results showed that the change amount of FxL was positively correlated to FN and FA values, and the correlation to FN was stronger than the correlation to FA. The results suggest that FN and FA values can be used to evaluate the motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment and FN is of more significance for evaluation.

Vector-induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury

Rewiring the injured corticospinal tract (CST) by promoting connections between CST axons and spared neurons is a strategy being explored experimentally to achieve improved recovery of motor function after spinal cord injury (SCI). Reliable interventions to promote and direct growth of collaterals from injured CST axons are in high demand to promote functionally relevant detour pathways. A promising tool is neurotrophin-3 (NT-3), which has shown growth-stimulating and chemo-attractive effects for spared CST axons caudal to a CST lesion. Yet, efforts to promote growth of injured CST axons rostral to a SCI with NT-3 have been less successful to date. Evidence indicates that immune activation in the local growth environment, either intrinsic or induced by the endotoxin lipopolysaccharide (LPS), can play a decisive role in the CST’s responsiveness to NT-3. Here, we test the potential of NT-3 as a tool to enhance and direct collateral growth from the injured CST rostral to a SCI (1) using long-term expression of NT-3 by adeno-associated viral vectors, (2) with and without stimulating the immune system with LPS. Our results indicate that inducing a growth response from injured CST axons into a region of vector-mediated NT-3 expression is possible in the environment of the spinal cord rostral to a SCI, but seems dependent on the distance between the responding axon and the source of NT-3. Our findings also suggest that injured CST axons do not increase their growth response to NT-3 after immune activation with LPS in this environment. In conclusion, this is to our knowledge the first demonstration that NT-3 can be effective at promoting growth of injured CST collaterals far rostral to a SCI. Making NT-3 available in close proximity to CST target axons may be the key to success when using NT-3 to rewire the injured CST in future investigations.

Recovery of the corticospinal tracts injured by subfalcine herniation: a diffusion tensor tractography study.

Recovery of the corticospinal tracts injured by subfalcine herniation: a diffusion tensor tractography study.

Short Hairpin RNA against PTEN Enhances Regenerative Growth of Corticospinal Tract Axons after Spinal Cord Injury

Developing approaches to promote the regeneration of descending supraspinal axons represents an ideal strategy for rebuilding neuronal circuits to improve functional recovery after spinal cord injury (SCI). Our previous studies demonstrated that genetic deletion of phosphatase and tensin homolog (PTEN) in mouse corticospinal neurons reactivates their regenerative capacity, resulting in significant regeneration of corticospinal tract (CST) axons after SCI. However, it is unknown whether nongenetic methods of suppressing PTEN have similar effects and how regenerating axons interact with the extrinsic environment. Herein, we show that suppressing PTEN expression with short-hairpin RNA (shRNA) promotes the regeneration of injured CST axons, and these axons form anatomical synapses in appropriate areas of the cord caudal to the lesion. Importantly, this model of increased CST regrowth enables the analysis of extrinsic regulators of CST regeneration in vivo. We find that regenerating axons avoid dense clusters of fibroblasts and macrophages in the lesion, suggesting that these cell types might be key inhibitors of axon regeneration. Furthermore, most regenerating axons cross the lesion in association with astrocytes, indicating that these cells might be important for providing a permissive bridge for axon regeneration. Lineage analysis reveals that these bridge-forming astrocytes are not derived from ependymal stem cells within the spinal cord, suggesting that they are more likely derived from a subset of mature astrocytes. Overall, this study reveals insights into the critical extrinsic and intrinsic regulators of axon regeneration and establishes shRNA as a viable means to manipulate these regulators and translate findings into other mammalian models.

STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury

If and how neurons remodel their connections after CNS injury critically influences recovery of function. Here, we investigate the role of the growth-initiating transcription factor STAT3 during remodelling of the injured corticospinal tract (CST). Endogenous STAT3 expression in lesioned cortical projection neurons is transient but can be sustained by viral gene transfer. Sustained activation of STAT3 enhances remodelling of lesioned CST fibres and induces de novo formation of collaterals from unlesioned CST fibres. In a unilateral pyramidotomy paradigm, this recruitment of unlesioned fibres leads to the formation of midline crossing circuits that establish ipsilateral forelimb activation and functional recovery.

Reticulospinal plasticity after cervical spinal cord injury in the rat involves withdrawal of projections below the injury

Restoring voluntary fine motor control of the arm and hand is one of the main goals following cervical spinal cord injury (SCI). Although the functional improvement achievable with rehabilitative training in rat models is frequently accompanied by corticospinal tract (CST) plasticity, CST rewiring alone seems insufficient to account for the observed recovery. Recent investigations in animal models of SCI have suggested that the reticulospinal tract (RtST) might contribute to mediating improved motor performance of the forelimb. Here we investigate whether the spared RtST can compensate for the loss of CST input and whether RtST projections rearrange in response to cervical SCI. Animals underwent unilateral ablation of the dorsal CST and rubrospinal tract at spinal level C4, while the ventral RtST projections were spared. At the end of the six-week recovery period, injured animals had made significant improvements in single pellet reaching. This was not accompanied by increased sprouting of the injured CST above the injury compared to uninjured control animals. Injury-induced changes in RtST fiber density within the gray matter, as well as in the number of RtST collaterals entering the gray matter or crossing the cord midline were minor above the injury. However, all analyses directly below the injured spinal level consistently point to a significant decrease of RtST projections. The mechanism and the functional relevance behind this new finding warrant further study. Our results also suggest that mechanisms other than anatomical plasticity, such as plastic changes on a cellular level, might be responsible for the observed spontaneous recovery.