Visualizing Wallerian degeneration in the corticospinal tract after sensorimotor cortex ischemia in mice

Stroke can cause Wallerian degeneration in regions outside of the brain,particularly in the corticospinal tract.To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract following stroke,we induced photochemical infarction of the sensorimotor cortex leading to Wallerian degeneration along the full extent of the corticospinal tract.We first used a routine,sensitive marker of axonal injury,amyloid precursor protein,to examine Wallerian degeneration of the corticospinal tract.An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the ischemic cortex,with no positive signal in distal parts of the corticospinal tract,at all time points.To improve visualization of Wallerian degeneration,we next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent protein-expressing axons.Using this approach,we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke.In addition,microglia mobilized and activated early,from day 7 after stroke,but did not maintain a phagocytic state over time.Meanwhile,astrocytes showed relatively delayed mobilization and a moderate response to Wallerian degeneration.Moreover,no anterograde degeneration of spinal anterior horn cells was observed in response to Wallerian degeneration of the corticospinal tract.In conclusion,our data provide evidence for dynamic,pathogenic spatiotemporal changes in major cellular components of the corticospinal tract during Wallerian degeneration.

Enhancing m^(6)A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine(m^(6)A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein(METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.

Diffusion tensor imaging detects Wallerian degeneration of the corticospinal tract early after cerebral infarction

To investigate the feasibility and time window of early detection of Wallerian degeneration in the corticospinal tract after middle cerebral artery infarction, 23 patients were assessed using magnetic resonance diffusion tensor imaging at 3.0T within 14 days after the infarction. The fractional anisotropy values of the affected corticospinal tract began to decrease at 3 days after onset and decreased in all cases at 7 days. The diffusion coefficient remained unchanged. Experimental findings indicate that diffusion tensor imaging can detect the changes associated with Wallerian degeneration of the corticospinal tract as early as 3 days after cerebral infarction.

Axonal remodeling of the corticospinal tract during neurological recovery after stroke

Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.

Effects of Fujian tablet on Nogo-A mRNA expression and plasticity of the corticospinal tract in a rat model of focal cerebral ischemia

The present study investigated the effects of Fujian tablet, a Chinese medicine compound that can nourish liver and kidney, on corticospinal tract plasticity and cervical cord microenvironment in rats with focal cerebral ischemia. Results showed that motor function of rats with right proximal middle cerebral artery occlusion was significantly improved following treatment with Fujian tablet, 9 g crude drug/kg. Anterograde tracing revealed significantly increased biotinylated dextran amine expression in the denervated （left） side of the cervical cord （C4-6） following Fujian tablet treatment, and significantly decreased Nogo-A mRNA expression was detected in the denervated side of the cervical cord （C4-6） using in situ hybridization. Pearson＇s correlation analysis showed a negative correlation between biotinylated dextran amine and Nogo-A mRNA expression （r = -0.943, P 〈 0.01）. Results demonstrated that Fujian tablet can promote corticospinal tract plasticity possibly through the inhibitory effect on Nogo-A mRNA expression in the cervical spinal cord, thereby improving motor dysfunction.

Pathological verification of corticospinal tract Wallerian degeneration in a rat model of brain ischemia

Although neuroimaging is commonly utilized to study Wallerian degeneration, it cannot display Wallerian degeneration early after brain injury. In the present study, we attempted to examine pathologically the process of Wallerian degeneration early after brain injury. Cerebral peduncle demyelination was observed at 3 weeks post brain ischemia, followed by demyelination in the cervical enlargement at 6 weeks. Anterograde tracing of the corticospinal tract with biotinylated dextran amine showed that following serious neurologic deficit, the tracing of the corticospinal tract of the intemal capsule, cerebral peduncle, and cervical enlargement indicated serious Wallerian degeneration.

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

The corticospinal tract （CST） is a major neuronal tract of motor function in the human brain （York, 1987; Davidoff, 1990; Jang, 2014）. Recovery of an injured CST is one of the motor recovery mechanisms in stroke patients （Hendricks et al., 2003; Jang et al., 2006, 2007; Swayne et al., 2008; Kwon et al., 2011, 2013; Kwon and Jang, 2012; Yeo and Jang, 2013; Rong et al., 2014）. Diffusion tensor tractography （DTT）, derived from diffusion tensor imaging （DTI）, and transcra- nial magnetic stimulation （TMS） have been widely used in demonstrating the recovery of an injured CST （Hendricks et al., 2003; Jang et al., 2006, 2007; Swayne et al., 2008; Pannek et al., 2009; Kwon et al., 2011, 2013; Kwon and Jang, 2012; Yeo and Jang, 2013; Rong et al., 2014）. DTT has the advan- tage of enabling visualization of the architecture and integ- rity of the CST at the subcortical level in three dimensions （Mori et al., 1999; Kunimatsu et al., 2004）.

Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury

As most spinal cord injuries （SCIs） are incomplete, an important target for promoting neural repair and recovery of lost motor function is to promote the connections of spared descending spinal pathways with spinal motor circuits. Among the pathways, the corticospinal tract （CST） is most associated with skilled voluntary functions in humans and many animals. CST loss, whether at its origin in the motor cortex or in the white matter tracts subcortically and in the spinal cord, leads to movement impairments and paraly- sis. To restore motor function after injury will require repair of the damaged CST. In this review, I discuss how knowledge of activity-dependent development of the CST--which establishes connectional speci- ficity through axon pruning, axon outgrowth, and synaptic competition among CST terminals--informed a novel activity-based therapy for promoting sprouting of spared CST axons after injur in mature animals. This therapy, which comprises motor cortex electrical stimulation with and without concurrent trans-spi- nal direct current stimulation, leads to an increase in the gray matter axon length of spared CST axons in the rat spinal cord and, after a pyramidal tract lesion, restoration of skilled locomotor movements. I discuss how this approach is now being applied to a C4 contusion rat model.

Corticospinal tract recovery in a patient with traumatic transtentorial herniation

Transtentorial herniation is one of the causes of motor weakness in traumatic brain injury. In this study, we report on a patient who underwent decompressive craniectomy due to traumatic intracerebral hemorrhage. Brain CT images taken after surgery showed intracerebral hemorrhage in the left fronto-temporal lobe and left transtentorial herniation. The patient presented with severe paralysis of the right extremities at the time of intracerebral hemorrhage onset, but the limb motor function recovered partially at 6 months after onset and to nearly normal level at 27 months. Through diffusion tensor tractography, the left corticospinal tract was disrupted below the cerebral peduncle at 1 month after onset and the disrupted left corticospinal tract was reconstructed at 27 months. These findings suggest that recovery of limb motor function in a patient with traumatic transtentorial herniation can come to be true by recovery of corticospinal tract.

Exercise promotes motor functional recovery in rats with corticospinal tract injury:anti-apoptosis mechanism

Studies have shown that exercise interventions can improve functional recovery after spinal cord injury, but the mechanism of action remains unclear. To investigate the mechanism, we estab-lished a unilateral corticospinal tract injury model in rats by pyramidotomy, and used a single pellet reaching task and horizontal ladder walking task as exercise interventions postoperatively. Functional recovery of forelimbs and forepaws in the rat models was noticeably enhanced after the exercises. Furthermore, TUNEL staining revealed signiifcantly fewer apoptotic cells in the spinal cord of exercised rats, and western blot analysis showed that spinal cord expression of the apopto-sis-related protein caspase-3 was signiifcantly lower, and the expression of Bcl-2 was signiifcantly higher, while the expression of Bax was not signiifantly changed after exercise, compared with the non-exercised group. Expression of these proteins decreased with time after injury, towards the levels observed in sham-operated rats, however at 4 weeks postoperatively, caspase-3 expression remained signiifcantly greater than in sham-operated rats. The present ifndings indicate that a re-duction in apoptosis is one of the mechanisms underlying the improvement of functional recovery by exercise interventions after corticospinal tract injury.

Biotinylated dextran amine anterograde tracing of the canine corticospinal tract

In this study, biotinylated dextran amine （BDA） was microinjected into the left cortical motor area of the canine brain. Fluorescence microscopy results showed that a large amount of BDA-labeled pyramidal cells were visible in the left cortical motor area after injection. In the left medulla oblongata, the BDA-labeled corticospinal tract was evenly distributed, with green fluorescence that had a clear boundary with the surrounding tissue. The BDA-positive corticospinal tract entered into the right lateral funiculus of the spinal cord and descended into the posterior part of the right lateral funiculus, close to the posterior horn, from cervical to sacral segments. There was a small amount of green fluorescence in the sacral segment. The distribution of BDA labeling in the canine central nervous system was consistent with the course of the corticospinal tract. Fluorescence labeling for BDA gradually diminished with time after injection. Our findings indicate that the BDA anterograde tracing technique can be used to visualize the localization and trajectory of the corticospinal tract in the canine central nervous system.

Age-related changes of the corticospinal tract in the human brain A diffusion tensor imaging study

The corticospinal tract （CST） is one of the most important neural tracts for motor function in the human brain. Little is known about age-related changes of the CST. tn this study, we tried to evaluate age-related changes of the CST using diffusion tensor imaging in 60 healthy subjects. The diffusion tensor imaging result revealed that the tract number and fractional anisotropy value were decreased, and the apparent diffusion coefficient （ADC） value was increased with aging. The distribution showed a semilog pattern for tract number, fractional anisotropy and ADC of the CST, and the pattern of each graph was near-linear. When compared with the diffusion tensor imaging parameters of subjects in the 20 s age group, tract number and fractional anisotropy values were significantly decreased in the 50 s-70 s age groups. Likewise, the ADC value was significantly higher in the 50 s-70 s age groups. The CST in the brain of normal subjects degenerated continuously from the 20 s to the 70 s, with a near-linear pattern, and degeneration of the CST began to manifest significantly in the subjects in their 50 s, compared with the subjects in their 20 s.

Characters of MR diffusion tensor imaging in cerebral ischemic corticospinal tract injury

BACKGROUND： Diffusion tensor imaging （DTI） is one of the noninvasive methods to study the morphological structure of brain white matter fibrous bands in vivo, and it has been applied primarily in clinic. DTI is acknowledged as the more effective imaging method to diagnose ultra-acute and/or acute cerebral infarction.OB_3ECTIVE： To observe the anisotropic characters of cerebral white matter fibrous bands in patients with ischemic stroke by using DTI, and investigate the correlation between the damage of corticospinal tract and muscle strength in patients with ischemic stroke at acute period.DESIGN： A case-control observationSEFIING： Department of Medical Imaging, Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA.PARTICIPANTS： Nine inpatients with injury of motor function induced by acute ischemic stroke （patient group） at 6 hours to 2 weeks after the attack were selected from the Department of Neurology, Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA from September 2005 to March 2006, and they all accorded with the present diagnostic standard for cerebrovascular disease in China. There were 5 males and 4 females, aged 16-87 years. At the same time, nine healthy right-handed physical examinees matched by age and sex with the patients were taken as the control group, and they all had no nervous disease, mental diseases, cerebrovascular abnormalities and injury history, etc. All the subjects were informed with the detected items and agreed to participate in the study.METHODS： All the 9 patients with ischemic stroke at acute period and 9 healthy subjects were examined with MRI, T1 weighted imaging, T2 weighted imaging and DTI. And the data were processed offline with dTV.II software, the images of fractional anisotropy and directional encoded color （DEC） were obtained, and the three-dimensional fibrous band images of bilateral corticospinal tracts were reconstructed. In the control group, the values of fractional anisotropy of main white matter fibrous bands were measured in the region of interest （ROI） of the anterior limb, knee and posterior limb of internal capsule. In the patient group, the values of fractional anisotropy of white matter were measured in the infarcted sites and corresponding contralateral sites of the patients. The ROI was set in bilateral cerebral peduncles to reconstruct three-dimensionally the bilateral corticospinal tracts. The muscle strength of the affected hand was assessed with Brunnstorm standard in the stroke patients.MAIN OUTCOME MEASURES ： The characters of DTI and images of the value of fractional anisotropy, and the manifestations of three-dimensional corticospinal tracts were observed in the two groups.RESULTS： All the data from the 9 patients and 9 healthy volunteers were involved in the analysis of results. In the control group, the white matter and gray matter could be distinguished clearly in the image of fractional anisotropic values, the fibers of different directions were shown by different colors in DEC picture, which clearly demonstrated the normal anatomic structure and direction of white matter fibers. In the patient group, the infarctions occurred in the gray matter or white matter could be distinguished in the images of fractional anisotropic values, DEC picture could clearly show the direct influence of the infarcted site on the white matter fibers. The fractional anisotropic values in different white matter structure of the same side were significantly different in the control group （t=-3.12, P 〈 0.05）, and the reconstructed images fractional anisotropic values and DEC picture could show most of the main white matter fibrous bands. The fractional anisotropic values of the infarcted sites were significantly lower than the contralateral ones in the patient group （t=-5.570, P 〈 0.01）. ② The reconstructed bilateral corticospinal tracts showed that the anatomic forms of the contralateral corticospinal tract of the patients were almost identical to those of normal people, it started from precentral gyrus, downward to the nternal capsule, and extended to pontine and medulla oblongata, each fibrous band was continuous, and the form had good consistency. Because of the involvement of infarction of different severity, the ipsilateral corticospinal tract manifested as continuous interruption and the loss of consistent anatomic structural form. The involved severity of corticospinal tract had significant correlation with that of muscle strength of the ipsilateral hand （r=-1.30, P 〈 0.01）.CONCLUSION： ① DTI can display the direction and distribution of cerebral white matter fibrous bands.② DTI images of fractional anisotropic values and DEC can show the directions and anisotropic degree of white matter fibers in the infarcted sites of stroke patients. ③ The three-dimensional images of fibrous bands can show the conditions of pyramidal tracts more directly. ④ The damaged severity of corticospinal tracts is correlated with that of muscle strength.

Axonal remodeling in the corticospinal tract after stroke： how does rehabilitative training modulate it？

Stroke causes long-term disability, and rehabilitative training is commonly used to improve the consecutive functional recovery. Following brain damage, surviving neurons undergo morphological alterations to reconstruct the remaining neural network. In the motor system, such neural network remodeling is observed as a motor map reorganization. Because of its significant correlation with functional recovery, motor map reorganization has been regarded as a key phenomenon for functional recovery after stroke. Although the mechanism underlying motor map reorganization remains unclear, increasing evidence has shown a critical role for axonal remodeling in the corticospinal tract. In this study, we review previous studies investigating axonal remodeling in the corticospinal tract after stroke and discuss which mechanisms may underlie the stimulatory effect of rehabilitative training. Axonal remodeling in the corticospinal tract can be classified into three types based on the location and the original targets of corticospinal neurons, and it seems that all the surviving corticospinal neurons in both ipsilesional and contralesional hemisphere can participate in axonal remodeling and motor map reorganization. Through axonal remodeling, corticospinal neurons alter their output selectivity from a single to multiple areas to compensate for the lost function. The remodeling of the corticospinal axon is influenced by the extent of tissue destruction and promoted by various therapeutic interventions, including rehabilitative training. Although the precise molecular mechanism underlying rehabilitation-promoted axonal remodeling remains elusive, previous data suggest that rehabilitative training promotes axonal remodeling by upregulating growth-promoting and downregulating growth-inhibiting signals.

Right lower limb apraxia in a patient with left supplementary motor area infarction: intactness of the corticospinal tract confirmed by transcranial magnetic stimulation

We reported a 50-year-old female patient with left supplementary motor area infarction who presented right lower limb apraxia and investigated the possible causes using transcranial magnetic stimulation. The patient was able to walk and climb stairs spontaneously without any assistance at 3 weeks after onset. However, she was unable to intentionally move her right lower limb although she understood what she supposed to do. The motor evoked potential evoked by transcranial magnetic stimulation from the right lower limb was within the normal range, indicating that the corticospinal tract innervating the right lower limb was uninjured. Thus, we thought that her motor dysfunction was not induced by motor weakness, and confirmed her symptoms as aprax- ia. In addition, these results also suggest that transcranial magnetic stimulation is helpful for diagnosing apraxia.

Activation of less affected corticospinal tract and poor motor outcome in hemiplegic pediatric patients:a diffusion tensor tractography imaging study

The less affected hemisphere is important in motor recovery in mature brains.However,in terms of motor outcome in immature brains,no study has been reported on the less affected corticospinal tract in hemiplegic pediatric patients.Therefore,we examined the relationship between the condition of the less affected corticospinal tract and motor function in hemiplegic pediatric patients.Forty patients with hemiplegia due to perinatal or prenatal injury（13.7±3.0 months）and 40 age-matched typically developing controls were recruited.These patients were divided into two age-matched groups,the high functioning group（20 patients）and the low functioning group（20 patients）using functional level of hemiplegia scale.Diffusion tensor tractography images showed that compared with the control group,the patient group of the less affected corticospinal tract showed significantly increased fiber number and significantly decreased fractional anisotropy value.Significantly increased fiber number and significantly decreased fractional anisotropy value in the low functioning group were observed than in the high functioning group.These findings suggest that activation of the less affected hemisphere presenting as increased fiber number and decreased fractional anisotropy value is related to poor motor function in pediatric hemiplegic patients.

Change in connection between corticospinal tract and Broca's area during motor recovery in a patient with an intracerebral hemorrhage

The present study reported a 42-year-old male patient who underwent conservative management for a spontaneous intracerebral hemorrhage in the left corona radiata and the basal ganglia. The patient presented with complete weakness of the right upper and lower extremities at the onset of intracerebral hemorrhage; however, he showed progressive motor recovery to the level that he was able to extent the affected extremities against some resistance at 5 weeks after onset. The corticospinal tract of the affected （left） hemisphere connected to the left Broca＇s area at 3 weeks after onset as shown by diffusion tensor tractography. By contrast, this connection had disappeared at 5 weeks after onset as shown by diffusion tensor tractogaphy. Transcranial magnetic stimulation study showed that no motor evoked potential was elicited from the affected （left） hemisphere at 3 weeks after onset, but motor evoked potentials were elicited at 5 weeks after onset. These findings suggest that the connection between the injured corticospinal tract and Broca＇s area in this patient appears to be a compensation for severe motor weakness; consequently, the connection seems to disappear with motor recovery.

Spared integrity of corticospinal tract within a pontine infarct A diffusion tensor tractography study

Integrity of the corticospinal tract is mandatory for good recovery of impaired motor function in patients who have suffered a stroke.A 67-year-old left hemiparetic female showed an infarct in the right pons.Three months after onset,motor function of the affected extremities recovered rapidly to a nearly complete state.Diffusion tensor tractography of both hemispheres showed that the corticospinal tract originated from the primary sensori-motor cortex and descended through the known corticospinal tract pathway.The tract of the affected（right）hemisphere descended through an area within the pontine infarct.The diffusion tensor tractography results suggest that from the onset,the integrity of the corticospinal tract appears to have been spared within the pontine infarct.

Isolated corticospinal tract in a patient with intracerebral hemorrhage A diffusion tensor tractography and transcranial magnetic stimulation study

Diffusion tensor tractography allows visualization of the corticospinal tract （CST） in three dimensions. Transcranial magnetic stimulation offers a unique advantage in that it can distinguish between the corticospinal tract and the non-CST by analyzing the characteristics of a motor-evoked potential. A 15 year-old female showed right hemiparesis, due to intracerebral hemorrhage in the left corona radiata, and the posterior limb of the internal capsule. Diffusion tensor tractography revealed that the tracts of both hemispheres originated from the precentral gyrus, and descended through the known CST pathway. Specifically, the tract of the affected hemisphere descended through an isolated area in the leukomalactic lesion at the posterior limb level. In addition, the characteristics of the motor-evoked potential obtained from the right hand when stimulating the hot spot of the left motor cortex corresponded to a CST. In conclusion, we report on a patient with intracerebral hemorrhage who showed an isolated CST in a leukomalactic lesion. This result suggests the importance of saving the adjacent area or penumbra around a hematoma after an intracerebral hemorrhage.

Recovery of corticospinal tract injury following subdural hematoma removal A diffusion tensor imaging study

Subdural hematoma can cause compression or damage to the neural tracts in the brain;however,very little is known about this injury.We report on a patient with subdural hematoma who was evaluated by diffusion tensor imaging prior to and after trephination and drainage of subdural hematoma.A 58-year-old male patient and ten age-matched normal control subjects were evaluated.The patient showed mild hemiparesis for 3 weeks prior to surgery.His hemiparesis recovered to a nearly normal state at 5 weeks post-surgery when the follow up diffusion tensor image was acquired.Two diffusion tensor image parameters,fractional anisotropy and apparent diffusion coefficient,were measured along the corticospinal tract.Pre-operative diffusion tensor image showed that the corticospinal tract of the affected hemisphere seemed to be injured or compressed.However,the follow up diffusion tensor image showed recovery of this corticospinal tract to a normal state.It would appear that diffusion tensor images are a useful tool for evaluation of the effects of subdural hematomas on neural tracts.