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Background: Acute brainstem infarction is associated with high morbidity and mortality, the integrity of corticospinal tract (CST) detected via diffusion tensor imaging (DTI) can assist in predicting the motor recovery of the patients. In addition to the damage caused by ischemia and reperfusion, sterile inflammation also contributes to the brain injury after stroke. However, the changes in CST integrity detected by DTI in acute brainstem infarction have yet to be fully elucidated, and it is still unclear whether sterile inflammation can cause damage to the CST. Methods: In this study, the acute brainstem infarction patients in the early (EABI patients, n = 19) and late (LABI patients, n = 21) stages and healthy controls (HCs, n = 22) are employed. The probabilistic tractography technique was used and the fractional anisotropy (FA) value was chosen to evaluated the integrity of the CST, the IL-6, IL-10, IL-17, IL-1β, and tumor necrosis factor (TNF)-α levels in the plasma are measured to evaluate the level of inflammation. Results: Compared to the HCs (F = 13.634, p ANOVA < 0.001), the CST FA values on the infarcted side were abnormally elevated in EABI patients (p LSD = 0.003), and decreased in LABI patients (p LSD = 0.034). The levels of IL-6 (F = 12.311, p ANOVA < 0.001, EABI vs HCs: p LSD < 0.001, LABI vs HCs: p LSD < 0.001), IL-10 (F = 11.329, p ANOVA < 0.001, EABI vs HCs: p LSD < 0.001, LABI vs HCs: p LSD = 0.017) and IL-1β (F = 15.986, p ANOVA < 0.001, EABI vs HCs: p LSD < 0.001, LABI vs HCs: p LSD < 0.001) were increased in both EABI and LABI patients, while the IL-17 levels were elevated only in LABI patients (F = 4.258, p ANOVA = 0.019, LABI vs HCs: p LSD = 0.027). Among these cytokines, the increased IL-6 (r = 0.663, p = 0.002) and IL-1β (r = 0.615, p = 0.005) levels of EABI patients might be related to the elevated CST FA values, while the increased IL-17 (r = -0.599, p = 0.004) levels of LABI patients might contribute to the decrease of the CST FA values. Conclusion: Our study reveals that the increased CST FA values in EABI patients may include signals generated by the immune cells which move along the CST. The sterile inflammation may contribute to the impairment of CST integrity in LABI patients. [ABSTRACT FROM AUTHOR]

BackgroundAcute brainstem infarction is associated with high morbidity and mortality, the integrity of corticospinal tract (CST) detected via diffusion tensor imaging (DTI) can assist in predicting the motor recovery of the patients. In addition to the damage caused by ischemia and reperfusion, sterile inflammation also contributes to the brain injury after stroke. However, the changes in CST integrity detected by DTI in acute brainstem infarction have yet to be fully elucidated, and it is still unclear whether sterile inflammation can cause damage to the CST.MethodsIn this study, the acute brainstem infarction patients in the early (EABI patients, n = 19) and late (LABI patients, n = 21) stages and healthy controls (HCs, n = 22) are employed. The probabilistic tractography technique was used and the fractional anisotropy (FA) value was chosen to evaluated the integrity of the CST, the IL-6, IL-10, IL-17, IL-1β, and tumor necrosis factor (TNF)-α levels in the plasma are measured to evaluate the level of inflammation.ResultsCompared to the HCs (F = 13.634, p ANOVA < 0.001), the CST FA values on the infarcted side were abnormally elevated in EABI patients (p LSD = 0.003), and decreased in LABI patients (p LSD = 0.034). The levels of IL-6 (F = 12.311, p ANOVA < 0.001, EABI vs HCs: p LSD < 0.001, LABI vs HCs: p LSD < 0.001), IL-10 (F = 11.329, p ANOVA < 0.001, EABI vs HCs: p LSD < 0.001, LABI vs HCs: p LSD = 0.017) and IL-1β (F = 15.986, p ANOVA < 0.001, EABI vs HCs: p LSD < 0.001, LABI vs HCs: p LSD < 0.001) were increased in both EABI and LABI patients, while the IL-17 levels were elevated only in LABI patients (F = 4.258, p ANOVA = 0.019, LABI vs HCs: p LSD = 0.027). Among these cytokines, the increased IL-6 (r = 0.663, p = 0.002) and IL-1β (r = 0.615, p = 0.005) levels of EABI patients might be related to the elevated CST FA values, while the increased IL-17 (r = -0.599, p = 0.004) levels of LABI patients might contribute to the decrease of the CST FA values.ConclusionOur study reveals that the increased CST FA values in EABI patients may include signals generated by the immune cells which move along the CST. The sterile inflammation may contribute to the impairment of CST integrity in LABI patients.

The corticospinal tract plays a major role in the control of voluntary limb movements, and its damage impedes voluntary limb control. We investigated the feasibility of closed-loop brain-controlled subdural spinal stimulation through a corticospinal interface for the modulation of wrist torque in the paralyzed forearm of monkeys with spinal cord injury at C4/C5. Subdural spinal stimulation of the preserved cervical enlargement activated multiple muscles on the paralyzed forearm and wrist torque in the range from flexion to ulnar-flexion. The magnitude of the evoked torque could be modulated by changing current intensity. We then employed the corticospinal interface designed to detect the firing rate of an arbitrarily selected "linked neuron" in the forearm territory of the primary motor cortex (M1) and convert it in real time to activity-contingent electrical stimulation of a spinal site caudal to the lesion. Linked neurons showed task-related activity that modulated the magnitude of the evoked torque and the activation of multiple muscles depending on the required torque. Unlinked neurons, which were independent of spinal stimulation and located in the vicinity of the linked neurons, exhibited task-related or -unrelated activity. Thus, monkeys were able to modulate the wrist torque of the paralyzed forearm by modulating the firing rate of M1 neurons including unlinked and linked neurons via the corticospinal interface. These results suggest that the corticospinal interface can replace the function of the corticospinal tract after spinal cord injury. [ABSTRACT FROM AUTHOR]

Background: The strength of connections between motor cortex (MCX) and muscle can be augmented with a variety of stimulation protocols. Augmenting MCX-to-muscle connection strength by neuromodulation may be a way to enhance the intact motor system's capacity for acquiring motor skills and promote function after injury to strengthen spared connections. But this enhancement must be maintained for functional improvements. Objective: We determined if brief MCX muscle evoked potential (MEP) enhancement produced by single-block intermittent theta burst stimulation (iTBS) can be converted into a longer and structurally durable form of response enhancement with repeated daily and longer-term application. Methods: Electrical iTBS was delivered through an implanted MCX epidural electrode and MEPs were recorded using implanted EMG electrodes in awake naïve rats. MCX activity was modulated further using chemogenetic (DREADDs) excitation and inhibition. Corticospinal tract (CST) axons were traced and immunochemistry used to measure CST synapses. Results: A single MCX iTBS block (600 pulses) produced MEP LTP lasting ∼30–45 min. Concatenating five iTBS blocks within a 30-min session produced MEP LTP lasting 24–48 h, which could be strengthened or weakened by bidirectional MCX activity modulation. Effect duration was not changed. Finally, daily induction of this persistent MEP LTP with daily iTBS for 10-days produced MEP enhancement outlasting the stimulation period by at least 10 days, and accompanied by CST axonal outgrowth and structural changes at the CST-spinal interneuron synapse. Conclusion: Our findings inform the mechanisms of iTBS and provide a framework for designing neuromodulatory strategies to promote durable enhancement of cortical motor actions.

Objective: Safe resection of gliomas involving motor pathways in asleepanesthesia requires the combination of brain mapping, to identify and spare essential motor sites, and continuous monitoring of motor-evoked potentials (MEPs), to detect possible vascular damage to the corticospinal tract (CST). MEP monitoring, according to intraoperative neurophysiology societies, is generally recommended by transcranial electrodes (TES), and no clear indications of direct cortical stimulation (DCS) or the preferential use of one of the two techniques based on the clinical context is available. The main aim of the study was to identify the best technique(s) based on different clinical conditions, evaluating the efficacy and prognostic value of both methodologies. Methods: A retrospective series of patients with tumors involving the motor pathways who underwent surgical resection with the aid of brain mapping and combined MEP monitoring via TES and DCS was evaluated. Irreversible MEP amplitude reduction (>50% compared to baseline) was used as an intraoperative warning and correlated to the postoperative motor outcome. Selectivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed for both techniques. Results: Four hundred sixty-two patients were retrospectively analyzed, and only 1.9% showed a long-term motor impairment. Both TES and DCS obtained high specificity and NPV for the acute and 1-month motor deficit. Sensitivity was rather low for the acute deficit but excellent considering the 1-month follow-up for both techniques. DCS was extremely reliable in predicting a postoperative motor decline (PPV of 100% and 90% for acute and long-term deficit, respectively). Conversely, TES produced a high number of false-positive results, especially for long-term deficits (65, 87.8% of all warnings) therefore obtaining poor PPV values (18% and 12% for acute and 1-month deficits, respectively). TES false-positive results were significantly associated with parietal tumors and lateral patient positioning. Conclusions: Data support the use of mapping and combined monitoring via TES and DCS. The sole TES monitoring is reliable in most procedures but not in parietal tumors or those requiring lateral positioning. Although no indications are available in international guidelines, DCS should be recommended, particularly for cases approached by a lateral position. [ABSTRACT FROM AUTHOR]

BackgroundMass flexion-extension co-excitation patterns during walking are often seen as a consequence of stroke, but there is limited understanding of the specific contributions of different descending motor pathways toward their control. The corticospinal tract is a major descending motor pathway influencing the production of normal sequential muscle coactivation patterns for skilled movements. However, control of walking is also influenced by non-corticospinal pathways such as the corticoreticulospinal pathway that possibly contribute toward mass flexion-extension co-excitation patterns during walking. The current study sought to investigate the associations between damage to corticospinal (CST) and corticoreticular (CRP) motor pathways following stroke and the presence of mass flexion-extension patterns during walking as evaluated using module analysis.MethodsSeventeen healthy controls and 44 stroke survivors were included in the study. We used non-negative matrix factorization for module analysis of paretic leg electromyographic activity. We typically have observed four modules during walking in healthy individuals. Stroke survivors often have less independently timed modules, for example two-modules presented as mass flexion-extension pattern. We used diffusion tensor imaging-based analysis where streamlines connecting regions of interest between the cortex and brainstem were computed to evaluate CST and CRP integrity. We also used a coarse classification tree analysis to evaluate the relative CST and CRP contribution toward module control.ResultsInterhemispheric CST asymmetry was associated with worse lower extremity Fugl-Meyer score (p = 0.023), propulsion symmetry (p = 0.016), and fewer modules (p = 0.028). Interhemispheric CRP asymmetry was associated with worse lower extremity Fugl-Meyer score (p = 0.009), Dynamic gait index (p = 0.035), Six-minute walk test (p = 0.020), Berg balance scale (p = 0.048), self-selected walking speed (p = 0.041), and propulsion symmetry (p = 0.001). The classification tree model reveled that substantial ipsilesional CRP or CST damage leads to a two-module pattern and poor walking ability with a trend toward increased compensatory contralesional CRP based control.ConclusionBoth CST and CRP are involved with control of modules during walking and damage to both may lead to greater reliance on the contralesional CRP, which may contribute to a two-module pattern and be associated with worse walking performance.

ObjectiveSafe resection of gliomas involving motor pathways in asleep-anesthesia requires the combination of brain mapping, to identify and spare essential motor sites, and continuous monitoring of motor-evoked potentials (MEPs), to detect possible vascular damage to the corticospinal tract (CST). MEP monitoring, according to intraoperative neurophysiology societies, is generally recommended by transcranial electrodes (TES), and no clear indications of direct cortical stimulation (DCS) or the preferential use of one of the two techniques based on the clinical context is available. The main aim of the study was to identify the best technique(s) based on different clinical conditions, evaluating the efficacy and prognostic value of both methodologies.MethodsA retrospective series of patients with tumors involving the motor pathways who underwent surgical resection with the aid of brain mapping and combined MEP monitoring via TES and DCS was evaluated. Irreversible MEP amplitude reduction (>50% compared to baseline) was used as an intraoperative warning and correlated to the postoperative motor outcome. Selectivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed for both techniques.ResultsFour hundred sixty-two patients were retrospectively analyzed, and only 1.9% showed a long-term motor impairment. Both TES and DCS obtained high specificity and NPV for the acute and 1-month motor deficit. Sensitivity was rather low for the acute deficit but excellent considering the 1-month follow-up for both techniques. DCS was extremely reliable in predicting a postoperative motor decline (PPV of 100% and 90% for acute and long-term deficit, respectively). Conversely, TES produced a high number of false-positive results, especially for long-term deficits (65, 87.8% of all warnings) therefore obtaining poor PPV values (18% and 12% for acute and 1-month deficits, respectively). TES false-positive results were significantly associated with parietal tumors and lateral patient positioning.ConclusionsData support the use of mapping and combined monitoring via TES and DCS. The sole TES monitoring is reliable in most procedures but not in parietal tumors or those requiring lateral positioning. Although no indications are available in international guidelines, DCS should be recommended, particularly for cases approached by a lateral position.

The strength of connections between motor cortex (MCX) and muscle can be augmented with a variety of stimulation protocols. Augmenting MCX-to-muscle connection strength by neuromodulation may be a way to enhance the intact motor system's capacity for acquiring motor skills and promote function after injury to strengthen spared connections. But this enhancement must be maintained for functional improvements. We determined if brief MCX muscle evoked potential (MEP) enhancement produced by single-block intermittent theta burst stimulation (iTBS) can be converted into a longer and structurally durable form of response enhancement with repeated daily and longer-term application. Electrical iTBS was delivered through an implanted MCX epidural electrode and MEPs were recorded using implanted EMG electrodes in awake naïve rats. MCX activity was modulated further using chemogenetic (DREADDs) excitation and inhibition. Corticospinal tract (CST) axons were traced and immunochemistry used to measure CST synapses. A single MCX iTBS block (600 pulses) produced MEP LTP lasting ∼30–45 min. Concatenating five iTBS blocks within a 30-min session produced MEP LTP lasting 24–48 h, which could be strengthened or weakened by bidirectional MCX activity modulation. Effect duration was not changed. Finally, daily induction of this persistent MEP LTP with daily iTBS for 10-days produced MEP enhancement outlasting the stimulation period by at least 10 days, and accompanied by CST axonal outgrowth and structural changes at the CST-spinal interneuron synapse. Our findings inform the mechanisms of iTBS and provide a framework for designing neuromodulatory strategies to promote durable enhancement of cortical motor actions. • Concatenating 5 motor cortex iTBS blocks produced MEP LTP that persisted for 24–48 h. • MEP LTP magnitude but not duration was enhanced by chemogenetic MCX activation. • Chronic daily iTBS produced durable MEP LTP accompanied by corticospinal synaptogenesis. • Daily persistent LTP induction by iTBS provides a framework for producing durable plasticity. [ABSTRACT FROM AUTHOR]

Background and Purpose: Motor deficits are the most common disability after stroke, and early prediction of motor outcomes is critical for guiding the choice of early interventions. Two main factors that may impact the response to rehabilitation are variations in the microstructure of the affected corticospinal tract (CST) and genetic polymorphisms in brain-derived neurotrophic factor (BDNF). The purpose of this article was to review the role of these factors in stroke recovery, which will be useful for constructing a predictive model of rehabilitation outcomes.Summary of Review: We review the microstructure of the CST, including its origins in the primary motor area (M1), primary sensory area (S1), premotor cortex (PMC), and supplementary motor area (SMA). Damage to these fibers is disease-causing and can directly affect rehabilitation after subcortical stroke. BDNF polymorphisms are not disease-causing but can indirectly affect neuroplasticity and thus motor recovery. Both factors are known to be correlated with motor recovery. Further work is needed using large longitudinal patient samples and animal experiments to better establish the role of these two factors in stroke rehabilitation.Conclusions: Microstructure and genetic polymorphisms should be considered possible predictors or covariates in studies investigating motor recovery after subcortical stroke. Future predictive models of stroke recovery will likely include a combination of structural and genetic factors to allow precise individualization of stroke rehabilitation strategies.

ObjectiveThe primary objective of this study was to retrospectively investigate associations between clinical magnetic resonance imaging-based (MRI) metrics of corticospinal tract (CST) status and paretic upper extremity (PUE) motor recovery in patients that completed acute inpatient rehabilitation (AR) post-stroke.MethodsWe conducted a longitudinal chart review of patients post-stroke who received care in the Emory University Hospital system during acute hospitalization, AR, and outpatient therapy. We extracted demographic information, stroke characteristics, and longitudinal documentation of post-stroke motor function from institutional electronic medical records. Serial assessments of paretic shoulder abduction and finger extension were estimated (E-SAFE) and an estimated Action Research Arm Test (E-ARAT) score was used to quantify 3-month PUE motor function outcome. Clinically-diagnostic MRI were used to create lesion masks that were spatially normalized and overlaid onto a white matter tract atlas delineating CST contributions emanating from six cortical seed regions to obtain the percentage of CST lesion overlap. Metric associations were investigated with correlation and cluster analyses, Kruskal-Wallis tests, classification and regression tree analysis.ResultsThirty-four patients met study eligibility criteria. All CST overlap percentages were correlated with E-ARAT however, ventral premotor tract (PMv) overlap was the only tract that remained significantly correlated after multiple comparisons adjustment. Lesion overlap percentage in CST contributions from all seed regions was significantly different between outcome categories. Using MRI metrics alone, dorsal premotor (PMd) and PMv tracts classified recovery outcome category with 79.4% accuracy. When clinical and MRI metrics were combined, AR E-SAFE, patient age, and overall CST lesion overlap classified patients with 88.2% accuracy.ConclusionsStudy findings revealed clinical MRI-derived CST lesion overlap was associated with PUE motor outcome post-stroke and that cortical projections within the CST, particularly those emanating from non-M1 cortical areas, prominently ventral premotor (PMv) and dorsal premotor (PMd) cortices, distinguished between PUE outcome groups. Exploratory predictive models using clinical MRI metrics, either alone or in combination with clinical measures, were able to accurately identify recovery outcome category for the study cohort during both the acute and early subacute phases of post-stroke recovery. Prospective studies are recommended to determine the predictive utility of including clinical imaging-based biomarkers of white matter tract structural integrity in predictive models of post-stroke recovery.

Objective: The primary objective of this study was to retrospectively investigate associations between clinical magnetic resonance imaging-based (MRI) metrics of corticospinal tract (CST) status and paretic upper extremity (PUE) motor recovery in patients that completed acute inpatient rehabilitation (AR) post-stroke. Methods: We conducted a longitudinal chart review of patients post-stroke who received care in the Emory University Hospital system during acute hospitalization, AR, and outpatient therapy. We extracted demographic information, stroke characteristics, and longitudinal documentation of post-stroke motor function from institutional electronic medical records. Serial assessments of paretic shoulder abduction and finger extension were estimated (E-SAFE) and an estimated Action Research Arm Test (E-ARAT) score was used to quantify 3-month PUE motor function outcome. Clinically-diagnostic MRI were used to create lesion masks that were spatially normalized and overlaid onto a white matter tract atlas delineating CST contributions emanating from six cortical seed regions to obtain the percentage of CST lesion overlap. Metric associations were investigated with correlation and cluster analyses, Kruskal-Wallis tests, classification and regression tree analysis. Results: Thirty-four patients met study eligibility criteria. All CST overlap percentages were correlated with E-ARAT however, ventral premotor tract (PMv) overlap was the only tract that remained significantly correlated after multiple comparisons adjustment. Lesion overlap percentage in CST contributions from all seed regions was significantly different between outcome categories. Using MRI metrics alone, dorsal premotor (PMd) and PMv tracts classified recovery outcome category with 79.4% accuracy. When clinical and MRI metrics were combined, AR E-SAFE, patient age, and overall CST lesion overlap classified patients with 88.2% accuracy. Conclusions: Study findings revealed clinical MRI-derived CST lesion overlap was associated with PUE motor outcome post-stroke and that cortical projections within the CST, particularly those emanating from non-M1 cortical areas, prominently ventral premotor (PMv) and dorsal premotor (PMd) cortices, distinguished between PUE outcome groups. Exploratory predictive models using clinical MRI metrics, either alone or in combination with clinical measures, were able to accurately identify recovery outcome category for the study cohort during both the acute and early subacute phases of post-stroke recovery. Prospective studies are recommended to determine the predictive utility of including clinical imaging-based biomarkers of white matter tract structural integrity in predictive models of post-stroke recovery. [ABSTRACT FROM AUTHOR]

Background and Purpose: Motor deficits are the most common disability after stroke, and early prediction of motor outcomes is critical for guiding the choice of early interventions. Two main factors that may impact the response to rehabilitation are variations in the microstructure of the affected corticospinal tract (CST) and genetic polymorphisms in brain-derived neurotrophic factor (BDNF). The purpose of this article was to review the role of these factors in stroke recovery, which will be useful for constructing a predictive model of rehabilitation outcomes. Summary of Review: We review the microstructure of the CST, including its origins in the primary motor area (M1), primary sensory area (S1), premotor cortex (PMC), and supplementary motor area (SMA). Damage to these fibers is disease-causing and can directly affect rehabilitation after subcortical stroke. BDNF polymorphisms are not disease-causing but can indirectly affect neuroplasticity and thus motor recovery. Both factors are known to be correlated with motor recovery. Further work is needed using large longitudinal patient samples and animal experiments to better establish the role of these two factors in stroke rehabilitation. Conclusions: Microstructure and genetic polymorphisms should be considered possible predictors or covariates in studies investigating motor recovery after subcortical stroke. Future predictive models of stroke recovery will likely include a combination of structural and genetic factors to allow precise individualization of stroke rehabilitation strategies. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study is to explore the effect of wrist-ankle acupuncture combined with 5-Hz repetitive transcranial magnetic stimulation (rTMS) on improving spastic state and motor function of children with spastic cerebral palsy by measuring electrophysiological parameters and behaviors. Methods: Twenty-five children with spastic cerebral palsy were enrolled in a single-blind and randomized controlled trial. The control group received 20 sessions of 5-Hz rTMS over the affected hemisphere with 1,000 pulses. The experimental group was given wrist-ankle acupuncture on the basis of the control group. Gross motor function measure (GMFM-66), muscle tension, and electrophysiological parameters of the two groups were assessed at baseline and after intervention. Results: After treatment, the GMFM-66 scores in the same groups were significantly improved (p < 0.001). Besides, the R -value of soleus, gastrocnemius, and hamstring muscle decreased (p < 0.05), and the results showed a trend of shortening MEP latency, increasing amplitude and duration (p < 0.05). Compared to the controlled group, the experimental group displayed more excellent changes in the GMFM-66 scores and motor evoked potential (MEP) latency. The statistical results showed that the increase of GMFM-66 score and the shortening of MEP latency in the experimental group were greater than that in the control group (p < 0.05). However, no significant differences were found in the assessment of muscle tension, amplitude, and duration of MEPs between two groups (p > 0.05). Conclusion: Wrist-ankle acupuncture combined with 5-Hz rTMS is optimal to improve gross motor function and enhance the conductivity of corticospinal tract in children with cerebral palsy but cannot highlight its clinical superiority in improving spasticity. Clinical Trial Registration: [http://www.chictr.org.cn/index.aspx], identifier [chictr2000039495]. [ABSTRACT FROM AUTHOR]

While the diagnosis of high-grade glioma (HGG) is still associated with a considerably poor prognosis, neurosurgical tumor resection provides an opportunity for prolonged survival and improved quality of life for affected patients. However, successful tumor resection is dependent on a proper surgical planning to avoid surgery-induced functional deficits whilst achieving a maximum extent of resection (EOR). With diffusion magnetic resonance imaging (MRI) providing insight into individual white matter neuroanatomy, the challenge remains to disentangle that information as correctly and as completely as possible. In particular, due to the lack of sensitivity and accuracy, the clinical value of widely used diffusion tensor imaging (DTI)-based tractography is increasingly questioned. We evaluated whether the recently developed multi-level fiber tracking (MLFT) technique can improve tractography of the corticospinal tract (CST) in patients with motor-eloquent HGGs. Forty patients with therapy-naïve HGGs (mean age: 62.6 ± 13.4 years, 57.5% males) and preoperative diffusion MRI [repetition time (TR)/echo time (TE): 5000/78 ms, voxel size: 2x2x2 mm3, one volume at b=0 s/mm2, 32 volumes at b=1000 s/mm2] underwent reconstruction of the CST of the tumor-affected and unaffected hemispheres using MLFT in addition to deterministic DTI-based and deterministic constrained spherical deconvolution (CSD)-based fiber tractography. The brain stem was used as a seeding region, with a motor cortex mask serving as a target region for MLFT and a region of interest (ROI) for the other two algorithms. Application of the MLFT method substantially improved bundle reconstruction, leading to CST bundles with higher radial extent compared to the two other algorithms (delineation of CST fanning with a wider range; median radial extent for tumor-affected vs. unaffected hemisphere – DTI: 19.46° vs. 18.99°, p=0.8931; CSD: 30.54° vs. 27.63°, p=0.0546; MLFT: 81.17° vs. 74.59°, p=0.0134). In addition, reconstructions by MLFT and CSD-based tractography nearly completely included respective bundles derived from DTI-based tractography, which was however favorable for MLFT compared to CSD-based tractography (median coverage of the DTI-based CST for affected vs. unaffected hemispheres – CSD: 68.16% vs. 77.59%, p=0.0075; MLFT: 93.09% vs. 95.49%; p=0.0046). Thus, a more complete picture of the CST in patients with motor-eloquent HGGs might be achieved based on routinely acquired diffusion MRI data using MLFT. [ABSTRACT FROM AUTHOR]

While the diagnosis of high-grade glioma (HGG) is still associated with a considerably poor prognosis, neurosurgical tumor resection provides an opportunity for prolonged survival and improved quality of life for affected patients. However, successful tumor resection is dependent on a proper surgical planning to avoid surgery-induced functional deficits whilst achieving a maximum extent of resection (EOR). With diffusion magnetic resonance imaging (MRI) providing insight into individual white matter neuroanatomy, the challenge remains to disentangle that information as correctly and as completely as possible. In particular, due to the lack of sensitivity and accuracy, the clinical value of widely used diffusion tensor imaging (DTI)-based tractography is increasingly questioned. We evaluated whether the recently developed multi-level fiber tracking (MLFT) technique can improve tractography of the corticospinal tract (CST) in patients with motor-eloquent HGGs. Forty patients with therapy-naïve HGGs (mean age: 62.6 ± 13.4 years, 57.5% males) and preoperative diffusion MRI [repetition time (TR)/echo time (TE): 5000/78 ms, voxel size: 2x2x2 mm3, one volume at b=0 s/mm2, 32 volumes at b=1000 s/mm2] underwent reconstruction of the CST of the tumor-affected and unaffected hemispheres using MLFT in addition to deterministic DTI-based and deterministic constrained spherical deconvolution (CSD)-based fiber tractography. The brain stem was used as a seeding region, with a motor cortex mask serving as a target region for MLFT and a region of interest (ROI) for the other two algorithms. Application of the MLFT method substantially improved bundle reconstruction, leading to CST bundles with higher radial extent compared to the two other algorithms (delineation of CST fanning with a wider range; median radial extent for tumor-affected vs. unaffected hemisphere – DTI: 19.46° vs. 18.99°, p=0.8931; CSD: 30.54° vs. 27.63°, p=0.0546; MLFT: 81.17° vs. 74.59°, p=0.0134). In addition, reconstructions by MLFT and CSD-based tractography nearly completely included respective bundles derived from DTI-based tractography, which was however favorable for MLFT compared to CSD-based tractography (median coverage of the DTI-based CST for affected vs. unaffected hemispheres – CSD: 68.16% vs. 77.59%, p=0.0075; MLFT: 93.09% vs. 95.49%; p=0.0046). Thus, a more complete picture of the CST in patients with motor-eloquent HGGs might be achieved based on routinely acquired diffusion MRI data using MLFT.

Objective: The goal of this study is to explore the effect of wrist-ankle acupuncture combined with 5-Hz repetitive transcranial magnetic stimulation (rTMS) on improving spastic state and motor function of children with spastic cerebral palsy by measuring electrophysiological parameters and behaviors.Methods: Twenty-five children with spastic cerebral palsy were enrolled in a single-blind and randomized controlled trial. The control group received 20 sessions of 5-Hz rTMS over the affected hemisphere with 1,000 pulses. The experimental group was given wrist-ankle acupuncture on the basis of the control group. Gross motor function measure (GMFM-66), muscle tension, and electrophysiological parameters of the two groups were assessed at baseline and after intervention.Results: After treatment, the GMFM-66 scores in the same groups were significantly improved (p < 0.001). Besides, the R-value of soleus, gastrocnemius, and hamstring muscle decreased (p < 0.05), and the results showed a trend of shortening MEP latency, increasing amplitude and duration (p < 0.05). Compared to the controlled group, the experimental group displayed more excellent changes in the GMFM-66 scores and motor evoked potential (MEP) latency. The statistical results showed that the increase of GMFM-66 score and the shortening of MEP latency in the experimental group were greater than that in the control group (p < 0.05). However, no significant differences were found in the assessment of muscle tension, amplitude, and duration of MEPs between two groups (p > 0.05).Conclusion: Wrist-ankle acupuncture combined with 5-Hz rTMS is optimal to improve gross motor function and enhance the conductivity of corticospinal tract in children with cerebral palsy but cannot highlight its clinical superiority in improving spasticity.Clinical Trial Registration: [http://www.chictr.org.cn/index.aspx], identifier [chictr2000039495].

Spinal cord injury (SCI) is a devastating lesion to the spinal cord, which determines the interruption of ascending/descending axonal tracts, the loss of supraspinal control of sensory-motor functions below the injured site, and severe autonomic dysfunctions, dramatically impacting the quality of life of the patients. After the acute inflammatory phase, the progressive formation of the astrocytic glial scar characterizes the acute-chronic phase: such scar represents one of the main obstacles to the axonal regeneration that, as known, is very limited in the central nervous system (CNS). Unfortunately, a cure for SCI is still lacking: the current clinical approaches are mainly based on early vertebral column stabilization, anti-inflammatory drug administration, and rehabilitation programs. However, new experimental therapeutic strategies are under investigation, one of which is to stimulate axonal regrowth and bypass the glial scar. One major issue in axonal regrowth consists of the different genetic programs, which characterize axonal development and maturation. Here, we will review the main hurdles that in adulthood limit axonal regeneration after SCI, describing the key genes, transcription factors, and miRNAs involved in these processes (seen their reciprocal influencing action), with particular attention to corticospinal motor neurons located in the sensory-motor cortex and subjected to axotomy in case of SCI. We will highlight the functional complexity of the neural regeneration programs. We will also discuss if specific axon growth programs, that undergo a physiological downregulation during CNS development, could be reactivated after a spinal cord trauma to sustain regrowth, representing a new potential therapeutic approach.

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.

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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Remote white matter and cortex reorganization may contribute to functional reorganization and clinical outcome after acute infarcts. To determine the microstructural changes in the remote intact corticospinal tract (CST) and precentral gyrus cortex connected to the acute infarct after subcortical stroke involving the CST over 6 months.Methods: Twenty-two patients with subcortical stroke involving the CST underwent magnetic resonance imaging (MRI) and clinical assessment in the acute phase (baseline) and 6 months (follow–up) after the stroke. The MRI sequences included T1-weighted imaging, T2–weighted imaging, fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), and diffusion kurtosis imaging. Fractional anisotropy (FA) and track–density imaging (TDI) values were generated using DTI data for the centrum semiovale, corona radiata, posterior limb of internal capsule, and cerebral peduncle. The mean kurtosis (MK) value of the precentral gyrus cortex was calculated. Changes in the FA, TDI, and MK values between the baseline and follow-up and the relationship between these changes were analyzed.Results: The TDI and FA values of all parts of the ipsilesional (IL) CST, including the noninvolved upper and lower parts, decreased at the 6-month follow-up (P < 0.001). The MK values of the stroke lesion (P < 0.001) and IL precentral gyrus cortex (P = 0.002) were lower at follow-up than at the baseline. The ΔTDI (r = 0.689, P < 0.001) and Δ FA values (r = 0.463, P = 0.03) of the noninvolved upper part of the IL CST were positively correlated with the ΔMK value of the IL precentral gyrus cortex.Conclusion: Secondary degeneration occurred in the remote part of the CST and the remote IL precentral gyrus cortex after subcortical stroke involving the CST. The secondary degeneration in the upper part of the CST was correlated with that in the IL precentral gyrus cortex.

Stroke is a leading cause of disability worldwide. Motor impairments occur in most of the patients with stroke in the acute phase and contribute substantially to disability. Diffusion tensor imaging (DTI) biomarkers such as fractional anisotropy (FA) measured at an early phase after stroke have emerged as potential predictors of motor recovery. In this narrative review, we: (1) review key concepts of diffusion MRI (dMRI); (2) present an overview of state-of-art methodological aspects of data collection, analysis and reporting; and (3) critically review challenges of DTI in stroke as well as results of studies that investigated the correlation between DTI metrics within the corticospinal tract and motor outcomes at different stages after stroke. We reviewed studies published between January, 2008 and December, 2018, that reported correlations between DTI metrics collected within the first 24 h (hyperacute), 2–7 days (acute), and >7–90 days (early subacute) after stroke. Nineteen studies were included. Our review shows that there is no consensus about gold standards for DTI data collection or processing. We found great methodological differences across studies that evaluated DTI metrics within the corticospinal tract. Despite heterogeneity in stroke lesions and analysis approaches, the majority of studies reported significant correlations between DTI biomarkers and motor impairments. It remains to be determined whether DTI results could enhance the predictive value of motor disability models based on clinical and neurophysiological variables.

Background and Purpose: Remote white matter and cortex reorganization may contribute to functional reorganization and clinical outcome after acute infarcts. To determine the microstructural changes in the remote intact corticospinal tract (CST) and precentral gyrus cortex connected to the acute infarct after subcortical stroke involving the CST over 6 months. Methods: Twenty-two patients with subcortical stroke involving the CST underwent magnetic resonance imaging (MRI) and clinical assessment in the acute phase (baseline) and 6 months (follow–up) after the stroke. The MRI sequences included T1-weighted imaging, T2–weighted imaging, fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), and diffusion kurtosis imaging. Fractional anisotropy (FA) and track–density imaging (TDI) values were generated using DTI data for the centrum semiovale, corona radiata, posterior limb of internal capsule, and cerebral peduncle. The mean kurtosis (MK) value of the precentral gyrus cortex was calculated. Changes in the FA, TDI, and MK values between the baseline and follow-up and the relationship between these changes were analyzed. Results: The TDI and FA values of all parts of the ipsilesional (IL) CST, including the noninvolved upper and lower parts, decreased at the 6-month follow-up (P < 0.001). The MK values of the stroke lesion (P < 0.001) and IL precentral gyrus cortex (P = 0.002) were lower at follow-up than at the baseline. The ΔTDI (r = 0.689, P < 0.001) and Δ FA values (r = 0.463, P = 0.03) of the noninvolved upper part of the IL CST were positively correlated with the ΔMK value of the IL precentral gyrus cortex. Conclusion: Secondary degeneration occurred in the remote part of the CST and the remote IL precentral gyrus cortex after subcortical stroke involving the CST. The secondary degeneration in the upper part of the CST was correlated with that in the IL precentral gyrus cortex. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of disability worldwide. Motor impairments occur in most of the patients with stroke in the acute phase and contribute substantially to disability. Diffusion tensor imaging (DTI) biomarkers such as fractional anisotropy (FA) measured at an early phase after stroke have emerged as potential predictors of motor recovery. In this narrative review, we: (1) review key concepts of diffusion MRI (dMRI); (2) present an overview of state-of-art methodological aspects of data collection, analysis and reporting; and (3) critically review challenges of DTI in stroke as well as results of studies that investigated the correlation between DTI metrics within the corticospinal tract and motor outcomes at different stages after stroke. We reviewed studies published between January, 2008 and December, 2018, that reported correlations between DTI metrics collected within the first 24 h (hyperacute), 2–7 days (acute), and >7–90 days (early subacute) after stroke. Nineteen studies were included. Our review shows that there is no consensus about gold standards for DTI data collection or processing. We found great methodological differences across studies that evaluated DTI metrics within the corticospinal tract. Despite heterogeneity in stroke lesions and analysis approaches, the majority of studies reported significant correlations between DTI biomarkers and motor impairments. It remains to be determined whether DTI results could enhance the predictive value of motor disability models based on clinical and neurophysiological variables. [ABSTRACT FROM AUTHOR]

Abstract Recovery from injury to the central nervous system (CNS) is limited in the mammalian adult. Nonetheless, some degree of spontaneous recovery occurs after partial CNS injury. Compensatory axonal growth from uninjured neurons, termed sprouting, contributes to this naturally occurring recovery process and can be modulated by molecular intervention. Extensive studies have depicted a long-held hypothesis that oligodendrocyte-derived Nogo restricts axonal sprouting and functional recovery after CNS injury. However, cell type-specific function of Nogo in compensatory sprouting, spinal axon repair or functional recovery after CNS injury has not been reported. Here we present data showing that inducible, cell type-specific deletion of Nogo from oligodendrocytes led to a ~50% increase in the compensatory sprouting of corticospinal tract (CST) axons in the cervical spinal cord after unilateral pyramidotomy in mice. In contrast to a previously proposed growth-promoting role of neuronal Nogo in the optic nerve, deleting neuronal Nogo did not significantly affect CST axon sprouting in the spinal cord. Sprouting axons were associated with the expression of synaptic marker VGLUT1 in both the oligodendrocytic Nogo deletion and control mice. However, we did not detect any functional improvement in fine motor control associated with the increased sprouting in oligodendrocytic Nogo deletion mice. These data show for the first time with genetic evidence that Nogo specifically expressed by oligodendrocytes restricts compensatory sprouting after CNS injury, supporting a longstanding but heretofore untested hypothesis. While implicating a focus on sprouting as a repair mechanism in the translational potential of targeting the myelin inhibitory pathway, our study illustrates the challenge to harness enhanced structural plasticity for functional improvement. Highlights • Inducible cell type-specific gene deletion validates growth inhibitory role of Nogo. • Oligodendrocytic Nogo inhibits corticospinal axon sprouting after CNS injury. • Neuronal Nogo does not have a growth-promoting role in corticospinal axon sprouting. • Functional recovery remains a challenge even with enhanced structural plasticity. [ABSTRACT FROM AUTHOR]

Accurate digital representation of major white matter bundles in the brain is an important goal in neuroscience image computing since the representations can be used for surgical planning, intra-patient longitudinal analysis and inter-subject population connectivity studies. Reconstructing desired fiber bundles generally involves manual selection of regions of interest by an expert, which is subject to user bias and fatigue, hence an automation is desirable. To that end, we first present a novel anatomical representation based on Neighborhood Resolved Fiber Orientation Distributions (NRFOD) along the fibers. The resolved fiber orientations are obtained by generalized q-sampling imaging (GQI) and a subsequent diffusion decomposition method. A fiber-to-fiber distance measure between the proposed fiber representations is then used in a density-based clustering framework to select the clusters corresponding to the major pathways of interest. In addition, neuroanatomical priors are utilized to constrain the set of candidate fibers before density-based clustering. The proposed fiber clustering approach is exemplified on automation of the reconstruction of the major fiber pathways in the brainstem: corticospinal tract (CST); medial lemniscus (ML); middle cerebellar peduncle (MCP); inferior cerebellar peduncle (ICP); superior cerebellar peduncle (SCP). Experimental results on Human Connectome Project (HCP)’s publicly available “WU-Minn 500 Subjects + MEG2 dataset” and expert evaluations demonstrate the potential of the proposed fiber clustering method in brainstem white matter structure analysis. [ABSTRACT FROM AUTHOR]

Objective To compare the results of magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients. Methods Nineteen ALS patients and thirteen age-matched healthy controls underwent MRS and DTI between October 2013 and July 2014. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were collected as the quantitative results of the imaging study. The ALS functional rating scale-revised (ALSFRS-R) and disease progression rate were evaluated to assess patients' disability. The imaging study results were compared between ALS patients and healthy controls. The relationship between disability assessment and imaging study results was analyzed. Results NAA/Cr in the motor cortex and FA in the corticospinal tract (CST) of both sides were significantly lower in patients than controls. There was no significant difference between the two groups in Cho/Cr, tract length, tract volume, ADC or NAA. No relationship was found between ALSFRS-R and FA (r = 0.243, p = 0.316) in the right CST; NAA (r = 0.095, p = 0.699) or NAA/Cr (r = 0.172, p = 0.481) in the left motor cortex; or NAA (r = 0.320, p = 0.182) or NAA/Cr (r = 0.193, p = 0.492) in the right motor cortex. There was no relationship between the disease progression rate and FA, NAA, or NAA/Cr on either side. Conclusion NAA/Cr and FA can help diagnose ALS. Regional brain NAA/Cr and FA values could not assess the ALSFRS-R or disease progression rate. [ABSTRACT FROM AUTHOR]

Highlights: [•] NT-3 induces sprouting from injured CST axons far rostral from a spinal injury. [•] NT-3 promotes growth from injured CST axons only when expressed close to axons. [•] LPS administration does not boost sprouting from injured CST. [ABSTRACT FROM AUTHOR]

Highlights: [•] Zebrafish offer an excellent alternative vertebrate model for studying motor neuron diseases. [•] It is suitable for exploring the functional effects of human mutations and environmental factors. [•] It represents a good predictive model for identifying chemical suppressors of human diseases. [Copyright &y& Elsevier]

Abstract: Spinal cord injury (SCI) is a devastating neurological disorder that affects thousands of individuals each year. Over the past decades an enormous progress has been made in our understanding of the molecular and cellular events generated by SCI, providing insights into crucial mechanisms that contribute to tissue damage and regenerative failure of injured neurons. Current treatment options for SCI include the use of high dose methylprednisolone, surgical interventions to stabilize and decompress the spinal cord, and rehabilitative care. Nonetheless, SCI is still a harmful condition for which there is yet no cure. Cellular, molecular, rehabilitative training and combinatorial therapies have shown promising results in animal models. Nevertheless, work remains to be done to ascertain whether any of these therapies can safely improve patient's condition after human SCI. This review provides an extensive overview of SCI research, as well as its clinical component. It starts covering areas from physiology and anatomy of the spinal cord, neuropathology of the SCI, current clinical options, neuronal plasticity after SCI, animal models and techniques to assess recovery, focusing the subsequent discussion on a variety of promising neuroprotective, cell-based and combinatorial therapeutic approaches that have recently moved, or are close, to clinical testing. [Copyright &y& Elsevier]

Highlights: [•] The first characterization of axonal pathology in a rat static compression spinal injury. [•] Loss of axonal proteins at the lesion epicenter occurs within 1day of injury. [•] At 6weeks, myelination by oligodendrocytes and Schwann cells follows early myelin loss. [•] The injury spreads both rostral and caudal to the epicenter. [Copyright &y& Elsevier]

Abstract: Cyclic AMP (cAMP) signalling pathways are involved in axonal growth and regeneration. The calcium–calmodulin- stimulated adenylate cyclase 1 (AC1), a regulator of cAMP levels, is strongly expressed in the corticospinal motor neurons (CSMN) in cerebral cortex layer V during development, but its role in the development of the corticospinal tract (CST) is unknown. Here, we analyse the organization of the CST pathway using anterograde and retrograde tracers in the barrelless (brl) mouse that carries an inactivating mutation of the AC1 gene. We show that in brl mice the general organization of the CST is normal but there is an increase in the number of axons in the ipsilateral contingent in the dorsal and ventral medial funiculi of the cervical spinal cord. The density of CSMN in layer V of the motor cortex is increased in brl compared to wild-type mice. Thus, lack of AC1 likely perturbs late phases of CSMN and CST development. Next, we examine the motor recovery after a spinal cord injury (SCI). We find that brl mice show enhanced locomotor functions as assessed by the BMS (Basso mouse scale) as early as 6h and up to 6 weeks after SCI, indicating a smaller responsiveness of brl mice to SCI. It is therefore possible that developmental effects on motor systems might decrease the locomotor effects consecutive to a SCI. This point is particularly important with regards to the use of transgenic animals for testing SCI recovery. [Copyright &y& Elsevier]

Highlights: [•] DTI was collected for 34 male adolescents, ages 15–17. [•] Aerobic fitness related to white matter connectivity in frontal and motor tracts. [•] HF had higher tractography streamline counts in CST and Fminor compared to LF. [•] A negative relationship was seen between VO2 peak and FA in the L CST. [•] Exercise is an important environmental factor to consider during neurodevelopment. [Copyright &y& Elsevier]

Highlights: [•] Forebrain axonal connections are highly specified by fate determinants. [•] Their pathfinding is controlled by stereotyped guidance mechanisms. [•] Guidance cue interactions are becoming relevant for topographical tracts. [•] Reprogramming forebrain connectivity is possible by master gene manipulations. [Copyright &y& Elsevier]

Highlights: [•] We provide a genetic mouse model with an isolated cortex to study the spinal cord. [•] Mice with an isolated cortex maintain basic motor function but are hyperactive. [•] No cortex input results in abnormalities of spinal motor neurons, muscles and NMJs. [•] Mutants have increased dopaminergic and serotoninergic spinal projections. [ABSTRACT FROM AUTHOR]

Highlights: [•] An interesting phenomenon related to the prevention of additional errors is post-error slowing. [•] Motor system acts as a final stream of action monitoring processes. [•] TMS tracks the excitability of the post-error ipsilateral motor system. [•] A reduction of corticospinal excitability in the ipsi-stimulated hemisphere is observed after erroneous responses. [•] Corticospinal system might decrease the excitatory input to prevent further slips. [ABSTRACT FROM AUTHOR]

Highlights: [•] New online system to evaluate tractography pipelines. [•] New connectivity-based quantitative measures (valid and invalid bundles/connections and average bundle coverage). [•] More than 57,000 different combinations of tractography pipelines compared from the FiberCup dataset. [•] Take-home messages for tractography users and insights on remaining open questions for the community. [Copyright &y& Elsevier]

Abstract: The extracellular matrix glycoprotein tenascin-C has been implicated in wound repair and axonal growth. Its role in mammalian spinal cord injury is largely unknown. In vitro it can be both neurite-outgrowth promoting and repellent. To assess its effects on glial reactions, extracellular matrix formation, and axonal regrowth/sprouting in vivo, 20 tenascin-C-deficient and 20 wild type control mice underwent lumbar spinal cord hemisection. One, three, seven and fourteen days post-surgery, cryostat sections of the spinal cord were examined by conventional histology and by immunohistochemistry using antibodies against F4/80 (microglia/macrophage), GFAP (astroglia), neurofilament, fibronectin, laminin and collagen type IV. Fibronectin immunoreactivity was significantly down-regulated in tenascin-C-deficient mice. Moreover, fourteen days after injury, immunodensity of neurofilament-positive fibers was two orders of magnitude higher along the incision edges of tenascin-C-deficient mice as compared to control mice. In addition, lymphocyte infiltration was seen two days earlier in tenascin-C-deficient mice than in control mice and neutrophil infiltration was increased seven days after injury. The increase in thin neurofilament positive fibers in tenascin-C-deficient mice indicates that lack of tenascin-C alters the inflammatory reaction and extracellular matrix composition in a way that penetration of axonal fibers into spinal cord scar tissue may be facilitated. [Copyright &y& Elsevier]

Abstract: Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35–55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies. [Copyright &y& Elsevier]

Abstract: Modeling spinal cord injury (SCI) in animals is challenging because an appropriate combination of lesion location, lesion severity and behavioral testing is essential to analyze recovery of motor function. For particular tests such as single pellet reaching, the contribution of individual descending tracts to recovery has been investigated using specific tract ablation or graded lesions. However, it has not been established whether single pellet reaching is sufficiently sensitive for assessing the efficacy of treatments for cervical SCI (e.g., one of the currently most successful treatment approaches: rehabilitative training). To address this issue, we trained adult rats in single pellet reaching before and after a cervical (C4) spinal lesion. Animals with lesions of increasing severity were grouped into categories based on damage to anatomical structures such as the corticospinal tract (CST) and the rubrospinal tract (RST), two descending motor tracts that have been implicated in fine motor control of the forelimb. We related lesion extent to spontaneous recovery and plasticity-promoting post injury training and found that reaching performance was not correlated with lesion size or the extent of CST or RST injury. Interestingly, the dorsolateral quadrant (DLQ) lesion category, in which the unilateral dorsal CST and most of the unilateral RST are lesioned, was the only category that showed a clear effect of plasticity-promoting treatment (i.e., training), indicating its usefulness as a lesion model for this testing paradigm. The DLQ lesion likely strikes a balance between tissue sparing and functional impairment and is, therefore, best suited to maximize the potential to observe treatment effects of plasticity-promoting treatments using single pellet reaching. Because of the specific lesion size that is necessary to observe treatment effects, the single pellet skilled reaching task can be considered a stringent behavioral test and therefore may be useful for predicting translational success of potential treatments. However, due to the variability in the success rate, the labor-intensive nature, and the limited usefulness to test functional outcome of a wide range of lesion severities, we are hesitant to continue to use single pellet reaching to assess the effectiveness of currently available treatments for cervical SCI. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Highlights: [•] Conditional deletion of ephrin B2 resulted in decreased gliosis over controls. [•] Ephrin B2 on astrocytes was inhibitory to neurite outgrowth in an in-vitro assay. [•] Ephrin B2 knockout mice exhibited improved regeneration of injured corticospinal tract axons. [•] Ephrin B2 deletion resulted in improved functional recovery over wild-type controls. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Early evaluation of the pyramidal tract is a prerequisite in patients with ischemic stroke in order to decide the optimal treatment or to assess appropriate rehabilitation. The aim of this study was to predict motor outcome using quantitative and qualitative diffusion tensor parameters and their correlations with severity of stroke as defined by the National Institutes of Health Stroke Scale (NIHSS). Materials and methods: Twenty-one patients presenting with ischemic stroke were studied with DTI. All patients had diffusion measurements such as FA values of the affected and unaffected regions and the FA ratio between them. Color FA maps of the pyramidal tract were constructed and the degree of infarctions was classified into groups according to the involvements of the pyramidal tracts. The motor performance of the upper and lower extremities was assessed using the NIHSS on the day of patients’ admission and discharge. The motor outcomes were correlated with the FA values of the pyramidal tract. Results: The FA values of the affected pyramidal tracts were significantly lower as compared with the unaffected side (p-value <0.01). The reduction in the FA values of the affected side was significantly correlated (r =0.41 and p-value <0.001) with the degree of pyramidal tract involvements that were significantly correlated with the motor outcome on patients’ discharge day. Conclusions: Quantitative (FA values) and qualitative (the diffusion tensor tractography) diffusion parameters have potential to predict motor outcome in patients with ischemic stroke. [Copyright &y& Elsevier]

Background. Recent studies have shown that focal injuries can have remote effects on network function that affect behavior, but these network-wide repercussions are poorly understood. Objective. This study tested the hypothesis that lesions specifically to the outflow tract of a distributed network can result in upstream dysfunction in structurally intact portions of the network. In the somatomotor system, this upstream dysfunction hypothesis predicted that lesions of the corticospinal tract might be associated with functional disruption within the system. Motor impairment might then reflect the dual contribution of corticospinal damage and altered network functional connectivity. Methods. A total of 23 subacute stroke patients and 13 healthy controls participated in the study. Corticospinal tract damage was quantified using a template of the tract generated from diffusion tensor imaging in healthy controls. Somatomotor network functional integrity was determined by resting state functional connectivity magnetic resonance imaging. Results. The extent of corticospinal damage was negatively correlated with interhemispheric resting functional connectivity, in particular with connectivity between the left and right central sulcus. Although corticospinal damage accounted for much of the variance in motor performance, the behavioral impact of resting connectivity was greater in subjects with mild or moderate corticospinal damage and less in those with severe corticospinal damage. Conclusions. Our results demonstrated that dysfunction of cortical functional connectivity can occur after interruption of corticospinal outflow tracts and can contribute to impaired motor performance. Recognition of these secondary effects from a focal lesion is essential for understanding brain–behavior relationships after injury, and they may have important implications for neurorehabilitation. [ABSTRACT FROM PUBLISHER]

The anatomy of the brain is extremely complex, and certain, even large structures, such as the corticospinal tract (CST), remain poorly understood. Diffusion tractography provides an opportunity to explore the white matter tracts in a fundamentally new way. In the current paper, we show how this technique has already added to our understanding of the anatomy of the CST. We also explore the future projects involving diffusion tractography of the motor white matter tracts that will advance this method and further our understanding of brain anatomy. [ABSTRACT FROM AUTHOR]

Abstract: We have developed a pyramidotomy model in mice to lesion the corticospinal tract at the level of the brainstem pyramidal tract, and evaluated the resultant impairments in motor function in a series of behavioural tests. Adult C57BL/6 mice received a unilateral pyramidotomy and a control group of mice underwent sham surgery. We studied the effects of this lesion on forepaw function using five behavioural paradigms, some of which have been widely used in rat studies but have not been fully explored in mice. The tests used were: a rearing test, which assesses forepaw use for weight support during spontaneous vertical exploration of a cylinder; a grid walking test, which assesses the ability to accurately place the forepaws during exploration of an elevated grid; a tape-removal test, which measures both sensory and motor function of the forepaw; a CatWalk automated gait analysis, which provides a number of quantitative measures including stride length and stride width during locomotion; and a staircase reaching task, which assesses skilled independent forepaw use. All tests revealed lesion effects on forepaw function with the tape removal, grid walking, rearing and CatWalk tests demonstrating robust effects throughout the testing period. The development of a pyramidotomy lesion model in mice, together with behavioural tests which can reliably measure functional impairments, will provide a valuable tool for assessing therapeutic strategies to promote regeneration and plasticity. [Copyright &y& Elsevier]

Abstract: The corticospinal tract is widely used to study regeneration and is essential for voluntary movements in humans. In young rats, corticospinal axons on the uninjured side sprout and grow into the denervated side. Neurotrophin-3 (NT-3) induces such crossed collateral sprouting in adults. We investigated whether local intraspinal NT-3 infusions would promote collateral sprouting of spared corticospinal terminals from within a partially denervated side, as this would be more appropriate for enhancing function of unilateral and specific movements. Adult rats received a partial bilateral transection of the pyramids, leaving approximately 40% of each tract intact. Vehicle or vehicle plus NT-3 (3 or 10 μg/day) was infused for 14 days into the left side of the cervical (C5/6) or lumbar (L2) cord. The corticospinal processes on the left side were anterogradely traced with cholera toxin B (CTB; which labeled gray matter processes more robustly than biotinylated dextran amine) injected into the front or hind limb area of the right sensorimotor cortex, respectively, 3 days before analysis. Unexpectedly, approximately 40% fewer CTB-labeled corticospinal processes were detectable in the cervical or lumbar gray matter of NT-3-treated rats than in vehicle-infused ones. Vehicle-infused injured rats had more corticospinal processes in the center of the cord than normal rats, evidence for lesion-induced collateral sprouting. NT-3 caused sprouting of local calcitonin gene-related peptide-positive fibers. These results suggest that NT-3 reduces collateral sprouting of spared corticospinal axons from within the denervated regions, possibly because of the injury environment or by increasing sprouting of local afferents. They identify an unexpected context-dependent outgrowth inhibitory effect of NT-3. [Copyright &y& Elsevier]

p21Cip1/WAF1, known as a cell-cycle inhibitory protein, facilitates neurite outgrowth from neurons when present in the cytoplasm. The molecular mechanism of this action is that p21Cip1/WAF1 forms a complex with Rho-kinase and inhibits its activity. As myelin-derived inhibitors of axonal outgrowth act on neurons by activating Rho, that is responsible for the lack of spontaneous regeneration of the injured central nervous system (CNS), Rho-kinase may be a good molecular target against injuries in the CNS. In this study, we delivered TAT-fusion protein of cytoplasmic p21Cip1/WAF1 locally after dorsal hemisection of the thoracic spinal cord in rats. The treatment significantly stimulated axonal regeneration and recovery of hindlimb function, and inhibited the cavity formation in the spinal cord after the injury. Cytoplasmic p21Cip1/WAF1 may provide a potential therapeutic agent that produces functional regeneration following CNS injuries. [Copyright &y& Elsevier]