BACKGROUND: Restoration of limb function for individuals with unilateral weakness typically requires volitional muscle control, which is often not present for individuals with severe impairment. Mirror therapy-interventions using a mirror box to reflect the less-impaired limb onto the more-impaired limb-can facilitate corticospinal excitability, leading to enhanced recovery in severely impaired clinical populations. However, the mirror box applies limitations on mirror therapy, namely that all movements appear bilateral and are confined to a small area, impeding integration of complex activities and multisensory feedback (e.g., visuo-tactile stimulation). These limitations can be addressed with virtual reality, but the resulting effect on corticospinal excitability is unclear.
OBJECTIVE: Examine how virtual reality-based unilateral mirroring, complex activities during mirroring, and visuo-tactile stimulation prior to mirroring affect corticospinal excitability.
METHODS: Participants with no known neurological conditions (n = 17) donned a virtual reality system (NeuRRoVR) that displayed a first-person perspective of a virtual avatar that matched their motions. Transcranial magnetic stimulation-induced motor evoked potentials in the nondominant hand muscles were used to evaluate corticospinal excitability in four conditions: resting, mirroring, mirroring with prior visuo-tactile stimulation (mirroring + TACT), and control. During mirroring, the movements of each participant\'s dominant limb were reflected onto the nondominant limb of the virtual avatar, and the avatar\'s dominant limb was kept immobile (i.e., unilateral mirroring). The mirroring + TACT condition was the same as the mirroring condition, except that mirroring was preceded by visuo-tactile stimulation of the nondominant limb. During the control condition, unilateral mirroring was disabled. During all conditions, participants performed simple (flex/extend fingers) and complex (stack virtual blocks) activities.
RESULTS: We found that unilateral mirroring increased corticospinal excitability compared to no mirroring (p < 0.001), complex activities increased excitability compared to simple activities during mirroring (p < 0.001), and visuo-tactile stimulation prior to mirroring decreased excitability (p = 0.032). We also found that these features did not interact with each other.
CONCLUSIONS: The findings of this study shed light onto the neurological mechanisms of mirror therapy and demonstrate the unique ways in which virtual reality can augment mirror therapy. The findings have important implications for rehabilitation for design of virtual reality systems for clinical populations.

D-waves (also called direct waves) result from the direct activation of fast-conducting, thickly myelinated corticospinal tract (CST) fibres after a single electrical stimulus. During intraoperative neurophysiological monitoring, D-waves are used to assess the long-term motor outcomes of patients undergoing surgery for intramedullary spinal cord tumours, selected cases of intradural extramedullary tumours and surgery for syringomyelia. In the present manuscript, we discuss D-wave monitoring and its role as a tool for monitoring the CST during spinal cord surgery. We describe the neurophysiological background and provide some recommendations for recording and stimulation, as well as possible future perspectives. Further, we introduce the concept of anti D-wave and present an illustrative case with successful recordings.

Whether and how the non-lesional sensorimotor cortex is activated and contributes to post-injury motor recovery is controversial. Here, we investigated the role of interhemispheric pathway from the contralesional to ipsilesional premotor cortex in activating the ipsilesional sensorimotor cortex and promoting recovery after lesioning the lateral corticospinal tract at the cervical cord, by unidirectional chemogenetic blockade in macaques. The blockade impaired dexterous hand movements during the early recovery stage. Electrocorticographical recording showed that the low frequency band activity of the ipsilesional premotor cortex around movement onset was decreased by the blockade during the early recovery stage, while it was increased by blockade during the intact state and late recovery stage. These results demonstrate that action of the interhemispheric pathway changed from inhibition to facilitation, to involve the ipsilesional sensorimotor cortex in hand movements during the early recovery stage. The present study offers insights into the stage-dependent role of the interhemispheric pathway and a therapeutic target in the early recovery stage after lesioning of the corticospinal tract.

OBJECTIVE: Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT).
METHODS: In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location.
RESULTS: Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71).
CONCLUSIONS: DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.

Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.

The purpose of this study was to investigate the effects of sex, muscle thickness, and subcutaneous fat thickness (SFT) on corticospinal excitability outcome measures of the biceps brachii. Eighteen participants (10 males and 8 females) completed this study. Ultrasound was used to assess biceps brachii muscle thickness and the overlying SFT. Transcranial magnetic stimulation (TMS) was used to determine corticospinal excitability by inducing motor-evoked potentials (MEPs) at eight different TMS intensities from 90% to 160% of active motor threshold (AMT) from the biceps brachii during an isometric contraction of the elbow flexors at 10% of maximum voluntary contraction (MVC). Biceps brachii maximal compound muscle action potential (Mmax) was also recorded prior to and after TMS. Males had higher (p < 0.001) biceps brachii muscle thickness and lower SFT, produced higher levels of MVC force and had, on average, higher (p < 0.001) MEP amplitudes at lower (p < 0.05) percentages of maximal stimulator output than females during the 10% elbow flexion MVC. Multiple linear regression modeling revealed that sex was not associated with any of the neurophysiological parameters examined, while SFT showed a positive association with the stimulation intensity required at AMT (p = 0.035) and a negative association with biceps brachii pre-stimulus electromyography (EMG) activity (p = 0.021). Additionally, there was a small positive association between muscle thickness and biceps brachii pre-stimulus EMG activity (p = 0.049). Overall, this study suggests that some measures of corticospinal excitability may be different between the sexes and influenced by SFT and muscle thickness.

BACKGROUND: Non-invasive brain mapping using navigated transcranial magnetic stimulation (nTMS) is a valuable tool prior to resection of malignant brain tumors. With nTMS motor mapping, it is additionally possible to analyze the function of the motor system and to evaluate tumor-induced neuroplasticity. Distinct changes in motor cortex excitability induced by certain malignant brain tumors are a focal point of research.
METHODS: A retrospective single-center study was conducted involving patients with malignant brain tumors. Clinical data, resting motor threshold (rMT), and nTMS-based tractography were evaluated. The interhemispheric rMT-ratio (rMTTumor/rMTControl) was calculated for each extremity and considered pathological if it was >110% or <90%. Distances between the corticospinal tract and the tumor (lesion-to-tract-distance - LTD) were measured.
RESULTS: 49 patients were evaluated. 16 patients (32.7%) had a preoperative motor deficit. The cohort comprised 22 glioblastomas (44.9%), 5 gliomas of Classification of Tumors of the Central Nervous System (CNS WHO) grade 3 (10.2%), 6 gliomas of CNS WHO grade 2 (12.2%) and 16 cerebral metastases (32.7%). 26 (53.1%) had a pathological rMT-ratio for the upper extremity and 35 (71.4%) for the lower extremity. All patients with tumor-induced motor deficits had pathological interhemispheric rMT-ratios, and presence of tumor-induced motor deficits was associated with infiltration of the tumor to the nTMS-positive cortex (p = 0.04) and shorter LTDs (all p < 0.021). Pathological interhemispheric rMT-ratio for the upper extremity was associated with cerebral metastases, but not with gliomas (p = 0.002).
CONCLUSIONS: Our study underlines the diagnostic potential of nTMS motor mapping to go beyond surgical risk stratification. Pathological alterations in motor cortex excitability can be measured with nTMS mapping. Pathological cortical excitability was more frequent in cerebral metastases than in gliomas.

BACKGROUND: Upper limb motor impairment commonly occurs after stroke, impairing quality of life. Brain network reorganization likely differs between subgroups with differing impairment severity. This study explored differences in functional connectivity (FC) and corticospinal tract (CST) integrity between patients with mild/moderate versus severe hemiplegia poststroke to clarify the neural correlates underlying motor deficits.
METHODS: Sixty chronic stroke patients with upper limb motor impairment were categorized into mild/moderate and severe groups based on Fugl-Meyer scores. Resting-state FC was assessed using functional near-infrared spectroscopy (fNIRS) to compare connectivity patterns between groups across motor regions. CST integrity was evaluated by inducing motor evoked potentials (MEP) via transcranial magnetic stimulation.
RESULTS: Compared to the mild/moderate group, the severe group exhibited heightened premotor cortex-primary motor cortex (PMC-M1) connectivity (t = 4.56, p < 0.01). Absence of MEP was also more frequent in the severe group (χ2 = 12.31, p = 0.01). Bayesian models effectively distinguished subgroups and identified the PMC-M1 connection as highly contributory (accuracy = 91.30%, area under the receiver operating characteristic curve [AUC] = 0.86).
CONCLUSIONS: Distinct patterns of connectivity and corticospinal integrity exist between stroke subgroups with differing impairments. Strengthened connectivity potentially indicates recruitment of additional motor resources to compensate for damage. These findings elucidate the neural correlates underlying motor deficits poststroke and could guide personalized, network-based therapies targeting predictive biomarkers to improve rehabilitation outcomes.

Studies suggest that amyotrophic lateral sclerosis (ALS) compromises the integrity of white matter fiber tracts, primarily affecting motor fibers. However, it remains uncertain whether the integrity of these fibers influences the risk of ALS. We performed bidirectional two-sample Mendelian randomization (MR) and multivariable MR analyses to evaluate the associative relationships between the integrity of fiber tracts [including the corticospinal tract (CST) and corpus callosum (CC)] and the risk of ALS. Genetic instrumental variables for specific fiber tracts were obtained from published genome-wide association studies (GWASs), including 33,292 European individuals from five diffusion magnetic resonance imaging (dMRI) datasets. Summary-level GWAS data for ALS were derived from 27,205 ALS patients and 110,881 controls. The MR results suggested that an increase in the first principal component (PC1) of fractional anisotropy (FA) in the genu of the CC (GCC) was correlated with an increased risk of ALS (PFDR = 0.001, odds ratio = 1.363, 95% confidence interval 1.178-1.577). Although other neuroimaging phenotypes [mean diffusivity in the CST, radial diffusivity (RD) in the CST, FA in the GCC, PC1 in the body of the CC (BCC), PC1 in the CST, and RD in the GCC] did not pass correction, they were also considered to have suggestive associations with the risk of ALS. No evidence revealed that ALS caused changes in the integrity of fiber tracts. In summary, the results of this study provide genetic support for the potential association between the integrity of specific fiber tracts and the risk of ALS. Greater fiber integrity in the GCC and BCC may be a risk factor for ALS, while greater fiber integrity in the CST may have a protective effect on ALS. This study provides insights into ALS development.

OBJECTIVE: The aim of this study was to investigate the relationship between sleep stages and neural microstructure - measured using diffusion tensor imaging - of the posterior limb of the internal capsule and corticospinal tract in preterm infants.
METHODS: A retrospective cohort of 50 preterm infants born between 24 + 4 and 29 + 3 weeks gestational age was included in the study. Sleep stages were continuously measured for 5-7 consecutive days between 29 + 0 and 31 + 6 weeks postmenstrual age using an in-house-developed, and recently published, automated sleep staging algorithm based on routinely measured heart rate and respiratory rate. Additionally, a diffusion tensor imaging scan was conducted at term equivalent age as part of standard care. Region of interest analysis of the posterior limb of the internal capsule was performed, and tractography was used to analyze the corticospinal tract. The association between sleep and white matter microstructure of the posterior limb of the internal capsule and corticospinal tract was examined using a multiple linear regression model, adjusted for potential confounders.
RESULTS: The results of the analyses revealed an interaction effect between sleep stage and days of invasive ventilation on the fractional anisotropy of the left and right posterior limb of the internal capsule (β = 0.04, FDR-adjusted p = 0.001 and β = 0.04, FDR-adjusted p = 0.02, respectively). Furthermore, an interaction effect between sleep stage and days of invasive ventilation was observed for the radial diffusivity of the mean of the left and right PLIC (β = -4.1e-05, FDR-adjusted p = 0.04).
CONCLUSIONS: Previous research has shown that, in very preterm infants, invasive ventilation has a negative effect on white matter tract maturation throughout the brain. A positive association between active sleep and white matter microstructure of the posterior limb of the internal capsule, may indicate a protective role of sleep in this vulnerable population.