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Early childhood is an important period for cognitive and brain development, though white matter changes specific to this period remain understudied. Here we utilize a novel analytic approach to quantify and track developmental changes in white matter micro- and macro-structure, calculated from individually oriented fiber-bundle populations, termed “fixels”. Fixel-based analysis and mixed-effects models were used to assess tract-wise changes in fiber density and bundle morphology in 73 girls scanned at baseline (ages 4.09–7.02, mean ​= ​5.47, SD ​= ​0.81), 6-month (N ​= ​7), and one-year follow-up (N ​= ​42). For comparison, we also assessed changes in commonly utilized diffusion tensor metrics: fractional anisotropy (FA), and mean, radial and axial diffusivity (MD, RD, AD). Maturational increases in fixel-metrics were seen in most major white matter tracts, with the most rapid increases in the corticospinal tract and slowest or non-significant increases in the genu of the corpus callosum and uncinate fasciculi. As expected, we observed developmental increases in FA and decreases in MD, RD and AD, though percent changes were smaller relative to fixel-metrics. The majority of tracts showed more substantial morphological than microstructural changes. These findings highlight early childhood as a period of dynamic white matter maturation, characterized by large increases in macroscopic fiber bundle size, mild changes in axonal density, and parallel, albeit less substantial, changes in diffusion tensor metrics. •White matter fiber density and bundle size increase with age in early childhood.•Increases in fiber density and bundle size occur in most major white matter tracts.•Rate of change is fastest in the corticospinal tract and slowest in frontal tracts.•Increases in fiber bundle size are more substantial than increases in fiber density.•These changes are more substantial than changes in diffusion tensor metrics.

•M1 showed age-related atrophy, hemodynamic decline, and iron/myelin alterations.•CST showed localized age-related microstructural degeneration near the M1.•CStrT exhibited more widespread age-related microstructural degeneration.•Integrity of tracts was associated with M1 structural and hemodynamic changes.•CStrT mediated the impact of M1 atrophy on both motor and cognitive decline. Motor and cognitive decline are hallmark features of aging. In the primary motor cortex (M1), pyramidal neurons project to the corticospinal tract (CST), a well-established motor pathway, and send collaterals to the ipsilateral striatum, forming the corticostriatal tract (CStrT). While the CST has been extensively studied, the role of the CStrT in motor and cognitive aging remains poorly understood. We analyzed T1- and T2-weighted MRI, multi-delay arterial spin labeling, and multi-shell diffusion MRI data from 339 right-handed healthy adults (aged 36–90 years) in the Human Connectome Project–Aging dataset. Age-related trajectories of M1 structure and hemodynamics, as well as CST and CStrT microstructure, were assessed. Segment-wise along-tract analyses were conducted to identify localized tract degeneration. Mediation analyses were performed to examine whether tract integrity linked M1 atrophy to motor and cognitive performance. With age, M1 exhibited reduced volume and hemodynamics, altered T1/T2 ratio, and increased cortical curvature, reflecting structural and hemodynamic alterations. Along-tract analyses revealed localized microstructural degeneration in the CST adjacent to M1, whereas the CStrT showed more extensive degeneration along its trajectory. These tract changes were associated with structural and hemodynamic alterations in M1. Furthermore, integrity of the dominant (left) CST and CStrT mediated the relationship between ipsilateral M1 atrophy and motor decline. Notably, CStrT integrity also mediated the association between M1 atrophy and motor cognition decline. These findings establish age-related structural and functional degeneration of M1 and its pathways, highlighting the CStrT as a critical mediator between motor cortical atrophy and both motor and cognitive decline. These normative imaging markers of healthy aging may help inform the early detection of neurodegenerative diseases.

ObjectiveNeuropathological studies in amyotrophic lateral sclerosis (ALS) have shown a dissemination in a regional sequence in four anatomically defined patterns. The aim of this retrospective study was to see whether longitudinal diffusion tensor imaging (DTI) data support the pathological findings.MethodsThe application of DTI analysis to fibre structures that are prone to be involved at each neuropathological pattern of ALS was performed in a monocentre sample of 67 patients with ALS and 31 controls that obtained at least one follow-up scan after a median of 6 months.ResultsAt the group level, longitudinal ALS data showed significant differences for the stage-related tract systems. At the individual level, 27% of the longitudinally scanned patients with ALS showed an increase in ALS stage, while the remaining were stable or were at the highest ALS stage. Longitudinal fractional anisotropy changes in the respective tract systems correlated significantly with the slope of the revised ALS functional rating scale.InterpretationThe DTI-based protocol was able to image the disease patterns of ALS in vivo cross-sectionally and longitudinally, in support of DTI as a technical marker to image ALS stages.

•Studied fMRI/DTI covariation in motor pathways (CST/CPCT/DTCT/DSCT) post-stroke.•Baseline covariation and its 30-day dynamics predict lower extremity motor recovery.•Higher FC predicts poorer outcomes specifically in patients with preserved DSCT integrity. To investigate the pathway-specific structure-function coupling induced by focal subcortical infarction and its influence on clinical symptoms. In this prospective study, 50 patients with unilateral subcortical infarction and motor impairment and 50 matched controls underwent resting state fMRI, DTI, and Fugl-Meyer-Assessment lower-extremity (FMA-LE) at 7–14- and 30-days post-infarction. To analyze the pathway-specific structure-function coupling, we evaluated the association between structural integrity of the corticospinal tract (CST), dentate thalamocortical tract (DTCT), cortico-pontocerebellar tract (CPCT), and dorsal spinocerebellar tract (DSCT) and functional connectivity (FC) of corresponding subregions. Moderation analysis assesses whether the structure-function coupling pathway moderates FMA-LE. At baseline, patients exhibited significantly lower structural integrity of DTCT, DSCT, and CST than controls. We found structure-function couplings in the three motor pathways of the cerebro-cerebellar circuit: (1) contralesional thalamus to ipsilesional cerebellum-crus_2 with dentate thalamocortical tract (DTCT), (2) contralesional thalamus to cerebellum vermis_10 with dorsal spinocerebellar tract (DSCT), (3) ipsilesional precentral gyrus to frontal medial gyrus with CST. The baseline DSCT structural integrity specificity modulates the relationship between FC and FMA-LE over 30 days. We observed that cerebro-cerebellar circuit structure-function coupling after infarction, based on its anatomy and mapped to motor function (with DSCT as the key pathway mediating/moderating prognosis), serves as a potent biomarker for lower limb prognosis and a basis for precise rehabilitation. [Display omitted]

The corticospinal tract (CST) is a critically important white matter fiber tract in the human brain that enables control of voluntary movements of the body. The CST exhibits a somatotopic organization, which means that the motor neurons that control specific body parts are arranged in order within the CST. Diffusion magnetic resonance imaging (MRI) tractography is increasingly used to study the anatomy of the CST. However, despite many advances in tractography algorithms over the past decade, modern, state‐of‐the‐art methods still face challenges. In this study, we compare the performance of six widely used tractography methods for reconstructing the CST and its somatotopic organization. These methods include constrained spherical deconvolution (CSD) based probabilistic (iFOD1) and deterministic (SD‐Stream) methods, unscented Kalman filter (UKF) tractography methods including multi‐fiber (UKF2T) and single‐fiber (UKF1T) models, the generalized q‐sampling imaging (GQI) based deterministic tractography method, and the TractSeg method. We investigate CST somatotopy by dividing the CST into four subdivisions per hemisphere that originate in the leg, trunk, hand, and face areas of the primary motor cortex. A quantitative and visual comparison is performed using diffusion MRI data ( N  = 100 subjects) from the Human Connectome Project. Quantitative evaluations include the reconstruction rate of the eight anatomical subdivisions, the percentage of streamlines in each subdivision, and the coverage of the white matter–gray matter (WM–GM) interface. CST somatotopy is further evaluated by comparing the percentage of streamlines in each subdivision to the cortical volumes for the leg, trunk, hand, and face areas. Overall, UKF2T has the highest reconstruction rate and cortical coverage. It is the only method with a significant positive correlation between the percentage of streamlines in each subdivision and the volume of the corresponding motor cortex. However, our experimental results show that all compared tractography methods are biased toward generating many trunk streamlines (ranging from 35.10% to 71.66% of total streamlines across methods). Furthermore, the coverage of the WM–GM interface in the largest motor area (face) is generally low (under 40%) for all compared tractography methods. Different tractography methods give conflicting results regarding the percentage of streamlines in each subdivision and the volume of the corresponding motor cortex, indicating that there is generally no clear relationship, and that reconstruction of CST somatotopy is still a large challenge. Overall, we conclude that while current tractography methods have made progress toward the well‐known challenge of improving the reconstruction of the lateral projections of the CST, the overall problem of performing a comprehensive CST reconstruction, including clinically important projections in the lateral (hand and face areas) and medial portions (leg area), remains an important challenge for diffusion MRI tractography.

•Comparison of methods for quantifying white matter intactness following stroke.•Only FA-method demonstrates compensatory importance of other tracts if CST is severely lesioned.•Tracts with low lesion load appear to be less informative for disconnection symptom mapping. Indirect structural disconnection‐symptom mapping allows white matter impairment to be determined without the need for multi-directional diffusion (MDDW) imaging for each individual. Although widely used this method has not been validated. We analyzed a multicenter dataset obtained from 166 individuals in the chronic stage after stroke with upper limb impairment quantified with Fugl-Meyer upper extremity score (FMUE) comprising stroke lesion maps and MDDW imaging. White matter integrity was quantified (1) by diffusion-tensor-imaging-based fractional anisotropy in preselected tracts (fractional anisotropy method; FAM) and (2) by extracting a percentage of tract disconnection by masking each tract of a predefined tractography atlas using the individual map (disconnection-symptom mapping; DSM). We also calculated a lateralization index for the fractional anisotropy between both hemispheres. The following tracts were tested: corticospinal tract (CST), superior lateral fasciculus (SLF) and corpus callosum (CC) but also optic radiation (OR) as a control tract. Both methods (FAM, DSM) showed comparable results for the association of white matter integrity of the CST with FMUE. DSM showed a strong association with FMUE likely because of the number of participants who failed to show an overlap of the tracts and lesion masks (for CST: n = 57 out of 166; for CC: n = 103 out of 166) whereas with FAM these participants could be used for further analyses. On the first view, our data support the use of white matter integrity quantification based on DSM in individuals with chronic stroke. However, at least one-third-of cases (for CC even worse) showed no overlap of lesion and tract resulting in artificially high associations with clinical parameters.

Subtle motor signs are a common feature in children with attention‐deficit/hyperactivity disorder (ADHD). It has long been suggested that white matter abnormalities may be involved in their presentation, though no study has directly probed this question. The aim of this study was to investigate the relationship between white matter organization and the severity of subtle motor signs in children with and without ADHD. Participants were 92 children with ADHD aged between 8 and 12 years, and 185 typically developing controls. Subtle motor signs were examined using the Physical and Neurological Examination for Soft Signs (PANESS). Children completed diffusion MRI, and fixel‐based analysis was performed after preprocessing. Tracts of interest were delineated using TractSeg including the corpus callosum (CC), the bilateral corticospinal tracts (CST), superior longitudinal fasciculus, and fronto‐pontine tracts (FPT). Fiber cross‐section (FC) was calculated for each tract. Across all participants, lower FC in the CST was associated with higher PANESS Total score (greater motor deficits). Within the PANESS, similar effects were observed for Timed Left and Right maneuvers of the hands and feet, with lower FC of the CST, CC, and FPT associated with poorer performance. No significant group differences were observed in FC in white matter regions associated with PANESS performance. Our data are consistent with theoretical accounts implicating white matter organization in the expression of motor signs in childhood. However, rather than contributing uniquely to the increased severity of soft motor signs in those with ADHD, white matter appears to contribute to these symptoms in childhood in general. Our data are consistent with theoretical accounts implicating white matter organization in the expression of motor signs in childhood. However, rather than contributing uniquely to the increased severity of soft motor signs in those with attention‐deficit/hyperactivity disorder, white matter appears to contribute to these symptoms in childhood in general.

BackgroundCorticospinal tract (CST) degeneration and cortical atrophy are consistent features of amyotrophic lateral sclerosis (ALS). We hypothesised that neurite orientation dispersion and density imaging (NODDI), a multicompartment model of diffusion MRI, would reveal microstructural changes associated with ALS within the CST and precentral gyrus (PCG) ‘in vivo’.Methods23 participants with sporadic ALS and 23 healthy controls underwent diffusion MRI. Neurite density index (NDI), orientation dispersion index (ODI) and free water fraction (isotropic compartment (ISO)) were derived. Whole brain voxel-wise analysis was performed to assess for group differences. Standard diffusion tensor imaging (DTI) parameters were computed for comparison. Subgroup analysis was performed to investigate for NODDI parameter differences relating to bulbar involvement. Correlation of NODDI parameters with clinical variables were also explored. The results were accepted as significant where p<0.05 after family-wise error correction at the cluster level, clusters formed with p<0.001.ResultsIn the ALS group NDI was reduced in the extensive regions of the CST, the corpus callosum and the right PCG. ODI was reduced in the right anterior internal capsule and the right PCG. Significant differences in NDI were detected between subgroups stratified according to the presence or absence of bulbar involvement. ODI and ISO correlated with disease duration.ConclusionsNODDI demonstrates that axonal loss within the CST is a core feature of degeneration in ALS. This is the main factor contributing to the altered diffusivity profile detected using DTI. NODDI also identified dendritic alterations within the PCG, suggesting microstructural cortical dendritic changes occur together with CST axonal damage.

NG101 is a recombinant antibody that neutralizes the nerve growth inhibitor Nogo-A, promoting neural repair and improving upper extremity motor function in spinal cord injury (SCI). This study evaluated spinal cord MRI biomarkers to detect treatment-related structural changes and enhance patient stratification using data from 106 participants with acute cervical SCI in the phase 2b NISCI trial. We assessed lesion volume, tissue bridges, and remote changes in cross-sectional cord area (CSA), and tract-specific myelin-sensitive magnetization transfer saturation (MTsat) over six months. Compared to placebo, NG101-treated participants exhibited faster lesion volume reduction and a slower decline of CSA and MTsat in the corticospinal tracts and dorsal columns. Crucially, multimodal stratification incorporating MRI and electrophysiological measures substantially enhanced the detection of clinical treatment effects. These findings suggest NG101 slows trauma-induced progressive macro- and microstructural degeneration or promotes fiber sprouting. Combining MRI with electrophysiology enables sensitive detection of treatment effects and efficient trial designs. ClinicalTrials.gov identifier: NCT03935321. NG101 treatment for acute cervical spinal cord injury mitigates structural degeneration compared to placebo. Stratifying patients via MRI and electrophysiology identifies clinical responder subgroups, optimizing future trial designs.

ObjectiveTo discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS).MethodsT1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3 T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed.ResultsGrey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls.ConclusionsRather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies.