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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.

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain 1 – 4 . Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway 5 , a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal–cortical–spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain. Somatosensory corticospinal neurons facilitate touch sensitivity and touch-evoked neuropathic pain in mice.

Grafting of caudalized rodent or human neural progenitor cells into sites of spinal cord injury enables true regeneration of damaged corticospinal axons in rodents. Regenerating axons form functional synapses within the graft, can extend beyond the lesion site, and help to support functional motor recovery. The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In murine models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of SCI. Corticospinal regeneration requires grafts to be driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, a process that is potentially related to the attenuation of the glial scar. Rat corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord 'replacement' with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of SCI research and offering new possibilities for clinical translation.

Individuals with shoulder impingement syndrome (SIS) exhibit changes in corticospinal excitability, scapular kinematics, and scapular muscle-activation patterns. To restore the scapular kinematics and muscle-activation patterns in individuals with SIS, treatment protocols usually include scapula-focused exercises, such as scapular-orientation and strength training. To investigate whether scapular-orientation and strength training can reverse the altered corticospinal excitability of recreational overhead athletes with SIS. Randomized controlled clinical trial. University laboratory. Forty-one recreational overhead athletes with SIS: 20 in the scapular-orientation group (age = 26.45 ± 4.13 years, height = 171.85 ± 7.88 cm, mass = 66.70 ± 10.68 kg) and 21 in the strengthening group (age = 26.43 ± 5.55 years, height = 171.62 ± 5.87 cm, mass = 68.67 ± 10.18 kg). Both groups performed a 30-minute training protocol consisting of 3 exercises to strengthen the lower trapezius (LT) and serratus anterior muscles without overactivating the upper trapezius muscles. Participants in the scapular-orientation group were instructed to consciously activate their scapular muscles with electromyographic biofeedback and cues, whereas the strengthening group did not receive biofeedback or cues for scapular motion. Corticospinal excitability was assessed using transcranial magnetic stimulation. Scapular kinematics and muscle activation during arm elevation were also measured. After training, both groups demonstrated an increase in motor-evoked potentials in the LT (P = .004) and increases in scapular upward rotation (P = .03), LT activation (P < .001), and serratus anterior activation (P < .001) during arm elevation. Moreover, the scapular-orientation group showed higher LT activation levels during arm elevation after training than the strengthening group (P = .03). With or without biofeedback and cues, scapula-focused exercises improved scapular control and increased corticospinal excitability. Adding biofeedback and cues for scapular control during exercise helped facilitate greater LT activation, so feedback and cues are recommended during scapula-focused training.

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.

Neurons in the central nervous system (CNS) display a high capacity for axon growth during early development but lose this ability at a pivotal differentiation stage marked by synaptic maturation, circuit integration, and a profound shift in gene transcription. Once mature, most CNS neurons fail to reverse this transcriptional switch after axon injury, fundamentally constraining their intrinsic capacity for axon regeneration. Here, we show with single-nucleus RNA sequencing that forced expression of the transcription factor Sox11 in mature corticospinal tract (CST) neurons produces large-scale and stable changes in gene expression that are highly enriched for growth-relevant processes, and which strongly resemble those of pre-synaptic embryonic stages. Moreover, Sox11 is equally effective when delivered to chronically injured CST neurons. These data reveal Sox11’s ability to reverse a critical step of neuronal maturation even in otherwise unperturbed neurons, clarifying the transcriptional underpinnings and highlighting Sox11 as a potent regulator of pro-regenerative gene networks.

Axon regeneration in the central nervous system normally fails, in part because of a developmental decline in the intrinsic ability of CNS projection neurons to extend axons. Members of the KLF family of transcription factors regulate regenerative potential in developing CNS neurons. Expression of one family member, KLF7, is down-regulated developmentally, and overexpression of KLF7 in cortical neurons in vitro promotes axonal growth. To circumvent difficulties in achieving high neuronal expression of exogenous KLF7, we created a chimera with the VP16 transactivation domain, which displayed enhanced neuronal expression compared with the native protein while maintaining transcriptional activation and growth promotion in vitro. Overexpression of VP16-KLF7 overcame the developmental loss of regenerative ability in cortical slice cultures. Adult corticospinal tract (CST) neurons failed to up-regulate KLF7 in response to axon injury, and overexpression of VP16-KLF7 in vivo promoted both sprouting and regenerative axon growth in the CST of adult mice. These findings identify a unique means of promoting CST axon regeneration in vivo by reengineering a developmentally down-regulated, growth-promoting transcription factor.

Aims Control of finger forces underlies our capacity for skilled hand movements acquired during development and reacquired after neurological injury. Learning force control by the digits, therefore, predicates our functional independence. Noninvasive neuromodulation targeting synapses that link corticospinal neurons onto the final common pathway via spike‐timing‐dependent mechanisms can alter distal limb motor output on a transient basis, yet these effects appear subject to individual differences. Here, we investigated how this form of noninvasive neuromodulation interacts with task repetition to influence early learning of force control during precision grip. Methods The unique effects of neuromodulation, task repetition, and neuromodulation coinciding with task repetition were tested in three separate conditions using a within‐subject, cross‐over design (n = 23). Results We found that synchronizing depolarization events within milliseconds of stabilizing precision grip accelerated learning but only after accounting for individual differences through inclusion of subjects who showed upregulated corticospinal excitability at 2 of 3 time points following conditioning stimulation (n = 19). Conclusions Our findings provide insights into how the state of the corticospinal system can be leveraged to drive early motor skill learning, further emphasizing individual differences in the response to noninvasive neuromodulation. We interpret these findings in the context of biological mechanisms underlying the observed effects and implications for emerging therapeutic applications. Sequencing depolorization events in the spinal cord via noninvasive stimulation has been shown to enhance motor output, offering possible therapeutic potential after neurological injury. Our findings show that this neuromodulation strategy enhances learning of force control underlying finger movements but depends on the physiological state of the intact corticospinal system and its responsiveness to neuromodulation.

Very preterm-born infants are at risk of adverse neurodevelopmental outcomes. Brain magnetic resonance imaging (MRI) at term equivalent age (TEA) can probe tissue microstructure and morphology, and demonstrates potential in the early prediction of outcomes. In this study, we use the recently introduced fixel-based analysis method for diffusion MRI to investigate the association between microstructure and morphology at TEA, and motor and cognitive development at 1 and 2 years corrected age (CA). Eighty infants born <31 weeks’ gestation successfully underwent diffusion MRI (3T; 64 directions; b ​= ​2000s/mm2) at term equivalent age, and had neurodevelopmental follow-up using the Bayley-III motor and cognitive assessments at 1 year (n ​= ​78) and/or 2 years (n ​= ​76) CA. Diffusion MRI data were processed using constrained spherical deconvolution (CSD) and aligned to a study-specific fibre orientation distribution template, yielding measures of fibre density (FD), fibre-bundle cross-section (FC), and fibre density and bundle cross-section (FDC). The association between FD, FC, and FDC at TEA, and motor and cognitive composite scores at 1 and 2 years CA, and change in composite scores from 1 to 2 years, was assessed using whole-brain fixel-based analysis. Additionally, the association between diffusion tensor imaging (DTI) metrics (fractional anisotropy FA, mean diffusivity MD, axial diffusivity AD, radial diffusivity RD) and outcomes was investigated. Motor function at 1 and 2 years CA was associated with CSD-based measures of the bilateral corticospinal tracts and corpus callosum. Cognitive function was associated with CSD-based measures of the midbody (1-year outcomes only) and splenium of the corpus callosum, as well as the bilateral corticospinal tracts. The change in motor/cognitive outcomes from 1 to 2 years was associated with CSD-based measures of the splenium of the corpus callosum. Analysis of DTI-based measures showed overall less extensive associations. Post-hoc analysis showed that associations were weaker for 2-year outcomes than they were for 1-year outcomes. Infants with better neurodevelopmental outcomes demonstrated higher FD, FC, and FDC at TEA, indicating better information transfer capacity which may be related to increased number of neurons, increased myelination, thicker bundles, and/or combinations thereof. The fibre bundles identified here may serve as the basis for future studies investigating the predictive ability of these metrics. •Brain measures at term are associated with outcomes at 1 and 2 years.•Infants with higher FD, FC and FDC at term perform better on Bayley-III.•DTI measures (FA, MD, AD, RD) show limited associations with outcomes.•Associations are stronger for 1-year outcomes than for 2-year outcomes.