Investigating female versus male differences in white matter neuroplasticity associated with complex visuo-motor learning.

Magnetic resonance imaging (MRI) has increasingly been used to characterize structure-function relationships during white matter neuroplasticity. Biological sex differences may be an important factor that affects patterns of neuroplasticity, and therefore impacts learning and rehabilitation. The current study examined a participant cohort before and after visuo-motor training to characterize sex differences in microstructural measures. The participants (N = 27) completed a 10-session (4 week) complex visuo-motor training task with their non-dominant hand. All participants significantly improved movement speed and their movement speed variability over the training period. White matter neuroplasticity in females and males was examined using fractional anisotropy (FA) and myelin water fraction (MWF) along the cortico-spinal tract (CST) and the corpus callosum (CC). FA values showed significant differences in the middle portion of the CST tract (nodes 38-51) across the training period. MWF showed a similar cluster in the inferior portion of the tract (nodes 18-29) but did not reach significance. Additionally, at baseline, males showed significantly higher levels of MWF measures in the middle body of the CC. Combining data from females and males would have resulted in reduced sensitivity, making it harder to detect differences in neuroplasticity. These findings offer initial insights into possible female versus male differences in white matter neuroplasticity during motor learning. This warrants investigations into specific patterns of white matter neuroplasticity for females versus males across the lifespan. Understanding biological sex-specific differences in white matter neuroplasticity may have significant implications for the interpretation of change associated with learning or rehabilitation.

Frontoparietal function and underlying structure reflect capacity for motor skill acquisition during healthy aging.

While capacity for motor skill acquisition changes with healthy aging, there has been little consideration of how age-related changes in brain function or baseline brain structure support motor skill acquisition. We examined: (1) age-dependent changes in functional reorganization related to frontoparietal regions during motor skill acquisition, and (2) whether capacity for motor skill acquisition relates to baseline white matter microstructure in frontoparietal tracts. Healthy older and younger adults engaged in 4 weeks of skilled motor practice. Resting-state functional connectivity (rsFC) assessed functional reorganization before and after practice. Diffusion tensor imaging indexed microstructure of a frontoparietal tract at baseline, generated by rsFC seeds. Motor skill acquisition was associated with decreases in rsFC in healthy older adults and increases in rsFC in healthy younger adults. Frontoparietal tract microstructure was lower in healthy older versus younger adults, yet it was negatively associated with rate of skill acquisition regardless of group. Findings indicate that age-dependent alterations in frontoparietal function and baseline structure of a frontoparietal tract reflect capacity for motor skill acquisition.

Females exhibit smaller volumes of brain activation and lower inter-subject variability during motor tasks.

Past work has shown that brain structure and function differ between females and males. Males have larger cortical and sub-cortical volume and surface area (both total and subregional), while females have greater cortical thickness in most brain regions. Functional differences are also reported in the literature, yet to date little work has systematically considered whether patterns of brain activity indexed with functional magnetic resonance imaging (fMRI) differ between females and males. The current study sought to remediate this issue by employing task-based whole brain motor mapping analyses using an openly available dataset. We tested differences in patterns of functional brain activity associated with 12 voluntary movement patterns in females versus males. Results suggest that females exhibited smaller volumes of brain activation across all 12 movement tasks, and lower patterns of variability in 10 of the 12 movements. We also observed that females had greater cortical thickness, which is in alignment with previous analyses of structural differences. Overall, these findings provide a basis for considering biological sex in future fMRI research and provide a foundation of understanding differences in how neurological pathologies present in females vs males.

Improved processing speed and decreased functional connectivity in individuals with chronic stroke after paired exercise and motor training.

After stroke, impaired motor performance is linked to an increased demand for cognitive resources. Aerobic exercise improves cognitive function in neurologically intact populations and may be effective in altering cognitive function post-stroke. We sought to determine if high-intensity aerobic exercise paired with motor training in individuals with chronic stroke alters cognitive-motor function and functional connectivity between the dorsolateral prefrontal cortex (DLPFC), a key region for cognitive-motor processes, and the sensorimotor network. Twenty-five participants with chronic stroke were randomly assigned to exercise (n = 14; 66 ± 11 years; 4 females), or control (n = 11; 68 ± 8 years; 2 females) groups. Both groups performed 5-days of paretic upper limb motor training after either high-intensity aerobic exercise (3 intervals of 3 min each, total exercise duration of 23-min) or watching a documentary (control). Resting-state fMRI, and trail making test part A (TMT-A) and B were recorded pre- and post-intervention. Both groups showed implicit motor sequence learning (p < 0.001); there was no added benefit of exercise for implicit motor sequence learning (p = 0.738). The exercise group experienced greater overall cognitive-motor improvements measured with the TMT-A. Regardless of group, the changes in task score, and dwell time during TMT-A were correlated with a decrease in DLPFC-sensorimotor network functional connectivity (task score: p = 0.025; dwell time: p = 0.043), which is thought to reflect a reduction in the cognitive demand and increased automaticity. Aerobic exercise may improve cognitive-motor processing speed post-stroke.

Exploring biomarkers of processing speed and executive function: The role of the anterior thalamic radiations.

INTRODUCTION: Processing speed and executive function are often impaired after stroke and in typical aging. However, there are no reliable neurological markers of these cognitive impairments. The trail making test (TMT) is a common index of processing speed and executive function. Here, we tested candidate MRI markers of TMT performance in a cohort of older adults and individuals with chronic stroke. METHODS: In 61 older adults and 32 individuals with chronic stroke, we indexed white matter structure with region-specific lesion load (of white matter hyperintensities (WMHs) and stroke lesions) and diffusion tensor imaging (DTI) from four regions related to TMT performance: the anterior thalamic radiations (ATR), superior longitudinal fasciculus (SLF), forceps minor, and cholinergic pathways. Regression modelling was used to identify the marker(s) that explained the most variance in TMT performance. RESULTS: DTI metrics of the ATR related to processing speed in both the older adult (TMT A: ß = -3.431, p < 0.001) and chronic stroke (TMT A: ß = 11.282, p < 0.001) groups. In the chronic stroke group executive function was best predicted by a combination of ATR and forceps minor DTI metrics (TMT B: adjustedR2 = 0.438, p < 0.001); no significant predictors of executive function (TMT B) emerged in the older adult group. No imaging metrics related to set shifting (TMT B-A). Regional DTI metrics predicted TMT performance above and beyond whole-brain stroke and WMH volumes and removing whole-brain lesion volumes improved model fits. CONCLUSIONS: In this comprehensive assessment of candidate imaging markers, we demonstrate an association between ATR microstructure and processing speed and executive function performance. Regional DTI metrics provided better predictors of cognitive performance than whole-brain lesion volumes or regional lesion load, emphasizing the importance of lesion location in understanding cognition. We propose ATR DTI metrics as novel candidate imaging biomarker of post-stroke cognitive impairment.

Early feeding behaviours of extremely preterm infants predict neurodevelopmental outcomes.

BACKGROUND: Infants born extremely preterm are at high risk for early feeding difficulties, as well as poor neurodevelopmental outcomes in childhood. Feeding, a complex motor skill, may be predictive of later neuromotor outcomes. AIMS: To determine the relationship between feeding behaviours of extremely preterm-born infants (<28 weeks gestational age) at 4-months corrected age (CA) and neurodevelopmental outcomes at 4-5 years. STUDY DESIGN: Retrospective cohort design with prospectively collected data. SUBJECTS: Infants born extremely preterm from September 1999 - October 2013 [n = 412, mean gestational age 25.4 (1.3) weeks; mean birth weight 771 (168) grams]. Oral feeding was assessed at 4-months CA by an experienced occupational therapist; infants were classified as either having poor suck-swallow ('feeding difficulties') or no feeding difficulties. OUTCOME MEASURES: Motor outcomes were assessed at 4-5 years using the Movement Assessment Battery for Children (MABC). Children were categorized as: (1) typical motor development (TMD; n = 214); (2) Developmental Coordination Disorder (DCD; n = 116); or (3) major neurodevelopmental disorder (MND; n = 82). RESULTS: Feeding behaviour at 4-months CA predicted DCD (OR = 2.95, CI 1.13-7.68) and MND (OR = 3.67, CI 1.35-9.96) after controlling for confounders. Infants with feeding difficulties were more likely to be diagnosed with DCD (40 % of poor feeders) or MND (36 %) at 4-5 years, compared to infants without feeding issues. CONCLUSIONS: Early feeding behaviours significantly predicted motor outcomes at 4-5 years. Infants born extremely preterm with early feeding difficulties should be identified as at high risk for poor motor outcomes later in childhood and screened for early diagnosis and intervention.

In vivo myelin imaging and tissue microstructure in white matter hyperintensities and perilesional white matter.

White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal-appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating the interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal-appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal-appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like effects in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Brain functional connectivity in children with developmental coordination disorder following rehabilitation intervention.

BACKGROUND: Children with developmental coordination disorder (DCD) show improved motor function after Cognitive Orientation to Occupational Performance (CO-OP) intervention; however, the neural basis for these improvements is unknown. METHODS: In this randomized waitlist-controlled trial, 78 children with DCD (with/without ADHD) were randomly assigned to either a treatment or waitlist group and underwent three resting-state MRI scans over six months. The treatment group received intervention between the first and second scan; the waitlist group received intervention between the second and third scan. RESULTS: After CO-OP intervention, children with DCD [13 male, 8 female; mean (SD) age: 10.0 (1.7) years] showed increased functional connectivity between the default mode network and right anterior cingulate gyrus (p < 0.01). Additional gains were noted at follow-up three months after the intervention, with greater functional connectivity between the dorsal attention network and precentral gyrus (p < 0.02). However, children with DCD + ADHD [18 male, 1 female; mean (SD) age: 10.0 (1.14) years] did not show brain changes following CO-OP. CONCLUSION: For children with DCD, increased functional connectivity in networks associated with self-, emotion-, and attention-regulation may underlie motor skill improvements observed after CO-OP intervention. Modifications to the CO-OP protocol may be required to induce similar brain changes in children with DCD + ADHD. IMPACT: This study provides neuroscientific evidence for the Cognitive Orientation to Occupational Performance (CO-OP) approach as an effective rehabilitation intervention to induce brain and behavioral changes in children with DCD. While children with DCD ± ADHD showed improved motor function after CO-OP, only children with DCD showed brain changes after intervention. Children with DCD showed increased functional connectivity in networks associated with self-, emotion-, and attention-regulation after the intervention. Treatment modifications may be required to induce similar brain changes in children with DCD + ADHD. Pediatricians are encouraged to refer children with DCD with and without ADHD for CO-OP intervention to improve their motor skills.

Resting State Connectivity Is Modulated by Motor Learning in Individuals After Stroke.

OBJECTIVE: Activity patterns across brain regions that can be characterized at rest (ie, resting-state functional connectivity [rsFC]) are disrupted after stroke and linked to impairments in motor function. While changes in rsFC are associated with motor recovery, it is not clear how rsFC is modulated by skilled motor practice used to promote recovery. The current study examined how rsFC is modulated by skilled motor practice after stroke and how changes in rsFC are linked to motor learning. METHODS: Two groups of participants (individuals with stroke and age-matched controls) engaged in 4 weeks of skilled motor practice of a complex, gamified reaching task. Clinical assessments of motor function and impairment, and brain activity (via functional magnetic resonance imaging) were obtained before and after training. RESULTS: While no differences in rsFC were observed in the control group, increased connectivity was observed in the sensorimotor network, linked to learning in the stroke group. Relative to healthy controls, a decrease in network efficiency was observed in the stroke group following training. CONCLUSIONS: Findings indicate that rsFC patterns related to learning observed after stroke reflect a shift toward a compensatory network configuration characterized by decreased network efficiency.

Children with developmental coordination disorder show altered functional connectivity compared to peers.

Developmental Coordination Disorder (DCD) is a neurodevelopmental disorder that affects a child's ability to learn motor skills and participate in self-care, educational, and leisure activities. The cause of DCD is unknown, but evidence suggests that children with DCD have atypical brain structure and function. Resting-state MRI assesses functional connectivity by identifying brain regions that have parallel activation during rest. As only a few studies have examined functional connectivity in this population, our objective was to compare whole-brain resting-state functional connectivity of children with DCD and typically-developing children. Using Independent Component Analysis (ICA), we compared functional connectivity of 8-12 year old children with DCD (N = 35) and typically-developing children (N = 23) across 19 networks, controlling for age and sex. Children with DCD demonstrate altered functional connectivity between the sensorimotor network and the posterior cingulate cortex (PCC), precuneus, and the posterior middle temporal gyrus (pMTG) (p < 0.0001). Previous evidence suggests the PCC acts as a link between functionally distinct networks. Our results indicate that ineffective communication between the sensorimotor network and the PCC might play a role in inefficient motor learning seen in DCD. The pMTG acts as hub for action-related information and processing, and its involvement could explain some of the functional difficulties seen in DCD. This study increases our understanding of the neurological differences that characterize this common motor disorder.

Rehabilitation-induced brain changes detected through magnetic resonance imaging in children with neurodevelopmental disorders: A systematic review.

AIM: The aim of this study was to systematically review evidence about rehabilitation-induced neuroplasticity measured by magnetic resonance imaging (MRI) in children with neurodevelopmental disorders. METHOD: The following databases were searched: MEDLINE, EMBASE, CINAHL, and PsycINFO. Two independent reviewers screened articles according to inclusion criteria: (1) peer-review study published in a scientific journal; (2) studies that evaluated a rehabilitation-based intervention; (3) participants aged less than 19 years with a neurodevelopmental disorder; and (4) studies that used at least one MRI modality as an outcome measure. Twenty-seven studies met the criteria for the review and their quality was assessed by two independent reviewers using the Effective Public Health Practice Project Quality Assessment Tool. RESULTS: Based on an assessment of bias and overall quality, 11% of the papers were rated as strong; 30% moderate; and 59% weak. Outcomes were categorized into structural connectivity, functional connectivity, cortical activation, and structural volume. Cortical activation and structural connectivity were the most commonly reported measures. Most studies were able to identify brain changes in children with neurodevelopmental disorders after therapy. INTERPRETATIONS: Rehabilitation is shown to induce MRI-detectable neuroplastic changes in children with neurodevelopmental disorders. Structural connectivity might need greater intensity and/or duration of intervention to induce change.