Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Atypical procedural learning in children with developmental coordination disorder: A combined behavioral and neuroimaging study.

While procedural learning (PL) has been implicated in delayed motor skill observed in developmental coordination disorder (DCD), few studies have considered the impact of co-occurring attentional problems. Furthermore, the neurostructural basis of PL in children remains unclear. We investigated PL in children with DCD while controlling for inattention symptoms, and examined the role of fronto-basal ganglia-cerebellar morphology in PL. Fifty-nine children (6-14 years; nDCD = 19, ncontrol = 40) completed the serial reaction time (SRT) task to measure PL. The Attention-Deficit Hyperactivity Disorder Rating Scale-IV was administered to measure inattention symptoms. Structural T1 images were acquired for a subset of participants (nDCD = 10, ncontrol = 28), and processed using FreeSurfer. Volume was extracted for the cerebellum, basal ganglia, and frontal regions. After controlling for inattention symptoms, the reaction time profile of controls was consistent with learning on the SRT task. This was not the case for those with DCD. SRT task performance was positively correlated with cerebellar cortical volume, and children with DCD trended towards lower cerebellar volume compared to controls. Children with DCD may not engage in PL during the SRT task in the same manner as controls, with this differential performance being associated with atypical cerebellar morphology.

Examination of Cerebellar Grey-Matter Volume in Children with Neurodevelopmental Disorders: a Coordinated Analysis Using the ACAPULCO Algorithm.

Alterations in cerebellar morphology relative to controls have been identified in children with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and developmental coordination disorder (DCD). However, it is not clear if common cerebellar regions are affected in each neurodevelopmental disorder and whether cerebellar morphological changes reflect a generic developmental vulnerability, or disorder-specific characteristic. The present study concatenated anatomical MRI scans from five existing cohorts, resulting in data from 252 children between the age of 7 and 12 years (ASD = 58, ADHD = 86, DCD = 22, Controls = 86). The ACAPULCO processing pipeline for cerebellar segmentation was conducted on T1-weighted images. A voxel-wise approach with general linear model was used to compare grey-matter volume of the 27 cerebellar lobules between each clinical group and controls. Our findings revealed that the ADHD group showed lower grey-matter volume in the left Crus I - part of the executive/non-motor portion of the cerebellum, relative to controls (p = 0.02). This no longer remained significant after controlling for medication status. There were no regions of significant differences in volume of the cerebellar lobules in ASD or DCD compared to controls. Future work will conduct harmonisation of behavioural data (cognitive and motor outcomes) across cohorts, enabling more advanced analyses to identify symptom cluster across neurodevelopmental disorders.

Structural-functional connectivity bandwidth of the human brain.

BACKGROUND: The human brain is a complex network that seamlessly manifests behaviour and cognition. This network comprises neurons that directly, or indirectly mediate communication between brain regions. Here, we show how multilayer/multiplex network analysis provides a suitable framework to uncover the throughput of structural connectivity (SC) to mediate information transfer-giving rise to functional connectivity (FC). METHOD: We implemented a novel method to reconcile SC and FC using diffusion and resting-state functional MRI connectivity data from 484 subjects (272 females, 212 males; age = 29.15 ± 3.47) from the Human Connectome Project. First, we counted the number of direct and indirect structural paths that mediate FC. FC nodes with indirect SC paths were then weighted according to their least restrictive SC path. We refer to this as SC-FC Bandwidth. We then mapped paths with the highest SC-FC Bandwidth across 7 canonical resting-state networks. FINDINGS: We found that most pairs of FC nodes were connected by SC paths of length two and three (SC paths of length >5 were virtually non-existent). Direct SC-FC connections accounted for only 10% of all SC-FC connections. The majority of FC nodes without a direct SC path were mediated by a proportion of two (44%) or three SC path lengths (39%). Only a small proportion of FC nodes were mediated by SC path lengths of four (5%). We found high-bandwidth direct SC-FC connections show dense intra- and sparse inter-network connectivity, with a bilateral, anteroposterior distribution. High bandwidth SC-FC triangles have a right superomedial distribution within the somatomotor network. High-bandwidth SC-FC quads have a superoposterior distribution within the default mode network. CONCLUSION: Our method allows the measurement of indirect SC-FC using undirected, weighted graphs derived from multimodal MRI data in order to map the location and throughput of SC to mediate FC. An extension of this work may be to explore how SC-FC Bandwidth changes over time, relates to cognition/behavior, and if this measure reflects a marker of neurological injury or psychiatric disorders.

ENIGMA brain injury: Framework, challenges, and opportunities.

Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury-related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest-ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group.

Association between Motor Planning and the Frontoparietal Network in Children: An Exploratory Multimodal Study.

OBJECTIVE: Evidence from adult literature shows the involvement of cortical grey matter areas of the frontoparietal lobe and the white matter bundle, the superior longitudinal fasciculus (SLF) in motor planning. This is yet to be confirmed in children. METHOD: A multimodal study was designed to probe the neurostructural basis of childhood motor planning. Behavioural (motor planning), magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) data were acquired from 19 boys aged 8-11 years. Motor planning was assessed using the one and two colour sequences of the octagon task. The MRI data were preprocessed and analysed using FreeSurfer 6.0. Cortical thickness and cortical surface area were extracted from the caudal middle frontal gyrus (MFG), superior frontal gyrus (SFG), precentral gyrus (PcG), supramarginal gyrus (SMG), superior parietal lobe (SPL) and the inferior parietal lobe (IPL) using the Desikan-Killiany atlas. The DWI data were preprocessed and analysed using ExploreDTI 4.8.6 and the white matter tract, the SLF was reconstructed. RESULTS: Motor planning of the two colour sequence was associated with cortical thickness of the bilateral MFG and left SFG, PcG, IPL and SPL. The right SLF was related to motor planning for the two colour sequence as well as with the left cortical thickness of the SFG. CONCLUSION: Altogether, morphology within frontodorsal circuity, and the white matter bundles that support communication between them, may be associated with individual differences in childhood motor planning.

Fixel-based Analysis of Diffusion MRI: Methods, Applications, Challenges and Opportunities.

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.

Indirect frontocingulate structural connectivity predicts clinical response to accelerated rTMS in major depressive disorder

Background: Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), but its clinical efficacy remains rather modest. One reason for this could be that the propagation of rTMS effects via structural connections from the stimulated area to deeper brain structures (such as the cingulate cortices) is suboptimal. Methods: We investigated whether structural connectivity ­ derived from diffusion MRI data ­ could serve as a biomarker to predict treatment response. We hypothesized that stronger structural connections between the patient-specific stimulation position in the left dorsolateral prefrontal cortex (dlPFC) and the cingulate cortices would predict better clinical outcomes. We applied accelerated intermittent theta burst stimulation (aiTBS) to the left dlPFC in 40 patients with MDD. We correlated baseline structural connectivity, quantified using various metrics (fractional anisotropy, mean diffusivity, tract density, tract volume and number of tracts), with changes in depression severity scores after aiTBS. Results: Exploratory results (p < 0.05) showed that structural connectivity between the patient-specific stimulation site and the caudal and posterior parts of the cingulate cortex had predictive potential for clinical response to aiTBS. Limitations: We used the diffusion tensor to perform tractography. A main limitation was that multiple fibre directions within voxels could not be resolved, which might have led to missing connections in some patients. Conclusion: Stronger structural frontocingular connections may be of essence to optimally benefit from left dlPFC rTMS treatment in MDD. Even though the results are promising, further investigation with larger numbers of patients, more advanced tractography algorithms and classic daily rTMS treatment paradigms is warranted. Clinical trial registration: http://clinicaltrials.gov/show/NCT01832805

Does fMRI repetition suppression reveal mirror neuron activity in the human brain? Insights from univariate and multivariate analysis.

Mirror neurons (MN) have been proposed as the neural substrate for a wide range of clinical, social and cognitive phenomena. Over the last decade, a commonly used tool for investigating MN activity in the human brain has been functional magnetic resonance (fMRI) repetition suppression (RS) paradigms. However, the available evidence is mixed, largely owing to inconsistent application of the methodological criteria necessary to infer MN properties. This raises concerns about the degree to which one can infer the presence (or absence) of MN activity from earlier accounts that adopted RS paradigms. We aimed to clarify this issue using a well-validated fMRI RS paradigm and tested for mirror properties by rigorously applying the widely accepted criteria necessary to demonstrate MN activity using traditional univariate techniques and Multivariate Pattern Analysis (MVPA). While univariate whole brain analysis in healthy adults showed uni-modal RS effects within the supplementary motor area, no evidence for cross-modal RS effects consistent with mirror neuron activity was found. MVPA on the other hand revealed a region along the anterior intraparietal sulcus that met the criteria for MN activity. Taken together, these results clarify disparate evidence from earlier RS studies, highlighting that traditional univariate analysis of RS data may not be sensitive for detecting MN activity when rigorously applying the requisite criteria. In light of these findings, we recommend that short of increasing sample sizes substantially, future studies using RS paradigms to investigate MNs across the human brain consider the use of MVPA.

Associations between brain morphology and motor performance in chronic neck pain: A whole-brain surface-based morphometry approach.

Changes in brain morphology are hypothesized to be an underlying process that drive the widespread pain and motor impairment in patients with chronic neck pain. However, no earlier research assessed whole-brain cortical morphology in these patients. This case-control study assesses group-differences in whole-brain morphology between female healthy controls (HC; n = 34), and female patients with chronic idiopathic neck pain (CINP; n = 37) and whiplash-associated disorders (CWAD; n = 39). Additionally, the associations between whole-brain morphology and motor performance including balance, strength, and neuromuscular control were assessed. Cortical volume, thickness, and surface area were derived from high resolution T1-weighted images. T2*-weighted images were obtained to exclude traumatic brain injury. Vertex-wise general-linear-model-analysis revealed cortical thickening in the left precuneus and increased volume in the left superior parietal gyrus of patients with CINP compared to HC, and cortical thickening of the left superior parietal gyrus compared to HC and CWAD. Patients with CWAD showed a smaller cortical volume in the right precentral and superior temporal gyrus compared to HC. ANCOVA-analysis revealed worse neuromuscular control in CWAD compared to HC and CINP, and in CINP compared to HC. Patients with CWAD showed decreased levels of strength and sway area compared to CINP and HC. Partial correlation analysis revealed significant associations between the volume of the precentral gyrus, and neuromuscular control and strength together with an association between the volume of the superior temporal gyrus and strength. Our results emphasize the role of altered gray matter alterations in women with chronic neck pain, and its association with pain and motor impairment.

Weight loss, behavioral change, and structural neuroplasticity in children with obesity through a multidisciplinary treatment program.

This study evaluated the effect of a multidisciplinary treatment program for children with obesity (OB) on motor competence, executive functioning (EF), and brain structure. Nineteen children with OB (7-11 years), who attended a multidisciplinary treatment program consisting of diet restriction, cognitive behavioral therapy, and physical activity, were compared with an age-matched control group of 24 children with a healthy weight (HW), who did not follow any treatment. For both groups, anthropometric measurements and tests of motor competence and EF were administered twice, with 5 months between pretest and posttest. Additionally, children's brain structure was assessed by performing a magnetic resonance imaging (MRI) scan at the pretest and posttest, which included a T1 anatomical scan, diffusion MRI scan, and magnetization transfer imaging scan. Compared to HW controls, children with OB lost a considerable amount of their body mass (p ≤ .001) and significantly improved their balance skills (p ≤ .001), while no transfer effects of the program were observed for EF. Furthermore, the program resulted in a significant increase in total (p ≤ .001) and cerebellar (p ≤ .001) gray matter volume in children with OB, while no change was observed in the HW controls. Finally, only weak to moderate (nonsignificant) correlations could be observed between structural brain alterations, weight-related changes, and behavioral improvements. Altogether, this is the first longitudinal study showing behavioral and structural brain alterations in response to a multidisciplinary weight loss program for children with OB. Our findings support the need for multidimensional intervention (and prevention) measures for children with OB to deal with this multifactorial health problem.

Focal application of accelerated iTBS results in global changes in graph measures.

Graph analysis was used to study the effects of accelerated intermittent theta burst stimulation (aiTBS) on the brain's network topology in medication-resistant depressed patients. Anatomical and resting-state functional MRI (rs-fMRI) was recorded at baseline and after sham and verum stimulation. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS). Using various graph measures, the different effects of sham and verum aiTBS were calculated. It was also investigated whether changes in graph measures were correlated to clinical responses. Furthermore, by correlating baseline graph measures with the changes in HDRS in terms of percentage, the potential of graph measures as biomarker was studied. Although no differences were observed between the effects of verum and sham stimulation on whole-brain graph measures and changes in graph measures did not correlate with clinical response, the baseline values of clustering coefficient and global efficiency showed to be predictive of the clinical response to verum aiTBS. Nodal effects were found throughout the whole brain. The distribution of these effects could not be linked to the strength of the functional connectivity between the stimulation site and the node. This study showed that the effects of aiTBS on graph measures distribute beyond the actual stimulation site. However, additional research into the complex interactions between different areas in the brain is necessary to understand the effects of aiTBS in more detail.

Structural connectivity and weight loss in children with obesity: a study of the "connectobese".

BACKGROUND: Previous studies suggest that obesity (OB) is associated with disrupted brain network organization; however, it remains unclear whether these differences already exist during childhood. Moreover, it should be investigated whether deviant network organization may be susceptible to treatment. METHODS: Here, we compared the structural connectomes of children with OB with age-matched healthy weight (HW) controls (aged 7-11 years). In addition, we examined the effect of a multidisciplinary treatment program, consisting of diet restriction, cognitive behavioral therapy, and physical activity for children with OB on brain network organization. After stringent quality assessment criteria, 40 (18 OB, 22 HW) data sets of the total sample of 51 participants (25 OB, 26 HW) were included in further analyses. For all participants, anthropometric measurements were administered twice, with a 5-month interval between pre- and post tests. Pre- and post T1- and diffusion-weighted imaging scans were also acquired and analyzed using a graph-theoretical approach and network-based statistics. RESULTS: Global network analyses revealed a significantly increased normalized clustering coefficient and small-worldness in children with OB compared with HW controls. In addition, regional analyses revealed increased betweenness centrality, reduced clustering coefficient, and increased structural network strength in children with OB, mainly in the motor cortex and reward network. Importantly, children with OB lost a considerable amount of their body mass after the treatment; however, no changes were observed in the organization of their brain networks. CONCLUSION: This is the first study showing disrupted structural connectomes of children with OB, especially in the motor and reward network. These results provide new insights into the pathophysiology underlying childhood obesity. The treatment did result in a significant weight loss, which was however not associated with alterations in the brain networks. These findings call for larger samples to examine the impact of short-term and long-term weight loss (treatment) on children's brain network organization.

Prefrontal and temporal cortical thickness in adolescents with traumatic brain injury.

AIM: To investigate the impact of traumatic injury on the developing prefrontal-temporal adolescent cortex, and correlated brain structural measures with neurocognitive functioning. METHOD: Nineteen adolescents (12 males, 7 females, age range: 11-17y, mean 15y 8mo, standard deviation 1y 7mo, median 15y 11mo) with traumatic brain injury (TBI) were included. Cortical thickness of frontal and temporal lobes was assessed using magnetic resonance imaging. We correlated cortical thickness of prefrontal-temporal regions with age, time since injury, and neurocognitive functioning, and compared these results with a matched control cohort without TBI. RESULTS: We found thinner prefrontal (p=0.039) and temporal cortices (p=0.002) in adolescents with TBI compared to typically developing children. Furthermore, significant age effect was observed on the prefrontal (r=-0.75, p=0.003) and temporal (r=-0.66, p=0.013) cortical thickness in typically developing adolescents, but not in adolescents with TBI. Executive function (measured using the Behaviour Rating Inventory of Executive Function questionnaire, with lower scores meaning higher functioning) was correlated with prefrontal cortical thickness in typically developing adolescents (r=0.72, p=0.009). Opposite trends were found for correlations between cortical thickness and executive function in the TBI and control cohort. INTERPRETATION: Structural maturation in typically developing adolescents correlates with functional development: the older the adolescent, the thinner the prefrontal cortex, the better executive function. In adolescents with TBI we observed an opposite trend, that appeared significantly different from the control group: the thinner the prefrontal and temporal cortex, the worse executive functioning. WHAT THIS PAPER ADDS: Cortical thickness is negatively correlated with age in typically developing adolescents. Prefrontal cortex thickness correlates negatively with executive function in typically developing adolescents. Correlations between cortical thickness and executive functioning rise for adolescents without traumatic brain injury (TBI). Correlations between cortical thickness and executive functioning fall for adolescents with TBI. Adolescents with TBI have a long-term impairment of adaptive functioning in daily living.

ESPESOR CORTICAL PREFRONTAL Y TEMPORAL EN ADOLESCENTES CON LESIÓN CEREBRAL TRAUMÁTICA: OBJETIVO: Investigar el impacto de la lesión traumática en el desarrollo de la corteza prefrontal-temporal en adolescentes y las medidas estructurales cerebrales correlacionadas con el funcionamiento neurocognitivo. MÉTODO: Diecinueve adolescentes (12 varones, siete mujeres, rango de edad: 11-17 años, media: 15 años 8 meses, desviación estándar: 1 años 7 meses, mediana: 15 años 11 meses) con lesión cerebral traumática (LCT). El grosor cortical de los lóbulos frontal y temporal se evaluó mediante imágenes de resonancia magnética. Se correlacionó el grosor cortical de las regiones prefrontal-temporales con la edad, el tiempo transcurrido desde la lesión y el funcionamiento neurocognitivo, y se compararon estos resultados con una cohorte de control emparejada sin TCE. RESULTADOS: Encontramos cortezas prefrontales (p = 0.039) y corticales temporales delgadas (p = 0.002) en adolescentes con LCT en comparación con niños con desarrollo típico. Además, se observó un efecto significativo de la edad en el grosor cortical prefrontal (r = -0.75, p = 0.003) y temporal (r = -0.66, p = 0.013) en adolescentes de desarrollo típico, pero no en adolescentes con LCT. La función ejecutiva (medida con el cuestionario Inventario de clasificación de la conducta de la función ejecutiva, con puntuaciones más bajas que significan un funcionamiento más alto) se correlacionó con el grosor cortical prefrontal en adolescentes con desarrollo típico (r = 0.72, p = 0.009). Se encontraron tendencias opuestas para las correlaciones entre el grosor cortical y la función ejecutiva en el LCT y la cohorte de control. INTERPRETACIÓN: La maduración estructural en adolescentes con desarrollo típico se correlaciona con el desarrollo funcional: cuanto mayor es el adolescente, más delgada es la corteza prefrontal, y mejor la función ejecutiva. En adolescentes con LCT observamos una tendencia opuesta, que parecía significativamente diferente del grupo de control: cuanto más delgada era la corteza prefrontal y temporal, peor el funcionamiento ejecutivo.

ESPESSURA PRÉ-FRONTAL E TEMPORAL EM ADOLESCENTES COM LESÃO CEREBRAL TRAUMÁTICA: OBJETIVO: Investigar o impacto da lesão cerebral traumática no córtex pré-frontal -temporal em desenvolvimento de adolescentes, e medidas cerebrais estruturais correlacionadas com o funcionamento cognitivo. MÉTODO: Dezenove adolescentes (12 do sexo masculino, sete do sexo feminino, variação de idade: 11-17a, média: 15a 8m, desvio padrão: 1a 7m, mediana: 15a 11m) com lesão cerebral traumática (LCT) foram incluídos. A espessura cortical dos lobos frontais e temporais foi avaliada usando ressonância magnética funcional. Correlacionamos a espessura cortical de regiões pré-frontais-temporais com a idade, tempo após a lesão, e funcionamento neurocognitivo, e comparamos estes resultados com uma coorte controle pareada, sem LCT. RESULTADOS: Encontramos córtex pré-frontal (p=0,039) e temporal (p=0,002) mais finos em adolescentes com LCT. Além disso, efeito significativo da idade foi observado na espessura pré-frontal (r=-0,75, p=0,003) e temporal (r=-0,66, p=0,013) em adolescentes com desenvolvimento típico, mas não nos com LCT. A função executiva (mensurada com o questionário Inventário de pontuação do comportamento da Função Executiva, com menor pontuação indicando maior funcionamento) foi correlacionada com a espessura cortical pré-frontal em adolescentes com desenvolvimento típico (r=0,72, p=0,009). Tendências opostas para as correlações entre espessura cortical e função executiva foram encontradas nas coortes com LCT e controle. INTERPRETAÇÃO: A maturação estrutural em adolescentes com desenvolvimento típico se correlaciona com o desenvolvimento functional: quanto mais velho o adolescente, mais fino o córtex e melhor a função executiva. Em adolescents com LCT observamos a tendência oposta, que foi significantemente diferente do grupo controle: quanto mais fino o córtex pré-frontal e temporal, pior a função cognitiva.

Do Active Video Games Improve Motor Function in People With Developmental Disabilities? A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To conduct a meta-analysis to examine the effectiveness of active video games (AVGs) interventions on motor function in people with developmental disabilities. DATA SOURCES: An electronic search of 7 databases (PubMed, EbscoHost, Informit, Scopus, ScienceDirect, Proquest, PsychInfo) was conducted for randomized controlled trials (RCTs) evaluating AVGs to improve motor function in people with developmental disability, published through to May 2018. STUDY SELECTION: Only articles in a peer-reviewed journal in English were selected and screened by 2 independent reviewers for RCTs that compared AVGs to conventional therapy. Twelve RCTs involving 370 people with developmental disabilities met the inclusion criteria for quantitative analysis. DATA EXTRACTION: Two independent reviewers assessed risk of bias and study quality using the Egger's R, grading of recommendation, assessment, development and evaluation, and Template for Intervention Description and Replication checklists. DATA SYNTHESIS: Three meta-analyses revealed a large effect size for AVGs to improve gross motor skills (Hedges' g=0.833, 95% confidence interval [95% CI]=0.247-1.420), small to medium effects for balance (g=0.458, 95% CI=0.023-0.948), and a small, nonsignificant effect for functional mobility (g=0.425, 95% CI= -0.03 to 0.881). Training frequency (ie, number of sessions per week) moderated the effect of AVGs on motor function in people with developmental disabilities. CONCLUSION: We conclude that AVGs show task-specific effectiveness for gross motor skills but the effects are moderated by training intensity. However, because of the low number of trials, diverse diagnoses, variable dosage, and multiple outcome measures of the included trials, these results need to be interpreted with caution.

Impaired rich club and increased local connectivity in children with traumatic brain injury: Local support for the rich?

Recent evidence has shown the presence of a "rich club" in the brain, which constitutes a core network of highly interconnected and spatially distributed brain regions, important for high-order cognitive processes. This study aimed to map the rich club organization in 17 young patients with moderate to severe TBI (15.71 ± 1.75 years) in the chronic stage of recovery and 17 age- and gender-matched controls. Probabilistic tractography was performed on diffusion weighted imaging data to construct the edges of the structural connectomes using number of streamlines as edge weight. In addition, the whole-brain network was divided into a rich club network, a local network and a feeder network connecting the latter two. Functional outcome was measured with a parent questionnaire for executive functioning. Our results revealed a significantly decreased rich club organization (p values < .05) and impaired executive functioning (p < .001) in young patients with TBI compared with controls. Specifically, we observed reduced density values in all three subnetworks (p values < .005) and a reduced mean strength in the rich club network (p = .013) together with an increased mean strength in the local network (p = .002) in patients with TBI. This study provides new insights into the nature of TBI-induced brain network alterations and supports the hypothesis that the local subnetwork tries to compensate for the biologically costly subnetwork of rich club nodes after TBI.

What do randomized controlled trials say about virtual rehabilitation in stroke? A systematic literature review and meta-analysis of upper-limb and cognitive outcomes.

BACKGROUND: Virtual-reality based rehabilitation (VR) shows potential as an engaging and effective way to improve upper-limb function and cognitive abilities following a stroke. However, an updated synthesis of the literature is needed to capture growth in recent research and address gaps in our understanding of factors that may optimize training parameters and treatment effects. METHODS: Published randomized controlled trials comparing VR to conventional therapy were retrieved from seven electronic databases. Treatment effects (Hedge's g) were estimated using a random effects model, with motor and functional outcomes between different protocols compared at the Body Structure/Function, Activity, and Participation levels of the International Classification of Functioning. RESULTS: Thirty-three studies were identified, including 971 participants (492 VR participants). VR produced small to medium overall effects (g = 0.46; 95% CI: 0.33-0.59, p < 0.01), above and beyond conventional therapies. Small to medium effects were observed on Body Structure/Function (g = 0.41; 95% CI: 0.28-0.55; p < 0.01) and Activity outcomes (g = 0.47; 95% CI: 0.34-0.60, p < 0.01), while Participation outcomes failed to reach significance (g = 0.38; 95% CI: -0.29-1.04, p = 0.27). Superior benefits for Body Structure/Function (g = 0.56) and Activity outcomes (g = 0.62) were observed when examining outcomes only from purpose-designed VR systems. Preliminary results (k = 4) suggested small to medium effects for cognitive outcomes (g = 0.41; 95% CI: 0.28-0.55; p < 0.01). Moderator analysis found no advantage for higher doses of VR, massed practice training schedules, or greater time since injury. CONCLUSION: VR can effect significant gains on Body Structure/Function and Activity level outcomes, including improvements in cognitive function, for individuals who have sustained a stroke. The evidence supports the use of VR as an adjunct for stroke rehabilitation, with effectiveness evident for a variety of platforms, training parameters, and stages of recovery.

Dynamics of the Human Structural Connectome Underlying Working Memory Training.

Brain region-specific changes have been demonstrated with a variety of cognitive training interventions. The effect of cognitive training on brain subnetworks in humans, however, remains largely unknown, with studies limited to functional networks. Here, we used a well-established working memory training program and state-of-the art neuroimaging methods in 40 healthy adults (21 females, mean age 26.5 years). Near and far-transfer training effects were assessed using computerized working memory and executive function tasks. Adaptive working memory training led to improvement on (non)trained working memory tasks and generalization to tasks of reasoning and inhibition. Graph theoretical analysis of the structural (white matter) network connectivity ("connectome") revealed increased global integration within a frontoparietal attention network following adaptive working memory training compared with the nonadaptive group. Furthermore, the impact on the outcome of graph theoretical analyses of different white matter metrics to infer "connection strength" was evaluated. Increased efficiency of the frontoparietal network was best captured when using connection strengths derived from MR metrics that are thought to be more sensitive to differences in myelination (putatively indexed by the [quantitative] longitudinal relaxation rate, R1) than previously used diffusion MRI metrics (fractional anisotropy or fiber-tracking recovered streamlines). Our findings emphasize the critical role of specific microstructural markers in providing important hints toward the mechanisms underpinning training-induced plasticity that may drive working memory improvement in clinical populations. SIGNIFICANCE STATEMENT: This is the first study to explore training-induced changes in the structural connectome using a well-controlled design to examine cognitive training with up-to-date neuroimaging methods. We found changes in global integration based on white matter connectivity within a frontoparietal attention network following adaptive working memory training compared with a nonadaptive comparison group. Furthermore, the impact of different diffusion MR metrics and more specific markers of white matter on the graph theoretical findings was evaluated. An increase in network global efficiency following working memory training was best captured when connection strengths were weighted by MR relaxation rates (influenced by myelination). These results are important for the optimization of cognitive training programs for healthy individuals and people with brain disease.

Dynamics of White Matter Plasticity Underlying Working Memory Training: Multimodal Evidence from Diffusion MRI and Relaxometry.

Adaptive working memory (WM) training may lead to cognitive benefits that are associated with white matter plasticity in parietofrontal networks, but the underlying mechanisms remain poorly understood. We investigated white matter microstructural changes after adaptive WM training relative to a nonadaptive comparison group. Microstructural changes were studied in the superior longitudinal fasciculus, the main parietofrontal connection, and the cingulum bundle as a comparison pathway. MRI-based metrics were the myelin water fraction and longitudinal relaxation rate R1 from multicomponent relaxometry (captured with the mcDESPOT approach) as proxy metrics of myelin, the restricted volume fraction from the composite hindered and restricted model of diffusion as an estimate of axon morphology, and fractional anisotropy and radial diffusivity from diffusion tensor imaging. PCA was used for dimensionality reduction. Adaptive training was associated with benefits in a "WM capacity" component and increases in a microstructural component (increases in R1, restricted volume fraction, fractional anisotropy, and reduced radial diffusivity) that predominantly loaded on changes in the right dorsolateral superior longitudinal fasciculus and the left parahippocampal cingulum. In contrast, nonadaptive comparison activities were associated with the opposite pattern of reductions in WM capacity and microstructure. No group differences were observed for the myelin water fraction metric suggesting that R1 was a more sensitive "myelin" index. These results demonstrate task complexity and location-specific white matter microstructural changes that are consistent with tissue alterations underlying myelination in response to training.

Mapping the functional connectome in traumatic brain injury: What can graph metrics tell us?

OBJECTIVE: Traumatic brain injury (TBI) is associated with cognitive and motor deficits, and poses a significant personal, societal, and economic burden. One mechanism by which TBI is thought to affect cognition and behavior is through changes in functional connectivity. Graph theory is a powerful framework for quantifying topological features of neuroimaging-derived functional networks. The objective of this paper is to review studies examining functional connectivity in TBI with an emphasis on graph theoretical analysis that is proving to be valuable in uncovering network abnormalities in this condition. METHODS: We review studies that have examined TBI-related alterations in different properties of the functional brain network, including global integration, segregation, centrality and resilience. We focus on functional data using task-related fMRI or resting-state fMRI in patients with TBI of different severity and recovery phase, and consider how graph metrics may inform rehabilitation and enhance efficacy. Moreover, we outline some methodological challenges associated with the examination of functional connectivity in patients with brain injury, including the sample size, parcellation scheme used, node definition and subgroup analyses. RESULTS: The findings suggest that TBI is associated with hyperconnectivity and a suboptimal global integration, characterized by increased connectivity degree and strength and reduced efficiency of functional networks. This altered functional connectivity, also evident in other clinical populations, is attributable to diffuse white matter pathology and reductions in gray and white matter volume. These functional alterations are implicated in post-concussional symptoms, posttraumatic stress and neurocognitive dysfunction after TBI. Finally, the effects of focal lesions have been found to depend critically on topological position and their role in the network. CONCLUSION: Graph theory is a unique and powerful tool for exploring functional connectivity in brain-injured patients. One limitation is that its results do not provide specific measures about the biophysical mechanism underlying TBI. Continued work in this field will hopefully see graph metrics used as biomarkers to provide more accurate diagnosis and help guide treatment at the individual patient level.