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.

White matter organisation of sensorimotor tracts is associated with motor imagery in childhood.

Despite the important role of motor imagery (MI) in motor development, our understanding of the contribution of white matter fibre properties to MI performance in childhood remains limited. To provide novel insight into the white matter correlates of MI performance, this study examined the association between white matter fibre properties and motor imagery performance in a sample of typically developing children. High angular diffusion weighted imaging data were collected from 22 typically developing children aged 6-14 years (12 female, MAge= 10.56). Implicit motor imagery performance was assessed using a mental hand rotation paradigm. The cerebellar peduncles and the superior longitudinal fasciculus were reconstructed using TractSeg, a semi-automated method. For each tract, white matter microstructure (fibre density, FD) and morphology (fibre bundle cross-section, FC) were estimated using Fixel-Based Analysis. Permutation-based inference testing and partial correlation analyses demonstrated that higher FC in the middle cerebellar peduncles was associated with better MI performance. Tract-based region of interest analyses showed that higher FC in the middle and superior cerebellar peduncles were associated with better MI performance. Results suggest that white matter connectivity along the cerebellar peduncles may facilitate MI performance in childhood. These findings advance our understanding of the neurobiological systems that underlie MI performance in childhood and provide early evidence for the relevance of white matter sensorimotor pathways to internal action representations.

Web-based cognitive rehabilitation intervention for cancer-related cognitive impairment following chemotherapy for aggressive lymphoma: protocol for a randomised pilot trial.

INTRODUCTION: Cancer-related cognitive impairment is common among people diagnosed with and treated for cancer. This can be a distressing and disabling side effect for impacted individuals. Interventions to mitigate cognitive dysfunction are available, but, to date, most have been trialled in samples that are largely or exclusively composed of people with solid tumours. Intervention strategies to support cognitive functioning are needed, but there is a paucity of research in this area. The main aim of this study is to test the feasibility and acceptability of methods and procedures intended for use in a definitive trial of a web-based cognitive rehabilitation programme, Responding to Cognitive Concerns (eReCog), in people who have received chemotherapy for aggressive lymphoma. METHODS AND ANALYSIS: The proposed study is a single-site, parallel-group, pilot randomised controlled trial, with one baseline and one follow-up (or postintervention) assessment. 38 people from the target population with low perceived cognitive function based on the Cognitive Change Screen will be recruited from a specialist cancer centre between July 2023 and June 2024. After baseline assessment, participants will be randomised one-to-one to receive usual care only (a factsheet about changes in memory and thinking for people with cancer) or eReCog plus usual care. The 4-week eReCog intervention consists of four online modules offering psychoeducation on cognitive impairment associated with cancer and its treatment, skills training for improving memory, and attention and relaxation training. Study outcomes will include the feasibility of recruitment and retention at follow-up assessment (primary outcomes), as well as adherence to, usability of and intrinsic motivation to engage with eReCog, and compliance with study measures. The potential efficacy of eReCog will also be evaluated. ETHICS AND DISSEMINATION: Ethical approval was granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee in Victoria, Australia (HREC/97384/PMCC). Study findings will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000705684.

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.

ENIGMA's simple seven: Recommendations to enhance the reproducibility of resting-state fMRI in traumatic brain injury.

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field.

Improving quantitative susceptibility mapping for the identification of traumatic brain injury neurodegeneration at the individual level.

BACKGROUND: Emerging evidence suggests that traumatic brain injury (TBI) is a major risk factor for developing neurodegenerative disease later in life. Quantitative susceptibility mapping (QSM) has been used by an increasing number of studies in investigations of pathophysiological changes in TBI. However, generating artefact-free quantitative susceptibility maps in brains with large focal lesions, as in the case of moderate-to-severe TBI (ms-TBI), is particularly challenging. To address this issue, we utilized a novel two-pass masking technique and reconstruction procedure (two-pass QSM) to generate quantitative susceptibility maps (QSMxT; Stewart et al., 2022, Magn Reson Med.) in combination with the recently developed virtual brain grafting (VBG) procedure for brain repair (Radwan et al., 2021, NeuroImage) to improve automated delineation of brain areas. We used QSMxT and VBG to generate personalised QSM profiles of individual patients with reference to a sample of healthy controls. METHODS: Chronic ms-TBI patients (N = 8) and healthy controls (N = 12) underwent (multi-echo) GRE, and anatomical MRI (MPRAGE) on a 3T Siemens PRISMA scanner. We reconstructed the magnetic susceptibility maps using two-pass QSM from QSMxT. We then extracted values of magnetic susceptibility in grey matter (GM) regions (following brain repair via VBG) across the whole brain and determined if they deviate from a reference healthy control group [Z-score < -3.43 or > 3.43, relative to the control mean], with the aim of obtaining personalised QSM profiles. RESULTS: Using two-pass QSM, we achieved susceptibility maps with a substantial increase in quality and reduction in artefacts irrespective of the presence of large focal lesions, compared to single-pass QSM. In addition, VBG minimised the loss of GM regions and exclusion of patients due to failures in the region delineation step. Our findings revealed deviations in magnetic susceptibility measures from the HC group that differed across individual TBI patients. These changes included both increases and decreases in magnetic susceptibility values in multiple GM regions across the brain. CONCLUSIONS: We illustrate how to obtain magnetic susceptibility values at the individual level and to build personalised QSM profiles in ms-TBI patients. Our approach opens the door for QSM investigations in more severely injured patients. Such profiles are also critical to overcome the inherent heterogeneity of clinical populations, such as ms-TBI, and to characterize the underlying mechanisms of neurodegeneration at the individual level more precisely. Moreover, this new personalised QSM profiling could in the future assist clinicians in assessing recovery and formulating a neuroscience-guided integrative rehabilitation program tailored to individual TBI patients.

Prediction of cognitive outcome after mild traumatic brain injury from acute measures of communication within brain networks.

A considerable but ill-defined proportion of patients with mild traumatic brain injury (mTBI) experience persistent cognitive sequelae; the ability to identify such individuals early can help their neurorehabilitation. Here we tested the hypothesis that acute measures of efficient communication within brain networks are associated with patients' risk for unfavorable cognitive outcome six months after mTBI. Diffusion and T1-weighted magnetic resonance imaging, alongside cognitive measures, were obtained to map connectomes both one week and six months post injury in 113 adult patients with mTBI (71 males). For task-related brain networks, communication measures (characteristic path length, global efficiency, navigation efficiency) were moderately correlated with changes in cognition. Taking into account the covariance of age and sex, more unfavorable communication within networks were associated with worse outcomes within cognitive domains frequently impacted by mTBI (episodic and working memory, verbal fluency, inductive reasoning, and processing speed). Individuals with more unfavorable outcomes had significantly longer and less efficient pathways within networks supporting verbal fluency (all t > 2.786, p < .006), highlighting the vulnerability of language to mTBI. Participants in whom a task-related network was relatively inefficient one week post injury were up to eight times more likely to have unfavorable cognitive outcome pertaining to that task. Our findings suggest that communication measures within task-related networks identify mTBI patients who are unlikely to develop persistent cognitive deficits after mTBI. Our approach and findings can help to stratify mTBI patients according to their expected need for follow-up and/or neurorehabilitation.

The Australian Traumatic Brain Injury Initiative: Systematic Review of Predictive Value of Biological Markers for People With Moderate-Severe Traumatic Brain Injury.

The Australian Traumatic Brain Injury Initiative (AUS-TBI) aims to co-design a data resource to predict outcomes for people with moderate-severe traumatic brain injury (TBI) across Australia. Fundamental to this resource is the data dictionary, which is an ontology of data items. Here, we report the systematic review and consensus process for inclusion of biological markers in the data dictionary. Standardized database searches were implemented from inception through April 2022. English-language studies evaluating association between a fluid, tissue, or imaging marker and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Records were screened using a prioritization algorithm and saturation threshold in Research Screener. Full-length records were then screened in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association, and high-value predictors were discussed in a consensus process. Searches retrieved 106,593 records; 1,417 full-length records were screened, resulting in 546 included records. Two hundred thirty-nine individual markers were extracted, evaluated against 101 outcomes. Forty-one markers were judged to be high-value predictors of 15 outcomes. Fluid markers retained following the consensus process included ubiquitin C-terminal hydrolase L1 (UCH-L1), S100, and glial fibrillary acidic protein (GFAP). Imaging markers included computed tomography (CT) scores (e.g., Marshall scores), pathological observations (e.g., hemorrhage, midline shift), and magnetic resonance imaging (MRI) classification (e.g., diffuse axonal injury). Clinical context and time of sampling of potential predictive indicators are important considerations for utility. This systematic review and consensus process has identified fluid and imaging biomarkers with high predictive value of clinical and long-term outcomes following moderate-severe TBI.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Mapping Essential Tremor to a Common Brain Network Using Functional Connectivity Analysis.

BACKGROUND AND OBJECTIVES: The cerebello-thalamo-cortical circuit plays a critical role in essential tremor (ET). However, abnormalities have been reported in multiple brain regions outside this circuit, leading to inconsistent characterization of ET pathophysiology. Here, we test whether these mixed findings in ET localize to a common functional network and whether this network has therapeutic relevance. METHODS: We conducted a systematic literature search to identify studies reporting structural or metabolic brain abnormalities in ET. We then used 'coordinate network mapping,' which leverages a normative connectome (n = 1,000) of resting-state fMRI data to identify regions commonly connected to findings across all studies. To assess whether these regions may be relevant for the treatment of ET, we compared our network with a therapeutic network derived from lesions that relieved ET. Finally, we investigated whether the functional connectivity of this ET symptom network is abnormal in an independent cohort of patients with ET as compared with healthy controls. RESULTS: Structural and metabolic brain abnormalities in ET were located in heterogeneous regions throughout the brain. However, these coordinates were connected to a common functional brain network, including the cerebellum, thalamus, motor cortex, precuneus, inferior parietal lobe, and insula. The cerebellum was identified as the hub of this network because it was the only brain region that was both functionally connected to the findings of over 90% of studies and significantly different in connectivity compared with a control data set of other movement disorders. This network was strikingly similar to the therapeutic network derived from lesions improving ET, with key regions aligning in the thalamus and cerebellum. Furthermore, positive functional connectivity between the cerebellar network hub and the sensorimotor cortices was significantly reduced in patients with ET compared with healthy controls, and connectivity within this network was correlated with tremor severity and cognitive functioning. DISCUSSION: These findings suggest that the cerebellum is the central hub of a network commonly connected to structural and metabolic abnormalities in ET. This network may have therapeutic utility in refining and informing new targets for neuromodulation of ET.

Large-scale activation likelihood estimation meta-analysis of parkinsonian disorders.

Parkinsonism is a feature of several neurodegenerative disorders, including Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy. Neuroimaging studies have yielded insights into parkinsonian disorders; however, due to variability in results, the brain regions consistently implicated in these disorders remain to be characterized. The aim of this meta-analysis was to identify consistent brain abnormalities in individual parkinsonian disorders (Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy) and to investigate any shared abnormalities across disorders. A total of 44 591 studies were systematically screened following searches of two databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 132 neuroimaging studies (69 Parkinson's disease; 23 progressive supranuclear palsy; 17 corticobasal syndrome; and 23 multiple system atrophy) utilizing anatomical MRI, perfusion or metabolism PET and single-photon emission computed tomography. Meta-analyses were performed in each parkinsonian disorder within each imaging modality, as well as across all included disorders. Results in progressive supranuclear palsy and multiple system atrophy aligned with current imaging markers for diagnosis, encompassing the midbrain, and brainstem and putamen, respectively. PET imaging studies of patients with Parkinson's disease most consistently reported abnormality of the middle temporal gyrus. No significant clusters were identified in corticobasal syndrome. When examining abnormalities shared across all four disorders, the caudate was consistently reported in MRI studies, whilst the thalamus, inferior frontal gyrus and middle temporal gyri were commonly implicated by PET. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders and the first to characterize brain regions implicated across parkinsonian disorders.

Exploring personalized structural connectomics for moderate to severe traumatic brain injury.

Graph theoretical analysis of the structural connectome has been employed successfully to characterize brain network alterations in patients with traumatic brain injury (TBI). However, heterogeneity in neuropathology is a well-known issue in the TBI population, such that group comparisons of patients against controls are confounded by within-group variability. Recently, novel single-subject profiling approaches have been developed to capture inter-patient heterogeneity. We present a personalized connectomics approach that examines structural brain alterations in five chronic patients with moderate to severe TBI who underwent anatomical and diffusion magnetic resonance imaging. We generated individualized profiles of lesion characteristics and network measures (including personalized graph metric GraphMe plots, and nodal and edge-based brain network alterations) and compared them against healthy reference cases (N = 12) to assess brain damage qualitatively and quantitatively at the individual level. Our findings revealed alterations of brain networks with high variability between patients. With validation and comparison to stratified, normative healthy control comparison cohorts, this approach could be used by clinicians to formulate a neuroscience-guided integrative rehabilitation program for TBI patients, and for designing personalized rehabilitation protocols based on their unique lesion load and connectome.

Structural-functional connectivity bandwidth predicts processing speed in mild traumatic brain Injury: A multiplex network analysis.

An emerging body of work has revealed alterations in structural (SC) and functional (FC) brain connectivity following mild TBI (mTBI), with mixed findings. However, these studies seldom integrate complimentary neuroimaging modalities within a unified framework. Multilayer network analysis is an emerging technique to uncover how white matter organization enables functional communication. Using our novel graph metric (SC-FC Bandwidth), we quantified the information capacity of synchronous brain regions in 53 mild TBI patients (46 females; age mean = 40.2 years (y), σ = 16.7 (y), range: 18-79 (y). Diffusion MRI and resting state fMRI were administered at the acute and chronic post-injury intervals. Moreover, participants completed a cognitive task to measure processing speed (30 Seconds and Counting Task; 30-SACT). Processing speed was significantly increased at the chronic, relative to the acute post-injury intervals (p = <0.001). Nonlinear principal components of direct (t = -1.84, p = 0.06) and indirect SC-FC Bandwidth (t = 3.86, p = <0.001) predicted processing speed with a moderate effect size (R2 = 0.43, p < 0.001), while controlling for age. A subnetwork of interhemispheric edges with increased SC-FC Bandwidth was identified at the chronic, relative to the acute mTBI post-injury interval (pFDR = 0.05). Increased interhemispheric SC-FC Bandwidth of this network corresponded with improved processing speed at the chronic post-injury interval (partial r = 0.32, p = 0.02). Our findings revealed that mild TBI results in complex reorganization of brain connectivity optimized for maximum information flow, supporting improved cognitive performance as a compensatory mechanism. Moving forward, this measurement may complement clinical assessment as an objective marker of mTBI recovery.

Individual differences in procedural learning are associated with fiber specific white matter microstructure of the superior cerebellar peduncles in healthy adults.

Functional neuroimaging has consistently implicated the fronto-basal ganglia-cerebellar circuit in procedural learning-defined as the incidental acquisition of sequence information through repetition. Limited work has probed the role of white matter fiber pathways that connect the regions in this network, such as the superior cerebellar peduncles (SCP) and the striatal premotor tracts (STPMT), in explaining individual differences in procedural learning. High angular diffusion weighted imaging was acquired from 20 healthy adults aged 18-45 years. Fixel-based analysis was performed to extract specific measures of white matter microstructure (fiber density; FD) and macrostructure (fiber cross-section; FC), from the SCP and STPMT. These fixel metrics were correlated with performance on the serial reaction time (SRT) task, and sensitivity to the sequence was indexed by the difference in reaction time between the final block of sequence trials and the randomized block (namely, the 'rebound effect'). Analyses revealed a significant positive relationship between FD and the rebound effect in segments of both the left and right SCP (pFWE < .05). That is, increased FD in these tracts was associated with greater sensitivity to the sequence on the SRT task. No significant associations were detected between fixel metrics in the STPMT and the rebound effect. Our results support the likely role of white matter organization in the basal ganglia-cerebellar circuit in explaining individual differences in procedural learning.

Individualised profiling of white matter organisation in moderate-to-severe traumatic brain injury patients.

BACKGROUND AND PURPOSE: Approximately 65% of moderate-to-severe traumatic brain injury (m-sTBI) patients present with poor long-term behavioural outcomes, which can significantly impair activities of daily living. Numerous diffusion-weighted MRI studies have linked these poor outcomes to decreased white matter integrity of several commissural tracts, association fibres and projection fibres in the brain. However, most studies have focused on group-based analyses, which are unable to deal with the substantial between-patient heterogeneity in m-sTBI. As a result, there is increasing interest and need in conducting individualised neuroimaging analyses. MATERIALS AND METHODS: Here, we generated a detailed subject-specific characterisation of microstructural organisation of white matter tracts in 5 chronic patients with m-sTBI (29 - 49y, 2 females), presented as a proof-of-concept. We developed an imaging analysis framework using fixel-based analysis and TractLearn to determine whether the values of fibre density of white matter tracts at the individual patient level deviate from the healthy control group (n = 12, 8F, Mage = 35.7y, age range 25 - 64y). RESULTS: Our individualised analysis revealed unique white matter profiles, confirming the heterogenous nature of m-sTBI and the need of individualised profiles to properly characterise the extent of injury. Future studies incorporating clinical data, as well as utilising larger reference samples and examining the test-retest reliability of the fixel-wise metrics are warranted. CONCLUSIONS: Individualised profiles may assist clinicians in tracking recovery and planning personalised training programs for chronic m-sTBI patients, which is necessary to achieve optimal behavioural outcomes and improved quality of life.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

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.

Longitudinal developmental trajectories of inhibition and white-matter maturation of the fronto-basal-ganglia circuits.

Response inhibition refers to the cancelling of planned (or restraining of ongoing) actions and is required in much of our everyday life. Response inhibition appears to improve dramatically in early development and plateau in adolescence. The fronto-basal-ganglia network has long been shown to predict individual differences in the ability to enact response inhibition. In the current study, we examined whether developmental trajectories of fiber-specific white matter properties of the fronto-basal-ganglia network was predictive of parallel developmental trajectories of response inhibition. 138 children aged 9-14 completed the stop-signal task (SST). A subsample of 73 children underwent high-angular resolution diffusion MRI data for up to three time points. Performance on the SST was assessed using a parametric race modelling approach. White matter organization of the fronto-basal-ganglia circuit was estimated using fixel-based analysis. Contrary to predictions, we did not find any significant associations between maturational trajectories of fronto-basal-ganglia white matter and developmental improvements in SST performance. Findings suggest that the development of white matter organization of the fronto-basal-ganglia and development of stopping performance follow distinct maturational trajectories.

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.

Associations of cardiorespiratory fitness and exercise with brain white matter in healthy adults: A systematic review and meta-analysis.

Magnetic resonance imaging (MRI) studies have revealed positive associations between brain structure and physical activity, cardiorespiratory fitness, and exercise (referred to here as PACE). While a considerable body of research has investigated the effects of PACE on grey matter, much less is known about effects on white matter (WM). Hence, we conducted a systematic review of peer-reviewed literature published prior to 5th July 2021 using online databases (PubMed and Scopus) and PRISMA guidelines to synthesise what is currently known about the relationship between PACE and WM in healthy adults. A total of 60 studies met inclusion criteria and were included in the review. Heterogeneity across studies was calculated using Qochran's q test, and publication bias was assessed for each meta-analysis using Begg and Mazumdar rank correlation test. A meta-regression was also conducted to explore factors contributing to any observed heterogeneity. Overall, we observed evidence of positive associations between PACE and global WM volume (effect size (Hedges's g) = 0.137, p < 0.001), global WM anomalies (effect size = 0.182, p < 0.001), and local microstructure integrity (i.e., corpus callosum: effect size = 0.345, p < 0.001, and anterior limb of internal capsule: effect size = 0.198, p < 0.001). These findings suggest that higher levels of PACE are associated with improved global WM volume and local integrity. We appraise the quality of evidence, and discuss the implications of these findings for the preservation of WM across the lifespan. We conclude by providing recommendations for future research in order to advance our understanding of the specific PACE parameters and neurobiological mechanisms underlying these effects.