Longitudinal assessment of brain lesions in children with cerebral palsy and association with motor functioning.

BACKGROUND: The semi-quantitative scale of structural brain Magnetic Resonance Imaging (sqMRI) is a valid and reliable measure of brain lesion extent in children with cerebral palsy (CP) >3-years. This system scores lesion burden for each major brain region. The sum of the scores gives a global score ranging from 0 to 48. PURPOSE: To investigate how sqMRI scores changed from infancy to school-age, and whether these were associated with lesion load, age at first assessment, and gross motor function and its changes. MATERIALS AND METHODS: Twenty-eight children with CP underwent MRI and motor (Gross Motor Function Measure-66; GMFM-66) assessments when <40-months and again when 8-12-years. We investigated whether (i) toddler/preschool-age sqMRI scores (Time 1) reflected school-age sqMRI scores (Time 2); (ii) temporal changes in sqMRI scores (Time 1-Time 2 difference) were related to the child's age at Time 1 and lesion extent; (iii) early or later sqMRI scores were associated with motor functioning; (iv) sqMRI scores' longitudinal changes were associated with motor changes. RESULTS: Except for the corticosubcortical (grey-matter only) layers, sqMRI scores were significantly higher ('higher lesion load') at Time 1 than at Time 2. Age at Time 1 was not associated with temporal changes in global sqMRI scores. Higher lesion load at Time 2, but not at Time 1, was associated with smaller temporal changes in the global sqMRI score. The sqMRI scores were associated with concurrent, but not future or past motor GMFM-66 scores. Longitudinal changes in sqMRI scores were not associated with longitudinal changes in motor GMFM-66 scores. CONCLUSION: sqMRI scores of brain lesion extent at school-age are lower and a better indication of later-life motor functioning than very early life sqMRI scores. It may be best to interpret MRI white matter lesions with caution in very early life due to possible changes in lesion appearance and the unpredictable role of functional plasticity.

TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions.

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

A transposase-derived gene required for human brain development.

DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes disorder of intellectual disability, movement and seizures. In mice, Pgbd5 is required for the developmental induction of post-mitotic DNA breaks and recurrent somatic genome rearrangements in neurons. Together, these studies nominate PGBD5 as the long-hypothesized neuronal DNA nuclease required for brain function in mammals.

School readiness of children at high risk of cerebral palsy randomised to early neuroprotection and neurorehabilitation: protocol for a follow-up study of participants from four randomised clinical trials.

INTRODUCTION: School readiness includes cognitive, socio-emotional, language and physical growth and development domains which share strong associations with life-course opportunities. Children with cerebral palsy (CP) are at increased risk of poor school readiness compared with their typically developing peers. Recently, earlier diagnosis of CP has allowed interventions to commence sooner, harnessing neuroplasticity. First, we hypothesise that early referral to intervention for children at-risk of CP will lead to improved school readiness at 4-6 years relative to placebo or care as usual. Second, we hypothesise that receipt of early diagnosis and early intervention will lead to cost-savings in the form of reduced healthcare utilisation. METHODS AND ANALYSIS: Infants identified as at-risk of CP ≤6 months corrected age (n=425) recruited to four randomised trials of neuroprotectants (n=1), early neurorehabilitation (n=2) or early parenting support (n=1) will be re-recruited to one overarching follow-up study at age 4-6 years 3 months. A comprehensive battery of standardised assessments and questionnaires will be administered to assess all domains of school readiness and associated risk factors. Participants will be compared with a historical control group of children (n=245) who were diagnosed with CP in their second year of life. Mixed-effects regression models will be used to compare school readiness outcomes between those referred for early intervention versus placebo/care-as-usual. We will also compare health-resource use associated with early diagnosis and intervention versus later diagnosis and intervention. ETHICS AND DISSEMINATION: The Children's Health Queensland Hospital and Health Service, The University of Queensland, University of Sydney, Monash University and Curtin University Human Research Ethics Committees have approved this study. Informed consent will be sought from the parent or legal guardian of every child invited to participate. Results will be disseminated in peer-reviewed journals, scientific conferences and professional organisations, and to people with lived experience of CP and their families. TRIAL REGISTRATION NUMBER: ACTRN12621001253897.

White matter microstructure and receptive vocabulary in children with cerebral palsy: The role of interhemispheric connectivity.

BACKGROUND: Communication and cognitive impairments are common impediments to participation and social functioning in children with cerebral palsy (CP). Bilateral language networks underlie the function of some high-level language-related cognitive functions. PURPOSE: To explore the association between receptive vocabulary and white-matter microstructure in the temporal lobes and the central part of the temporo-temporal bundles in children with CP. MATERIALS AND METHODS: 37 children with spastic motor type CP (mean age 9.6 years, 25 male) underwent a receptive vocabulary test (Peabody Picture Vocabulary Test, PPVT-IV) and 3T MRI. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for the temporal lobes and the interhemispheric bundles traversing the splenium of the corpus callosum and the anterior commissure. Associations between microstructure and receptive vocabulary function were explored using univariable linear regression. RESULTS: PPVT-IV scores were significantly associated with mean white matter MD in the left temporal lobe, but not the right temporal lobe. There was no association between PPVT-IV and mean white matter FA in the temporal lobes. PPVT-IV scores were not significantly associated with the laterality of these diffusion tensor metrics. Within the corpus callosum, FA, but not MD of the temporo-temporal bundles was significantly associated with the PPVT-IV scores. Within the anterior commissure no equivalent relationship between diffusion metrics and PPVT-IV was found. CONCLUSION: Our findings add further understanding to the pathophysiological basis underlying receptive vocabulary skills in children with CP that could extend to other patients with early brain damage. This study highlights the importance of interhemispheric connections for receptive vocabulary.

Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants.

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born <31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development - Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm.

Predicting motor and cognitive outcomes from MRIs of brain structure in children with acquired brain injury: A pilot study.

BACKGROUND: Acquired Brain Injury (ABI) describes a range of brain injuries occurring after birth, including tumor, traumatic brain injury or stroke. Although MRIs are routinely used for diagnosis, prediction of outcome following brain injury is challenging. Quantitative structural information from brain images may provide an opportunity to predict patient outcomes; however, due to the high prevalence of severe pathology in children with ABI, quantitative approaches must be robust to injury severity. METHODS: In this pilot cross-sectional study, automated quantitative measures were extracted from the MRIs of a cohort of children with ABI (n = 30, 8-16 years, follow up MRI taken 1.8-13.4 years after time of injury) as well as 36 typically developing controls with no brain injury (7-17 years) using a pathology-robust technique. Measures of brain volume, lesion volume and cortical morphology were associated with concurrent motor, behavioral, visual and communicative function using Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS: These regression models were validated on a separate test set (n = 8 of the ABI cohort), which revealed significant correlations between measures of brain structure with motor, cognitive, visual and communicative function (r = 0.65-0.85, all p < 0.01). Furthermore, comparisons of the structural measures to the typically developing cohort revealed overall reductions in global grey matter volume among the ABI cohort, as well as cortical thinning in several cortical areas. CONCLUSIONS: These preliminary associations reveal that motor and behavioral function can be estimated from MRI alone, highlighting the potential utility of the proposed pathology-robust MRI quantification tools to provide estimates of long-term clinical prognosis of children with ABI following injury.

Cognitive, academic, executive and psychological functioning in children with spastic motor type cerebral palsy: Influence of extent, location, and laterality of brain lesions.

PURPOSE: To investigate, in spastic motor-type cerebral palsy, the association between 1) the location and extent of brain lesions and numerous psychological outcomes; 2) the laterality of brain lesions and performance of verbal-related cognitive functions. METHODS: The semi-quantitative scale for MRI (sqMRI) was scored for 101 children with cerebral palsy. Non-verbal and verbal proxy intelligence quotients (IQ), word reading, spelling, numerical operations skills, executive functioning, and psychological adjustment were assessed. Relationships between global and regional sqMRI scores and clinical scores were examined. The best multivariable linear regression model for each outcome was identified using the Bayesian Information Criteria. Regional sqMRI scores, gross motor functioning, manual ability, and epilepsy status were considered for inclusion as covariables. Where sqMRI scores made statistically significant contributions to models of verbal-related functioning, data were reanalysed including these sqMRI scores' laterality index. Verbal-related outcomes were compared between participants with left-sided versus bilateral brain lesions. RESULTS: Medial dorsal thalamus and parietal lobe lesions significantly accounted for poorer verbal proxy-IQ. Left-hemisphere lateralization of temporal lobe lesions was associated with poorer verbal proxy-IQ. Participants with bilateral lesions performed significantly better than those with unilateral left-sided lesions in verbal cognitive functions. Controlling for epilepsy diagnosis, participants with ventral posterior lateral thalamus lesions presented with better Behaviour Rating Inventory of Executive Function scores, although within the normal range. sqMRI scores were not significantly associated with some psychological outcomes or these only bordered on significance after accounting for relevant control variables. CONCLUSION: The laterality of early-life lesions influences the development of verbal-related cognitive functions.

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.

The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Prediction of childhood brain outcomes in infants born preterm using neonatal MRI and concurrent clinical biomarkers (PREBO-6): study protocol for a prospective cohort study.

INTRODUCTION: Infants born very preterm are at risk of adverse neurodevelopmental outcomes, including cognitive deficits, motor impairments and cerebral palsy. Earlier identification enables targeted early interventions to be implemented with the aim of improving outcomes. METHODS AND ANALYSIS: Protocol for 6-year follow-up of two cohorts of infants born <31 weeks gestational age (PPREMO: Prediction of Preterm Motor Outcomes; PREBO: Prediction of Preterm Brain Outcomes) and a small term-born reference sample in Brisbane, Australia. Both preterm cohorts underwent very early MRI and concurrent clinical assessment at 32 and 40 weeks postmenstrual age (PMA) and were followed up at 3, 12 and 24 months corrected age (CA). This study will perform MRI and electroencephalography (EEG). Primary outcomes include the Movement Assessment Battery for Children second edition and Full-Scale IQ score from the Wechsler Intelligence Scale for Children fifth edition (WISC-V). Secondary outcomes include the Gross Motor Function Classification System for children with cerebral palsy; executive function (Behavior Rating Inventory of Executive Function second edition, WISC-V Digit Span and Picture Span, Wisconsin Card Sorting Test 64 Card Version); attention (Test of Everyday Attention for Children second edition); language (Clinical Evaluation of Language Fundamentals fifth edition), academic achievement (Woodcock Johnson IV Tests of Achievement); mental health and quality of life (Development and Well-Being Assessment, Autism Spectrum Quotient-10 Items Child version and Child Health Utility-9D). AIMS: Examine the ability of early neonatal MRI, EEG and concurrent clinical measures at 32 weeks PMA to predict motor, cognitive, language, academic achievement and mental health outcomes at 6 years CA.Determine if early brain abnormalities persist and are evident on brain MRI at 6 years CA and the relationship to EEG and concurrent motor, cognitive, language, academic achievement and mental health outcomes. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Human Research Ethics Committees at Children's Health Queensland (HREC/19/QCHQ/49800) and The University of Queensland (2019000426). Study findings will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12619000155190p. WEB ADDRESS OF TRIAL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619000155190p.

Predicting motor outcome in preterm infants from very early brain diffusion MRI using a deep learning convolutional neural network (CNN) model.

BACKGROUND AND AIMS: Preterm birth imposes a high risk for developing neuromotor delay. Earlier prediction of adverse outcome in preterm infants is crucial for referral to earlier intervention. This study aimed to predict abnormal motor outcome at 2 years from early brain diffusion magnetic resonance imaging (MRI) acquired between 29 and 35 weeks postmenstrual age (PMA) using a deep learning convolutional neural network (CNN) model. METHODS: Seventy-seven very preterm infants (born <31 weeks gestational age (GA)) in a prospective longitudinal cohort underwent diffusion MR imaging (3T Siemens Trio; 64 directions, b â€‹= â€‹2000 â€‹s/mm2). Motor outcome at 2 years corrected age (CA) was measured by Neuro-Sensory Motor Developmental Assessment (NSMDA). Scores were dichotomised into normal (functional score: 0, normal; n â€‹= â€‹48) and abnormal scores (functional score: 1-5, mild-profound; n â€‹= â€‹29). MRIs were pre-processed to reduce artefacts, upsampled to 1.25 â€‹mm isotropic resolution and maps of fractional anisotropy (FA) were estimated. Patches extracted from each image were used as inputs to train a CNN, wherein each image patch predicted either normal or abnormal outcome. In a postprocessing step, an image was classified as predicting abnormal outcome if at least 27% (determined by a grid search to maximise the model performance) of its patches predicted abnormal outcome. Otherwise, it was considered as normal. Ten-fold cross-validation was used to estimate performance. Finally, heatmaps of model predictions for patches in abnormal scans were generated to explore the locations associated with abnormal outcome. RESULTS: For the identification of infants with abnormal motor outcome based on the FA data from early MRI, we achieved mean sensitivity 70% (standard deviation SD 19%), mean specificity 74% (SD 39%), mean AUC (area under the receiver operating characteristic curve) 72% (SD 14%), mean F1 score of 68% (SD 13%) and mean accuracy 73% (SD 19%) on an unseen test data set. Patch-based prediction heatmaps showed that the patches around the motor cortex and somatosensory regions were most frequently identified by the model with high precision (74%) as a location associated with abnormal outcome. Part of the cerebellum, and occipital and frontal lobes were also highly associated with abnormal NSMDA/motor outcome. DISCUSSION/CONCLUSION: This study established the potential of an early brain MRI-based deep learning CNN model to identify preterm infants at risk of a later motor impairment and to identify brain regions predictive of adverse outcome. Results suggest that predictions can be made from FA maps of diffusion MRIs well before term equivalent age (TEA) without any prior knowledge of which MRI features to extract and associated feature extraction steps. This method, therefore, is suitable for any case of brain condition/abnormality. Future studies should be conducted on a larger cohort to re-validate the robustness and effectiveness of these models.

Understanding the impact of bilateral brain injury in children with unilateral cerebral palsy.

The presence of bilateral brain injury in patients with unilateral cerebral palsy (CP) may impact neuroplasticity in the ipsilateral hemisphere; however, this pattern of injury is typically under-analyzed due to the lack of methods robust to severe injury. In this study, injury-robust methods have been applied to structural brain magnetic resonance imaging (MRI) data of a cohort of 91 children with unilateral CP (37 with unilateral and 54 with bilateral brain injury, 4-17 years) and 44 typically developing controls (5-17 years), to determine how brain structure is associated with concurrent motor function, and if these associations differ between patients with unilateral or bilateral injury. Regression models were used to associate these measures with two clinical scores of hand function, with patient age, gender, brain injury laterality, and interaction effects included. Significant associations with brain structure and motor function were observed (Pearson's r = .494-.716), implicating several regions of the motor pathway, and demonstrating an accurate prediction of hand function from MRI, regardless of the extent of brain injury. Reduced brain volumes were observed in patients with bilateral injury, including volumes of the thalamus and corpus callosum splenium, compared to those with unilateral injury, and the healthy controls. Increases in cortical thickness in several cortical regions were observed in cohorts with unilateral and bilateral injury compared to controls, potentially suggesting neuroplasticity might be occurring in the inferior frontal gyrus and the precuneus. These findings identify prospective useful target regions for transcranial magnetic stimulation intervention.

Quantifying deep grey matter atrophy using automated segmentation approaches: A systematic review of structural MRI studies.

The deep grey matter (DGM) nuclei of the brain play a crucial role in learning, behaviour, cognition, movement and memory. Although automated segmentation strategies can provide insight into the impact of multiple neurological conditions affecting these structures, such as Multiple Sclerosis (MS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Cerebral Palsy (CP), there are a number of technical challenges limiting an accurate automated segmentation of the DGM. Namely, the insufficient contrast of T1 sequences to completely identify the boundaries of these structures, as well as the presence of iso-intense white matter lesions or extensive tissue loss caused by brain injury. Therefore in this systematic review, 269 eligible studies were analysed and compared to determine the optimal approaches for addressing these technical challenges. The automated approaches used among the reviewed studies fall into three broad categories, atlas-based approaches focusing on the accurate alignment of atlas priors, algorithmic approaches which utilise intensity information to a greater extent, and learning-based approaches that require an annotated training set. Studies that utilise freely available software packages such as FIRST, FreeSurfer and LesionTOADS were also eligible, and their performance compared. Overall, deep learning approaches achieved the best overall performance, however these strategies are currently hampered by the lack of large-scale annotated data. Improving model generalisability to new datasets could be achieved in future studies with data augmentation and transfer learning. Multi-atlas approaches provided the second-best performance overall, and may be utilised to construct a "silver standard" annotated training set for deep learning. To address the technical challenges, providing robustness to injury can be improved by using multiple channels, highly elastic diffeomorphic transformations such as LDDMM, and by following atlas-based approaches with an intensity driven refinement of the segmentation, which has been done with the Expectation Maximisation (EM) and level sets methods. Accounting for potential lesions should be achieved with a separate lesion segmentation approach, as in LesionTOADS. Finally, to address the issue of limited contrast, R2*, T2* and QSM sequences could be used to better highlight the DGM due to its higher iron content. Future studies could look to additionally acquire these sequences by retaining the phase information from standard structural scans, or alternatively acquiring these sequences for only a training set, allowing models to learn the "improved" segmentation from T1-sequences alone.

A systematic review of structural MRI biomarkers in autism spectrum disorder: A machine learning perspective.

Autism Spectrum Disorder (ASD) affects approximately 1% of the population and leads to impairments in social interaction, communication and restricted, repetitive behaviours. Establishing robust neuroimaging biomarkers of ASD using structural magnetic resonance imaging (MRI) is an important step for diagnosing and tailoring treatment, particularly early in life when interventions can have the greatest effect. However currently, there is mixed findings on the structural brain changes associated with autism. Therefore in this systematic review, recent (post-2007), high-resolution (3 T) MRI studies investigating brain morphology associated with ASD have been collated to identify robust neuroimaging biomarkers of ASD. A systematic search was conducted on three databases; PubMed, Web of Science and Scopus, resulting in 123 reviewed articles. Patients with ASD were observed to have increased whole brain volume, particularly under 6 years of age. Other consistent changes observed in ASD patients include increased volume in the frontal and temporal lobes, increased cortical thickness in the frontal lobe, increased surface area and cortical gyrification, and increased cerebrospinal fluid volume, as well as reduced cerebellum volume and reduced corpus callosum volume, compared to typically developing controls. Findings were inconsistent regarding the developmental trajectory of brain volume and cortical thinning with age in ASD, as well as potential volume differences in the white matter, hippocampus, amygdala, thalamus and basal ganglia. To elucidate these inconsistencies, future studies should look towards aggregating MRI data from multiple sites or available repositories to avoid underpowered studies, as well as utilising methods which quantify larger-scale image features to reduce the number of statistical tests performed, and hence risk of false positive findings. Additionally, studies should look to perform a thorough validation strategy, to ensure generalisability of study findings, as well as look to leverage the improved image resolution of 3 T scanning to identify subtle brain changes related to ASD.

Brain lesion scores obtained using a simple semi-quantitative scale from MR imaging are associated with motor function, communication and cognition in dyskinetic cerebral palsy.

Purpose: To characterise brain lesions in dyskinetic cerebral palsy (DCP) using the semi-quantitative scale for structural MRI (sqMRI) and to investigate their relationship with motor, communication and cognitive function. Materials and methods: Thirty-nine participants (19 females, median age 21y) with DCP were assessed in terms of motor function, communication and a variety of cognitive domains. Whole-head magnetic resonance imaging (MRI) was performed including T1-MPRAGE, T2 turbo spin echo (axial plane), and fluid attenuated inversion recovery images (FLAIR). A child neurologist visually assessed images for brain lesions and scored these using the sqMRI. Ordinal, Poisson and binomial negative regression models identified which brain lesions accounted for clinical outcomes. Results: Brain lesions were most frequently located in the ventral posterior lateral thalamus and the frontal lobe. Gross (B = 0.180, p < .001; B = 0.658, p < .001) and fine (B = 0.136, p = .003; B = 0.540, p < .001) motor function were associated with global sqMRI score and parietal involvement. Communication functioning was associated with putamen involvement (B = 0.747, p < .028). Intellectual functioning was associated with global sqMRI score and posterior thalamus involvement (B = -0.018, p < .001; B = -0.192, p < .001). Selective attention was associated with global sqMRI score (B = -0.035, p < .001), parietal (B = -0.063, p = .023), and corpus callosum involvement (B = -0.448, p < .001). Visuospatial and visuoperceptive abilities were associated with global sqMRI score (B = -0.078, p = .007) and medial dorsal thalamus involvement (B = -0.139, p < .012), respectively. Conclusions: Key clinical outcomes in DCP are associated with specific observable brain lesions as indexed by a simple lesion scoring system that relies only on standard clinical MRI.

Identifying relevant biomarkers of brain injury from structural MRI: Validation using automated approaches in children with unilateral cerebral palsy.

Previous studies have proposed that the early elucidation of brain injury from structural Magnetic Resonance Images (sMRI) is critical for the clinical assessment of children with cerebral palsy (CP). Although distinct aetiologies, including cortical maldevelopments, white and grey matter lesions and ventricular enlargement, have been categorised, these injuries are commonly only assessed in a qualitative fashion. As a result, sMRI remains relatively underexploited for clinical assessments, despite its widespread use. In this study, several automated and validated techniques to automatically quantify these three classes of injury were generated in a large cohort of children (n = 139) aged 5-17, including 95 children diagnosed with unilateral CP. Using a feature selection approach on a training data set (n = 97) to find severity of injury biomarkers predictive of clinical function (motor, cognitive, communicative and visual function), cortical shape and regional lesion burden were most often chosen associated with clinical function. Validating the best models on the unseen test data (n = 42), correlation values ranged between 0.545 and 0.795 (p<0.008), indicating significant associations with clinical function. The measured prevalence of injury, including ventricular enlargement (70%), white and grey matter lesions (55%) and cortical malformations (30%), were similar to the prevalence observed in other cohorts of children with unilateral CP. These findings support the early characterisation of injury from sMRI into previously defined aetiologies as part of standard clinical assessment. Furthermore, the strong and significant association between quantifications of injury observed on structural MRI and multiple clinical scores accord with empirically established structure-function relationships.

Brain changes following four weeks of unimanual motor training: Evidence from behavior, neural stimulation, cortical thickness, and functional MRI.

Although different aspects of neuroplasticity can be quantified with behavioral probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right-handed participants practiced a sequence of finger-thumb opposition movements for 10 min each day with their left hand. After 4 weeks, performance for the practiced sequence improved significantly (P < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practiced, 6.5% control) and right (21.0%; 15.8%) hands. Training also induced significant (cluster p-FWE < 0.001) reductions in functional MRI activation for execution of the trained sequence, relative to the control sequence. These changes were observed as clusters in the premotor and supplementary motor cortices (right hemisphere, 301 voxel cluster; left hemisphere 700 voxel cluster), and sensorimotor cortices and superior parietal lobules (right hemisphere 864 voxel cluster; left hemisphere, 1947 voxel cluster). Transcranial magnetic stimulation over the right ("trained") primary motor cortex yielded a 58.6% mean increase in a measure of motor evoked potential amplitude, as recorded at the left abductor pollicis brevis muscle. Cortical thickness analyses based on structural MRI suggested changes in the right precentral gyrus, right post central gyrus, right dorsolateral prefrontal cortex, and potentially the right supplementary motor area. Such findings are consistent with LTP-like neuroplastic changes in areas that were already responsible for finger sequence execution, rather than improved recruitment of previously nonutilized tissue. Hum Brain Mapp 38:4773-4787, 2017. © 2017 Wiley Periodicals, Inc.

Measuring neuroplasticity associated with cerebral palsy rehabilitation: An MRI based power analysis.

Researchers in the field of child neurology are increasingly looking to supplement clinical trials of motor rehabilitation with neuroimaging in order to better understand the relationship between behavioural training, brain changes, and clinical improvements. Randomised controlled trials are typically accompanied by sample size calculations to detect clinical improvements but, despite the large cost of neuroimaging, not equivalent calculations for concurrently acquired imaging neuroimaging measures of changes in response to intervention. To aid in this regard, a power analysis was conducted for two measures of brain changes that may be indexed in a trial of rehabilitative therapy for cerebral palsy: cortical thickness of the impaired primary sensorimotor cortex, and fractional anisotropy of the impaired, delineated corticospinal tract. Power for measuring fractional anisotropy was assessed for both region-of-interest-seeded and fMRI-seeded diffusion tractography. Taking into account practical limitations, as well as data loss due to behavioural and image-processing issues, estimated required participant numbers were 101, 128 and 59 for cortical thickness, region-of-interest-based tractography, and fMRI-seeded tractography, respectively. These numbers are not adjusted for study attrition. Although these participant numbers may be out of reach of many trials, several options are available to improve statistical power, including careful preparation of participants for scanning using mock simulators, careful consideration of image processing options, and enrolment of as homogeneous a cohort as possible. This work suggests that smaller and moderate sized studies give genuine consideration to harmonising scanning protocols between groups to allow the pooling of data.