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.

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.

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.

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.

Using ventricular modeling to robustly probe significant deep gray matter pathologies: Application to cerebral palsy.

Understanding the relationships between the structure and function of the brain largely relies on the qualitative assessment of Magnetic Resonance Images (MRIs) by expert clinicians. Automated analysis systems can support these assessments by providing quantitative measures of brain injury. However, the assessment of deep gray matter structures, which are critical to motor and executive function, remains difficult as a result of large anatomical injuries commonly observed in children with Cerebral Palsy (CP). Hence, this article proposes a robust surrogate marker of the extent of deep gray matter injury based on impingement due to local ventricular enlargement on surrounding anatomy. Local enlargement was computed using a statistical shape model of the lateral ventricles constructed from 44 healthy subjects. Measures of injury on 95 age-matched CP patients were used to train a regression model to predict six clinical measures of function. The robustness of identifying ventricular enlargement was demonstrated by an area under the curve of 0.91 when tested against a dichotomised expert clinical assessment. The measures also showed strong and significant relationships for multiple clinical scores, including: motor function (r2 = 0.62, P < 0.005), executive function (r2 = 0.55, P < 0.005), and communication (r2 = 0.50, P < 0.005), especially compared to using volumes obtained from standard anatomical segmentation approaches. The lack of reliance on accurate anatomical segmentations and its resulting robustness to large anatomical variations is a key feature of the proposed automated approach. This coupled with its strong correlation with clinically meaningful scores, signifies the potential utility to repeatedly assess MRIs for clinicians diagnosing children with CP. Hum Brain Mapp 37:3795-3809, 2016. © 2016 Wiley Periodicals, Inc.

Alterations in regional shape on ipsilateral and contralateral cortex contrast in children with unilateral cerebral palsy and are predictive of multiple outcomes.

Congenital brain lesions result in a wide range of cerebral tissue alterations observed in children with cerebral palsy (CP) that are associated with a range of functional impairments. The relationship between injury severity and functional outcomes, however, remains poorly understood. This research investigates the differences in cortical shape between children with congenital brain lesions and typically developing children (TDC) and investigates the correlations between cortical shape and functional outcome in a large cohort of patients diagnosed with unilateral CP. Using 139 structural magnetic resonance images, including 95 patients with clinically diagnosed CP and 44 TDC, cortical segmentations were obtained using a modified expectation maximization algorithm. Three shape characteristics (cortical thickness, curvature, and sulcal depth) were computed within a number of cortical regions. Significant differences in these shape measures compared to the TDC were observed on both the injured hemisphere of children with CP (P < 0.004), as well as on the apparently uninjured hemisphere, illustrating potential compensatory mechanisms in these children. Furthermore, these shape measures were significantly correlated with several functional outcomes, including motor, cognition, vision, and communication (P < 0.012), with three out of these four models performing well on test set validation. This study highlights that cortical neuroplastic effects may be quantified using MR imaging, allowing morphological changes to be studied longitudinally, including any influence of treatment. Ultimately, such approaches could be used for the long term prediction of outcomes and the tailoring of treatment to individuals. Hum Brain Mapp 37:3588-3603, 2016. © 2016 Wiley Periodicals, Inc.

Automated, quantitative measures of grey and white matter lesion burden correlates with motor and cognitive function in children with unilateral cerebral palsy.

White and grey matter lesions are the most prevalent type of injury observable in the Magnetic Resonance Images (MRIs) of children with cerebral palsy (CP). Previous studies investigating the impact of lesions in children with CP have been qualitative, limited by the lack of automated segmentation approaches in this setting. As a result, the quantitative relationship between lesion burden has yet to be established. In this study, we perform automatic lesion segmentation on a large cohort of data (107 children with unilateral CP and 18 healthy children) with a new, validated method for segmenting both white matter (WM) and grey matter (GM) lesions. The method has better accuracy (94%) than the best current methods (73%), and only requires standard structural MRI sequences. Anatomical lesion burdens most predictive of clinical scores of motor, cognitive, visual and communicative function were identified using the Least Absolute Shrinkage and Selection operator (LASSO). The improved segmentations enabled identification of significant correlations between regional lesion burden and clinical performance, which conform to known structure-function relationships. Model performance was validated in an independent test set, with significant correlations observed for both WM and GM regional lesion burden with motor function (p < 0.008), and between WM and GM lesions alone with cognitive and visual function respectively (p < 0.008). The significant correlation of GM lesions with functional outcome highlights the serious implications GM lesions, in addition to WM lesions, have for prognosis, and the utility of structural MRI alone for quantifying lesion burden and planning therapy interventions.

Optimization of MRI-based scoring scales of brain injury severity in children with unilateral cerebral palsy.

BACKGROUND: Several scoring systems for measuring brain injury severity have been developed to standardize the classification of MRI results, which allows for the prediction of functional outcomes to help plan effective interventions for children with cerebral palsy. OBJECTIVE: The aim of this study is to use statistical techniques to optimize the clinical utility of a recently proposed template-based scoring method by weighting individual anatomical scores of injury, while maintaining its simplicity by retaining only a subset of scored anatomical regions. MATERIALS AND METHODS: Seventy-six children with unilateral cerebral palsy were evaluated in terms of upper limb motor function using the Assisting Hand Assessment measure and injuries visible on MRI using a semiquantitative approach. This cohort included 52 children with periventricular white matter injury and 24 with cortical and deep gray matter injuries. A subset of the template-derived cerebral regions was selected using a data-driven region selection algorithm. Linear regression was performed using this subset, with interaction effects excluded. RESULTS: Linear regression improved multiple correlations between MRI-based and Assisting Hand Assessment scores for both periventricular white matter (R squared increased to 0.45 from 0, P < 0.0001) and cortical and deep gray matter (0.84 from 0.44, P < 0.0001) cohorts. In both cohorts, the data-driven approach retained fewer than 8 of the 40 template-derived anatomical regions. CONCLUSION: The equal or better prediction of the clinically meaningful Assisting Hand Assessment measure using fewer anatomical regions highlights the potential of these developments to enable enhanced quantification of injury and prediction of patient motor outcome, while maintaining the clinical expediency of the scoring approach.

The need for improved brain lesion segmentation techniques for children with cerebral palsy: A review.

Cerebral palsy (CP) describes a group of permanent disorders of posture and movement caused by disturbances in the developing brain. Accurate diagnosis and prognosis, in terms of motor type and severity, is difficult to obtain due to the heterogeneous appearance of brain injury and large anatomical distortions commonly observed in children with CP. There is a need to optimise treatment strategies for individual patients in order to lead to lifelong improvements in function and capabilities. Magnetic resonance imaging (MRI) is critical to non-invasively visualizing brain lesions, and is currently used to assist the diagnosis and qualitative classification in CP patients. Although such qualitative approaches under-utilise available data, the quantification of MRIs is not automated and therefore not widely performed in clinical assessment. Automated brain lesion segmentation techniques are necessary to provide valid and reproducible quantifications of injury. Such techniques have been used to study other neurological disorders, however the technical challenges unique to CP mean that existing algorithms require modification to be sufficiently reliable, and therefore have not been widely applied to MRIs of children with CP. In this paper, we present a review of a subset of available brain injury segmentation approaches that could be applied to CP, including the detection of cortical malformations, white and grey matter lesions and ventricular enlargement. Following a discussion of strengths and weaknesses, we suggest areas of future research in applying segmentation techniques to the MRI of children with CP. Specifically, we identify atlas-based priors to be ineffective in regions of substantial malformations, instead propose relying on adaptive, spatially consistent algorithms, with fast initialisation mechanisms to provide additional robustness to injury. We also identify several cortical shape parameters that could be used to identify cortical injury, and shape modelling approaches to identify anatomical injury. The benefits of automatic segmentation in CP is important as it has the potential to elucidate the underlying relationship between image derived features and patient outcome, enabling better tailoring of therapy to individual patients.

Optofluidic needle probe integrating targeted delivery of fluid with optical coherence tomography imaging.

We present an optofluidic optical coherence tomography (OCT) needle probe capable of modifying the local optical properties of tissue to improve needle-probe imaging performance. The side-viewing probe comprises an all-fiber-optic design encased in a hypodermic needle (outer diameter 720 µm) and integrates a coaxial fluid-filled channel, terminated by an outlet adjacent to the imaging window, allowing focal injection of fluid to a target tissue. This is the first fully integrated OCT needle probe design to incorporate fluid injection into the imaging mechanism. The utility of this probe is demonstrated in air-filled sheep lungs, where injection of small quantities of saline is shown, by local refractive index matching, to greatly improve image penetration through multiple layers of alveoli. 3D OCT images are correlated against histology, showing improvement in the capability to image lung structures such as bronchioles and blood vessels.