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The clinical translation of new nanoparticle-based therapies for high-grade glioma (HGG) remains extremely poor. This has partly been due to the lack of suitable preclinical mouse models capable of replicating the complex characteristics of recurrent HGG (rHGG), namely the heterogeneous structural and functional characteristics of the blood-brain barrier (BBB). The goal of this study is to compare the characteristics of the tumor BBB of rHGG with two different mouse models of HGG, the ubiquitously used U87 cell line xenograft model and a patient-derived cell line WK1 xenograft model, in order to assess their suitability for nanomedicine research. Method: Structural MRI was used to assess the extent of BBB opening in mouse models with a fully developed tumor, and dynamic contrast enhanced MRI was used to obtain values of BBB permeability in contrast enhancing tumor. H&E and immunofluorescence staining were used to validate results obtained from the in vivo imaging studies. Results: The extent of BBB disruption and permeability in the contrast enhancing tumor was significantly higher in the U87 model than in rHGG. These values in the WK1 model are similar to those of rHGG. The U87 model is not infiltrative, has an entirely abnormal and leaky vasculature and it is not of glial origin. The WK1 model infiltrates into the non-neoplastic brain parenchyma, it has both regions with intact BBB and regions with leaky BBB and remains of glial origin. Conclusion: The WK1 mouse model more accurately reproduces the extent of BBB disruption, the level of BBB permeability and the histopathological characteristics found in rHGG patients than the U87 mouse model, and is therefore a more clinically relevant model for preclinical evaluations of emerging nanoparticle-based therapies for HGG.

1AbstractMagnetic Resonance Imaging (MRI) motion artefacts frequently complicate structural and diffusion MRI analyses. While diffusion imaging is easily ‘scrubbed’ of motion affected volumes, the same is not true for structural images. Structural images are critical to most diffusion-imaging pipelines thus their corruption can lead to disproportionate data loss. To enable diffusion-image processing when structural images have been corrupted, we propose a means by which synthetic structural images can be generated from diffusion MRI. This technique combines multi-tissue constrained spherical deconvolution, which is central to many existing diffusion analyses, with the Bloch equations which allow simulation of MRI intensities given scanner parameters and magnetic resonance (MR) tissue properties. We applied this technique to 32 scans, including those acquired on different scanners, with different protocols and with pathology present. The resulting synthetic T1w and T2w images were visually convincing and exhibited similar tissue contrast to acquired structural images. These were also of sufficient quality to drive a Freesurfer-based tractographic analysis. In this analysis, probabilistic tractography connecting the thalamus to the primary sensorimotor cortex was delineated with Freesurfer, using either real or synthetic structural images. Tractography for real and synthetic conditions was largely identical in terms of both voxels encountered (Dice 0.88 – 0.95) and mean fractional anisotropy (intrasubject absolute difference 0.00 – 0.02). We provide executables for the proposed technique in the hope that these may aid the community in analysing datasets where structural image corruption is common, such as studies of children or cognitively impaired persons.HighlightsWe propose a simple means of synthesizing T1w and T2w images from diffusion dataThe proposed method worked well for a variety of acquisitionsSynthetic images showed tissue contrast akin to acquired imagesSynthetic images were high enough quality to be used for Freesurfer seeded diffusion tractographyThis method enables analysis of datasets where motion has corrupted acquired structural MRIs

Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well‐recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer's Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer's Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT: a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust pre‐processing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 696 scans of predominantly healthy participants (539 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer's Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan‐rescan error of this distance was 1 mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer's Loop with clinically feasible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post‐processing methods., Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well‐recognised complication of temporal lobectomy. We demonstrated a fully automated pipeline that could delineate this structure reliably and realistically on more than 500 unique brains, including both advanced and more clinically‐accessible acquisitions. Results were in line with historical dissections studies and median scan‐rescan error was 1 mm.

International audience; Magnetic Resonance Imaging (MRI) motion artefacts frequently complicate structural and diffusion MRI analyses. While diffusion imaging is easily ’scrubbed’ of motion affected volumes, the same is not true for T1w or T2w ’structural’ images. Structural images are critical to most diffusion-imaging pipelines thus their corruption can lead to disproportionate data loss. To enable diffusion-image processing when structural images are missing or have been corrupted, we propose a means by which synthetic structural images can be generated from diffusion MRI. This technique combines multi-tissue constrained spherical deconvolution, which is central to many existing diffusion analyses, with the Bloch equations that allow simulation of MRI intensities for given scanner parameters and magnetic resonance (MR) tissue properties. We applied this technique to 32 scans, including those acquired on different scanners, with different protocols and with pathology present. The resulting synthetic T1w and T2w images were visually convincing and exhibited similar tissue contrast to acquired structural images. These were also of sufficient quality to drive a Freesurfer-based tractographic analysis. In this analysis, probabilistic tractography connecting the thalamus to the primary sensorimotor cortex was delineated with Freesurfer, using either real or synthetic structural images. Tractography for real and synthetic conditions was largely identical in terms of both voxels encountered (Dice 0.88-0.95) and mean fractional anisotropy (intrasubject absolute difference 0.00-0.02). We provide executables for the proposed technique in the hope that these may aid the community in analysing datasets where structural image corruption is common, such as studies of children or cognitively impaired persons.

1AbstractQuadrantanopia caused by inadvertent severing of Meyer’s Loop of the optic radiation is a well-recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer’s Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer’s Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT – a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust preprocessing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 694 scans of predominantly healthy participants (538 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer’s Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan-rescan error of this distance was 1mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer’s Loop with clinically accessible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post-processing methods.HighlightsWe propose a fully automated means of delineating the optic radiation using diffusion MRI from DICOM dataAnatomical measurements from tractography of over 500 brains align well with previous dissection studiesThe proposed pipeline works well with clinically accessible and advanced acquisitionsMedian scan-rescan error was 1mmPlausible tractography was generated when pathology was present

Diffusion MRI tractography is commonly used to delineate white matter tracts. These delineations can be used for planning neurosurgery or for identifying regions of interest from which microstructural measurements can be taken. Probabilistic tractography produces different delineations each time it is run, potentially leading to microstructural measurements or anatomical delineations that are not reproducible. Generating a sufficiently large number of streamlines is required to avoid this scenario, but what constitutes “sufficient” is difficult to assess and so streamline counts are typically chosen in an arbitrary or qualitative manner. This work explores several factors influencing tractography reliability and details two methods for estimating this reliability. The first method automatically estimates the number of streamlines required to achieve reliable microstructural measurements, whilst the second estimates the number of streamlines required to achieve a reliable binarised trackmap than can be used clinically. Using these methods, we calculated the number of streamlines required to achieve a range of quantitative reproducibility criteria for three anatomical tracts in 40 Human Connectome Project datasets. Actual reproducibility was checked by repeatedly generating the tractograms with the calculated numbers of streamlines. We found that the required number of streamlines varied strongly by anatomical tract, image resolution, number of diffusion directions, the degree of reliability desired, the microstructural measurement of interest, and/or the specifics on how the tractogram was converted to a binary volume. The proposed methods consistently predicted streamline counts that achieved the target reproducibility. Implementations are made available to enable the scientific community to more-easily achieve reproducible tractography.

Background Cerebral palsy (CP) is frequently associated with specific cognitive impairments, such as executive dysfunction which are related to participation and quality of life (QOL). The proposed study will examine whether a computerized executive function (EF) training programme could provide superior benefits for executive functioning, participation, QOL and brain plasticity, as compared to usual care. Methods A single-blind randomized controlled trial (RCT) design will be performed. Thirty children with CP aged 8 to 12 years will participate in a home-based computerized multi-modal executive training programme (12 weeks, 5 days a week, 30 min a day training, total dose = 30 h). Thirty children with CP matched by age, sex, motor and intelligence quotient (IQ) will compose the waitlist group. Cognitive, behavioural, emotional, participation and QOL measures will be obtained at three time points: before, immediately after and 9 months after completing the training. Additionally, structural and functional (resting state) magnetic resonance images (MRI) will be obtained in a subsample of 15 children from each group. Outcomes between groups will be compared following standard principles for RCTs. Discussion The study will test whether the cognitive training programme exerts a positive effect not only on neuropsychological and daily functioning of children with CP but also on other measures such as participation and QOL. We will also use brain MRI to test brain functional and structural changes after the intervention. If this on-line and home-based training programme proves effective, it could be a cost-effective intervention with short- and long-term effects on EF, participation or QOL in CP. Trial registration ClinicalTrials.gov: NCT04025749. Registered 19 July 2019. Retrospectively registered.

Estimation of structural biomarkers and covariance networks from MRI have provided valuable insight into the morphological processes and organisation of the human brain. State-of-the-art analyses such as linear mixed effects (LME) models and pairwise descriptive correlation networks are usually performed independently, providing an incomplete picture of the relationships between the biomarkers and network organisation. Furthermore, descriptive network analyses do not generalise to the population level. In this work, we develop a Bayesian generative model based on wombling that allows joint statistical inference on biomarkers and connectivity covariance structure. The parameters of the wombling model were estimated via Markov chain Monte Carlo methods, which allow for simultaneous inference of the brain connectivity matrix and the association of participants’ biomarker covariates. To demonstrate the utility of wombling on real data, the method was used to characterise intrahemispheric cortical thickness and networks in a study cohort of subjects with Alzheimer’s disease (AD), mild-cognitive impairment and healthy ageing. The method was also compared with state-of-the-art alternatives. Our Bayesian modelling approach provided posterior probabilities for the connectivity matrix of the wombling model, accounting for the uncertainty for each connection. This provided superior inference in comparison with descriptive networks. On the study cohort, there was a loss of connectivity across diagnosis levels from healthy to Alzheimer’s disease for all network connections (posterior probability ≥ 0.7). In addition, we found that wombling and LME model approaches estimated that cortical thickness progressively decreased along the dementia pathway. The major advantage of the wombling approach was that spatial covariance among the regions and global cortical thickness estimates could be estimated. Joint modelling of biomarkers and covariance networks using our novel wombling approach allowed accurate identification of probabilistic networks and estimated biomarker changes that took into account spatial covariance. The wombling model provides a novel tool to address multiple brain features, such as morphological and connectivity changes facilitating a better understanding of disease pathology.

Background High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood–brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor. Methods Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET–CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue. Results The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected. Conclusions FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

We have reported reliable changes in behavior, brain structure, and function in 24 healthy right‐handed adults who practiced a finger‐thumb opposition sequence task with their left hand for 10 min daily, over 4 weeks. Here, we extend these findings by using diffusion MRI to investigate white‐matter changes in the corticospinal tract, basal‐ganglia, and connections of the dorsolateral prefrontal cortex. Twenty‐three participant datasets were available with pre‐training and post‐training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group P

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

Aims To investigate the extent of white matter damage in children with unilateral cerebral palsy (UCP) caused by periventricular white matter lesions comparing between unilateral and bilateral lesions; and to investigate a relationship between white matter microstructure and hand function. Methods and procedures Diffusion MRI images from 46 children with UCP and 18 children with typical development (CTD) were included. Subjects were grouped by side of hemiparesis and unilateral or bilateral lesions. A voxel-wise white matter analysis was performed to identify regions where fractional anisotropy (FA) was significantly different between UCP groups and CTD; and where FA correlated with either dominant or impaired hand function (using Jebsen Taylor Hand Function Test). Outcomes and results Children with unilateral lesions had reduced FA in the corticospinal tract of the affected hemisphere. Children with bilateral lesions had widespread reduced FA extending into all lobes. In children with left hemiparesis, impaired hand function correlated with FA in the contralateral corticospinal tract. Dominant hand function correlated with FA in the posterior thalamic radiations as well as multiple other regions in both left and right hemiparesis groups. Conclusions and implications Periventricular white matter lesions consist of focal and diffuse components. Focal lesions may cause direct motor fibre insult resulting in motor impairment. Diffuse white matter injury is heterogeneous, and may contribute to more global dysfunction. What this paper adds ⿢ Focal white matter alterations are observed in the corticospinal tract in UCP with unilateral white matter lesions ⿢ Diffuse white matter alterations throughout all cerebral lobes are observed in UCP with bilateral white matter lesions ⿢ Fractional anisotropy in the posterior thalamic radiations correlates with dominant hand function

Direct measurement of recovery from brain injury is an important goal in neurorehabilitation, and requires reliable, objective, and interpretable measures of changes in brain function, referred to generally as “neuroplasticity.” One popular imaging modality for measuring neuroplasticity is task-based functional magnetic resonance imaging (t-fMRI). In the field of neurorehabilitation, however, assessing neuroplasticity using t-fMRI presents a significant challenge. This commentary reviews t-fMRI changes commonly reported in patients with cerebral palsy or acquired brain injuries, with a focus on studies of motor rehabilitation, and discusses complexities surrounding their interpretations. Specifically, we discuss the difficulties in interpreting t-fMRI changes in terms of their underlying causes, that is, differentiating whether they reflect genuine reorganisation, neurological restoration, compensation, use of preexisting redundancies, changes in strategy, or maladaptive processes. Furthermore, we discuss the impact of heterogeneous disease states and essential t-fMRI processing steps on the interpretability of activation patterns. To better understand therapy-induced neuroplastic changes, we suggest that researchers utilising t-fMRI consider concurrently acquiring information from an additional modality, to quantify, for example, haemodynamic differences or microstructural changes. We outline a variety of such supplementary measures for investigating brain reorganisation and discuss situations in which they may prove beneficial to the interpretation of t-fMRI data.

Background Of children with hemiplegic cerebral palsy, 75% have impaired somatosensory function, which contributes to learned non-use of the affected upper limb. Currently, motor learning approaches are used to improve upper-limb motor skills in these children, but few studies have examined the effect of any intervention to ameliorate somatosensory impairments. Recently, Sense© training was piloted with a paediatric sample, seven children with hemiplegic cerebral palsy, demonstrating statistically and clinically significant change in limb position sense, goal performance and bimanual hand-use. This paper describes a protocol for a Randomised Controlled Trial of Sense© for Kids training, hypothesising that its receipt will improve somatosensory discrimination ability more than placebo (dose-matched Goal Directed Therapy via Home Program). Secondary hypotheses include that it will alter brain activation in somatosensory processing regions, white-matter characteristics of the thalamocortical tracts and improve bimanual function, activity and participation more than Goal Directed Training via Home Program. Methods and design This is a single blind, randomised matched-pair, placebo-controlled trial. Participants will be aged 6–15 years with a confirmed description of hemiplegic cerebral palsy and somatosensory discrimination impairment, as measured by the sense©_assess Kids. Participants will be randomly allocated to receive 3h a week for 6 weeks of either Sense© for Kids or Goal Directed Therapy via Home Program. Children will be matched on age and severity of somatosensory discrimination impairment. The primary outcome will be somatosensory discrimination ability, measured by sense©_assess Kids score. Secondary outcomes will include degree of brain activation in response to a somatosensory task measured by functional MRI, changes in the white matter of the thalamocortical tract measured by diffusion MRI, bimanual motor function, activity and participation. Discussion This study will assess the efficacy of an intervention to increase somatosensory discrimination ability in children with cerebral palsy. It will explore clinically important questions about the efficacy of intervening in somatosensation impairment to improve bimanual motor function, compared with focusing on motor impairment directly, and whether focusing on motor impairment alone can affect somatosensory ability. Trial registration This trial is registered with the Australian New Zealand Clinical Trials Registry, registration number: ACTRN12618000348257. World Health Organisation universal trial number: U1111–1210-1726. Electronic supplementary material The online version of this article (10.1186/s12887-018-1217-5) contains supplementary material, which is available to authorized users.

Image noise and motion degrade the quality of MR images. Block-matching methods are a well-demonstrated means of improving signal-to-noise ratios in such images. Ideally, block-matching methods would search within the entire image for matching patches to a target, leveraging an image’s full informational redundancy, but this carries impractical computational costs. A well-known workaround, implemented in the traditional Non-Local Means (NLM) filter, is to search for matching patches only within a local neighborhood. Here, we detail a Global Approximate Block-matching (GAB) method that, via a self-organizing map, rapidly searches an entire image for patches similar to a target. Four sets of five T1 + five FLAIR images were acquired. GAB and NLM both denoised the T1s; the results were compared to subject-wise mean images with very low noise. GAB reliably produced images that were more similar to these ‘templates’ than NLM. This was repeated for the same images with motion-like artefacts artificially added. GAB, again, outperformed NLM. For this task, GAB further improved with multichannel inputs, even if the FLAIR image contained artefacts. GAB’s competitive performance appeared to be due to a better balance between preserving image features and removing noise/artefacts. The performance of GAB and NLM variants hinted that GAB’s advantage was not brute-force processing, but its ability to effectively search the whole image.

Deep learning techniques for tissue segmentation require large amounts of data for training, testing, and cross-validation. Manually generating such segmentations, however, is extremely time-consuming. This can lead to such techniques being limited to imaging modalities and populations for which ground truths already exist, overfitting, or the use of data that is not expert-checked and so likely to contain errors. A need exists for a means of accelerating expert tissue-segmentation, such as automated techniques that require little correction and have little reliance on existing atlases. Here, we describe a method which can reliably perform registration-free tissue-segmentation using a single atlas that is only partially complete. This Global Approximate Block-matching method utilizes a self-organizing map, an unorthodox artificial neural network. This network trains quickly only on the provided partial atlas and allows these labels to be propagated throughout the target image via block-matching. Using this technique we segmented brains of 22 subjects and compared its performance to expert ground truths. When provided with an atlas for which only 2% of voxels were labelled, this achieved mean dice similarity coefficients of 0.88 (grey-matter) and 0.92 (white matter). Performance improved as higher amounts of atlas were provided, up to a maximum of 0.93 (grey-matter) and 0.96 (white matter) when a single whole-brain atlas was provided. Although segmentations produced by this technique are sufficiently accurate to be used directly for many purposes, its primary use case may lie in accelerating the creation of expert atlases for deep-learning techniques.

Brain injury constitutes a significant health burden worldwide, and outcomes are generally poor. To improve treatment, we must better understand how injury affects brain function, how the brain responds to learning pressures (neuroplasticity), and the interaction between the two. This is difficult, however, because of current technological shortcomings. This thesis focusses on the measurement of neuroplasticity in response to motor training in situations such as rehabilitation following brain injury. Although the principles and methods discussed generalise to many forms of brain pathology, discussion is generally focussed on unilateral cerebral palsy (UCP) because altered brain-development in UCP makes analyses particularly difficult. This begins with a literature review (Chapter 2) that outlines UCP, rehabilitative approaches, and the relationship between atypical brain organisation and early-life brain injury. Also discussed is how novel rehabilitation strategies may stem from studying brain changes induced by rehabilitation, and why the most informative findings are likely to come from studies utilising multiple imaging modalities. Blood Oxygen-Level Dependent Functional Magnetic Resonance Imaging (fMRI) measures brain activity indirectly and has been used to study neuroplasticity in both healthy participants and those with brain pathology. Although fMRI confounds are well understood, no published work has explored their cumulative effect when brain injury is present. Resultantly, confounds have largely been ignored, leading to heterogeneous findings that have provided little toward understanding brain changes, biologically speaking. Chapter 3 examines the cumulative effect of fMRI confounds, assumptions, and other issues, when attempting to measure neuroplasticity in participants with brain injury. This work concludes that, although fMRI can be expected to locate approximate regions of brain activation in an individual scan, numerous confounding factors make its interpretation, in terms of neuroplasticity, difficult without additional information acquired through alternative means. Diffusion MRI (dMRI) is an imaging modality that is typically used to identify the brain's white-matter pathways and calculate metrics that are influenced by factors such as myelination or axonal density. Standard dMRI analyses are ill suited to studying brain injury due to their reliance on brain 'atlases' which indicate relationships between brain regions and brain functions. Brain pathology can prevent reliable atlas registration, and alter relationships between structure and function. Chapter 4 details a novel dMRI analysis designed to measure neuroplasticity, addressing the need for a sensitive and reliable alternative to standalone-fMRI. This method utilises surface-based fMRI analyses, rather than brain atlases, to locate regions involved in motor execution. Corticospinal (CST) and thalamocortical tracts emanating from these regions are delineated using dMRI tractography and machine learning. This method was applied to children with UCP - the majority of whom presented with significant brain pathology. Relationships between dMRI measures of CST microstructure and clinical measures of motor function were identified. In these and other measures, the present method outperformed a cutting-edge voxelwise fMRI+dMRI technique applied to the same data. Studying plasticity in participants with brain injury requires first understanding the neuroplastic processes of healthy people. Imaging literature in this area is largely fragmented: studies are typically mono-modal and have incomparable methodologies. Chapter 5 and Chapter 6 address this through a multimodal investigation into motor-learning driven neuroplasticity. Twenty-four healthy adults practised a finger-thumb opposition sequence with their non-dominant hand daily. After four weeks, task performance improved and fMRI activation associated with trained-sequence execution decreased. In 'trained' motor areas, transcranial magnetic stimulation mean evoked potentials (MEPs; at the pollicis brevis) increased; MEP map volume did not. These responses overlapped spatially with fMRI and potential cortical thickness increases. These results imply that a long-term-potentiation-like process occurred predominantly in regions already responsible for conducting the task, improving task-processing efficiency. Potential cortical thickness increases were also found in the dorsolateral prefrontal cortex (dlPFC). Diffusion changes were seen in striatal regions connected to the dlPFC and connections between these regions. The aforementioned fMRI-driven dMRI method revealed changes to the CST consistent with myelination. Chapter 7 describes an attempt to take this analysis further: to measure brain changes in 14 children with UCP who participated in 20 weeks of virtual reality therapy. Clinical improvements were limited and no changes in associated white matter microstructure were detected. The fMRI-driven dMRI method demonstrated a high degree of test-retest reliability in the 13 enrolled controls, and so it is likely that statistical power was limited by degrees of clinical improvement. The number of enrolees required to achieve meaningful power for such measurements, however, was unexplored in the literature. These results make clear that a barrier to investigating neurorehabilitation-induced neuroplasticity is uncertainty surrounding statistical power. Chapter 8 describes power analyses for paediatric UCP neurorehabilitation trials measuring cortical thickness and dMRI changes. Calculations were based on results presented in the preceding chapters. The results can be utilised to formally plan study numbers, preventing underpowered trials. This analysis also allowed a number of recommendations to be made that may further reduce barriers to successful neurorehabilitative trials.

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.

Background Dyskinetic cerebral palsy (CP) is one of the most disabling motor types of CP and has been classically associated with injury to the basal ganglia and thalamus. Although cognitive dysfunction is common in CP, there is a paucity of published quantitative analyses investigating the relationship between white matter (WM) microstructure and cognition in this CP type. Aims This study aims (1) to compare brain WM microstructure between people with dyskinetic CP and healthy controls, (2) to identify brain regions where WM microstructure is related to intelligence and (3) to identify brain regions where WM microstructure is related to executive function in people with dyskinetic CP and (4) to identify brain regions where the correlations are different between controls and people with CP in IQ and executive functions. Patients and methods Thirty-three participants with dyskinetic CP (mean ± SD age: 24.42 ± 12.61, 15 female) were age and sex matched with 33 controls. Participants underwent a comprehensive neuropsychological battery to assess intelligence quotient (IQ) and four executive function domains (attentional control, cognitive flexibility, goal setting and information processing). Diffusion weighted MRI scans were acquired at 3T. Voxel-based whole brain groupwise analyses were used to compare fractional anisotropy (FA) and of the CP group to the matched controls using a general lineal model. Further general linear models were used to identify regions where white matter FA correlated with IQ and each of the executive function domains. Results White matter FA was significantly reduced in the CP group in all cerebral lobes, predominantly in regions connected with the parietal and to a lesser extent the temporal lobes. There was no significant correlation between IQ or any of the four executive function domains and WM microstructure in the control group. In participants with CP, lower IQ was associated with lower FA in all cerebral lobes, predominantly in locations that also showed reduced FA compared to controls. Attentional control, goal setting and information processing did not correlate with WM microstructure in the CP group. Cognitive flexibility was associated with FA in regions known to contain connections with the frontal lobe (such as the superior longitudinal fasciculus and cingulum) as well as regions not known to contain tracts directly connected with the frontal lobe (such as the posterior corona radiata, posterior thalamic radiation, retrolenticular part of internal capsule, tapetum, body and splenium of corpus callosum). Conclusion The widespread loss in the integrity of WM tissue is mainly located in the parietal lobe and related to IQ in dyskinetic CP. Unexpectedly, executive functions are only related with WM microstructure in regions containing fronto-cortical and posterior cortico-subcortical pathways, and not being specifically related to the state of fronto-striatal pathways which might be due to brain reorganization. Further studies of this nature may improve our understanding of the neurobiological bases of cognitive impairments after early brain insult., Graphical abstract Image 4, Highlights • There is widespread loss in the integrity of WM in dyskinetic CP. • WM integrity is mainly reduced in regions near the parietal cortex. • IQ is related to FA in the majority of the regions showing a reduced WM integrity. • Executive function is related with cortico-cortical and posterior cortico-subcortical WM FA. • Executive function is not associated with WM FA of the fronto-striatal circuit in dyskinetic CP.

We have reported reliable changes in behaviour, brain structure and function in 24 healthy right-handed adults who practiced a finger-thumb opposition sequence task with their left hand for 10 mins daily, over four weeks. Here we extend these findings by employing diffusion MRI to investigate white-matter changes in the corticospinal tract, basal-ganglia, and connections of the dorsolateral prefrontal cortex. Twenty-three participant datasets were available with pre-training and post-training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group p

Although different aspects of neuroplasticity can be quantified with behavioural 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 practised a sequence of finger-thumb opposition movements for 10 minutes each day with their left hand. After four weeks, performance for the practised sequence improved significantly (p < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practised, 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 learned 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), as well as 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 non-utilised tissue.

Diffusion MRI (dMRI) tractography analyses are difficult to perform in the presence of brain pathology. Automated methods that rely on cortical parcellation for structural connectivity studies often fail, while manually defining regions is extremely time consuming and can introduce human error. Both methods also make assumptions about structure-function relationships that may not hold after cortical reorganisation. Seeding tractography with functional-MRI (fMRI) activation is an emerging method that reduces these confounds, but inherent smoothing of fMRI signal may result in the inclusion of irrelevant pathways. This paper describes a novel fMRI-seeded dMRI-analysis pipeline based on surface-meshes that reduces these issues and utilises machine-learning to generate task specific white matter pathways, minimising the requirement for manually-drawn ROIs. We directly compared this new strategy to a standard voxelwise fMRI-dMRI approach, by investigating correlations between clinical scores and dMRI metrics of thalamocortical and corticomotor tracts in 31 children with unilateral cerebral palsy. The surface-based approach successfully processed more participants (87%) than the voxel-based approach (65%), and provided significantly more-coherent tractography. Significant correlations between dMRI metrics and five clinical scores of function were found for the more superior regions of these tracts. These significant correlations were stronger and more frequently found with the surface-based method (15/20 investigated were significant; R2 = 0.43-0.73) than the voxelwise analysis (2 sig. correlations; 0.38 & 0.49). More restricted fMRI signal, better-constrained tractography, and the novel track-classification method all appeared to contribute toward these differences.

Cerebral palsy is a childhood-onset, lifelong neurological disorder that primarily impairs motor function. Unilateral cerebral palsy (UCP), which impairs use of one hand and perturbs bimanual co-ordination, is the most common form of the condition. The main contemporary upper limb rehabilitation strategies for UCP are constraint-induced movement therapy and bimanual intensive therapy. In this Review, we outline the factors that are crucial to the success of motor rehabilitation in children with UCP, including the dose of training, the relevance of training to daily life, the suitability of training to the age and goals of the child, and the ability of the child to maintain close attention to the tasks. Emerging evidence suggests that the first 2 years of life are a critical period during which interventions for UCP could be more effective than in later life. Abnormal brain organization in UCP, and the effects of development on rehabilitation, must also be understood to develop new effective interventions. Therefore, we also consider neuroimaging methods that can provide insight into the neurobiology of UCP and how the condition responds to existing therapies. We discuss how these methods could shape future rehabilitative strategies based on the neurobiology of UCP and the therapy-induced changes seen in the brain.

Background Our understanding of the effect of ataxia–telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. Methods Diffusion MRI were obtained from 12 patients (age range: 7–22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8–23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. Results Reduced fractional anisotropy along all analyzed patient tracts were observed (p, Highlights • Corticomotor and corticospinal ataxia telangiectasia patient tracts were analyzed. • Decreases in fractional anisotropy occurred along patient tracts. • Mean diffusivity was reduced in cerebellar peduncles in patients. • Patient corticospinal streamline number and apparent fiber density were reduced. • Young ataxia telangiectasia patients show advanced white matter degeneration.

[This corrects the article DOI: 10.1371/journal.pone.0159540.].