Cognitive outcome and its neural correlates after cardiorespiratory arrest in childhood.

Hypoxia-ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia-ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life. Here, we studied the long-term outcome of 28 children who suffered early CA (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, sex and socio-economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by academic attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter. In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum. We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities. RESEARCH HIGHLIGHTS: Our data shed light on the long-term outcome and associated neural mechanisms after paediatric hypoxia-ischaemia as a result of cardiorespiratory arrest. Patients had impaired scores on memory, language and academic attainment. Memory impairments were associated with smaller hippocampi, thalami, and striatum. Lower academic attainment correlated with reduced fractional anisotropy of the superior cerebellar peduncle.

Characterisation of paediatric brain tumours by their MRS metabolite profiles.

1H-magnetic resonance spectroscopy (MRS) has the potential to improve the noninvasive diagnostic accuracy for paediatric brain tumours. However, studies analysing large, comprehensive, multicentre datasets are lacking, hindering translation to widespread clinical practice. Single-voxel MRS (point-resolved single-voxel spectroscopy sequence, 1.5 T: echo time [TE] 23-37 ms/135-144 ms, repetition time [TR] 1500 ms; 3 T: TE 37-41 ms/135-144 ms, TR 2000 ms) was performed from 2003 to 2012 during routine magnetic resonance imaging for a suspected brain tumour on 340 children from five hospitals with 464 spectra being available for analysis and 281 meeting quality control. Mean spectra were generated for 13 tumour types. Mann-Whitney U-tests and Kruskal-Wallis tests were used to compare mean metabolite concentrations. Receiver operator characteristic curves were used to determine the potential for individual metabolites to discriminate between specific tumour types. Principal component analysis followed by linear discriminant analysis was used to construct a classifier to discriminate the three main central nervous system tumour types in paediatrics. Mean concentrations of metabolites were shown to differ significantly between tumour types. Large variability existed across each tumour type, but individual metabolites were able to aid discrimination between some tumour types of importance. Complete metabolite profiles were found to be strongly characteristic of tumour type and, when combined with the machine learning methods, demonstrated a diagnostic accuracy of 93% for distinguishing between the three main tumour groups (medulloblastoma, pilocytic astrocytoma and ependymoma). The accuracy of this approach was similar even when data of marginal quality were included, greatly reducing the proportion of MRS excluded for poor quality. Children's brain tumours are strongly characterised by MRS metabolite profiles readily acquired during routine clinical practice, and this information can be used to support noninvasive diagnosis. This study provides both key evidence and an important resource for the future use of MRS in the diagnosis of children's brain tumours.

Attention and motor profiles in children with developmental coordination disorder: A neuropsychological and neuroimaging investigation.

AIM: This study aimed to (1) quantify attention and executive functioning in children with developmental coordination disorder (DCD), (2) assess whether some children with DCD are more likely to show attention difficulties, and (3) characterize brain correlates of motor and attention deficits. METHOD: Fifty-three children (36 with DCD and 17 without) aged 8 to 10 years underwent T1-weighted and diffusion-weighted magnetic resonance imaging, and standardized attention and motor assessments. Parents completed questionnaires of executive functioning and symptoms of inattention and hyperactivity. We assessed regional cortical thickness and surface area, and cerebellar, callosal, and primary motor tract structure. RESULTS: Analyses of covariance and one-sample t-tests identified impaired attention, non-motor processing speed, and executive functioning in children with DCD, yet partial Spearman's rank correlation coefficients revealed these were unrelated to one another or the type or severity of the motor deficit. Robust regression analyses revealed that cortical morphology in the posterior cingulate was associated with both gross motor skills and inattentive symptoms in children with DCD, while gross motor skills were also associated with left corticospinal tract (CST) morphology. INTERPRETATION: Children with DCD may benefit from routine attention and hyperactivity assessments. Alterations in the posterior cingulate and CST may be linked to impaired forward modelling during movements in children with DCD. Overall, alterations in these regions may explain the high rate of non-motor impairments in children with DCD. WHAT THIS PAPER ADDS: Children with developmental coordination disorder have difficulties in attention, processing speed, and executive functioning. Non-motor impairments were not interrelated or correlated with the type or severity of motor deficit. Posterior cingulate morphology was associated with gross motor skills and inattention. Gross motor skills were also associated with left corticospinal tract morphology.

Increased white matter fibre dispersion and lower IQ scores in adults born preterm.

Preterm birth has been associated with altered microstructural properties of the white matter and lower cognitive ability in childhood and adulthood. Due to methodological limitations of the diffusion tensor model, it is not clear whether alterations in myelination or variation in fibre orientation are driving these differences. Novel models applied to multi-shell diffusion imaging have been used to disentangle these effects, but to date this has not been used to study the preterm brain in adulthood. This study investigated whether novel advanced diffusion MRI metrics such as microscopic anisotropy and orientation dispersion are altered in adults born preterm, and whether this was associated with cognitive performance. Seventy-two preterm born participants (<37 weeks gestational age) were recruited from a 1982-1984 cohort (33 males, mean age 33.5 ± 1.0 years). Seventy-two term born (>37 weeks gestational age) controls (34 males, mean age 30.9 ± 4.0 years) were recruited from the general population. Tensor FA was calculated with FSL, while microscopic FA and orientation dispersion entropy (ODE) were estimated using the Spherical Mean Technique (SMT). Estimated Full Scale IQ (FSIQ), Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) were obtained from the WASI-II (abbreviated) IQ test. Voxel-wise comparisons using FSL's tract-based spatial statistics were performed to test between-group differences in diffusion MRI metrics as well as within-group associations of diffusion MRI metrics and IQ outcomes. The preterm group had significantly lower FSIQ, VCI and PRI scores. Preterm subjects demonstrated widespread decreases in ODE reflecting increased fibre dispersion, but no differences in microscopic FA. Tensor FA was increased in a small area in the anterior corona radiata. Lower FA values in the preterm population were associated with lower FSIQ and PRI scores. An increase in fibre dispersion in white matter and lower IQ scores after preterm birth exist in adulthood. Advanced diffusion MRI metrics such as the orientation dispersion entropy can be used to monitor white matter alterations across the lifespan in preterm born individuals. Although not significantly different between preterm and term groups, tensor FA values in the preterm group were associated with cognitive outcome.

The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.

Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.

Comparative genomics of the niche-specific plant pathogen Streptomyces ipomoeae reveal novel genome content and organization.

IMPORTANCE: While most plant-pathogenic Streptomyces species cause scab disease on a variety of plant hosts, Streptomyces ipomoeae is the sole causative agent of soil rot disease of sweet potato and closely related plant species. Here, genome sequencing of virulent and avirulent S. ipomoeae strains coupled with comparative genomic analyses has identified genome content and organization features unique to this streptomycete plant pathogen. The results here will enable future research into the mechanisms used by S. ipomoeae to cause disease and to persist in its niche environment.

Effects of regional brain volumes on cognition in sickle cell anemia: A developmental perspective.

Background and objectives: Cognitive difficulties in people with sickle cell anemia (SCA) are related to lower processing speed index (PSI) and working memory index (WMI). However, risk factors are poorly understood so preventative strategies have not been explored. Brain volumes, specifically white matter volumes (WMV) which increases through early adulthood, have been associated with better cognition in healthy typically developing individuals. In patients with SCA, the reduced WMV and total subcortical volumes noted could explain cognitive deficits. We therefore examined developmental trajectories for regional brain volumes and cognitive endpoints in patients with SCA. Methods: Data from two cohorts, the Sleep and Asthma Cohort and Prevention of Morbidity in SCA, were available. MRI data included T1-weighted axial images, pre-processed before regional volumes were extracted using Free-surfer. PSI and WMI from the Weschler scales of intelligence were used to test neurocognitive performance. Hemoglobin, oxygen saturation, hydroxyurea treatment and socioeconomic status from education deciles were available. Results: One hundred and twenty nine patients (66 male) and 50 controls (21 male) aged 8-64 years were included. Brain volumes did not significantly differ between patients and controls. Compared with controls, PSI and WMI were significantly lower in patients with SCA, predicted by increasing age and male sex, with lower hemoglobin in the model for PSI but no effect of hydroxyurea treatment. In male patients with SCA only, WMV, age and socioeconomic status predicted PSI, while total subcortical volumes predicted WMI. Age positively and significantly predicted WMV in the whole group (patients + controls). There was a trend for age to negatively predict PSI in the whole group. For total subcortical volume and WMI, age predicted decrease only in the patient group. Developmental trajectory analysis revealed that PSI only was significantly delayed in patients at 8 years of age; the rate of development for the cognitive and brain volume data did not differ significantly from controls. Discussion: Increasing age and male sex negatively impact cognition in SCA, with processing speed, also predicted by hemoglobin, delayed by mid childhood. Associations with brain volumes were seen in males with SCA. Brain endpoints, calibrated against large control datasets, should be considered for randomized treatment trials.

Potential vision tester using adaptive optics, Maxwellian view, and small pupil.

We demonstrate a free-space, trolley-mounted potential vision tester (PVT), designed to study and improve the accuracy of visual acuity (VA) measurements in the aging eye. Key features include a high-resolution visual display presented in Maxwellian view, a 3 mm pupil to limit wavefront (WF) aberrations, and a moderate cost deformable mirror to induce or correct higher order optical aberrations. The visual display supported accurate measurement of visual acuities down to 20/5. The moderate cost, piezo deformable mirror induced seven nominal aberrations, calibrated as 0, -0.32, -0.23, + 0.27, and +0.39 microns spherical aberration; + 0.49 microns Y coma; and -0.51 microns X coma. A custom Hartmann Shack (HS) calibration (HSc) system demonstrated that induced aberrations were repeatable and stable. A Badal optometer provided the coarse focus. WF aberrations were measured for five normal subjects with a commercially available HS device (HSP) (OCULUS Pentacam AXL Wave), providing estimates of WF errors for 3 mm and other pupil sizes. VA was measured using four alternative forced-choice for a single black on white E stimulus in each trial. Using the method of constant stimuli yielded robust standard deviation measurements. The 50% fit for VA plotted against induced aberration resulted in linear functions for each subject for the range of our positive and negative spherical aberration data. Subjects differed, but higher order terms were unnecessary to describe data across spherical aberrations.

Brain structure correlates with auditory function in children diagnosed with auditory neuropathy spectrum disorder.

INTRODUCTION: Auditory neuropathy spectrum disorder (ANSD) is a term for a collection of test results which indicate disruption of the auditory signal at some point along the neural pathway. This results in a spectrum of functional outcomes, ranging from reasonably normal hearing to profound hearing loss. This study assessed brain structure changes and behavioral correlates in children diagnosed with ANSD. METHODS: Seventeen children who had previously been diagnosed with ANSD were recruited to the study and underwent a battery of behavioral measures of hearing, language, and communication, along with structural MR imaging. Analysis of cortical thickness of temporal lobe structures was carried out using FreeSurfer. Tract-based spatial statistics were performed on standard diffusion parameters of fractional anisotropy and diffusivity metrics. The control group comprised imaging data taken from a library of MRI scans from neurologically normal children. Control images were matched as closely as possible to the ANSD group for age and sex. RESULTS: Reductions in right temporal lobe cortical thickness were observed in children with ANSD compared to controls. Increases in medial diffusivity in areas including the corpus callosum and in the right occipital white matter were also seen in the group with ANSD compared to controls. Speech perception abilities, both in quiet and in noise, were correlated with cortical thickness measurements for several temporal lobe structures in children with ANSD, and relationships were also seen between diffusion metrics and measures of auditory function. CONCLUSION: This study shows that children with ANSD have structural brain differences compared to healthy controls. It also demonstrates associations between brain structure and behavioral hearing abilities in children diagnosed with ANSD. These results show that there is a potential for structural imaging to be used as a biomarker in this population with the possibility of predicting functional hearing outcome.

A Comparison of MRI Quantitative Susceptibility Mapping and TRUST-Based Measures of Brain Venous Oxygen Saturation in Sickle Cell Anaemia.

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Yv) to improve neurological risk prediction. T2-relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Yv in patients with sickle cell anemia (SCA). However, prior studies comparing Yv in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T2 to Yv, is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Yv in SCA as blood magnetic susceptibility is linearly dependent upon Yv, and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Yv using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Yv was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T2, within a similar but much smaller region, were converted to Yv using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Yv between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Yv, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Yv varied with method. The TRUST-HbBV and QSM methods suggested decreased Yv in SCA relative to healthy controls, while the TRUST-HbS (p < 0.01) and TRUST-HbA models suggested increased Yv in SCA as in previous studies. Further validation of all MRI measures of Yv, relative to ground truth measures such as O15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction.

Drug-resistant focal epilepsy in children is associated with increased modal controllability of the whole brain and epileptogenic regions.

Network control theory provides a framework by which neurophysiological dynamics of the brain can be modelled as a function of the structural connectome constructed from diffusion MRI. Average controllability describes the ability of a region to drive the brain to easy-to-reach neurophysiological states whilst modal controllability describes the ability of a region to drive the brain to difficult-to-reach states. In this study, we identify increases in mean average and modal controllability in children with drug-resistant epilepsy compared to healthy controls. Using simulations, we purport that these changes may be a result of increased thalamocortical connectivity. At the node level, we demonstrate decreased modal controllability in the thalamus and posterior cingulate regions. In those undergoing resective surgery, we also demonstrate increased modal controllability of the resected parcels, a finding specific to patients who were rendered seizure free following surgery. Changes in controllability are a manifestation of brain network dysfunction in epilepsy and may be a useful construct to understand the pathophysiology of this archetypical network disease. Understanding the mechanisms underlying these controllability changes may also facilitate the design of network-focussed interventions that seek to normalise network structure and function.

Spatiotemporal changes in along-tract profilometry of cerebellar peduncles in cerebellar mutism syndrome.

Cerebellar mutism syndrome, characterised by mutism, emotional lability and cerebellar motor signs, occurs in up to 39% of children following resection of medulloblastoma, the most common malignant posterior fossa tumour of childhood. Its pathophysiology remains unclear, but prior studies have implicated damage to the superior cerebellar peduncles. In this study, the objective was to conduct high-resolution spatial profilometry of the cerebellar peduncles and identify anatomic biomarkers of cerebellar mutism syndrome. In this retrospective study, twenty-eight children with medulloblastoma (mean age 8.8 ± 3.8 years) underwent diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 ± 4.2 years), scanned at a single timepoint, served as age- and sex-matched controls. Automated Fibre Quantification was used to segment cerebellar peduncles and compute fractional anisotropy (FA) at 30 nodes along each tract. Thirteen patients developed cerebellar mutism syndrome. FA was significantly lower in the distal third of the left superior cerebellar peduncle pre-operatively in all patients compared to controls (FA in proximal third 0.228, middle and distal thirds 0.270, p = 0.01, Cohen's d = 0.927). Pre-operative differences in FA did not predict cerebellar mutism syndrome. However, post-operative reductions in FA were highly specific to the distal left superior cerebellar peduncle, and were most pronounced in children with cerebellar mutism syndrome compared to those without at the 1-4 month follow up (0.325 vs 0.512, p = 0.042, d = 1.36) and at the 1-year follow up (0.342, vs 0.484, p = 0.038, d = 1.12). High spatial resolution cerebellar profilometry indicated a site-specific alteration of the distal segment of the superior cerebellar peduncle seen in cerebellar mutism syndrome which may have important surgical implications in the treatment of these devastating tumours of childhood.

Training data distribution significantly impacts the estimation of tissue microstructure with machine learning.

PURPOSE: Supervised machine learning (ML) provides a compelling alternative to traditional model fitting for parameter mapping in quantitative MRI. The aim of this work is to demonstrate and quantify the effect of different training data distributions on the accuracy and precision of parameter estimates when supervised ML is used for fitting. METHODS: We fit a two- and three-compartment biophysical model to diffusion measurements from in-vivo human brain, as well as simulated diffusion data, using both traditional model fitting and supervised ML. For supervised ML, we train several artificial neural networks, as well as random forest regressors, on different distributions of ground truth parameters. We compare the accuracy and precision of parameter estimates obtained from the different estimation approaches using synthetic test data. RESULTS: When the distribution of parameter combinations in the training set matches those observed in healthy human data sets, we observe high precision, but inaccurate estimates for atypical parameter combinations. In contrast, when training data is sampled uniformly from the entire plausible parameter space, estimates tend to be more accurate for atypical parameter combinations but may have lower precision for typical parameter combinations. CONCLUSION: This work highlights that estimation of model parameters using supervised ML depends strongly on the training-set distribution. We show that high precision obtained using ML may mask strong bias, and visual assessment of the parameter maps is not sufficient for evaluating the quality of the estimates.

High-resolution microscopic diffusion anisotropy imaging in the human hippocampus at 3T.

PURPOSE: Several neurological conditions are associated with microstructural changes in the hippocampus that can be observed using DWI. Imaging studies often use protocols with whole-brain coverage, imposing limits on image resolution and worsening partial-volume effects. Also, conventional single-diffusion-encoding methods confound microscopic diffusion anisotropy with size variance of microscopic diffusion environments. This study addresses these issues by implementing a multidimensional diffusion-encoding protocol for microstructural imaging of the hippocampus at high resolution. METHODS: The hippocampus of 8 healthy volunteers was imaged at 1.5-mm isotropic resolution with a multidimensional diffusion-encoding sequence developed in house. Microscopic fractional anisotropy (µFA) and normalized size variance (CMD ) were estimated using q-space trajectory imaging, and their values were compared with DTI metrics. The overall scan time was 1 hour. The reproducibility of the protocol was confirmed with scan-rescan experiments, and a shorter protocol (14 minutes) was defined for situations with time constraints. RESULTS: Mean µFA (0.47) was greater than mean FA (0.20), indicating orientation dispersion in hippocampal tissue microstructure. Mean CMD was 0.17. The reproducibility of q-space trajectory imaging metrics was comparable to DTI, and microstructural metrics in the healthy hippocampus are reported. CONCLUSION: This work shows the feasibility of high-resolution microscopic anisotropy imaging in the human hippocampus at 3 T and provides reference values for microstructural metrics in a healthy hippocampus.

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial.

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.

On the potential for mapping apparent neural soma density via a clinically viable diffusion MRI protocol.

Diffusion MRI is a valuable tool for probing tissue microstructure in the brain noninvasively. Today, model-based techniques are widely available and used for white matter characterisation where their development is relatively mature. Conversely, tissue modelling in grey matter is more challenging, and no generally accepted models exist. With advances in measurement technology and modelling efforts, a clinically viable technique that reveals salient features of grey matter microstructure, such as the density of quasi-spherical cell bodies and quasi-cylindrical cell projections, is an exciting prospect. As a step towards capturing the microscopic architecture of grey matter in clinically feasible settings, this work uses a biophysical model that is designed to disentangle the diffusion signatures of spherical and cylindrical structures in the presence of orientation heterogeneity, and takes advantage of B-tensor encoding measurements, which provide additional sensitivity compared to standard single diffusion encoding sequences. For the fast and robust estimation of microstructural parameters, we leverage recent advances in machine learning and replace conventional fitting techniques with an artificial neural network that fits complex biophysical models within seconds. Our results demonstrate apparent markers of spherical and cylindrical geometries in healthy human subjects, and in particular an increased volume fraction of spherical compartments in grey matter compared to white matter. We evaluate the extent to which spherical and cylindrical geometries may be interpreted as correlates of neural soma and neural projections, respectively, and quantify parameter estimation errors in the presence of various departures from the modelling assumptions. While further work is necessary to translate the ideas presented in this work to the clinic, we suggest that biomarkers focussing on quasi-spherical cellular geometries may be valuable for the enhanced assessment of neurodevelopmental disorders and neurodegenerative diseases.

Tractographic and Microstructural Analysis of the Dentato-Rubro-Thalamo-Cortical Tracts in Children Using Diffusion MRI.

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I-IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors.

Neurosurgical applications of tractography in the UK.

INTRODUCTION: Tractography derived from diffusion MRI can provide important insights into human brain microstructure in vivo. Neurosurgeons were quick to adopt the technique at the turn of the century, but it remains plagued by technical fallibilities. This study aims to describe how tractography is deployed clinically in a modern-day, public healthcare system, serving as a snapshot from the 'shop floor' of British neurosurgical practice. METHODS: An 11-question survey was circulated to the mailing lists of the Society of British Neurological Surgeons and British Neurosurgical Trainees' Association, including questions on frequency, indication, tracts reconstructed, specific details of techniques used and personnel by whom it was performed, and a free-text section on the limitations of tractography. RESULTS: 58 survey responses were received, covering all 40 neurosurgical units in the UK and Ireland. Overall, responses were received from neurosurgeons at 36 units (90.0%) stating tractography was in use at that unit. 74.1% of the responses were from Consultants. The most common indication for tractography was in tumour resection. It was most commonly performed by neuroradiologists or imaging scientists. 75.9% of respondents stated that the model used to process tractography was the diffusion tensor (DTI). Many respondents were unaware of which algorithm (74.1%) or software tools (65.6%) were used by the operator to produce tractography visualisations. The corticospinal tract was the most commonly reconstructed tract. The most commonly cited limitations of the technique were perceived inaccuracy and brain shift. CONCLUSIONS: In this UK-based survey of practising neurosurgeons, we show that 90% of neurosurgical units in the UK and Ireland use tractography regularly; that predominantly DTI-based reconstructions are used; that tumour resection remains the most frequent use of the technique; and that large tracts such as the corticospinal tract are most frequently identified. Many neurosurgeons remain unfamiliar with the underlying methods used to produce tractography visualisations.

Quantitative MRI demonstrates abnormalities of the third ventricle subventricular zone in neurofibromatosis type-1 and sporadic paediatric optic pathway glioma.

BACKGROUND: The subventricular zone of the third ventricle (TVZ) is a germinal stem cell niche, identified as the possible location of optic pathway glioma (OPG) cell origin. Paediatric OPGs are predominantly diagnosed as low-grade astrocytomas, which are either sporadic or are associated with neurofibromatosis type-1 (NF1). These tumours often cause a significant impairment to visual acuity (VA). Infiltrative/invasive tumour activity is associated with increased apparent diffusion coefficient (ADC) and cerebral blood flow (CBF). This study aimed to determine whether TVZ imaging features differed between sporadic-OPG, NF1-OPG and controls, and whether the ADC and CBF profile at the germinal stem cell niche (the TVZ) correlated with the primary outcome of VA. METHODS: ADC and CBF MRI data were acquired from 30 paediatric OPG patients (median age 6 years; range 8 months-17 years), along with VA measurements, during clinical surveillance of their tumour. Values for mean ADC and maximum CBF were measured at the TVZ, and normalized to normal-appearing grey matter. These values were compared between the two OPG groups and the healthy control subjects, and multivariate linear regression was used to test the linear association between these values and patient's VA. RESULTS: In the TVZ, normalized mean ADC was higher in NF1-associated OPG patients (N = 15), compared to both sporadic OPG patients (N = 15; p = 0.010) and healthy controls (N = 14; p < 0.001). In the same region, normalized maximum CBF was higher in sporadic OPG patients compared to both NF1-OPG patients (p = 0.016) and healthy controls (p < 0.001). In sporadic OPG patients only, normalized mean ADC in the TVZ was significantly correlated with visual acuity (R2 = 0.41, p = 0.019). No significant correlations were found between TVZ CBF and ADC values and visual acuity in the NF1-associated OPG patients. CONCLUSION: Quantitative MRI detects TVZ abnormalities in both sporadic and NF1-OPG patients, and identifies TVZ features that differentiate the two. TVZ features may be useful MRI markers of interest in future predictive studies involving sporadic OPG.

Subcortical nuclei volumes are associated with cognition in children post-convulsive status epilepticus: Results at nine years follow-up.

PURPOSE: The purpose of the present study was to investigate the relationship between subcortical nuclei volume and cognition in children with post-convulsive status epilepticus (CSE). METHODS: Structural T1-weighted magnetic resonance imaging (MRI) scans (Siemens Avanto, 1.5 T) and neuropsychological assessments (full-scale intelligence quotient (FSIQ) and Global Memory Scores (GMS)) were collected from subjects at a mean 8.5 years post-CSE (prolonged febrile seizures (PFS), n = 30; symptomatic/known, n = 28; and other, n = 12) and from age- and sex-matched healthy controls (HC). Subjects with CSE were stratified into those with lower cognitive ability (LCA) (CSE+, n = 22) and those without (CSE-, n = 48). Quantitative volumetric analysis using Functional MRI of the Brain Software Library (FSL) (Analysis Group, FMRIB, Oxford) provided segmented MRI brain volumes. Univariate analysis of covariance (ANCOVA) was performed to compare subcortical nuclei volumes across subgroups. Multivariable linear regression was performed for each subcortical structure and for total subcortical volume (SCV) to identify significant predictors of LCA (FSIQ <85) while adjusting for etiology, age, socioeconomic status, sex, CSE duration, and intracranial volume (ICV); Bonferroni correction was applied for the analysis of individual subcortical nuclei. RESULTS: Seventy subjects (11.8 ±â€¯3.4 standard deviation (SD) years; 34 males) and 72 controls (12.1 ±â€¯3.0SD years; 29 males) underwent analysis. Significantly smaller volumes of the left thalamus, left caudate, right caudate, and SCV were found in subjects with CSE+ compared with HC, after adjustment for intracranial, gray matter (GM), or cortical/cerebellar volume. When compared with subjects with CSE-, subjects with CSE+ also had smaller volumes of the left thalamus, left pallidum, right pallidum, and SCV. Individual subcortical nuclei were not associated, but SCV was associated with FSIQ (p = 0.005) and GMS (p = 0.014). Intracranial volume and etiology were similarly predictive. CONCLUSIONS: Nine years post-CSE, SCV is significantly lower in children who have LCA compared with those that do not. However, in this cohort, we are unable to determine whether the relationship is independent of ICV or etiology. Future, larger scale studies may help tease this out.