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Christopher A. Clark

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5 papers

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YNICL Journal 2022 Journal Article

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

Sebastian M. Toescu
Lisa Bruckert
Rashad Jabarkheel
Derek Yecies
Michael Zhang
Christopher A. Clark
Kshitij Mankad
Kristian Aquilina

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.

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YNIMG Journal 2021 Journal Article

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

Noemi G. Gyori
Christopher A. Clark
Daniel C. Alexander
Enrico Kaden

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.

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YNICL Journal 2020 Journal Article

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

Natalie R. Boonzaier
Patrick W. Hales
Felice D'Arco
Bronwen C. Walters
Ramneek Kaur
Kshitij Mankad
Jessica Cooper
Alki Liasis

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: = 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.

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YNICL Journal 2019 Journal Article

White matter microstructural abnormalities in children with severe congenital hypothyroidism

Hannah E. Cooper
Enrico Kaden
Lorna F. Halliday
Doris-Eva Bamiou
Kshitij Mankad
Catherine Peters
Christopher A. Clark

This study assessed white matter microstructural integrity and behavioral correlates for children with severe congenital hypothyroidism (CH) who were identified and treated early following newborn screening. Eighteen children with severe CH and 21 healthy controls underwent a battery of behavioral measures of hearing, language and communication, along with diffusion MR imaging. Tract-based spatial statistics were performed on standard diffusion parameters of fractional anisotropy and diffusivity metrics. Microscopic diffusion anisotropy mapping based on the Spherical Mean Technique was also used to evaluate biologically specific metrics. Compared with age-matched controls, children with severe CH had poorer hearing and communication skills, albeit generally within normal limits. Children with severe CH had fractional anisotropy that was significantly lower in the cerebellum, bilateral thalami and right temporal lobe, and radial diffusivity that was significantly higher in the cerebellum and bilateral thalami. Microscopic fractional anisotropy and intra-neurite volume fraction were also significantly decreased, and transverse microscopic diffusivity was significantly increased, in the CH group in areas including the cerebellum, thalamus, occipital lobe, and corpus callosum, and in the white matter adjacent to sensorimotor cortex, particularly in the left hemisphere. Significant and widespread correlations were observed between behavioral measures and measures of white matter microstructural integrity in children with CH. The results indicate that children with severe CH who are identified through newborn screening may have significant brain white matter microstructural abnormalities despite early treatment.

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YNIMG Journal 2016 Journal Article

FIACH: A biophysical model for automatic retrospective noise control in fMRI

Tim M. Tierney
Louise J. Weiss-Croft
Maria Centeno
Elhum A. Shamshiri
Suejen Perani
Torsten Baldeweg
Christopher A. Clark
David W. Carmichael

Different noise sources in fMRI acquisition can lead to spurious false positives and reduced sensitivity. We have developed a biophysically-based model (named FIACH: Functional Image Artefact Correction Heuristic) which extends current retrospective noise control methods in fMRI. FIACH can be applied to both General Linear Model (GLM) and resting state functional connectivity MRI (rs-fcMRI) studies. FIACH is a two-step procedure involving the identification and correction of non-physiological large amplitude temporal signal changes and spatial regions of high temporal instability. We have demonstrated its efficacy in a sample of 42 healthy children while performing language tasks that include overt speech with known activations. We demonstrate large improvements in sensitivity when FIACH is compared with current methods of retrospective correction. FIACH reduces the confounding effects of noise and increases the study's power by explaining significant variance that is not contained within the commonly used motion parameters. The method is particularly useful in detecting activations in inferior temporal regions which have proven problematic for fMRI. We have shown greater reproducibility and robustness of fMRI responses using FIACH in the context of task induced motion. In a clinical setting this will translate to increasing the reliability and sensitivity of fMRI used for the identification of language lateralisation and eloquent cortex. FIACH can benefit studies of cognitive development in young children, patient populations and older adults.

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