Biology subjects

Parker, G. D.

Publications and source records attributed to Parker, G. D..

11 recordsLinked to original sources

bioRxiv2023

Differences in white matter detected by ex vivo 9.4T MRI are associated with axonal changes in the R6/1 model of Huntington's Disease

White matter (WM) volume loss has been reported in people with Huntingtons disease (HD), but the cellular basis of this deficit remains to be elucidated. To address this, we assessed ex vivo WM microstructure in the transgenic R6/1 mouse model of HD with magnetic resonance imaging (MRI) and studied the neurobiological basis of the MRI brain signals with histological and electron microscopy analyses in a separate cohort of age- and sex-matched mice. Differences in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) as a proxy myelin measure, and the intra-axonal signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) as a proxy marker of axon density, were assessed alongside diffusion tensor imaging (DTI) parameters. A tractometry approach was employed to inspect region-specific differences across the corpus callosum (CC). Furthermore, voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to explore brain-wise WM macro- and microstructure abnormalities. To gain insight into disease-associated impairments in attentional and visuospatial processing, a third cohort of age-matched mice was assessed with the 5-choice serial reaction time task (5-CSRTT). We report cognitive impairments in R6/1 mice and, by evaluating MRI and light and electron microscopy results, we show that this HD mouse model presents disruptions in axonal morphology (i.e. less complex, thinner axons) and organization (i.e. more densely packed axons). Furthermore, we show that, at least early in disease progression, R6/1 mice present a reduction in the expression or content of myelin-associated proteins without significant alterations in the structure of myelin sheaths. Finally, our findings indicate that neuroinflammation-driven glial and axonal swelling might also affect this mouse model early in disease progression. Crucially, we demonstrate the potential of FR, an in vivo estimate of axon density, as a novel MRI biomarker of HD-associated changes in WM microstructure.

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bioRxiv2022

Tract-specific white matter microstructure alterations among young adult APOE ε4 carriers: A replication and extension study

The parahippocampal cingulum bundle (PHCB) connects regions known to be vulnerable to early Alzheimers disease (AD) pathology, such as posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at-risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) {varepsilon}4 allele - the strongest common genetic risk factor for AD - showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and connectivity have a significant role in posteromedial cortex vulnerability to amyloid-{beta} and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.s finding in a larger sample (N = 128; 40 APOE {varepsilon}4 carriers, 88 APOE {varepsilon}4 non-carriers) of young adults (age range: 19-33). Extending this work further, we also conducted exploratory analyses using a more advanced measure of microstructure: hindrance modulated orientational anisotropy (HMOA). These analyses included an investigation of hemispheric asymmetry in PHCB and ILF HMOA. Contrary to the original study, we observed no difference in PHCB microstructure between APOE {varepsilon}4 carriers and non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. APOE {varepsilon}4-related differences in ILF HMOA asymmetry were evident, however, with carriers demonstrating lower leftward asymmetry. Our findings indicate that young adult APOE {varepsilon}4 carriers do not show alterations in PHCB microstructure, as observed by Hodgetts et al., but may show altered asymmetry in ILF microstructure.

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bioRxiv2021

Mutation-related apparent myelin, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI

White matter (WM) alterations have been observed early in Huntingtons disease (HD) progression but their role in the disease-pathophysiology remains unknown. We exploited ultra-strong-gradient MRI to tease apart contributions of myelin (with the magnetization transfer ratio), and axon density (with the restricted volume fraction from the Composite Hindered and Restricted Model of Diffusion) to WM differences between premanifest HD patients and age- and sex-matched controls. Diffusion tensor MRI (DT-MRI) measures were also assessed. We used tractometry to investigate region-specific changes across callosal segments with well-characterized early- and late-myelinating axonal populations, while brain-wise alterations were explored with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. We detected lower myelin in the rostrum of patients (tractometry: p = 0.0343; TBCA: p = 0.030), but higher myelin in their splenium (p = 0.016). Importantly, patients myelin and mutation size were positively associated (all p-values < 0.01), indicating that increased myelination might be a direct result of the mutation. Finally, myelin was higher than controls in younger patients but lower in older patients (p = 0.003), suggesting detrimental effects of increased myelination later in the course of the disease. Higher FR in patients left cortico-spinal tract (CST) (p = 0.03) was detected, and was found to be positively associated with MTR in the posterior callosum (p = 0.033), possibly suggesting compensation to myelin alterations. This comprehensive, ultra-strong gradient MRI investigation provides novel evidence of CAG-driven myelin alterations in premanifest HD which may reflect neurodevelopmental, rather than neurodegenerative disease-associated changes.

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bioRxiv2021

Short Association Fibre Tractography

It is estimated that in the human brain, short association fibres (SAF) represent more than half of the total white matter volume and their involvement has been implicated in a range of neurological and psychiatric conditions. This population of fibres, however, remains relatively understudied in the neuroimaging literature. Some of the challenges pertinent to the mapping of SAF include their variable anatomical course and proximity to the cortical mantle, leading to partial volume effects and potentially affecting streamline trajectory estimation. This work considers the impact of seeding and filtering strategies and choice of scanner, acquisition, data resampling to propose a whole-brain, surface-based short ([≤]30-40 mm) SAF tractography approach. The framework is shown to produce longer streamlines with a predilection for connecting gyri as well as high cortical coverage. We further demonstrate that certain areas of subcortical white matter become disproportionally underrepresented in diffusion-weighted MRI data with lower angular and spatial resolution and weaker diffusion weighting; however, collecting data with stronger gradients than are usually available clinically has minimal impact, making our framework translatable to data collected on commonly available hardware. Finally, the tractograms are examined using voxel- and surfacebased measures of consistency, demonstrating moderate reliability, low repeatability and high between-subject variability, urging caution when streamline count-based analyses of SAF are performed.

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bioRxiv2020

Distributional changes in myelin-specific MRI markers uncover dynamics in the fornix following spatial navigation training

Increasing evidence implicates white matter (WM) dynamics supporting learning in the mature brain. Recent MRI studies, mostly using diffusion tensor MRI (DT-MRI), have demonstrated learning-induced WM changes at the microstructural level. However, while DT-MRI-derived measures have sensitivity to general WM microstructural changes, they lack compartmental specificity, making them difficult to relate to underlying cellular mechanisms, stymying deeper understanding of mechanisms supporting training-induced gains in performance. Gaining a deeper understanding demands a more detailed characterization of changes in specific WM sub-components. To this end, four microstructural MRI techniques were employed to study alterations in rat brains after 5-days of water maze training: DT-MRI; Composite Hindered and Restricted Model of Diffusion (CHARMED); magnetization transfer (MT) imaging; quantitative susceptibility mapping and R2*. The hypothesis tested here was that microstructural changes would be: (i) observed in tracts supporting spatial navigation, i.e., fornix and corpus callosum (CC); and (ii) more pronounced in the myelin-specific measures. Medians and distributions of microstructural parameters were derived along the fornix, CC and cingulum (as a comparison tract) using the tractometry approach. Summary measures were derived from different metrics using unsupervised data reduction. Significant pre-vs-post training differences were found in the medians of two principal components loading on: (i) anisotropy indices; and (ii) MT ratio. The most striking effect, however, was seen in the distributions of pre-vs-post training MT ratio in the fornix, consistent with the primary hypothesis, and highlighting the value of this alternative to the standard approach (i.e., comparing means/medians of DT-MRI parameters) for studying neuroplasticity in vivo. Significance statementRecent MRI-studies have demonstrated that white matter (WM) dynamics support learning, even in the mature brain. However, most studies are based on diffusion tensor MRI (DT-MRI) measures, which although providing sensitivity to WM microstructural changes, do not provide a direct translation to the underlying cellular mechanisms making interpretation difficult. Using alternative quantitative MRI approaches, this study provided more specific subcomponent microstructural insights into the brains WM response to water-maze training. We show that myelin-specific MR measures show more marked changes than axonal-specific and DT-MRI measures, in WM tracts responsible for spatial navigation. The results promote adoption of these alternative approaches to DT-MRI for studying neuroplasticity in vivo.

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bioRxiv2020

Impact of b-value on estimates of apparent fibre density

Recent advances in diffusion magnetic resonance imaging (dMRI) analysis techniques have improved our understanding of fibre-specific variations in white matter microstructure. Increasingly, studies are adopting multi-shell dMRI acquisitions to improve the robustness of dMRI-based inferences. However, the impact of b-value choice on the estimation of dMRI measures such as apparent fibre density (AFD) derived from spherical deconvolution is not known. Here, we investigate the impact of b-value sampling scheme on estimates of AFD. First, we performed simulations to assess the correspondence between AFD and simulated intra-axonal signal fraction across multiple b-value sampling schemes. We then studied the impact of sampling scheme on the relationship between AFD and age in a developmental population (n=78) aged 8-18 (mean=12.4, SD=2.9 years) using hierarchical clustering and whole brain fixel-based analyses. Multi-shell dMRI data were collected at 3.0T using ultra-strong gradients (300 mT/m), using 6 diffusion-weighted shells ranging from 0 - 6000 s/mm2. Simulations revealed that the correspondence between estimated AFD and simulated intra-axonal signal fraction was improved with high b-value shells due to increased suppression of the extra-axonal signal. These results were supported by in vivo data, as sensitivity to developmental age-relationships was improved with increasing b-value (b=6000 s/mm2, median R2 = .34; b=4000 s/mm2, median R2 = .29; b=2400 s/mm2, median R2 = .21; b=1200 s/mm2, median R2 = .17) in a tract-specific fashion. Overall, estimates of AFD and age-related microstructural development were better characterised at high diffusion-weightings due to improved correspondence with intra-axonal properties.

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bioRxiv2019

Curious connections: white matter pathways supporting individual differences in epistemic and perceptual curiosity

Across the lifespan, curiosity motivates us to learn, yet curiosity varies strikingly between individuals. Such individual differences have been shown for two distinct dimensions of curiosity: epistemic curiosity (EC), the desire to acquire conceptual knowledge, and perceptual curiosity (PC), the desire for sensory information. It is not known, however, whether both dimensions of curiosity depend on different brain networks and whether inter-individual differences in curiosity depend on variation in anatomical connectivity within these networks. Here, we investigated the neuroanatomical connections underpinning individual variation in trait curiosity. Fifty-one female participants underwent a two-shell diffusion MRI sequence and completed questionnaires measuring EC and PC. Using deterministic spherical deconvolution tractography we extracted microstructural metrics (fractional anisotropy (FA) and mean diffusivity (MD)) from two key white matter tracts: the fornix (implicated in novelty processing, exploration, information seeking and episodic memory) and the inferior longitudinal fasciculus (ILF) (implicated in semantic learning and memory). In line with our predictions, we found that EC - but not PC - correlated with ILF microstructure. Fornix microstructure, in contrast, correlated with both EC and PC, with posterior hippocampal fornix fibres - associated with posterior hippocampal network connectivity - linked to PC specifically. These findings suggest that differences in distinct dimensions of curiosity map systematically onto specific white matter tracts underlying well characterized brain networks. Furthermore, the results pave the way to study the anatomical substrates of inter-individual differences in dimensions of trait curiosity that motivate the learning of distinct forms of knowledge and skills.

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bioRxiv2019

Mammillothalamic disconnection alters hippocampo-cortical oscillatory activity and microstructure: Implications for diencephalic amnesia

Diencephalic amnesia can be as disruptive as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. We used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampo-cortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting important role for the mammillary bodies in the co-ordination of hippocampo-cortical activity.

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bioRxiv2019

Dimensionality Reduction of Diffusion MRI Measures for Improved Tractometry of the Human Brain

Various diffusion MRI measures have been proposed for characterising tissue microstructure over the last 15 years. Despite the growing number of experiments using different diffusion measures in assessments of white matter, there has been limited work on: 1) examining their covariance along specific pathways; and on 2) combining these different measures to study tissue microstructure. In this work, we first demonstrate redundancies in the amount of information captured by 10 diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) measures. Using a data-reduction approach, we identified two biologically-interpretable components that capture 80% of the variance in commonly-used DTI and HARDI measures profiled along 22 brain pathways extracted from typically developing children aged 8 - 18 years (n = 36). The first derived component captures properties related to hindrance and restriction in tissue microstructure, while the second component reflects characteristics related to tissue complexity and orientational dispersion. We demonstrate that the components generated by this approach preserve the biological relevance of the original measurements by showing age-related effects across developmentally sensitive pathways. Our results also suggest that HARDI measures are more sensitive at detecting age-related changes in tissue microstructure than DTI measures.

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bioRxiv2019

Tractography in the presence of white matter lesions in multiple sclerosis

Accurate anatomical localisation of specific white matter tracts and the quantification of their tractspecific microstructural damage in multiple sclerosis (MS) can contribute to a better understanding of symptomatology, disease progression and intervention effects. Diffusion MRI-based tractography is being used increasingly to segment white matter tracts as regions-of-interest for subsequent quantitative analysis. Since MS lesions can interrupt the tractography algorithms tract reconstruction, clinical studies frequently resort to atlas-based approaches, which are convenient but ignorant to individual variability in tract size and shape. Here, we revisit the problem of individual tractography in MS, comparing tractography algorithms using: (i) The diffusion tensor framework; (ii) constrained spherical deconvoution (CSD); and (iii) damped Richardson-Lucy (dRL) deconvolution. Firstly, using simulated and in vivo data from 29 MS patients and 19 healthy controls, we show that the three tracking algorithms respond differentially to MS pathology. While the tensor-based approach is unable to deal with crossing fibres, CSD produces spurious stream-lines, in particular in tissue with high fibre loss and low diffusion anisotropy. With dRL, streamlines are increasingly interrupted in pathological tissue. Secondly, we demonstrate that despite the effects of lesion on the fibre orientation reconstruction algorithms, fibre tracking algorithms are still able to segment tracts that pass areas with high prevalence of lesions. Combining dRL-based tractography with an automated tract segmentation tool on data from 131 MS patients, the corticospinal tracts and arcuate fasciculi were successfully reconstructed in more than 90% of individuals. Comparing tractspecific microstructural parameters (fractional anisotropy, radial diffusivity and magnetisation transfer ratio) in individually segmented tracts to those from a tract probability map, we showed that there is no systematic disease-related bias in the individually reconstructed tracts, suggesting that lesions and otherwise damaged parts are not systematically omitted during tractography. Thirdly, we demonstrate modest anatomical correspondence between the individual and tract probability-based approach, with a spatial overlap between 35 and 55%. Correlations between tract-averaged microstructural parameters in individually segmented tracts and the probability-map approach ranged between r = .52 (p < .001) for radial diffusivity in the right cortico-spinal tract and r = .97 (p < .001) for magnetization transfer ratio in the arcuate fasciculi. Our results show that MS white matter lesions impact fibre orientation reconstructions but this does not appear to hinder the ability to anatomically localise white matter tracts in MS. Individual tract segmentation in MS is feasible on a large scale and could prove a powerful tool for investigating diagnostic and prognostic markers.

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bioRxiv2018

Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white matter structures

Genomic copy number variants (CNVs) are amongst the most highly penetrant genetic risk factors for neuropsychiatric disorders. The scarcity of carriers of individual CNVs and their phenotypical heterogeneity limits investigations of the associated neural mechanisms and endophenotypes. We applied a novel design based on CNV penetrance for schizophrenia and developmental delay that allows us to identify structural sequelae that are most relevant to neuropsychiatric disorders. Our focus on brain structural abnormalities was based on the hypothesis that convergent mechanisms contributing to neurodevelopmental disorders would likely manifest in the macro- and microstructure of white matter and cortical and subcortical grey matter. 21 adult participants carrying neuropsychiatric risk CNVs (including those located at 22q11.2, 15q11.2, 1q21.1, 16p11.2, and 17q12) and 15 age- and gender matched controls underwent T1-weighted structural, diffusion and quantitative T1 relaxometry MRI.\n\nThe macro- and microstructural properties of the cingulum bundles were associated with penetrance for both developmental delay and schizophrenia, in particular curvature along the anterior-posterior axis (Sz: pcorr=0.026; DD: pcorr=0.035) and intracellular volume fraction (Sz: pcorr=0.019; DD: pcorr=0.064) Further principal component analysis showed alterations in the interrelationships between the volumes of several mid-line white matter structures (Sz: pcorr=0.055; DD, pcorr=0.027). In particular, the ratio of volumes in the splenium and body of the corpus callosum was significantly associated with both penetrance scores (Sz: p=0.037; DD; p=0.006). Our results are consistent with the notion that a significant alteration in developmental trajectories of mid-line white-matter structures constitutes a common neurodevelopmental aberration contributing to risk for schizophrenia and intellectual disability.

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