Karla L Miller

University of Oxford | OX · Oxford Centre for Functional MRI of the Brain (FMRIB Centre)

Carnivorans are an important study object for comparative neuroscience, as they exhibit a wide range of behaviours, ecological adaptations, and social structures. Previous studies have mainly examined relative brain size, but a comprehensive understanding of brain diversity requires the investigation of other aspects of their neuroanatomy. Here, we...

Carnivorans are an important study object for comparative neuroscience, as they exhibit a wide range of behaviours, ecological adaptations, and social structures. Previous studies have mainly examined relative brain size, but a comprehensive understanding of brain diversity requires the investigation of other aspects of their neuroanatomy. Here, we...

Preclinical diffusion MRI (dMRI) has proven value in methods development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI...

High-resolution diffusion MRI (dMRI) provides valuable insights into brain microstructure, particularly at submillimeter resolutions, where it enables more precise delineations of curved and crossing white matter pathways. However, achieving high-quality submillimeter dMRI in-vivo poses significant challenges due to the intrinsically low signal-to-...

Biophysical modelling of diffusion MRI (dMRI) is used to non-invasively estimate microstructural features of tissue, particularly in the brain. However, meaningful description of tissue requires many unknown parameters, resulting in a model that is often ill-posed. The Bayesian EstimatioN of CHange (BENCH) framework was specifically designed to cir...

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who had required...

3D multi-slab acquisitions are an appealing approach for diffusion MRI because they are compatible with the imaging regime delivering optimal SNR efficiency. In conventional 3D multi-slab imaging, shot-to-shot phase variations caused by motion pose challenges due to the use of multi-shot k-space acquisition. Navigator acquisition after each imaging...

Introduction The analysis tools and statistical methods used in large neuroimaging research studies differ from those applied in clinical contexts, making it unclear whether these techniques can be translated to a memory clinic setting. The Oxford Brain Health Clinic (OBHC) was established in 2020 to bridge this gap between research studies and mem...

While the hippocampus is key for human cognitive abilities, it is also a phylogenetically old cortex and paradoxically considered evolutionarily preserved. Here, we introduce a comparative framework to quantify preservation and reconfiguration of hippocampal organisation in primate evolution, by analysing the hippocampus as an unfolded cortical sur...

This chapter provides an overview of deep learning techniques for improving the spatial resolution of MRI, ranging from convolutional neural networks, generative adversarial networks, to more advanced models including transformers, diffusion models, and implicit neural representations. Our exploration extends beyond the methodologies to scrutinize...

Motivation: Joint modelling of diffusion MRI and microscopy can leverage their complementary strengths to improve the estimation of fibre orientations. Ideally, these benefits would extend beyond the few datasets where dMRI and microscopy are acquired in the same brain to improve orientation estimates in in-vivo data. Goal: To translate the unique...

Although functional magnetic resonance imaging (fMRI) is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B 0 . Increasing field strength enables higher spatial resolution and improved sensitivity to bl...

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as “TDP-43 proteinopathies”. Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usual...

3D multi-slab acquisitions are an appealing approach for diffusion MRI because they are compatible with the imaging regime delivering optimal SNR efficiency. In conventional 3D multi-slab imaging, shot-to-shot phase variations caused by motion pose challenges due to the use of multi-shot k-space acquisition. Navigator acquisition after each imaging...

Neuroanatomical tract tracing methods are fundamental in providing “gold standard” estimates of brain connectivity. However, tracer methods cannot be performed in humans and even in animals, we can only study projections from typically one or two injection sites per animal sacrificed. Orientation-sensitive microscopy techniques such as PLI provide...

Diffusion MRI of the infant brain allows investigation of the organizational structure of maturing fibers during brain development. Post-mortem imaging has the potential to achieve high resolution by using long scan times, enabling precise assessment of small structures. Technical development for post-mortem diffusion MRI has primarily focused on s...

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as TDP-43 proteinopathies. Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ~50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually...

Combining histology and ex vivo MRI from the same mouse brain is a powerful way to study brain microstructure. Mouse brains prepared for ex vivo MRI are often kept in storage solution for months, potentially becoming brittle and showing reduced antigenicity. Here, we describe a protocol for mouse brain dissection, tissue processing, paraffin embedd...

The hippocampus is involved in numerous cognitive functions, some of which have uniquely human aspects, such as autobiographical memory. Hippocampal anatomy, however, is typically considered conserved across primates and its evolutionary diversification is rarely studied. Comparing hippocampal structure and function is, therefore, critical for unde...

Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal chara...

Introduction Cerebral microbleeds (CMBs) are associated with white matter damage, and various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) i...

A lab handbook is a flexible document that outlines the ethos of a research lab or group. A good handbook will outline the different roles within the lab, explain what is expected of all lab members, provide an overview of the culture the lab aims to create, and describe how the lab supports its members so that they can develop as researchers. Here...

Purpose To develop a new method for high‐fidelity, high‐resolution 3D multi‐slab diffusion MRI with minimal distortion and boundary slice aliasing. Methods Our method modifies 3D multi‐slab imaging to integrate blip‐reversed acquisitions for distortion correction and oversampling in the slice direction (kz) for reducing boundary slice aliasing. Ou...

We built a novel pipeline to register 290 high-resolution multi-contrast microscopy sections in the BigMac dataset to post-mortem MRI with sub-millimetre accuracy. The MRI-microscopy alignment is optimised over all microscopy sections jointly, to achieve high-quality co-registration whilst ensuring the slide order and separation is consistent with...

The BigMac dataset is an open access resource combining in vivo MRI, postmortem MRI and multi-contrast microscopy data in a single, whole macaque brain. Here we perform data-driven segmentation of the BigMac histology slides to extract quantitative microscopy metrics for myelin, cell density, and cellular morphology (e.g. soma size and packing). Ut...

Diffusion MRI is a useful neuroimaging tool for non-invasive mapping of human brain microstructure and structural connections. The analysis of diffusion MRI data often requires brain segmentation, including volumetric segmentation and cerebral cortical surfaces, from additional high-resolution T1-weighted (T1w) anatomical MRI data, which may be una...

Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship bet...

Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases. Methods: 7,8-DHF was administered systemically to...

Background Accurate registration between microscopy and MRI data is necessary for validating imaging biomarkers against neuropathology, and to disentangle complex signal dependencies in microstructural MRI. Existing registration methods often rely on serial histological sampling or significant manual input, providing limited scope to work with a la...

The Oxford Brain Health Clinic (BHC) is a joint clinical-research service that provides memory clinic patients and clinicians access to high-quality assessments not routinely available, including brain MRI aligned with the UK Biobank imaging study (UKB). In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for m...

Noninvasive diffusion magnetic resonance imaging (dMRI) has been widely employed in both clinical and research settings to investigate brain tissue microstructure. Despite the evidence that dMRI-derived fractional anisotropy (FA) correlates with white matter properties, the metric is not specific. Recent studies have reported that FA is dependent o...

Introduction Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high...

The value of preclinical diffusion MRI (dMRI) is substantial. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages including higher signal-to-noise ratio and spatial resolution compared to in...

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from...

Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal chara...

The Oxford Brain Health Clinic (BHC) is a joint clinical-research service that provides memory clinic patients and clinicians access to high-quality assessments not routinely available, including brain MRI aligned with the UK Biobank imaging study (UKB). In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for m...

Background: Accurate registration between microscopy and MRI data is necessary for validating imaging biomarkers against neuropathology, and to disentangle complex signal dependencies in microstructural MRI. Existing registration methods often rely on serial histological sampling or significant manual input, providing limited scope to work with a l...

To estimate microstructure-related parameters from diffusion MRI data, biophysical models make strong, simplifying assumptions about the underlying tissue. The extent to which many of these assumptions are valid remains an open research question. This study was inspired by the disparity between the estimated intra-axonal axial diffusivity from lite...

Background Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher...

Purpose We investigate the use of TURBINE, a 3D radial‐Cartesian acquisition scheme in which EPI planes are rotated about the phase‐encoding axis to acquire a cylindrical k‐space for high‐fidelity ultrahigh isotropic resolution fMRI at 7 Tesla with minimal distortion and blurring. Methods An improved, completely self‐navigated version of the TURBI...

A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and c...

Microscopy data can provide detailed descriptions of how cortical microstructure varies across the brain. However, the relationship between cortical microstructure and MRI signals remains relatively unexplored. Here we develop a pipeline to extract cortical profiles from co-registered MRI and microscopy data in the BigMac dataset. We compare cortic...

There is strong evidence for brain-related abnormalities in COVID-191-13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51-81) imaged twice...

Reproduction and survival in most primate species reflects management of both competitive and cooperative relationships. Here, we investigated the links between neuroanatomy and sociality in free-ranging rhesus macaques. In adults, the number of social partners predicted the volume of the mid-superior temporal sulcus and ventral-dysgranular insula,...

Post-mortem MRI provides the opportunity to acquire high-resolution datasets to investigate neuroanatomy, and validate the origins of image contrast through microscopy comparisons. We introduce the Digital Brain Bank (open.win.ox.ac.uk/DigitalBrainBank), a data release platform providing open access to curated, multimodal post-mortem neuroimaging d...

The acquisition of MRI and histology in the same post-mortem tissue sample enables direct correlation between MRI and histologically-derived parameters. However, there still lacks a standardised automated pipeline to process histology data, with most studies relying on heavy manual intervention. Here, we introduce an automated pipeline to extract q...

Purpose To estimate dynamic off‐resonance due to vigorous body motion in accelerated fMRI of awake behaving nonhuman primates (NHPs) using the echo‐planar imaging reference navigator, in order to attenuate the effects of time‐varying off‐resonance on the reconstruction. Methods In NHP fMRI, the animal’s head is usually head‐posted, and the dynamic...

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2 * -weighted gradient recalled echo (T2 * -GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detec...

Cerebral microbleeds (CMBs) are associated with white matter damage, various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to thei...

Large-scale comparative neuroscience requires data from many species and, ideally, at multiple levels of description. Here, we contribute to this endeavor by presenting diffusion and structural MRI data from eight primate species that have not or rarely been described in the literature. The selected samples from the Primate Brain Bank cover a prosi...

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images w...

Background Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV2 infection on the brain by diverse potentially pathogenic mechanisms, and with high rel...

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect aut...

Formalin fixation has been shown to substantially reduce T2 estimates, primarily driven by the presence of fixative in tissue. Prior to scanning, post-mortem samples are often placed into a fluid that has more favourable imaging properties. This study investigates whether there is evidence for a change in T2 in regions close to the tissue surface d...

A key aim of epidemiological neuroscience studies is the identification of novel markers to assess brain health and evaluate the efficacy of therapeutic interventions. A broad range of tissue constituents associated with healthy brain functions and diseases (e.g., iron, myelin and calcium) are characterised by unique magnetic properties, motivating...

Diffusion MRI of the neonatal brain allows investigation of the organisational structure of maturing fibres during brain development. Post-mortem imaging has the potential to achieve high resolution by using long scan times, enabling precise assessment of small structures. The Forget-Me-Not study, part of the Developing Human Connectome Project (dH...

Post-mortem MRI provides the opportunity to acquire high-resolution datasets to investigate neuroanatomy, and validate the origins of image contrast through microscopy comparisons. We introduce the Digital Brain Bank (open.win.ox.ac.uk/DigitalBrainBank), an interactive data discovery and release platform providing open access to curated, multimodal...

There is strong evidence for brain-related abnormalities in COVID-19 1-13 . It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51-81) imaged twi...

Acceleration methods in fMRI aim to reconstruct high fidelity images from under-sampled k-space, allowing fMRI datasets to achieve higher temporal resolution, reduced physiological noise aliasing, and increased statistical degrees of freedom. While low levels of acceleration are typically part of standard fMRI protocols through parallel imaging, th...

The BigMac dataset is a unique resource that includes extensive MRI and densely sampled microscopy data acquired in a single, whole macaque brain. However, the high-resolution microscopy currently only informs on the fibre orientations in the 2D plane of sampled slides, precluding 3D reconstruction of the microscopy connectome. Here we use precise...

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images w...