Combining advanced MR techniques to investigate mild Traumatic Brain Injury and its cognitive consequences

PhD ThesisMild Traumatic Brain Injury (TBI) is a major health concern due to its high incidence and lasting cognitive consequences for the patient. Diffuse Axonal Injury (DAI); diffuse damage to axons caused by inertial forces during the TBI, is hypothesised to be a leading cause for these impairments. MRI-based research which has examined mild, acute cases has produced findings which indicate that the mechanisms and progression of mild TBI may be unique and not simply a less pronounced version of severe TBI. This thesis describes a set of experiments which used a variety of advanced MRI techniques to examine the physiological presentation and progression of mild TBI, and how this related to cognitive outcome. Forty-four mild and 9 moderate TBI patients were recruited an average of 6 days post-injury, scanned using a variety MRI techniques and administered a neuropsychological test battery. Twenty-three of these patients (18 mild and 5 moderate) returned one year later and repeated all testing. Thirty-three matched controls were also recruited and given the same set of tests. At the acute time-point patients underperformed on a variety of cognitive tests, although performance at the chronic time-point had normalised compared to controls. The distribution of visible lesions (as identified on quantitative T1 / T2 and T1W scans) was found to be similar to patterns previously reported in severe patients. Results also indicated more lesions to be related to greater acute cognitive deficit. Diffusion Tensor Imaging experimentation revealed a number of unexpected, cognitively-relevant metric changes at the acute and chronic time-points. Magnetic Resonance Spectroscopy investigation also showed a number of unusual metabolite concentration changes and also found these to relate to cognitive functioning. Novel hypotheses were formed from these findings. This work has demonstrated a number of cognitively-relevant physiological changes following TBI which appear unique to mild injury

Brain Connectivity After Concussion

Mild traumatic brain injury (mTBI) accounts for over one million emergency visits in the United States each year. While most mTBI patients have normal findings in clinical neuroimaging, alterations in brain structure and functional connectivity have frequently been reported. In this study, we investigated the large-scale brain structural and functional connectivity using diffusion MRI and resting-state fMRI data. Data from 40 mTBI patients was acquired at the acute stage (within 24 hrs after injury). 35 patients returned for data acquisition at a follow-up (4-6 weeks after injury). Data was also collected from a cohort of 58 healthy subjects, 36 of whom returned for data acquisition at the second time point, 4-6 weeks later. All data was collected at Wayne State University, Detroit, Michigan, USA. We also evaluated the relationship between functional connectivity findings at the acute stage and neurocognitive symptoms at follow up to assess the feasibility of using neuroimaging data to predict neurocognitive complications after mTBI. Moreover, we developed the connectivity domain, a new analysis method which can potentially improve reproducibility and ability to compare findings across datasets

Traumatic brain injury : relationships between brain structural abnormalities and cognitive function

Traumatic brain injury (TBI) is the leading cause of disability in young adults and a major public health problem. Persistent cognitive impairments are common, and constitute a significant source of long-term disability. The specific pathophysiological mechanisms underlying these impairments remain poorly understood. As it disconnects brain networks, white matter damage can be a key determinant of cognitive impairment after TBI. Neuroimaging and neuropsychological methods were employed to explore the relationships between indices of brain structure and cognitive function. The participants were 40 TBI patients and 40 healthy controls. First, relationships between focal lesions and cognitive performance were investigated using structural magnetic resonance imaging (MRI) and a battery of neuropsychological tests. The results demonstrated that lesion location and load are not good indices of the cognitive deficits - probably because diffuse axonal injury is poorly assessed by standard MRI. By contrast, diffusion tensor imaging (DTI) can be used to quantify the microstructure of white matter. A ‘whole-brain’ technique, tract-based spatial statistics (TBSS), was used to flexibly analyse the structure of white matter tracts. Despite only small amounts of focal damage observed using standard MRI, TBSS revealed widespread white matter abnormalities after TBI. White matter damage was found in patients with no evidence of focal damage, and in patients classified as ‘mild’ clinically. Relationships between white matter tract structure and specific cognitive functions were then explored. The structure of the fornix, an important white matter pathway of the hippocampus, correlated with verbal associative memory across the patient and control groups. By contrast, structure of frontal lobe connections showed distinct relationships with executive function in these two groups. The results emphasise the importance of white matter pathology after TBI and suggest that disruption to specific white matter tracts is associated with particular patterns of cognitive impairment, but also highlight the complexity of these relationships.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. DISCUSSION: Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial desig

Traumatic brain injury: relationships between brain structural abnormalities and cognitive function

Traumatic brain injury (TBI) is the leading cause of disability in young adults and a major public health problem. Persistent cognitive impairments are common, and constitute a significant source of long-term disability. The specific pathophysiological mechanisms underlying these impairments remain poorly understood. As it disconnects brain networks, white matter damage can be a key determinant of cognitive impairment after TBI. Neuroimaging and neuropsychological methods were employed to explore the relationships between indices of brain structure and cognitive function. The participants were 40 TBI patients and 40 healthy controls. First, relationships between focal lesions and cognitive performance were investigated using structural magnetic resonance imaging (MRI) and a battery of neuropsychological tests. The results demonstrated that lesion location and load are not good indices of the cognitive deficits - probably because diffuse axonal injury is poorly assessed by standard MRI. By contrast, diffusion tensor imaging (DTI) can be used to quantify the microstructure of white matter. A ‘whole-brain’ technique, tract-based spatial statistics (TBSS), was used to flexibly analyse the structure of white matter tracts. Despite only small amounts of focal damage observed using standard MRI, TBSS revealed widespread white matter abnormalities after TBI. White matter damage was found in patients with no evidence of focal damage, and in patients classified as ‘mild’ clinically. Relationships between white matter tract structure and specific cognitive functions were then explored. The structure of the fornix, an important white matter pathway of the hippocampus, correlated with verbal associative memory across the patient and control groups. By contrast, structure of frontal lobe connections showed distinct relationships with executive function in these two groups. The results emphasise the importance of white matter pathology after TBI and suggest that disruption to specific white matter tracts is associated with particular patterns of cognitive impairment, but also highlight the complexity of these relationships

Computational Modeling of the Human Brain for mTBI Prediction and Diagnosis

Sports related concussions and mild traumatic brain injuries have seen an increase in frequency over the past decade. The creation of highly biofidelic computational head models is an important step in understanding the mechanisms of these mild brain injuries and preventing them. Hence, the purpose of this research is to combine state-of-the-art computational models, brain imaging modalities and traditional head injury assessment protocols to simulate and predict the brains responses during traumatic head impacts. A novel, atlas-based, parcellated axon fiber embedded head model was developed which allows for in-depth analysis of the brain’s structural connectome tracts for injury diagnosis and analysis. New axon strain metrics were developed along with traditional head kinematic methodologies to create one of the most advanced finite element head models for concussion injury reconstruction which allows for comparison to patient symptoms through tract injury level prediction

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces