The contribution of brain reorganisation to recovery in patients with optic neuritis

In this thesis, the mechanisms of damage and repair in clinically isolated optic neuritis (ON) were investigated in vivo, by combining magnetic resonance imaging (MRI), electrophysiology and optical coherence tomography (OCT). ON is a demyelinating, inflammatory condition of the optic nerve, which may be the first presentation of multiple sclerosis. The visual prognosis is generally good, despite optic nerve demyelination and axonal loss, but some patients fail to recover. The aim of this thesis was to determine the reasons underlying recovery. The hypothesis was that neuroplastic grey matter reorganisation might contribute to visual outcome. Structural MRI, electrophysiology and OCT were used to quantify optic nerve oedema, inflammation, myelination and neuroaxonal loss, and optic radiation and visual cortical pathology, in a cohort of patients with acute ON, followed up over the following year. Visual functional MRI (fMRI) was employed to investigate neuroplasticity. Acutely, measures of optic nerve inflammation and conduction block were associated with the severity of acute visual loss, and were used to inform an fMRI analysis, in order to dissect complex structure-function interactions. Evidence was found for neuroplasticity in dorsal higher visual areas, which may act to modulate acute visual dysfunction. Subsequent longitudinal analyses identified associations between early fMRI activation in the lateral occipital complexes, a ventral stream higher visual area, and longer term visual outcome, which were evident on stimulation of either eye, and independent of measures of myelination and neuroaxonal loss in the visual pathways. A quadrant-specific fMRI stimulation paradigm was used to investigate recovery from visual field defects, finding no evidence for field defect-specific neuroplastic responses. It was concluded that cortical neuroplasticity appears more important to recovery from ON than was previously thought, and its contribution is independent of measures of tissue damage. This may provide a target for future therapeutic approaches in demyelinating disease

Characterization of Pupillary Light Response Features for the Classification of Patients with Optic Neuritis

Pupillometry is a promising technique for the potential diagnosis of several neurological pathologies. However, its potential is not fully explored yet, especially for prediction purposes and results interpretation. In this work, we analyzed 100 pupillometric curves obtained by 12 subjects, applying both advanced signal processing techniques and physics methods to extract typically collected features and newly proposed ones. We used machine learning techniques for the classification of Optic Neuritis (ON) vs. Healthy subjects, controlling for overfitting and ranking the features by random permutation, following their importance in prediction. All the extracted features, except one, turned out to have significant importance for prediction, with an average accuracy of 76%, showing the complexity of the processes involved in the pupillary light response. Furthermore, we provided a possible neurological interpretation of this new set of pupillometry features in relation to ON vs. Healthy classification

Imaging of cognitive outcomes in patients with autoimmune encephalitis

Die Autoimmunenzephalitis ist eine kürzlich beschriebene entzündliche Erkrankung des zentralen Nervensystems, die Gedächtnisdefizite, Psychosen, oder epileptische Anfälle hervorrufen kann. Derzeit ist hingegen noch nicht ausreichend verstanden, welche pathologischen Veränderungen zu den kognitiven Defiziten führen und welche neuropsychologischen und bildgebenden Langzeitoutcomes zu erwarten sind. Anhand von strukturellen und funktionellen Bildgebungsanalysen zeigt diese Dissertation, dass kognitive Defizite auch nach der akuten Phase der Autoimmunenzephalitis fortbestehen können. Bei der LGI1-Enzephalitis gehen Gedächtnisdefizite mit fokalen strukturellen Läsionen im Hippocampus einher. Durch eine funktionelle Störung der Resting-State-Konnektivität des Default-Mode- und Salienznetzwerkes beeinträchtigen diese Hippocampusläsionen auch Hirnregionen außerhalb des limbischen Systems. Bei Patient:innen mit NMDA-Rezeptor-Enzephalitis finden sich in der longitudinalen neuropsychologischen Untersuchung trotz guter allgemeiner Genesung auch noch mehrere Jahre nach der Akutphase persistierende Defizite des Gedächtnisses und exekutiver Funktionen. Zuletzt zeigt eine transdiagnostische Analyse, dass der anteriore Hippocampus eine erhöhte Vulnerabilität gegenüber immunvermittelten pathologischen Prozessen aufweist. Diese Ergebnisse legen nahe, dass kognitive Symptome auch noch nach der Entlassung aus der stationären Behandlung fortbestehen können. Sowohl umschriebene strukturelle Hippocampusläsionen als auch Veränderungen in makroskopischen funktionellen Hirnnetzwerken tragen zur pathophysiologischen Erklärung dieser Symptome bei. Zudem erlauben diese Ergebnisse einen Einblick in neuroplastische Veränderungen des Gehirns und haben weitreichende Implikationen für die Langzeitversorgung und das Design zukünftiger klinischer Studien.Autoimmune encephalitis is a recently described inflammatory disease of the central nervous system that can cause memory deficits, psychosis, or seizures. The trajectory of cognitive dysfunction and the underlying long-term imaging correlates are, however, not yet fully understood. By using advanced structural and functional neuroimaging, this thesis shows that cognitive deficits persist beyond the acute phase. In LGI1 encephalitis, MRI postprocessing revealed that memory deficits are related to focal structural hippocampal lesions. These hippocampal lesions propagate to brain areas outside the limbic system through aberrant resting-state connectivity of the default mode network (DMN) and the salience network. In NMDA receptor encephalitis, a longitudinal analysis of neuropsychological data describes persistent cognitive deficits, especially in the memory and executive domains, despite good physical recovery several years after the acute disease. Lastly, a transdiagnostic analysis reveals that the anterior hippocampus is particularly vulnerable to immune-mediated damage. In conclusion, these results demonstrate that cognitive symptoms in autoimmune encephalitis can persist beyond discharge from neurological care. Both discrete structural hippocampal damage and changes in macroscopic functional networks shed light on the pathophysiological basis of these symptoms. These findings help to explain how the brain responds to pathological damage and have substantial implications for long-term patient care and the design of future clinical studies

Identification of neurobiological mechanisms associated with attention deficits in adults post traumatic brain injury

Traumatic Brain Injury (TBI) is one of the major public health concerns with approximately 70 million new cases occurring worldwide per year. It is often caused by a forceful bump, blow, or jolt to the head, resulting in brain tissue damage and normal brain functions disruption. All grades of TBI, ranging from mild to severe, can cause wide-ranging and long-term effects on affected individuals, resulting in physical impairments, and neurocognitive consequences that permanently affect their abilities to perform daily activities. Attention deficits are the most common persisting neurocognitive consequences following TBI, which significantly contribute to poor academic and social functioning, and life-long learning difficulties of affected individuals. However, attention deficits have been evaluated and treated based on symptom endorsements from subjective observations, with few therapeutic interventions successfully translated to the clinic. The consensus regarding appropriate evaluation and treatment of TBI induced attention deficits in this cohort is rather limited due to the lack of investigations of the neurobiological substrates associated with this syndrome. The overall aim of this dissertation research is to systematically investigate the neurobiological mechanisms associated with attention deficits in adults post TBI by utilizing multiple powerful neuroimaging techniques including the functional near-infrared spectroscopy (fNIRS) and multimodal magnetic resonance imaging (MRI), with an ultimate goal of translating hypothesis-driven neurobiological correlates into the quantitatively measurable biomarkers for diagnosis of TBI-induced attention deficits and development of more refined long-term treatment and intervention strategies. This dissertation research is conducted through three specific projects. Project 1 focuses on the investigation of brain functional patterns including the regional cortical brain activation and between-regional pairwise functional connectivity responding to visual sustained attention processing in individuals with and without TBI, by utilizing the fNIRS technique. Project 2 continues the examination of brain functional patterns by assessing the whole brain network topological properties responding to visual sustained attention processing in a larger sample of individuals with and without TBI, by utilizing the functional MRI technique and a graph theoretic approach. Project 3, on the other hand, investigates the brain structural characteristics based on the same sample involved in Project 2, by utilizing the structural MRI and diffusion tensor imaging techniques. For all these three projects, the differences of these brain imaging measures are compared between the groups of TBI and control. Correlation analyses are further conducted between those brain imaging measures which shows significant between-group differences and attention-related behaviors. In addition, Project 3 additionally investigates gender-specific patterns of the altered brain structural properties in TBI patients, relative to controls. The outcome of this novel and valuable dissertation research may shed light on the neural mechanisms of attention deficits in adults post TBI, and may suggest the neurobiological targets for treatment of this severe and common condition. It may also provide important neural foundation for future research to develop effective rehabilitation strategies to improve attention processing in adults post TBI

Investigation of multiple sclerosis spinal cord using high field MRI with multi-transmit technology

This thesis explores abnormalities in the multiple sclerosis (MS) spinal cord and their relationship with physical disability through the use of conventional and quantitative magnetic resonance imaging (MRI). Firstly, an hypothesis was tested that spinal cord atrophy would be associated with disability, independently from brain atrophy and lesion load, in long disease duration MS. The results presented confirm that cord atrophy is significantly associated with higher levels of physical disability after more than twenty years of MS. Following this observation, the next experiment investigated whether a combination of an active surface model (ASM) and high resolution axial images, would provide a more reproducible measure of spinal cord cross-sectional area; compared to previously described methodologies. The results presented show the superior reproducibility of the ASM combined with axial images for the measurement of cord area in MS, which may be of relevance to future clinical trials utilising cord atrophy as an outcome measure. The pathology of MS in the spinal cord was also explored in several ways using MRI. Firstly, spinal cord lesion morphology was studied, to investigate whether focal lesions, that traversed two or more spinal cord columns and involved the grey matter, would be associated with progressive MS. The results presented confirm this association and also that diffuse abnormalities are more frequently seen in progressive disease. Secondly, spinal cord lesion load was measured quantitatively on axial images, to investigate if this measure would be associated with disability independently from cord atrophy. The functional importance of focal lesions in MS is highlighted by demonstrating an independent association between lesion load and disability. Thirdly, magnetisation transfer ratio (MTR) measures of the outer spinal cord were obtained, in an area expected to contain the pia mater and subpial tissue, to investigate whether outer cord abnormalities could be seen in MS compared to healthy controls and if such abnormalities would be associated with cord atrophy. The results presented show that significant decreases in MTR occur in the outer cord early in the disease course, prior to the development of cord atrophy and further decreases in MTR were seen in progressive MS. Furthermore, an independent association is presented between outer cord MTR and cord atrophy, suggesting that spinal cord meningeal inflammation may be associated with axonal loss in MS. Lastly, diffusion tensor imaging was used in the spinal cord grey matter, in order to investigate whether microstructural abnormalities in this structure would be associated with physical disability. The results of this study identified an association between grey matter radial diffusivity and disability, independently from cord atrophy, suggesting a significant contribution of spinal cord grey matter pathology to clinical dysfunction. In summary, this thesis shows that MS spinal cord abnormalities may be visualised and quantified using high field MRI, and are significantly associated with disability. The observations presented may of relevance to future MRI studies and clinical trials in MS that aim to understand and potentially prevent the pathological processes underlying irreversible physical disability

Pathogenesis of Encephalitis

Many infectious agents, such as viruses, bacteria, and parasites, can cause inflammation of the central nervous system (CNS). Encephalitis is an inflammation of the brain parenchyma, which may result in a more advanced and serious disease meningoencephalitis. To establish accurate diagnosis and develop effective vaccines and drugs to overcome this disease, it is important to understand and elucidate the mechanism of its pathogenesis. This book, which is divided into four sections, provides comprehensive commentaries on encephalitis. The first section (6 chapters) covers diagnosis and clinical symptoms of encephalitis with some neurological disorders. The second section (5 chapters) reviews some virus infections with the outlines of inflammatory and chemokine responses. The third section (7 chapters) deals with the non-viral causative agents of encephalitis. The last section (4 chapters) discusses the experimental model of encephalitis. The different chapters of this book provide valuable and important information not only to the researchers, but also to the physician and health care workers

Multimodal neuroimaging of vestibular and postural networks: Investigating the pathophysiology of idiopathic dizziness in older adults

Successful ageing - the preservation of good performance into old age, is an aspiration for many and a challenge for society. Modifiable factors which account for ageing-related functional decline should thus be identified and reduced. As life expectancy increases, brain ageing and its functional consequences become an increasingly important target for research and intervention. Cerebral small vessel disease, largely driven by vascular risk factors, has emerged as a strong contributor to cognitive and balance decline in late life. Though the early effects of cerebral small vessel disease on cognition are increasingly better understood, its symptomatic effects on other functional systems are not well characterised. In this thesis, I investigated the long recognised, but pathophysiologically enigmatic syndrome of dizziness in older adults, not accounted for by neurological disease or vestibular dysfunction. I considered the hypothesis that this ‘idiopathic dizziness’ is secondary to cerebral small vessel disease through its deleterious effects on white matter networks which subserve vestibular perceptual processes and/or the control of balance. I first defined the functional anatomy of the core human vestibular cortex by its functional connectivity (Chapter 3). I related the resulting anatomical subregions to behavioural and task neuroimaging data to define a vestibular network involved in self-motion perception. I proceeded to characterise the syndrome of idiopathic dizziness using clinical, cognitive and behavioural (vestibular function, balance and gait) data from patients and controls (Chapter 4). I combined this data with structural and diffusion magnetic resonance imaging data to investigate the pathophysiology of idiopathic dizziness. I found that frontal white matter tracts relevant to the control of balance had lower integrity in patients with idiopathic dizziness than controls. These findings occurred in the context of excess vascular risk, and markers of cerebral small vessel disease. Additionally, I found vestibular function and perception were normal in patients with idiopathic dizziness. The results suggest disrupted balance control may underpin idiopathic dizziness in cerebral small vessel disease. I proceeded to investigate whether neural correlates of balance control were altered in idiopathic dizziness as a model for mild balance impairment in cerebral small vessel disease (Chapter 5). To do this, I applied electroencephalography during quiet standing and related brain activity to spontaneous sway. I showed idiopathic dizziness was linked to altered cortical activity in relation to balance control, and this cortical activity was influenced by the burden of cerebral small vessel disease. Additionally, patients with idiopathic dizziness uniquely engaged a low frequency postural connectivity network, consistent with a different mode of postural control. Overall, the results within this thesis show a relationship between idiopathic dizziness and vascular injury to frontal tracts involved in the control of balance in cerebral small vessel disease. Small vessel disease may disrupt the cortical control of balance as a basis for symptoms in this syndrome.Open Acces

Sensorimotor integration processing in Diabetic Retinopathy and Diabetic Peripheral Neuropathy

This study evaluated the direct link between visual perception and related motor output responses during an optic flow stimulation which induced a perception of forward movement, and during a driving task using a simulator. The experiments focussed on the evaluation of two different complications of diabetes, diabetic retinopathy and diabetic peripheral neuropathy (DPN), in order to evaluate the different contributions of both central and peripheral nervous factors in affecting the sensorimotor integration process in diabetes. Study I. The aim was to assess how optic flow processing contributes to the control of posture and whether it requires the predominant activation of cortical networks involved in motion perception or the intervention of subcortical loops. People with retinopathy and people who had undergone laser treatment showed a higher postural instability compared to control subjects. Differing retinal functionality produced different postural strategies. Based on these findings, postural control seems to be a process dependent on perceptual analysis via feed-forward cortical circuits. Study II. The aim was to assess whether diabetes was associated with alterations of visual gaze behaviour and/or neuromuscular impairment that might adversely affect driving performance. The potential for impaired driving performance with diabetes seems to be represented by diminished eye-steering coordination. While proprioception function seems to indicate the potential for improvement, a slower production of strength in the plantar flexor muscles seems not to influence accelerator pedal control during a driving simulation task in people with diabetes (with and without diabetic peripheral neuropathy). These results confirm the role of visual perception and eye movements in guiding human movements during dailylife activities. In particular, we demonstrated the detrimental effects of diabetes and the different contribution of diabetic retinopathy and diabetic peripheral neuropathy in affecting both central and peripheral components of the sensorimotor integration process