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

Multimodal imaging of human brain activity: rational, biophysical aspects and modes of integration

Until relatively recently the vast majority of imaging and electrophysiological studies of human brain activity have relied on single-modality measurements usually correlated with readily observable or experimentally modified behavioural or brain state patterns. Multi-modal imaging is the concept of bringing together observations or measurements from different instruments. We discuss the aims of multi-modal imaging and the ways in which it can be accomplished using representative applications. Given the importance of haemodynamic and electrophysiological signals in current multi-modal imaging applications, we also review some of the basic physiology relevant to understanding their relationship

Spatio-Temporal Brain Mapping of Motion-Onset VEPs Combined with fMRI and Retinotopic Maps

Neuroimaging studies have identified several motion-sensitive visual areas in the human brain, but the time course of their activation cannot be measured with these techniques. In the present study, we combined electrophysiological and neuroimaging methods (including retinotopic brain mapping) to determine the spatio-temporal profile of motion-onset visual evoked potentials for slow and fast motion stimuli and to localize its neural generators. We found that cortical activity initiates in the primary visual area (V1) for slow stimuli, peaking 100 ms after the onset of motion. Subsequently, activity in the mid-temporal motion-sensitive areas, MT+, peaked at 120 ms, followed by peaks in activity in the more dorsal area, V3A, at 160 ms and the lateral occipital complex at 180 ms. Approximately 250 ms after stimulus onset, activity fast motion stimuli was predominant in area V6 along the parieto-occipital sulcus. Finally, at 350 ms (100 ms after the motion offset) brain activity was visible again in area V1. For fast motion stimuli, the spatio-temporal brain pattern was similar, except that the first activity was detected at 70 ms in area MT+. Comparing functional magnetic resonance data for slow vs. fast motion, we found signs of slow-fast motion stimulus topography along the posterior brain in at least three cortical regions (MT+, V3A and LOR)

Multifocal visual evoked potentials in demyelinating diseases of the visual pathway

Multifocal visual evoked potentials (mfVEP) provide an objective functional measure of the integrity of the visual pathway. This thesis constitutes a comprehensive assessment of mfVEP changes in demyelinating diseases of the visual pathway. The efficacy of the mfVEP technique was compared to full-field pattern-reversal visual evoked potential and the results illustrate a superiority of the mfVEP in detecting focal visual field defects in patients with different visual pathway disorders. The evolution of mfVEP parameters’ changes following acute optic neuritis (ON) was assessed in a longitudinal study of affected and fellow eyes in a large cohort of patients during the first 12 months after attack. The results indicated that mfVEP amplitude can be used as an early predictor of post-ON axonal loss. Additionally, the apparently more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. The analysis of latency delay in fellow eyes in ON patients indicated that the observed changes are most likely due to subclinical demyelination in the visual pathway and a reflection of the burden of disease in MS patients rather than a result of adaptive cortical plasticity to compensate for delayed transmission of visual information. The last study evaluated the relationship between mfVEP latency and posterior visual pathway lesions in MS patients which demonstrated a significant evidence linking the mfVEP changes with retro-geniculate inflammatory demyelinating lesions

Effect of Contrast, Stimulus Density, and Viewing Distance on Multifocal Steady-State Visual Evoked Potentials (MSVs)

We investigated the effects of image contrast, stimulus density, and viewing distance upon a multifocal steady-state visual evoked potential (MSV) method. Fourteen adults with normal vision (mean age = 27.0 ± 6.6 years; 6 males) participated in the stud

Cortical oscillatory dysrhythmias in visual snow syndrome: a magnetoencephalography study

Visual Snow refers to the persistent visual experience of static in the whole visual field of both eyes. It is often reported by patients with migraine and co-occurs with conditions like tinnitus and tremor. The underlying pathophysiology of the condition is poorly understood. Previously we hypothesised, that visual snow syndrome may be characterised by disruptions to rhythmical activity within the visual system. To test this, data from 18 patients diagnosed with visual snow syndrome, and 16 matched controls, were acquired using magnetoencephalography. Participants were presented with visual grating stimuli, known to elicit decreases in alpha-band (8-13Hz) power and increases in gamma-band power (40-70Hz). Data were mapped to source-space using a beamformer. Across both groups, decreased alpha power and increased gamma power localised to early visual cortex. Data from the primary visual cortex were compared between groups. No differences were found in either alpha or gamma peak frequency or the magnitude of alpha power, p>0.05. However, compared with controls, our visual snow syndrome cohort displayed significantly increased primary visual cortex gamma power, p=0.035. This new electromagnetic finding concurs with previous functional MRI and PET findings suggesting that in visual snow syndrome, the visual cortex is hyper-excitable. The coupling of alpha-phase to gamma amplitude within the primary visual cortex was also quantified. Compared with controls, the visual snow syndrome group had significantly reduced alpha-gamma phase-amplitude coupling, p<0.05, indicating a potential excitation-inhibition imbalance in visual snow syndrome, as well as a potential disruption to top-down “noise-cancellation” mechanisms. Overall, these results suggest that rhythmical brain activity in primary visual cortex is both hyperexcitable and disorganised in visual snow syndrome, consistent with this being a condition of thalamocortical dysrhythmia

The Developmental Trajectory of Contour Integration in Autism Spectrum Disorders

Sensory input is inherently ambiguous and complex, so perception is believed to be achieved by combining incoming sensory information with prior knowledge. One model envisions the grouping of sensory features (the local dimensions of stimuli) to be the outcome of a predictive process relying on prior experience (the global dimension of stimuli) to disambiguate possible configurations those elements could take. Contour integration, the linking of aligned but separate visual elements, is one example of perceptual grouping. Kanizsa-type illusory contour (IC) stimuli have been widely used to explore contour integration processing. Consisting of two conditions which differ only in the alignment of their inducing elements, one induces the experience of a shape apparently defined by a contour and the second does not. This contour has no counterpart in actual visual space – it is the visual system that fills-in the gap between inducing elements. A well-tested electrophysiological index associated with this process (the IC-effect) provided us with a metric of the visual system’s contribution to contour integration. Using visually evoked potentials (VEP), we began by probing the limits of this metric to three manipulations of contour parameters previously shown to impact subjective experience of illusion strength. Next we detailed the developmental trajectory of contour integration processes over childhood and adolescence. Finally, because persons with autism spectrum disorders (ASDs) have demonstrated an altered balance of global and local processing, we hypothesized that contour integration may be atypical. We compared typical development to development in persons with ASDs to reveal possible mechanisms underlying this processing difference. Our manipulations resulted in no differences in the strength of the IC-effect in adults or children in either group. However, timing of the IC-effect was delayed in two instances: 1) peak latency was delayed by increasing the extent of contour to be filled-in relative to overall IC size and 2) onset latency was delayed in participants with ASDs relative to their neurotypical counterparts

Simultaneous EEG-fMRI at ultra-high field for the study of human brain function

Scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have highly complementary domains, and their combination has been actively sought within neuroscience research. The important gains in fMRI sensitivity achieved with higher field strengths open exciting perspectives for combined EEG-fMRI; however, simultaneous acquisitions are subject to highly undesirable interactions between the two modalities, which can strongly compromise data quality and subject safety, and most of these interactions are increased at higher fields. The work described in this thesis was centered on the development of simultaneous EEG-fMRI in humans at 7T, covering aspects of subject safety, signal quality assessment, and quality improvement. Additionally, given the potential value of high-field EEG-fMRI to study the neuronal correlates of so-called negative BOLD responses, an initial fMRI study was dedicated to these phenomena. The initial fMRI study aimed to characterize positive (PBR) and negative BOLD responses (NBR) to visual checkerboard stimulation of varying contrast and duration, focusing on NBRs occurring in visual and in auditory cortical regions. Results showed that visual PBRs and both visual and auditory NBRs significantly depend on stimulus contrast and duration, suggesting a dynamic system of visual-auditory interactions, sensitive to stimulus contrast and duration. The neuronal correlates of these interactions could not be addressed in higher detail with fMRI alone, yet could potentially be clarified in future work with combined EEG-fMRI. Moving on to simultaneous EEG-fMRI implementation, the first stage comprised an assessment of potential safety concerns at 7T. The safety tests comprised numerical simulations of RF power distribution and real temperature measurements on a phantom during acquisition. Overall, no significant safety concerns were found for the setup tested. A characterization of artifacts induced on MRI data due to the presence of EEG components was then performed. With the introduction of the EEG system, functional and anatomical images exhibited general losses in spatial SNR, with a smaller loss in temporal SNR in fMRI data. B0 and B1 field mapping pointed towards RF pulse disruption as the major degradation mechanism affecting MRI data. The main part of this work focused on EEG artifacts induced by MRI. The first step focused on optimizing signal transmission between the EEG cap and amplifiers, to minimize artifact contamination at this important stage. Along this line, adequate cable shortening and bundling effectively reduced environment noise in EEG recordings. Simultaneous acquisitions were then performed on humans using the optimized setup. On average, EEG data exhibited clear alpha modulation and average visual evoked potentials (VEP), with concomitant BOLD signal changes. In the second step, a novel approach for head motion artifact detection was developed, based on a simple modification of the EEG cap, and simultaneous acquisitions were performed in volunteers undergoing visual checkerboard stimulation. After gradient artifact correction, EEG signal variance was found to be largely dominated by pulse artifacts, but contributions from spontaneous motion were still comparable to those of neuronal activity. Using a combination of pulse artifact correction, motion artifact correction and ICA denoising, strong improvements in data quality could be obtained, especially at a single-trial level

Data-driven analysis of simultaneous EEG/fMRI using an ICA approach

Due to its millisecond-scale temporal resolution, EEG allows to assess neural correlates with precisely defined temporal relationship relative to a given event. This knowledge is generally lacking in data from functional magnetic resonance imaging (fMRI) which has a temporal resolution on the scale of seconds so that possibilities to combine the two modalities are sought. Previous applications combining event-related potentials (ERPs) with simultaneous fMRI BOLD generally aimed at measuring known ERP components in single trials and correlate the resulting time series with the fMRI BOLD signal. While it is a valuable first step, this procedure cannot guarantee that variability of the chosen ERP component is specific for the targeted neurophysiological process on the group and single subject level. Here we introduce a newly developed data-driven analysis procedure that automatically selects task-specific electrophysiological independent components (ICs). We used single-trial simultaneous EEG/fMRI analysis of a visual Go/Nogo task to assess inhibition-related EEG components, their trial-to-trial amplitude variability, and the relationship between this variability and the fMRI. Single-trial EEG/fMRI analysis within a subgroup of 22 participants revealed positive correlations of fMRI BOLD signal with EEG-derived regressors in fronto-striatal regions which were more pronounced in an early compared to a late phase of task execution. In sum, selecting Nogo-related ICs in an automated, single subject procedure reveals fMRI-BOLD responses correlated to different phases of task execution. Furthermore, to illustrate utility and generalizability of the method beyond detecting the presence or absence of reliable inhibitory components in the EEG, we show that the IC selection can be extended to other events in the same dataset, e.g., the visual responses

Characterisation of the optic radiations in children in health and disease

The normal and abnormal development of the optic radiations through childhood was examined in terms of their anatomical development, using MRI tractography, and their functional development, using visual evoked potentials (VEPs). Neurosurgical applications of these imaging techniques were assessed. Control cohorts of 74 children and 13 adults were recruited from Great Ormond Street Hospital. The anatomical development of the optic radiations in children from birth was described using tractography. A novel method to improve tractography analysis using VEP data was developed. VEP-enhanced tractography showed a more defined optic radiation in the gathering of the visual cortex, which caused a significant reduction in the mean FA in the adult cohort. Paediatric patients diagnosed with optic nerve hypoplasia (ONH) were recruited and 23 were compared with a matched control cohort using tractography. ONH patients presented reduced mean FA in the left optic radiation. TBSS analysis of the DTI scans showed that white matter FA was also lower in other areas of the brain outside of the visual system. Two paediatric seizure patient cohorts were recruited: 21 patients with a single episode of prolonged febrile convulsions and 20 regular users of anti-epileptic medicines. Both cohorts were compared with matched control cohorts using DTI tractography. The anti-epileptic user cohort presented lower mean FA at the front of both optic radiations, but the prolonged febrile convulsions cohort had no statistically-significant differences in mean FA, compared to controls. Two brain tumour case studies demonstrated that tractography is a valuable surgical tool in complicated paediatric neurosurgical cases where detailed description of white matter tracts can improve the surgical outcome and assist with counselling patients. Two hydrocephalus case studies demonstrated that VEP-enhanced tractography offers a novel method to identify white matter tracts in cases where conventional imaging techniques provide very limited information due to highly-distorted anatomies