Imaging physiological brain activity and epilepsy with Electrical Impedance Tomography

Electrical Impedance Tomography (EIT) allows reconstructing conductivity changes into images. EIT detects fast impedance changes occurring over milliseconds, due to ion channel opening, and slow impedance changes, appearing in seconds, due to cell swelling/increased blood flow. The purpose of this work was to examine the feasibility of using EIT for imaging a gyrencephalic brain with implanted depth electrodes during seizures. Chapter 1 summarises the principles of EIT. In Chapter 2, it is investigated whether recent technical improvements could enable EIT to image slow impedance changes upon visual stimulation non-invasively. This was unsuccessful so the remaining studies were undertaken on intracranial recordings. Chapter 3 presents a computer modelling study using data from patients, for whom the detection of simulated seizure-onset perturbations for both, fast and slow impedance changes, were improved with EIT compared to stereotactic electroencephalography (SEEG) detection or EEG inverse-source modelling. Chapter 4 describes the development of a portable EIT system that could be used on patients. The system does not require averaging and post-hoc signal processing to remove switching artefacts, which was the case previously. Chapter 5 describes the use of the optimised method in chemically-induced focal epilepsy in anaesthetised pigs implanted with depth electrodes. This shows for the first time EIT was capable of producing reproducible images of the onset and spread of seizure-related slow impedance changes in real-time. Chapter 6 presents a study on imaging ictal/interictal-related fast impedance changes. The feasibility of reconstructing ictal-related impedance changes is demonstrated for one pig and interictal-related impedance changes were recorded for the first time in humans. Chapter 7 summarises all work and future directions. Overall, this work suggests EIT in combination with SEEG has a potential to improve the diagnostic yield in epilepsy and demonstrates EIT can be performed safely and ethically creating a foundation for further clinical trials

Fluctuations of attention network activation during the resting state reflect fluctuations in subjective attentional state.

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Functional network correlates of language and semiology in epilepsy

Epilepsy surgery is appropriate for 2-3% of all epilepsy diagnoses. The goal of the presurgical workup is to delineate the seizure network and to identify the risks associated with surgery. While interpretation of functional MRI and results in EEG-fMRI studies have largely focused on anatomical parameters, the focus of this thesis was to investigate canonical intrinsic connectivity networks in language function and seizure semiology. Epilepsy surgery aims to remove brain areas that generate seizures. Language dysfunction is frequently observed after anterior temporal lobe resection (ATLR), and the presurgical workup seeks to identify the risks associated with surgical outcome. The principal aim of experimental studies was to elaborate understanding of language function as expressed in the recruitment of relevant connectivity networks and to evaluate whether it has value in the prediction of language decline after anterior temporal lobe resection. Using cognitive fMRI, we assessed brain areas defined by parameters of anatomy and canonical intrinsic connectivity networks (ICN) that are involved in language function, specifically word retrieval as expressed in naming and fluency. fMRI data was quantified by lateralisation indices and by ICN_atlas metrics in a priori defined ICN and anatomical regions of interest. Reliability of language ICN recruitment was studied in 59 patients and 30 healthy controls who were included in our language experiments. New and established language fMRI paradigms were employed on a three Tesla scanner, while intellectual ability, language performance and emotional status were established for all subjects with standard psychometric assessment. Patients who had surgery were reinvestigated at an early postoperative stage of four months after anterior temporal lobe resection. A major part of the work sought to elucidate the association between fMRI patterns and disease characteristics including features of anxiety and depression, and prediction of postoperative language outcome. We studied the efficiency of reorganisation of language function associated with disease features prior to and following surgery. A further aim of experimental work was to use EEG-fMRI data to investigate the relationship between canonical intrinsic connectivity networks and seizure semiology, potentially providing an avenue for characterising the seizure network in the presurgical workup. The association of clinical signs with the EEG-fMRI informed activation patterns were studied using the data from eighteen patients’ whose seizures and simultaneous EEG-fMRI activations were reported in a previous study. The accuracy of ICN_atlas was validated and the ICN construct upheld in the language maps of TLE patients. The ICN construct was not evident in ictal fMRI maps and simulated ICN_atlas data. Intrinsic connectivity network recruitment was stable between sessions in controls. Amodal linguistic processing and the relevance of temporal intrinsic connectivity networks for naming and that of frontal intrinsic connectivity networks for word retrieval in the context of fluency was evident in intrinsic connectivity networks regions. The relevance of intrinsic connectivity networks in the study of language was further reiterated by significant association between some disease features and language performance, and disease features and activation in intrinsic connectivity networks. However, the anterior temporal lobe (ATL) showed significantly greater activation compared to intrinsic connectivity networks – a result which indicated that ATL functional language networks are better studied in the context of the anatomically demarked ATL, rather than its functionally connected intrinsic connectivity networks. Activation in temporal lobe networks served as a predictor for naming and fluency impairment after ATLR and an increasing likelihood of significant decline with greater magnitude of left lateralisation. Impairment of awareness served as a significant classifying feature of clinical expression and was significantly associated with the inhibition of normal brain functions. Canonical intrinsic connectivity networks including the default mode network were recruited along an anterior-posterior anatomical axis and were not significantly associated with clinical signs

Cerebral mechanism of breathlessness and its relief

The perception of clinical breathlessness is a complex experience, modulated by physical and psychological factors. Distinguishable types of breathlessness arising from different peripheral mechanisms have been delineated, experimental models of these specific types have been developed and advances have been made in multidimensional assessments. However, current knowledge about cerebral mechanisms of breathlessness is lacking. Functional brain imaging studies have identified involvement of certain cortical structures but interpretations of these data are limited by various assumptions. Aim:The primary purpose of this thesis was to interrogate the validity of the conclusions drawn by recent brain imaging studies and to draw further inferences about cerebral mechanisms of dyspnoea from neurological patients undergoing deep brain stimulation (DBS) for relief of other symptoms. Focusing on experimentally induced ‘air hunger’ (the most unpleasant form of clinical breathlessness) two primary working hypotheses were generated: (i) Perceptual sensitivity to experimentally induced breathlessness will be greater during MRI brain scans due to greater anxiety associated with the MRI milieu (ii) DBS of motor-thalamic nuclei generates breathlessness Method:(i) Experimental breathlessness was induced in healthy subjects in simulated brain scanners to measure the effects of psychological stress associated with the functional magnetic resonance imaging (fMRI) scanner. (ii) Experimental breathlessness was induced in patients with DBS of the ventral intermediate (VIM) and ventralis oralisposterior (VOP) nuclei of the thalamus when the implanted electrodes are activated(switched ‘ON’ to stimulate the brain tissue) and when they are not activated (switched ‘OFF’ to stop stimulating the brain tissue).The Dyspnoea-12 multidimensional tool was also used to assess breathlessness. (iii)Probabilistic tractography was used to estimate the white fibre connectivity from the seed area (VIM) in the brain to brain regions of interest and to compare these in patients who responded differently in (ii). Results: (i) Healthy volunteers with anxiety scores at or above average levels increased air hunger sensitivity in the simulated fMRI environment whereas those with low anxiety responded in the opposite direction. (ii) Contrary to the hypothesis posed, motorThalamic DBS resulted in relief of air hunger in all but one of the 6 patients studied. (iii) Tractography suggested that those patients who improved with DBS ‘ON’ had stronger connections to the anterior parts of the brain (orbitofrontal cortex) in contrast to the stronger connectivity to the posterior areas of the brain in the one patient who improved with DBS ‘OFF’. Conclusion :( i) Future functional brain imaging studies of breathlessness should screen healthy volunteers for anxiety in order to improve interpretation of activations detected. (ii) Neurological patients undergoing DBS provide a useful clinical model to explore cerebral mechanisms of breathlessness. While the dataare largely inconclusive due to limited numbers of patients, the orbitofrontal connections for dyspnoea relief has been flagged as being an important element of a cerebral network for dyspnoea. Potential new thalamic targets for dyspnoea relief are suggested. The novel findings of this study lay the groundwork for better understanding of cerebral mechanisms of dyspnoea and therefore potential new and more effective targets for relief of intractable dyspnoea – a goal that remains an urgent clinical need