Feasibility of imaging evoked activity throughout the rat brain using electrical impedance tomography

Electrical Impedance Tomography (EIT) is an emerging technique which has been used to image evoked activity during whisker displacement in the cortex of an anaesthetised rat with a spatiotemporal resolution of 200 μm and 2 ms. The aim of this work was to extend EIT to image not only from the cortex but also from deeper structures active in somatosensory processing, specifically the ventral posterolateral (VPL) nucleus of the thalamus. The direct response in the cortex and VPL following 2 Hz forepaw stimulation were quantified using a 57-channel epicortical electrode array and a 16-channel depth electrode. Impedance changes of -0.16 ± 0.08% at 12.9 ± 1.4 ms and -0.41 ± 0.14% at 8.8±1.9 ms were recorded from the cortex and VPL respectively. For imaging purposes, two 57-channel epicortical electrode arrays were used with one placed on each hemisphere of the rat brain. Despite using parameters optimised toward measuring thalamic activity and undertaking extensive averaging, reconstructed activity was constrained to the cortical somatosensory forepaw region and no significant activity at a depth greater than 1.6 mm below the surface of the cortex could be reconstructed. An evaluation of the depth sensitivity of EIT was investigated in simulations using estimates of the conductivity change and noise levels derived from experiments. These indicate that EIT imaging with epicortical electrodes is limited to activity occurring 2.5 mm below the surface of the cortex. This depth includes the hippocampus and so EIT has the potential to image activity, such as epilepsy, originating from this structure. To image deeper activity, however, alternative methods such as the additional implementation of depth electrodes will be required to gain the necessary depth resolution

EIT-MESHER – Segmented FEM Mesh Generation and Refinement

EIT-MESHER (https://github.com/EIT-team/Mesher) is C++ software, based on the CGAL library, which generates high quality Finite Element Model tetrahedral meshes from binary masks of 3D volume segmentations. Originally developed for biomedical applications in Electrical Impedance Tomography (EIT) to address the need for custom, non-linear refinement in certain areas (e.g. around electrodes), EIT-MESHER can also be used in other fields where custom FEM refinement is required, such as Diffuse Optical Tomography (DOT)

Imaging Circuit Activity in the Rat Brain with Fast Neural EIT and Depth Arrays

Few techniques are specialized for neuroscience at the 'mesoscopic' level of neural circuits. Fast neural electrical impedance tomography (fnEIT) is a novel imaging technique that offers affordability, portability, and high spatial (∼100 μm) and temporal (1 ms) resolution. fnEIT with depth arrays offers the opportunity to study the dynamics of circuits in the brains of animal models. However, current depth array geometries are not optimized for this imaging modality. They feature small, closely packed electrodes with high impedance that do not provide sufficient SNR for high resolution EIT image reconstruction. They also have a highly limited range. It is necessary to develop depth arrays suitable for fnEIT and evaluate their performance in a representative setting for circuit neuroscience. In this study, we optimized the geometry of depth arrays for fnEIT, and then investigated the prospects of imaging thalamocortical circuit activity in the rat brain. Optimization was consistent with the hypothesis that small, closely spaced electrodes were not suitable for fnEIT. In vivo experiments with the optimized geometry then showed that fnEIT can image thalamocortical circuit activity at a high enough resolution to see the activity propagating from specific thalamic nuclei to specific regions of the somatosensory cortex. This bodes well for fnEIT's potential as a technique for circuit neuroscience

Overcoming temporal dispersion for measurement of activity-related impedance changes in unmyelinated nerves

OBJECTIVE: Fast neural Electrical Impedance Tomography (FnEIT) is an imaging technique that has been successful in visualising electrically evoked activity of myelinated fibres in peripheral nerves by measurement of the impedance changes (dZ) accompanying excitation. However, imaging of unmyelinated fibres is challenging due to temporal dispersion (TP) which occurs due to variability in conduction velocities of the fibres and leads to a decrease of the signal below the noise with distance from the stimulus. To overcome TP and allow EIT imaging in unmyelinated nerves, a new experimental and signal processing paradigm is required allowing dZ measurement further from the site of stimulation than compound neural activity is visible. The development of such a paradigm was the main objective of this study. APPROACH: A FEM-based statistical model of temporal dispersion in porcine subdiaphragmatic nerve was developed and experimentally validated ex-vivo. Two paradigms for nerve stimulation and processing of the resulting data - continuous stimulation and trains of stimuli, were implemented; the optimal paradigm for recording dispersed dZ in unmyelinated nerves was determined. MAIN RESULTS: While continuous stimulation and coherent spikes averaging led to higher signal-to-noise ratios (SNR) at close distances from the stimulus, stimulation by trains was more consistent across distances and allowed dZ measurement at up to 15 cm from the stimulus (SNR = 1.8±0.8) if averaged for 30 minutes. SIGNIFICANCE: The study develops a method that for the first time allows measurement of dZ in unmyelinated nerves in simulation and experiment, at the distances where compound action potentials are fully dispersed

Investigating the safety of fast neural electrical impedance tomography in the rat brain

Objective. Electrical Impedance Tomography (EIT) can be used to image impedance changes which arise due to fast electrical activity during neuronal depolarisation and so holds therapeutic potential for improving the localisation of epileptic seizure foci in patients with treatment-resistant epilepsy to aid surgical resection of epileptogenic tissue. Prolonged cortical stimulation may, however, induce neural injury through excitotoxicity and electrochemical reactions at the tissue-electrode interface. The purpose of this work was to assess whether current levels used in fast neural EIT studies induce histologically detectable tissue damage when applied continuously to the rat cerebral cortex. Approach. A 57-electrode epicortical array was placed on one or both hemispheres of adult Sprague-Dawley rats anaesthetised with isoflurane. In an initial series of experiments, current was injected simultaneously at 10, 25, 50, 75 and 100 µA for 1 hour at 1.725 kHz through five electrodes across two epicortical arrays to provide a preliminary indication of the safety of these current levels. Since no obvious cortical damage was observed in these rats, the current level chosen for further investigation was 100 µA, the upper-bound of the range of interest. In a separate series of experiments, 100 µA was applied through a single electrode for 1 hour at 1.725 kHz to verify its safety. Following termination of stimulation, brain samples were fixed in formalin and histologically processed with Haematoxylin and Eosin (H&E) and Nissl stains. Main results. Histological analysis revealed that continuous injection of 100 µA current, equating to a current density of 354 Am-2, into the rat cortex at 1.725 kHz does not cause cortical tissue damage or any alterations to neuronal morphology. Significance. The safety of current injections during typical EIT protocols for imaging fast neural activity have been validated. The current density established to be safe for continuous application to the cortex, 354 Am-2, exceeds the present safety limit of 250 Am-2 which has been complied with to date, and thus encourages the application of more intensified fast neural EIT protocols. These findings will aid protocol design for future clinical and in vivo EIT investigations aimed at imaging fast neural activity, particularly in situations where the signal-to-noise ratio is considerably reduced

Feasibility of imaging evoked activity throughout the rat brain using electrical impedance tomography

Electrical Impedance Tomography (EIT) is an emerging technique which has been used to image evoked activity during whisker displacement in the cortex of an anaesthetised rat with a spatiotemporal resolution of 200 μm and 2 ms. The aim of this work was to extend EIT to image not only from the cortex but also from deeper structures active in somatosensory processing, specifically the ventral posterolateral (VPL) nucleus of the thalamus. The direct response in the cortex and VPL following 2 Hz forepaw stimulation were quantified using a 57-channel epicortical electrode array and a 16-channel depth electrode. Impedance changes of −0.16 ± 0.08% at 12.9 ± 1.4 ms and −0.41 ± 0.14% at 8.8±1.9 ms were recorded from the cortex and VPL respectively. For imaging purposes, two 57-channel epicortical electrode arrays were used with one placed on each hemisphere of the rat brain. Despite using parameters optimised toward measuring thalamic activity and undertaking extensive averaging, reconstructed activity was constrained to the cortical somatosensory forepaw region and no significant activity at a depth greater than 1.6 mm below the surface of the cortex could be reconstructed. An evaluation of the depth sensitivity of EIT was investigated in simulations using estimates of the conductivity change and noise levels derived from experiments. These indicate that EIT imaging with epicortical electrodes is limited to activity occurring 2.5 mm below the surface of the cortex. This depth includes the hippocampus and so EIT has the potential to image activity, such as epilepsy, originating from this structure. To image deeper activity, however, alternative methods such as the additional implementation of depth electrodes will be required to gain the necessary depth resolution

Imaging fast neural activity in the brain during epilepsy with electrical impedance tomography

Electrical impedance tomography (EIT) is a medical imaging technique which reconstructs images of the internal conductivity of an object using boundary measurements obtained by applying current through pairs of non-penetrating surface electrodes. EIT is able to image impedance changes which arise during neural activity at a high spatiotemporal resolution through the rat cerebral cortex and therefore represents a novel method for understanding neuronal network dynamics in epilepsy. Additionally, it holds therapeutic potential for improving the presurgical localisation of epileptogenic foci in individuals with drug-resistant epilepsy. This thesis was aimed at developing EIT for imaging epileptiform activity in vivo and assessing its potential for clinical use. Chapter 1 is a review of existing functional neuroimaging modalities, the principles of EIT and previous studies that have used EIT for imaging epileptic events. In Chapter 2, the safety of continuous current application to the rat cortical surface at 10-100 μA and 1725 Hz, parameters that are representative of fast neural EIT protocols, was verified by histological evaluation. Chapter 3 details the development of two acute rat models of focal epilepsy, the cortical and hippocampal epileptic afterdischarges models, for assessing the feasibility of imaging epileptiform activity with fast neural EIT using epicortical electrode arrays. In Chapter 4, EIT was used to image the propagation of ictal spike-and-wave activity through the cerebral cortex at a resolution of 2 ms and ≤300 µm. In order to enable imaging of epileptiform discharges in deeper subcortical structures, the optimal carrier frequency for current application was determined in Chapter 5. Results demonstrated that the maximal signal-to-noise ratio of fast neural impedance changes during ictal discharges is obtained at 1355 Hz. Finally, in Chapter 6, epileptiform activity in the hippocampus was imaged, with a localisation accuracy of ≤400 µm, using epicortical impedance measurements obtained at this optimised carrier frequency

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