Neuroimaging techniques such as fMRI are used in pre-surgical evaluations to aid in the characterisation of the epileptogenic zone however they require an understanding of neurovascular coupling during epileptic events. To describe this interaction, I applied multi-modal imaging in a group of paediatric focal epilepsy patients via simultaneous EEG-fMRI (Chapters 2-3) and EEG-NIRS (Chapters 4-5), thereby allowing for both electrical and haemodynamic changes to be measured.
7.1.1 Network Connectivity Reductions are Due to IEDs
Epilepsy is increasingly considered to be a network disease with multi-nodal representations of epileptogenic cortex. In turn, the areas with increased epileptic activity seem to interact with intrinsic connectivity networks, as changes have been reported in large scale resting state networks that can be measured using fMRI. However the impact of IEDs on these networks has yet to be fully explored.
The results presented in Chapter 2 give us a better understanding of the impact of interictal epileptiform activity on these network abnormalities. Uniquely a natural stimulus task was used to target executive control and visual networks while controlling for age differences, patient movement and wakefulness.
EEG-fMRI results showed that intra-network connectivity was decreased in patients with epilepsy, which is likely to be associated with poorer network function and in turn cognitive behavioural performance. Interictal activity seemed to be a major driver of these functional connectivity differences in patients versus controls; this result is particularly relevant as epilepsy can be conceptualised as a network disease. This indicates a pervasive impact of IEDs on network connectivity and subsequently cognition. Therefore, connectivity changes in relation to clinically relevant factors such as seizures or disease duration can only be accurately investigated when controlling for IEDs. This can be achieved by recording and modelling the IEDs as done here.
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However, this raises concerns with previous resting state studies and their inferences on network connectivity because, without simultaneous haemodynamic-electrical recordings, there is no way to confirm that differences between groups of patients and controls are not altered by the transient effects of IEDs.
Furthermore, the transient effects of IEDs may progress to more permanent changes, however, if and when this occurs is still unknown. Therefore an interesting topic of study for future work would be to determine whether development from childhood to adulthood promotes the evolution from transient to permanent changes prompted by the loss of brain plasticity. Another question that remains is how IEDs transform over different brain regions, and how this relative transformation impacts network connectivity? For example, what is the impact of IEDs on the epileptogenic network and how does the strength of connectivity from the SOZ to other brain regions compare to controls when IEDs are accounted for? Finally, from a more clinical perspective the pervasive influence of IEDs in a heterogeneous cohort raises questions about whether IED suppression should be included in treatment plans of future focal epilepsy patients. Though it is beyond the scope of this thesis, it is of interest for future clinical work to explore the effects of IED suppression and its subsequent effects on connectivity networks and cognition.
7.1.2 FIR and Quantifying the fMRI Response to Epileptic Spikes
EEG-fMRI has traditionally been reliant on an assumption regarding the relationship between IEDs and haemodynamics: that it is similar to the canonical response to a stimulus. However recent works have raised doubts about applying the canonical HRF in children with epilepsy in response to epileptic activity. Other approaches such as individual HRFs, multi-peak functions, and canonical HRFs with derivatives, have been attempted (Lu et al., 2006; Hawco et al., 2007; Moeller et al., 2008; Jacobs et al., 2009; Rathakrishnan et al., 2010; Rollings et al., 2016), unfortunately all of these methods have their drawbacks such as lack of flexibility, sensitivity, and over- fitting.
Therefore in Chapter 3 we aimed to determine the validity of the canonical model in paediatric patients with focal epilepsy. We found an early haemodynamic response in relation to electrical activity, thereby confirming the need for a new HRF model. The
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current canonical HRF was tested against a new model (IED-HRF) to determine the most representative HRF model for a group of paediatric epilepsy patients.
Results for the IED-HRF model showed that haemodynamic responses preceded IED onset. These results indicated that a new basis set should be applied taking this into account. Once this new IED-HRF basis set was tested, a 64% improvement in sensitivity was found in defining the focus from EEG-fMRI maps of the epileptogenic cortex, where previously the canonical model had failed. Therefore, this observed haemodynamic change prior to IED onsets should be taken into account in the future.
The reason for this early response is unclear but could be influenced by neuromodulators and neurotransmitters such as extracellular potassium, oxygen, ATP consumption, and glucose supply. As many of these events cannot be measured by traditional neuroimaging methods such as EEG, it would be interesting for future studies to determine the impact of these components via animal models or invasive measurement techniques.
7.1.3 NIRS Identifying Oxygenation Changes in Seizure Focus
In Chapter 3 a new shape for the IED-HRF was defined. This shape was highly unusual in that the time to peak was much earlier than observed in previous studies. We therefore set out to gain a greater understanding of the underlying physiological responses to IEDs.
Though the BOLD response measured in Chapter 3 is representative of local changes in haemodynamics involving CBF, CBV and CMRO2, the occurrence of oxygenation
changes (oxyHb and deoxyHb) prior to epileptic events are better characterised by EEG-NIRS. Therefore, the aim of Chapter 4 was to adapt optical imaging to the clinical environment to extract a haemodynamic response more sensitive to oxygenation changes. The popular cap design for measuring NIRS was not practical for use in paediatric epilepsy patients during clinical video-telemetry. A new flexible grid optode holder design was created and tested (using a series of well-defined tasks in a group of healthy adults) and proven to be more beneficial in the clinical setting
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than the standard cap design. After the NIRS holder design was established, the feasibility of using this technique on video-telemetry in-patients was also tested.
The new flexible grid design was able to reliably determine changes in haemodynamics via EEG-NIRS recordings during focal seizures (Chapter 5). Out of a group of 10 paediatric focal epilepsy patients, three had seizure events during simultaneous EEG-NIRS recordings. Results are consistent with previous studies in that there is an increase in oxyHb and HbT after seizure onset. Furthermore, changes prior to seizure onset can also be seen in HbDiff representing cerebral oxygen saturation thereby confirming efficacy of the flexible grid design, and its ability to measure changes in haemodynamics both prior/after the onset of seizure events.
Though pre-ictal/pre-IED changes were seen, results were inconsistent between patients. This was because results were confounded by both physiological and motion artefact. Therefore, future work should correct for systemic physiological parameters such as CO2 concentration, blood pressure, cerebral blood flow, and a
measure of cellular oxidative metabolism (i.e.: cytochrome c oxidase), as well as prospective (motion sensors) and retrospective (FIACH) motion artefact corrections. This will hopefully allow for interpretation of patient semiology and morphological changes seen in single subject HRFs.
7.1.4 The Potential for Invasive Blood Flow Measurements
The fMRI BOLD signal (Chapters 2-3) and the NIRS –oxy and –deoxy haemoglobin changes (Chapters 4-5) describe a combined effect of blood flow, blood volume, oxygen consumption, and changes in the oxygenation state of haemoglobin. However, the independent effect of blood flow in relation to epileptic activity can be better measured by simultaneous iEEG-LD.
Unfortunately, the historical LD-iEEG data was corrupted by noise due to design flaws of the probe (Chapter 6). Since then, the probe design has advanced and most of these defects have been repaired. The goal was to re-test the Laser Doppler in humans, but due to unforeseen difficulties this project could not advance within the time scale of this thesis. Therefore, a possible alternative for future work is to
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investigate blood flow using simultaneous iEEG and LD in an animal model, which should prevent the barriers associated with testing paediatric focal epilepsy patients.
7.2 Summary
This thesis includes a wide breadth of research topics under the general theme of understanding the relationship between regional haemodynamic changes and focal epileptic events in children. The use of multi-modal imaging answers questions regarding neurovascular coupling that would otherwise be impossible when using single imaging modalities. The overall outcome illustrated that by utilizing both EEG-fMRI and EEG-NIRS a greater understanding of the haemodynamic changes surrounding epileptic events in children can be obtained. Furthermore, the haemodynamic response from epileptic events is not equivalent to the canonical response to a stimulus described in healthy controls. Therefore epileptic events (i.e.: IEDs) need to be carefully modelled to allow appropriate inference regarding the brain regions showing associated responses to them and interactions between ongoing brain activity and IEDs.
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