The haemodynamic responses to IED events derived from simultaneous EEG-NIRS were highly variable. Although some patients displayed oxyHb changes prior to discharge onset, there was no significant change detected from the baseline haemodynamic response. This can possibly be explained by the spatial extent of IED haemodynamic changes which are likely to be less widespread than seizures. Therefore the NIRS recordings may not often record the relatively small and localised haemodynamic changes
IEDs represent summations of thousands of neurons in hypersynchronous events. Neurons within epileptogenic tissue experience abnormally long depolarisations, followed by a train of action potentials also known as paroxysmal depolarisations shift (PDS; see section 1.1 for more details). During a seizure, PDS can spread due to failure of inhibitory mechanisms leading to large widespread changes in network function. Therefore an IED can represent smaller localised potentials of its larger seizure counterpart, making it more difficult to detect. It is possible that NIRS is best for picking up large changes in haemodynamics such as seizures, while subtle and more variable events such as IEDs are more difficult to capture. In this case, EEG- fMRI might be more sensitive to changes involving IED events (as seen in previous Chapters 2-3).
Nevertheless, in some subjects there was a clear increase in oxyhaemoglobin changes prior to the IED discharge which was consistent with previous results (Chapter 3) in which HRF peaks occurred up to ~20 seconds prior to IED onset in EEG-fMRI. This is particularly interesting considering that seizures did not display oxyHb changes prior to electrographic onset, suggesting that the haemodynamic response to IEDs is
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inherently different to that of seizures. Future recording of both EEG-fMRI and EEG-NIRS in the same cohort would be advantageous to cross-validate the IED responses and spatial locations.
5.6.3 Deoxyhaemoglobin and Meeting Metabolic Demands of the
Seizure Focus
Previous reports on changes in deoxyHb concentration are mixed. Studies found deoxyHb could decrease, remain unchanged, or increase during seizures (Buchheim et al., 2004; Wallois et al., 2009; Nguyen et al., 2012; Nguyen et al., 2013; Peng et al., 2016). Some suggest that the increase in deoxyHb could lead to hypoxic damage during ictal events (Wallois et al., 2009), while others show a stable deoxyHb concentration throughout the seizure indicating sufficient oxyHb supply to the tissue (Nguyen et al., 2013). These mixed results could be due to a number of factors involving seizure duration, spatial specificity, age, or reliability of measurements.
Seizure duration is highly variable, however longer seizures are generally thought of as being more toxic with increased likelihood of neuronal cell death (Dingledine et al., 2014). While animal models have demonstrated inadequate oxygenation during both status epilepticus (Meldrum and Brierly, 1973; Meldrum and Horton, 1973; Kreisman et al., 1984), as well as shorter-duration events (Bahar et al., 2006; Zhao et al., 2007; Zhao et al., 2009), work in humans has been more variable. Studies with long mesial temporal lobe seizures found deoxyHb increases (Nguyen et al., 2012), while short frontal lobe seizures demonstrated adequate oxygenation (Nguyen et al., 2013); however there were still individual variations reported within these samples. The current study was able to capture seizures of both frontal (n=2) and temporal lobe (n=1) onset, and found both to have adequate oxygen supply. Although it is difficult to compare these patients as they have differing seizure semiology; Nguyen et al. (2012) captures seizures from patients with mesial temporal focus while the current study has seizures from the middle temporal lobe in a patient with TS. Additionally, other neuroimaging techniques such as EEG-fMRI have reported similar results with positive BOLD changes (signal corresponding to decreases in deoxyHb; see section 1.3) in the seizure onset zone suggesting sufficient tissue oxygenation (Thornton et al., 2010; Chaudhary et al., 2013).
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Another potential reason for heterogeneous reports of deoxyHb changes is that different brain regions associated with the seizures show differing deoxyHb changes. Any spatial variability is difficult to characterise due to the lack of spatial specificity of NIRS and the difficulty in identifying the spatial correspondence between the SOZ and the tissue interrogated by the NIRS optodes. This is further complicated by the typical clinical uncertainty in the SOZ which can range between 18-56% in children from routine clinical EEG (Wirrell et al., 2010). Additionally, as focal epilepsy is considered a network disease (Centeno and Carmichael, 2014; Laufs et al., 2014), it is possible that differing haemodynamic changes may be seen in different nodes of the network, specifically in propagated areas within the epileptogenic network. Finally, the haemodynamic changes seen in children may be different from those seen in adults. There are very few NIRS studies looking at children, and of those that do, many combine the results of both adults and children. For example, previous fMRI studies have previously shown differences in haemodynamic coupling dependent on age (Yamada et al., 2000; Jacobs et al., 2008) as has work in this thesis (see section 3.11). This stresses the importance of studying epilepsy during its development and changes associated with maturation.
Another point to consider is the mechanical properties of early NIRS optodes. In earlier NIRS studies, the wavelength sensitive to deoxyhaemoglobin was not well defined, and it wasn’t until recently that the wavelength most sensitive to deoxyHb was determined to be 690nm (Sato et al., 2004). Therefore the measurements using the 780nm optodes, although are representative of deoxyHb concentrations, could be improved by using a more sensitive wavelength.
In summary, the current study shows consistent change in oxyHb, deoxyHb, HbT, and HbDiff, indicating that seizures are characterised by a preictal change in HbDiff followed by increases in both oxyHb and HbT. Despite mixed previous reports, in the three subjects studied here deoxyHb showed little change from baseline levels, however when interpreting these results the well-known instability of deoxyHb measurements should be taken into account.
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5.6.4 Haemodynamics Contralateral to the Seizure Focus
In addition to haemodynamic changes over the epileptic focus, our study reveals modulations in contralateral homologous regions, which almost mirrored those seen ipsilaterally. This has been seen in previous studies in both animal (Schwartz and Bonhoeffer, 2001) and human work in adults (Nguyen et al., 2013). Therefore, this contralateral change does not seem to be dependent on age, and is a general finding.
5.6.5 Limitations
The limited number of patients participating in this study was due to a number of reasons: 1) not all patients that come through telemetry have a strong spatial hypothesis for SOZ, 2) patients with deep cortical foci could not participate due to the spatial restraints of NIRS, and 3) many patients with dense (and dark) hair were excluded due to the possibility of signal interference. Nevertheless, we were able to capture haemodynamic changes in a heterogeneous group of children with focal epilepsy. Furthermore, this is the largest multi-channel NIRS study done in this cohort (children with heterogeneous focal epilepsy) in a video telemetry environment.
5.6.6 Future Work
Determining a corresponding relationship between significant morphological changes in single subject HRFs with patient semiology would be an interesting topic for future work. However, for this to be realised, a large sample of patients must be collected with simultaneous clinical EEG recordings along with systemic physiological parameters such as CO2 concentration, blood pressure, cerebral blood
flow, and a measure of cellular oxidative metabolism (i.e.: cytochrome c oxidase) to disentangle the input of different physiological variables involved in the resulting patient HRF. The practicality of measuring all of these parameters simultaneously in patients on the ward is challenging but could be highly beneficial.
The EEG is rich in content and can provide information on the minute electrical changes surrounding epileptic events. Seizure progression can be subdivided into ictal phases such as 1) preictal, 2) ictal onset, 3) ictal established, and 4) late ictal, as done in Chaudhary et al. (2012) to define the evolution of the electrographic pattern
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and clinical semiology. These electrographic changes can be analysed to determine their associated haemodynamic change using EEG-NIRS.
Another question regarding haemodynamics and children which has yet to be fully answered is the accurate modelling of seizures in EEG-fMRI data. It would be interesting to apply the results acquired in the current study to create a valid haemodynamic response function applicable for seizure events, as EEG-fMRI has been used for SOZ localisation.