# Structure-Function Coupling Reveals Seizure Onset Connectivity Patterns
## 4 Discussion
However, a more extensive structure-function coupling model may be needed to understand whether the poor laterality can be attributed to the equally high structural connectivity in both hemispheres or some other biophysical phenomenon. Further, our model demonstrated a specific region with high structure-function coupling for Patient 8, who was initially considered poorly lateralised on EEG. Such cases highlight that dMRI may offer endorsement of a specific onset zone to support an otherwise inconclusive EEG recording. Interestingly, the presence of high structure-function coupling in an electrode pair containing a middle electrode (FZ, CZ, PZ) was observed in several patients with a seizure laterality score of 2 or lower. For example, patients 5, 7, 8 and 9 had at least one middle electrode in the electrode pairs that showed high structure-function coupling. Their poor seizure lateralisation could be due to the electrophysiological activity beneath the middle electrode, which may drive the contralateral seizure propagation. Given the scope of the current work, some methodological considerations may aid the interpretation of the results. Firstly, the mapping method did not appear to impact the results as well-lateralised patients had a similar number of variances in the electrode-to-region mapping as the less well-lateralised patients, for whom the structural data provided little additional information. However, laterality alone may not account for the results from patients who displayed high structure-function coupling congruent with the expected onset zone. Our selection of time window and bandwidth may have impacted the coherence score. The one-second window was perhaps not brief enough to capture the highly coherent initial EEG activity. We observed high coherence in the ipsilateral hemisphere at the 0-100 millisecond (ms) scale for some patients. The lengthy time window may have confounded this high coherence. Further, the proposition that microscopic signal aberrations in EEG may not be observed from a macroscopically normal EEG signal is worth considering [2]. The uncertainty of empirical, visual evaluation of EEG to localise the seizure onset zone has been shown [45]. Thus, in the current work, the true onset zone for some individuals may not be observable on the raw EEG, yet may have been captured in the processed EEG coherence data. However, such postulations must be verified using high-definition EEG or intracranial/stereo EEG. Alternatively, since we combined microscopic MRI and EEG data, it is also possible that our model captured the genuine seizure onset zone. Supposing the seizure began in a different region, it could have fused in millisecond time with other active regions and thus was visually revealed in a different region on the raw EEG. Such an explanation is conceivable for individuals with FBTC or multi-onset seizures and is a topic for future investigation. Lastly, it is feasible that the structural topology has a diminished relationship with the functional activity in some individuals. Numerous mechanisms mould the seizure propagation pathways, and within-patient variance has been shown [46]. Lateralisation may be inextricably linked to the seizure duration. However, based on our experimental design (i.e., time window selection) and modest sample size, it was not plausible to extrapolate any biophysical mechanisms that may be in force. The individuals in the third group may have less well-defined circuits, or a different epileptic pattern, i.e., multi-onset or deep structural connections or functional activity, that was not captured in the connectome reconstruction or on the scalp EEG. These concepts are the subject of ongoing work to further elaborate on this feasibility study and better explain the individual differences in the outcomes. Although our methodology may explain some of the findings, potential limitations were inevitable. The generalisation of the results is limited by the small sample size, endorsing the need to extend this work to a larger cohort.