# Cortical Connectivity Response to Hyperventilation in Focal Epilepsy: A Stereo-EEG Study
## 1 Introduction  
Hyperventilation (HV) is a well-known activation technique performed during routine Electroencephalography (EEG) recording, recommended by the international guideline of the main clinical neuro-physiology and epilepsy societies [1]. In practice, HV involves deep and regular breathing at a rate of approximately 20 breaths per minute for a duration of 2 to 4 min. This technique was introduced in clinical practice by [PERSON] who, in 1925, observed that HV could trigger _latent epilepsy_[2]. After the broad diffusion of EEG, HV became one of the most common procedures to elicit epileptic activities, offering valuable information for the medical management of epilepsy [3]. In the past years, several studies have demonstrated that the main HV effect is a physiological slowing of background EEG activity. Particularly, in people with epilepsy, it has been observed that HV could increase focal and generalized Interictal EppleptiformDischarges (IEDs) [4]. A possible explanation for such a phenomenon relies on the vasoconstriction associated with cerebral hypoxia and the intracellular pH increment associated with respiratory hypocapnia. More specifically, it has been shown that cerebral hypoxia induces a negative DC shift variation over the EEG signal [5], while respiratory hypocapnia leads to higher excitatory postsynaptic potentials [6]. On the other hand, other studies have hypothesized that the cortical response to HV is due to sympathetic over-activation, which is notoriously considered a seizure trigger in temporal lobe epilepsy [7]. The effectiveness of HV is well established in generalized epilepsy: in the case of absence seizures, it has been demonstrated that HV generates a spike-and-wave complex in over 90% of the cases and triggers clinical seizures in around 50% of the cases [8]. On the other hand, there is limited agreement regarding the role of HV as an activation maneuver in focal epilepsy, especially in adults, who, notably, also present less significant autonomic abnormalities compared to the pediatric population [9]. A study carried out on a large patient cohort demonstrated that HV rarely triggers clinical seizures or increases the IED frequency [10]. However, other authors found that temporal lobe epilepsy might be more sensitive to HV than other types of epilepsy, suggesting its potential role in shortening presurgical evaluations [11]. A deeper comprehension of HV effects could be offered by using quantitative approaches for analyzing cortical or scalp EEG signals. In this context, the naive approach consists of analyzing the recorded signals in the time-frequency domain, evaluating the energy spectral density and the distribution of the signal phase. Other approaches aim to estimate the interdependency within different signals, considering connectivity-based metrics, which have proven to be extremely valuable for detecting epileptiform activities or discerning different populations [12]. Interestingly, most recent connectivity techniques focus on the analysis of the phase distribution of the EEG signals, using algorithms such as the Phase Locking Value (PLV), the Phase Lag Index (PLI), or the Phase Transfer Entropy (PTE) [13]. The latter algorithm combines the analysis of the signal instantaneous phase with the Granger causality and enables the estimation of the effective relations between signals generated by different brain structures [14]. A recent study concluded that HV increases the magnitude of the EEG power spectra, especially in the cingulate cortex, and demonstrated that different brain regions respond differently to respiratory hypocapnia [15]. The same study denoted how HV leads to a higher increase in cortical connectivity in people with epilepsy than in healthy individuals. Nevertheless, quantitative analysis of EEG traces during HV is scarce in the current literature, and it is still unclear how HV impacts the epileptogenic network.