Discussion
Graph theory has been proposed for detailed understanding of structural connectivity between cortical areas (Sporns et al., 2005). In this study, graph theory revealed that SWI in drug-resistant TLE increased from beta frequency and had a markedly high level in gamma frequency. A recent study also found that in patients with focal epilepsy, SWI tended to increase in gamma frequency (30–45Hz) (Hatlestad-Hall et al., 2021). Our study presented all the SWI trends from delta to gamma (30–90Hz) in TLE patients. SWI is used to describe the balance between the local connectedness and the global integration of a network. Small-world organization is intermediate between random networks, short overall path length associated with a low level of local clustering, regular networks or lattices, and the high-level of clustering, which is accompanied by a long path length (Vecchio et al., 2014). Hypersynchronous neuronal activity associated with epilepsy could cause widespread functional network alterations. The elevated beta and gamma SWI in drug-resistant TLE may reflect increased post-synaptic activity of local neurons. Increased neuronal activity changes the ionic environment of neurons and leads to increased burst firing of neurons (Heinemann et al., 1986; Jensen et al., 1994). Intensified gamma networks may be related with the epileptic characteristics and cortical neuron excitation.
Interestingly, we showed that SWI increased at beta frequency in patients with TLE and cognitive deficits and then markedly declined at gamma frequencies. The change was significant at 50-70 Hz, compared to that in patients with normal cognition. The correlation between gamma-SWI and cognition has been demonstrated in previous studies (Vecchio et al., 2017; Vecchio et al., 2016), that lower gamma SWI in AD is associated with better short-term memory and a smaller hippocampal volume. Graph analysis suggests less efficient interaction and disconnection between brain regions in patients with Alzheimer’s disease, and gamma activity is closely correlated with cognitive functions (Engel et al., 2001). Our study showed that gamma SWI could be influenced by focal epilepsy, but a comparison between patients with drug-resistant TLE to eliminate the influence of epilepsy revealed that gamma SWI was positively correlated with cognition level, especially in high gamma. Moreover, TLE patients with cognitive deficits may have reduced efficiency of network communication in gamma bands in the context of hypersynchronous neuronal activity. Additionally, the alpha SWI in both TLE groups was not significantly different from that in the healthy controls, may due to the small sample and multiple test correction. However, alpha SWI in TLE showed a positive association with IQ and MQ scores.
Spectral analyses revealed a reduction of spectral power in the alpha band and increased power in the delta and theta bands in patients with drug-resistant TLE, compared to healthy controls. Changes in patients with cognitive impairment were more pronounced. This indicated that the general EEG was slow in drug-resistant TLE. Increased delta power is mainly localized over the anterior head, especially in the temporal region. The results are corresponding to temporal lesions in TLE. Decreased gamma power was detected in the temporal, central, and frontal lobes; however, the average rPSD in the entire head was not significantly different. Previous studies have suggested reduced resting-state gamma power/synchronization in Alzheimer’s disease (Koenig et al., 2005; Ribary et al., 1991; Stam et al., 2002). The present study revealed that interictal EEG without epileptiform discharges in TLE had lower gamma power in the temporal and frontal regions. No group differences of gamma power were detected between the TLE groups. But the gamma-communicating functional network was influenced by cognitive impairment in TLE.
Pathological changes were significant in epilepsy patients with cognitive deficits, including Aβ and p-Tau deposition in the resected hippocampus. The current study showed that amyloid and p-Tau loads were increased in TLE patients with cognitive deficits compared to patients with normal cognition. Both Aβ and p-Tau deposits have been documented in drug-resistant TLE tissue (Gourmaud et al., 2020; Tai et al., 2016). Increased Aβ1–42 peptide and hyperphosphorylated Tau in the hippocampus are associated with cognitive deficits and have been reported in temporal lobe epilepsy (Gourmaud et al., 2020). Aβ peptides play a key role in Alzheimer’s disease pathogenesis (Karran et al., 2011). The findings of our and previous studies indicate that Aβ and p-Tau deposits may be correlated with impaired cognition in drug-resistant TLE. Gamma frequency entrainment can attenuate amyloid load and improve cognition in AD and wild-type animal models (Iaccarino et al., 2016; Park et al., 2020; Tian et al., 2021). Considering these data, we propose that alterations in gamma frequency may be a potential therapeutic target for drug-resistant TLE with cognitive deficits.