AEDs, as a common choice for epileptic patients in clinical practice, play an important role in the different transmitter systems to achieve remission of seizures. The distinct regions might be affected by AEDs, so network analysis would provide a new sight to investigate the influence of AEDs. The present study based on noninvasive brain imaging and brain network analysis characterized alterations of functional and structural connectivity and their coupling in patients with and without receiving AEDs. We found that both patient groups showed a stable increase in structural connection strength among DMN, FPN, and VN relative to healthy controls, suggesting that the structural alteration observed in GTCS patients was obstinate even through receiving AEDs. The DNP group showed the significantly widely enhanced functional connectivity, involving the DMN, FPN, limbic network, and VN, but only one connection between DMN and FPN was heightened in the DRP group. Thus, the functional connectivity would be sensitive to AEDs. In addition, the structural and functional coupling was decreased in connections within DMN, between DMN and VAN, and between the limbic network and SMN. However, patients with AEDs showed decreased coupling in only one connection between limbic network and SMN, and the coupling within DMN was significantly increased compared with patients without AEDs. In all, the present findings suggested that medical treatment might be more effective in improving functional abnormalities rather than structural connections. Consistent SC abnormality in the DNP and DRP groups indicated that the structural abnormality might be a fundamental phenomenon of the disease. Furthermore, AEDs could reverse the alteration of structural and functional coupling in epilepsy.
In previous studies (Parsons, Bowden, Vogrin, & D'Souza, 2020; Zanao, Lopes, de Campos, Yasuda, & Cendes, 2019), it has been reported that abnormally connectivity was observed between the DMN and other functional networks during interictal discharges, thus, the DMN is considered to associate with the generation of epileptic discharges(Jiang, Li, Liu, Yao, & Luo, 2021). Accumulated studies based on the electroencephalogram have suggested that enhanced FC might be a crucial feature corresponding to epileptic cortical discharges(Adeli, Zhou, & Dadmehr, 2003; Schevon et al., 2007), which was consistent with the theory "Neurons that fire together, Wire Together" by Donald Hebb et al.(Hebb, 1949). Matching this view, the current work also identified the enhancement of functional connectivity within DMN and that between DMN and the other networks in patient groups. This widespread enhancement of connections might be a byproduct of the rapid transmission of electrical signals through the brain during seizures(Dixon et al., 2018; Wei et al., 2015). Besides, the present results showed a specifically increased functional and structural connection between DMN and FPN in the DRP group, implying that the cortical changes caused by the epileptic activation were not completely ameliorated by the medicine, and these brain regions might still be affected by the epileptic disorder, but for the area without effects of epileptic activation, the medicine has obvious improvement effect. Consistent with previous findings, our results indicated that the medical treatments have a potential effect to affect the interaction of the DMN with the other networks. However, compared with the HC group, higher connectivity strength between DMN and FPN in the DNP group was found not only in functional networks but also in structural networks. Moreover, the DRP group had the same abnormal alterations as the DNP group. These phenomena unaffected by drugs might represent a fundamental pathologic brain state in patients with GTCS. Therefore, we speculate that medication was easier to affect FC to alleviate the disease than to structural networks. This might be one of the reasons why curing epilepsy is difficult. In addition, the synergy between functional and structural networks is very important, which maintains physiological activities. The stable structural and functional connection between FMN and FPN in patients with and without AEDs might contribute to the reasons why patients who received antiepileptic drugs were more likely to remain seizures.
FPN is also one of the higher-order networks of the brain, which is responsible for executing cognitive control functions, such as work memory and attention selection(Corbetta, 1998; Vincent, Kahn, Snyder, Raichle, & Buckner, 2011). The enhanced connection between FPN and the other networks such as VN and limbic might reflect the intrinsic information over-integration between the generation and propagation networks of epileptic activities. A common phenomenon related to this alteration is that patients with epilepsy usually lose their sense of the environment and the ability to control themselves during seizures(Thurman et al., 2011). Increased functional connections were also observed in this work between the FPN and the limbic network in patients with GTCS. Since the limbic network is related to emotional cognition(Delfino-Pereira et al., 2020; Hayes & Northoff, 2011), such enhancement might explain the phenomenon of cognitive impairment accompanied by epilepsy. Besides(Krzeminski et al., 2020; Weng et al., 2020), this study also found abnormally enhanced connections within the primary networks, mainly including the limbic network, SMN, and VN. Both SMN and VN are important components of the primary-sensory perceptual cortices(Roland et al., 2017). It has been demonstrated that the coordination of visual and motor activities is associated with the synchrony of certain nerve rhythms(P. Avanzini et al., 2012; Muthukumaraswamy, Johnson, Gaetz, & Cheyne, 2004), however, this synchronicity might be disrupted by epileptic discharges, and the resulting phenomenon was abnormally enhanced connections within the primary networks(Hebb, 1949). These phenomena might be reasons why abnormal behavior existed in patients with epilepsy, such as convulsions and absence.
The fusion of multimodal provides an effective instrument to integrate the advantage of different neuroimages(Sisi Jiang et al., 2021; Qin et al., 2021). The fusion on the network-level might be adaptive for the disorders of the brain network(Sisi Jiang et al., 2021). Our previous study proposed the NWCP focused on the static and dynamic functional connections , which would reflect the coupling between structural and functional connectivity. The previous findings suggested that AEDs might be able to modulate the brain function of patients with GTCS. However, the effect of the drug on the structural network might be weak. The structural and functional coupling was only decreased in connections between the limbic network and SMN in GTCS in addition to connections within DMN and between DMN and VAN, reflecting antagonism of alteration of functional and structural networks in the DNP group. The limbic network and sensory-motor cortex were also important for generalized epilepsy. For example, limbic may take part in the generalized discharges generation(Badawy, Jackson, Berkovic, & Macdonell, 2013; Badawy, Lai, Vogrin, & Cook, 2013; Moguilner et al., 2017), and SMN may be related to motor symptoms in GTCS(Jiang et al., 2020). Thus, the structural and functional decoupling between the limbic network and SMN was comprehensible. Interestingly, patients with AEDs also showed the decreased coupling of this connection, supporting the importance of the connection on epilepsy. In addition, coupling within DMN was significantly increased compared to patients with AEDs to ones without AEDs. Therefore, we suggested that medical treatment can improve the abnormal brain network by affecting the structural and functional coupling relationship.
There are still some limitations in our study. First, due to the present study being a cross-sectional study, a comparison is lacking between before and after medication treatment. Although patients with or without treatment were collected, it is necessary for a longitudinal study. Because individual differences can be avoided. Then, the differences are not quantified in the cognitive evaluation between groups so that the effects of treatment on cognitive changes are not clear. Finally, we will recruit more subjects to increase the stability of our results.