Searching for a paradigm shift in the research on the epilepsies and associated neuropsychiatric comorbidities. From ancient historical knowledge to the challenge of contemporary systems complexity and emergent functions

A complex systems view on the current hypotheses of epilepsy pharmacoresistance

“…26 These are commendable steps in the right direction; the current approach, however, still focuses mainly into models of temporal lobe epilepsy and do not reflect our current understanding of the epilepsies and their complexity. 2,27 Therefore, it will be interesting to see if the number of models of the ETSP can be increased over time to include not only new rodent models (or less frequently used, such as the genetic ones) but also new in vitro and in silico models, as well as non-rodent models such as Caenorhabditis elegans and zebrafish.…”

“…[48][49][50] Briefly, the next following step, more than 12 years ago was to propose, based upon Kuhn's "The Structures of Scientific Revolutions," 51 that a paradigm shift was needed, in the case of the epilepsies, first of all, using a "puzzle-solving strategy," to identify semiology and next, epileptogenic networks. 2,39,52 Naturally, if the nervous system itself is a multiscale entity and is organized into different spatiotemporal and topological scales, 53 likewise, are brain networks. Neuronal networks are capable of generating complex patterns of synchronized activity, which are, in fact, essential for the normal functioning of the brain.…”

“…Epilepsy is a highly prevalent chronic neurological disorder estimated to affect about 50 million people worldwide 1 . From ancient cultures' recognition of the epilepsies as brain‐dependent phenomena to their contemporary treatment, executed with rational, non‐supernatural views and tools, three generations of antiseizure medications (ASMs) have been developed 2,3 . However, despite the exponential increase of clinically available ASMs over the past decades, an estimated 30% of the patients are still unable to achieve sustained seizure freedom through pharmacological treatment 3,4 .…”

“…While the mechanisms proposed in the transporter, 8–11,74–83 pharmacokinetic, 8–11,84–89 target, 8–11,90–97 neural networks, 8–11,52,98–103 and intrinsic severity hypotheses 8–11,81,86,104 may offer a more direct association between alterations and drug resistance, mechanisms proposed in the gene variant 8–11,73,82,96,105–108 and neuroinflammatory 8–11,78,109–111 hypotheses offer a more integrative view, that could serve as the basis for the emergence of the other mechanisms (Table 1; Figure 2B). 2,8,9 Epigenetic changes associated with DRE have been previously identified and are likely another important regulatory component involved in the control of other mechanisms associated with drug resistance, but currently, there is not much evidence to support this hypothesis, the reason why it was omitted in Table 1 9,11,112 . The combination of those hypotheses makes it possible to build a much better and more cohesive framework of ideas, which may allow a new approach to the problem of DRE.…”

“…The current ETSP was reformulated from what used to be known as the Anticonvulsant Screening Program (ASP). The renaming and the revision from the original ASP reflect the new emphasis of the program on the identification of novel antiseizure agents for the treatment of patients with DREs, as well as disease‐modifying substances that could “ameliorate or even cure established epilepsy and its comorbidities.” 26 These are commendable steps in the right direction; the current approach, however, still focuses mainly into models of temporal lobe epilepsy and do not reflect our current understanding of the epilepsies and their complexity 2,27 . Therefore, it will be interesting to see if the number of models of the ETSP can be increased over time to include not only new rodent models (or less frequently used, such as the genetic ones) but also new in vitro and in silico models, as well as non‐rodent models such as Caenorhabditis elegans and zebrafish.…”