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.

In this review, we will discuss in four scenarios our challenges to offer possible solutions for the puzzle associated with the epilepsies and neuropsychiatric comorbidities. We need to recognize that (1) since quite old times, human wisdom was linked to the plural (distinct global places/cultures) perception of the Universe we are in, with deep respect for earth and nature. Plural ancestral knowledge was added with the scientific methods; however, their joint efforts are the ideal scenario; (2) human behavior is not different than animal behavior, in essence the product of Darwinian natural selection; knowledge of animal and human behavior are complementary; (3) the expression of human behavior follows the same rules that complex systems with emergent properties, therefore, we can measure events in human, clinical, neurobiological situations with complexity systems' tools; (4) we can use the semiology of epilepsies and comorbidities, their neural substrates, and potential treatments (including experimental/computational modeling, neurosurgical interventions), as a source and collection of integrated big data to predict with them (e.g.: machine/deep learning) diagnosis/prognosis, individualized solutions (precision medicine), basic underlying mechanisms and molecular targets. Once the group of symptoms/signals (with a myriad of changing definitions and interpretations over time) and their specific sequences are determined, in epileptology research and clinical settings, the use of modern and contemporary techniques such as neuroanatomical maps, surface electroencephalogram and stereoelectroencephalography (SEEG) and imaging (MRI, BOLD, DTI, SPECT/PET), neuropsychological testing, among others, are auxiliary in the determination of the best electroclinical hypothesis, and help design a specific treatment, usually as the first attempt, with available pharmacological resources. On top of ancient knowledge, currently known and potentially new antiepileptic drugs, alternative treatments and mechanisms are usually produced as a consequence of the hard, multidisciplinary, and integrated studies of clinicians, surgeons, and basic scientists, all over the world. The existence of pharmacoresistant patients, calls for search of other solutions, being along the decades the surgeries the most common interventions, such as resective procedures (i.e., selective or standard lobectomy, lesionectomy), callosotomy, hemispherectomy and hemispherotomy, added by vagus nerve stimulation (VNS), deep brain stimulation (DBS), neuromodulation, and more recently focal minimal or noninvasive ablation. What is critical when we consider the pharmacoresistance aspect with the potential solution through surgery, is still the pursuit of localization-dependent regions (e.g.: epileptogenic zone (EZ)), in order to decide, no matter how sophisticated are the brain mapping tools (EEG and MRI), the size and location of the tissue to be removed. Mimicking the semiology and studying potential neural mechanisms and molecular targets - by means of experimental and computational modeling - are fundamental steps of the whole process. Concluding, with the conjunction of ancient knowledge, coupled to critical and creative contemporary, scientific (not dogmatic) clinical/surgical, and experimental/computational contributions, a better world and of improved quality of life can be offered to the people with epilepsy and neuropsychiatric comorbidities, who are still waiting (as well as the scientists) for a paradigm shift in epileptology, both in the Basic Science, Computational, Clinical, and Neurosurgical Arenas. This article is part of the Special Issue "NEWroscience 2018".