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Drug-resistant epilepsies: diagnostic challenges, associated comorbidities and new experimental approaches

Grant number: 16/17882-4
Support type:Research Projects - Thematic Grants
Duration: August 01, 2017 - July 31, 2022
Field of knowledge:Health Sciences - Medicine
Principal Investigator:João Pereira Leite
Grantee:
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto, SP, Brazil
Co-Principal Investigators:Antonio Carlos dos Santos
Assoc. researchers: Ana Paula Andrade Hamad ; Carlos Gilberto Carlotti Júnior ; Daniel Leite Góes Gitaí ; Helio Rubens Machado ; Jaime Eduardo Cecilio Hallak ; Jorge Eduardo Moreira ; Kette Dualibi Ramos Valente ; Maria José da Silva Fernandes ; Rodrigo Neves Romcy Pereira ; Tonicarlo Rodrigues Velasco

Abstract

Nearly half of the patients with Epilepsy have poor seizure control, even after more than a century of advances in pharmacological treatment. For some of these drug-resistant cases, surgery may be the indicated treatment. In these cases, surgical success is directly linked to the correct location of the epileptogenic zone (EZ; i.e., the brain area responsible for seizure generation), and both Magnetic Resonance Imaging (MRI) and Electroencephalography (EEG) are crucial for defining the boundaries of the EZ. Hippocampal sclerosis and cortical dysplasia are the most frequent pathologies seen in drug-resistant cases, being detected as changes in volume and signal intensity of the various MRI protocols and typical patterns found in video-EEG examinations. However, even with the use of optimized video-EEG and high-field MRI protocols, a considerable percentage of cases remains without a clearly identifiable EZ. As a result, the complete resection of the EZ is incomplete, leaving a significant number of patients with poor seizure control. This lack of proper seizure control has a high impact on the patient's life quality since, in addition to the seizure's impact per se, uncontrolled seizures lead to significant cognitive deficits and are associated with psychiatric comorbidities such as Depression and Interictal Psychosis. The latest technological advances, such as 7 Tesla MR machines and images constructed by EEG data (electrical source imaging, high-density EEG) are promising for a better definition of the EZ. Moreover, experimental studies in multi unitary electrophysiology and optogenetics contributed to a better understanding of the generation and synchronization of neuronal activity that leads to the seizures and the emergence of associated comorbidities. Recent publications from various centers and our group have shown, in patients with medically resistant Epilepsy, different patterns of structural, neurochemistry, and connectivity changes between brain structures associated with cognitive and psychiatric comorbidities. Studies of this nature are essential for the development of future therapeutic approaches to the drug-resistant patients. Thus, the central focus of the present thematic project is the pathologic, cognitive, and behavioral changes associated with drug-resistant Epilepsy, with particular attention to cases where the EZ is poorly defined. With this aim, the proposed studies is divided into 3 main project groups, as follows: a) diagnosis and treatment improvement for drug-resistant patients, especially those with normal MRI; b) a better characterization of structural and functional changes (neuroimaging, neuropathological and molecular approaches) in drug-resistant patients with cognitive and psychiatric comorbidities; c) the development of electrophysiological and optogenetic approaches to a better understanding of the mechanisms underlying seizure onset, behavioral and cognitive changes seen in animal models of drug-resistant epilepsy. (AU)

Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LOPES BORN, JOAO PAULO; MATOS, HELOISA DE CARVALHO; DE ARAUJO, MYKAELLA ANDRADE; CASTRO, OLAGIDE WAGNER; DUZZIONI, MARCELO; PEIXOTO-SANTOS, JOSE EDUARDO; LEITE, JOAO PEREIRA; GARCIA-CAIRASCO, NORBERTO; PACO-LARSON, MARIA LUISA; GOES GITAI, DANIEL LEITE. Using Postmortem hippocampi tissue can interfere with differential gene expression analysis of the epileptogenic process. PLoS One, v. 12, n. 8 AUG 4 2017. Web of Science Citations: 0.
RUGGIERO, RAFAEL N.; ROSSIGNOLI, MATHEUS T.; DE ROSS, JANA B.; HALLAK, JAIME E. C.; LEITE, JOAO P.; BUENO-JUNIOR, LEZIO S. Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research. FRONTIERS IN PHARMACOLOGY, v. 8, JUN 21 2017. Web of Science Citations: 0.
ROSSIGNOLI, MATHEUS TEIXEIRA; LOPES-AGUIAR, CLEITON; RUGGIERO, RAFAEL NAIME; DO VAL DA SILVA, RAQUEL ARAUJO; BUENO-JUNIOR, LEZIO SOARES; KANDRATAVICIUS, LUDMYLA; PEIXOTO-SANTOS, JOSE EDUARDO; CRIPPA, JOSE ALEXANDRE; CECILIO HALLAK, JAIME EDUARDO; ZUARDI, ANTONIO WALDO; SZAWKA, RAPHAEL ESCORSIM; ANSELMO-FRANCI, JANETE; LEITE, JOAO PEREIRA; ROMCY-PEREIRA, RODRIGO NEVES. SELECTIVE POST-TRAINING TIME WINDOW FOR MEMORY CONSOLIDATION INTERFERENCE OF CANNABIDIOL INTO THE PREFRONTAL CORTEX: REDUCED DOPAMINERGIC MODULATION AND IMMEDIATE GENE EXPRESSION IN LIMBIC CIRCUITS. Neuroscience, v. 350, p. 85-93, MAY 14 2017. Web of Science Citations: 1.
DO VAL-DA SILVA, RAQUEL A.; PEIXOTO-SANTOS, JOSE E.; KANDRATAVICIUS, LUDMYLA; DE ROSS, JANA B.; ESTEVES, INGRID; DE MARTINIS, BRUNO S.; ALVES, MARCELA N. R.; SCANDIUZZI, RENATA C.; HALLAK, JAIME E. C.; ZUARDI, ANTONIO W.; CRIPPA, JOSE A.; LEITE, JOAO P. Protective Effects of Cannabidiol against Seizures and Neuronal Death in a Rat Model of Mesial Temporal Lobe Epilepsy. FRONTIERS IN PHARMACOLOGY, v. 8, MAR 17 2017. Web of Science Citations: 1.
BUENO-JUNIOR, LEZIO S.; RUGGIERO, RAFAEL N.; ROSSIGNOLI, MATHEUS T.; DEL BEL, ELAINE A.; LEITE, JOAO P.; UCHITEL, OSVALDO D. Acetazolamide potentiates the afferent drive to prefrontal cortex in vivo. PHYSIOLOGICAL REPORTS, v. 5, n. 1 JAN 2017. Web of Science Citations: 1.
PEIXOTO-SANTOS, JOSE EDUARDO; KANDRATAVICIUS, LUDMYLA; VELASCO, TONICARLO RODRIGUES; ASSIRATI, JOAO ALBERTO; CARLOTTI, CARLOS GILBERTO; SCANDIUZZI, RENATA CALDO; GARRIDO SALMON, CARLOS ERNESTO; DOS SANTOS, ANTONIO CARLOS; LEITE, JOAO PEREIRA. Individual hippocampal subfield assessment indicates that matrix macromolecules and gliosis are key elements for the increased T2 relaxation time seen in temporal lobe epilepsy. Epilepsia, v. 58, n. 1, p. 149-159, JAN 2017. Web of Science Citations: 2.

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