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

• Grant number: 16/17882-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: August 01, 2017
• End date: January 31, 2024
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: João Pereira Leite
• Grantee: João Pereira Leite
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Antonio Carlos dos Santos
• Associated researchers: Ana Paula Andrade Hamad ; Carlos Gilberto Carlotti Jr ; Daniel Leite Góes Gitaí ; Helio Rubens Machado ; Jaime Eduardo Cecilio Hallak ; Jorge Eduardo Moreira ; José Eduardo Peixoto Santos ; Kette Dualibi Ramos Valente ; Maria José da Silva Fernandes ; Rafael Naime Ruggiero ; Rodrigo Neves Romcy Pereira ; Tonicarlo Rodrigues Velasco
• Associated research grant(s): 19/08146-0 - EMU granted in the process 2016/17882-4: multichannel system for Electrophysiology/Optogenetics Plexon, AP.EMU
• Associated scholarship(s): 22/16812-3 - Study of the neural decoding of depression-related behavioral states by the oscillatory dynamics of large-scale brain networks, BP.PD; 20/14642-8 - Frequency of psychiatric comorbidities in drug-resistant Temporal Lobe Epilepsy patients with different types of hippocampal sclerosis, BP.IC; 20/08205-4 - Design of neural probes for neural recording: enabling the EMU program for cutting-edge electrophysiological studies, BP.TT; + associated scholarships 20/01510-6 - Study of the neural processing of meso-cortico-limbic circuitry during anhedonic-type behavior and its modulation by the endocannabinoid system, BP.PD; 19/03445-0 - Behavioral validation of a new animal model to study the neural processing of controllability over aversive stimuli, BP.IC; 18/18014-1 - Interactions between epilepsy and homeostatic plasticity: how seizures recurrence modulates homeostatic plasticity and how parvalbuminergic hypofunction facilitates seizures induction., BP.PD; 18/23644-4 - Breeding and handling of transgenic mice: addressing the effect of specific neuron subtypes on epilepsies and related comorbidities, BP.TT; 18/16920-5 - Controlling prefrontal cortex pyramidal cells with optogenetics: from methodological standardization to immunohistochemical and electrophysiological validation, BP.IC; 18/02303-4 - Study of the meso-cortico-limbic connectivity in animals submitted to early-life Status epilepticus and its relationship with psychiatric comorbidities, BP.PD - associated scholarships

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

(24)

(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-AGUIAR, CLEITON; RUGGIERO, RAFAEL N.; ROSSIGNOLI, MATHEUS T.; ESTEVES, INGRID DE MIRANDA; PEIXOTO-SANTOS, JOSE EDUARDO; ROMCY-PEREIRA, RODRIGO N.; LEITE, JOAO P.. Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo. SCIENTIFIC REPORTS, v. 10, n. 1, APR 28 2020. (16/17882-4, 18/02303-4, 14/18211-0)

MARQUES, DANILO BENETTE; RUGGIERO, RAFAEL NAIME; BUENO-JUNIOR, LEZIO SOARES; ROSSIGNOLI, MATHEUS TEIXEIRA; LEITE, JOAO PEREIRA. Prediction of Learned Resistance or Helplessness by Hippocampal-Prefrontal Cortical Network Activity during Stress. JOURNAL OF NEUROSCIENCE, v. 42, n. 1, p. 81-96, JAN 5 2022. (18/02303-4, 16/17882-4, 11/04467-5, 20/01510-6, 12/06123-4)

LEITE, JOAO PEREIRA; PEIXOTO-SANTOS, JOSE EDUARDO. Glia and extracellular matrix molecules: What are their importance for the electrographic and MRI changes in the epileptogenic zone?. Epilepsy & Behavior, v. 121, n. B, AUG 2021. (15/20840-9, 16/17882-4)

MENDES, RENAN AUGUSTO VIANA; ZACHARIAS, LEONARDO RAKAUSKAS; RUGGIERO, RAFAEL NAIME; LEITE, JOAO PEREIRA; MORAES, MARCIO FLAVIO DUTRA; LOPES-AGUIAR, CLEITON. Hijacking of hippocampal-cortical oscillatory coupling during sleep in temporal lobe epilepsy. Epilepsy & Behavior, v. 121, n. B, AUG 2021. (18/02303-4, 16/17882-4)

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. (15/20840-9, 16/17882-4)

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; et al. 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. (12/23918-0, 15/20840-9, 16/17882-4, 14/09772-9)

BUENO-JUNIOR, LEZIO S.; LEITE, JOAO P.. Input Convergence, Synaptic Plasticity and Functional Coupling Across Hippocampal-Prefrontal-Thalamic Circuits. FRONTIERS IN NEURAL CIRCUITS, v. 12, MAY 23 2018. (12/06123-4, 16/17882-4)

FIGUEIREDO LEAL, SUENIA TIMOTHEO; SANTOS, MARCELO VOLPON; THOME, URSULA; MACHADO, HELIO RUBENS; ESCORSI-ROSSET, SARA; DOS SANTOS, ANTONIO CARLOS; WICHERT-ANA, LAURO; LEITE, JOAO PEREIRA; FRANCA FERNANDES, REGINA MARIA; SAKAMOTO, AMERIKO CEIKI; et al. Impact of epilepsy surgery on quality of life and burden of caregivers in children and adolescents. Epilepsy & Behavior, v. 106, MAY 2020. (16/17882-4)

SAUTE, RICARDO LUTZKY; PEIXOTO-SANTOS, JOSE EDUARDO; VELASCO, TONICARLO R.; LEITE, JOAO PEREIRA. Improving surgical outcome with electric source imaging and high field magnetic resonance imaging. SEIZURE-EUROPEAN JOURNAL OF EPILEPSY, v. 90, n. SI, p. 145-154, AUG 2021. (17/03739-8, 16/17882-4)

BUENO-JUNIOR, LEZIO S.; PEIXOTO-SANTOS, JOSE E.; RUGGIERO, RAFAEL N.; AVILA, MILTON A. V.; MARQUES, DANILO B.; LOPES-AGUIAR, CLEITON; LEITE, JOAO P.. Interaction between hippocampal-prefrontal plasticity and thalamic-prefrontal activity. SCIENTIFIC REPORTS, v. 8, JAN 22 2018. (16/17882-4, 15/20840-9, 14/18211-0, 12/06123-4, 12/23918-0)

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.; et al. 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. (15/20840-9, 16/17882-4)

PEIXOTO-SANTOS, JOSE EDUARDO; DRUMOND DE CARVALHO, LUCIANA ESTEFANI; KANDRATAVICIUS, LUDMYLA; BESERRA DINIZ, PAULA REJANE; SCANDIUZZI, RENATA CALDO; CORAS, ROLAND; BLUEMCKE, INGMAR; ASSIRATI, JOAO ALBERTO; CARLOTTI, CARLOS GILBERTO; MARCONATO SIMOES MATIAS, CAIO CESAR; et al. Manual Hippocampal Subfield Segmentation Using High-Field MRI: Impact of Different Subfields in Hippocampal Volume Loss of Temporal Lobe Epilepsy Patients. FRONTIERS IN NEUROLOGY, v. 9, NOV 20 2018. (17/03739-8, 15/20840-9, 16/17882-4)

DOMBROSKI, THAIS CAROLINE DALLABONA; PEIXOTO-SANTOS, JOSE EDUARDO; MACIEL, KARINA; BAQUI, MUNIRA MUHAMMAD ABDEL; VELASCO, TONICARLO RODRIGUES; SAKAMOTO, AMERICO CEIKI; ASSIRATI, JOAO ALBERTO; CARLOTTI, CARLOS GILBERTO; MACHADO, HELIO RUBENS; SOUSA, GLEICE KELLY DE; et al. Drebrin expression patterns in patients with refractory temporal lobe epilepsy and hippocampal sclerosis. Epilepsia, v. 61, n. 8, JUL 2020. (18/03677-5, 16/17882-4)

PEIXOTO-SANTOS, JOSE EDUARDO; VELASCO, TONICARLO R.; CARLOTTI, CARLOS GILBERTO; ASSIRATI, JOAO ALBERTO; DE SOUZA E REZENDE, GUSTAVO HENRIQUE; KOBOW, KATJA; CORAS, ROLAND; BLUMCKE, INGMAR; GARRIDO SALMON, CARLOS ERNESTO; DOS SANTOS, ANTONIO CARLOS; et al. Histological correlates of hippocampal magnetization transfer images in drug-resistant temporal lobe epilepsy patients. NEUROIMAGE-CLINICAL, v. 28, 2020. (16/17882-4, 15/20840-9)

GODOY, LIVEA DORNELA; PRIZON, TAMIRIS; ROSSIGNOLI, MATHEUS TEIXEIRA; LEITE, JOAO PEREIRA; LIBERATO, JOSE LUIZ. Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention. FRONTIERS IN INTEGRATIVE NEUROSCIENCE, v. 16, p. 28-pg., 2022-02-17. (16/17882-4, 20/01510-6)

RUGGIERO, RAFAEL NAIME; PEIXOTO-SANTOS, JOSE EDUARDO; BUENO-JUNIOR, LEZIO SOARES; VALENTE, KETTE D.; LEITE, JOAO PEREIRA. Editorial: Psychiatric Comorbidities in the Epilepsies: Extensive Mechanisms and Broad Questions. FRONTIERS IN INTEGRATIVE NEUROSCIENCE, v. 16, p. 4-pg., 2022-06-17. (16/17882-4, 18/02303-4)

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. (15/20840-9, 16/17882-4)

RUGGIERO, RAFAEL N.; ROSSIGNOLI, MATHEUS T.; LOPES-AGUIAR, CLEITON; LEITE, JOAO P.; BUENO-JUNIOR, LEZIO S.; ROMCY-PEREIRA, RODRIGO N.. Lithium modulates the muscarinic facilitation of synaptic plasticity and theta-gamma coupling in the hippocampal-prefrontal pathway. Experimental Neurology, v. 304, p. 90-101, JUN 2018. (05/56447-7, 16/17882-4)

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. (12/23918-0, 16/17882-4)

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. (12/23918-0, 12/06123-4, 16/17882-4)

ARRUDA, RIVUS FERREIRA; ARRUDA, IANNE LUCENA; SILVEIRA, RAYANNE M. B.; SARTI, TALITA H. M.; GUILHOTO, LAURA M. F. F.; CARRETE JUNIOR, HENRIQUE; STAVALE, JOAO NORBERTO; PEIXOTO-SANTOS, JOSE EDUARDO; CENTENO, RICARDO SILVA; GUARANHA, MIRIAN S. B.; et al. The challenge of epilepsy surgery and intraoperative neurophysiological monitoring in an underweight young infant. EPILEPTIC DISORDERS, v. 24, n. 6, p. 4-pg., 2022-12-01. (16/17882-4, 21/01098-0)

RUGGIERO, RAFAEL NAIME; ROSSIGNOLI, MATHEUS TEIXEIRA; MARQUES, DANILO BENETTE; DE SOUSA, BRUNO MONTEIRO; ROMCY-PEREIRA, RODRIGO NEVES; LOPES-AGUIAR, CLEITON; LEITE, JOAO PEREIRA. Neuromodulation of Hippocampal-Prefrontal Cortical Synaptic Plasticity and Functional Connectivity: Implications for Neuropsychiatric Disorders. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 15, OCT 11 2021. (20/01510-6, 16/17882-4, 18/02303-4)

DE MARIA FROTA VASCONCELOS, THAIS; SAUTE, RICARDO LUTZKY; PODOLSKY-GONDIM, GUILHERME; ALEXANDRE, VERIANO; DALIO, MARINA TEIXEIRA RAMALHO PEREIRA; NAKANO, FREDERICO NAKANE; VELASCO, TONICARLO RODRIGUES; LEITE, JOAO PEREIRA; SAKAMOTO, AMERICO CEIKI. The foramen ovale correlate of 14 and 6/second positive bursts. EPILEPTIC DISORDERS, v. 25, n. 2, p. 3-pg., 2023-05-06. (16/17882-4)

DE SOUSA, BRUNO MONTEIRO; DE OLIVEIRA, ELIEZYER FERMINO; DA SILVA BERALDO, IKARO JESUS; POLANCZYK, RAFAELA SCHUTTENBERG; LEITE, JOAO PEREIRA; AGUIAR, CLEITON LOPES. An open-source, ready-to-use and validated ripple detector plugin for the Open Ephys GUI. JOURNAL OF NEURAL ENGINEERING, v. 19, n. 4, p. 21-pg., 2022-08-01. (16/17882-4, 15/25275-8)