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Research on neural circuits and biological markers involved in obsessive-compulsive disorder using behavioral paradigms of fear and anxiety

Grant number: 11/21357-9
Support type:Research Projects - Thematic Grants
Duration: December 01, 2012 - November 30, 2017
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Eurípedes Constantino Miguel Filho
Grantee:Eurípedes Constantino Miguel Filho
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Co-Principal Investigators:Carlos Alberto de Bragança Pereira ; Guilherme Vanoni Polanczyk ; Helena Paula Brentani ; Marcus Lira Brandão ; Roseli Gedanke Shavitt
Assoc. researchers:Erich Talamoni Fonoff ; Giovanni Abrahão Salum Júnior ; Koichi Sameshima ; Leonardo Franklin da Costa Fontenelle ; Luis Augusto Paim Rohde ; Marcus Lira Brandão ; Renato Teodoro Ramos ; Roseli Gedanke Shavitt
Associated scholarship(s):16/05865-8 - Ventromedial prefrontal cortex metabolite levels in obsessive-compulsive patients: a proton magnetic resonance spectroscopy study, BP.PD
15/10704-0 - Peripheral gene expression profile from Obsessive Compulsive Disorder (OCD) patients, unaffected siblings and controls: a pilot study, BP.IC
15/07002-4 - Intraoperative electrophysiological study in patients with OCD submitted to deep brain stimulation, BP.PD
+ associated scholarships 14/15879-0 - Study of peripheral biomarkers in patients with obsessive-compulsive disorder and controls, BP.PD
14/00591-1 - Studies of co-expression gene networks of the orbitofrontal cortex and striatum (postmortem study) of patients with OCD and controls, BP.DR
13/24652-7 - Predictor factors for metabolic diseases in obsessive-compulsive disorder patients, BP.IC - associated scholarships

Abstract

The obsessive-compulsive disorder (OCD) is the fourth most common psychiatric disorder and is related to significant disability, poor quality of life and disrupted family functioning. Despite the existence of effective therapeutic interventions for OCD (e.g. serotonin reuptake inhibitors and behavior psychotherapy), up to half of OCD patients do not respond satisfactorily with treatment. Therefore, new therapeutic alternatives are still needed. Moreover, the neurobiological mechanisms that underlie OCD etiology and the effect of treatments are only partially comprehended. To fill this gap in the literature, we concluded, after analyzing the results of our studies as well as others, that the conceptualization of OCD as a unitary disorder is outdated and that it is necessary to improve our investigative methods. We aim to comprehend OCD having the specific components of its behavioral chain as our starting point. We will investigate the behavioral components known as unconditioned fear response (inate response or reflex also known as "startle"), conditioned fear response after matching with aversive stimuli, the inhibition of the unconditioned fear response (prepulse inihibition), and several neuropsychological measures related to executive functions and attentional bias. In prallel, we will investigate both health subjects and OCD patients with functional neuroimaging, electroencephalography, peripheral biomarkers (such as oxytocin and BDNF) and peripheral markers of gene expression related to the immunological system. A portion of our patients we also be followed during treatment with a selective serotonin reuptake inhibitor and we will be able to investigate if any alterations in the response to the behavioral paradigms, neuropsycholagical tests or peripheral biomarkers will be associated with treatment response. As well, in another portion of patients, we will evaluate the effect of neurosurgical interventions (gamaknife neurosurgery and deep brain stimulation) as treatment strategies for refractory OCD. Inserted in a translational perspective, we will work with an animal model for OCD (injection of oxytocin in the central nucleus of the amygdala inducing grooming behaviors). The animals will be evaluated according equivalents of the behavioral paradigms and treatment interventions used in humans. The manipulation of variables and the access to brain material is much easier within animal models so we will be able to isolate the effect of specific variables over the pharmacological treatment response as well as to understand the molecular mechanisms underneath. We will also be able to study brain material of OCD patients post-mortem. These analyses will provide us with clues linking the peripheral alterations to the processes in the brain. With the results obtained in this study, we expect to improve the comprehension of which neurocircuits and neurophysiologic mechanisms are involved in OCD etiology and response to pharmacological as well as neurosurgical treatment. We aim to understand the OCD related manifestations in the light of the circuits responsible for the phenomena of fear response and aversive stimuli discrimination; and to make the link between observed behavioral phenomena and underlying molecular mechanisms. (AU)

Scientific publications (18)
(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)
TAKASHIMA, SHIRO; NAJMAN, FERNANDO ARAUJO; RAMOS, RENATO TEODORO. Disruption of volitional control in obsessive-compulsive disorder: Evidence from the Bereitschaftspotential. PSYCHIATRY RESEARCH-NEUROIMAGING, v. 290, p. 30-37, AUG 30 2019. Web of Science Citations: 0.
SKINAZI, MICHELE; DE MATHIS, MARIA A.; COHAB, TATIANA; DE MARCO E SOUZA, MARINA; SHAVITT, ROSELI G.; MIGUEL, EURIPEDES C.; HOEXTER, MARCELO Q.; BATISTUZZO, MARCELO C. No evidence of attentional bias toward angry faces in patients with obsessive-compulsive disorder. Revista Brasileira de Psiquiatria, v. 41, n. 3, p. 257-260, MAY-JUN 2019. Web of Science Citations: 0.
MIGUEL, EURIPEDES C.; LOPES, ANTONIO C.; MCLAUGHLIN, NICOLE C. R.; NOREN, GEORG; GENTIL, ANDRE F.; HAMANI, CLEMENT; SHAVITT, ROSELI G.; BATISTUZZO, MARCELO C.; VATTIMO, EDOARDO F. Q.; CANTERAS, MIGUEL; DE SALLES, ANTONIO; GORGULHO, ALESSANDRA; SALVAJOLI, JOAO VICTOR; FONOFF, ERICH TALAMONI; PADDICK, IAN; HOEXTER, MARCELO Q.; LINDQUIST, CHRISTER; HABER, SUZANNE N.; GREENBERG, BENJAMIN D.; SHETH, SAMEER A. Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder. MOLECULAR PSYCHIATRY, v. 24, n. 2, p. 218-240, FEB 2019. Web of Science Citations: 12.
DE OLIVEIRA, KATIA CRISTINA; GRINBERG, LEA TENENHOLZ; HOEXTER, MARCELO QUEIROZ; BRENTANI, HELENA; SUEMOTO, CLAUDIA KIMIE; NERY, FABIANO GONCALVES; LIMA, LUZIA CARREIRA; DI LORENZO ALHO, ANA TEREZA; FARFEL, JOSE MARCELO; DE LUCENA FERRETTI-REBUSTINI, RENATA ELOAH; PARAIZO LEITE, RENATA ELAINE; MORETTO, ARIANE CRISTINE; DA SILVA, ALEXANDRE VALOTTA; LAFER, BENY; MIGUEL, EURIPEDES CONSTANTINO; NITRINI, RICARDO; JACOB-FILHO, WILSON; HEINSEN, HELMUT; PASQUALUCCI, CARLOS AUGUSTO. Layer-specific reduced neuronal density in the orbitofrontal cortex of older adults with obsessive-compulsive disorder. Brain Structure & Function, v. 224, n. 1, p. 191-203, JAN 2019. Web of Science Citations: 2.
TAKASHIMA, SHIRO; CRAVO, ANDRE M.; SAMESHIMA, KOICHI; RAMOS, RENATO T. The effect of conscious intention to act on the Bereitschaftspotential. Experimental Brain Research, v. 236, n. 8, p. 2287-2297, AUG 2018. Web of Science Citations: 1.
REIMER, ADRIANO EDGAR; DE OLIVEIRA, AMANDA RIBEIRO; DINIZ, JULIANA BELO; HOEXTER, MARCELO QUEIROZ; MIGUEL, EURIPEDES CONSTANTINO; MILAD, MOHAMMED RAGIB; BRANDAO, MARCUS LIRA. Fear extinction in an obsessive-compulsive disorder animal model: Influence of sex and estrous cycle. Neuropharmacology, v. 131, p. 104-115, MAR 15 2018. Web of Science Citations: 4.
PAIVA, RAQUEL R.; BATISTUZZO, MARCELO C.; MCLAUGHLIN, NICOLE C.; CANTERAS, MIGUEL M.; DE MATHIS, MARIA E.; REQUENA, GUARACI; SHAVITT, ROSELI G.; GREENBERG, BENJAMIN D.; NOREN, GEORG; RASMUSSEN, STEVEN A.; TAVARES, HERMANO; MIGUEL, EURIPEDES C.; LOPES, ANTONIO C.; HOEXTER, MARCELO Q. Personality measures after gamma ventral capsulotomy in intractable OCD. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 81, p. 161-168, FEB 2 2018. Web of Science Citations: 2.
TRAMBAIOLLI, LUCAS R.; BIAZOLI, JR., CLAUDINEI E.; BALARDIN, JOANA B.; HOEXTER, MARCELO Q.; SATO, JOAO R. The relevance of feature selection methods to the classification of obsessive compulsive disorder based on volumetric measures. Journal of Affective Disorders, v. 222, p. 49-56, NOV 2017. Web of Science Citations: 4.
FOUCHE, JEAN-PAUL; DU PLESSIS, STEFAN; HATTINGH, COENIE; ROOS, ANNERINE; LOCHNER, CHRISTINE; SORIANO-MAS, CARLES; SATO, JOAO R.; NAKAMAE, TAKASHI; NISHIDA, SEIJI; KWON, JUN SOO; JUNG, WI HOON; MATAIX-COLS, DAVID; HOEXTER, MARCELO Q.; ALONSO, PINO; DE WIT, STELLA J.; VELTMAN, DICK J.; STEIN, DAN J.; VAN DEN HEUVEL, ODILE A.; CONSORTIUM, OCD BRAIN IMAGING. Cortical thickness in obsessive compulsive disorder: multisite mega-analysis of 780 brain scans from six centres. BRITISH JOURNAL OF PSYCHIATRY, v. 210, n. 1, p. 67-74, JAN 2017. Web of Science Citations: 28.
KARINA SOARES DE OLIVEIRA; ANA GABRIELA HOUNIE; CAROLINA CAPPI; JULIANA BELO DINIZ. Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety. Jornal Brasileiro de Psiquiatria, v. 65, n. 3, p. -, Set. 2016.
DINIZ, JULIANA BELO; FOSSALUZA, VICTOR; DE BRAGANCA PEREIRA, CARLOS ALBERTO; WECHSLER, SERGIO. Rain dance: the role of randomization in clinical trials. OPEN ACCESS JOURNAL OF CLINICAL TRIALS, v. 8, p. 21-32, 2016. Web of Science Citations: 0.
HOEXTER, MARCELO Q.; DINIZ, JULIANA B.; LOPES, ANTONIO C.; BATISTUZZO, MARCELO C.; SHAVITT, ROSELI G.; DOUGHERTY, DARIN D.; DURAN, FABIO L. S.; BRESSAN, RODRIGO A.; BUSATTO, GERALDO F.; MIGUEL, EURIPIDES C.; SATO, JOAO R. ORBITOFRONTAL THICKNESS AS A MEASURE FOR TREATMENT RESPONSE PREDICTION IN OBSESSIVE-COMPULSIVE DISORDER. DEPRESSION AND ANXIETY, v. 32, n. 12, p. 900-908, DEC 2015. Web of Science Citations: 6.
REIMER, ADRIANO EDGAR; DE OLIVEIRA, AMANDA RIBEIRO; DINIZ, JULIANA BELO; HOEXTER, MARCELO QUEIROZ; CHIAVEGATTO, SILVANA; BRANDAO, MARCUS LIRA. Rats with differential self-grooming expression in the elevated plus-maze do not differ in anxiety-related behaviors. Behavioural Brain Research, v. 292, p. 370-380, OCT 1 2015. Web of Science Citations: 10.
GORENSTEIN, GABRIELA; GORENSTEIN, CLARICE; DE OLIVEIRA, MELAINE CRISTINA; ASBAHR, FERNANDO RAMOS; SHAVITT, ROSELI GEDANKE. Child-focused treatment of pediatric OCD affects parental behavior and family environment. PSYCHIATRY RESEARCH, v. 229, n. 1-2, p. 161-166, SEP 30 2015. Web of Science Citations: 6.
BATISTUZZO, MARCELO C.; HOEXTER, MARCELO Q.; TAUB, ANITA; GENTIL, ANDRE F.; CESAR, RAONY C. C.; JOAQUIM, MARINES A.; D'ALCANTE, CARINA CHAUBET; MCLAUGHLIN, NICOLE C.; CANTERAS, MIGUEL M.; SHAVITT, ROSELI G.; SAVAGE, CARY R.; GREENBERG, BENJAMIN D.; NOREN, GEORG; MIGUEL, EURIPEDES C.; LOPES, ANTONIO C. Visuospatial Memory Improvement after Gamma Ventral Capsulotomy in Treatment Refractory Obsessive-Compulsive Disorder Patients. NEUROPSYCHOPHARMACOLOGY, v. 40, n. 8, p. 1837-1845, JUL 2015. Web of Science Citations: 9.
SUBIRA, MARTA; SATO, JOAO R.; ALONSO, PINO; DO ROSARIO, MARIA C.; SEGALAS, CINTO; BATISTUZZO, MARCELO C.; REAL, EVA; LOPES, ANTONIO C.; CERRILLO, ESTER; DINIZ, JULIANA B.; PUJOL, JESUS; ASSIS, RACHEL O.; MENCHON, JOSE M.; SHAVITT, ROSELI G.; BUSATTO, GERALDO F.; CARDONER, NARCIS; MIGUEL, EURIPEDES C.; HOEXTER, MARCELO Q.; SORIANO-MAS, CARLES. Brain structural correlates of sensory phenomena in patients with obsessive-compulsive disorder. JOURNAL OF PSYCHIATRY & NEUROSCIENCE, v. 40, n. 4, p. 232-240, JUL 2015. Web of Science Citations: 14.
DINIZ, JULIANA B.; COSTA, DANIEL L. C.; CASSAB, RAONY C. C.; PEREIRA, CARLOS A. B.; MIGUEL, EURIPEDES C.; SHAVITT, ROSELI G. The impact of comorbid body dysmorphic disorder on the response to sequential pharmacological trials for obsessive-compulsive disorder. JOURNAL OF PSYCHOPHARMACOLOGY, v. 28, n. 6, p. 603-611, JUN 2014. Web of Science Citations: 3.

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