Non-implantable neuromodulation therapies: a perspective for the depressed brain

• Grant number: 19/06009-6
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2021
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Geraldo Busatto Filho
• Grantee: Geraldo Busatto Filho
• Host Institution: Instituto de Psiquiatria Doutor Antonio Carlos Pacheco e Silva (IPq). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Geraldo Busatto Filho ; Giovanni Abrahão Salum Júnior ; Isabela Judith Martins Bensenor ; Ives Cavalcante Passos ; Laiss Bertola de Moura Ricardo ; Leandro da Costa Lane Valiengo ; Maria da Graça Morais Martin ; Maurício Henriques Serpa ; Paulo Andrade Lotufo ; Renério Fráguas Junior ; Vanessa de Jesus Rodrigues de Paula ; Wagner Farid Gattaz
• Associated scholarship(s): 24/15007-5 - Validation of a non-invasive neuromodulation system with high temporal precision guided by neural oscillations in real time with relevance for the treatment of depression, BP.PD; 24/17643-6 - Project Manager and Research Assistant for the Randomized Clinical Trial Comparing Convulsive Therapy Techniques, BP.TT; 23/09042-0 - Non-Implantable Neuromodulation therapies: a perspective for the depressed brain, BP.TT; + associated scholarships 22/12373-5 - Management of Digital and Hybrid Clinical Trials in Non-Implantable Neuromodulation, BP.TT; 22/09535-3 - Hot and cold cognition in patients with depression: a RCT study comparing MST and ECT, BP.TT; 22/08423-7 - Treatment of COVID-19 post-acute cognitive impairment sequelae (PASC) with portable brain stimulation: a double-blind, randomized trial, BP.IC; 22/00654-0 - Computational modeling of electrical fields induced by transcranial electrical stimulation in the brains of depressed adolescents: comparison with depressed adults and practical implications, BP.IC; 22/06125-9 - Project Manager of RCT1: home-use tDCS plus internet behavioral therapy (iBT) in unipolar depression, BP.TT; 21/10827-6 - Evaluation of left dorsolateral prefrontal cortex volume as a predictor of clinical response to the use of theta-burst stimulation in the treatment of unipolar depression, BP.DR; 22/03266-0 - Investigation of neuroimaging assessments and current flow modeling as target engagement and predictor biomarkers of convulsive therapies, BP.PD; 22/01197-1 - Non-implantable Neuromodulation Therapies: A perspective for the depressed brain, BP.TT; 21/10574-0 - Prognostic enhancement in depressed patients on different non-implantable neuromodulation interventions, BP.PD; 21/09730-8 - Management of clinical trial data in the Precision Non-Implantable Neuromodulation project using REDcap, BP.TT; 21/05237-5 - Using machine-learning approaches in non-invasive brain stimulation trials to identify clusters of symptoms associated with clinical response, BP.IC; 21/04294-5 - Structural and functional neuroimaging predictor and state biomarkers in depression after non-invasive brain stimulation and ECT: systematic review and meta-analysis, BP.IC; 21/02845-4 - Project manager of RCT1: home-use tDCS plus internet behavioral therapy (iBT) in unipolar depression, BP.TT - associated scholarships

Abstract

Major Depressive Disorder (MDD) is a condition with high prevalence and morbidity worldwide. Treatments have limited efficacy and are curbed by adverse effects (Pharmacotherapy) or availability and costs (psychotherapy). Thus, developing novel interventions is tremendously relevant and can bring major gains in psychiatric care. Non-Implantable Neuromodulatory (NIN) approaches such as transcranial Direct Current Stimulation (tDCS) and Magnetic Seizure Therapy (MST) represent a third therapeutic principle, i.e. neuronal network modulation, which can benefit from making full use of the large body of data in MDD derived from neuroimaging and neurophysiology research. Moreover, the development of NIN addresses the need for innovative interventions in MDD. This project focuses on MDD at different stages of therapy-resistance and investigates tDCS and MST for gaining a deeper understanding of their mechanisms of action and developing both interventions towards a wider clinical application. Two Randomized Clinical Trials (RCTs) were designed to investigate the efficacy of state-of-the-art NIN techniques, which represent novel developments from previous NIN approaches that are only moderately effective or associated with cognitive side effects. RCT1 uses a 3-arm, double-blind design to compare the efficacy of 24 sessions (6 times per week in 3 weeks, then twice a week until week 6) home-use tDCS combined with internet-Based behavioral Therapy (iBT) modules versus tDCS-only and versus sham in 210 adult patients with unipolar depression. RCT2 uses a non-inferiority design to compare 8-16 sessions over 6 weeks of Magnetic Seizure Therapy (MST) versus ECT in treatment-resistant depressed, adult patients, considering both clinical efficacy and cognitive changes as co-primary outcomes. In addition, we will investigate cognition (module 1) and neuroimaging (module 2, only for RCT2) as putative clinical and biological endophenotypes that predict treatment response and change according to treatment. Predictors will be examined using statistical approaches and machine learning algorithms in the Prognostic Enhancement module (module 3). This thematic project will take place at two Institutions (University Hospital and Institute of Psychiatry at USP) with experience in trials using devices and includes an advisory board of international researchers from 12 universities in the US, Canada, UK, Australia, Germany, Switzerland, and Belgium that will leverage collaborations and dissemination of results. (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)

RAZZA, LAIS B.; DE SMET, STEFANIE; MOFFA, ADRIANO; SUDBRACK-OLIVEIRA, PEDRO; VANDERHASSELT, MARIE-ANNE; BRUNONI, ANDRE R.. Follow-up effects of transcranial direct current stimulation (tDCS) for the major depressive episode: A systematic review and meta-analysis. PSYCHIATRY RESEARCH, v. 302, AUG 2021. (19/06009-6, 19/10760-9, 19/07256-7, 18/10861-7)

ANTAL, ANDREA; LUBER, BRUCE; BREM, ANNA-KATHARINE; BIKSON, MAROM; BRUNONI, ANDRE R.; KADOSH, ROI COHEN; DUBLJEVIC, VELJKO; FECTEAU, SHIRLEY; FERRERI, FLORINDA; FLOEEL, AGNES; et al. Non-invasive brain stimulation and neuroenhancement. CLINICAL NEUROPHYSIOLOGY PRACTICE, v. 7, p. 20-pg., 2022-06-14. (19/06009-6, 18/21722-8)

BELLINI, HELENA; CRETAZ, ERIC; CARNEIRO, ADRIANA MUNHOZ; DA SILVA, PEDRO HENRIQUE RODRIGUES; DOS SANTOS, LEONARDO AFONSO; GALLUCCI-NETO, JOSE; BRUNONI, ANDRE RUSSOWSKY. Magnetic Waves vs. Electric Shocks: A Non-Inferiority Study of Magnetic Seizure Therapy and Electroconvulsive Therapy in Treatment-Resistant Depression. BIOMEDICINES, v. 11, n. 8, p. 17-pg., 2023-08-01. (19/06009-6)

VALIENGO, LEANDRO; MAIA, ANA; COTOVIO, GONCALO; GORDON, PEDRO C.; BRUNONI, ANDRE R.; FORLENZA, ORESTES, V; OLIVEIRA-MAIA, ALBINO J.. Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Older Adults: Systematic Review and Meta-analysis. JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, v. 77, n. 4, p. 10-pg., 2021-08-25. (19/06009-6, 14/50873-3, 18/10861-7, 16/01302-9)

CARNEIRO, ADRIANA MUNHOZ; DA SILVA, PEDRO HENRIQUE RODRIGUES; DA SILVA, VALQUIRIA APARECIDA; BRUNONI, ANDRE RUSSOWSKY. No relation between fMRI findings and thought distortion in mood disorder? A claim for new studies. FRONTIERS IN PSYCHIATRY, v. 16, p. 3-pg., 2025-03-07. (18/10861-7, 22/03266-0, 24/06902-0, 19/06009-6)

DIEGO FREITAS TAVARES; PAULO SUEN; DORIS HUPFELD MORENO; EDUARD VIETA; RICARDO ALBERTO MORENO; ANDRÉ R. BRUNONI. Distractibility, anxiety, irritability, and agitation symptoms are associated with the severity of depressive and manic symptoms in mixed depression. Revista Brasileira de Psiquiatria, 2022-09-30. (18/10861-7, 19/06009-6)

L.B. RAZZA; M.A. VANDERHASSELT; M.S. LUETHI; J. REPPLE; G. BUSATTO; C.A. BUCHPIGUEL; A.R. BRUNONI; P.H.R. DA SILVA. Cortical thickness is related to working memory performance after non-invasive brain stimulation. Brazilian Journal of Medical and Biological Research, v. 56, 2023-10-20. (21/10574-0, 19/07256-7, 18/10861-7, 22/03266-0, 19/06009-6)

LAIS B. RAZZA; MILES WISCHNEWSKI; PAULO SUEN; STEFANIE DE SMET; PEDRO HENRIQUE RODRIGUES DA SILVA; BEATRIZ CATOIRA; ANDRÉ R. BRUNONI; MARIE-ANNE VANDERHASSELT. An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS). Revista Brasileira de Psiquiatria, v. 45, n. 6, p. 518-529, 2024-02-12. (19/06009-6, 18/10861-7, 22/03266-0)

ECHEVARRIA, M. A. N.; BATISTUZZO, M. C.; SILVA, R. M. F.; BRUNONI, A. R.; SATO, J. R.; MIGUEL, E. C.; HOEXTER, M. Q.; SHAVITT, R. G.. Increases in functional connectivity between the default mode network and sensorimotor network correlate with symptomatic improvement after transcranial direct current stimulation for obsessive-compulsive disorder. Journal of Affective Disorders, v. 355, p. 9-pg., 2024-04-01. (19/06009-6, 21/05332-8, 14/50917-0, 18/04654-9, 18/21934-5, 19/27250-3, 12/20911-5)

DA SILVA, PEDRO HENRIQUE RODRIGUES; LEFFA, DOUGLAS T.; LUETHI, MATTHIAS S.; SILVA, ROBERTA F.; FERRAZZA, CAROLINA PRIETTO; PICON, FELIPE ALMEIDA; GREVET, EUGENIO HORACIO; BAU, CLAITON HENRIQUE DOTTO; ROVARIS, DIEGO LUIZ; RAZZA, LAIS B.; et al. Baseline brain volume predicts home-based transcranial direct current stimulation effects on inattention in adults with attention-deficit/ hyperactivity disorder. JOURNAL OF PSYCHIATRIC RESEARCH, v. 177, p. 9-pg., 2024-07-31. (21/10574-0, 19/06009-6, 22/03266-0, 18/10861-7)

BORRIONE, LUCAS; KLEIN, IZIO; RAZZA, LAIS B.; SUEN, PAULO; BRUNONI, ANDRE R.. Use of app-based psychological interventions in combination with home-use transcranial direct current stimulation for the treatment of major depressive disorder: A case series. Journal of Affective Disorders, v. 288, p. 189-190, JUN 1 2021. (18/10861-7, 19/06009-6)

ROSSON, STELLA; DE FILIPPIS, RENATO; CROATTO, GIOVANNI; COLLANTONI, ENRICO; PALLOTTINO, SIMONE; GUINART, DANIEL; BRUNONI, ANDRE R.; DELL'OSSO, BERNARDO; PIGATO, GIORGIO; HYDE, JOSHUA; et al. Brain stimulation and other biological non-pharmacological interventions in mental disorders: An umbrella review. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 139, p. 18-pg., 2022-06-27. (19/06009-6, 18/10861-7)

TAVARES, DIEGO FREITAS; SUEN, PAULO; MORENO, DORIS HUPFELD; VIETA, EDUARD; MORENO, RICARDO ALBERTO; BRUNONI, ANDRE R.. Distractibility, anxiety, irritability, and agitation symptoms are associated with the severity of depressive and manic symptoms in mixed depression. Revista Brasileira de Psiquiatria, v. 44, n. 6, p. 8-pg., 2022-11-01. (17/19237-1, 18/10861-7, 19/06009-6)

RAZZA, LAIS B.; LUETHI, MATTHIAS S.; ZANAO, TAMIRES; DE SMET, STEFANIE; BUCHPIGUEL, CARLOS; BUSATTO, GERALDO; PEREIRA, JULIANA; KLEIN, IZIO; KAPPEN, MITCHEL; MORENO, MARINA; et al. Transcranial direct current stimulation versus intermittent theta-burst stimulation for the improvement of working memory performance. INTERNATIONAL JOURNAL OF CLINICAL AND HEALTH PSYCHOLOGY, v. 23, n. 1, p. 8-pg., 2022-09-12. (18/10861-7, 19/07256-7, 19/06009-6)

CAVENAGHI, VITOR BRESEGHELLO; CARNEIRO, ADRIANA M.; CRETAZ, ERIC; CABRAL, BIANCA; CARDOSO, CAROLINE BENIGNO; BRUNONI, ANDRE RUSSOWSKY. Magnetic seizure therapy for unipolar and bipolar depression: An up to date systematic review. WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, v. 26, n. 1, p. 11-pg., 2024-12-18. (19/06009-6, 24/06902-0)

BERTO, LAURA F.; SUEMOTO, CLAUDIA K.; MORENO, ARLINDA B.; FONSECA, MARIA DE JESUS M.; NUNES, MARIA ANGELICA A.; MOLINA, MARIA DEL CARMEN B.; BARRETO, SANDHI M.; DINIZ, MARIA DE FATIMA HAUEISEN SANDER; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; et al. Increased Prevalence of Depression and Anxiety Among Subjects With Metabolic Syndrome in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). JOURNAL OF THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY, v. 63, n. 6, p. 10-pg., 2022-12-14. (20/06887-0, 19/06009-6, 18/10861-7)

WU, MING-KUNG; SATOGAMI, KAZUMI; LIANG, CHIH-SUNG; STUBBS, BRENDON; CARVALHO, ANDRE F.; BRUNONI, ANDRE R.; SU, KUAN-PIN; TU, YU-KANG; WU, YI-CHENG; CHEN, TIEN-YU; et al. Multiple comparison of different noninvasive brain stimulation and pharmacologic interventions in patients with methamphetamine use disorders: A network meta-analysis of randomized controlled trials. PSYCHIATRY AND CLINICAL NEUROSCIENCES, v. 76, n. 12, p. 11-pg., 2022-10-08. (19/06009-6, 18/10861-7)

ELTON DINIZ; LAIS FONSECA; DEYVIS ROCHA; ALISSON TREVIZOL; RAPHAEL CERQUEIRA; BRUNO ORTIZ; ANDRÉ R. BRUNONI; RODRIGO BRESSAN; CHRISTOPH U. CORRELL; ARY GADELHA. Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates. Revista Brasileira de Psiquiatria, v. 45, n. 5, p. 448-458, 2023-11-27. (19/06009-6, 18/10861-7, 11/50740-5)