Circuit-Guided Neuromodulation for Anorexia Nervosa (RestrEAT)
Re-tuning Restrictive Eating Circuits: From Lesion Network Mapping to Personalized Neuromodulation Targets
The goal of this clinical trial is to find out whether personalized, non-invasive brain stimulation can temporarily change communication within brain networks related to restrictive eating in adults with anorexia nervosa.
The main questions this study aims to answer are:
- Does personalized transcranial magnetic stimulation (TMS) change functional connectivity within a brain network related to restrictive eating compared with sham stimulation?
- Do different types of TMS affect measures related to inhibitory control, body image, eating-disorder symptoms, mood, and anxiety, and are they safe and well tolerated?
Participants will:
- Attend four study visits, separated by at least one week.
- Complete clinical and psychological assessments and undergo brain magnetic resonance imaging (MRI).
- Receive three stimulation conditions in random order at separate visits: intermittent theta-burst stimulation (iTBS), continuous theta-burst stimulation (cTBS), and sham stimulation.
- Complete brain MRI scans and research tasks so that the effects of the three stimulation conditions can be compared.
Researchers will compare the effects of iTBS and cTBS with sham stimulation on brain connectivity and other study measures.
This is an exploratory proof-of-concept study designed to test whether personalized brain stimulation can engage the targeted brain circuit. It is not designed to determine whether TMS is an effective treatment for anorexia nervosa, and direct clinical benefit to participants is not expected.
Přehled studie
Postavení
Podmínky
Detailní popis
RestrEAT is a mechanistic, proof-of-concept investigation designed to evaluate a personalized, circuit-guided targeting strategy for prefrontal theta-burst stimulation (TBS) in anorexia nervosa.
The targeting framework is based on a lesion-defined restrictive-eating network derived from brain lesions associated with restrictive eating and anorexia-nervosa-like psychopathology. For each participant, individualized electric-field modelling using SimNIBS is combined with functional connectivity derived from the participant's baseline fMRI data. Candidate TMS-accessible prefrontal sites are evaluated, and the stimulation site is selected according to the similarity between its individual functional connectivity profile and the lesion-defined network. The individualized target is subsequently implemented using neuronavigation.
The study is intended to generate mechanistic target-engagement data rather than establish the therapeutic efficacy of TMS for anorexia nervosa. The within-subject crossover design was selected because the effects of a single TBS session are expected to be acute and transient, allowing comparison of stimulation conditions within the same participant while reducing variability related to inter-individual differences in functional connectivity and cognitive performance.
The results are intended to evaluate the feasibility and biological validity of the personalized targeting approach, characterize effect-size estimates, and inform the design of a subsequent adequately powered therapeutic clinical trial if supported by the findings.
Typ studie
Zápis (Odhadovaný)
Fáze
- Nelze použít
Kontakty a umístění
Studijní kontakt
- Jméno: Gonçalo Cotovio, MD, PhD
- Telefonní číslo: +351 210 480 200
- E-mail: goncalo.cotovio@neuro.fchampalimaud.org
Studijní místa
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Lisbon District
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Lisbon, Lisbon District, Portugalsko, 1400-038
- Champalimaud Foundation
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Vrchní vyšetřovatel:
- Albino J. Oliveira-Maia, MD, MPH, PhD
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Vrchní vyšetřovatel:
- Gonçalo Cotovio, MD, PhD
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Kontakt:
- Gonçalo Cotovio, MD, PhD
- Telefonní číslo: +351 210 480 200
- E-mail: goncalo.cotovio@neuro.fchampalimaud.org
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
Inclusion Criteria:
- Age between 18 and 65 years, inclusive.
- Established diagnosis of anorexia nervosa according to DSM-5 criteria, confirmed by the Structured Clinical Interview for DSM-5 (SCID-5) at Visit 1.
- Capacity to provide written informed consent, as assessed by the investigator at Visit 1.
- Fluency in European Portuguese sufficient to complete the study assessments.
Exclusion Criteria:
- Current manic or psychotic episode.
- Major or minor neurocognitive disorder.
- Neurodevelopmental disorder, including attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD).
- Any medical or psychiatric condition requiring immediate hospitalization at the time of enrollment. Psychiatry day hospital care does not constitute an exclusion criterion.
- History of a structural lesion of the central nervous system.
- Presence of electrical or metallic implants incompatible with TMS or MRI, including cochlear implants, deep brain stimulators, vagus nerve stimulators, cardiac pacemakers, implantable cardioverter-defibrillators, intracardiac lines, or aneurysm clips or coils, in accordance with the manufacturer's contraindications.
- Personal history of epilepsy or unexplained loss of consciousness.
- Any contraindication to TMS or MRI.
- Pregnancy or breastfeeding at the time of enrollment.
- For participants of childbearing potential, lack of use of an effective method of contraception throughout the study period.
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Základní věda
- Přidělení: Randomizované
- Intervenční model: Crossover Assignment
- Maskování: Dvojnásobek
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
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Experimentální: Intermittent Theta-Burst Stimulation (iTBS)
Participants receive one session of personalized prefrontal intermittent theta-burst stimulation (iTBS) during one of the three randomized crossover stimulation visits. Each participant receives this condition once, with a washout interval of at least one week between stimulation visits. |
A single session of neuronavigated intermittent theta-burst stimulation (iTBS) is delivered using a MagVenture MagPro X100 with MagOption and the appropriate active coil (Cool-B65 or Cool-D-B80) selected according to the individualized target. Stimulation is delivered at 80% of the individual resting motor threshold (RMT) to a personalized prefrontal site defined using lesion network mapping and SimNIBS. Bursts are delivered at 5 Hz, with 3 pulses at 50 Hz per burst, in an intermittent pattern of 2 seconds ON and 8 seconds OFF, for a total of 600 pulses over approximately 190 seconds. |
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Experimentální: Continuous Theta-Burst Stimulation (cTBS)
Participants receive one session of personalized prefrontal continuous theta-burst stimulation (cTBS) during one of the three randomized crossover stimulation visits. Each participant receives this condition once, with a washout interval of at least one week between stimulation visits. |
A single session of neuronavigated continuous theta-burst stimulation (cTBS) is delivered using a MagVenture MagPro X100 with MagOption and the appropriate active coil (Cool-B65 or Cool-D-B80) selected according to the individualized target. Stimulation is delivered at 80% of the individual resting motor threshold (RMT) to a personalized prefrontal site defined using lesion network mapping and SimNIBS. Bursts are delivered at 5 Hz, with 3 pulses at 50 Hz per burst, continuously without interruption, for a total of 600 pulses over approximately 40 seconds. |
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Falešný srovnávač: Sham Theta-Burst Stimulation
Participants receive one session of sham theta-burst stimulation during one of the three randomized crossover stimulation visits. Each participant receives this condition once, with a washout interval of at least one week between stimulation visits. |
A single session of sham theta-burst stimulation is delivered using the MagVenture MagPro X100 with MagOption and a shielded sham coil at the individualized prefrontal target. Coil positioning, neuronavigation display, and auditory and somatosensory characteristics are matched as closely as possible to the active conditions. The programmed sham protocol uses 5-Hz bursts with 3 pulses at 50 Hz per burst, an intermittent pattern of 5 seconds ON and 10 seconds OFF, 600 pulses, a session duration of 110 seconds, and an intensity setting of 80% of the individual RMT. |
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
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Post-Stimulation Target-to-Network Resting-State fMRI Functional Connectivity
Časové okno: Within approximately 30 minutes after each stimulation session at crossover Visits 2, 3, and 4 (Weeks 2, 4, and 6; visits separated by at least 1 week)
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Resting-state fMRI functional connectivity between the individualized prefrontal stimulation target and the lesion-defined restrictive-eating network, quantified using the target-to-network connectivity index. The measure is assessed after each iTBS, cTBS, and sham session and compared within participants across the three stimulation conditions. |
Within approximately 30 minutes after each stimulation session at crossover Visits 2, 3, and 4 (Weeks 2, 4, and 6; visits separated by at least 1 week)
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Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
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GNAT Inhibitory-Control Performance (d-prime) After Stimulation
Časové okno: During post-stimulation task-based fMRI at crossover Visits 2, 3, and 4, within approximately 30 minutes after stimulation
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Inhibitory-control performance assessed using the Go/No-Go Association Task (GNAT) with food and non-food stimuli. The pre-specified outcome metric is d-prime, assessed following each stimulation condition and compared within participants across iTBS, cTBS, and sham. |
During post-stimulation task-based fMRI at crossover Visits 2, 3, and 4, within approximately 30 minutes after stimulation
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Body Discrepancy Index After Stimulation
Časové okno: During post-stimulation task-based fMRI at crossover Visits 2, 3, and 4, within approximately 30 minutes after stimulation
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Body-image evaluation assessed using a 7-silhouette body-image task adapted for scanner administration. The primary metric is the body discrepancy index, based on the difference between perceived and ideal body silhouettes, and is compared within participants across iTBS, cTBS, and sham conditions. |
During post-stimulation task-based fMRI at crossover Visits 2, 3, and 4, within approximately 30 minutes after stimulation
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Post-Stimulation Task-Based fMRI BOLD Signal in the Lesion-Defined Network
Časové okno: During post-stimulation task-based fMRI at crossover Visits 2, 3, and 4, within approximately 30 minutes after stimulation
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Blood-oxygen-level-dependent (BOLD) signal measured in pre-specified regions of interest within the lesion-defined restrictive-eating network during the GNAT and body-image task paradigms. BOLD responses are compared within participants across iTBS, cTBS, and sham conditions. |
During post-stimulation task-based fMRI at crossover Visits 2, 3, and 4, within approximately 30 minutes after stimulation
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Eating Disorder Psychopathology Assessed With the EDE-Q
Časové okno: Pre-stimulation at crossover Visits 2, 3, and 4 (approximately Weeks 2, 4, and 6; visits separated by at least 1 week)
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Eating-disorder psychopathology assessed using the Eating Disorder Examination Questionnaire (EDE-Q), version 6.0. The pre-specified metric is the EDE-Q total score. Higher scores indicate greater eating-disorder psychopathology. The EDE-Q is administered before stimulation at each crossover visit. |
Pre-stimulation at crossover Visits 2, 3, and 4 (approximately Weeks 2, 4, and 6; visits separated by at least 1 week)
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Další výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
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Incidence and Nature of Adverse Events and Device-Related Safety Events
Časové okno: From enrollment at Visit 1 through completion of Visit 4 (approximately 4-7 weeks per participant)
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Incidence and nature of adverse events (AEs), serious adverse events (SAEs), serious adverse device effects (SADEs), and device deficiencies. Pre-specified TMS-specific safety events include seizure, syncope, severe headache, and severe mood change. Events will be summarized descriptively by stimulation condition. |
From enrollment at Visit 1 through completion of Visit 4 (approximately 4-7 weeks per participant)
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Spolupracovníci a vyšetřovatelé
Sponzor
Vyšetřovatelé
- Vrchní vyšetřovatel: Gonçalo Cotovio, MD, PhD, Champalimaud Foundation
- Ředitel studie: Albino J. Oliveira-Maia, MD, MPH, PhD, Champalimaud Foundation
Publikace a užitečné odkazy
Obecné publikace
- Weigand A, Horn A, Caballero R, Cooke D, Stern AP, Taylor SF, Press D, Pascual-Leone A, Fox MD. Prospective Validation That Subgenual Connectivity Predicts Antidepressant Efficacy of Transcranial Magnetic Stimulation Sites. Biol Psychiatry. 2018 Jul 1;84(1):28-37. doi: 10.1016/j.biopsych.2017.10.028. Epub 2017 Nov 10.
- Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry. 2011 Jul;68(7):724-31. doi: 10.1001/archgenpsychiatry.2011.74.
- Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.
- Seybert C, Cotovio G, Rodrigues da Silva D, Faro Viana F, Pereira P, Oliveira-Maia AJ. Replicability of motor cortex-excitability modulation by intermittent theta burst stimulation. Clin Neurophysiol. 2023 Aug;152:22-33. doi: 10.1016/j.clinph.2023.04.014. Epub 2023 May 18.
- Siddiqi SH, Schaper FLWVJ, Horn A, Hsu J, Padmanabhan JL, Brodtmann A, Cash RFH, Corbetta M, Choi KS, Dougherty DD, Egorova N, Fitzgerald PB, George MS, Gozzi SA, Irmen F, Kuhn AA, Johnson KA, Naidech AM, Pascual-Leone A, Phan TG, Rouhl RPW, Taylor SF, Voss JL, Zalesky A, Grafman JH, Mayberg HS, Fox MD. Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease. Nat Hum Behav. 2021 Dec;5(12):1707-1716. doi: 10.1038/s41562-021-01161-1. Epub 2021 Jul 8.
- Dalton B, Maloney E, Rennalls SJ, Bartholdy S, Kekic M, McClelland J, Campbell IC, Schmidt U, O'Daly OG. A pilot study exploring the effect of repetitive transcranial magnetic stimulation (rTMS) treatment on cerebral blood flow and its relation to clinical outcomes in severe enduring anorexia nervosa. J Eat Disord. 2021 Jul 9;9(1):84. doi: 10.1186/s40337-021-00420-w.
- Treasure J, Zipfel S, Micali N, Wade T, Stice E, Claudino A, Schmidt U, Frank GK, Bulik CM, Wentz E. Anorexia nervosa. Nat Rev Dis Primers. 2015 Nov 26;1:15074. doi: 10.1038/nrdp.2015.74.
- Cotovio G, Ventura F, Rodrigues da Silva D, Pereira P, Oliveira-Maia AJ. Regulatory Clearance and Approval of Therapeutic Protocols of Transcranial Magnetic Stimulation for Psychiatric Disorders. Brain Sci. 2023 Jul 5;13(7):1029. doi: 10.3390/brainsci13071029.
- Cotovio G, Oliveira-Maia AJ. Functional neuroanatomy of mania. Transl Psychiatry. 2022 Jan 24;12(1):29. doi: 10.1038/s41398-022-01786-4.
- Cotovio G, Seybert C, Rodrigues da Silva D, Faro Viana F, Estrela JP, Pereira P, Oliveira-Maia AJ. Conventional Repetitive Transcranial Magnetic Stimulation for Depression: A Step-by-Step Protocol. J Vis Exp. 2025 Nov 21;(225). doi: 10.3791/68891.
- Soeby M, Gribsholt SB, Clausen L, Richelsen B. Overall and cause-specific mortality in anorexia nervosa; impact of psychiatric comorbidity and sex in a 40-year follow-up study. Int J Eat Disord. 2024 Sep;57(9):1842-1853. doi: 10.1002/eat.24223. Epub 2024 Jun 12.
- Wonderlich SA, Bulik CM, Schmidt U, Steiger H, Hoek HW. Severe and enduring anorexia nervosa: Update and observations about the current clinical reality. Int J Eat Disord. 2020 Aug;53(8):1303-1312. doi: 10.1002/eat.23283. Epub 2020 May 2.
- Zipfel S, Giel KE, Bulik CM, Hay P, Schmidt U. Anorexia nervosa: aetiology, assessment, and treatment. Lancet Psychiatry. 2015 Dec;2(12):1099-111. doi: 10.1016/S2215-0366(15)00356-9. Epub 2015 Oct 27.
- Lakritz C, Iceta S, Duriez P, Makdassi M, Masetti V, Davidenko O, Lafraire J. Measuring implicit associations between food and body stimuli in anorexia nervosa: a Go/No-Go Association Task. Eat Weight Disord. 2023 Nov 2;28(1):93. doi: 10.1007/s40519-023-01621-9.
- Wu K, Lo YT, Cavaleri J, Bergosh M, Ipe J, Briggs RG, Jann KB, Murray SB, Mason XL, Liu CY, Lee DJ. Neuromodulation of Eating Disorders: A Review of Underlying Neural Network Activity and Neuromodulatory Treatments. Brain Sci. 2024 Feb 22;14(3):200. doi: 10.3390/brainsci14030200.
- Longo P, Bevione F, Lacidogna MC, Lavalle R, Abbate Daga G, Preti A. Neuromodulatory techniques in eating disorders: From electroconvulsive therapy to transcranial magnetic stimulation and beyond: A mixed method systematic meta-review. Psychiatry Res. 2025 Feb;344:116346. doi: 10.1016/j.psychres.2024.116346. Epub 2024 Dec 27.
- Takahashi S, Ikeda S, Ueda M, Harada T, Ishii R. rTMS Therapy for Eating Disorders: Scoping Review on Efficacy, Safety, Stimulation Parameters and Study Subjects. Eur Eat Disord Rev. 2026 Mar;34(2):464-475. doi: 10.1002/erv.70046. Epub 2025 Oct 29.
- Bartholdy S, McClelland J, Kekic M, O'Daly OG, Campbell IC, Werthmann J, Rennalls SJ, Rubia K, David AS, Glennon D, Kern N, Schmidt U. Clinical outcomes and neural correlates of 20 sessions of repetitive transcranial magnetic stimulation in severe and enduring anorexia nervosa (the TIARA study): study protocol for a randomised controlled feasibility trial. Trials. 2015 Dec 3;16:548. doi: 10.1186/s13063-015-1069-3.
- McClelland J, Kekic M, Bozhilova N, Nestler S, Dew T, Van den Eynde F, David AS, Rubia K, Campbell IC, Schmidt U. A Randomised Controlled Trial of Neuronavigated Repetitive Transcranial Magnetic Stimulation (rTMS) in Anorexia Nervosa. PLoS One. 2016 Mar 23;11(3):e0148606. doi: 10.1371/journal.pone.0148606. eCollection 2016.
- Bahadori AR, Javadnia P, Bordbar S, Zafari R, Taherkhani T, Davari A, Tafakhori A, Shafiee S, Ranji S. Efficacy of transcranial magnetic stimulation in anorexia nervosa: a systematic review and meta-analysis. Eat Weight Disord. 2025 Jan 15;30(1):4. doi: 10.1007/s40519-025-01716-5.
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Odhadovaný)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
Další identifikační čísla studie
- RestrEAT
- 723209 (Identifikátor registru: Registo Nacional de Estudos Clínicos (RNEC), Portugal)
- 2626CI_RESTREAT (Jiný identifikátor: INFARMED - Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.)
Plán pro data jednotlivých účastníků (IPD)
Plánujete sdílet data jednotlivých účastníků (IPD)?
Popis plánu IPD
There is currently no plan to make individual participant data (IPD) or associated data dictionaries available to external researchers. Any future data-sharing proposal would be considered on a case-by-case basis and would require appropriate authorization by the Sponsor and Data Protection Officer and compliance with applicable data-protection requirements.
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Studuje lékový produkt regulovaný americkým FDA
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