Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial

Fanny Thomas, Noomane Bouaziz, Cécile Gallea, Palmyre Schenin-King Andrianisaina, Florence Durand, Ombline Bolloré, René Benadhira, Clémence Isaac, Sonia Braha-Zeitoun, Virginie Moulier, Antoni Valero-Cabré, Dominique Januel, Fanny Thomas, Noomane Bouaziz, Cécile Gallea, Palmyre Schenin-King Andrianisaina, Florence Durand, Ombline Bolloré, René Benadhira, Clémence Isaac, Sonia Braha-Zeitoun, Virginie Moulier, Antoni Valero-Cabré, Dominique Januel

Abstract

Background: The potential of non-invasive repetitive transcranial magnetic stimulation (rTMS) to improve auditory verbal hallucinations (AVH) in schizophrenia patients has been increasingly explored over the past decade. Despite highly promising results, high inter-individual variability of clinical response and ineffective outcomes in a significant number of patients underscored the need to identify factors associated with the clinical response to rTMS. It should help improve the efficacy of rTMS in patients with medication-resistant AVH, and allow a better understanding of its neural impact. Here, we describe an exploratory study protocol which aims to identify structural and functional brain biomarkers associated with clinical response after an rTMS treatment for medication-resistant AVH in schizophrenia.

Methods: Forty-five schizophrenia patients with medication-resistant AVH will be enrolled in a double-blind randomized sham-controlled monocentric clinical trial. Patients will be assigned to a regime of 20 sessions of active or sham 1 Hz rTMS delivered twice a day, 5 days a week for 2 weeks over the left temporo-parietal junction. Response will be assessed after rTMS and patients will be classified in responders or non-responders to treatment. Magnetic resonance imaging (MRI) sessions including diffusion weighted imaging and resting-state functional MRI sequences will be recorded before the onset of the rTMS treatment and 3 days following its discontinuation. The primary outcome measure is difference in fractional anisotropy between responder and non-responder patients at baseline. Differences in resting-state functional MRI data at baseline will be also investigated between responder and non-responder groups. Clinical, neuropsychological, neurophysiological, and blood serum BDNF assessments will be performed at baseline, 3 days, 1 month, and 3 months following rTMS.

Discussion: The aim of this research project is to identify and assess the biomarker value of MRI-based structural and functional biomarkers predicting clinical response to rTMS for AVH in schizophrenia patients. The outcome of the trial should improve patient care by offering them a novel suitable therapy and deepen our understanding on how rTMS may impact AVH and develop more effective therapies adapted to individual patient needs.

Trial registration: ClinicalTrials.gov, NCT02755623 . Registered on 22 April 2016.

Keywords: Schizophrenia; auditory verbal hallucinations; clinical response; clinical trial; functional connectivity; non-invasive brain stimulation; predictive biomarkers; repetitive transcranial magnetic stimulation; structural connectivity.

Conflict of interest statement

Ethics approval and consent to participate

The protocol was approved by the CPP Ile-de-France III ethics committee (reference: ID RCB N°2014-A01595–420) and is in accordance with the Declaration of Helsinki and French legislation (article L1121–1 and R1121–1 of the Public Health Code). All participants gave written informed consent, which were gathered by the main investigator. This study is registered on ClinicalTrials.gov (NCT02755623).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow chart of the study design
Fig. 2
Fig. 2
Description of the enrolment, treatment, and assessments during the study protocol AHRS Auditory Hallucinations Rating Scale, BDI Beck Depression Inventory, BDNF brain-derived neurotrophic factor, HCS Hallucination Change Score, MRI magnetic resonance imaging, PANSS Positive And Negative Syndrome Scale, MEP motor-evoked potentials, PSYRATS Psychotic Symptom Rating Scale, rTMS repetitive transcranial magnetic stimulation, t time point, W week.
Fig. 3
Fig. 3
TMS-targeted region and coil placement. The left TPJ will be targeted using established spatial coordinates for the Wernicke’s area in the left TPJ (Montreal Neurological Institute (MNI) coordinates: x = − 69, y = − 41, z = 11; Hoffman et al. [25]). Axial (a), coronal (b), and sagittal (c) MRI views of the location for the TMS targeted left TPJ are shown in this figure. This brain area will be labeled on a 3D rendering of the patient’s individual T1 MRI sequence on each patient. The TMS coil will be positioned tangential to the scalp location overlying the left TPJ using an MRI-based frameless stereotactic neuronavigation system (d and e)

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