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

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. Electronic supplementary material The online version of this article (10.1186/s13063-019-3311-x) contains supplementary material, which is available to authorized users.

Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

“…Using Bayesian model selection, we determined which model (i.e., symptoms metric) better explains the between-subjects variability in connections. Given the anecdotal evidence as discussed above, we expected the severity of positive symptoms, rather than negative symptoms, to relate to the frontostriatal effective connectivity [ 47 ]. In addition, given that only a subset of patients is likely to experience exacerbated positive symptoms, we aim to identify the connectivity pattern that can predict this adverse outcome of prefrontal HF-rTMS in schizophrenia.…”

Transdiagnostic Symptom Subtypes to Predict Response to Therapeutic Transcranial Magnetic Stimulation in Major Depressive Disorder and Posttraumatic Stress Disorder

“…In addition to clarifying the underlying mechanisms of TMS, such markers would optimize TMS use and predict tailored treatments, resulting in a more efficient time and economic profile. In this context, studies based on neurophysiological and functional neuroimaging methods have examined and identified several TMS response biomarkers [36][37][38]. Nevertheless, these approaches are primarily high cost, technically complex, and time consuming, limiting their feasibility in the clinical setting.…”

Omówienie wybranych metod współczesnej terapii schizofrenii

“…Pole magnetyczne oddziałuje na istotę szarą mózgowia, indukując w niej przepływ prądu i doprowadzając do depolaryzacji błony komórkowej neuronów [104] oraz wytwarzania potencjałów czynnościowych [105]. Gdy impulsy są powtarzane, zmniejszają lub zwiększają pobudliwość kory (zależnie od parametrów stymulacji), co stanowi potencjał terapeutyczny tej metody [106].…”

“…Kilka metaanaliz potwierdza znaczące zmniejszenie nasilenia halucynacji słuchowo-werbalnych (AVH, auditory verbal hallucinations) w schizofrenii po wielodniowych seriach rTMS o częstotliwości 1 Hz. Wzbudza to nadzieje na wykorzystanie rTMS w tym wskazaniu [106]. Wyniki badań rTMS w leczeniu objawów negatywnych schizofrenii okazują się obiecujące.…”

“…Wyniki badań rTMS w leczeniu objawów negatywnych schizofrenii okazują się obiecujące. Serie (10 Hz, 15-20 sesji) stosowane na lewą stronę [grzbietowo-boczna kora przedczołowa (dlPFC, dorsolateral prefrontal cortex)] powodują zmniejszenie nasilenia symptomów negatywnych ocenianych skalą samooceny objawów negatywnych (SANS, Scale for Assessment of Negative Symptoms) [113,114] oraz PANSS [106,115].…”