Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial

Abstract

Objective: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials.

Methods: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1).

Results: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm.

Conclusion: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.

Keywords: Cerebellar vermis; Negative symptoms; Randomized controlled trial; Resting state functional connectivity; Schizophrenia; Transcranial magnetic stimulation.

Copyright © 2021 Elsevier B.V. All rights reserved.

Figures

Fig. 1.

CONSORT flow diagram. Legend: Consolidated Standards for Reporting Trials (CONSORT) flow diagram depicting the recruitment of participants into the trial from screening to inclusion of data in the final statistical analysis. ITT = Intention to treat; iTBS = intermittent theta burst stimulation.

Fig. 2.

Comparison of change in negative symptom severity between the 2 groups. Legend: A: Scatter+Box+Violin plots showing the change in severity of negative symptoms across time-points in the 2 groups with no significant difference (Group * Time interaction effect, p = 0.602). The notch of the inset boxplot corresponds to the median, the red dot represents the mean, the whiskers show the first and the third quartiles and the points represent the individual scores. B & C: Percentage of change in severity of negative symptoms of individual participants belonging to the two groups. SANS=Scale for the Assessment of Negative Symptoms, iTBS = intermittent theta burst stimulation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Percentage of change=Baseline SANS−Day−6/Week−6SANSBaseline SANS*100

Fig. 3.

Change in resting state functional connectivity in real iTBS arm. Legend: Sagittal, coronal, and axial (from left to right in each panel) sections of the brain demonstrating increased resting state functional connectivity between cerebellar seed, vermal area VIIB and A. Right inferior frontal gyrus (pcluster-FWER = 0.033), B. right pallidum (pcluster-FWER = 0.042) and C. right frontal pole (pcluster-FWER = 0.047) from baseline to post-intervention in the real iTBS arm. iTBS = intermittent theta burst stimulation, pcluster-FWER = threshold-free cluster enhancement and a family-wise error rate (FWER) corrected cluster significance.