Transcranial Magnetic Stimulation of the Default Mode Network to Improve Sleep in Individuals With Insomnia Symptoms: Protocol for a Double-Blind Randomized Controlled Trial

Abstract

Background: Cortical hyperarousal and ruminative thinking are common aspects of insomnia that have been linked with greater connectivity in the default mode network (DMN). Therefore, disrupting network activity within the DMN may reduce cortical and cognitive hyperarousal and facilitate better sleep.

Objective: This trial aims to establish a novel, noninvasive method for treating insomnia through disruption of the DMN with repetitive transcranial magnetic stimulation, specifically with continuous theta burst stimulation (cTBS). This double-blind, pilot randomized controlled trial will assess the efficacy of repetitive transcranial magnetic stimulation as a novel, nonpharmacological approach to improve sleep through disruption of the DMN prior to sleep onset for individuals with insomnia. Primary outcome measures will include assessing changes in DMN functional connectivity before and after stimulation.

Methods: A total of 20 participants between the ages of 18 to 50 years with reported sleep disturbances will be recruited as a part of the study. Participants will then conduct an in-person screening and follow-on enrollment visit. Eligible participants then conduct at-home actigraphic collection until their first in-residence overnight study visit. In a double-blind, counterbalanced, crossover study design, participants will receive a 40-second stimulation to the left inferior parietal lobule of the DMN during 2 separate overnight in-residence visits. Participants are randomized to the order in which they receive the active stimulation and sham stimulation. Study participants will undergo a prestimulation functional magnetic resonance imaging scan and a poststimulation functional magnetic resonance imaging scan prior to sleep for each overnight study visit. Sleep outcomes will be measured using clinical polysomnography. After their first in-residence study visit, participants conduct another at-home actigraphic collection before returning for their second in-residence overnight study visit.

Results: Our study was funded in September 2020 by the Department of Defense (W81XWH2010173). We completed the enrollment of our target study population in the October 2022 and are currently working on neuroimaging processing and analysis. We aim to publish the results of our study by 2024. Primary neuroimaging outcome measures will be tested using independent components analysis, seed-to-voxel analyses, and region of interest to region of interest analyses. A repeated measures analysis of covariance (ANCOVA) will be used to assess the effects of active and sham stimulation on sleep variables. Additionally, we will correlate changes in functional connectivity to polysomnography-graded sleep.

Conclusions: The presently proposed cTBS protocol is aimed at establishing the initial research outcomes of the effects of a single burst of cTBS on disrupting the network connectivity of the DMN to improve sleep. If effective, future work could determine the most effective stimulation sites and administration schedules to optimize this potential intervention for sleep problems.

Trial registration: ClinicalTrials.gov NCT04953559; https://clinicaltrials.gov/ct2/show/NCT04953559.

International registered report identifier (irrid): DERR1-10.2196/51212.

Keywords: cTBS; continuous theta burst stimulation; default mode network; insomnia; randomized controlled trial; sleep; transcranial magnetic stimulation.

Figure 1

Overview of the pilot randomized controlled trial study design. Participants first complete a web-based eligibility survey screening for sleep disturbances. Potentially eligible volunteers complete an in-lab enrollment process and baseline assessment (visit 1) at a large Southwestern University medical research center. Participants are then randomized to a stimulation order condition. After at least 5 days with actigraphically measured sleep, participants return for an 18-hour overnight session involving 2 MRI scans and overnight sleep (visit 2) at the medical research center. Depending on their condition assignment order, they either receive active cTBS or sham intervention. Participants then undergo a washout period of at least 5 days that includes actigraphically measured sleep. They then return for an identical overnight visit that involves the alternate intervention condition. cTBS: continuous theta burst stimulation; MRI: magnetic resonance imaging.

Figure 2

Timeline of the in-residence laboratory testing for the pilot randomized controlled trial. Participants arrive at the lab at 1500 and undergo cognitive testing followed by a preintervention MRI scan. The intervention is administered between 1900 and 2000 and is randomly assigned as either active cTBS stimulation or an identical appearing sham condition. After stimulation, participants complete a postintervention series of MRI scans, followed by a brief cognitive testing battery. At 2200, they are escorted to the sleep lab and PSG electrodes are applied. Lights out occur at 2300 and the participant is provided with an 8-hour undisturbed period for PSG-monitored sleep. Following wake-up at 0700 the next morning, the participant is provided a light breakfast and completes a final battery of cognitive tests. This procedure is repeated on separate weeks for the active cTBS and placebo conditions. cTBS: continuous theta burst stimulation; MRI: magnetic resonance imaging; PSG: polysomnography.

Figure 3

Transcranial magnetic intervention system set-up for the pilot randomized controlled trial. Left: (A) the continuous theta burst stimulation is administered with a MagVenture Cool-B65 stimulator that included an active and sham side; (B) the resting motor threshold was determined using a MagPro X100 stimulator with a figure-of-8 coil; (C) the transcranial magnetic stimulation system is maintained at a constant temperature using an active cooling system. Middle: the stimulation is directed by a computerized system that detected the orientation of the head in space using (D) an antenna camera and correlate it with the individual’s coregistered magnetic resonance imaging scan. Right: An image showing the Neuronavigation system used to administer the transcranial magnetic stimulation to the precise default mode network locations.