Low-Frequency rTMS for In-Hospital Sleep Disturbance After Lung Transplantation

This is an investigator-initiated, single-center, prospective, randomized, double-blind, parallel-group, sham-controlled trial conducted in adult recipients of a first single- or double-lung transplantation. Eligible participants will be enrolled during postoperative days 7-21 after clinical stabilization and must have evidence of in-hospital sleep disturbance, defined by a mean Richards-Campbell Sleep Questionnaire (RCSQ) score below 70 across two consecutive valid inpatient nights together with an Insomnia Severity Index (ISI) score of at least 8.

Participants will be randomized 1:1 to active or sham stimulation. Active treatment will consist of 1-Hz repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex at the F3 position, delivered at 100% of the resting motor threshold with 1,800 pulses per session over approximately 30 minutes. One session will be administered daily for a total of 10 sessions completed within 10-14 days. The sham group will undergo matched procedures using a dedicated sham coil or validated active/sham masking module with the same target, positioning, rhythm, sound, duration, and interaction procedures but without intended therapeutic cortical stimulation.

Participants and outcome assessors will remain blinded to treatment allocation. Clinical study personnel and statistical personnel will also remain blinded as specified in the protocol; stimulation operators cannot be blinded because of device-operation requirements but will not participate in recruitment, outcome assessment, data entry, or statistical analysis.

The primary outcome is the participant-level mean RCSQ total score obtained on the mornings after the nights following stimulation sessions 8, 9, and 10. The RCSQ ranges from 0 to 100, with higher scores indicating better sleep. The primary analysis will compare active and sham groups using an ANCOVA/linear-regression model adjusted for baseline RCSQ and prespecified randomization stratification factors.

Secondary and exploratory outcomes include total sleep time measured using the Lifesense HR6 wearable device, ISI and other sleep measures, pain and opioid exposure, delirium, cognitive function, anxiety, depressive symptoms, fatigue, health-related quality of life, hospital and transplant-related outcomes, treatment feasibility, and adverse events. Resting-state 64-channel EEG and a prespecified TMS-EEG mechanistic substudy will explore changes in spectral power, alpha peak frequency, functional connectivity, network topology, and TMS-evoked cortical responses.

All participants will continue to receive standard post-transplant clinical care and standardized inpatient sleep-support measures. Necessary clinical treatment will take priority over study procedures, and the study intervention will not be used to delay treatment, rehabilitation, transfer, or discharge.

Inclusion criteria

Age 18-70 years and able to provide independent written informed consent. First single- or double-lung transplantation. Postoperative day 7-21 at randomization; extubated for at least 48 hours, off ECMO, and off vasoactive medications for at least 24 hours.

Resting SpO2 ≥92% with stable oxygen requirements and able to complete study procedures in a seated or semi-recumbent position.

Negative CAM/CAM-ICU assessment during the preceding 24 hours, with clear consciousness and ability to complete sleep and cognitive assessments.

Stable trends in blood pressure, blood glucose, serum sodium, serum magnesium, and renal function; immunosuppressant concentrations considered acceptable by the transplant team.

Mean RCSQ score <70 across two consecutive valid inpatient nights and baseline ISI score ≥8.

Able to complete RCSQ, sleep diary, Lifesense HR6 monitoring, and 64-channel EEG assessments.

Expected to remain hospitalized for at least 10 days and able to complete 10 stimulation sessions and the primary outcome assessment within 14 days.

Exclusion criteria

Unable to provide valid informed consent, unwilling to participate, or unable to reliably complete the primary RCSQ assessment.

History of epilepsy or unexplained seizures, active intracranial hemorrhage, significant cerebral edema, elevated intracranial pressure, recent stroke, or severe traumatic brain injury.

Intracranial ferromagnetic metal, cochlear implant, deep brain stimulator, cardiac pacemaker/implantable cardioverter-defibrillator, or other TMS-incompatible implant.

Severe scalp infection, open wound, or inability to safely position the TMS coil or EEG cap.

Pregnancy or any condition considered by the investigator to pose unacceptable risk.

Repeat lung transplantation, multiorgan transplantation, or current requirement for ECMO, mechanical ventilation, or vasoactive support.

Active delirium, encephalopathy, posterior reversible encephalopathy syndrome (PRES), central nervous system infection, new focal neurological deficit, or seizure within the previous 30 days.

Suspected calcineurin-inhibitor neurotoxicity, uncontrolled hypertension, clinically significant hypomagnesemia, hyponatremia, hypoglycemia, or other metabolic abnormality that may lower the seizure threshold.

Uncontrolled sepsis, active rejection requiring urgent intensified treatment, or rapidly deteriorating clinical status.