Low-Frequency rTMS for Sleep After Thoracoscopic Lung Resection

Participants will be randomized in a 1:1 ratio to active low-frequency rTMS or matched sham stimulation using variable block sizes of 4 and 6. Randomization will be stratified by planned resection extent (wedge or segmental resection versus lobectomy or greater resection) and baseline Insomnia Severity Index (ISI) category (<15 versus ≥15). Allocation will be concealed with sequentially numbered, opaque, sealed envelopes or an equivalent controlled allocation system.

Active treatment will target the left dorsolateral prefrontal cortex at F3 using a figure-of-eight coil, 1 Hz stimulation, 100% of resting motor threshold, and 1,800 pulses over approximately 30 minutes per session. The five planned sessions are preoperative day -2, preoperative day -1, 2-6 hours after awake extubation when clinically stable, postoperative day 1, and postoperative day 2. No more than one session may be performed on any calendar day. The sham arm will use a dedicated compatible sham coil or coded active/sham module with matched procedures and no intended cortical stimulation.

The primary analysis will compare the participant-level mean RCSQ total score across postoperative inpatient nights 1-3. A nightly score is eligible when at least 4 of 5 RCSQ visual-analogue items are completed. The participant-level value will be the arithmetic mean of at least two eligible nightly scores; thus, it may be based on two or three nights. The model will adjust for the most recent evaluable pre-randomization inpatient RCSQ score, randomization strata, and regular hypnotic use.

The planned enrollment is 220 participants (110 per group). The protocol assumes a between-group RCSQ difference of 10 points, a common standard deviation of 20 points, a two-sided alpha of 0.05, and 90% power, requiring 86 evaluable participants per group before a 20% allowance for non-evaluable primary outcomes.

Inclusion criteria

• Age 18-80 years and able to provide written informed consent.
• Primary lung cancer confirmed by pathology or multidisciplinary evaluation and scheduled for elective thoracoscopic lung resection, including wedge resection, segmentectomy, lobectomy, bilobectomy, or pneumonectomy.
• American Society of Anesthesiologists physical status I-III, with awake extubation and reliable self-report expected after surgery.
• Protocol-defined sleep impairment: Insomnia Severity Index score ≥8 or the most recent evaluable preoperative inpatient RCSQ total score <70.
• Baseline TMS safety screening, resting motor threshold, RCSQ, ISI, HR6 actigraphy, and 64-channel EEG can be completed before randomization and the first study stimulation.
• The clinical schedule permits two preoperative and three postoperative sessions and at least three postoperative inpatient nights without delaying necessary clinical care or discharge.

Exclusion criteria

• History of epilepsy or seizure; intracranial hemorrhage, cerebral edema, increased intracranial pressure, recent stroke, or recent traumatic brain injury judged to increase TMS risk.
• Ferromagnetic or electronic implants incompatible with TMS, including incompatible intracranial metal, cochlear implant, deep-brain stimulator, or other implanted electronic device near the stimulation field.
• Severe scalp infection, open wound, or other local condition preventing safe coil placement.
• Pregnancy or another condition judged by the investigator to create unacceptable risk from study procedures.
• Emergency surgery, planned open thoracotomy, planned prolonged postoperative mechanical ventilation or deep sedation, or another perioperative plan that makes the stimulation and assessment schedule infeasible.
• Regular opioid treatment for chronic pain or baseline chest-wall pain numeric rating scale score ≥3.
• Unstable consciousness, respiratory status, circulation, or another acute condition that prevents reliable self-report or safe study procedures.