Transcranial Temporal Interference Stimulation (tTIS) for Chronic Insomnia

Background and Rationale:

Chronic insomnia involves not only difficulty initiating sleep but also continuous central hyperarousal, severely impairing daytime function and quality of life. Current sedative-hypnotic drugs typically provide only nighttime suppression of the central nervous system, which can lead to tolerance and next-day residual effects, and they fail to fundamentally restore normal brain network states. There is a clinical need for non-invasive neuromodulation targeting abnormal brain networks. The left dorsolateral prefrontal cortex (DLPFC) is implicated in regulating emotion and suppressing central hyperarousal. Transcranial temporal interference stimulation (tTIS) is a novel non-invasive technique that uses two high-frequency carriers to create a modulated envelope (e.g., 10Hz) at a specific cortical target. The 10Hz modulation is hypothesized to modulate alpha activity, potentially reducing cortical hyperarousal. This study will evaluate the clinical safety and preliminary efficacy of tTIS targeting the left DLPFC, and will test whether it is associated with network-level changes in insomnia patients.

Study Objective:

The primary objective is to evaluate the preliminary clinical efficacy of tTIS targeting the left DLPFC in treating chronic insomnia, utilizing the reduction rate of the Insomnia Severity Index (ISI) score as the primary endpoint. Secondary objectives include evaluating the clinical response rate and objective sleep structural changes via polysomnography (PSG) and sleep bands. The study will also explore the neurophysiological mechanisms by analyzing electroencephalogram (EEG) Alpha band power. Additionally, it will assess improvements in subjective arousal (PSAS) and emotional states (STAI-S, PHQ-9, GAD-7).

Study Design and Methodology:

This is a prospective, single-center, randomized, double-blind (participant and evaluator), sham-controlled exploratory clinical trial. Thirty eligible patients with primary or mild emotionally accompanied chronic insomnia will be enrolled and randomly assigned to either the experimental group (10Hz difference frequency tTIS) or the control group (0Hz difference frequency tTIS) in a 1:1 ratio. The study location is Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

Intervention Details:

Both groups will receive stimulation targeting the left DLPFC. The experimental group will receive 10Hz difference frequency tTIS (carrier frequencies of 2000Hz and 2010Hz), which creates an amplitude-modulated envelope. The control group will receive 0Hz difference frequency stimulation (identical carrier frequencies), which does not create a therapeutic modulated envelope. The intervention will be administered daily for 30 minutes per session, 5 times a week, over a continuous 2-week period (10 sessions in total). Follow-up assessments will cover the baseline, the end of the intervention, and one month post-intervention.

Inclusion criteria

• Aged 18 to 65 years old, male or female.
• Eligibility required an ICD-11 diagnosis of chronic insomnia disorder, determined by investigator-administered clinical interviews (≥3 nights/week for ≥3 months, despite adequate opportunity/conditions for sleep, with daytime distress or functional impairment).
• Insomnia Severity Index (ISI) total score ≥ 15 at screening or baseline assessment.
• Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) total scores both ≤ 9 at screening assessment.
• Has full civil capacity, is able to proficiently operate a smartphone and wearable sleep band, and can understand and cooperate with clinical scale assessments and neurophysiological examinations.
• Voluntarily participates, can ensure on-time hospital visits for 10 transcranial temporal interference stimulation (tTIS) sessions over 2 consecutive weeks, and can cooperate with the 1-month longitudinal follow-up.
• Fully understands the study purpose, intervention procedures, and potential risks, and voluntarily signs the written informed consent form.

Exclusion criteria

• Psychiatric conditions: (1) schizophrenia spectrum disorder or bipolar disorder, determined based on participant self-report of prior clinician diagnosis and treatment history and, when feasible, review of available medical records; (2) moderate-to-severe depressive or anxiety symptoms (PHQ-9 ≥ 10 or GAD-7 ≥ 10; either threshold met); (3) current suicidal ideation/behavior or elevated suicide risk as assessed by the investigator.
• Secondary sleep disorders: Severe obstructive sleep apnea (OSA; AHI ≥ 30), restless legs syndrome (RLS), narcolepsy, or severe circadian rhythm disorders.
• Epilepsy risk: History of seizures/convulsions or a clear family history of epilepsy.
• Intracranial metal and implanted electronic devices: Intracranial metal implants (e.g., aneurysm clips, metal stents, repair patches; fixed dental fillings excluded) or implanted electronic devices (e.g., cardiac pacemakers, deep brain stimulators [DBS], vagus nerve stimulators [VNS]).
• Medical history (neurologic): Recent craniotomy, severe traumatic brain injury, or organic brain lesions (e.g., brain tumors).
• Special populations: Pregnant, lactating, or planning pregnancy during the study period.
• Skin and physical restrictions: Skin damage, infection, or severe rash at the scalp stimulation site (especially over the left DLPFC and the return electrode site), or severe allergy to conductive gel/electrodes.
• Somatic comorbidities/substance use: Severe cardiac, pulmonary, hepatic, or renal dysfunction, or other conditions deemed by the investigator to potentially affect participant safety or study assessments (e.g., severe alcohol or drug abuse).