Effects of Accelerated rTMS on Sleep Architecture in Chronic Insomnia Disorder

BACKGROUND AND RATIONALE

Chronic insomnia disorder affects approximately 10-12% of adults worldwide and is associated with increased risk of psychiatric disorders, cardiovascular disease, and reduced quality of life. While cognitive behavioral therapy for insomnia (CBT-I) is the recommended first-line treatment, access remains limited. Pharmacological options carry concerns regarding long-term efficacy, dependency, and adverse effects.

The hyperarousal model of insomnia suggests that excessive activation of arousal systems contributes to the disorder. The left dorsolateral prefrontal cortex (DLPFC) has been identified as a critical node in insomnia pathophysiology, with altered functional connectivity patterns correlating with poor sleep quality and changes in sleep architecture, including increased beta/gamma activity and reduced slow-wave sleep. These findings support the rationale for targeted neuromodulation of this brain region.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the DLPFC has demonstrated improvements in both subjective sleep quality and objective sleep parameters, with reported response rates of approximately 55% and remission rates of approximately 68%. Protocols using 3-4 sessions per week have shown sustained benefits at 6-12 month follow-up. However, most prior studies have relied primarily on subjective outcome measures with limited polysomnographic or EEG-based sleep data, and optimal stimulation parameters and age-related differences in treatment response remain poorly characterized.

STUDY PROCEDURES

Screening Phase (Day -25 to Day -1):

Screening is conducted in two parts. Part 1 (Day -25 to Day -15) includes a general health assessment, medical history review, vital signs, and subjective sleep evaluation using the Consensus Sleep Diary - Morning Administration (CSD-M) collected over a minimum of 7 consecutive days and the Insomnia Severity Index (ISI). Subjects taking hypnotic medications at the time of consent must complete a minimum 5-day washout before CSD-M and ISI administration. CSD-M data from Part 1 are also used to determine each participant's median habitual bedtime for standardizing subsequent at-home sleep monitoring.

Part 2 (Day -14 to approximately Day -5) includes objective sleep assessment using the Somfit™ home EEG device over 2 consecutive nights. The first night's recording is used to screen for periodic limb movements/restless legs syndrome, sleep-disordered breathing, and parasomnias. Both nights' recordings are used to confirm objective insomnia criteria. Two training sessions for the cognitive test battery and body sway assessments are also completed during Part 2 to reduce learning effects.

For subjects aged 65 years and older, a Mini-Mental State Examination (score ≥25 required) is administered during screening to ensure capacity for safe participation. Motor threshold determination is also performed during screening to calibrate stimulation intensity; the motor threshold is defined as the minimum stimulus intensity required to induce visible contraction of the right thumb.

Open-Label Treatment Phase (Day 1 to approximately Day 14):

The night before the first treatment session, participants complete an at-home Somfit™ sleep recording to establish baseline objective sleep data. On Day 1, pre-treatment assessments are completed, including vital signs, CSD-M, ISI, Pittsburgh Sleep Quality Index (PSQI), Clinical Global Impression - Severity (CGI-S), Patient Global Impression - Severity (PGI-S), and Perceived Stress Scale (PSS).

Treatment consists of 6 rTMS sessions administered 3 times per week over 2 weeks using the EXOMIND™ device (BTL-699-2). Each session delivers 6,300 pulses at alternating frequencies of 12, 15, and 18 Hz, with a total session duration of 24 minutes and 30 seconds. The stimulation target is the left DLPFC, localized using the standard 5.5-cm anterior method. All sessions are conducted at the research site with medical staff present. Blood pressure and heart rate are recorded at the beginning and end of each session, and adverse events are monitored using a standardized checklist derived from existing TMS safety literature.

On the day of the 6th (final) treatment session, post-treatment assessments are completed, including vital signs, CSD-M, PSQI, ISI, CGI-S, CGI - Improvement (CGI-I), PGI-S, PGI - Improvement (PGI-I), and PSS.

Follow-Up Phase:

Participants return for follow-up visits at 1 month and 3 months after the last treatment session. Safety assessments and outcome measures are repeated at each visit. If a participant withdraws prematurely, end-of-study assessments are performed as soon as possible.

OBJECTIVE SLEEP MONITORING

Objective sleep architecture is assessed using the Somfit™ home EEG monitoring device at screening (2 nights), baseline (1 night before Day 1), and at post-treatment and follow-up time points. Parameters recorded include sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE), Stage N3 duration, and slow-wave activity (SWA).

AGE GROUP COMPARISON

The study enrolls both adult (18-64 years) and elderly (65-85 years) participants, with approximately equal proportions targeted in each group (neither group exceeding approximately 60% of total enrollment). This design allows exploratory comparison of treatment response across age groups, addressing a gap in the existing literature regarding age-related differences in rTMS efficacy for insomnia.

STATISTICAL APPROACH

Descriptive statistics will summarize demographic and baseline characteristics. The primary analysis will use repeated measures ANOVA to assess changes in outcome scores across four time points (baseline, post-intervention, 1-month follow-up, and 3-month follow-up). Paired t-tests will evaluate within-subject changes in secondary measures between baseline and each post-treatment time point. A p-value of less than 0.05 will be considered statistically significant.

Inclusion criteria

• Subject must be 18 to 85 years of age, inclusive, on the day of signing informed consent.
• Subject must meet DSM-5 criteria for insomnia disorder：

A predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms:

Difficulty initiating sleep Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings Early-morning awakening with inability to return to sleep. The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning.

The sleep difficulty occurs at least 3 nights per week. The sleep difficulty is present for at least 3 months. The sleep difficulty occurs despite adequate opportunity for sleep. The insomnia is not better explained by and does not occur exclusively during the course of another sleep-wake disorder (eg, narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia).

The insomnia is not attributable to the physiological effects of a substance (eg, a drug of abuse, a medication).

Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia.

• Subject must have an ISI total score ≥15 at screening.
• Subject must have an sSOL ≥45 minutes and an sWASO ≥60 minutes on at least 3 nights over any 7-day period during Part 1 of screening, using the CSD-M, prior to screening Somfit™ sleep test assessments.
• Subject must demonstrate a 2-night mean SOL of ≥25 minutes (with neither night <20 minutes), a 2-night mean WASO ≥30 minutes, and a 2-night mean TST ≤6.5 hours, with neither night >7 hours.
• Subject must be otherwise healthy or present with stable, well-controlled, chronic conditions on the basis of physical examination, medical history, vital signs, 12-lead ECG (if necessary), and clinical laboratory tests (if necessary) performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population. If the results of the clinical laboratory tests are outside the normal reference ranges, the subject may be included only if the investigator and the sponsor's Safety Physician judge the abnormality or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject's source documents and initiated by the investigator.
• Body mass index between 18 and 35 kg/m2 inclusive (body mass index = weight/height^2).
• For subjects ≥65 years of age, a Mini-Mental State Examination score of ≥25 to rule out cognitive impairment in the interest of subject safety.
• Ability to determine the motor threshold of the participant. The participant's motor threshold could be established as the minimum stimulus required to induce contraction of the right thumb.
• Subjects willing and able to abstain from partaking in any treatments other than the study procedure for the improvement in sleep quality and reduction of stress, including non-invasive brain stimulation treatments other than the study procedure during study participation.
• Subjects willing and able to maintain their regular (pre-procedure) diet and exercise regimen without affecting significant change in either direction during study participation.
• Willingness to comply with study instructions and to return to the clinic for the required visits.
• Women of child-bearing potential are required to use birth control measures during the whole duration of the study.
• If applicable, subjects will be maintained on pre-study prescribed medications at a stable therapeutic dosage for at least 2 months prior to study entry.
• Subject is not using any sleeping medication or is using over-the-counter pills (except Valerian and St. John's Wort) no more than 4 times a week.
• Subject must usually spend between 6 and 9 hours in bed during the night and go to bed between 8 PM and 1 AM and typically get out of bed between 5 AM and 9 AM.
• Subject must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
• Subjects must sign a separate ICF if he or she agrees to provide an optional DNA sample for research (where local regulations permit). Refusal to give consent for the optional DNA research samples does not exclude a subject from participation in the study.

Exclusion criteria

• Has history of or current clinically significant and/or unstable liver (moderate or severe hepatic impairment [Child-Pugh Score ≥7]) or renal insufficiency (severe renal impairment [estimated creatinine clearance below 30 mL/min]; serum creatinine >2 mg/dL); significant and/or unstable cardiac, vascular, pulmonary (eg, acute or severe respiratory failure), gastrointestinal, endocrine, neurologic (eg, myasthenia gravis, narcolepsy), hematologic, rheumatologic, immunologic, or metabolic disturbances. Organic brain disease, epilepsy, dementia, narcolepsy, narrow angle glaucoma and known or suspected mental retardation are exclusionary. Any clinically relevant medical condition that is likely to result in deterioration of the subject's condition or affect the subject's safety during the study (eg, medically frail subject with history of hospitalization due to fractures) or could potentially alter the absorption, metabolism, or excretion of the study drug is exclusionary.

Note: Subjects with chronic but stable, well-controlled conditions may be allowed in the study upon agreement with the investigator and the sponsor's Safety Physician.

• Has uncontrolled hypertension (supine systolic blood pressure >150 mm Hg in adult subjects or >160 mm Hg in elderly subjects or supine diastolic blood pressure >90 mm Hg, despite diet, exercise, or a stable dose of allowed antihypertensive therapy) at screening or Day 1. (A subject with hypertension may be included if the subject's hypertension has been controlled for at least 3 months prior to screening, and the dosage of any antihypertensive medication has been stable for the past 3 months).
• Has clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at screening. Subjects with non-insulin dependent diabetes mellitus who are adequately controlled (hemoglobin A1c [HbA1c] ≤8%) may be eligible to participate if otherwise medically healthy. It is expected that laboratory values will generally be within the normal range, though minor deviations, which are not considered to be of clinical significance to both the investigator and the sponsor's Safety Physician, are acceptable.
• Has clinically significant ECG abnormalities at screening or Day 1 prior to treatment defined as:

T interval corrected according to Fridericia's formula: ≥450 msec (males);

≥470 msec (females). Evidence of 2nd and 3rd degree atrioventricular block, or 1st degree atrioventricular block with PR interval >210 msec, left bundle branch block.

Features of new ischemia. Other clinically important arrhythmia. Note: Subjects with right bundle branch block may be allowed provided confirmation that right bundle branch block is not associated with underlying cardiac/lung diseases.

• Electronic implants in or near the head - rTMS devices are contraindicated for use in patients who have active or inactive implants in or near the head including device leads, deep brain stimulators, cochlear implants, ocular implants, and vagus nerve stimulators, implanted devices such as cardiac pacemakers, defibrillators, and neurostimulators.
• Metallic, ferromagnetic or other magnetic-sensitive implants/objects in or near the head - rTMS devices are contraindicated for use in patients who have conductive, ferromagnetic or other magnetic-sensitive metals implanted in their head (with some exceptions in the mouth - see Operator's Manual) or within 12 in (30 cm) of the therapy coil. (Examples include implanted electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry, hair barrettes and tattoos with metallic ink), drug pumps (within 12 in (30 cm) of the therapy coil) application in the heart area.
• Has significant hypersomnia not related to night time insomnia (based on clinical judgment of the investigator).
• Moderate-to-severe obstructive sleep apnea (AHI ≥15 events/hour) that is untreated or inadequately controlled (residual AHI ≥5 events/hour on CPAP therapy).
• Regularly naps more than 3 times per week.
• Has a current diagnosis or recent history of psychotic disorder, MDD, bipolar disorder, or posttraumatic stress disorder, or other psychiatric condition that, in the investigator's opinion, would interfere with the subject's ability to participate in the trial.
• Has a current or recent history of serious suicidal ideation within the past 6 months, or a history of suicidal behavior within the past year. Subjects with a prior suicide attempt of any sort, or prior serious suicidal ideation/plan within the past 6 months, should be carefully screened for current suicidal ideation and only subjects with non-serious items may be included at the discretion of the investigator.
• Has insomnia related to RLS (defined as PLM-arousal index of ≥10 PLM-related electroencephalograph (EEG) arousals per hour of sleep for adult subjects or >15 for elderly subjects), sleep breathing disorder (defined as an apnea-hypopnea index ≥10 cumulative apneas and hypopneas per hour of EEG sleep for adult subjects or >15 for elderly subjects), or parasomnias. These disorders will be ruled out by the first PSG recording during Part 2 of screening.
• Is a shift worker or has a significantly shifted diurnal activity pattern.
• Has experienced transmeridian travel across 2 or more time zones within the 2 weeks prior to screening, or plans to travel across 2 or more time zones during study participation.
• Has a known malignancy or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, that in the opinion of the investigator, with the concurrence with the sponsor's Safety Physician, is considered cured with minimal risk of recurrence).
• Has a history of substance or alcohol use disorder of moderate to severe severity according to DSM-5 criteria within 6 months before screening or positive test result(s) for alcohol or drugs of abuse (including barbiturates, opiates [including methadone], cocaine, cannabinoids, methamphetamines, amphetamines, 3,4-Methylenedioxymethamphetamine, and BZD) at screening or at baseline.
• Smokes >10 cigarettes per day and/or has quit smoking within 1 month prior to screening.
• Consumes >500 mg of caffeine per day in any form (tea/coffee/cocoa/cola/energy drinks) averagely. Refer to caffeineinformer.com/the-caffeine-database for average caffeine content of various beverages.
• Had clinically significant acute illness within 7 days prior to study rTMS treatment.
• Is under ongoing psychological treatments focused on insomnia (eg, Cognitive Behavior Therapy), initiated within 2 months prior to Day 1. A subject who has been receiving ongoing psychological treatment for a period of greater than 2 months is eligible, if the investigator deems the psychological treatment to be of stable duration and frequency. The subject's psychological treatment should be maintained during participation in the study.
• Has donated 1 or more units (approximately 450 mL) of blood or acute loss of an equivalent amount of blood within 60 days prior to study.
• Is pregnant or breastfeeding while enrolled in this study or within 1 month after the last session of study rTMS treatment.
• Has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 3 months before the planned first dose of study drug or is currently enrolled in an investigational study.
• Has psychologic and/or emotional problems, which would render the informed consent invalid, or limit the ability of the subject to comply with the study requirements, or is a vulnerable subject due to involuntary detention (such as for legal reasons).
• Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Has had major surgery, (eg, requiring general anesthesia) within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Note: Subjects with planned surgical procedures to be conducted under local anesthesia may participate.
• Is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.