Feasibility of rTMS combined with dexmedetomidine in chronic insomnia disorder

Abstract

To explore the efficacy and mechanism of repetitive transcranial magnetic stimulation (rTMS) combined with dexmedetomidine (DEX) in treating chronic insomnia disorder. 42 participants were divided into two groups: DEX (N = 23) and rTMS + DEX (N = 19). rTMS was processed with a frequency of 1 Hz, at an intensity of 100% resting motor threshold (RMT), with 1000 stimulation administered to the left dorsolateral prefrontal cortex (DLPFC), occurring 4 times a week for 4 weeks. DEX was administered nightly with an automatic intravenous infusion device for 4 weeks. The Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), actigraphy, and the dosage of sedative and hypnotic drugs were recorded at baseline, therapy termination, and follow-up at 1, 3 and 6 month. Concentrations of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in plasma were measured at baseline and therapy termination using enzyme-linked immunosorbent assay (ELISA). The PSQI, HAMA and HAMD scores at therapy termination and follow-up period showed a significant decrease compared to baseline (P < 0.01). Light sleep duration and awakening times at therapy termination and follow-up period demonstrated a decrease compared to baseline, along with an increase in deep sleep and rapid eye movement (REM) sleep (P < 0.01). The concentrations of IL-6 and TNF-α in the rTMS + DEX group were lower than those in the DEX group, whereas the GSH-Px and SOD were higher (P < 0.05). The treatment-related adverse reactions primarily included dry mouth, thirst, bradycardia and hypertension. rTMS combined with DEX could improve the structure and quality of sleep with chronic insomnia disorder, and also alleviate anxiety and depression, with the efficacy persisting for 6 months. The improvement in sleep with rTMS might be associated with an increase in concentrations of GSH-Px and SOD, and a decrease in IL-6 and TNF-α. This trial was registered with the Chinese Clinical Trial Registry (Number: ChiCTR2100050114) on 16/08/2021.

Introduction

Insomnia disorder is characterized by frequent and persistent difficulties in initiating and maintaining sleep under suitable conditions, leading to dissatisfaction with the duration and quality of sleep; it is also accompanied by impaired social functioning during the day. The main symptoms of insomnia disorder include difficulty falling asleep (sleep latency ≧ 30 min), frequent awakenings (≧ 2 times) or prolonged awakenings (≧ 60 min), and awakening earlier than desired. In addition, patients also experience daytime symptoms such as fatigue, sleepiness, emotional changes, and cognitive decline. The prevalence of insomnia disorder has been increasing recently, presumably due to rise social pressure. The incidence among adults worldwide is estimated to range between 15 and 20%¹. Chronic insomnia disorder is a prolonged episode of insomnia that lasts more than three months. And this condition significantly increases the risk of developing various multi-system diseases, including hypertension, stroke, diabetes, cognitive impairment, depression, and even raises the mortality rate associated with these diseases². There has been an increase in symptoms due to the Coronavirus disease 2019 (COVID-19) outbreak, with over 75% of patients with COVID-19 subsequently developing chronic insomnia disorder. Moreover, COVID-19 patients have experienced a concurrent increase in the prevalence of anxiety and sadness, which has negatively affected both their prognosis and quality of life³.

Repetitive transcranial magnetic stimulation (rTMS), a painless and non-invasive procedure, is widely used in treating various diseases such as Alzheimer’s Disease (AD), Parkinson’s disease (PD), pain, depression, and anxiety⁴. By targeting specific areas of the brain, magnetic field pulses are transmitted through the skull, resulting in the generation of induced currents in the underlying regions. These induced currents directly impact excitability of nerve cells in those regions. Depending on the frequency used, rTMS can either enhance or inhibit cortical excitability. In the case of low-frequency rTMS, it may effectively alleviate insomnia by reducing the excitability of the cerebral cortex⁵. Dexmedetomidine (DEX) is an α2-adrenergic receptor agonist known for its high selectivity. Previous studies have demonstrated some effectiveness of DEX in treating chronic insomnia disorder⁶. With the application of DEX, the symptoms of insomnia gradually improve, and the dosage of medication is reduced until discontinuation. During the follow-up period, no recurrence of insomnia has been observed⁶. Additionally, DEX has shown potential in alleviating anxiety, depression, and other related symptoms in patients with insomnia disorder. As far as we know, there is no research on the combination of rTMS and DEX for the treatment of chronic insomnia disorder. Therefore, the aim of this study was to evaluate the effectiveness and safety of rTMS combined with DEX in treating chronic insomnia disorder, while also investigating aspects of its underlying mechanism.

Methods

Patient

This clinical trial was conducted at three medical centers: The Aviation General Hospital of China Medical University, the Affiliated Hospital of Shandong Second Medical University, and the West China Tianfu Hospital of Sichuan University. The trial spanned from July 1st, 2021, to December 31st, 2022. Patients suffering from chronic insomnia disorder who met the criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published by the American Psychiatric Association (APA), were enrolled. To be diagnosed with chronic insomnia disorder, patients must meet the following criteria: dissatisfaction with the quality or quantity of sleep, experiencing more than one of the following sleep difficulties: difficulty initiating and maintaining sleep, early morning awakening, or non-restorative sleep, and significant interference with daytime functioning, such as fatigue, pain, memory decline, or dysfunction of the immune system, despite having adequate opportunity and circumstances for sleep. These issues must occur at least 3 times a week for a duration of more than 3 months.

The inclusion criteria for patients were as follows: age between 18 and 75 years old, a score on the Pittsburgh Sleep Quality Index (PSQI) > 7, no neurological or psychiatric disorders such as depression, anxiety, and no other sleep disorder (including sleep-related movement disorder, hypersomnia, and parasomnia) as determined clinically and through polysomnography. The exclusion criteria included the presence of metal implants within the body, such as pacemakers, stents, inner ear hearing aids, and other metal objects, a history of epileptic seizures, severe neuropsychiatric diseases (AD, PD, schizophrenia, and bipolar affective disorder); severe cardiopulmonary, liver, and kidney diseases (including acute and chronic respiratory failure, heart failure, nephritis, and liver cirrhosis); malignant tumors, such as liver cancer and leukemia; severe malnutrition and autoimmune system diseases; infectious and parasitic diseases, including viral hepatitis, tuberculosis, and liver hydatid disease; and pregnancy or lactation. Subjects would be discontinued from the study if any of the following conditions occurred: Severe illness or death; loss to follow-up; participants request to withdraw; or following a medical judgment deeming it necessary for the subject to suspend participation in the study.

Ethics approval and consent to participate

All participants provided signed informed consent before being included in the study. The institutional ethics committee approved the study in accordance with the Helsinki Declaration of 1975, as revised in Fortaleza, Brazil in 2013. This trial was granted approval by the Ethics Committee of the Aviation General Hospital (2021-KY-01–08).

Study protocol

The general information gathered encompassed age, gender, ethnicity, marital status, educational years, occupation, medical history, body mass index (BMI), heart rate and blood pressure. All patients underwent an initial evaluation of their sleep quality using the PSQI (ranging from 0 to 21) and actigraphy (FRA-B19, Huawei, China). Additionally, mental condition was assessed using the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA). The administered medication doses were also documented. The PSQI, HAMD, HAMA, actigraphy, and medication doses were reassessed at the therapy termination and during the observational follow-up period (at 1, 3, and 6 month). Blood samples were collected at baseline and the therapy termination. Any adverse events related to treatment were also recorded. The trial design is presented in Table 1.

Table 1.

Trial process chart.

	Baseline	Treatment-period		Follow-up
	Day -1	Day 0	Day 28	Month 1	Month 3	Month 6
Patients
Enrollment	/
Signed consent	/
Medical history	/
Blood sample	/		/
Primary outcomes
PSQI	/		/	/	/	/
Secondary outcomes
Actigraphy	/		/	/	/	/
HAMD	/		/	/	/	/
HAMA	/		/	/	/	/
Drug dose	/		/	/	/	/
Compliance	/		/

Enzyme-linked immunosorbent assay for blood sample

4 mL of venous blood was collected from patients’ upper arm and centrifuged at 4,000 r/min for 10 min in a refrigerated centrifuge to separate the plasma. The plasma samples were then placed into 1,500 μL EP tubes, frozen, and stored in a − 80℃ refrigerator for subsequent detection. The contents of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were tested using an enzyme-linked immunosorbent assay (ELISA). (1) Dilution of the standard substance: The standard substance was diluted to a concentration of 20 ng/mL and subsequently further diluted across various concentration gradients. (2) Solution preparation: The antibody was diluted to a 1:100 ratio for detection, and the washing solution was diluted to a 1:30 ratio for storage. (3) Incubation: The sample was added to the sample well and incubated at 37℃ for 60 min. (4) Antibody incubation: After washing, the antibody was added and the sample was incubated at 37℃ for 60 min. (5) Enzyme antibody reaction: Added the HRP-labeled detection antibody, incubated for 30 min at 37℃. (6) Color development: The TMB substrate was added and the reaction was developed in the dark for 20 min. Following the termination of the reaction, the optical density 450 value was measured. (7) Data analysis: The standard curve was generated by plotting the logarithm of the reference substance concentration against the optical density values, enabling the calculation of the concentrations of GSH-Px, SOD, IL-6, TNF-α, and IFN-γ in the samples.

Interventions

rTMS procedure

The intervention employed a transcranial magnetic stimulator (RT-100, Sichuan Junjian Wang Medical Equipment Co., Ltd., China) equipped with an "8" shaped coil. The stimulation parameters consisted of a frequency of a frequency at 1 Hz and an intensity set at 100% of resting motor threshold (RMT). To conduct the RMT test, patients were seated in a chair with their hand muscles relaxed and palms facing upward. The recording electrode was connected to the muscle of the abductor pollicis longus, and the reference electrode was connected to the muscle of the abductor pollicis brevis, while the ground electrode was attached to the wrist. Following the standard 10/20 system for electroencephalogram electrode positioning, the M1 region was located 2 cm lateral and 2 cm anterior to the Cz point. During magnetic stimulation, the single-pulse mode was employed to stimulate the central point of the M1 region with the coil’s position held constant. The intensity of the stimulation was gradually increased until the minimum stimulation intensity that elicited a motor evoked potential of more than 50 µV in at least 5 out of 10 stimulations was determined as RMT. The left dorsolateral prefrontal cortex (DLPFC) was located 5 cm anterior to the left primary motor cortex (M1) center point along the midline, and was stimulated as follows: 1000 stimulation were divided into 50 sets, each consisting of 20 pulses, with a pulse width of 70 ms and an interval of 2 s between each set⁷. This rTMS intervention was conducted 4 times weekly over a period of 4 weeks.

Application of DEX

Titration

Prior to this procedure, the patient fasted for 6 h without food and 2 h without water. The patient was positioned in a supine position, and an intravenous infusion of 250–500 mL of 0.9% NaCl solution was administered. DEX (H20183219, Yangtse River Pharmaceutical Group Co., Ltd., China) was diluted to a concentration of 4 µg/mL using 0.9% NaCl solution and administered via a constant-speed syringe pump (KL-605T, Beijing Kelly Med Co., Ltd., China). The injection occurred at a constant rate of 60 mL/h. Upon the patient entering the N3 stage of sleep, the injection was ceased. Should the patient not achieve N3 stage, the injection was discontinued once the DEX dosage reached 120 µg. A background infusion rate was set at 0.1 mL/h, with continuous monitoring of blood pressure, electrocardiogram, pulse, oxygen saturation, bispectral index, and polysomnography throughout the titration process. If the blood pressure dropped by more than 20% from the baseline value, the infusion rate of DEX was reduced or an intravenous injection of 4 µg norepinephrine was administered. Should the heart rate fall below 45 beats per minute, an intravenous injection of 2 mg of anisodamine was given until the heart rate rose above 45 beats per minute. In cases where oxygen saturation dropped below 90%, oxygen supplementation or a lateral decubitus position was implemented, and the DEX titration process was immediately halted. If the symptoms persisted despite these interventions, the patient was closely monitored and assessed for additional treatment.

Sleep induction and maintenance

This process entailed administering DEX to the patients via a drug administration device, according to preset parameters, to facilitate earlier sleep onset and extend sleep duration. The patient control system encompassed parameters such as the initial dose, single dose, and the duration of the lock-out interval. The initial dose of DEX was administered to induce N3 stage, whereas a single dose was given for sleep of N1 stage. The lock-out interval for each dose is set at 10 min. A 4-week intervention utilizing a DEX-based protocol was conducted on all patients. Heart rate and oxygen saturation were monitored regularly throughout the sleep period⁶.

Statistics analysis

SPSS 22.0 (SPSS Inc., Chicago, Illinois, USA) was utilized for data analysis. Paired sample t-tests were used to compare the differences between before and after treatment for variables that followed a normal distribution, while independent sample t-tests were used to compare the differences between groups. Nonparametric tests were used for variables that did not follow a normal distribution. The statistical description was reported as the mean plus or minus the standard deviation (Mean ± SD). A level of P < 0.05 was deemed as statistically significant for comparison. The graphical figures were developed using GraphPad Prism software (version 8.0.1, San Diego, CA, USA).

Results

Patient characteristics

The experimental process was outlined in Fig. 1. Of the 89 individuals with insomnia, 47 participants were excluded for various reasons, resulting in the inclusion of 42 patients with chronic insomnia disorder. The intervention and follow-up observation were completed by 23 patients in the DEX group, 19 patients in the rTMS + DEX group, totaling 42 subjects. Table 2 demonstrated that there were no significant differences in age, BMI value, duration of education, and length of insomnia between the two groups (P > 0.05).

Fig. 1.

Study Flowchart.

Table 2.

The characteristics of patients in two groups.

	rTMS + DEX	DEX	Z	P
Age	45.95 ± 12.53	47.04 ± 12.91	0.041	0.840
BMI (kg/m2)	23.21 ± 2.88	22.42 ± 2.88	0.266	0.609
Educational years	11.58 ± 2.06	10.44 ± 2.81	0.439	0.512
Years of insomnia	6.57 ± 7.25	6.98 ± 10.12	0.651	0.425

Efficacy

There were no significant differences in PSQI scores between the two groups at baseline, therapy termination, and follow-up points, as indicated in Table 3 (P > 0.05). Within the rTMS + DEX group, PSQI scores at the baseline (14.21 ± 1.99) showed significant increases compared to those at therapy termination (7.53 ± 1.35) and at the 1-month (7.79 ± 1.51), 3-month (7.90 ± 1.33), and 6-month follow-ups (8.37 ± 1.30) (P < 0.01). And there were no significant differences in PSQI scores between therapy termination and the follow-up period (P > 0.05). Within the DEX group, PSQI scores at therapy termination (7.83 ± 2.10) and at the 1-month (8.13 ± 1.91), 3-month (8.22 ± 1.98), and 6-month follow-ups (8.17 ± 1.50) were significantly lower than the baseline scores (13.83 ± 2.55) (P < 0.01). Similarly, there were no significant differences in PSQI scores between therapy termination and the 1-month, 3-month, and 6-month follow-ups (P > 0.05) (depicted in Fig. 2).

Table 3.

The comparison of PSQI scores at variable assessment points in two groups.

	rTMS + DEX	DEX	Z	P
Baseline	14.21 ± 1.99	13.83 ± 2.55	-0.428	0.668
Therapy termination	7.53 ± 1.35	7.83 ± 2.10	-0.208	0.835
Follow-up 1 month	7.79 ± 1.51	8.13 ± 1.91	-0.607	0.544
Follow-up 3 month	7.90 ± 1.33	8.22 ± 1.98	-0.504	0.651
Follow-up 6 month	8.37 ± 1.30	8.17 ± 1.50	-0.162	0.872

Fig. 2.

The changes in PSQI scores over time in two groups. Compared to baseline, ** P < 0.01, ## P < 0.01.

The parameters of actigraphy were compared between two groups at baseline, therapy termination, and during follow-up period. The results showed that the rTMS + DEX group experienced a longer duration of rapid eye movement (REM) sleep at therapy termination than the DEX group (P < 0.05). Additionally, the rTMS + DEX group exhibited more deep sleep at therapy termination and during the follow-up period compared to the DEX group, although the difference was not statistically significant (P > 0.05). Both groups experienced a reduction in short sleep duration and the number of awakenings, as well as an increase in deep sleep and REM sleep at therapy termination and during the follow-up period, compared to baseline (P < 0.01) (shown in Fig. 3A, 3B, 3C, 3D).

Fig. 3.

The changes in actigraphy, HAMA, and HAMD Scores over time in two groups. (A) The variation in duration of light sleep at the baseline, therapy termination, and follow-up period. (B) The variation in duration of REM sleep at the baseline, therapy termination, and follow-up period. (C) The variation in duration of deep sleep at the baseline, therapy termination, and follow-up period. (D) The variation in awakening time at the baseline, therapy termination, and follow-up period. (E) The variation in HAMA scores at the baseline, therapy termination, and follow-up period. (F) The variation in HAMD scores at the baseline, therapy termination, and follow-up period. Compared to baseline, ** P < 0.01, ## P < 0.01.

There were no significant differences in HAMA and HAMD scores between the two groups at baseline, therapy termination, and during the follow-up periods (P > 0.05). In the rTMS + DEX group, the HAMA scores at baseline (17.32 ± 2.94) were significantly higher compared to therapy termination (9.58 ± 2.55), as well as at the 1-month (9.90 ± 2.23), 3-month (10.58 ± 1.87), and 6-month follow-ups (11.00 ± 2.05) (P < 0.01). There were no significant differences in HAMA scores between therapy termination and the follow-up periods (P > 0.05). In the DEX group, the HAMA scores at baseline (16.78 ± 4.48) were also significantly higher compared to those at therapy termination (10.00 ± 3.40), as well as at the 1-month (10.78 ± 3.48), 3-month (11.04 ± 3.36), and 6-month follow-ups (11.22 ± 2.43) (P < 0.01). Additionally, there were no significant differences in HAMA scores between therapy termination and the follow-up periods (P > 0.05) (depicted in Fig. 3E). In the rTMS + DEX group, the HAMD scores were significantly reduced at therapy termination (9.21 ± 2.10), as well as at the 1-month (9.63 ± 2.09), 3-month (9.74 ± 1.82), and 6-month follow-ups (9.95 ± 1.58), compared to baseline (15.26 ± 3.45) (P < 0.01). There were no significant differences in the HAMD scores between therapy termination and the follow-up periods (P > 0.05). And similar results were observed in the DEX group. The HAMD scores at therapy termination, as well as at the 1-month (9.48 ± 2.79), 3-month (9.96 ± 2.90), and 6-month follow-ups (10.00 ± 2.35), were all significantly reduced compared to the baseline (16.22 ± 3.87) (P < 0.01). There were no significant differences in the HAMD scores between therapy termination and the follow-up periods (P > 0.05). The changes in HAMD scores are illustrated in Fig. 3F.

The comparison of DEX dosage pre/post-treatment between the two groups revealed that the initial dosage in the rTMS + DEX group (182.63 ± 37.41 ug) was significantly greater than the dose at therapy termination (134.32 ± 31.27 ug) (P < 0.01). Similarly, the initial dosage in the DEX group (168.49 ± 45.46 ug) was significantly greater than the dose at therapy termination (129.36 ± 28.50 ug) (P < 0.01). Both groups displayed a decrease in dosage after treatment, with the rTMS intervention resulting in a greater reduction, as indicated in Table 4.

Table 4.

Comparison of DEX dosage in two groups at baseline and therapy termination.

	Baseline	Therapy termination	Z	P
rTMS + DEX	182.63 ± 37.41	134.32 ± 31.27	-3.171	0.002**
DEX	168.49 ± 45.46	129.36 ± 28.50	-3.385	0.001**

**: P < 0.01.

The indicators in plasma were compared between the two groups, revealing no significant variance in GSH-Px, SOD, IFN-γ, IL-6, and TNF-α at baseline (P > 0.05). However, after the intervention, the rTMS + DEX group exhibited lower levels of IL-6 and TNF-α compared to the DEX group. Conversely, the rTMS + DEX group displayed higher levels of GSH-Px and SOD than the DEX group (P < 0.05), as indicated in Table 5.

Table 5.

Comparison of factors in plasma between the two groups.

project		rTMS + DEX	DEX	Z	P
GSH-Px(nmol/min/mL)	Baseline	795.53 ± 117.27	762.21 ± 93.69	-0.909	0.379
	Therapy termination	872.88 ± 126.44	765.11 ± 93.06	-2.648	0.008**
SOD(U/mL)	Baseline	64.19 ± 9.96	57.68 ± 8.93	-1.621	0.110
	Therapy termination	67.96 ± 11.68	58.22 ± 10.26	-2.078	0.038*
IL-6(pg/mL)	Baseline	18.96 ± 3.12	19.50 ± 4.06	-0.277	0.800
	Therapy termination	12.30 ± 2.55	14.56 ± 2.11	-2.372	0.018*
TNF-α(pg/mL)	Baseline	23.69 ± 3.44	26.52 ± 7.84	-1.008	0.318
	Therapy termination	19.82 ± 6.59	24.27 ± 3.63	-2.550	0.011*
IFN-γ(pg/mL)	Baseline	298.25 ± 47.85	313.54 ± 47.19	-1.067	0.299
	Therapy termination	275.52 ± 56.20	309.91 ± 53.89	-1.878	0.060

*: P < 0.05, **: P < 0.01.

The alteration of sedative and hypnotic drug dosages in patients were shown in Table 6. In the intervention stage (0–4 weeks), there was no increase in the dosages of medication for both the rTMS + DEX and DEX groups. However, during the follow-up period (4–28 weeks), 21.05% of patients in the rTMS + DEX group experienced an increase in dosing, while the remaining 78.95% did not. Similarly, in the DEX group, 26.09% of patients experienced an increase in dosing, while the remaining 73.91% did not.

Table 6.

Comparison of dose with oral medication in two groups.

		rTMS + DEX(n = 19)	DEX(n = 23)
Treatment-period	Number of patients whose dose increased (%)	0 (0%)	0 (0%)
	Number of patients whose dose did not increase (%)	19 (100%)	23 (100%)
Follow-up	Number of patients with an increase in dose (%)	4(21.05%)	6(26.09%)
	Number of patients with no increase in dose (%)	15(78.95%)	17(73.91%)

Safety

Adverse reactions were observed in both groups. In the rTMS + DEX group, 6 patients complained of dizziness and nausea, which accounted for 31.58% of the group, while in the DEX group, 8 patients reported these symptoms, making up 34.78%. Thirst was reported by 7 patients (36.84%) in the rTMS + DEX group and 10 patients (43.48%) in the DEX group. Additionally, local pain at the injection site was reported by 4 patients (21.05%) in the rTMS + DEX group and 5 patients (21.74%) in the DEX group. Furthermore, the incidence of hypertension (defined as an increase of more than 25% over initial blood pressure or an absolute value of 140/90) in the rTMS + DEX and DEX groups was reported in 5 (26.32%) and 6 (26.09%) patients, respectively. Bradycardia (defined as a decrease of more than 25% from baseline or an absolute value of less than 45 beats/min) was recorded in 5 (26.32%) and 7 (30.43%) patients, respectively. No serious adverse events were observed in any of the patients during the intervention and follow-up period, as indicated in Table 7.

Table 7.

The adverse events in two groups.

	rTMS + DEX(n = 19)	DEX(n = 23)
Dizziness	6(31.58%)	8(34.78%)
Thirst	7(36.84%)	10(43.48%)
Local pain	4(21.05%)	5(21.74%)
Hypertension	5(26.32%)	6(26.09%)
Bradycardia	5(26.32%)	7(30.43%)
Irritability, cardiac arrest and death	0 (0%)	0 (0%)

Discussion

The prevalence of insomnia disorder has been rising and often leads to a variety of complications¹. Unfortunately, the current treatment options for chronic insomnia disorder are limited and have shown poor efficacy. rTMS is a complementary and alternative therapy for insomnia, avoiding medication-related adverse events. Researches have indicated that rTMS may pose a positive impact on patients with depression, anxiety, AD, PD, and other neuropsychiatric disorders^4,8. DEX can target the brainstem locus coeruleus-norepinephrine pathway in the central nervous system (CNS), producing a simulated physiological sleep effect. In this study, patients diagnosed with chronic insomnia disorder were recruited and treated using a combination of low-frequency rTMS and DEX as an intervention. We also investigated the effectiveness and safety of this combined approach for treating chronic insomnia disorder, as well as explored the underlying mechanisms involved.

The sleep status of patients in the two groups was assessed using the PSQI and actigraphy data. The PSQI scores at therapy termination were significantly lower than the baseline scores in the group treated with rTMS. Actigraphy data indicated that all patients in both groups experienced a reduction in the duration of light sleep and the frequency of wakefulness, while the duration of deep sleep and REM sleep increased compared to baseline. The findings indicated that the combination of rTMS and DEX increased the duration of deep sleep and REM sleep, while simultaneously decreasing the duration of light sleep and awakening times. These changes led to an improvement in sleep structure and enhanced sleep quality in patients with chronic insomnia disorder. Furthermore, the therapeutic effects persisted for six months.

A research demonstrated similar results in terms of reduced PSQI scores and sleep latency, increased deep sleep, and overall sleep efficiency through rTMS intervention⁹. Another one compared the effects of rTMS with those of medication and psychological treatment, finding that treatment with rTMS significantly improved sleep structure, reduced the number of awakenings, increased slow wave sleep (SWS) and REM sleep, and provided a better prognosis by decreasing hyperactivity in the hypothalamic–pituitary–adrenal axis (HPA) and hypothalamic-pituitary-thyroid (HPT) axes¹⁰. It had also been suggested that rTMS could enhance the release of serotonin, melatonin, and gamma-aminobutyric acid (GABA) in the brain. This effect decreased dopamine levels, which contributed to regulate the sleep–wake cycle and increase non-rapid eye movement (NREM) sleep, ultimately reducing metabolite levels in the CNS and down-regulating HPA and HPT activities¹¹. Previous research indicated that applying low-frequency rTMS on DLPFC had shown promising outcomes in improving the sleep structure, quality, and cognitive function in individuals with insomnia¹². A meta-analysis suggested that rTMS may effectively aid in regulating sleep structure by extending the duration of SWS and REM sleep, thereby leading to a satisfactory improvement in sleep quality¹³.

Insomnia showed closely associated with negative emotions in individuals, and prolonged insomnia could exacerbate or trigger anxiety and depression. Patients with chronic insomnia disorder usually suffered from anxiety or depression, and further research confirmed a genetic link between insomnia, depression, and other mental characteristics^14,15. In this study, the combination of low-frequency rTMS and DEX treatment significantly reduced the severity of anxiety and depression in patients. Some studies suggested that high-quality sleep could decrease the occurrence of negative moods and enhance happiness, possibly due to the improvement in cognitive function during sleep, which leading to better suppression of negative emotion¹⁶. A comparative analysis of HAMD and HAMA in the two groups revealed that intervention of low-frequency rTMS and DEX significantly decreased depression and anxiety in patients. These results suggested that the combination of rTMS and DEX could diminish the severity of depression and anxiety in patients with chronic insomnia disorder, with effects lasting at least 6 months. The application of rTMS to the DLPFC may ameliorate various symptoms, including memory impairment, depression, anxiety, and fatigue, by affecting distinct brain regions¹⁷. Furthermore, the calming properties of DEX may contribute to the relief of depression and anxiety among individuals suffering from insomnia. These findings align closely with the outcomes observed in our study.

The dosage of DEX administered to patients in the two groups was significantly lower at therapy termination when compared to the baseline. DEX was a highly selective α2-adrenergic receptor agonist that possesses analgesic, sedative, and anxiolytic effects¹⁸. Moreover, it impacted the locus coeruleus-norepinephrine pathway, suppressing multiple arousal regions within the CNS and reducing excessive wakefulness. A research revealed that DEX may extend the duration of deep sleep in patients with insomnia, thereby inducing a state akin to natural sleep¹⁹. Through chemical neural regulation, DEX could correct the disrupted sleep structure. Some studies had indicated that DEX might mitigate neuronal apoptosis caused by sleep deprivation and exhibit neuroprotective properties^20,21. Additionally, DEX may enhance the flow of cerebrospinal fluid (CSF) in the CNS by reducing the release of norepinephrine, promoting sleep, increasing intercellular space and reducing lymphatic flow resistance. These changes may ultimately contribute to an improvement in the efficiency of waste removal in the brain²². Our findings demonstrated that the implementation of low-frequency rTMS could lead to a greater reduction in the dosage of DEX, and the outcome may be attributed to the combined impact of rTMS and DEX on the neural regulation of individuals suffering from insomnia.

During the treatment period, there was no increase in sedative and hypnotic medications to any of the patients. However, during the follow-up period, the dose of medications was increased for certain patients. Adverse reactions related to the treatment encompassed thirst, dizziness, nausea, bradycardia, hypertension, and localized pain. DEX produced a more pronounced impact on blood pressure and heart rate, demonstrating a dual-phase effect on blood pressure. Hypotension may occur due to variations in drug concentration in the blood, which could also lead to hypertension. Notably, no serious adverse reactions, such as allergies, cardiac arrest, or fatalities, were observed in our patients. In short, the combination of low-frequency rTMS and DEX yielded a significant therapeutic effect on chronic insomnia disorder, while maintaining a high level of safety and a positive prognosis.

Patients with chronic insomnia disorder experienced a prolonged inflammatory stimulus that increased the expression of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α. This inflammatory response was once believed to be the underlying mechanism of insomnia disorder²³. In this study, we reported that patients with chronic insomnia disorder who underwent rTMS exhibited lower levels of IL-6 and TNF-α in blood plasma. Conversely, the levels of GSH-Px and SOD, which served as key antioxidant factors essential for maintaining the delicate balance between oxidation and antioxidant processes, were significantly elevated in patients undergoing rTMS treatment. Notably, the duration of REM sleep was significantly prolonged in patients undergoing rTMS therapy compared to those not receiving the intervention. These findings indicated that low-frequency rTMS not only effectively alleviated insomnia symptoms but may also bolstered antioxidant defenses by elevating critical factors like GSH-Px and SOD, while simultaneously suppressing the production of pro-inflammatory mediators such as IL-6 and TNF-α. Other studies demonstrated that rTMS could inhibit the increase of IL-6 and TNF-α by reducing microglial activation and alleviating depression in mice²⁴. Additionally, it was proposed that the application of low-frequency rTMS to patients with insomnia disorder may suppress the activities of the HPA and HPT axis by enhancing the release of melatonin, serotonin, and norepinephrine, ultimately improving sleep quality²⁵.

Limitations

There are several limitations in this clinical trial. Firstly, the sample size is constrained. Future studies will require large-scale, multi-center clinical trials with an expanded sample size and longer follow-up periods to verify and evaluate efficacy over extended periods of time. Secondly, a sham rTMS intervention group was not established in this study to exclude the placebo effect of the intervention. Thirdly, this study was grouped entirely based on the patients’ intentions, thus it did not did not adhere to the principle of randomization, which might increase the risk of potential selection bias. And more rigorous randomized controlled trials should be designed in the future. Fourthly, insomnia disorder is known to impair alertness, attention, and memory, resulting in a decrease in cognitive function. The Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) would be incorporated to assess changes in patients’ cognitive abilities in future studies. Fifthly, polysomnography, recognized as a standard method for the objective evaluation of sleep structure, has the capability to accurately represent sleep structure and would be employed to assess patients at variable time intervals. Lastly, due to presence of the blood–brain barrier, the levels of indicators in plasma differ from those in CSF. Therefore, the indicators measured in peripheral blood serve as preliminary indicators.

Conclusion

In the clinical trial, we found that the combination of low-frequency rTMS and DEX effectively decreased the duration of light sleep and the frequency of awakening, while increasing the duration of deep sleep and REM sleep. These changes served to an improved overall sleep structure, resulting in enhanced sleep quality for patients suffering from chronic insomnia disorder. Moreover, the approach of rTMS and DEX also helped to reduce anxiety and depression degree, with the positive effects persisting for six months. The improvement in REM sleep through rTMS was associated with an increased expression of antioxidant factors including GSH-Px and SOD, and a reduction in pro-inflammatory factors such as IL-6 and TNF-α.

Abbreviations

AD

Alzheimer’s disease

APA

American psychiatric association

BMI

Body mass index

CNS

Central nervous system

COVID-19

Coronavirus disease 2019

CSF

Cerebrospinal fluid

DEX

Dexmedetomidine

DLPFC

Dorsolateral prefrontal cortex

DSM-5

Diagnostic and statistical manual of mental disorders, fifth edition

ELISA

Enzyme-linked immunosorbent assay

GABA

Gamma aminobutyric acid

GSH-Px

Glutathione peroxidase

HAMA

Hamilton anxiety rating scale

HAMD

Hamilton depression rating scale

HPA

Hypothalamic-pituitary-adrenal axis

HPT

Hypothalamic-pituitary-thyroid

IL-6

Interleukin-6

IFN-γ

Interferon-γ

MMSE

Mini-mental state examination

MoCA

Montreal cognitive assessment

NREM

Non-rapid eye movement

PD

Parkinson’s disease

PSQI

Pittsburgh Sleep Quality Index

REM

Rapid eye movement

RMT

Resting motor threshold

rTMS

Repetitive transcranial magnetic stimulation

SOD

Superoxide dismutase

SWS

Slow wave sleep

TNF-α

Tumor necrosis factor-α

Author contributions

Xin Zheng was responsible for the study design, acquisition of data and statistical analysis, as well as the initial drafting of the manuscript. Qian-Nan Zhao and Qi-Wu Fang helped to collect data and revise the manuscript for important intellectual content. Ruo-Guo Wang and Bao-Feng Ma contributed to acquisition, interpretation of data, and manuscript modification. John P Williams modified the final manuscript. Jian-Feng Zhang contributed to acquisition, interpretation of data, and manuscript revision. Jian-Xiong An was contributed to the study design and administrative, financial, or material support. The final manuscript was read and approved by all authors.

Funding

This trial was funded by the National Key Research and Development Program of China (2024YFC2510200) and the National Natural Science Foundation of China (82405553).

Data availability

The data that support the findings of this study are not publicly accessible due to sensitivity concerns and can be available from the corresponding author upon a reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Ethics

Before participation in the study, all subjects gave their informed consent in writing. The study received approval from the Ethics Committee of the Aviation General Hospital (2021-KY-01–08), adhering to the principles of the 1975 Helsinki Declaration, as amended in Fortaleza, Brazil in 2013.

Consent for publication

Consent to publish this paper was obtained from all authors.