Study Population
This study was a prospective, randomized, double-blind, and sham-controlled study. This project was registered in the Chinese Clinical Trial Register (ChiCTR) (Registration for trial number ChiCTR1800016463 was retrospectively completed on June 3,2018) and was performed according to the CONSORT 2010 extension to randomized pilot and feasibility trials [28]. The patients were admitted to the Second People's Hospital of Chengdu due to ischemic stroke within 14 days of symptom onset between January 2015 and December 2018. Ischemic stroke was confirmed by brain computed tomography or magnetic resonance imaging.
Depression Screening
Patients screened positive for depressive symptoms, and whose diagnosis of clinical depression was verified by a diagnostic interview using DSM V criteria. Depression screening was carried out by 30-item Geriatric Depression Scale (GDS),which consists of 30 questions, are scored as 1 point individually, resulting in 0-30 points and being classified as: 0-10, no depression; 11-20, mild depression; 21-30, moderate depression. The diagnosis of depression was validated by Hamilton Rating Scale for Depression (HRSD) in those who scored ≥11 on the GDS and consented to the full study. Stroke severity was assessed based on National Institutes of Health Stroke Scale (NIHSS). The study was approved by the ethics committees of the Second People's Hospital of Chengdu. Informed consent was signed by all the participants.
Inclusion and exclusion criteria
Patients were included if they fulfilled all the following criteria: (1) admission for first-ever ischemic stroke within 14 days, (2) no neurological or psychiatric disease before stroke, (3) no aphasia,(4) no drug abuse, (5) severe hearing deficit unable to complete the scale, (6) right-handed, (7) no serious dysarthria and (8) able to co-operate,(9) no active malignancies;(10) patients could appropriately communicate.
Study Design and grouping
Patients were divided into two groups: the sham and PMES groups. The patients in PMES group received PMES treatment as an add-on to antidepressant and the patients in sham group received sham stimulation and antidepressant.
Treatment methods
After cleaning the bilateral mastoid skin behind the ears, stimulation electrodes were placed. The electrode size was 42x24mm and the conductive area was 19mm (Figure 1). The stimulus parameters were set as follows: pulse width 90 mS for both PMES and sham, frequency 1.8 kHz for PMES and 10 Hz for sham, peak current 10mA for PMES and 0.18mA for sham [29]. Previous studies have shown that 10mA is very safe, and some patients may have slight tingling, but no skin redness or burn [29]. In order to reduce the surface sensation caused by current stimulation, we modulated the low-frequency signal (13-45hz) to the intermediate frequency signal of 1.8kHz and set 1.0-1.2v as the voltage range of the low-frequency signal. This change in the modulation signal in this range causes a slight squeeze. The intermediate-frequency signal was the exponential decay signal with a base of ‘‘a’’ (0<a<1). The signal was a non-polar exponential waveform, which was composed of positive and negative pulse waves and equivalent charges. Negative pulse can depolarize the nerve fiber, while positive pulse can balance the charge, thus eliminating the accumulation of electrostatic charge and reducing the adverse electrochemical reaction. In order to reduce the energy of single pulse, we reduce the base value "a", not the pulse width, thus reducing the degree of extrusion. The surface sensation of real stimulus was close to the surface sensation of sham stimulus, which was a periodic point-contact sense of touch. PMES group and sham group were treated 45 minutes/day lasted 6 months.
In this study, selective serotonin reuptake inhibitor (SSRI) was recommended as the first choice for depressive patients, and sertraline was recommended as the initial antidepressant because of its tolerance to medical treatment and relatively low incidence of cardiovascular side effects. The patients were prescribed sertraline 50mg/day, the dose was adjusted starting from day 7 into 100 mg/day(maximum dose 400mg/day). If patients could not tolerate the side effects of sertraline, another antidepressant was prescribed (escitalopram or paroxetine).
Randomization and double blinding
Patients who met the criteria were assigned to treatment groups according to a predefined randomization plan by using a block size of 4, a ratio of 1:1, and stratified by study team. A computer-generated block randomization list has been prepared by the Clinical Research Unit of The Second People’s Hospital of Chengdu. The randomization was conducted by a statistical analyzer who was not involved in other parts of the study. Patients, investigators and all study personnel were blinded to the treatment allocation. The PMES and sham stimulators had the same external appearances, user manuals and electrodes. They could not be distinguished by their external appearance. We took the following measures to guarantee double-blinding: enrolled patients were not acquainted with each other, there was no physical contact or communication (such as sensory perception) between patients during visits, and all of the patients would be told when enrolled that it was not possible to accurately judge whether they were receiving true or sham stimulation only based on the surface sensation.
Data Collection
Baseline characteristics including demographics, stroke characteristics, NIHSS, risk factors. All patients underwent depressive state and cognitive assessment at 2 weeks (baseline) and 6 months after ischemic stroke.
Depressive state was assessed using HRSD score. Treatment response was defined as ≥50% reduction in HRSD score. Remission has been defined variably as HRSD score of ≤9 (no longer meeting depression criterion), ≤7 (absence of any depressive symptoms) ,or ≤3 (equivalent to healthy controls). We used HRSD score of ≤9 and ≥50% reduction in HRSD score for comparison with baseline. Cognitive state was assessed using the Montreal Cognitive Assessment (MoCA), scores range from 0 to 30 points, with a lower score reflecting greater cognitive impairment, and a cut-off of <26 was considered as indicative of cognitive impairment.
All patients were followed up for 6 months. After discharge, the patients completed treatment at home or nursing home. The patients or caregivers in both groups were trained in using the PMES and sham. All patients were followed up once a month by face-to-face interview or telephone interview.
The change in HRSD and MoCA score was detected at 6 months after treatment. Primary outcomes were treatment response (≥50% reduction in HRSD score) and depression remission (HRSD score≤9) at 6 months after ischemic stroke. Secondary outcome was the percentage of 6-month MoCA score <26.
Statistical analysis
The treat response rate of the PMES group and sham group were about 55% and 35%, respectively. To examine the significant difference between these two groups, the bilateral significance level was established at 5%, and the power of the test was 80%. Considering a 20% loss to follow-up, the sample size of each group was estimated at approximately 120 cases.
Demographic characteristics and vascular risk factors were compared between sham and PMES groups. Continuous data were expressed as mean values (±standard deviation), using the Mann–Whiney U test. Categorical data were described using frequency and percentage, using Pearson χ2 test, Fisher exact 2-sided test. The data were analyzed using SPSS software (SPASS 22.0). P values<0.05 were considered as statistically significant.