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 number: ChiCTR-ICR-15006273) and was performed according to the CONSORT 2010 extension to randomised pilot and feasibility trials [15]. The patients were admitted to the Second People's Hospital of Chengdu due to ischemic stroke within 2 weeks of symptom onset between January 2015 and December 2018. All patient with a clinical diagnosis of ischemic stroke confirmed by brain computed tomography or magnetic resonance imaging.
Depression Screening
The diagnosis of clinical depression was verified by 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. Stoke severity was assessed based on National Institutes of Health Stroke Scale (NIHSS). The study was approved by the ethics committees of the medical centers. 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 14d, (2)no neurological or psychiatric disease before stroke, (3) no aphasia,(4) no drug, (5) no hearing deficit, (6) right-handed, (7) Finnish-speaking 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 stimulation parameters: the pulse width of PMES and sham was 9 μS, the pulse frequency of PMES and sham was 1.8khz,10Hz, respectively. The peak current of PMES and sham was 10mA and 0.18 mA, respectively. Previous studies have shown that 10mA is very safe, and some patients may have slight tingling, but no skin redness or burn [16]. 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 3 months.
In this study, selective serotonin reuptake inhibitor (SSRI) is recommended as the first choice for depressive patients, and sertraline is recommended as the initial antidepressant because of its tolerance to medical treatment and relatively low incidence of cardiovascular side effects.
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 center. 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 without a detection device. 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 cognitive and depressive state assessment at 2 weeks (baseline) and 6 months after stroke.
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. Depressive state was assessed using HRSD. Treatment response was defined as ≥50% reduction in HRSD. 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 for comparison with baseline.
All patients were followed up for 6 months. The change in HRSD and MoCA was detected at 6 months after treatment. The clinical outcome was defined as treatment response(≥50% reduction in HRSD) and depression remission (HRSD≤9)at 6 months after stroke onset.
Statistical analysis
Firstly, patients were classified into sham and PMES groups. Demographic characteristics, vascular risk factors, current smoking, and so on were compared between the 2 subgroups in univariate analysis, using Pearson χ2 test, Fisher exact 2-sided test, or Student t test, mean values(±standard deviation) were calculated for continuous variables. Mann-Whitney U test was used to test differences between two groups. Secondly, We then performed logistic regressions analyses to determine the association between PMES and treatment response, depression remission and MoCA <26, adjusting for all confounders (age, NIHSS, sex, BMI,hypertension, current smoking, current drinking, diabetes, hyperlipidemia, atrial fibrillation, family history of stroke, baseline MoCA score or 6-month MoCA score, HRSD score , medications use, infarct location). Results were expressed as adjusted odds ratios (OR) with the corresponding 95% confidence interval (CI). The data were analyzed using SPSS software (SPASS 22.0). P values<0.05 were considered as statistically significant.