This study was a single-blind (participant), sham-controlled randomized clinical trial conducted at the Chen Wai Wai Vivien Foundation Therapeutic Physical Mental Exercise Centre at the Department of Psychiatry of the Chinese University of Hong Kong from August 2016 to March 2019 (ChiCTR-IOR-16008191). The logistics of this trial was followed the Consolidated Standards of Reporting Trials (CONSORT) flow diagram (Figure 1). Eligible participants were enrolled and randomly assigned to a three-week intervention of either active rTMS or sham rTMS. After the intervention, participants were followed for 8 weeks.
The inclusion criteria include : (1) Aged from 60 to 90 years old; (2) DSM-5 diagnosis of either major neurocognitive disorder due to Alzheimer’s disease (NCD-AD) or major neurocognitive disorder due to vascular disease (NCD-vascular), including significant cognitive decline in the core domains of cognitive function (attention, memory, perceptual-motor, language and executive function), and with clinical or neuroimaging features indicative of either AD or small vessel disease; (4) Cornell scale for depression in dementia (CSDD) with a rating score of 7 or above, indicating clinically depression . Throughout the trial, anti-dementia and other psychotropic medication were kept constant and recorded.
We excluded the participants who had a history of primary bipolar or other psychotic disorders, and major neurological disorders, including stroke, transient ischemic attack or traumatic brain injury. The participants were also excluded if they were unable to attend the MRI scanning and rTMS session due to contraindications (e.g., metal on or inside the body).
Randomization and masking
We randomly assigned the participants (1:1) to receive either active rTMS or sham rTMS. We masked the participants, caregivers, and assessors at the center to intervention assignment. The research staff performing the rTMS was open to the randomization status. The participants who voluntarily withdrew or discontinued the rTMS treatment due to a serious adverse event, no further data from the point of withdrawal was collected.
Pre-intervention and preparation
Structural magnetic resonance imaging (sMRI) data was acquired using a 3T MRI scanner (Philips Healthcare, Best, Netherlands) at the Prince of Wales Hospital in Hong Kong. The T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence was empirically optimized for the grey-white contrast, with repetition time (TR) = 7.6 ms, echo time (TE) = 3.5ms, field of view (FOV) = 230 mm, thickness = 0.6 mm, axial acquisition with a 256 × 256 × 192 matrix, flip angle (FA) = 15o and the voxel size of 1 mm × 1 mm × 1 mm.
Neuronavigated rTMS intervention
As shown in Figure 2, the pipeline of neuronavigated rTMS intervention contained three parts: (1) Reconstruction and localization: Based on individual sMRI data, we firstly reconstructed the scalp and cortex, and then localized the targets of interest labelled with the Montreal Neurological Institute (MNI) coordinates (x, y, z) (Figure 2A); (2) Measurement of motor threshold (MT) : MT was measured through the single-pulse TMS over left primary motor cortex (M1, hand area) prior to the first treatment. The MT was defined as the minimum stimulus intensity required to evoke an motor evoked potential (MEP) with a peak-to-peak amplitude ≥ 50μV in at least 5 out of 10 consecutive trials recorded in the electromyography (EMG) system (Figure 2B); (3) Treatment: 10 Hz high-frequency rTMS over left DLPFC was provided by using Magstim Super Rapid stimulator (Magstim, UK) that generates short duration biphasic pulses. The Magstim 70 mm figure-8 coil (AirFilm® Coil AFC) was held in place with a custom-made stand tangential to the scalp with the handle pointing back and away from the midline at 45˚ (Figure 2C).
An MRI-to-head coregistration was performed to localize the anatomical landmarks individually. Once successfully coregistered, a real-time infrared tracking system (Polaris Northern Digital) was used to monitor the coil position and the orientation of the stimulation targets. As mentioned, we targeted the location of left DLPFC with the MNI coordinates as [x = –46, y = 45, z = 38], being carefully to locate this region within the grey matter on the top of middle frontal gyrus in the Brainsight system [26-28].
The HF-rTMS intensity was set at 120% of MT, and 30 trains of 10 Hz stimulation with 5-second stimulation duration and 25-second interval. This protocol resulted in the delivery of 1500 pulses in each rTMS treatment session. The treatment schedule was 1 session per day, 5 days per week, lasting for 3 weeks. In the condition of sham rTMS, same coil was used for single blind trial in order to compensate for the acoustic and other non-specific effect .
Fifteen sessions of HF-rTMS were conducted by trained clinician. Outcome measures were collected at T0 (baseline), T1 (3rd week, post-intervention), T2 (6th week, 3 weeks post-intervention,) and T3 (12th week, 6 weeks post-intervention). All research staffs were trained to ensure the data accuracy, consistency and completeness.
- Severity of depression: Cornell Scale for Depression in Dementia (CSDD) was used for assessing depressive symptoms. In this study, a cutoff score of 7 indicated clinically significant depression in NCD patients. Responders were defined as having a 50% reduction in the CSDD scores from the baseline [30,31].
- Global cognitive function: The Montreal Cognitive Assessment (MoCA) Hong Kong version was used to measure the global cognitive changes associated with intervention [32,33].
- Neuropsychiatric symptoms: The Chinese Neuropsychiatric Inventory (NPI) was used to assess the changes of neuropsychiatric symptoms across twelve domains .
- Quality of life: Quality of Life in Alzheimer's disease scale (QoL-AD), including both patient and caregiver components, is a 13-item scale designed for generic measure of the quality of life in dementia patients .
- Brain-derived neurotrophic factor (BDNF) level was used as a peripheral marker of neuroplastic response . Serum BDNF was assayed in duplicate according to the manufacturer's instructions (R&D Systems, Inc., Minneapolis, MN, USA).
- Adverse events: Adverse Event Checklist (AEC) covering the potential adverse effect associated with HF-rTMS administration was conducted in each assessment point through the study .
Analyses were on an intention-to-treat basis. Linear mixed models were conducted to assess the differences between intervention groups on the primary and secondary outcomes at each time point. Treatment, time points, and their interaction were modeled as fixed effect. Participants were modeled as random effect at different time points. Score changes of depression score and global cognition from baseline to each follow-up point and intervention group were tested with occasions (time points) at level one and participants at level two. Cohen’s d was calculated as a measure of effect size, of which Cohen’s d ≥ 0.8 refers to a strong effect, 0.5 ≤ Cohen’s d < 0.8 refers to a moderate effect and Cohen’s d < 0.5 means the effect is statistically significant but weak . All analyses were performed using SPSS Statistics 24.0 (IBM, Armonk, NY).