Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001264673
Ethics application status
Approved
Date submitted
29/09/2023
Date registered
6/12/2023
Date last updated
6/12/2023
Date data sharing statement initially provided
6/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Closed loop transcranial alternating current stimulation in depression (tACS-Depression)
Scientific title
Investigating transcranial alternating current stimulation effects on mood and theta brain activity in patients with depression
Secondary ID [1] 310707 0
None
Universal Trial Number (UTN)
Trial acronym
tACS-Depression
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 331630 0
Condition category
Condition code
Mental Health 328358 328358 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial Alternating Current (tACS) is a form of non-invasive brain stimulation that delivers a weak electrical current that alternates at a specified frequency back and forth between electrodes. Administration of tACS will be provided using a custom-built tACS-EEG device called the Rio Transceiver, manufactured by eemagine Medical Imaging Solutions GmbH. The device consists of a battery-driven unit that allows for the combined recording of electroencephalography (EEG) signals and administration of tACS. The device delivers a voltage controlled current across stimulation electrodes made of conductive rubber encases in commercially supplied saline soaked sponges held in fitted cap. Stimulating electrodes will be positioned on the scalp at the 10-20 EEG system location of F5, F6 and Fz.
To date, there have been an increasing number of studies exploring the potential uses of tACS and EEG, especially for improving aspects of cognition and mood in those with depression. We aim to optimize tACS treatment by individualizing the stimulation frequency delivered. This is determined by using EEG to measure the in-phase peak theta activation for each individual (individual theta frequency; ITF). The ITF will be measured with EEG at the beginning of each session and will be recalibrated and adjusted by the device accordingly during the rest periods between blocks (creating a closed-loop tACS-EEG design). For all active tACS conditions, a peak-to-peak intensity of 1.5mA will be administered for each participant for a maximum of 20 minutes with a 10s ramp-up and 10s ramp-down every time the stimulation starts and stops.
Participant will be asked to complete daily treatment sessions (i.e 5 days/week) over 4 weeks.
On site: During a given treatment session, participant is required to be awake, alert and aware. The study researcher will provide clear instructions on where the participant is to be seated and demonstrate how to prepare the tACS-EEG cap and fit it to the participant's head. The stimulation and EEG electrodes in the cap are connected to a battery driven, portable device (i.e. the Rio Transceiver). Administration of tACS and recording with EEG will be automatically triggered while participants complete a series of working memory tasks. Participants will be aware that tACS is given while they complete each block of the working memory tasks. Each block is designed to run for 5 minutes over 4 blocks. tACS ceases at the end of each block, during which participants can rest from the task. After a minimum of 30 sec rest (participant can take a longer break if needed), participants will be given instructions on the screen to press a key to continue with the next block. The total duration of the breaks between blocks may vary depending on participants needs, although it will be recommended that the breaks do not exceed 5 minutes. EEG will be used to record brain activity for 1 minute, during which participants are instructed to remain still and relaxed with their eyes open. Following the completion of the working memory tasks, the study researcher will remove the cap and demonstrate how to clean and care for the equipment.
Sessions on-site are not limited; participants will be able to attend all sessions on-site until competency to carry out at home sessions is clearly demonstrated.
At home: All procedures outlined above will be presented to participants in a way that will teach them how to self-administer treatment at home. As the treatment itself (tACS and EEG) is pre-programmed into the device and triggered by participants as they complete a highly guided series of working memory tasks. Participants will primarily need to know how to prepare the cap and clean the cap for each session. Prior to being allowed to proceed with home-based treatment, participants will need to complete a competency assessment for self-administration. The first 2 at home sessions will be supervised by study researchers via video call. In addition, the device is designed to collect data about the location, date, start and end times of stimulation, side effects experienced, and comments. This data is for researchers to monitor and view and will be used to ensure compliance to the protocol. If participants miss a scheduled treatment session, this will be evident to researchers as there will be absences in data stored. We will also remain in close contact with participants throughout to ensure continued appropriate use and address issues as they arise promptly.
Intervention code [1] 327106 0
Treatment: Devices
Comparator / control treatment
In the sham condition, the current will be delivered at an intensity of 1.5mA in the first and last 30 seconds (including the 10s ramp-up/down) at the ITF, to emulate sensations associated with tACS administration without producing any enduring psychological effects.
Control group
Placebo

Outcomes
Primary outcome [1] 336569 0
Changes in clinical severity of Depression
Timepoint [1] 336569 0
Baseline, mid-treatment (~week 2 post baseline) and end of treatment (~week 4 post baseline).
Secondary outcome [1] 427298 0
Changes in theta power
Timepoint [1] 427298 0
baseline and post-treatment (within 3 days of final treatment session)
Secondary outcome [2] 427299 0
Changes in clinical severity of Depression and anxiety
Timepoint [2] 427299 0
End of each treatment week (~4 weeks of treatment)
Secondary outcome [3] 427300 0
Changes in behavioural performance
Timepoint [3] 427300 0
Baseline and post-treatment (within 3 days of final treatment session)
Secondary outcome [4] 428827 0
Changes in behavioural performance
Timepoint [4] 428827 0
Baseline and post-treatment (within 3 days of final treatment session)

Eligibility
Key inclusion criteria
- Diagnosis of major depressive disorder as a single or recurrent episode, in accordance with the Diagnostic and Statistical Manual of Mental Disorders edition 5 (DSM-V)
-18 to 80 years of age
- Montgomery-Asberg Depression Rating Scale (MADRS) score of > 19 ( moderate-severe depression)
- No change or initiation of new antidepressant (or other psychoactive) therapy in the four weeks prior to treatment
- Demonstrated capacity to give informed consent
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability to provide informed consent
- Medically unstable
- concomitant active neurological disorder
- Patients who are pregnant or breastfeeding
- Active suicidal intent
- Any psychotic disorder or current active psychotic symptoms
- Patients with intracranial implants
- Another Axis I or Axis II disorder judged to impact on the likelihood of response to treatment.
- fails tACS safety screening (e.g. says yes to having a metal implant in head)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation of participants into intervention or sham condition will occur through a computer-generated randomisation list and an investigator who has no direct contact with participants will be responsible for programming the tACS devices prior to handing them over to participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated to treatment or sham groups using computerised sequence generation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The most comparable study from which to estimate effect sizes for a power analysis provided much shorter periods of non-personalized stimulation (5 days) and showed differences in clinical and EEG variables between tACS and sham with only 10/11 subjects per group. 20 subjects per group will give us 80% power to detect a 10 point difference in performance (SD=10) on a 2 group analysis with 20% drop out. Therefore, we will include 25 subjects per group.

Pre-processing: Data will be pre-processed to remove non-neural artifacts using established processing pipelines validated in a number of studies. Steps will include 1) filtering data to remove 50Hz line noise and low frequency drift caused by skin conductance changes, 2) rejection of atypical periods of EEG data reflecting non-neural electromagnetic activity, 3) independent component analysis to eliminate remaining eye movement, muscle related, and environmental electrical artifacts.
Theta power/activity: Following processing of the EEG data, the Randomised Graphical User Interface (RAGU) will be used to determine if differences between groups in overall theta power or the distribution of theta activity are present.
RAGU uses powerful randomization statistics to make comparisons between groups including activity from all electrodes and time points simultaneously, while still using robust multiple comparison controls. Differences detected at the scalp level using this approach indicate differences in the underlying sources generating the neural activity. Following demonstration of differences in the generators of neural activity using RAGU, source analysis of EEG data can be applied to identify the underlying sources generating the neural activity.

We will run mixed model analyses to study change in depression severity (MADRS and IDAS-II) and emotional Stroop and working memory parameters across time. The repeated measurements of these outcome variables will be analysed by fitting linear mixed models using restricted maximum likelihood (REML) – this will allow all available data to be used without the need for imputation of missing values, the selection of the most suitable variance-covariance model for the repeated measures, using Akaike’s Information Criterion, and the investigation of commonality of any nonlinear trends over time via smoothing splines. The F-test will be used to test for a treatment by time interaction and comparisons between treatment groups at each time point will be based on t-tests that utilize the predicted means and standard errors of difference that are recovered from the fitted mixed model. Diagnostic plots of residuals will be assessed and if deemed necessary, variance-stabilizing transformations will be applied to the outcome variables and inferences will be based on the analyses conducted on the transformed scale. In a series of exploratory analyses, mixed models with covariates for gender, age and time since diagnosis, and their interactions with treatment group and time, will be fitted in order to identify possible moderating effects.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/01/2024
Actual
Date of last participant enrolment
Anticipated
31/10/2025
Actual
Date of last data collection
Anticipated
2/11/2026
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT

Funding & Sponsors
Funding source category [1] 314923 0
Government body
Name [1] 314923 0
NHMRC (MRFF National Critical Research Infrastructure Grant)
Country [1] 314923 0
Australia
Primary sponsor type
University
Name
Australian National University
Address
The Australian National University, Canberra, ACT 2600
Country
Australia
Secondary sponsor category [1] 316928 0
None
Name [1] 316928 0
Address [1] 316928 0
Country [1] 316928 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313914 0
ACT Health HREC
Ethics committee address [1] 313914 0
Building 10, Level 6, Canberra Hospital Yamba Drive, Garran ACT 2605
Ethics committee country [1] 313914 0
Australia
Date submitted for ethics approval [1] 313914 0
09/08/2023
Approval date [1] 313914 0
18/10/2023
Ethics approval number [1] 313914 0
2023.ETH.00138

Summary
Brief summary
Major depressive disorder (MDD) is a severe and common illness. It has been well established that approximately 30% of patients with MDD have an inadequate response to standard medication and psychological therapies. These patients remain disabled for long time as treatment options are limited.
Current brain stimulation treatment options for MDD are costly and can be inconvenient as they may require daily trips to clinics for long treatment sessions that happen over the course of 6 weeks or more. Additionally, we are technically constrained in what we can achieve and current technologies and approach to treat MDD have generally used a ‘one size fits all’ method.
Transcranial alternating current stimulation (tACS) is a novel, non-invasive brain stimulation method that delivers a weak electrical current to the brain and is able to modulate brain oscillatory activity. tACS has potential to change the lives of patients with MDD by specifically targeting brain circuits and oscillations relevant to MDD. Our approach aims to change the ‘one size fits all’ method by conducting a proof-of-concept study demonstrating the feasibility, clinical and electrophysiological impact of closed-loop theta tACS. The study will specifically aim to confirm whether theta oscillations and mood in patients with MDD can be successfully modulated by tACS.
We hypothesize that a series of personalized theta tACS sessions applied to the dorsolateral prefrontal cortex (DLPFC) in patients with depression can modulate the following to a greater degree in participants who are receiving active treatment compared to sham stimulation:
1. Modulate theta activity at rest and during cognitive tasks (measured using EEG) on and emotional Stroop task and a working memory task
2. Modulate behavioral performance on both the emotional Stroop and working memory tasks.
3. Modulate depression symptoms (clinician rated and self-reported).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129774 0
Prof Paul Fitzgerald
Address 129774 0
Rm 1.27, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT 2601
Country 129774 0
Australia
Phone 129774 0
+61 2 6125 2622
Fax 129774 0
Email 129774 0
paul.fitzgerald@anu.edu.au
Contact person for public queries
Name 129775 0
Ms Jeydhurga Raveendran
Address 129775 0
Rm 1.46, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT, 2601
Country 129775 0
Australia
Phone 129775 0
+61 2 6125 4153
Fax 129775 0
Email 129775 0
jeydhurga.raveendran@anu.edu.au
Contact person for scientific queries
Name 129776 0
Dr Stephanie Gotsis
Address 129776 0
Rm 1.46, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT, 2601
Country 129776 0
Australia
Phone 129776 0
+61 2 6125 4153
Fax 129776 0
Email 129776 0
stephanie.gotsis@anu.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The PI has not decided whether IPD will be made available on public directories.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.