Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001314617
Ethics application status
Approved
Date submitted
22/11/2023
Date registered
15/12/2023
Date last updated
15/12/2023
Date data sharing statement initially provided
15/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating individualised theta transcranial alternating current stimulation (tACS) effects in healthy brain (tACS-theta 1)
Scientific title
The effects of individualising theta transcranial alternating current stimulation on theta power, working memory performance, and mood in healthy subjects
Secondary ID [1] 311015 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 332128 0
Condition category
Condition code
Mental Health 328854 328854 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial alternating current stimulation (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.
Theta-tACS involves applying low-frequency alternating current to the scalp to modulate theta brainwave activity. Specifically, the study investigates whether theta-tACS produces greater effects when applied at individualised theta frequency (matched-ITF) or at 1 Hz below ITF (offset-ITF) and comparing both conditions to sham tACS.
Administration of tACS will occur via 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 encased in commercially supplied saline soaked sponges and are held in place with a fitted cap.
A within-subjects design will be utilised with all participants completing each stimulation condition. Participants will attend 3 sessions where they will complete working memory tasks while receiving one of the 3 stimulation conditions at each visit:
1. individualised theta frequency (aka matched-ITF),
2. offset at 1Hz below the ITF (aka offset-ITF), and
3. sham tACS (aka sham-tACS)

The sessions will be held at the Clinical Suites of the John Curtin School of Medical Research, ANU. All procedures are conducted in person and performed under the direction/supervision of a study researcher. Participants will initially be sent an online tACS safety form to complete prior to their first visit. This will determine if they can safely receive tACS and participate in the study.

Upon arrival to the initial visit, participants completed tACS safety will be reviewed by the study researcher, consent for participation obtained, and participants will complete a demographic information survey and the state-trait anxiety inventory (STAI). At all visits, participants will also complete 3 visual analogue scales that assess mood, anxiety, and quality of sleep. Initially, electroencephalography (EEG) will be used to record brain activity during a working memory (WM) task in the absence of tACS to determine the fronto-midline ITF for each participant prior to the stimulation period. Participants will undergo the WM task a second time while exposed to a tACS condition. The iTF will be recalibrated during breaks offered throughout the working memory task to account for any drift from the initial ITF determined. The applied tACS frequency will be updated accordingly for subsequent stimulating periods while completing the task. The WM task will be completed a third time in the absence of tACS with EEG, and the same visual analogue scale to assess mood and anxiety will be completed for a second time. Resting EEG will be recorded before and after the completion of each WM task. The WM tasks will be presented in 4 blocks of 5-minute stimulation with a 1-minute rest period between blocks.
The WM task used is called n-back task, where letters are systematically presented on the screen. Participants are required to identify target letters which is a current letter that matches a previous letter that was 'n' back. For example, in a 3-back task, the target will be a current letter that matches the letter presented 3 letters prior.
For the two active tACS conditions, a peak-to-peak intensity of 1.5mA will be administered for a maximum of 20 minutes, with a 10s ramp-up and 10s ramp-down every time stimulation starts and stops. In the sham condition, the current will be delivered at an intensity of 1.5mA in the first and last 30 seconds at the ITF (including 10s ramp up and down) to emulate tACS associated sensations without producing enduring physiological effects.
A minimum of 72 hours and up to 3 weeks is required between sessions.
Intervention code [1] 327454 0
Treatment: Devices
Comparator / control treatment
In the sham condition, the current will be delivered at an intensity of 1.5mA for a shorter period of time to emulate sensations associated with tACS administration without producing any enduring physiological effects.
Sham tACS as 'reference' comparator
Control group
Active

Outcomes
Primary outcome [1] 336650 0
Individualised theta tACS effects on theta power.
Timepoint [1] 336650 0
Before and after stimulation at each visit
Secondary outcome [1] 429176 0
Individualised theta tACS effects on working memory performance
Timepoint [1] 429176 0
Before and after stimulation at each visit
Secondary outcome [2] 429177 0
Changes in anxiety level
Timepoint [2] 429177 0
At the beginning of Visit 1 and at the end of Visit 3
Secondary outcome [3] 429178 0
Changes in mood
Timepoint [3] 429178 0
Start and end of each treatment session
Secondary outcome [4] 429179 0
Changes in anxiety level
Timepoint [4] 429179 0
Start and end of each treatment session
Secondary outcome [5] 429180 0
Changes in sleep quality
Timepoint [5] 429180 0
Start and end of each treatment session

Eligibility
Key inclusion criteria
Aged between 18 and 50 years
No active medical illness
No current psychiatric illness or a history of a psychotic disorder or bipolar disorder
Able to provide informed consent
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Failure of a tACS safety screen (e.g., contraindications to tACS such as metal implant in head or history of epilesy and/seizures)
Pregnancy or breastfeeding

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by a computer software. All participants will receive all three stimulation conditions, however the order of the conditions will be randomly assigned for each participant (i.e. Participant A may receive stimulation condition 3 followed by 1 and then 2)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size/Power
20 healthy participants will be recruited to participate in each study. The required sample size was calculated using the G*power statistical power analysis program, where effect size f = 0.3, power = 80%, 3 groups, 1 measure, and correlation between repeated measures of 0.5.

Analyses
Repeated measures Analyses of Variance (ANOVA’s) and correlational analyses (or their equivalent designs using EEG-specific permutations testing analysis methods) will be used to investigate the relationships between tACS conditions (matched-ITF vs. Offset-ITF vs. Sham) on outcome variables (theta power, working memory performance on the N-back task, and Visual Analogue scales for mood, anxiety, and sleep)

Pre- and Post-resting EEG - Data will be pre-processed to remove non-neural artifacts using our previously validated processing pipeline. 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 using automated and objective measures established by previous research, (3) wavelet enhanced independent component analysis to reduce remaining eye movement, muscle related, and environmental electrical artifacts.

Theta Power - Data will be further processed using an extended version (eBOSC) of the Better OSCillation (BOSC) method. This method was designed to detect the arrhythmic, non-oscillatory portion of the EEG signal (which shows a 1/f power/frequency distribution). Thus, at a given frequency, BOSC detects increases in power above the non-oscillatory EEG activity of a specific minimum duration thereby removing non-oscillatory contribution to the spectral amplitude, ensuring only oscillatory activity remains. In eBOSC, rhythm detection benchmarks are derived using simulations to further characterize rhythmicity. The output of eBOSC includes a power spectrum, where individual frequencies of interest can be averaged across the theta window for example, enabling us to determine whether our stimulation conditions have modulated theta oscillatory power. The removal of the non-oscillatory 1/f activity ensures our peak frequency calculations are not influenced by the non-oscillatory activity (which shows a 1/f distribution and can shift peak frequency power estimates towards the lower frequencies).

Endogenous theta frequency - in addition to the analysis of theta power using eBOSC, we will examine the averaged theta peak frequency. We will compute this both from electrodes of interest lying over the stimulated brain regions using eBOSC as described above and using a generalised eigenvector decomposition (GED) and frequency clustering-based method known as gedBounds. This method decomposes data into the maximum difference between an oscillatory frequency of interest and the broadband frequency signal using the GED approach, then uses a clustering approach to determine the boundaries of oscillatory frequencies, providing an empirical method to detect oscillatory frequencies generated by underlying neural networks. Applying both of these methods will provide confirmatory evidence that theta peak oscillations are modulated by the tACS when detected at the scalp level (with eBOSC) and in the source space (using gedBounds).

Individualised theta frequency (ITF) - The ITF applied to the stimulation protocol for each individual participant will be based on the dominant endogenous theta frequency measured across fronto-midline brain areas recorded with EEG.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/01/2024
Actual
Date of last participant enrolment
Anticipated
1/11/2025
Actual
Date of last data collection
Anticipated
1/01/2026
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT

Funding & Sponsors
Funding source category [1] 315278 0
Government body
Name [1] 315278 0
NHMRC (MRFF National Critical Research Infrastructure Grant)
Country [1] 315278 0
Australia
Primary sponsor type
University
Name
Australian National University
Address
The Australian National University, Canberra, ACT 2600
Country
Australia
Secondary sponsor category [1] 317316 0
None
Name [1] 317316 0
Address [1] 317316 0
Country [1] 317316 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314197 0
ACT Health HREC
Ethics committee address [1] 314197 0
Building 10, Level 6, Canberra Hospital Yamba Drive, Garran ACT 2605
Ethics committee country [1] 314197 0
Australia
Date submitted for ethics approval [1] 314197 0
04/06/2023
Approval date [1] 314197 0
25/10/2023
Ethics approval number [1] 314197 0
2023.ETH.00117

Summary
Brief summary
Theta tACS is a potentially efficacious treatment for depression that warrants development. However, there are inconsistent findings in the tACS literature making the optimal selection of stimulation parameters challenging. In our proposed research, we aim to explore several tACS protocols to identify an optimal procedure that can be used to modify theta activity. We aim to explore 2 stimulation approaches to modify theta oscillations (as well as mood and performance on working memory task to explore behavioural correlates of changes in theta activity) in healthy individuals.

Specifically, we aim to investigate whether theta-tACS produces greater effects when applied at individualised theta frequency (i.e., matched-ITF tACS) or at 1Hz below the ITF (offset-ITF tACS) with both compared to a sham tACS condition. We will investigate effects on theta power, working memory and mood.

We hypothesise that:
1.Matched-ITF tACS will increase theta power to a greater degree than offset-ITF tACS and sham tACS
2.Matched-ITF tACS will increase working memory to a greater degree than offset-ITF tACS and sham tACS
3.Matched-ITF tACS will transiently increase positive mood to a greater degree than offset-ITF tACS and sham tACS
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130758 0
Prof Paul Fitzgerald
Address 130758 0
Rm 1.27, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT 2601
Country 130758 0
Australia
Phone 130758 0
+61 2 6125 2622
Fax 130758 0
Email 130758 0
paul.fitzgerald@anu.edu.au
Contact person for public queries
Name 130759 0
Ms Jeydhurga Raveendran
Address 130759 0
Rm 1.46, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT, 2601
Country 130759 0
Australia
Phone 130759 0
+61 2 6125 4153
Fax 130759 0
Email 130759 0
jeydhurga.raveendran@anu.edu.au
Contact person for scientific queries
Name 130760 0
Dr Stephanie Gotsis
Address 130760 0
Rm 1.46, Florey Building, 54 Mills Road, The Australian National University, Canberra ACT, 2601
Country 130760 0
Australia
Phone 130760 0
+61 2 6125 4153
Fax 130760 0
Email 130760 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


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.