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Trial registered on ANZCTR


Registration number
ACTRN12621001649808
Ethics application status
Approved
Date submitted
13/10/2021
Date registered
1/12/2021
Date last updated
1/12/2021
Date data sharing statement initially provided
1/12/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Transforming treatments for schizophrenia: Virtual reality, brain stimulation and social cognition.
Scientific title
Transforming treatments for schizophrenia: Investigating changes in Electroencephalogram (EEG) theta spectral power at the right temperoparietal junction (rTPJ) following combined virtual reality and theta tACS.
Secondary ID [1] 301038 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
schizophrenia 317090 0
social cognition 317091 0
schizoaffective disorder 324288 0
Condition category
Condition code
Mental Health 315255 315255 0 0
Schizophrenia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial Alternating Current Stimulation (tACS) is a gentle non-invasive brain stimulation technique that can be used to change the activity of the brain. It uses a small amount of electric current that is passed between two electrodes placed on your scalp (head).Virtual reality is a technology that can be used to teach people new skills in a computerised virtual environment that feels like real-life.

Participants will attend three research sessions at the Epworth Centre for Innovation in Mental Health (ECIMH) of approximately 2-3 hours.

Session 1:
Participants will be consented into the study and will participate in cognitive and social cognitive tasks as well as a clinical interview regarding current symptoms.

Assessments completed during this session are outlined below. All assessments will be carried out by the PhD Candidate who has undergone training in the administration of all clinical, cognitive and social cognitive tasks.

Clinical Assessments
- Relevant demographic and health-related information.
- Mini International Neuropsychiatric Interview 7.0.2 (MINI): The MINI is a brief diagnostic screening interview
- Positive and Negative Syndrome Scale (PANSS) – Schizophrenia participants only

Cognitive Assessments
- MATRICS subtests (i.e. Trail-Making Task A, Brief Assessment of Cognition in Schizophrenia: Symbol Coding [BACS SC], Brief Visuospatial Memory Test-Revised [BVMT-R], Category Fluency: Animal Naming, Hopkins Verbal Learning Test-Revised [HVLT-R])
- Digit Span subtest from the Wechsler Adult Intelligence Scale (WAIS-IV) Working Memory Index.

Social Cognitive Assessments
- ToM: Abbreviated Faux Pas Task extracted from MINI-SEA
- Attributional Bias: Internal, Personal and Situational Attributions Questionnaire (IPSAQ)
- Social Knowledge: Situational Feature Recognition Test (SFRT)
- Virtual Reality emotion recognition task and ToM task (a version of Penn Emotion Recognition task, Reading the Mind in the Eyes task, Hinting task)

Disability and Functioning Questionnaires
- Sheehan disability scale (SDS): self-report
- Interpersonal Reactivity Index (IRI): self-report
- Empathy Quotient (EQ): self-report

Sessions 2 and 3:
Participants will participate in two lab sessions separated by at least 72 hours. Both lab sessions will be the same except that for one session, participants will receive active 5Hz theta tACS while in the other, they will receive sham. Which condition participants receive and at what time is randomised and double blinded. Each participant will receive the active condition once and the sham condition once.
Participants will also have recordings taken of their brainwaves at rest and while completing a social cognition computer task that is separate to the VR task.

Virtual Reality:
Participants will complete a theory of mind (ToM) VR task to allow activation of the right temporal parietal junction (rTPJ). Participants will wear a head mounted display (HMD) VR (i.e., Oculus Quest 2) to allow for increased possibility of immersion in the virtual environment. Within the tasks, participants will navigate social interactions with virtual avatars and will be required to evaluate the thought processes and intentions of these avatars to interact with them (e.g. a waiter brings out the wrong food to the participant at the restaurant. The program asks "you tell the waiter that they brought you the wrong meal. How should they respond?". Participants select the option they think is most true/correct from a multiple choice selection of possible responses such as "they offer to take it back and bring you the correct meal" or "they tell you to eat it anyway"). Feedback will be provided through the VR task about the participant interpretation of the avatars’ social interactions or cues. While participants are in the virtual environment completing this task, they will receive simultaneous theta-tACS to further modulate rTPJ activity; or sham-tACS to allow a comparison for the active condition.

tACS:
Theta tACS will be administered at a frequency of 5Hz, with a 1.75mA stimulation intensity. Stimulation duration will be limited to 16 minutes per session (including 30 seconds of “ramping up” at commencement, and 30 seconds “ramping down” at 15 minutes 30 seconds). These stimulation parameters are well within the currently recommended safe limits. Sham tACS will comprise 30 seconds of “ramping up” to peak intensity followed immediately by 30 seconds of “ramping down” to zero intensity stimulation at the beginning of the session to improve blinding by causing the characteristic scalp sensations, while not eliciting significant biological effects in proximity to experimental task completion. he tACS montage uses circular PiStim electrodes with water soluble gel (contact area 3.14cm2) at the 10-20 system locations of C4, C6, P2 and P4. The participants will begin the VR task immediately after the 30 seconds of ramp up stimulation.
Intervention code [1] 317346 0
Treatment: Devices
Comparator / control treatment
There will be a placebo/sham stimulation. This comprises a brief period of “ramping up” to peak intensity followed immediately by “ramping down” to zero intensity stimulation. This is a standard sham process used in tACS protocols.
Control group
Placebo

Outcomes
Primary outcome [1] 329168 0
This study will follow a within-subjects repeated measures design comparing the effects of two tACS conditions (i.e., theta-tACS and sham-tACS) combined with a VR theory of mind task in a group of participants with a diagnosis of schizophrenia (23 participants) and age and gender matched healthy controls (23 participants).

The sample size is powered for theta frequency band power as the primary outcome. This will be analysed using EEG recordings taken of participants at rest as well as while completing a ToM computer task (i.e. the Intention Attribution Task). These EEG recordings are completed both pre and post participants receiving tACS while in VR. The data analysis program MATLAB will be used to analyse all EEG data.
Timepoint [1] 329168 0
Pre vs immediately post VR and tACS/sham stimulation.
Secondary outcome [1] 401712 0
Event related potentials (ERP) in brain activity. i.e. brain response at time point of interest to ToM stimuli while completing an intention attribution ToM computer task. This will be analysed using EEG recordings taken of participants at rest as well as while completing a ToM computer task (i.e. the Intention Attribution Task). These EEG recordings are completed both pre and post participants receiving tACS while in VR. The data analysis program MATLAB will be used to analyse all EEG data.
Timepoint [1] 401712 0
Pre- vs immediately post-VR and tACS/sham tACS

Eligibility
Key inclusion criteria
Participants with a diagnosis of schizophrenia or schizoaffective disorder:

- Adults between 18 and 55 years of age.
- Diagnosis of schizophrenia or schizoaffective disorder as confirmed by the MINI 7.0.2.
- Ability to provide informed consent and show understanding of participation by relaying key information to researcher.

Healthy Volunteers:
- Adults aged 18-55 years
- No history of mental illness confirmed with MINI
- No unstable medical conditions
- No contraindications to receiving tACS (mentioned in exclusion criteria)
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Commencement or significant dosage alteration of other psychotropic medications (i.e., anti-depressants, anti-psychotics) during the four weeks prior to an experimental session.
- Currently taking any medication shown to interfere with the effects of tACS; namely benzodiazepines
- A current substance use or alcohol use disorder
- Any history of significant head injury or traumatic brain injury, as defined by a loss of consciousness greater than 30 minutes or requiring a hospital admission.
- Unstable medical or neurological illness.
- Pregnancy or breastfeeding.
- An uncorrected hearing or visual impairment (including difficulty with colour perception).
- Significant difficulties with understanding or communicating in English.

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 involves contacting the holder of the allocation schedule who provides unblinding information
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. 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

Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The study is powered for the primary outcome variable of theta power. Based on previous research (Pahor & JauĊĦovec, 2014) a conservatively small effect size was estimated (d=0.20). Resulting in a total sample size of 46 (23 schizophrenia, 23 healthy controls) calculated via G*Power (Faul, Erdfelder, Lang, & Buchner, 2007). Based on this calculation, we will have a 90% power to identify a difference at p = < .05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
4/08/2021
Date of last participant enrolment
Anticipated
31/12/2022
Actual
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
46
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20702 0
Epworth Rehabilitation Camberwell - Camberwell
Recruitment postcode(s) [1] 35504 0
3124 - Camberwell

Funding & Sponsors
Funding source category [1] 305479 0
University
Name [1] 305479 0
Monash University
Country [1] 305479 0
Australia
Funding source category [2] 309911 0
Charities/Societies/Foundations
Name [2] 309911 0
Epworth Medical Foundation
Country [2] 309911 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Monash University
Wellington Rd
Clayton
Victoria 3800
Australia
Country
Australia
Secondary sponsor category [1] 310891 0
None
Name [1] 310891 0
Address [1] 310891 0
Country [1] 310891 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305796 0
Monash Health
Ethics committee address [1] 305796 0
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 305796 0
Australia
Date submitted for ethics approval [1] 305796 0
13/11/2019
Approval date [1] 305796 0
15/01/2020
Ethics approval number [1] 305796 0
RES-19-0000892E

Summary
Brief summary
Theory of mind is a social cognitive domain impaired in people with schizophrenia and has significant impact on functioning including difficulty in social interactions, poor interpersonal relationships and reduced conflict resolution ability. Current interventions are highly intensive, require significant resources and have only modest effects on functional outcomes and new innovative treatments are needed. Virtual reality (VR) and transcranial alternating current stimulation (tACS) will be combined to engage the rTPJ while undergoing theory of mind tasks and use electrical currents to further engage and enhance abnormal neural firing patterns simultaneously. Forty-six participants (23 schizophrenia, 23 controls) will attend 3 research sessions. One comprehensive baseline assessment completing a short interview and cognitive and social cognitive tasks as well as two VR social cognition tasks with simultaneous tACS. At the end of session three participants will have received one sham tACS and one active tACS session simultaneously with VR. We are investigating the effects of combining tACS with VR in single sessions on brain activity to inform future research and potential treatment. Participants will also complete short questionnaires regarding their experience.
Trial website
Trial related presentations / publications
Public notes
Due to significant COVID-19-related delays as a result of Federal, State, local and organisational restrictions, while ethics approval was granted in January 2020, participant recruitment was unable to commence until August 2021.

Contacts
Principal investigator
Name 101622 0
Prof Kate Hoy
Address 101622 0
Epworth Centre for Innovation in Mental Health
888 Toorak Rd
Camberwell
Vic, 3124
Country 101622 0
Australia
Phone 101622 0
+61 03 9805 4287
Fax 101622 0
Email 101622 0
kate.hoy@monash.edu
Contact person for public queries
Name 101623 0
Kirsten Gainsford
Address 101623 0
Epworth Centre for Innovation in Mental Health
888 Toorak Rd
Camberwell
Vic, 3124
Country 101623 0
Australia
Phone 101623 0
+61 03 9805 4287
Fax 101623 0
Email 101623 0
kirsten.gainsford@monash.edu
Contact person for scientific queries
Name 101624 0
Kirsten Gainsford
Address 101624 0
Epworth Centre for Innovation in Mental Health
888 Toorak Rd
Camberwell
Vic, 3124
Country 101624 0
Australia
Phone 101624 0
+61 03 9805 4287
Fax 101624 0
Email 101624 0
kirsten.gainsford@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Only group data will be published or available on open access data repositories. Participants will never be identifiable in publications or presentations. As a requirement of publishing results in scientific journals, de-identified data may need to be placed in an open access data repository. No identifiable information that links this data back to the participant will ever be provided.
When will data be available (start and end dates)?
currently unknown
Available to whom?
When data is requested to be placed in an open access data repository when publishing a journal article, this de-identified data would be available to other researchers in the field.
Available for what types of analyses?
currently unknown.
How or where can data be obtained?
It is likely that the only place that the de-identified data would be obtainable is through an open access data repository if requested to be included when publishing the data in a scientific journal.


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.