Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001719224
Ethics application status
Approved
Date submitted
5/10/2018
Date registered
18/10/2018
Date last updated
20/05/2021
Date data sharing statement initially provided
20/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effects of Brain Training Using Infraslow Neurofeedback on the Autonomic Nervous System
Scientific title
The Effects of Infraslow Neurofeedback on the Autonomic Nervous System in a Healthy Population: a randomised, double-blind, placebo-controlled, pilot study
Secondary ID [1] 296265 0
Nil known
Universal Trial Number (UTN)
U1111-1216-4452
Trial acronym
ISANS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dysautonomia 309944 0
Condition category
Condition code
Neurological 308717 308717 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
20 healthy men and 20 healthy women between the ages of 18-60 will be recruited from the from the community. Recruitment will be via advertisement on notice boards and in local newspapers over a 6 months period with an invitation to participate in a potential therapeutic method to modulate the ANS. Individuals who contact the researchers will be emailed an information sheet to read over before meeting the investigators. Individuals who show an interest will be asked to attend a screening session at the clinic of the University Hospital of Otago, Dunedin. Initially, potential participants will be assessed to see if they meet the inclusion criteria and do not have any existing exclusion criteria. Recruitment of participants will continue until the sample size of 20 for both men and women is achieved.

Those who are eligible (n=20 men, n=20 women) will be randomised to either i) real infraslow neurfeedack (ISF; n=10 men, n=10 women) or ii) placebo ISF (P-ISF; n=10 men, n=10 women). Participants will receive a total of 6 sessions of ISF/P-ISF. An EEG and a battery of ANS assessments will be performed at screening (T0), prior to and following their first ISF/P-ISF session (T1) and last ISF/P-ISF session (T6), 1 week post ISF/P-ISF (T7), 1 month post ISF/P-ISF (T8) and 3 months post ISF/P-ISF (T9). In addition, all participants will fill out questionnaires and perform brief tests (i.e. Stroop tests) assessing various aspects of health including sleep, stress, well-being, affect and cognition (T0, T6, T7, T8 & T9). Furthermore, they will be asked to perform at-home collection of saliva samples on 2 consecutive weekdays following each ANS testing session (T0, T1, T6, T7, T8 & T9).

Infraslow neurofeedback (ISF) is a non-invasive technique that measures brain activity using electroencephalogram (EEG) and generate a sound when your brain exhibits the targeted infraslow brain activity. EEG uses small electrodes or metal discs placed on scalp to measure, track and record changes in the brain’s electrical activity. Participants will complete a total of 6 ISF/P-ISF sessions. Training will be administered in a hospital setting by a doctor/researcher with prior experience and training delivering Brainmaster Inc. ISF/P-ISF training. There will be 3 sessions a week for 2 weeks. Each session will be 20 minutes with the exception of the first session which will be only 10 minutes. sLORETA ISF/P-ISF will be implemented with a 24 channel DC coupled amplifier produced by Brainmaster Inc. Training will be administered with participants sitting in a comfortable chair with their eyes closed. After careful skin preparation, the appropriate Comby EEG cap (Ag/AgCl) will be placed on the participant’s head with reference electrodes at the mastoids. The impedances of the active electrodes will be kept below 5 kilo-ohms. Before the training period, participants will be instructed to relax and listen to the sound being played. A distinct tone will be used for ISF reinforcement at the dorsal anterior cingulate cortex (dACC). Reward threshold will be adjusted in real time at above 90%. In other words, for 90% of the time, a sound will be played (reward) when the participant’s brain activity meets the infraslow magnitude (threshold).

Prior to their first training session, a simple explanation will be given to participants. They will be informed that research has shown that attenuation of sympathetic nervous system activity may be of health benefit and that the sound they hear during ISF/P-ISF reflects whether they are doing well. There will be a total of 10 clinic visits in order to assess primary and secondary outcome measures both pre and post intervention. Sessions will run from 30 minutes to 2 hours depening on the assessments and interventions employed.

Researchers will maintain contact via email throughout the trial to help ensure protocol adherence. A Case Report Form (CRF) will be used for the purposes of recording participant specific data including the number of sessions attended. The researchers will compare baseline characteristics between those who complete the trial and those who do not in order to help inform strategies for improved compliance in the event larger trials are performed.
Intervention code [1] 312615 0
Treatment: Devices
Comparator / control treatment
P-ISF will be given to half of our healthy participants (n=10 men and n=10 womenn) who will act as our control groups. The instructions given to P-ISF participants will be identical to those who receive ISF, however, for P-ISF, the simulation protocol by Brainmaster Inc will be administered. The simulation protocol will play the distinct tone at random. thereby not reinforcing changes in infraslow activity.
Control group
Placebo

Outcomes
Primary outcome [1] 307692 0
Salivary cortisol (cortisol diurnal slope),

Salivary diurnal cortisol will be assessed on 2 consecutive weekdays following each ANS testing session through at-home collection of saliva upon waking and at bedtime using the passive drool method of saliva collection. Whole saliva samples will be collected with 0.5ml non-sterile microcentrifuge tubes (sourced from Interlab LTD, Wellington, NZ). Participants will receive written and verbal instructions regarding standard collection and storage protocol. All samples will be analysed in the Diabetes and Lipid Laboratory of the Department of Nutrition at the University of Otago (Dunedin, NZ).
Timepoint [1] 307692 0
Following T0(screening), T1 (1st ISF/P-ISF session), T6 (last ISF/P-ISF session), T7 (1 week post ISF/P-ISF; primary endpoint), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF). Saliva samples are collected on the first two consecutive weekdays following their clinic visit.
Primary outcome [2] 307693 0
Galvanic skin response {Primary Outcome]

Galvanic skin response (GSR) will be assessed with bipolar finger electrodes [MLT118F GSR finger electrodes; FE116 GSR Amplifier, ADInstruments]. A stimulus is required to stimulate sudomotor activity, therefore participants will be asked to perform an inspiratory gasp and the change in electrical conductance from baseline will be recorded.
Timepoint [2] 307693 0
T0(screening), T1 (immediately pre and post 1st ISF/P-ISF session), T6 (immediately pre and post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF; primary endpoint), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF).

Primary outcome [3] 307694 0
Cardiovascular autonomic nervous system function (heart rate/heart rate variability/blood pressure/heart rate recovery) [Primary Outcome]

Heart rate & blood pressure will be measured and their responses assessed at rest (6 minutes), during changes in breathing pattern (paced breathing at 15 breaths per minute for 6 minutes and deep breathing paced at 6 breaths per minute for 6-8 breaths), and during and following a Valsalva manoeuvre. Heart rate is measured with a standard limb lead (lead II) electrocardiogram, beat-to-beat blood pressure with finger-photoplethysmography [Finometer Midi (regularly calibrated with automated sphygmomanometer; Connex ProBP 3400 series Welch Allyn)], and respiratory rate with a respiratory belt transducer placed around the chest. The pressure and time of the strain during the Valsalva manoeuvre is recorded with a calibrated pressure transducer. Heart variability is calculated using the a commercially avaliable HRV module in Labchart 8 (ADInstruments,Dunedin, NZ) using standard frequency and time domain analysis. All cardiovascular primary outcome measures are collected simultaneously with an analogue-to-digital converter (Powerlab/3508/P).

To assess heart rate recovery, participants will perform a maximal incremental exercise test on a cycle ergometer (Model: E100 P, COSMED), while HR, BP, ECG and metabolic variables [VO2, VCO2, and R (i.e., VCO2/ VO2); Quark CPET, COSMED)] are monitored and measured at each stage. The protocol will start at 50w and increased at a magnitude of 25w or 50w (individualized for each participant) every 2 min, until volitional exhaustion. During recovery participants will remain quietly seated on the cycle while maintaining an upright posture as ECG, BP and respiration are monitored for 5-6 minutes.
Timepoint [3] 307694 0
T0(screening), T1 (immediately pre and post 1st ISF/P-ISF session), T6 (immediately pre and post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF; primary endpoint), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF). Note: heart-rate recovery will only be assessed at T0(screening), T7 (1 week post ISF/P-ISF; primary endpoint)
Secondary outcome [1] 352639 0
Resting-state brain activity

Resting state EEG will be sampled continuously at 500 Hz using a Mitsar-EEG 202 DC amplifier. Briefly, EEG will be recorded with 19 electrodes (Fp1, Fp2, F7, F3, Fz, F4, F8, T7, C3, Cz, C4, T8, P7, P3, Pz, P4, P8, O1 O2) according to the 10-20 placement. Linked mastoids reference will be used and all electrode impedances kept below 5 kO. EEGs will be recorded with participants sitting upright in a comfortable chair with their eyes closed. All EEGs will be recorded for 6 minutes. Raw data will be resampled at 128 Hz, filtered from 0.001 Hz to 44 Hz, plotted, and carefully inspected for manual artefact rejection on EEGLAB. Subsequently, average cross-spectral matrices will be computed for bands infraslow (0.01-0.1 Hz), delta (2-3.5 Hz), theta (4-7.5Hz), alpha (8-12 Hz), beta (12.5-30Hz) and gamma (30.5-44 Hz).
Timepoint [1] 352639 0
T0(screening), T1 (immediately pre and post 1st ISF/P-ISF session), T6 (immediately pre and post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF).



Secondary outcome [2] 352644 0
Perceived Stress Scale (PSS)

The PSS is a 10-item scale assessing the perception of stress.
Timepoint [2] 352644 0
T0(screening), T6 (immediately post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF)
Secondary outcome [3] 352648 0
World Health Organization 5 (WHO-5) Well-being index

The WHO-5 has 5 items assessing aspects of wellbeing.
Timepoint [3] 352648 0
T0(screening), T6 (immediately post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF)
Secondary outcome [4] 352649 0
Behavioural Inhibition and Activation Scale (BIS/BAS)

The BIS/BAS assesses aversive and appetative motives.
Timepoint [4] 352649 0
T0(screening), T6 (immediately post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF)
Secondary outcome [5] 352650 0
Pittsburgh Sleep Quality Index (PSQI)

The PSQI is a 19-item questionnaire used to identify sleep disturbances
Timepoint [5] 352650 0
T0(screening), T6 (immediately post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF)
Secondary outcome [6] 352651 0
Positive and Negative Affect Schedule (PANAS-GEN)

The PANAS-GEN consists of two 10-item scales to assess positive and negative affect
Timepoint [6] 352651 0
T0(screening), T6 (immediately post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF)
Secondary outcome [7] 352652 0
Stroop Test

The Stroop Test assesses the ability to inhibit cognitive interference.
Timepoint [7] 352652 0
T0(screening), T6 (immediately post last ISF/P-ISF session), T7 (1 week post ISF/P-ISF), T8 (1 month post ISF/P-ISF), and T9 (3 months post ISF/P-ISF)

Eligibility
Key inclusion criteria
1. Men and women aged 18-60 years. With respect to our female participants, only women currently using monophasic hormonal contraception will be recruited as hormonal fluctuations that occur during the menstrual cycle are known to alter ANS function.
2..Right handedness as handedness affects EEG interpretation.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Certain medications (e.g. antidepressants and other psychotic medications)
2. Recent significant head injuries. e.g. concussion where consciousness is lost or surgery
3. Psychiatric disorders with psychotic symptoms or manic symptoms
4. Other health problems – diabetes, cancer, heart disease, uncontrolled hypertension
5. History of epilepsy
6. Metal implants or implanted electronics (pacemaker)
7. Recurring headaches
8. Currently pregnant

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)
An independent researcher from the department will seal each allocation in a consecutively numbered opaque envelope before handing them to the enrolling researcher. During enrolment and randomisation of a new participant, the enrolling researcher will write the participant's ID before opening the sealed envelope and retrieving the allocation from inside.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using a validated randomisation program utilised by clinical trial researchers. To ensure balanced sample size across the placebo and ISF groups over time, block randomisation will be performed.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Alterations in ANS with ISF/P-ISF be investigated and quantified from the aforementioned battery of tests. These dependent variables will then be statistically compared using mixed 2-way repeated measures ANOVA. The direction and the magnitude of change in the dependent variables will inform the underpinning change in ANS function and whether it is clinically meaningful.

sLORETA will be used to perform a voxel by voxel analysis for the different frequency bands of the current density distribution to identify potential differences in brain electrical activity between the two groups at baseline, after one, six sessions and one week follow-up. Non-parametric statistical analyses of functional sLORETA images (SnPM) will be performed for each contrast using sLORETA’s build-in voxel wise randomisation test (5000 permutations) and employing a log-F-ratio statistic for independent groups with a threshold of p<0.05.

To date, this is the first study examining the effect of ISF on the ANS in healthy individuals, thus no formal power calculations were made.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
1/11/2018
Actual
1/01/2019
Date of last participant enrolment
Anticipated
1/05/2019
Actual
1/06/2019
Date of last data collection
Anticipated
1/08/2019
Actual
1/06/2019
Sample size
Target
40
Accrual to date
Final
30
Recruitment outside Australia
Country [1] 20900 0
New Zealand
State/province [1] 20900 0
Otago

Funding & Sponsors
Funding source category [1] 300859 0
Charities/Societies/Foundations
Name [1] 300859 0
Neurological Foundation
Country [1] 300859 0
New Zealand
Primary sponsor type
Individual
Name
Professor Dirk De Ridder
Address
University of Otago
Department of Surgical Sciences, Neurosurgery
201 Great King St
Dunedin, 9016
Country
New Zealand
Secondary sponsor category [1] 300412 0
Individual
Name [1] 300412 0
Dr Tyson Perez
Address [1] 300412 0
University of Otago
Department of Surgical Sciences, Neurosurgery
201 Great King St
Dunedin, 9016
Country [1] 300412 0
New Zealand
Other collaborator category [1] 280382 0
Individual
Name [1] 280382 0
Dr Luke Wilson
Address [1] 280382 0
University of Otago
Department of Medicine
201 Great King St
Dunedin, 9016
Country [1] 280382 0
New Zealand
Other collaborator category [2] 280391 0
Individual
Name [2] 280391 0
Dr Sook Ling Leong
Address [2] 280391 0
University of Otago
Department of Surgical Sciences, Neurosurgery
201 Great King St
Dunedin, 9016
Country [2] 280391 0
New Zealand
Other collaborator category [3] 280392 0
Individual
Name [3] 280392 0
Assoc. Professor Sven Vanneste
Address [3] 280392 0
University of Texas at Dallas
School of Behavioral and Brain Sciences,
800 W Campbell Rd, Richardson, TX 75080,
Country [3] 280392 0
United States of America
Other collaborator category [4] 280393 0
Individual
Name [4] 280393 0
Mark Smith
Address [4] 280393 0
Neurofeedback Services of New York,
140 West 79th Street, #2B
New York, NY 10024
Country [4] 280393 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301634 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 301634 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 301634 0
New Zealand
Date submitted for ethics approval [1] 301634 0
17/09/2018
Approval date [1] 301634 0
04/10/2018
Ethics approval number [1] 301634 0
18/STH/187

Summary
Brief summary
The autonomic nervous system is vital for regulating ‘automatic’ functions of your body such as heart rate, blood pressure and the release of hormones. It is generally composed of two main branches; the sympathetic (fight or flight) and parasympathetic (rest and digest) systems. An imbalance in these two systems is termed 'dysautonomia' and is associated with numerous diseases.

Our research group is undertaking a clinical trial in healthy adults that will investigate the effectiveness of a novel type of therapy known as infraslow neurofeedback in the regulation of the autonomic nervous system. Infraslow neurofeedback is a completely non-invasive therapy whereby we monitor the brain’s electrical activity with a device called an EEG. Through real-time feedback, participants essentially learn to self-regulate their brain activity with the aid of ‘rewards’ in the form of pleasant sounds given when their brain displays the desired activity (i.e. less or more infraslow activity). This type of learning which incorporates immediate feedback and positive reinforcement is known as operant conditioning. By teaching people to self-regulate the activity of very specific regions of the brain involved in controlling their autonomic nervous system, our hope is that we will see an improvement in the balance between the sympathetic and parasympathetic branches. As far as we know, we are the first in the world to study the potential effects of infraslow training on the autonomic nervous system.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87606 0
Prof Dirk De Ridder
Address 87606 0
University of Otago
Department of Surgical Sciences, Neurosurgery
201 Great King St
Dunedin, 9016
Country 87606 0
New Zealand
Phone 87606 0
+64 3 470 9337
Fax 87606 0
Email 87606 0
dirk.deridder@otago.ac.nz
Contact person for public queries
Name 87607 0
Dr Tyson Perez
Address 87607 0
University of Otago
Department of Surgical Sciences, Neurosurgery
201 Great King St
Dunedin, 9016
Country 87607 0
New Zealand
Phone 87607 0
+64 03 474 0999 (ext 58847)
Fax 87607 0
Email 87607 0
perty770@student.otago.ac.nz
Contact person for scientific queries
Name 87608 0
Prof Dirk De Ridder
Address 87608 0
University of Otago
Department of Surgical Sciences, Neurosurgery
201 Great King St
Dunedin, 9016
Country 87608 0
New Zealand
Phone 87608 0
+64 3 470 9337
Fax 87608 0
Email 87608 0
dirk.deridder@otago.ac.nz

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11731Ethical approval    376137-(Uploaded-09-11-2018-08-25-52)-Study-related document.pdf



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