Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000911291
Ethics application status
Approved
Date submitted
18/05/2018
Date registered
30/05/2018
Date last updated
17/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of brain training using Infraslow Neurofeedback on the control of the heart and blood vessels in healthy men
Scientific title
Effects of Infraslow Neurofeedback on alterations in heart rate and blood pressure in healthy men - a double blind randomised exploratory study
Secondary ID [1] 294914 0
nil
Universal Trial Number (UTN)
U1111-1211-0349
Trial acronym
INCAS
Linked study record
nil

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular Disease 307883 0
Mental Health 307999 0
Condition category
Condition code
Cardiovascular 306932 306932 0 0
Normal development and function of the cardiovascular system
Cardiovascular 307028 307028 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
20 healthy men between the ages of 18-64 years will be recruited from the community using advertisement in newspapers and on notice boards.

Those who are interested will be asked to attend a screening session at the clinic and will be provided with the participant information sheet. During this visit, consent will be obtained. The researcher will screen potential participants for eligibility. If eligible, the participant will undergo an electroencephalogram (EEG), cardiovascular autonomic nervous system assessments (ANS) and fill out a battery of questionnaires.

Subsequently, they will be randomised and will undergo either treatment infraslow (T-ISF)(n=10) or placebo infraslow (P-ISF) (n=10) for 6 sessions, This will be administered with 3 sessions during the first week, 2 sessions in the second week and 1 session in the third week. During the first session, the neurofeedback training will be for 10 minutes and the subsequent 5 sessions will be 20 minutes each. The duration for the first clinic session will take 30 mins while the other 5 sessions will take 45 minutes each.

During each session, participants will be asked to sit in a chair in an upright position and relax for 5 minutes. After careful skin preparation, the appropriate Comby EEG cap will be placed on the participant's head with reference electrodes at the mastoids. The impedance of the active electrodes will be kept between 2 to 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 T-ISF reinforcement at the Posterior Cingulate Cortex (PCC). 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). For P-ISF, the simulation protocol by Brainmaster Inc will be administered.

Both T-ISF and P-ISF infraslow sLORETA neurofeedback will be implemented with a 24 channel DC coupled amplifier produced by Brainmaster Inc at the research clinic. During the training period, participants will be sitting upright in the chair with the infraslow Comby EEG cap attached. Throughout the sessions, participants will be asked to keep their eyes closed, relax and listen to the sound being played by the device.

Infraslow training will be administered by a researcher who has undergone training by Brainmaster Inc.

The researcher administering infraslow training will record the number of sessions attended. Primary and secondary outcomes will be assessed after the first neurofeedback session, after six sessions and two weeks after the last neurofeedback session.
The researchers will compare baseline characteristics (wellbeing, psychological variables) of those who complete the study to those who did not. This will help inform the researchers on strategies to improve compliance if a larger clinical trial is to be conducted.
Intervention code [1] 301236 0
Treatment: Devices
Comparator / control treatment
The P-ISF set-up and instructions given to participants for P-ISF will be the same to T-ISF. However the simulation protocol by Brainmaster Inc. delivers a distinct tone at random thereby not reinforcing changes in infraslow activity and therefore acting as the control group.
Control group
Placebo

Outcomes
Primary outcome [1] 305916 0
Heart rate/R-R interval

Seated heart rate will be continuously measured for 7 minutes and their responses assessed during alterations in breathing pattern – paced at 15 breaths per minute for 7 minutes and deep breathing paced at 6 breaths per minute for 6 – 8 breaths, and during and following a Valsalva manoeuvre.

Heart rate/R-R interval are measured with a standard limb lead (lead II) electrocardiogram.

All primary outcome measures are collected simultaneously with an analogue-to-digital converter (Powerlab/3508/P).
Timepoint [1] 305916 0
Before and immediately after 1 session of infraslow training, 6 sessions of infraslow training and 1 week after the last infraslow training session.

This primary outcome measure along with primary outcomes 2 and 3 will be used to inform changes in cardiovascular autonomic function caused by the Infraslow intervention.
Primary outcome [2] 305917 0
Blood Pressure

Seated blood pressure will be continuously measured for 7 minutes and their responses assessed during alterations in breathing pattern – paced at 15 breaths per minute for 7 minutes and deep breathing paced at 6 breaths per minute for 6 – 8 breaths, and during and following a Valsalva manoeuvre.

Beat-to-beat blood pressure is measured at the finger with photoplethysmography using a Finometer Midi [regularly calibrated with automated sphygmomanometer; (Connex ProBP 3400 series Welch Allyn)].

All primary outcome measures are collected simultaneously with an analogue-to-digital converter (Powerlab/3508/P).
Timepoint [2] 305917 0
Before and immediately after 1 session of infraslow training, 6 sessions of infraslow training and 1 week after the last infraslow training session.

This primary outcome measure along with primary outcomes 1 and 3 will be used to inform changes in cardiovascular autonomic function caused by the Infraslow intervention.
Primary outcome [3] 306010 0
Heart rate variability.

Heart rate variability will be assessed from the ECG signal collected in Primary outcome 1 during 5 minutes of steady-state data taken from the baseline and paced breathing conditions.

Heart variability is calculated using the a commercially avaliable HRV module in Labchart 8 (ADInstruments,Dunedin, NZ) using standard frequency and time domain analysis.
Timepoint [3] 306010 0
Before and immediately after 1 session of infraslow training, 6 sessions of infraslow training and 1 week after the last infraslow training session.

This primary outcome measure along with primary outcomes 1 and 2 will be used to inform changes in cardiovascular autonomic function caused by the Infraslow intervention.
Secondary outcome [1] 347021 0
Exploratory resting state brain activity.

Resting state EEG will be sampled using the international standard 19 electrode 10-20 system. EEG will be recorded continuously at 500 Hz using a Mitsar-EEG 202 DC amplifier for six minutes. Reference electrodes which are linked are place on the ears. Each electrode impedances are kept below 5 kilo-ohm for reliable recordings. The raw data recordings will be resampled at 128 Hz, band-pass filtered from 0.001 Hz to 44 Hz, plotted, and carefully inspected for manual artefact rejection on EEGLAB. Next, average power spectral matrices will be computed for bands infraslow (0.01 – 0.1 Hz), delta (2 – 3.5 Hz), theta (4 – 7.5 Hz), alpha (8 – 12 Hz), beta (12.5 – 30 Hz) and gamma (30 – 44 Hz).
Timepoint [1] 347021 0
Before and immediately after 1 session of infraslow training, 6 sessions of infraslow training and 1 week after the last infraslow training session.
Secondary outcome [2] 347022 0
World-Health Organization five well-being index.
A 5-item continuous scale assessing aspects of wellbeing within the last 1 week.
Timepoint [2] 347022 0
After six sessions of infraslow training and 1 week after the last infraslow training session.
Secondary outcome [3] 347023 0
Behaviour Activation (BAS)
The BAS assesses appetitive motives..
Timepoint [3] 347023 0
After six sessions of infraslow training and 1 week after the last infraslow training session.
Secondary outcome [4] 347024 0
Pittsburgh Sleep Quality Index (PSQI).
The PSQI is a 19-item questionnaire used to identify sleep disturbances.
Timepoint [4] 347024 0
After six sessions of infraslow training and 1 week after the last infraslow training session.
Secondary outcome [5] 347294 0
Behaviour Inhibition Scale (BIS)

The BIS assesses aversive motives
Timepoint [5] 347294 0
After six sessions of infraslow training and 1 week after the last infraslow training session.
Secondary outcome [6] 347479 0
Perceived Stress Scale.
A 10-item continuous scale assessing the perception of stress during the last month.
Timepoint [6] 347479 0
After six sessions of infraslow training and 1 week after the last infraslow training session.

Eligibility
Key inclusion criteria
1.Men aged 18-64 years and being right handed. For this pilot study we have pre-selected male participants because cardiovascular mortality is five times higher in men than in women across adulthood and the menstrual cycle is known to alter ANS function.
2. For this pilot study we have only included participants who are right handed as handedness affects the interpretation of electroencephalogram (EEG).
Minimum age
18 Years
Maximum age
64 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Antidepressants and other psychotic medications; recent significant head injuries, psychiatric disorders, significant health problems (diabetes, cancer, heart disease, uncontrolled hypertension), history of epilepsy, metal implants or implanted pacemakers, recurring headaches.

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)
To ensure that sample size is balanced across the T-ISF and P-ISF groups over time, block randomisation will be applied. The independent researcher will use a validated computerised program for this purpose.
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
nil
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
This is the first (pilot) study examining the effects of infraslow neurofeedback on cardiovascular ANS in healthy participants, thus, no formal power calculations are made.

Alterations in ANS with T-ISF and P-ISF will be investigated from the fore mentioned battery of tests, where in each condition, resting heart rate and HRV and blood pressure and their changes during alterations in breathing (rate and depth) and in response to a Valsalva manoeuvre will be quantified. These dependent variables will then be statistical compared using mixed two-way repeated measures ANOVA. The direction and the magnitude of change in the dependent variables will inform the underpinning change in cardiovascular 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.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2018
Actual
11/06/2018
Date of last participant enrolment
Anticipated
31/10/2018
Actual
Date of last data collection
Anticipated
14/12/2018
Actual
Sample size
Target
20
Accrual to date
9
Final
Recruitment outside Australia
Country [1] 10409 0
New Zealand
State/province [1] 10409 0
Dunedin

Funding & Sponsors
Funding source category [1] 299491 0
University
Name [1] 299491 0
University of Otago
Country [1] 299491 0
New Zealand
Primary sponsor type
Individual
Name
Professor Dirk De Ridder
Address
Department of Surgical Sciences, Neurosurgery
University of Otago
201 Great King St, Dunedin, 9016
Country
New Zealand
Secondary sponsor category [1] 298796 0
Individual
Name [1] 298796 0
Dr Luke Wilson
Address [1] 298796 0
Department of Medicine,
University of Otago
201 Great King St. Dunedin, 9016
Country [1] 298796 0
New Zealand
Secondary sponsor category [2] 298803 0
Individual
Name [2] 298803 0
Dr Sook Ling Leong
Address [2] 298803 0
Department of Surgical Sciences, Neurosurgery
University of Otago
201 Great King St, Dunedin, 9016
Country [2] 298803 0
New Zealand
Other collaborator category [1] 280110 0
Individual
Name [1] 280110 0
Assoc. Professor Sven Vanneste
Address [1] 280110 0
School of Behavioral and Brain Sciences,
University of Texas at Dallas,
800 W Campbell Rd, Richardson, TX 75080,
USA
Country [1] 280110 0
United States of America
Other collaborator category [2] 280111 0
Individual
Name [2] 280111 0
Mark Smith
Address [2] 280111 0
Neurofeedback Services of New York,
140 West 79th Street, #2B
New York, NY 10024
USA
Country [2] 280111 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300397 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 300397 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 300397 0
New Zealand
Date submitted for ethics approval [1] 300397 0
21/03/2018
Approval date [1] 300397 0
16/05/2018
Ethics approval number [1] 300397 0
18/STH/69

Summary
Brief summary
Cardiovascular disease is a major health problem and is a leading cause of death nationally and worldwide. Cardiovascular autonomic nervous system imbalance, characterised by excessive sympathetic and reduced parasympathetic activity is a hallmark of cardiovascular disease and is independently associated with morbidity and mortality. Parasympathetic nervous system regulation has to involve brain areas of the default mode network, specifically the posterior cingulate cortex. This pilot study investigates whether non-invasive neurofeedback training technique, targeted at the posterior cingulate cortex can improve cardiovascular autonomic nervous system function.

Twenty healthy men will be randomised to either six sessions of neurofeedback or placebo over a two week period. Cardiovascular autonomic function testing with validated battery of tests which encompasses measurement of resting blood pressure, and heart rate and its variability, as well as their responses to breathing alterations and the Valsalva Manoeuvre. Brain activity will also be assessed using encephalogram. Questionnaires will be utilised to measure wellbeing and sleep quality. Assessments will be carried out before and after the first and sixth session of neurofeedback, and then one week following neurofeedback training.

This is the first randomised trail investigating the effects of neurofeedback on the cardiovascular autonomic nervous system. If this pilot study shows positive finding, we will test the therapeutic potential of neurofeedback in patient cohorts with known cardiovascular disease risk and as a preconditioning tool in those who are to undergo surgery. This novel technique is not used in any other group in New Zealand. Neurofeedback has no known side-effects and is a promising non-pharmacological treatment therapy for a wide spectrum of individuals who are at risk of cardiovascular disease. Neurofeedback can be conducted using a reasonably low cost portable device and carried out by trained technicians in outpatient clinics. With further advances in technology, portable home-based systems are likely to be developed.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 83526 0
Prof Dirk De Ridder
Address 83526 0
Department of Surgical Sciences, Neurosurgery
201 Great King Street
Dunedin Hospital
Dunedin 9054
Country 83526 0
New Zealand
Phone 83526 0
+64 03 474 9337
Fax 83526 0
Email 83526 0
[email protected]
Contact person for public queries
Name 83527 0
Dr Sook Ling Leong
Address 83527 0
Department of Surgical Sciences, Neurosurgery
201 Great King Street
Dunedin Hospital
Dunedin 9054
Country 83527 0
New Zealand
Phone 83527 0
+64 03 474 9337
Fax 83527 0
Email 83527 0
[email protected]
Contact person for scientific queries
Name 83528 0
Prof Dirk De Ridder
Address 83528 0
Department of Surgical Sciences, Neurosurgery
201 Great King Street
Dunedin Hospital
Dunedin 9054
Country 83528 0
New Zealand
Phone 83528 0
+64 03 474 9337
Fax 83528 0
Email 83528 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



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