Previous studies with fMRI-neurofeedback in depression have demonstrated a good safety
profile and considerable symptom reduction. The goal of this clinical trial is to compare
fMRI-neurofeedback plus standard care with standard care in patients with depression.

Participants will either receive standard care, or standard care plus a fMRI
neurofeedback training, consisting of 5 neurofeedback training sessions. Symptom severity
will be assessed before, immediately after and 6 months after the intervention.

FMRI-neurofeedback in Depression

Depression, Unipolar

Rationale: Previous studies with fMRI-neurofeedback in depression have demonstrated a
good safety profile and considerable symptom reduction but a comparison between standard
care and standard care plus fMRI-neurofeedback has not yet been carried out.

Objective: To assess the efficacy of fMRI-neurofeedback plus standard care in comparison
with standard care in patients with depression.

Study design: Single-blind RCT. Patients will be randomly allocated to fMRI-neurofeedback
plus standard care or standard care. Assessments will be conducted by assessors who are
blinded to group allocation.

Patients will be randomised to the two groups using a block randomisation procedure (10
participants per block). Depression severity at baseline (IDS scores) will be used as
minimisation variable to ensure equal severity in both groups. The study team will
receive a code for group allocation. The study team and patient will be aware of the
group allocation (by the nature of the study design), but assessors performing baseline,
post-intervention and follow-up assessments will be blinded. During interim analyses, the
analysts will remain blinded to the conditions.

If the stopping criterion is reached before the maximal N, any patients already
randomised will complete the study and their data will be included in the secondary
analyses.

Study population: Currently symptomatic adult patients with depression.

Sample size calculation: A Sequential Bayes Factor (SBF) sampling plan will be used. SBF
allows accumulating evidence for (or against) an effect until a certain threshold, i.e. a
Bayes Factor (BF), or max N is reached. This is one main advantage compared to
frequentist statistics (which is biased against the null hypothesis). Moreover, type-I
and type-II error rates do not exist, allowing for flexible stopping rules. This property
renders SBF a more resource efficient (in particular for small to medium effect sizes)
compared to (traditional frequentist) fixed-N sampling plans. Since type-II errors do not
exist in Bayesian statistics, there is no concept of statistical power as in traditional
frequentist statistics. However, sensitivity analyses can be carried out a priori to help
determining the sample size required to reach a pre-declared level of evidence (given an
assumed effect size and a specific prior distribution) that serves as a stopping
criterion, For the current sampling plan a BF >= 6 (for either the alternative or the
null hypothesis) will be used as a stopping criterion, a value that is in line with
recent recommendations. The analysis is carried out with an informed prior t-distribution
(t(μ = 0.35, df = 3, r = 0.102)), which reflects a moderate effect size that the
investigators would expect given the current design and is in line with suggested
informed prior distributions in Psychology. The first interim analysis will be carried
out with a minimum N=26 patients per group who have completed the primary endpoint. This
minimum N is in line with recommendations for SBF sampling plans. If a BF of 6 for either
the alternative or the null is hypothesis is not met, sequential sampling will be carried
out with interim tests for every new patient who completes the primary endpoint until
either the BF stopping criterion is met or a maximum N=38 is reached (max N). An effect
size of Cohen's d = 0.6 was set as the smallest effect size of interest given the
restricted resources and previously reported effect sizes reported by pre-registered
randomised clinical trials of emotion self-regulation based fMRI neurofeedback. An N max
of 38 per group yields 80% sensitivity to detect an effect size of 0.6 under flexible
stopping as suggested by simulations (Monte Carlo with 10,000 iterations). Hence, such
design is more resource efficient compared to a traditional frequentist fixed-N design
(which requires N=45 to reach 80% sensitivity to detect an effect size Cohen's d = 0.6).
Further, the false negative rate (i.e. the probability to accumulate erroneously
sufficient evidence against the effect and stop the trial early) is only 0.1%, the false
positive rate is 12%. The investigators accept this higher false positive rate (compared
to the nominal 5%) given that the technology is safe to use. If the BF reaches a value
BF>=3 (but smaller than 6) for either the alter-native or null hypothesis, the
investigators will revaluate available resources for a potential third sampling phase
with N max of 60 per group. The sampling plan thus follows recent recommendations of best
practice.

Intervention: FMRI-neurofeedback will be administered in 5 sessions of about 1 hour each,
each including a visual stimulation protocol for the localisation of areas responsive to
positive emotions and appr. 30 minutes of upregulation training of these areas by means
of neurofeedback, using real-time fMRI signals.

Main study parameters/endpoints:

Primary outcome: symptom severity (measured by the clinician-administered Inventory of
Depressive Symptomatology) after the intervention.

Secondary outcomes: measures of depression, anxiety and general mental health (Beck
Depression Inventory, Self-Efficacy Scale, Hospital Anxiety and Depression Scale, Quality
Of Life scale and EuroQol research foundation questionnaire), predictive value of several
trait measures (moderator analysis), changes in brain activation patterns measured by
fMRI for the neurofeedback group.

In the analysis, outcomes will be controlled for the measurements at baseline.

fMRI-based neurofeedback

A Randomised Controlled Trial of fMRI-neurofeedback in Depression

30 item clinician rated depression scale (Rush et al., 1986; Rush, Gullion, Basco,
Jarrett, & Trivedi, 1996)

Self-rated depression scale (Beck, Steer, & Brown, 1996)

Self-rated depression and anxiety scale (Zigmond & Snaith, 1983). The questionnaire
comprises 7 questions for anxiety and 7 for depression. Each scale has a minumum score of
0 and a maximum score of 21. A higher score means more severe anxiety- or depression
complaints.

Self-rated quality of life scale. A higher score reflects a better quality of life.

Self-rated scale of five dimensions of health (Brooks & Group, 1996)

One week after baseline and one week before the end of intervention measurement
partic-ipants will undergo an experience sampling procedure. Experience sampling will be
acquired through the PsyMate application (https://www.psymate.eu) on patients' own or
provided smartphones. Participants will thereby digitally complete a brief questionnaire
including current affect (positive affect and negative affect items) as well as current
context and activ-ities ("daily life activities", "persons present", "physical activity",
and "events")

Self-rated scale assessing self efficacy (Sherer et al., 1982). The total scores range
from 10 to 40. A higher score means more self-efficacy.

NF protocol targeting emotion networks (NFE) (plus standard care)

FMRI-neurofeedback in Depression

About this trial

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Placebo

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