A randomized controlled trial into the efficacy of neurofeedback for treatment of major depressive disorder

Evidence-based treatments for major depressive disorder (MDD) possess moderate
efficacy. However, applicability, availability and acceptability of these
treatments are limited. Antidepressant treatment is not acceptable for a vast
number of patients with MDD, resulting in high rates of non-compliance.
Short-term psychotherapy is not effective in the majority of these patients and
not routinely available. Moreover, It is estimated that at least 10-20% of all
patients do not respond at all to these treatments even when applied
simultaneously and in residential contexts. Therefore, new, acceptable, and
efficacious treatments for MDD will help to fill the therapeutic gap that is
left by current evidence-based treatments.
There is a growing interest in neurofeedback (NF) as a treatment for
psychiatric disorders including MDD. It is thought that this technique, within
an operant conditioning framework, helps individuals to regulate cortical
elektroencephalographic (EEG) activity while receiving feedback from a visual
or acoustic signal. The resulting change in EEG activity is presumed to be
associated with a change in underlying cortical activation, and subsequently to
result in a reduction of associated psychiatric symptoms. NF is an outstanding
example of a non-invasive brain-computer interface which may be particularly
appealing to younger patients. Despite widespread claims of efficacy of NF in
MDD, the scientific literature consists only of some case-reports and 1
case-control study.
Nevertheless, NF may be an efficacious treatment for MDD. Results from
fundamental research indicate that MDD appears to be characterized by
relatively more left than right resting (alpha, 8-13 Hz) activity in prefrontal
regions, although some inconclusive studies exist . This finding has become
known as alpha-asymmetry (AA) in MDD. AA is considered as a representation of
reduced approach-related behaviours and reduced sensitivity to rewards in MDD.

In this study, we have the following research objectives:
1. To examine if NF, by applying the above mentioned AA-protocol, is an
efficacious treatment for major depressive disorder. We will conduct a RCT in
which active NF will be compared to sham-NF. We expect an equivalent efficacy
in comparison to existing treatments.
2. To examine the associations between changes in elektrophysiological cortical
activity and clinical outcome.
3. To address the specificity of the intervention on the target cortical
locations (F3-F4) and the target brain-waves (alpha activity) in the real and
sham condition. Changes in other frequencies and locations are expected to be
minimal.
4. To examine underlying changes in elektrophysiological cortical activity in
both real as well as sham-NF. We expect that some participants in the
sham-condition will improve due to non-specific factors like activation (coming
to the lab on a regular basis), and the attention by the research team. The
current project provides a unique opportunity to study temporal changes in
brain-activity as a result of a placebo-intervention. Earlier research used
brain-imaging techniques that only provided pre-post cross-sectional data.
5. To examine enduring therapeutic effects at 3 months follow-up.

RCT with 50 participants of which 25 will receive active neurofeedback
treatment and 25 will receive sham-neurofeedback. Both participants and all
members of the research team will be blind to the condition applied to each
participant.

After signing informed consent, participants will be invited to the
neurofeedback laboratory of the school for Mental Health and Neuroscience
(MheNS). This laboratory is a facility that meets the requirements as outlined
in NEN 60601 by the Nederlands Normalisatie-instituut. The intervention will
take place while participants sit behind a table and look at a monitor on top
of this table. The monitor displays a visual feedback signal (thermometer)
based on real-time analysis of their elektrophysiologidal data. The
participants are instructed to raise the bar of the thermometer (which is
indicative of a decrease in AA). During the NF sessions, while being in the
laboratory, participants are in constant contact with the research assistant
through an audio-channel, additionally there is constant video-surveillance.
Prior to the NF session, depression-severity will be assessed (see outcome
measurements)
EEG-elektrodes will be attached following the international 10-20 system at F3,
F4, C3, C4, P3 en P4. EEG will be referenced by 2 elektrodes attached to the
earlobes. Under and above the left eye an elektrode will be placed to measure
EOG. The elektrode will be applied after cleaning the skin with scrubgel. The
impedance on all locations will be kept lower than 5 K*.
Each 0.512 second, the power within the alpha frequency band (7.8 Hz - 13.1 Hz)
of both F3 and F4 is calculated. AA at F3-F4 will computed as the difference of
the natural log-transformed F3 and F4-alpha power. Based on this calculation,
subjects will receive AA visual feedback on a flatscreen. Goal in each session
is to decrease the asymmetry in comparison to the asymmetry as assessed at
baseline prior to each session.
The sham-NF will be delivered with the same data acquisition protocol,
but the AA will be randomly multiplied by +1 or -1, which reduces the
correlation between measured brain activity and the visual feedback signal to
almost zero.
Prior to the start of the study, an independent, non-involved
technician will generate the randomization sequence (using the sequence
generator on www.random.org) and pre-program the NF equipment accordingly in a
random sequence of real and sham NF treatments for consecutive participants. A
research assistant will only have to activate the NF procedure without knowing
whether a real or sham treatment is applied. In this fashion, each participants
will be double blind assigned to either a real of a sham NF-treatment.

At the start of each NF session, the baseline EEG is being measures without NF
to assess baseline AA which serves as a starting point for feedback. Measuring
baseline prior to each session is necessary as can be expected that, at least
in the active arm, AA decreases over time. Data collection will be channeled
through an acquisition PC with a BrainAmp DC EEG amplifier (Brain Products)
using a 1000 Hz sample frequency. Online calculations are done by a filter
written for BrainVision RecView. The data will be epoched online into 2.048-s
epochs that overlap by 75% and then transformed by a fast Fourier transform
(FFT) to the frequency domain (frequency resolution 0.488 Hz). Every 0.512
second, the power within the alpha frequency band (7.8 Hz - 13.1 Hz) of both F3
and F4 will be calculated. AA is computed as the difference of the natural
log-transformed F3 and F4-alpha power: Ln(F3-alpha) - Ln(F4-Alpha). Current
asymmetry is subsequently compared to the personal mean baseline asymmetry. The
result of the calculation will be sent to a stimulus PC running Presentation
stimulus delivery software (Neurobehavioral Systems) with an 8-bit parallel
port (LPT-port) to control a paradigm showing a visual representation of the
asymmetry. In the Presentation paradigm, the last 20 values of the asymmetry
are used in a moving average to prevent *jitter* in the feedback. Participants
receive feedback with visual feedback; they are instructed to increase the
level of a thermometer that is shown on a flatscreen. Additionally, a numerical
score below the thermometer indicates their actual total performance. This
score is adjusted (i.e. increased) continuously by a number ranging from 0 and
128, depending on the level of the thermometer. In this way a good actual
performance (a shift in asymmetry in the desired direction) results in an
increasing total score. A big shift in the desired direction results in a
rapidly increasing total score, whereas a small shift in the desired direction
results in a slow increasing total score. A shift in the undesired direction
produced no change in total score. The purpose of this total performance score
is to give participants feedback on the differential effect of the sessions.

After informed consent is obtained, the NF intervention will consist of 18
sessions, each lasting 3 x 6 minutes divided by 2 breaks of 4 minutes. Prior to
and after each session, baseline EEG alpha-activity will be measured at right-
and left frontal regions. Sessions will be done 3 times a week. Based on our
pilotdata in which clinical response emerged between 15-20 NF sessions, the
total intervention will consist of 18 sessions during 6 weeks to minimize
burden on participants. If no clinical response occurs, participants will be
offered an evidence-based treatment at the unit for treatment of mood disorders
at the RIAGG Maastricht. Additionally, the NF treatment will be stopped in
cases of severe suicidality (HDRS item # 3 with a score >2) or severe
depression symptomatology ( HDRS score > 25). In these cases, the research
assistant will contact the principal investigators who will responsible for
referral for standard depression treatment.

Participants will be receive written and verbal information about the procedure
and have the right to discontinue participation at any moment. Partcipants wil
receive either an experimental or sham experimental treatment for their
depressive disorder. To minimize burden resulting from participation in the
study, the duration of the study is kept to a maximum of 6 weeks. This duration
is based on data from our pilot-study and is totally comparable to the duration
of RCT*s that examine novel antidepressants with the use of placebo. Given the
extensive waiting-lists for regular evidence-based treatments for depression
(3-4 months), participation in the study does not lead to additional delay in
the start of standard therapy. Thus, those participants that wish to receive
standard antidepressant treatment after participation in the study, will
receive such treatment within a normal time-frame.
As mentioned earlier, no side-effects of NF are reported in the
literature. Moreover, in our pilot-study in depressed participants, we did not
observe any side-effects.
There will be an independent physician available to address all questions and
concerns of potential participants. All participants will provide written
informed consent. Their data will be collected in a anonymized in a central
database in our laboratory. Participants can withdraw consent at any moment
without any restrictions. If requested, all participants can be informed of the
final results after completion of the study.
As already indicated, we carried out a pilot-study in depressed participants
with application of the same NF intervention as described in the current
proposal. No complications occurred during this study. The MEC approved this
study, correspondence can be found under reference number MEC 08-2-115.