rTMS and cognitive control training in the context of depression

rTMS is increasingly used to treat depression at various stages of severity and
has been shown to be effective, however, with response percentages of about 40%
and remission percentages of about 30%, there is still room for improvement
(Berlim, Van den Eynde, & Daskalakis, 2013a, 2013b; Berlim, van den Eynde,
Tovar-Perdomo, & Daskalakis, 2014). One of the theories regarding the working
mechanisms of rTMS concerns neural modulation of brain regions mediating
cognitive control. Cognitive control is closely associated with affective
disorders, as it plays a critical role in emotion regulation processes (Ochsner
& Gross, 2005). Mood improvement after treatment with rTMS could be the result
of improved cognitive control or emotion regulation processes. Indeed, studies
have shown that rTMS over the left DLPFC increases the excitability of this
region (Fitzgerald et al., 2006; Schutter, 2010), which has been implicated as
the functional basis of cognitive control (Carter & van Veen, 2007; Miller,
2000). Additionally, cognitive control has been shown to improve in both
healthy participants and depressed patients after stimulating the DLPFC with
rTMS (Corlier et al., 2020; Pulopulos et al., 2020). Cognitive control training
is another treatment strategy that has been used for depression. CCT has been
shown to be effective in reducing depressive symptoms (Siegle, Ghinassi, &
Thase, 2007; Siegle et al., 2014), and results in increased efficiency of the
frontoparietal network and other brain regions implicated in affective and
cognitive control, notably the anterior cingulate cortex (Kim, Chey, & Lee,
2017; Schweizer, Grahn, Hampshire, Mobbs, & Dalgleish, 2013). In addition, the
n-back task, which is often used in CCT, has been shown to robustly activate
the DLPFC (Owen, McMillan, Laird, & Bullmore, 2005).
Both rTMS and CCT are effective treatment strategies for depression, and both
target and activate the DLPFC, which is thought to play a hub function in the
dynamic shift between the cognitive executive and salience network in
particular (Peters, Dunlop, & Downar, 2016). In a previous experiment we have
shown that active versus sham stimulation of the left DLPFC resulted in a
different susceptibility to mood induction (Mobius et al., 2017), which in turn
may affect cognitive control. Negative mood induction is a common experimental
manipulation, aimed at momentarily changing the mood of a participant in a
controlled manner.

In this study, we want to combine rTMS and CCT to assess whether the
combination of these two treatment would have synergistic effects and
strengthen each other. We specifically want to assess the effect on mood and
cognitive control, in a group of healthy participants. We hypothesize that the
combination of active rTMS and CCT results in a smaller decrease in mood after
negative mood induction as compared to either treatment alone. We also
hypothesize that the combination of active rTMS and CCT will result in a
smaller decrease in cognitive control, as a result of the negative mood
induction, as compared to either treatment alone.

Primary Objective: Our primary objective is to assess the effect of the
combination of active rTMS and CCT on mood after negative mood induction in
healthy participants, compared to rTMS combined with a control task and sham
rTMS combined with CCT.

Secondary Objective(s): Our secondary objective is to assess the effect of the
combination of active rTMS and CCT on cognitive control after negative mood
induction in healthy participants, rTMS combined with a control task and sham
rTMS combined with CCT.

We want to include 40 participants in this randomized single-blind cross-over
study. Participants will be seen thrice in the lab, with a one-week interval.
The estimated total time is 3 hours and 45 minutes. Session one has an
estimated duration of 45 minutes, whereas the estimated time for session 2 and
3 is 1,5 hours each. See figure 1 for an overview of the study design.

The first 20 participants will receive the control condition consisting of
active rTMS combined with a control task. The order of the control and
experimental condition will be counterbalanced. After 20 participants, we will
perform an interim analysis to assess the results thus far. If the results are
in line with our hypotheses, we will include the next 20 participants, which
will receive the experimental condition and the other control condition,
consisting of sham rTMS combined with CCT. The order will again be
counterbalanced. If we do not find a difference between the experimental
condition and control condition 1 based on the interim analysis, we will
terminate the study. With this cost-effective design we hope to first establish
whether the combination of rTMS and CCT adds something to the current
situation, which is rTMS alone. In our study, this is represented as rTMS
combined with a control task. After we have established this, we can further
examine the effects of the treatment by also looking into sham rTMS combined
with CCT.

Transcranial Magnetic Stimulation (TMS)
TMS will be performed in line with the DCCN Standard Operating Procedure for
non-invasive brain stimulation. Transcranial magnetic stimulation (TMS) is a
widely used non-invasive brain stimulation technique, based on the principle of
electromagnetic induction (Rossi et al., 2020). During stimulation, the
participant will likely hear the clicks of the TMS pulses and experience
stimulation of nerves and muscles in the scalp. All known side-effects of TMS
are transient and occur during or immediately after the stimulation session.
Importantly there is no evidence for long-lasting side-effects of TMS. The
stimulation parameters relevant for the assessment of the safety, risk and
burden of online and short-term TMS studies are the intensity, quantity,
frequency, and duration of stimulation (with higher doses elevating the risks),
and the site of stimulation (with stimulation over facial muscles and nerves
being less comfortable than stimulation elsewhere). In addition, for long-term
TMS studies the repetition rate and number of stimulation sessions is also
relevant.
The most common side-effect of online and short-term TMS protocols is a
transient light headache (2-4% occurrence) which is usually short lasting and
can be sufficiently treated with light painkillers like paracetamol. A severe
headache is uncommon (0.3-0.5% occurrence). There have been several reports of
reflexive syncope occurring in relation to TMS stimulation, but it is unclear
if the stimulation itself or the context of study participation is causative of
this side-effect (Rossi et al., 2020). In rare cases an epileptic seizure has
been unintentionally induced by TMS before international consensus guidelines
were established. Importantly, there is no report of TMS causing a severe
adverse event (including epileptic seizures) in healthy participants when using
TMS protocols that accord to the published safety guidelines (Rossi et al.,
2020). When stimulation parameters significantly exceed these guidelines (e.g.,
a higher intensity, frequency, or otherwise higher doses of stimulation), or
when patients with a lowered cortical excitability threshold (e.g., as a
consequence of epilepsy or drug treatment) are stimulated, the risk of inducing
a seizure is still minimal. Please note that all parameters of online and
short-term TMS protocols are within the range considered safe according to the
latest published safety guidelines (Rossi et al., 2020). For example, to assess
whether the risk of a TMS study protocol is considered minimal, we follow
(Rossi et al., 2020) which refers to table 4 of (Rossi, Hallett, Rossini, &
Pascual-Leone, 2009). This table lists guidelines for stimulation frequency,
intensity, and number of pulses.

Different tasks can be used for cognitive control training, the n-back task is
one of them (Koster, Hoorelbeke, Onraedt, Owens, & Derakshan, 2017). In this
study, we will use the version of the task that has been described elsewhere
(Jaeggi et al., 2007; Jaeggi, Buschkuehl, Jonides, & Perrig, 2008). In this
dual n-back task, squares are presented at eight different locations
sequentially on a computer screen. The stimulus is presented for 500 ms, the
inter-stimulus interval is 2500 ms. Simultaneous with the presentation of the
squares, one of eight consonants will be presented sequentially through
headphones. A response is required when one of the presented stimuli, either
auditory or visually, matches one of the stimuli presented n positions back in
the sequence. The value of n is the same for both auditory and visual stimuli.
There will be six auditory and six visual targets per block (four appearing in
only one modality, and two appearing in both modalities simultaneously), and
their positions will be determined randomly. Participants respond by pressing
on the letter *A* for visual targets, and on the letter *L* for auditory
targets. No responses are required for non-targets. The level of difficulty
will be varied by changing the level of n. After each block, the performance of
a participant is analysed, and in the following block, the level of n is
adapted accordingly. If the participants makes fewer than three mistakes per
modality, n is increased by one. If more than five mistakes are made, n is
decreased by 1. In all other cases, n remains unchanged. The task consists of
20 blocks, each consisting of 20 + n trials, resulting in a total of ~ 25
minutes.
As a control task, the single n-back task will be used. In this version, only
visual stimuli are presented. Furthermore, n will remain constant at 1, to make
this an easier version of the n-back task used for CCT that is still very
similar.

Considering the extensive exclusion criteria, the screening procedure, constant
monitoring of the subjects we do not expect (S)AE side effects. MRI
measurements themselves do not pose any risk, if appropriate precautions are
made. However, the noise and the relative confined space of the MRI scanner may
cause discomfort to some subjects.
As described in the Donders non-invasive brain stimulation SOP: transcranial
magnetic stimulation (TMS) is a widely used non-invasive brain stimulation
technique, based on the principle of electromagnetic induction (Rossi et al.,
2020). During stimulation, the partici-pant will likely hear the clicks of the
TMS pulses and experience stimulation of nerves and muscles in the scalp. The
most common side-effect of online and short-term TMS proto-cols is a light
transient headache. A severe transient headache is uncommon. In TMS stud-ies of
patient populations (e.g. epilepsy) or those exceeding the standard TMS
protocols (e.g. long-term TMS protocols) epileptic seizures have been reported
in rare cases. Online and short-term TMS protocols are considered safe
according to the latest published inter-national safety guidelines. All
subjects are screened for their relevant medical history and other TMS safety
aspects (e.g. metal parts in the head). In summary, the risk and burden
associated with participation can be considered minimal and no serious adverse
events are expected during online and short-term TMS studies.
The consent discussion starts sufficiently in advance of the initiation of
study-related pro-cedures to allow potential subjects time to reflect on the
potential benefits and risks and possible discomforts. Participants are
informed about our standard studies when they are screened (usually days before
inclusion) and the risk associated with participation in this study can be
regarded as minimal.
Further discomfort might be caused by procedures such as filling out
questionnaires and the time spend on the study.
The results of this study will provide us with better insight into two
treatments for depres-sion and how we can combine them to increase efficacy and
better help patients with de-pression.
In case of an incidental finding concerning a deviation in the MRI scan, step
1, the re-searcher will immediately contact the MRI lab manager:
a. If it concerns a healthy subject the MRI lab manager will send the images
out for as-sessment by a radiologist. At this stage the participant is not
informed, but the incidental finding will be documented (proceed to step 2).
b. If it concerns a patient and/or minor the researcher is required to consult
the responsible study MD.
- The responsible MD is trained to judge the images adequately proceed step 3.
- The responsible MD is not trained to judge the images proceed step 1a.
Step 2, if, according to a written report of the radiologist,
a. No clinically relevant finding is obtained, the participant will not be
informed, but the documentation updated.
b. A clinical relevant finding is obtained; the home physician will receive a
letter. Also the participant will receive a letter, which, however, does not
reveal any diagnosis but which asks the participant to contact his/ her home
physician.
c. The incidental finding will be centrally documented at the DCCN.
Step 3, if the responsible MD considers the abnormality as clinically relevant
the home physician or the treating specialist will be personally contacted by
the responsible MD. (for details see K6b).