Enhancing effect of dual interventions versus conventional TMS in the treatment of
depression

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment option for depression (level A evidence, definite efficacy; LeFaucheur et al., 2020). Unfortunately, not every patient responds (fully) to rTMS. Cognitive control training is proven effective as add-on treatment on top of treatment as usual, with less relapse during follow-up, and it can even induce synergistic effects. When simultaneously administering rTMS and a cognitive task, the *state-dependent* effects of rTMS are boosted might which results in an optimization of the therapeutic response. As rTMS is a time-consuming treatment, with patients receiving on average 25-30 30-minute treatment sessions, combining the two interventions leads to an efficient, pragmatic and cost-effective solution to increase effectiveness.

rTMS is an intensive but effective treatment that could benefit from further optimization. Cognitive control training (CCT) engages the same underlying neural circuitry as rTMS and has been shown to improve therapeutic response (Koster et al., 2017; Motter et al., 2016; Legemaat et al., 2022).  Simultaneous application of rTMS and a CCT task might further enhance treatment effectiveness in an efficient manner (Li et al., 2016). Our primary objective is therefore to assess the (cost-)effectiveness of rTMS augmented with CCT as opposed to rTMS combined with a placebo task.

A randomized multicenter clinical trial consisting of eight weeks of treatments and follow-up assessments up to twelve months.

Treatment will consist of 30 rTMS sessions in an 8-week period. The rMT will be defined in each participant during the baseline assessment. Treatment will target the left dorsolateral prefrontal cortex (DLPFC). We will use BeamF3 (freely available software) to find the DLPFC, which is based on electrode position F3 from the EEG 10-20 system. The coil will be positioned over this location at an angle of 45° relative to the midline. rTMS will be conducted using a high-frequent protocol, applying 75 trains of 10Hz pulses with a duration of 4s and an inter-train interval of 11s over the left DLPFC (40 pulses per train, 3000 pulses per session), with an intensity of 120% of the rMT.

A progressive dual n-back task as described by Jaeggi et al. will be used as CCT task. Visuospatial and auditory stimuli will be presented simultaneously to the patient. The patient has to remember the location of stimuli and auditory sounds and is supposed to respond when either the location or sound is the same as n-turns back, starting at n=2. If the patient scores >=0.9 the level of the dual n-back is increased, to for instance n=3. If the score of the patient is <=0.9 the n-back level is lowered. One block consists of 20+n trials, each trial has a duration of 3000 ms. The visual spatial stimuli consist of blue squares projected on a computer screen at 9 different locations. The auditory stimuli consist of eight consonants presented through headphones. In the placebo condition patients will be passively view the visuospatial stimuli and passively listen to the auditory stimuli.

Benefits: Decrease in depressive symptoms

Risks: Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique, based on the principle of electromagnetic induction. The discharge of the TMS coil generates a hearable noise (*click*) and the participant might experience sensations originating from the potential stimulation of peripheral nerves outside the skull and the potential contraction of facial or neck muscles. The most common side effect 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 is no report of TMS causing a severe adverse event (such as an epileptic seizure) 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 amount 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 are increased from negligible to minimal. Please note that that all TMS parameters are within the range considered safe according to the latest published safety guidelines. The magnetic field of TMS can affect metal and electrical devices close to the coil. Therefore, large or ferromagnetic metal parts in the head (except for a dental wire behind the teeth), or the presence of a cardiac pacemaker or neurostimulator are strict exclusion criteria. All subjects are screened for their relevant medical history and other aspects concerning the safety of TMS application. All investigators involved in the study are well trained and qualified, and the used equipment adheres to the required international safety standards. In summary, because the risk and burden associated with participation can be considered negligible-to-minimal, we do not expect serious adverse events during the project.