Improving outcome through improving cognition in Severe Mental Illness: Cognitive Remediation Training combined with transcranial Direct Current Stimulation, a randomized, sham-controlled, multi-center trial.

People with a serious mental illness (SMI) such as schizophrenia, bipolar
disorder or major depression often experience major problems in daily life,
such as in the area of household skills (grocery shopping, cleaning) and
organization of daily life (keeping a calendar, financial organization).
Sometimes such problems are so great that people can no longer live
independently and fall back on forms of sheltered housing. Often these problems
in daily life are caused by disorders in thinking ability (cognitive
disorders). Moreover, research shows that cognitive impairments are associated
with reduced brain ability to change and adapt to the environment (also called
neural plasticity) in people with EPA.

A possible treatment approach is cognitive remediation training (CR), a
training developed to target cognitive deficits with the ultimate aim to
improve daily functioning. Participants engage in cognitive exercises, learn
more about their own cognition and the use of (cognitive) strategies to
compensate for deficits. However, in people with SMI, neural plasticity is
reduced, which might hinder newly learned cognitive skills to sustain and limit
the benefits from CR. For this reason, people with SMI may benefit from the
combination of CR with a method that may promote neural plasticity:
transcranial direct current stimulation (tDCS).

In a pragmatic, triple-blinded, randomized, sham-controlled, multi-center trial
with a multiple baseline design, we will investigate the effectiveness of
combining CR and tDCS in helping participants reach personal goals, minimizing
problems in daily functioning and improving cognitive functioning. 126 service
users with SMI will receive 16-20 weeks of twice-weekly CR combined with active
(N=63) or sham tDCS (N=63). We will perform functional, cognitive, and clinical
outcome assessments at baseline, after a 16-week waiting period, post-treatment
and 6-months post-treatment and compare the effects within-participants
(waiting period vs. treatment period) and between-participants (CR+active tDCS
vs. CR+sham tDCS).

CIRCuiTS. Computerized Interactive Remediation of Cognition and Thinking Skills
(CIRCuiTS) is a computer training composed of tasks that improve cognitive
skills in the domains of attention, memory, working memory and planning. The
training is adaptive, so if a participant does the tasks well, the training
becomes more difficult. CIRCuiTS encourages generalization of learned cognitive
skills to everyday life in several ways. Participants 1) learn more about their
own thinking skills by indicating how difficult they find tasks; 2) evaluate
their goals, strengths and difficulties at pre-planned times; 3) learn to make
a plan of action by choosing cognitive strategies prior to a task and
evaluating how useful they were afterwards. Furthermore, tasks are programmed
to take place in a virtual village with e.g. a library, train station and
supermarket, which encourages generalization.

tDCS. We use an Eldith DC stimulator (NeuroConn, Germany) to stimulate the
target brain region, the left dorsolateral prefrontal cortex (DLPFC). We place
the anode at C3 and the cathode at Fp1, in accordance with the international
10-20 system. To check whether the brain stimulation stimulates the DLPFC, we
simulated the effects when placing the electrodes at these locations with
computational modeling using the software SimNIBS. We fix conductive rubber
electrodes (5cm x 5cm) with conductive paste (Ten20, Neurodiagnostic Paste).
For active tDCS, we use a current of 2 mA, for 20 min with a fade in/out of
30s. Longer stimulation appears to have no additional effect, moreover,
stimulation acts 2-4 h after (Monte Silva et al., 2013). For sham tDCS, we
apply an identical fade-in, which will then disappear in 30s.

In a previous pilot study, we showed that a combined CR+tDCS intervention was
feasible and acceptable in the target population. Participants reported
enjoying the CR training and that the intervention helped them achieve their
goals. In addition, they indicated that they were not burdened by the tDCS.
Participants also indicated that they expect that other people with EPA could
also benefit from the intervention. The pilot study found that participants
could handle the four-month, twice-weekly duration well and that it was not too
intensive. In fact, most participants were surprised that they were already
four months into the training and just didn't want to miss any training. If we
can show in a larger-scale study that CIRuiTS is effective and that possibly
tDCS has an additive effect, this intervention could meet a large patient need.