Adding rTMS to exposure therapy in PTSD in a placebo-controlled design : a pilot study

Repetitive transcranial magnetic stimulation (rTMS) is widely used both in
fundamental cognitive neuroscientific studies as well as clinical applied
studies investigating its potential mood stabilizing role. Recently, potential
use of rTMS has proven to be potentially promising in the treatment of
post-traumatic stress disorder (PTSD), one of the most common anxiety
disorders. Although the pathophysiology of PTSD remains unclear, growing
evidence from functional neuroimaging studies suggest that it is consistently
associated with hypoactivation of the prefrontal cortex (including medial and
dorsolateral regions) and hyperactivation of deeper brain structures, such as
the amygdala (Etkin et al. 2007, Hazes et al., 2012, Patel et al. 2012). The
DLPFC, in particular, is involved in many complex cognitive and behavioural
functions that are relevant to PTSD. An exploratory meta-analysis (Berlim et
al., 2014b) suggests that active rTMS applied to the dorsolateral prefrontal
cortex (DLPFC) seems to be effective and acceptable for treating PTSD.

While these results are in principle promising the complexity of the PTSD makes
it necessary to combine psychotherapeutic with potential new neuromodulatory
treatment options in the form of an add-on treatment. Thus far, rTMS was mainly
provided to PTSD-patients who did not (yet) receive guideline psychological
treatments, such as Exposure Therapy. However, an additional intervention
should ideally be provided only to those patients that show no improvements
after those first step treatments.

Primary Objective:
To investigate treatment (sham rTMS/rTMS) differences in PTSD symptom severity,
as measured with a clinician and self-rated instrument.

Secondary Objective:
To investigate the effect of rTMS and sham rTMS on general anxiety, comorbid
depressive symptoms and mood, and posttraumatic cognitions, as assessed by
clinician and self-rated instruments

The study takes place at the Department of Psychiatry and is designed as a
within-patients experiment. To exclude placebo effects on the one hand but also
optimize the proportionality of the sham treatment, patients will be randomized
to receive in the first 2 weeks 10 real or 10 sham HF-rTMS sessions (1
sessions/day for 5 consecutive days) and in the second 2 weeks of treatment of
the other condition. In between these two type of sessions and after the final
treatment there will be a break of a week at the end of which patients will be
reassessed in terms of symptom reduction.

RTMS and sham treatment will be done using Magstim Rapid 2. All rTMS parameters
used in the proposed study are within the range considered safe according to
the latest published safety guidelines (Rossi et al., 2009, 2011; Obermann et
al., 2011) and are based on a large multi-center study (O*Reardon et al., 2007)
as well as meta-analyses (see for example Schutter et al., 2009). Firstly, the
resting motor threshold (rMT) will be defined in each subject as the minimal
stimulation intensity evoking an MEP of * 0.05 mV in 50% of the trials in the
muscle of the right thumb (M. abductor pollicis brevis). Note that rMT will be
determined before every treatment/sham session. TMS will be conducted in the
form of *conventional rTMS*, whereby 20 trains of 10 Hz pulses with a duration
of 5 seconds and an inter-train interval of 25 seconds are applied to the right
DLPFC (50 pulses per train, 1000 pulses per session).
We aim to control for placebo effects merely evoked by the regular treatment
and therefore include a so-called sham condition using a sham-coil,which
applies a similar electrical sensation to the skull.

Possible benefit resulting from the treatment cannot be guaranteed to
participants. Transcranial magnetic stimulation (TMS) is a widely used
non-invasive brain stimulation technique, based on the principle of
electromagnetic induction. During stimulation the participant will likely hear
the clicks of the TMS pulses and experience stimulation of nerves and muscles
of the head. The most common side effect is a light transient headache (2-4%
occurrence). A severe headache is uncommon (0.3-0.5% occurrence). In the
current study patients will be stimulated with a protocol that falls within the
safety guidelines. All participants are screened for their relevant medical
history and other TMS safety aspects (e.g. presence of metal parts in the
head). The study will give insight whether rTMS can become an efficient add/on
therapy in PTSD, which is highly relevant given the amount of patients who do
not fully respond to the current treatment options. The cross-over design is
setup in such way that it minimizes the burden of a placebo-control as much as
possible and improves power using a within-subject design.