Enhancement of one exposure session for social anxiety disorder with transcranial alternating current stimulation: a proof-of-concept study

With a lifetime prevalence of 13.3%, social anxiety disorder (SAD) is the most
common anxiety disorder and among the most common pyschiatric disorders
(Kessler et al., 1994). If untreated, the disorder typically follows a chronic,
unremitting course leading to substantial impairments in vocational and social
functioning. Exposure therapy is a proven effective treatment for SAD, but
remission rates tend to be low (Blanco et al., 2010; Davidson et al., 2004),
underscoring the need for new treatment strategies that enhance remission
rates. This can be done by pairing exposure therapy with an additional
intervention that boosts its underlying mechanisms of fear reactivity.
Avoidance is the main hampering factor in exposure therapy: as long as patients
avoid, fear cannot be extinguished and patients cannot learn new behaviours
(Beckers & Craske, 2017). Avoidance, for instance, can predict treatment
outcome, suggesting that improving in-session avoidance might augment the
treatment effects. Using a proof-of-concept study (Hutschemaekers et al.,
2021), we previously showed that improving control over in-session avoidance
can indeed augment the efficacy of exposure therapy and improve in-session fear
reactivity (i.e. higher peaks and steeper reductions in fear levels). However,
those studies used an invasive method (pharmacological intervention). Recent
developments in neuromodulation have shown that non-invasive methods can
effectively improve control social avoidance in healthy and anxious
participants (Bramson et al., 2020; Meijer et al., 2023).

Cortical oscillations play an important role in the control over automatic
social emotional action tendencies. Specifically, social emotional action
control has been shown to be supported by a mechanism where the phase of
theta-band oscillations in the anterior prefrontal cortex (aPFC) is coupled to
the amplitude of gamma-band rhythms in sensorimotor cortex (SMC). A
transcranial alternating current stimulation (tACS) protocol has been developed
that mimics this endogenous mechanism by stimulating the aPFC and the SMC with
theta- and gamma-band rhythms respectively, and by coupling the phase of the
theta stimulation to the amplitude of the gamma stimulation. It was shown that
in-phase aPFC-SMC stimulation facilitates the selection of an appropriate
emotional action alternative, improving social-emotional control in both
healthy and socially-anxious individuals (Bramson et al., 2020; Meijer et al.,
2023).

In this proof-of-concept study, we aim to investigate whether these effects of
in-phase aPFC-SMC tACS can be used to non-invasively enhance an exposure
session. We plan to conduct a double-blind intervention study comparing one
session of exposure plus in-phase aPFC-SMC tACS against exposure plus an active
sham tACS stimulation (anti-phase aPFC-SMC) as placebo. Standardized brief
exposure will be delivered according to the protocol developed by Rodebaugh and
colleagues (2013): in this clinical assay consisting of two exposure sessions
one week apart, participants need to prepare and deliver a speech (6 - 8
minutes) in front of an audience and a video camera. The first exposure session
is enhanced with tACS, and the second exposure session is not enhanced,
allowing the detection of transfer effects. We expect to detect verum vs
placebo effects on response to exposure in terms of improved fear reactivity
during the first enhanced exposure session. Furthermore, we will investigate
whether this effect is mediated by in-session changes in avoidance (as measured
by body posture, speech prosody, and eye gaze during the speech delivery), and
whether these effects transfer to a second exposure session without
enhancement.

To investigate the effects of aPFC-SMC phase-coupled tACS on exposure for SAD.

The planned study is a double-blind intervention study.

Participants will receive brief standardized exposure consisting of two
exposure sessions one week apart in which participants give a speech in front
of an audience and a video camera. The first exposure is enhanced, and the
second exposure is not. Participants will be randomly allocated to either
in-phase aPFC-SMC tACS enhancement or active sham (anti-phase aPFC-SMC) tACS
enhancement. tACS will be applied concurrently with the speech preparation and
delivery (20 minutes).

We believe the burden and the risk to be limited. Participants will visit the
site three times, but each visit is necessary: the baseline
neuroimaging/behavioural/questionnaire data measured during the first visit are
crucial to obtain predictors of the tACS effects, and the subsequent two
exposure visits are required to investigate the effects of our intervention,
i.e. both immediate as well as persistent effects of combined tACS-exposure.
Moreover, tACS is considered to be safe (Antal et al., 2017), and our
stimulation parameters have been tested before (Bramson et al., 2020; Meijer et
al., 2023).

There are no direct benefits for the participants in the present study.
Possibly, participants that receive in-phase tACS will have benefits compared
to standard exposure, however this has yet to be determined. Participants will
contribute to knowledge on a potential enhancer of exposure efficacy for SAD.

We require participants that meet the DSM-5 criteria for SAD so that our
findings can be clinically-relevant and provide ground for future clinical
trials.