Brain Stimulation 14 (2021) 1298e1300
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Brain Stimulation
journal homepage: http://www.journals.elsevier.com/brain-stimulation
Anodal HD-tDCS for cognitive inflexibility in autism spectrum
disorder: A pilot study
Cognitive inflexibility is thought to contribute to the core symp-
tom of restricted and repetitive behaviour and interests (RRBI) in
autism spectrum disorder (ASD) [1]. The ventrolateral prefrontal
cortex (vlPFC) has been strongly implicated in cognitive flexibility.
Reduced activation of the vlPFC in ASD has been linked with
impaired stimulus valuation and rule acquisition aspects of cogni-
tive flexibility [2,3]. The vlPFC appears a promising target for
non-invasive brain stimulation (NIBS) in ASD, raising the prospect
of a new therapeutic intervention that could ameliorate cognitive
flexibility difficulties in people with ASD.
Preliminary studies of transcranial direct current stimulation
(tDCS) in ASD have demonstrated short-term improvements in
ASD symptomatology, cognitive function, and motor ability [4,5].
To this end, we conducted a pilot study that compared the effects
of active and sham (placebo) anodal high-definition transcranial
direct current stimulation (aHD-tDCS) over the right vlPFC in ado-
lescents and young adults diagnosed with DSM-5 ASD. Outcome
measures included four indices of cognitive flexibility (behavioural,
electrophysiological, cognitive, and clinical). We also assessed
safety and tolerability of aHD-tDCS in ASD.
This was a randomised, sham-controlled, double-blind, cross-
over clinical trial (see Supplementary Materials, 1.2). aHD-tDCS,
generally thought to increase cortical excitability, was administered
at 1.693mA for 20 minutes over the right vlPFC on four consecutive
days (see Fig. 1).
Participants underwent both active and sham aHD-tDCS, with a
three-week interval between conditions. The final sample included
twelve participants with ASD (7 Males, mean age ¼ 25.08 years
[SD ¼ 7.20]; see Supplementary Materials, 1.1). Ten participants
completed both aHD-tDCS conditions. Two participants only
completed active aHD-DCS (withdrawing prior to the second rand-
omised condition due to travel difficulties and transportation time).
This study was approved by the Human Research Ethics Committee
of Deakin University (Melbourne, Australia) and prospectively
registered on the Australian New Zealand Clinical Trial Registry
(ANZCTR) (ACTRN12616001045404).
aHD-tDCS was administered using a wireless (Bluetooth) Neuro-
electrics Star Stim control box (HD-tDCS device) and corresponding
NIC2 software. The aHD-tDCS montage design, intensity, and elec-
trode positioning over the right vlPFC was derived by Neuroelec-
trics (See Supplementary Materials, 1.3). During the
administration of aHD-tDCS, participants also completed the Stop
Task, which engages vlPFC, in an attempt to produce stronger,
longer-lasting effects of stimulation [6] (see Supplementary
Materials, 1.4).
https://doi.org/10.1016/j.brs.2021.08.020
1935-861X/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Cognitive flexibility was assessed across four measures (pre and
post aHD-tDCS conditions). The Probabilistic Reversal Learning
Task (PRLT) provides a direct approach to examining flexible choice
behaviour. It can quantify and differentiate between cognitive con-
structs, including reversal errors. During the PRLT, 64-channel elec-
troencephalography (EEG; SynAmps RT, Compumedics Neuroscan;
Abbotsford, Victoria, Australia) was recorded to measure Feedback
Related Negativity (FRN), an event-related potential (ERP) associ-
ated with flexibility. FRN amplitudes were extracted from two trial
types, reversal errors (measured during the reversal phase) and
first positive after reversal (the first correct response after behav-
ioural switching in the reversal phase) in the PRLT. We also admin-
istered the Behaviour Rating Inventory of Executive Functioning
(BRIEF; shift subscale) and Repetitive Behaviour Questionnaire 2A
(RBQ-2A; total score). The safety and feasibility of aHD-tDCS ses-
sions were systematically assessed using a NIBS Post-Stimulation
Interview (See Supplementary Materials, Section 2).
Generalised linear mixed models were used to examine the ef-
fect of aHD-tDCS on FRN, PRLT, BRIEF-A, and RBQ-2A with treat-
ment (active versus sham) and time (pre versus post) as fixed
effects. Interaction terms were also included in the model. A
random intercept was included to account for the clustering of
time and condition within participants. Satterthwaite approxima-
tion was used for degrees of freedom and robust estimation was
used to address violations of model assumptions. All analyses
were conducted using SPSS 26.0 (IBM Corp; Armonk, NY). For EEG
data analysis see Ref. [7].
There was no interaction effect between treatment condition
(active versus sham) and time (pre versus post) on PRLT reversal er-
rors, F(1, 40) ¼ 0.29, p ¼ .594, FRN, F(1, 12) ¼ 3.82, p ¼ .081, the
BRIEF-A Shift Scale, F(1, 4) ¼ 2.10, p ¼ .226, or the RBQ-2A total,
F(1, 0) ¼ 0.25, p ¼ .918.
No serious adverse events were noted. During active aHD-tDCS,
three participants reported minor symptoms (Sessions: x6 pins/
needles, x1 face pain, x1 fatigue). A range of mild transient symp-
toms were reported for sham aHD-tDCS. All symptoms immedi-
ately subsided at the conclusion of stimulation (see
Supplementary Materials, Section 5). In terms of feasibility, visit
compliance was excellent, with participants attending all sched-
uled visits. Only two participants withdrew from the study prior
to the second condition (three-week interval). aHD-tDCS sessions
were successfully completed within 1-h (set up, 20 mins aHD-
tDCS, clean up).
The current pilot study did not provide support for aHD-tDCS ef-
ficacy over the right vlPFC when targeting cognitive flexibility
D. Parmar, P.G. Enticott and N. Albein-Urios
Fig. 1. Simulation of the HD-tDCS electric field. A) Electric field strength. B) Normal
component of the electric field. Positive (red) values indicate current flowing into the
cortex, while negative (blue) values indicate current flowing out of the cortex. (For
interpretation of the references to colour in this figure legend, the reader is referred to
the Web version of this article.)
difficulties in ASD. There was support for short-term safety and
tolerability, as no serious side effects or adverse events were re-
ported for aHD-tDCS. Additionally, participants in our study
showed high adherence rates during the trial, which importantly
demonstrates the viability of this study design for future tDCS
research in ASD.
Although improvements in cognitive flexibility following stimu-
lation was not observed, there are several important consider-
ations. Firstly, evidence for abnormal vlPFC activation in ASD is
not consistent in the literature, with evidence of both reduced
and/or enhanced activation in frontoparietal and insular regions
[2,8,9]. This inconsistency across studies reflects the heterogeneous
neurobiology of ASD and indicates the need for individualised stim-
ulation protocols to account for structural morphology and func-
tional activation patterns. Secondly, our sample size was small
and treatment duration limited; any effects of stimulation are likely
smaller than we were able to detect, or additional stimulation may
be required. In addition, although we successfully implemented our
blinding procedure, we did not include a specific assessment for
blinding integrity, which should be incorporated in future studies.
Lastly, there is significant demographic (e.g., age, sex) and clinical
variability in ASD (e.g., comorbid neurological and psychiatric dis-
order) that likely impact the response to NIBS. The use of larger
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Brain Stimulation 14 (2021) 1298e1300
sample sizes (e.g., via multisite trials) in this heterogenous clinical
population is crucial to better understand responses to NIBS and
sources of inter-individual variability. We recommend that any
future studies of aHD-tDCS in ASD should (a) consider pairing stim-
ulation with neuroimaging/neurophysiological techniques, as this
can importantly validate functional changes in response to HD-
tDCS, and (b) incorporate growing knowledge on ASD-specific bio-
markers [10].
Declaration of competing interest
The authors declare that there is no conflict of interest.
Acknowledgements
This research was supported by the Faculty of Health Postdoc-
toral Fellowship Scheme from Deakin University (Australia). NAU
was supported by the Faculty of Health Postdoctoral Fellowship
Scheme from Deakin University (Australia). PGE was supported
by a Future Fellowship from the Australian Research Council
(Australia). We would like to thank the research team and the par-
ticipants of the study.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.brs.2021.08.020.
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Dinisha Parmar
Cognitive Neuroscience Unit, School of Psychology, Deakin University,
Geelong, Victoria, Australia
D. Parmar, P.G. Enticott and N. Albein-Urios Brain Stimulation 14 (2021) 1298e1300

*
Peter G. Enticott
Cognitive Neuroscience Unit, School of Psychology, Deakin University,
Geelong, Victoria, Australia
Natalia Albein-Urios*
Cognitive Neuroscience Unit, School of Psychology, Deakin University,
Geelong, Victoria, Australia
Corresponding author. School of Psychology, Deakin University,
221 Burwood Hwy, Burwood, Victoria, 3125, Australia.
E-mail address: natalia.albeinurios@deakin.edu.au (N. Albein-
Urios).
5 August 2021
Available online 24 August 2021

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