Anodal HD-tDCS for cognitive inflexibility in autism spectrum disorder: A pilot study

Cognitive inflexibility is thought to contribute to the core symptom of restricted and repetitive behaviour and interests (RRBI) in autism spectrum disorder (ASD) [[1]Dajani D.R. Uddin L.Q. Demystifying cognitive flexibility: implications for clinical and developmental neuroscience.Trends Neurosci. 2015; 38: 571-578https://doi.org/10.1016/j.tins.2015.07.003Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar]. 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 cognitive flexibility [[2]Ishii-Takahashi A. Takizawa R. Nishimura Y. Kawakubo Y. Kuwabara H. Matsubayashi J. Kawasaki S. Prefrontal activation during inhibitory control measured by near-infrared spectroscopy for differentiating between autism spectrum disorders and attention deficit hyperactivity disorder in adults.Neuroimage: Clinical. 2014; 4: 53-63https://doi.org/10.1016/j.nicl.2013.10.002Crossref PubMed Scopus (35) Google Scholar,[3]Nelson E.E. Guyer A.E. The development of the ventral prefrontal cortex and social flexibility.Dev. Cogn. Neurosci. 2011; 1: 233-245https://doi.org/10.1016/j.dcn.2011.01.002Crossref PubMed Scopus (102) Google Scholar]. 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]Rivera-Urbina G.N. Nitsche M.A. Vicario C.M. Molero-Chamizo A. Applications of transcranial direct current stimulation in children and pediatrics.Rev Neurosci. 2017; 28: 173-184https://doi.org/10.1515/revneuro-2016-0045Crossref PubMed Scopus (20) Google Scholar,[5]García-González S. Lugo-Marín J. Setien-Ramos I. Gisbert-Gustemps L. Arteaga -Henríquez G. Díez-Villoria E. Ramos-Quiroga J.A. Transcranial direct current stimulation in Autism Spectrum Disorder: a systematic review and meta- analysis.Eur Neuropsychopharmacol. 2021; https://doi.org/10.1016/j.euroneuro.2021.02.017Crossref PubMed Scopus (6) Google Scholar]. 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 adolescents 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, crossover 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 = 25.08 years [SD = 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 randomised 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) Neuroelectrics Star Stim control box (HD-tDCS device) and corresponding NIC2 software. The aHD-tDCS montage design, intensity, and electrode positioning over the right vlPFC was derived by Neuroelectrics (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]Hogeveen J. Grafman J. Aboseria M. David A. Bikson M. Hauner K.K. Effects of high-definition and conventional tDCS on response inhibition.Brain Stimul. 2016; 9: 720-729https://doi.org/10.1016/j.brs.2016.04.015Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar] (see Supplementary Materials, 1.4). 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 constructs, including reversal errors. During the PRLT, 64-channel electroencephalography (EEG; SynAmps RT, Compumedics Neuroscan; Abbotsford, Victoria, Australia) was recorded to measure Feedback Related Negativity (FRN), an event-related potential (ERP) associated 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 behavioural switching in the reversal phase) in the PRLT. We also administered 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 sessions were systematically assessed using a NIBS Post-Stimulation Interview (See Supplementary Materials, Section 2). Generalised linear mixed models were used to examine the effect of aHD-tDCS on FRN, PRLT, BRIEF-A, and RBQ-2A with treatment (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 approximation 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]Albein-Urios N. Chase H. Clark L. Kirkovski M. Davies C. Enticott P.G. Increased perseverative errors following high-definition transcranial direct current stimulation over the ventrolateral cortex during probabilistic reversal learning.Brain Stimul. 2019; 12: 959-966https://doi.org/10.1016/j.brs.2019.02.013Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. There was no interaction effect between treatment condition (active versus sham) and time (pre versus post) on PRLT reversal errors, F(1, 40) = 0.29, p = .594, FRN, F(1, 12) = 3.82, p = .081, the BRIEF-A Shift Scale, F(1, 4) = 2.10, p = .226, or the RBQ-2A total, F(1, 0) = 0.25, p = .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 symptoms were reported for sham aHD-tDCS. All symptoms immediately subsided at the conclusion of stimulation (see Supplementary Materials, Section 5). In terms of feasibility, visit compliance was excellent, with participants attending all scheduled 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 efficacy over the right vlPFC when targeting cognitive flexibility difficulties in ASD. There was support for short-term safety and tolerability, as no serious side effects or adverse events were reported 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 stimulation was not observed, there are several important considerations. 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]Ishii-Takahashi A. Takizawa R. Nishimura Y. Kawakubo Y. Kuwabara H. Matsubayashi J. Kawasaki S. Prefrontal activation during inhibitory control measured by near-infrared spectroscopy for differentiating between autism spectrum disorders and attention deficit hyperactivity disorder in adults.Neuroimage: Clinical. 2014; 4: 53-63https://doi.org/10.1016/j.nicl.2013.10.002Crossref PubMed Scopus (35) Google Scholar,[8]Shafritz K.M. Dichter G.S. Baranek G.T. Belger A. The neural circuitry mediating shifts in behavioral response and cognitive set in autism.Biol Psychiatr. 2008; 63: 974-980https://doi.org/10.1016/j.biopsych.2007.06.028Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar,[9]Schmitz N. Rubia K. Daly E. Smith A. Williams S. Murphy D.G. Neural correlates of executive function in autistic spectrum disorders.Biol Psychiatr. 2006; 59: 7-16https://doi.org/10.1016/j.biopsych.2005.06.007Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar]. This inconsistency across studies reflects the heterogeneous neurobiology of ASD and indicates the need for individualised stimulation protocols to account for structural morphology and functional 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 disorder) that likely impact the response to NIBS. The use of larger 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 stimulation with neuroimaging/neurophysiological techniques, as this can importantly validate functional changes in response to HD-tDCS, and (b) incorporate growing knowledge on ASD-specific biomarkers [[10]McPartland J.C. Bernier R.A. Jeste S.S. Dawson G. Nelson C.A. Chawarska K. Webb S.J. The autism biomarkers consortium for clinical trials (ABC-CT): scientific context, study design, and progress toward biomarker qualification.Front Integr Neurosci. 2020; 14: 16https://doi.org/10.3389/fnint.2020.00016Crossref PubMed Scopus (21) Google Scholar]. The authors declare that there is no conflict of interest. This research was supported by the Faculty of Health Postdoctoral 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 participants of the study. 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