Clinical trial NCT03947086: Neurostimulation for Cognitive Rehabilitation in Autistic Spectrum Disorders
Official title: Transcranial Direct Current Stimulation for Cognitive Rehabilitation of Children With Autistic Spectrum Disorders
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Autistic Disorders Spectrum
Keywords: Autistic disorder
Neuromodulation
Social cognition
Executive functions
Eye tracking
Lead sponsor: Federal University of Paraíba
Sponsor class: OTHER
First posted: 2019-05-13
Enrollment: 16
Sex: MALE
Minimum age (years): 8
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: this study is a sham-controlled, double-blind, randomized clinical trial aiming to evaluate the efficacy of anodic TDCS in aspects of social cognition of children between 8 and 12 years old with mild ASD. In total there will be 16 children, diagnosed with ASD according DSM-V, will be randomized to two groups, one with active stimulation (1.5 mA) and the other with a placebo current, in which the anode will be positioned over the left dorsolateral prefrontal cortex (F3), while the cathode (reference electrode) will be placed in the right supraorbital area. The intervention will be applied for 5 consecutive days for 20 minutes. Participants and investigators will be blinded. Furthermore, everyone will receive Social Cognition Training concomitantly with neurostimulation to enhance social skills in children with ASD. Patients will undergo three social cognitive assessments: at baseline, week 2 (after stimulation), and 1 month later (follow up).
Primary purpose: TREATMENT

Brief summary: This study is a clinical trial aims investigate the effects of neurostimulation in the treatment of children with mild ASD, specifically the action of tDCS on social cognition skills. tDCS can modulate neuronal activity in patients with ASD. Specifically, this technique has shown to be a promising tool in the promotion of social neuroplasticity, aiming at more adaptive social interactions. In this sense, it was hypothesized that participants treated with active tDCS will present better performance in social cognition tests than those submitted to sessions with simulated current.

Detailed description: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that has multiple causes and very heterogeneous degrees. The main symptoms involve deficits in social interactions, difficulties in verbal and nonverbal communication, repetitive and stereotyped movements, and restricted patterns of interest. In the context of ASD rehabilitation, there is no specific treatment for autism so far, being the behavioral therapy the most used therapeutic strategy, but with still unsatisfactory results. Transcranial Direct Current Stimulation (tDCS) has been shown to be a promising technique for the treatment of different disorders, including ASD. The tDCS consists of electrical signals emitted through two electrodes in different areas of the scalp, according to the purpose of the study. The anodic current reduces the firing threshold of the neurons that are located in the cortex (that is, they increase the spontaneous firing of these neurons), whereas the cathodic current increases the firing threshold of the neurons (that is, it inhibits the activity of these neurons). Considering neuroplasticity mechanisms as fundamental in cognitive processing, tDCS becomes a promising tool in neuropsychological rehabilitation in the treatment of autistic symptoms. Previous research using protomagnetic resonance spectroscopy (H-MRS) showed lower levels of N-acetyl aspartate (NAA, a marker of mitochondrial function and neuronal density) in the left DLFPC (F3) of autistic patients, compared to healthy individuals. The findings suggest that left DLFPC dysfunction may be a component of the pathogenesis of autism. Such aspects could explain why anodic neurostimulation in F3 can improve the efficacy of autism treatment through the beneficial effects on the cognitive processes associated with DLFPC activity, such as attention and memory, executive functions, and social cognition. Social cognition can be understood as a neurobiological process that facilitates the interpretation of social signs, leading individuals to behave adaptively. In this perspective, investigations have been made that use noninvasive neuromodulatory techniques as promising tools for the promotion of social neuroplasticity, that is, the modulation of the functional and structural substrates of the nervous system associated with social cognition aiming at more adaptive social interactions.In this sense, this study is a sham-controlled, double-blind, randomized clinical trial aiming to evaluate the efficacy of anodic tDCS in aspects of social cognition of children with mild ASD. Considering that tDCS can modulate neuronal activity in patients with ASD, presented as a promising tool in the promotion of social neuroplasticity, it was hypothesized that participants treated with active current will present better performance in the social cognition tests than those submitted to sessions with simulated current. Participants treated with active current will present less number and duration of fixations in the ocular tracing during the execution of the test of recognition of emotional expressions than those submitted to the sessions with simulated current. Furthermore, cognitive processes such as executive functions are essential for social cognition because they enable the individual to engage in socially relevant activities, make decisions and behaviors to achieve goals. Deficits in social cognition as well as executive functioning have been considered central elements in the understanding and functionality of people with ASD. Thus, it was hypothesized that participants who are treated with active current will present better performance in the tests of executive functions than those submitted to the sessions with simulated current. Participants treated with active current will present less number and duration of fixations during ocular screening in the executive function test than those submitted to the simulated current sessions. Considering that there were no prior data on the effects of tDCS on patients with ASD using the primary outcome measure of the present study, a formal sample size calculation was not possible; thus, it was estimated that enrolling 20 patients would be a reasonable approach for an exploratory trial. Patients are being recruited from the appointment of rehabilitators of multidisciplinary rehabilitation centers for temporary or permanent disability and global developmental disorders in Paraíba, Brazil. Children diagnosed with ASD according DSM-V, will be randomized to two groups, one with active stimulation (1.5 mA) and the other with a sham current, in which the anode will be positioned over the left dorsolateral prefrontal cortex (F3), while the cathode (reference electrode) will be placed in the right supraorbital area. The intervention will be applied for 5 consecutive days for 20 minutes. Furthermore, everyone will receive Social Cognition Training concomitantly with neurostimulation to enhance social skills in children with ASD. To control adverse effects, reports of patients with feelings/sensations of itching, tingling, burning, headache or other discomfort (1 none, 2 mild, 3 moderate, or 4 strong) will be recorded, along with whether this effect could be related to stimulation on a Likert scale; 1 (no relation) to 5 (strongly related).

The Descriptive and inferential statistical analyzes will be performed through SPSS (Statistical package for the social sciences), version 20. The design of the statistical analyzes is based on previous literature studies of randomized and placebo-controlled clinical trials using tDCS. The intention-to-treat analysis will be used with the last observation carried forward method for patients who initiate treatment and receive at least 1 session. In this way, all participants, including in case of withdrawal of the treatment before its completion, will be included in the analysis. It will be used as significance level p \<0.05.

The descriptive statistics will be used to describe the clinical and sociodemographic characteristics, as well as the primary and secondary outcomes of each group in T0. The groups will be compared using Student's t test for continuous variables, or chi-square, for categorical variables.

The evaluation and efficacy of tDCS in all variables of the primary and secondary outcomes will be examined with mixed two-way ANOVA, repeated measures, one dependent variable and two independent variables, one intra-group (time, with 3 levels, T0, T2 and T3), and between-groups (two levels: Active, Sham). Covariance analyzes (ANCOVA) will be used to identify significant differences between groups using the T0 scores as covariables. In addition, adverse effects will be analyzed using the chi-square test.

Linear logistic regression will be used to identify predictors of response. The independent variables are: tDCS active and sham, the predictive variables, analyzed one at a time, will be: age and severity of symptoms. Patients will undergo three social cognitive assessments: at baseline, week 2 (after stimulation), and 1 month later. Adverse effects will be computed at each session. Thus, this clinical trial aims to investigate the combined effects of transcranial direct current stimulation and social cognition training in improving the social skills of children with ASD.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of ASD
* Degree of mild autistic symptomatology
* Normal or corrected acuity.

Exclusion Criteria:

* Intellectual deficits
* Cardiac pacemaker or implanted metallic or electronic device
* Severe neurological disorders
* Poor skull formation
* Epilepsy

Primary outcomes:
measure: Facial emotion recognition
timeFrame: The test will be measured immediately before the intervention.
measure: Facial emotion recognition
timeFrame: The test will be measured immediately after the intervention.
measure: Facial emotion recognition
timeFrame: The test will be measured 4 weeks after the intervention.
measure: Theory of mind- Verbal task
timeFrame: The test will be measured immediately before the intervention.
measure: Theory of mind- Contextual task
timeFrame: The test will be measured immediately before the intervention.
measure: Theory of mind- Verbal task
timeFrame: The test will be measured immediately after the intervention.
measure: Theory of mind- Contextual task
timeFrame: The test will be measured immediately after the intervention.
measure: Theory of mind- Verbal task
timeFrame: The test will be measured 4 weeks after the intervention.
measure: Theory of mind- Contextual task
timeFrame: The test will be measured 4 weeks after the intervention.
Secondary outcomes:
measure: Memory for Digit Span
timeFrame: The test will be measured immediately before the intervention.
measure: Memory for Digit Span
timeFrame: The test will be measured immediately after the intervention.
measure: Memory for Digit Span
timeFrame: The test will be measured 4 weeks after the intervention.
measure: Trail Making Test A e B
timeFrame: The test will be measured immediately before the intervention.
measure: Trail Making Test A e B
timeFrame: The test will be measured immediately after the intervention.
measure: Trail Making Test A e B
timeFrame: The test will be measured 4 weeks after the intervention.
measure: Seven Errors Test
timeFrame: The test will be measured immediately before the intervention.
measure: Seven Errors Test
timeFrame: The test will be measured immediately after the intervention.
measure: Seven Errors Test
timeFrame: The test will be measured 4 weeks after the intervention.
Other outcomes:
Locations:
city: João Pessoa
country: Brazil
facility: Gabriela Medeiros
state: Paraíba
Study officials:
affiliation: Federal University of Paraíba
name: Jéssica B Santana, Master
role: PRINCIPAL_INVESTIGATOR
affiliation: Federal University of Paraíba
name: Natanael A Santos, PhD
role: STUDY_DIRECTOR
References:
citation: Amatachaya A, Auvichayapat N, Patjanasoontorn N, Suphakunpinyo C, Ngernyam N, Aree-Uea B, Keeratitanont K, Auvichayapat P. Effect of anodal transcranial direct current stimulation on autism: a randomized double-blind crossover trial. Behav Neurol. 2014;2014:173073. doi: 10.1155/2014/173073. Epub 2014 Oct 30.
citation: Amatachaya A, Jensen MP, Patjanasoontorn N, Auvichayapat N, Suphakunpinyo C, Janjarasjitt S, Ngernyam N, Aree-uea B, Auvichayapat P. The short-term effects of transcranial direct current stimulation on electroencephalography in children with autism: a randomized crossover controlled trial. Behav Neurol. 2015;2015:928631. doi: 10.1155/2015/928631. Epub 2015 Mar 12.
citation: Jamil A, Batsikadze G, Kuo HI, Labruna L, Hasan A, Paulus W, Nitsche MA. Systematic evaluation of the impact of stimulation intensity on neuroplastic after-effects induced by transcranial direct current stimulation. J Physiol. 2017 Feb 15;595(4):1273-1288. doi: 10.1113/JP272738. Epub 2016 Nov 8.
citation: Boggio PS, Asthana MK, Costa TL, Valasek CA, Osorio AA. Promoting social plasticity in developmental disorders with non-invasive brain stimulation techniques. Front Neurosci. 2015 Sep 1;9:294. doi: 10.3389/fnins.2015.00294. eCollection 2015.
citation: Brunoni AR, Nitsche MA, Bolognini N, Bikson M, Wagner T, Merabet L, Edwards DJ, Valero-Cabre A, Rotenberg A, Pascual-Leone A, Ferrucci R, Priori A, Boggio PS, Fregni F. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul. 2012 Jul;5(3):175-195. doi: 10.1016/j.brs.2011.03.002. Epub 2011 Apr 1.
citation: Couture SM, Penn DL, Roberts DL. The functional significance of social cognition in schizophrenia: a review. Schizophr Bull. 2006 Oct;32 Suppl 1(Suppl 1):S44-63. doi: 10.1093/schbul/sbl029. Epub 2006 Aug 17.
citation: Demirtas-Tatlidede A, Vahabzadeh-Hagh AM, Pascual-Leone A. Can noninvasive brain stimulation enhance cognition in neuropsychiatric disorders? Neuropharmacology. 2013 Jan;64:566-78. doi: 10.1016/j.neuropharm.2012.06.020. Epub 2012 Jun 28.
citation: Dillon MR, Kannan H, Dean JT, Spelke ES, Duflo E. Cognitive science in the field: A preschool intervention durably enhances intuitive but not formal mathematics. Science. 2017 Jul 7;357(6346):47-55. doi: 10.1126/science.aal4724.
citation: Gao X, Maurer D. Influence of intensity on children's sensitivity to happy, sad, and fearful facial expressions. J Exp Child Psychol. 2009 Apr;102(4):503-21. doi: 10.1016/j.jecp.2008.11.002. Epub 2009 Jan 4.
citation: Kucharska-Pietura K, Mortimer A. Can antipsychotics improve social cognition in patients with schizophrenia? CNS Drugs. 2013 May;27(5):335-43. doi: 10.1007/s40263-013-0047-0.
citation: Kuo MF, Paulus W, Nitsche MA. Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage. 2014 Jan 15;85 Pt 3:948-60. doi: 10.1016/j.neuroimage.2013.05.117. Epub 2013 Jun 4.
citation: Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008 Jul;1(3):206-23. doi: 10.1016/j.brs.2008.06.004. Epub 2008 Jul 1.
citation: Muszkat D, Polanczyk GV, Dias TG, Brunoni AR. Transcranial Direct Current Stimulation in Child and Adolescent Psychiatry. J Child Adolesc Psychopharmacol. 2016 Sep;26(7):590-7. doi: 10.1089/cap.2015.0172. Epub 2016 Mar 30.