Modulation of the Activity of the Cerebellum in Autism (MACA) (MACA)

Modulation of the Activity in the Cerebellum With Transcranial Direct Current Stimulation in Autistic Participants

Research on the involvement of the cerebellum in social understanding behavior and the mentalizing brain system has just begun. Knowledge about the neurobiology of social understanding is important for understanding the ways to manipulate these processes. Like cerebral tDCS, cerebellar tDCS could then be used to enhance more complex processes, such as mentalizing, in healthy individuals. It can eventually also be examined as a therapeutic tool for patients with mentalizing difficulties such as patients with ASD. In this study, it is examined whether anodal tDCS at the right posterior cerebellum influences social understanding and which cerebro-cerebellar networks play a role in this process.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder
• Intervention / Treatment: Device: tDCS

Detailed Description

Autism Spectrum Disorders (ASD) are a group of lifelong neurodevelopmental disorders characterized by social and communicative difficulties and repetitive and stereotyped behaviors. Research has shown that cerebellar abnormalities are among the most important etiological factors for ASD. The cerebellum is found to be most frequently involved in tasks where participants must remember or imagine past or future autobiographical events, judge persons or situations based on behavioral sentences, make trait inferences of others using stories, words or faces, and describe persons or objects based on behavioral or object pictures. Recent research has also provided evidence on the involvement of the posterior areas of the cerebellum in social cognition.

Specifically, the areas crus I and crus II, located at the lateral hemispheres of the posterior cerebellum, are associated with more complex cognitive and social processes, such as mentalizing. Mentalizing is the cognitive ability to attribute mental states, such as desires, intentions, and beliefs, to other people. This ability is needed to understand and predict other people's behavior and is the main component of social cognition. Problems with mentalizing, including the attribution of false beliefs to others, are characteristic for autism spectrum disorder (ASD). A sequencing task (that included social and non social conditions) showing that cerebellar patients performed worse than healthy participants.

Facial emotion recognition refers to the ability to derive emotional meaning from facial expressions and has been shown to underlie social competency. Recent literature reviews have reported significant facial emotion recognition impairments in individuals with ASD. These impairments take various forms, such as a reduced accuracy in labeling facial emotions or reduced specificity in rating facial emotions of varying intensity . Thus, there is evidence suggesting that ASD is associated with a selective impairment in facial emotion recognition.

Transcranial direct current stimulation (tDCS) is a noninvasive technique that can produce long-lasting changes in the excitability and spontaneous activity of the stimulated brain areas. Therefore, tDCS is investigated as a possible treatment for different psychiatric diseases. Cerebellar tDCS have shown to also produce prolonged changes successfully at the neural and behavioral level. However, due to the high density of neurons in the cerebellum and diffuse connections to the cerebrum, it is more difficult to understand the working mechanisms of cerebellar as compared to cerebral tDCS. In addition, the electrical current will spread across more neurons in the cerebellum by cerebellar tDCS and will functionally affect the cerebral regions to which these cerebellar neurons are connected as well. Therefore, the type of behavioral effect, such as an improvement of performance after anodal tDCS or an impairment of performance after cathodal tDCS, is harder to predict for cerebellar than cerebral tDCS.

Modulation of social understanding with tDCS has been studied by stimulating the key mentalizing regions mPFC and TPJ. In healthy participants, an improvement on tasks was found that required the enhancement or inhibition of representation of the self or of others, which is important for mentalizing, after anodal tDCS at the TPJ compared to sham tDCS or cathodal tDCS. The effect of cerebellar tDCS on social understanding using action sequences has not yet been examined.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Beatriz Catoira, Msc; Phone Number: +32456267472; Email: Beatriz.catoira@vub.be
• Study Contact Backup: Name: Nathalie Vanderbruggen; Phone Number: 02/ 4763599; Email: Nathalie.Vanderbruggen@uzbrussel.be

Study Locations

• Belgium
  • Brussels
    • Jette, Brussels, Belgium, 1090
      • Recruiting
      • UZ Brussel
      • Contact: Beatriz Catoira; Phone Number: 0032 0456267472; Email: beatriz.catoira@vub.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Participant Inclusion/exclusion criteria:

• Participants must be more than 18 years old
• normal eyesight and hearing;
• Dutch, French or English speaking;

Neurotypical participants inclusion/exclusion criteria:

• No disorder (now or in the past) that could have affected the brain such as cerebrovascular accidents (CVA), neurodegenerative disorders, or essential tremor;
• No neurological diseases that could affect reasoning or intellectual abilities (such as Parkinson's Disease, Epilepsy, and Multiple Sclerosis)
• Neurotypical participants will be matched on age and gender to the ASD population;

ASD participants inclusion/exclusion criteria:

Patients with a formal diagnosis of high-functioning ASD as determined by the clinical psychologist/psychiatrist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ASD_anodalstimulation; ASD participant, anodal stimulation on the first session, sham stimulation on the second sesion	Device: tDCS; Anodal and Sham cerebellar tDCS will be used in each participant in a counterbalanced order
Sham Comparator: ASD_shamstimulation; ASD participant, sham stimulation on the first session, anodal stimulation on the second sesion	Device: tDCS; Anodal and Sham cerebellar tDCS will be used in each participant in a counterbalanced order
Active Comparator: NT_anodalstimulation; Neurotypical participant, anodal stimulation on the first session, sham stimulation on the second sesion	Device: tDCS; Anodal and Sham cerebellar tDCS will be used in each participant in a counterbalanced order
Sham Comparator: NT_shamstimulation; Neurotypical participant, sham stimulation on the first session, anodal stimulation on the second sesion	Device: tDCS; Anodal and Sham cerebellar tDCS will be used in each participant in a counterbalanced order
Active Comparator: H-AQ_anodalstimulation; non diagnosed autistic participant,anodal stimulation on the first session, sham stimulation on the second sesion	Device: tDCS; Anodal and Sham cerebellar tDCS will be used in each participant in a counterbalanced order
Sham Comparator: H-AQ_shamstimulation; non diagnosed autistic participant, sham stimulation on the first session, anodal stimulation on the second sesion	Device: tDCS; Anodal and Sham cerebellar tDCS will be used in each participant in a counterbalanced order

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PS_RT	Reaction Time in the pictorial sequencing time	assessment will begin 10 minutes after stimulation and last up to 15 minutes
PS_accuracy	Accuracy in the pictorial sequencing task	assessment will begin 10 minutes after stimulation and last up to 15 minutes
ER_RT	Reaction Times in the emotion recognition task	assessment will begin 20 minutes after stimulation and last up to 5 minutes
ER_accuracy	Accuracy in the emotion recognition task	assessment will begin 20 minutes after stimulation and last up to 5 minutes
Brain activity at the emotion recognition task	Brain activity (fMRI) in regions of interest/whole brain analysis. Differences between stimulation and sham, between task conditions and between sessions as well as possible interactions in between those factors and covariates (AQ scores, age, gender...)	assessment will begin 20 minutes after stimulation and last up to 5 minutes
Brain activity at resting state	Brain activity (fMRI) in regions of interest/whole brain analysis. Differences between stimulation and sham, between task conditions and between sessions as well as possible interactions in between those factors and covariates (AQ scores, age, gender...)	assesment will begin concurrent with stimulation and last up to 20 minutes
Brain activity at the pictorial sequencing task	Brain activity (fMRI) in regions of interest/whole brain analysis. Differences between stimulation and sham, between task conditions and between sessions as well as possible interactions in between those factors and covariates (AQ scores, age, gender...)	assessment will begin 10 minutes after stimulation and last up to 15 minutes
White matter integrity in the cerebellum	White matter integrity matrix (FA, MD, RD) in the cerebellum using tract-based spatial statistics in the cerebellum & differences between groups	assessment will begin immediately after stimulation and last up to 10 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Connectivity_PStask	Brain connectivity (fMRI) analysis on the pictorial sequencing task	assessment will begin 10 minutes after stimulation and last up to 15 minutes
Connectivity_ERtask	Brain connectivity (fMRI) analysis on the emotion recognition task	assessment will begin 20 minutes after stimulation and last up to 5 minutes
Connectivity_stimulation	Brain connectivity (fMRI) analysis during stimulation	assesment will begin concurrent with stimulation and last up to 20 minutes
Fiber tractography between the cerebellum and the default mode/ mentalizing network	Fiber tractography (Diffusion weighted imaging) between the cerebellum and the default mode / mentalizing network, by extraction of white matter integrity parameters on each fiber tract	assessment will begin immediately after stimulation and last up to 10 minutes
ROI-based structural connectivity	Structural connectivity (DWI) between ROIs from the default mode/mentalizing network	assessment will begin immediately after stimulation and last up to 10 minutes
Whole brain structural network construction	Structural connectivity (DWI) within the whole brain using graph theory	assessment will begin immediately after stimulation and last up to 10 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electrical Field Simulations	Simulation of the electric field generated by the tDCS stimulation.	First 10 minutes of assessment
Correlations between DWI, behavioural data, simulation and functional data	The primary outcome measures from the diffusion weighted imaging will provide different measures for structural connectivity per participant. The correlation of these measures with behavioural and/or functional data will be computed.	assessment will include data from the 60 minutes that are spent in the scanner in the session

Collaborators and Investigators

• Sponsor: Beatriz Catoira
• Collaborators: Universitair Ziekenhuis Brussel; University Ghent; Vrije Universiteit Brussel

Publications and helpful links

General Publications

• Santiesteban I, Banissy MJ, Catmur C, Bird G. Enhancing social ability by stimulating right temporoparietal junction. Curr Biol. 2012 Dec 4;22(23):2274-7. doi: 10.1016/j.cub.2012.10.018. Epub 2012 Nov 1.
• Van Overwalle F, Baetens K, Marien P, Vandekerckhove M. Social cognition and the cerebellum: a meta-analysis of over 350 fMRI studies. Neuroimage. 2014 Feb 1;86:554-72. doi: 10.1016/j.neuroimage.2013.09.033. Epub 2013 Sep 27.
• Buckner RL, Krienen FM, Castellanos A, Diaz JC, Yeo BT. The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol. 2011 Nov;106(5):2322-45. doi: 10.1152/jn.00339.2011. Epub 2011 Jul 27.
• Murphy CM, Wilson CE, Robertson DM, Ecker C, Daly EM, Hammond N, Galanopoulos A, Dud I, Murphy DG, McAlonan GM. Autism spectrum disorder in adults: diagnosis, management, and health services development. Neuropsychiatr Dis Treat. 2016 Jul 7;12:1669-86. doi: 10.2147/NDT.S65455. eCollection 2016.
• Murphy DG, Beecham J, Craig M, Ecker C. Autism in adults. New biologicial findings and their translational implications to the cost of clinical services. Brain Res. 2011 Mar 22;1380:22-33. doi: 10.1016/j.brainres.2010.10.042. Epub 2010 Oct 20.
• D'Mello AM, Stoodley CJ. Cerebro-cerebellar circuits in autism spectrum disorder. Front Neurosci. 2015 Nov 5;9:408. doi: 10.3389/fnins.2015.00408. eCollection 2015.
• Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, Chauhan A, Chauhan V, Dager SR, Dickson PE, Estes AM, Goldowitz D, Heck DH, Kemper TL, King BH, Martin LA, Millen KJ, Mittleman G, Mosconi MW, Persico AM, Sweeney JA, Webb SJ, Welsh JP. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012 Sep;11(3):777-807. doi: 10.1007/s12311-012-0355-9.
• Sathyanesan A, Zhou J, Scafidi J, Heck DH, Sillitoe RV, Gallo V. Emerging connections between cerebellar development, behaviour and complex brain disorders. Nat Rev Neurosci. 2019 May;20(5):298-313. doi: 10.1038/s41583-019-0152-2.
• Heleven E, van Dun K, Van Overwalle F. The posterior Cerebellum is involved in constructing Social Action Sequences: An fMRI Study. Sci Rep. 2019 Jul 31;9(1):11110. doi: 10.1038/s41598-019-46962-7.
• Van Overwalle F, Van de Steen F, Marien P. Dynamic causal modeling of the effective connectivity between the cerebrum and cerebellum in social mentalizing across five studies. Cogn Affect Behav Neurosci. 2019 Feb;19(1):211-223. doi: 10.3758/s13415-018-00659-y.
• Leggio M, Olivito G. Topography of the cerebellum in relation to social brain regions and emotions. Handb Clin Neurol. 2018;154:71-84. doi: 10.1016/B978-0-444-63956-1.00005-9.
• Frith CD, Frith U. Interacting minds--a biological basis. Science. 1999 Nov 26;286(5445):1692-5. doi: 10.1126/science.286.5445.1692.
• Mier D, Lis S, Neuthe K, Sauer C, Esslinger C, Gallhofer B, Kirsch P. The involvement of emotion recognition in affective theory of mind. Psychophysiology. 2010 Nov;47(6):1028-39. doi: 10.1111/j.1469-8986.2010.01031.x.
• Baron-Cohen S, Leslie AM, Frith U. Does the autistic child have a "theory of mind"? Cognition. 1985 Oct;21(1):37-46. doi: 10.1016/0010-0277(85)90022-8. No abstract available.
• Leggio MG, Tedesco AM, Chiricozzi FR, Clausi S, Orsini A, Molinari M. Cognitive sequencing impairment in patients with focal or atrophic cerebellar damage. Brain. 2008 May;131(Pt 5):1332-43. doi: 10.1093/brain/awn040. Epub 2008 Mar 11.
• Izard C, Fine S, Schultz D, Mostow A, Ackerman B, Youngstrom E. Emotion knowledge as a predictor of social behavior and academic competence in children at risk. Psychol Sci. 2001 Jan;12(1):18-23. doi: 10.1111/1467-9280.00304. Erratum In: Psychol Sci 2001 Jul;12(4):352.
• Uljarevic M, Hamilton A. Recognition of emotions in autism: a formal meta-analysis. J Autism Dev Disord. 2013 Jul;43(7):1517-26. doi: 10.1007/s10803-012-1695-5.
• Kennedy DP, Adolphs R. The social brain in psychiatric and neurological disorders. Trends Cogn Sci. 2012 Nov;16(11):559-72. doi: 10.1016/j.tics.2012.09.006. Epub 2012 Oct 6.
• Morya E, Monte-Silva K, Bikson M, Esmaeilpour Z, Biazoli CE Jr, Fonseca A, Bocci T, Farzan F, Chatterjee R, Hausdorff JM, da Silva Machado DG, Brunoni AR, Mezger E, Moscaleski LA, Pegado R, Sato JR, Caetano MS, Sa KN, Tanaka C, Li LM, Baptista AF, Okano AH. Beyond the target area: an integrative view of tDCS-induced motor cortex modulation in patients and athletes. J Neuroeng Rehabil. 2019 Nov 15;16(1):141. doi: 10.1186/s12984-019-0581-1.
• Ferrucci R, Priori A. Transcranial cerebellar direct current stimulation (tcDCS): motor control, cognition, learning and emotions. Neuroimage. 2014 Jan 15;85 Pt 3:918-23. doi: 10.1016/j.neuroimage.2013.04.122. Epub 2013 May 9.
• O'Reilly JX, Beckmann CF, Tomassini V, Ramnani N, Johansen-Berg H. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb Cortex. 2010 Apr;20(4):953-65. doi: 10.1093/cercor/bhp157. Epub 2009 Aug 14.
• van Dun K, Bodranghien FC, Marien P, Manto MU. tDCS of the Cerebellum: Where Do We Stand in 2016? Technical Issues and Critical Review of the Literature. Front Hum Neurosci. 2016 May 11;10:199. doi: 10.3389/fnhum.2016.00199. eCollection 2016.
• Oldrati V, Schutter DJLG. Targeting the Human Cerebellum with Transcranial Direct Current Stimulation to Modulate Behavior: a Meta-Analysis. Cerebellum. 2018 Apr;17(2):228-236. doi: 10.1007/s12311-017-0877-2.
• Hogeveen J, Obhi SS, Banissy MJ, Santiesteban I, Press C, Catmur C, Bird G. Task-dependent and distinct roles of the temporoparietal junction and inferior frontal cortex in the control of imitation. Soc Cogn Affect Neurosci. 2015 Jul;10(7):1003-9. doi: 10.1093/scan/nsu148. Epub 2014 Dec 5.
• Rogers TD, McKimm E, Dickson PE, Goldowitz D, Blaha CD, Mittleman G. Is autism a disease of the cerebellum? An integration of clinical and pre-clinical research. Front Syst Neurosci. 2013 May 10;7:15. doi: 10.3389/fnsys.2013.00015. eCollection 2013.
• Yeung MK, Lee TL, Chan AS. Impaired Recognition of Negative Facial Expressions is Partly Related to Facial Perception Deficits in Adolescents with High-Functioning Autism Spectrum Disorder. J Autism Dev Disord. 2020 May;50(5):1596-1606. doi: 10.1007/s10803-019-03915-3.

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2022
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): October 30, 2024

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: March 20, 2023
• First Posted (Actual): March 23, 2023

Study Record Updates

• Last Update Posted (Actual): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 4, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: tDCS; autism; neuromodulation; Cerebellum
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autistic Disorder; Autism Spectrum Disorder
• Other Study ID Numbers: 22064MACA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No