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The Cerebellum and Brainstem Reshape with Compulsive Behaviour and Symptom Severity in Autism Spectrum Disorder and Obsessive Compulsive Disorder

Muriel M. Bruchhage1*, Ali Amad1, David L. Lythgoe1, Marcel P. Zwiers2, Iulia Dud1, Jilly Naaijen2, Saskia De Ruiter2, Sophie Akkermans2, Vincent T. Mensen3, Regina Boecker-Schlier4, Sarah Durston3, Barbara Franke5, Rick M. Dijkhuizen3, Tom Heskes6, Bob Oranje3, Daniel Brandeis4, Jeffrey C. Glennon5, Ralf W. Dittmann4, Jan Buitelaar2 and Steven C. Williams1
  • 1 King's College London, Centre for Neuroimaging Sciences, United Kingdom
  • 2 Radboud University Medical Center, Department of Cognitive Neuroscience, Netherlands
  • 3 University Medical Center Utrecht, UMC Utrecht Brain Center Rudolf Magnus, Netherlands
  • 4 Central Institute of Mental Health Mannheim, Department of Child and Adolescent Psychiatry and Psychotherapy, Germany
  • 5 Radboud University Medical Center, Department of Cognitive Neuroscience, Netherlands
  • 6 Radboud University, Institute for Computing and Information Sciences (iCIS), Netherlands

INTRODUCTION Neurodevelopmental disorders such as autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share genetic vulnerability (Jacob et al., 2009), patterns of abnormal brain development (Ameis et al., 2016) and overlap in diagnostic symptoms (Jacob et al., 2009). Specifically, the tendency to perform repetitive acts in a ritualised manner (Chamberlain & Menzies, 2009) is one of the earliest signs of the autism phenotype (Leekam et al., 2011) and the main characteristic of OCD (Association, 2000), with lesion studies connecting the cerebellum and brainstem to compulsive behaviour (Figee et al., 2013). During the transition from childhood to adolescence, control over compulsive behaviour is established (Arain et al., 2013), accompanied by ongoing maturation of brain regions including the cerebellum (Tiemeier et al., 2010) and brainstem (Geva & Feldman, 2008). Longitudinal studies revealed that during this developmental period, brainstem volume (Jou et al., 2013) and cerebellar vermis volume increase, while total cerebellar volume decrease in ASD (Courchesne et al., 2011), specifically in the posterior cerebellar lobe (Stoodley, 2015). In contrast, overall cerebellar volume is increased in paediatric OCD when compared to controls (Eng et al., 2015). Furthermore, overall symptom severity is positively correlated with cerebellum and brainstem volume in OCD (Zarei et al., 2011), and negatively with posterior cerebellar volume in ASD (Pierce & Courchesne, 2001). Thus, abnormal cerebellum and brainstem development might affect the establishment of compulsive behaviour control, possibly with regional rather than overall differences driving dysfunctional behaviour. However, regional cerebellar and brainstem differences in OCD have not been investigated and whether both are comparable across disorders regarding their correlation with compulsive behaviour remains unclear. Furthermore, volume differences only give a summation value and might not detect subtle regional changes. Here, we are investigating cerebellum and brainstem shape across two paediatric ASD and OCD cohorts in order to identify regional differences and their correlation with compulsive behaviour and symptom severity. METHODS Sample: 58 right-handed children DSM-IV-TR (American Psychiatric Association, 2000) diagnosed with ASD (45 male, 13 female), 30 diagnosed with OCD (15 male, 15 female) and 61 age-matched right-handed healthy controls (42 male, 19 female), all aged 8 to 15 years were included. Exclusion criteria for all participants was a history of neurological disorders, any contraindications for MRI, a total IQ<70, as well as comorbidity with the other disorder of interest. No DSM axis I disorders were allowed in any relatives up to two generations back for the control group. Ethical approval for the study was obtained for all sites separately. Compulsive Behaviour Measures: Compulsive behaviour was assessed for all groups on a behavioural level using the Repetitive Behaviour Scale Revised (RBS-R; Lam & Aman, 2007) and symptom severity using overall scores on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Scahill et al., 2014) and Autism Diagnostic Interview Revised (ADI-R; Lord et al., 1994) respectively. All measures used were part of a larger test battery and described in detail elsewhere (Naaijen et al., 2016). MRI acquisition: Structural T1-weighted scanning sequences based on the ADNI GO protocol (Jack et al., 2008) were acquired on comparable 3T scanners at the individual sites (Radboud University Medical Center, Nijmegen, The Netherlands; University Medical Center Utrecht, Utrecht, The Netherlands; King’s College London, London, UK; Central Institute of Mental Health, Mannheim, Germany). To assure MR quality and reliability, ‘travelling-head’ and phantom data were collected across sites (Naaijen et al., 2016). Each structural scan was visually inspected, and only scans with no or minimal movement artefacts were included in analyses. Shape Analysis: FSL FIRST version 5.0.8 (Patenaude et al., 2011) was used to perform shape and appearance deformations of the cerebellum and brainstem. For this, shape was modelled using a surface-based point distribution model, constraining shape space to the linear combination of the mean shape and eigenvectors of the vertex coordinates. Vectors indicate the direction of difference, with inward direction indicating smaller/thinner structure, and vice versa. FSL’s25 general linear model was used to create group contrasts, as well as correlation analyses with compulsive behaviour and symptom severity. All analyses were controlled for age, gender and scanning site. RESULTS Compared to controls, both disorders showed significant group differences of the cerebellum and brainstem shape, with stronger overall reshaping in the ASD group and anterior as well as lateral posterior reshaping in both groups (Figure 1). Furthermore, the direction of the reshaping differed in the right posterior cerebellum between both patient groups (inward in ASD, outward in OCD; Figure 1). While the anterior brainstem correlated with compulsive behaviour in both groups, larger reshaping of the cerebellum was only shown in the OCD group (Figure 2). Symptom severity was correlated in the brainstem for both patient groups, with more medial reshaping in the OCD but anterior and lateral reshaping in the ASD group (Figure 3). DISCUSSION In this study, we demonstrate differences from controls in brainstem and cerebellum shape in both disorders (Figure 1). Brainstem differences were further correlated with compulsive behaviour and symptom severity in both groups, but in the cerebellum only in the OCD group (Figures 2, 3). Our results parallel previous findings of cerebellar volume increase in OCD (Eng et al., 2015) and decrease in posterior cerebellar volume in ASD (Stoodley, 2015). In addition, the mainly posterior cerebellar and anterior lateral brainstem correlated with compulsive behaviour and symptom severity in our OCD cohort could reflect the positive symptom-volume correlation previously shown for both regions (Zarei et al., 2011), and posterior cerebellar thinning the negative symptom-volume correlation in ASD (Pierce & Courchesne, 2001). Furthermore, we were able to depict regional differences unrestricted to lobular boundaries and display their vector directions. However, while we were not able to replicate previous findings of brainstem expansion (Jou et al., 2013) in the ASD group, this might be because we studied both male and female ASD participants, while the study by Jou et al. (2013) only investigated male ASD subjects. Our findings underline the importance of regional cerebellum and brainstem dysfunction in ASD and OCD, highlighting the role of the brainstem in compulsive behaviour across both disorders and the cerebellum in paediatric OCD.

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Acknowledgements

The authors would like to thank additional TACTICS Consortium members Ilse van de Vondervoort, Katarzyna Kapusta, Natalia Bielczyk, Houshang Amiri, Geert Poelmans, Janita Bralten, Elena Sokolova, Tobias Banaschewski, Konstantin Mechler, Ruth Berg, Isabella Wolf, Alexander Häge, John Cryan, Tracey Petryshen, Daphna Joel, Sabine Bahn, Angelique Heckman, Ameli Schwalber, and our funding partner European Community’s Seventh Framework Programme (FP7/2007-2013) TACTICS under grant agreement no. 2.

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Keywords: Autism spectrum disorder (ASD), Obsessive-compulsive disorder (OCD), Transdiagnostic, Compulsive Behavior, Vertex analysis

Conference: The Cerebellum inside out: cells, circuits and functions , ERICE (Trapani), Italy, 1 Dec - 5 Dec, 2016.

Presentation Type: poster

Topic: Integrative nuroscience and MRI

Citation: Bruchhage MM, Amad A, Lythgoe DL, Zwiers MP, Dud I, Naaijen J, De Ruiter S, Akkermans S, Mensen VT, Boecker-Schlier R, Durston S, Franke B, Dijkhuizen RM, Heskes T, Oranje B, Brandeis D, Glennon JC, Dittmann RW, Buitelaar J and Williams SC (2019). The Cerebellum and Brainstem Reshape with Compulsive Behaviour and Symptom Severity in Autism Spectrum Disorder and Obsessive Compulsive Disorder. Conference Abstract: The Cerebellum inside out: cells, circuits and functions . doi: 10.3389/conf.fncel.2017.37.000030

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Received: 30 Nov 2016; Published Online: 25 Jan 2019.

* Correspondence: Ms. Muriel M Bruchhage, King's College London, Centre for Neuroimaging Sciences, London, United Kingdom, muriel.bruchhage@kcl.ac.uk