Abstract
Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8–13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Alexander GE, Delong MR, Strick PL (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357–381.
Alonso P, Gratacós M, Segalàs C, Escaramís G, Real E, Bayés M et al (2012). Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder. J Psychiatry Neurosci 37: 273–281.
American Psychiatric Association (2000) Diagnostic Criteria From DSM-IV-TR. American Psychiatric Association: Washington, DC, USA.
Anholt GE, Cath DC, van Oppen P, Eikelenboom M, Smit JH, van Megen H et al (2010). Autism and ADHD symptoms in patients with OCD: are they associated with specific OC symptom dimensions or OC symptom severity? J Autism Dev Disord 40: 580–589.
Bak LK, Schousboe A, Waagepetersen HS (2006). The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98: 641–653.
Bejjani A, O’Neill J, Kim Ja, Frew AJ, Yee VW, Ly R et al (2012). Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI. PLoS One 7: e38786.
Bordin IA, Rocha MM, Paula CS, Teixeira MC, Achenbach TM, Rescorla LA et al (2013). Child Behavior Checklist (CBCL),Youth Self-Report (YSR) and Teacher’s Report Form(TRF): an overview of the development of the original and Brazilian versions. Cad Saude Publica 29: 13–28.
Brennan BP, Rauch SL, Jensen JE Jr, Pope HG (2013). A critical review of magnetic resonance spectroscopy studies of obsessive-compulsive disorder. Biol Psychiatry 73: 24–31.
Chamberlain SR, Menzies L (2009). Endophenotypes of obsessive-compulsive disorder: rationale, evidence and future potential. Expert Rev Neurother 9: 1133–1146.
Conover WJ, Iman RL (1981). Rank transformations as a bridge between parametric and nonparametric statistics. Am Stat 35: 124–129.
Cuthbert BN (2014). The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry 13: 28–35.
Dalley JW, Everitt BJ, Robbins TW (2011). Impulsivity, compulsivity, and top-down cognitive control. Neuron 69: 680–694.
Fatemi SH (2008). The hyperglutamatergic hypothesis of autism. Prog Neuropsychopharmacol Biol Psychiatry 32: 911.
Fineberg Na, Potenza MN, Chamberlain SR, Berlin Ha, Menzies L, Bechara A et al (2010). Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology 35: 591–604.
Fuccillo MV (2016). Striatal circuits as a common node for autism pathophysiology. Front Neurosci 10: 27.
Gasparovic C, Song T, Devier D, Bockholt HJ, Caprihan A, Mullins PG et al (2006). Use of tissue water as a concentration reference for proton spectroscopic imaging. Magn Reson Med 55: 1219–1226.
Gnanavel S, Sharan P, Khandelwal S, Sharma U, Jagannathan NR (2014). Neurochemicals measured by (1)H-MR spectroscopy: putative vulnerability biomarkers for obsessive compulsive disorder. MAGMA 27: 407–417.
Goodman R, Ford T, Richards H, Gatward R, Meltzer H (2000). The Development and Well-Being Assessment: description and initial validation of an integrated assessment of child and adolescent psychopathology. J Child Psychol Psychiatry 41: 645–655.
Haase A, Frahm J, Hänicke W, Matthaei D (1985). 1H NMR chemical shift selective (CHESS) imaging. Phys Med Biol 30: 341–344.
Hassan TH, Abdelrahman HM, Abdel NR, El-masry NM, Hashim HM, El-gerby KM et al (2013). Research in Autism spectrum disorders blood and brain glutamate levels in children with autistic disorder. Res Autism Spectr Disord 7: 541–548.
Hess AT, Van Der Kouwe AJW, Mbugua KK, Laughton B, Meintjes EM (2013). Quality of 186 child brain spectra using motion and b0 shim navigated single voxel spectroscopy. J Magn Reson Imaging 40: 958–965.
Horska A, Kaufmann WE, Brant LJ, Naidu S, Harris JC, Barker PB (2002). In vivo quantitative proton MRSI study of brain development from childhood to adolescence. J Magn Reson Imaging 15: 137–143.
Hyder F, Fulbright RK, Shulman RG, Rothman DL (2013). Glutamatergic function in the resting awake human brain is supported by uniformly high oxidative energy. J Cereb Blood Flow Metab 33: 339–347.
Jack CR, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D et al (2008). The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging 27: 685–691.
Joshi G, Biederman J, Wozniak J, Goldin RL, Crowley D, Furtak S (2012). Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: a pilot study at 4T. Eur Arch Psychiatry Clin Neurosci 263: 379–384.
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P et al (1997). Schedule for affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36: 980–988.
Klumpp H, Ho SS, Taylor SF, Phan KL, Abelson JL, Liberzon I (2011). Trait anxiety modulates anterior cingulate activation to threat interference. Depress Anxiety 28: 194–201.
Kreis R (2015). The trouble with quality filtering based on relative Cramèr-Rao lower bounds. Magn Reson Med 75: 15–18.
Lam KS, Aman MG (2007). The Repetitive Behavior Scale-Revised: independent validation in individuals with autism spectrum disorders. J Autism Dev Disord 37: 855–866.
Lee IA, Preacher KJ (2013). Calculation for the test of the difference between two dependent correlations with one variable in common. (Comput Software). Available at http://quantpsy.org/corrtest/corrtest2.htm.
Lord C, Rutter M, Couteur AL (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24: 659–685.
Meier SM, Petersen L, Schendel DE, Mattheisen M, Mortensen PB, Mors O (2015). Obsessive-compulsive disorder and autism spectrum disorders: longitudinal and offspring risk. PLoS One 10: e0141703.
Modi S, Rana P, Kaur P, Rani N, Khushu S (2014). Glutamate level in anterior cingulate predicts anxiety in healthy humans: a magnetic resonance spectroscopy study. Psychiatry Res 224: 34–41.
Naaijen J, Lythgoe DJ, Amiri H, Buitelaar JK, Glennon JC (2015). Fronto-striatal glutamatergic compounds in compulsive and impulsive syndromes: a review of magnetic resonance spectroscopy studies. Neurosci Biobehav Rev 52: 74–88.
Page LA, Daly E, Schmitz N, Simmons A, Toal F, Deeley Q et al (2006). In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry 163: 2189–2192.
Pittenger C, Bloch MH, Williams K (2011). Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther 132: 314–332.
Pizzarelli R, Cherubini E (2011). Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast 2011: 297153.
Provencher SW (2001). Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed 14: 260–264.
Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD (2012). Neurocognitive endophenotypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends Cogn Sci 16: 81–91.
Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ (2000). Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry 39: 1096–1103.
Rosenberg DR, Mirza Y, Russell A, Tang J, Smith JM, Banerjee SP et al (2004). Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. J Am Acad Child Adolesc Psychiatry 43: 1146–1153.
Ruzzano L, Borsboom D, Geurts HM (2015). Repetitive behaviors in autism and obsessive-compulsive disorder: new perspectives from a network analysis. J Autism Dev Disord 45: 192–202.
Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK et al (1997). Children’s Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 36: 844–852.
Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000). NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 39: 28–38.
Somerville LH, Casey BJ (2010). Developmental neurobiology of cognitive control and motivational systems. Curr Opin Neurobiol 20: 271–277.
Thakkar KN, Polli FE, Joseph RM, Tuch DS, Hadjikhani N, Barton JJ et al (2008). Response monitoring, repetitive behaviour and anterior cingulate abnormalities in autism spectrum disorders (ASD). Brain 131: 2464–2478.
Torres AR, Fontenelle LF, Shavitt RG, Ferrão YA, Do Rosário MC, Storch EA et al (2016). Comorbidity variation in patients with obsessive-compulsive disorder according to symptom dimensions: results from a large multicentre clinical sample. J Affect Disord 190: 508–516.
Voon V, Derbyshire K, Rück C, Irvine MA, Worbe Y, Enander J et al (2014). Disorders of compulsivity: a common bias towards learning habits. Mol Psychiatry 20: 345–352.
Wechsler D (2002) WISC-III Handleiding. The Psychological Corporation: London.
Whiteside SP, Port JD, Deacon BJ, Abramowitz JS (2006). A magnetic resonance spectroscopy investigation of obsessive-compulsive disorder and anxiety. Psychiatry Res 146: 137–147.
Yücel M, Wood SJ, Wellard RM, Harrison BJ, Fornito A, Pujol J et al (2008). Anterior cingulate glutamate-glutamine levels predict symptom severity in women with obsessive-compulsive disorder. Aust NZ J Psychiatry 42: 467–477.
Acknowledgements
The TACTICS Consortium consists of Jan Buitelaar, Saskia de Ruiter, Jilly Naaijen, Sophie Akkermans, Maarten Mennes, Marcel Zwiers, Shahrzad Ilbegi, Leonie Hennissen, Jeffrey Glennon, Ilse van de Vondervoort, Katarzyna Kapusta, Natalia Bielczyk, Houshang Amiri, Martha Havenith, Barbara Franke, Geert Poelmans, Janita Bralten, Tom Heskes, Elena Sokolova, Perry Groot from Radboud University Medical Center Nijmegen, the Netherlands; Steven Williams, David Lythgoe, Muriel Bruchhage, Iulia Dud from Kings College London, United Kingdom; Ralf Dittmann, Tobias Banaschewski, Daniel Brandeis, Konstantin Mechler, Ruth Berg, Isabella Wolf, Alexander Häge, Sarah Hohmann, Regina Boecker, Matthias Ruff from Central Institute of Mental Health, University of Heidelber, Mannheim, Germany; Rick Dijkhuizen, Erwin Blezer, Kajo van der Marel, Pim Pullens, Wouter Mol, Annette van der Toorn, Willem Otte, Caroline van Heijningen, Sarah Durston, Vincent Mensen, Bob Oranje, René Mandl from University Medical Center Utrecht, Utrecht, the Netherlands; Daphna Joel from Tel Aviv University, Tel Aviv, Israel; John Cryan from University College Cork, Cork City, Ireland; Tracey Petryshen, David Pauls, Mai Saito from Massachusetts General Hospital, Boston, USA; Angelique Heckman from Genoway, Lyon, France; Sabine Bahn from University of Cambridge, Cambridge, United Kingdrom; Ameli Schwalber from Concentris, München, Germany; and Philippe Auby from Lundbeck, Valby, Denmark.
We gratefully acknowledge and thank all the participants for their enthusiastic involvement in the study. Data contributing to this research were presented as a scientific poster at the European College for Neuropsychopharmacology (ECNP) meeting 2015, Amsterdam, The Netherlands, and 2016, Vienna, Austria.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Competing interests
The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013) TACTICS under grant agreement no. 278948. This research was also supported from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300 (EU-AIMS), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007 - 2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution. B Franke is supported by a Vici grant of the Netherlands Organization for Scientific Research (NWO, grant number (016-130-669). D Brandeis serves as an unpaid scientific advisor for an EU-funded Neurofeedback trial unrelated to the present work. T Banaschewski served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Medice, Novartis, Oxford outcomes, PCM scientific, Shire, and Viforpharma. He received conference support or speaker’s fee by Medice, Novartis, and Shire. He is/has been involved in clinical trials conducted by Shire and Viforpharma. The present work is unrelated to the grants and relationships noted earlier. JC Glennon has acted as a consultant for Boehringer Ingelheim GmbH. B. Franke received an educational speaking fee from Merz. JK Buitelaar has been consultant to/member of advisory board of and/or speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, Shering Plough, UCB, Shire, Novartis, and Servier. He is not an employee of any of these companies, nor a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. DJ Lythgoe has acted as a consultant for Ixico PLC. The remaining authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Supplementary information
Rights and permissions
About this article
Cite this article
Naaijen, J., Zwiers, M., Amiri, H. et al. Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder. Neuropsychopharmacol 42, 2456–2465 (2017). https://doi.org/10.1038/npp.2016.260
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2016.260
This article is cited by
-
Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: A Systematic Review
Journal of Autism and Developmental Disorders (2025)
-
Excitatory Amino Acid Transporters as Therapeutic Targets in the Treatment of Neurological Disorders: Their Roles and Therapeutic Prospects
Neurochemical Research (2025)
-
Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls
Nature Communications (2023)
-
Cortical inhibition in neurofibromatosis type 1 is modulated by lovastatin, as demonstrated by a randomized, triple-blind, placebo-controlled clinical trial
Scientific Reports (2022)
-
Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: a systematic review and meta-analysis
BMC Pharmacology and Toxicology (2021)
