Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin

Molecular Autism

Dorothea L. Floris¹  Charlotte M. Pretzsch²  Eileen Daly²  Declan G. M. Murphy²  Gráinne M. McAlonan²  Malka Elsahib²  Bogdan Voinescu³  Robert Wichers⁴  Maria A. Mendez⁵  Laura Ajram⁶  Elise Pretzsch⁷  Steven Williams⁸  Glynis Ivin⁹  Martin Heasman⁹ 

[1] Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF, London, UK;Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF, London, UK;Department of Liaison Psychiatry, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK;Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF, London, UK;Department of Psychiatry GGZ Geest, Amsterdam, The Netherlands;Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF, London, UK;Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, SE5 8AF, London, UK;Medicines Discovery Catapult, Alderley Park, SK10 4TG, Alderley Edge, Cheshire, UK;Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany;Department of Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK;South London and Maudsley NHS Foundation Trust Pharmacy, London, UK;

关键词: Autism spectrum disorder;    Autism spectrum condition;    Cannabidivarin;    CBDV;    Functional connectivity;    Striatum;   

DOI  :  10.1186/s13229-021-00454-6

来源: Springer

【 摘 要 】

BackgroundAutism spectrum disorder (ASD) has a high cost to affected individuals and society, but treatments for core symptoms are lacking. To expand intervention options, it is crucial to gain a better understanding of potential treatment targets, and their engagement, in the brain. For instance, the striatum (caudate, putamen, and nucleus accumbens) plays a central role during development and its (atypical) functional connectivity (FC) may contribute to multiple ASD symptoms. We have previously shown, in the adult autistic and neurotypical brain, the non-intoxicating cannabinoid cannabidivarin (CBDV) alters the balance of striatal ‘excitatory–inhibitory’ metabolites, which help regulate FC, but the effects of CBDV on (atypical) striatal FC are unknown.MethodsTo examine this in a small pilot study, we acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study. We then used a seed-based approach to (1) compare striatal FC between groups and (2) examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout.ResultsCompared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions (which have been associated with emotion, motor, and vision processing). Further, they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level.LimitationsOur findings should be considered in light of several methodological aspects, in particular our participant group (restricted to male adults), which limits the generalizability of our findings to the wider and heterogeneous ASD population.ConclusionIn conclusion, here we show atypical striatal FC with regions commonly associated with ASD symptoms. We further provide preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms.Trial registrationclinicaltrials.gov, Identifier: NCT03537950. Registered May 25th, 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03537950?term=NCT03537950&draw=2&rank=1.

【 授权许可】

CC BY