TY - JOUR
T1 - Modulation of atypical brain activation during executive functioning in autism
T2 - a pharmacological MRI study of tianeptine
AU - Wichers, Robert H
AU - Findon, James L
AU - Jelsma, Auke
AU - Giampietro, Vincent
AU - Stoencheva, Vladimira
AU - Robertson, Dene M
AU - Murphy, Clodagh M
AU - Blainey, Sarah
AU - McAlonan, Grainne
AU - Ecker, Christine
AU - Rubia, Katya
AU - Murphy, Declan G M
AU - Daly, Eileen M
N1 - Funding Information:
The authors would like to thank all the volunteers for their participation. The authors acknowledge support from the Clinical Biochemistry Department at King?s College Hospital, the Maudsley Pharmacy Department and the Neurodevelopmental Clinic at the Maudsley Hospital. The authors acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience King?s College London. This article presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Funding Information:
The authors would like to thank all the volunteers for their participation. The authors acknowledge support from the Clinical Biochemistry Department at King’s College Hospital, the Maudsley Pharmacy Department and the Neurodevelopmental Clinic at the Maudsley Hospital. The authors acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience King’s College London. This article presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Funding Information:
This study was funded by a grant (to Prof. D.G Murphy) from European Autism Interventions—A Multicentre Study for Developing New Medications (EU-AIMS) (receiving support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement 115300, which includes financial contributions from the EU Seventh Framework Programme [FP7/2007–2013] and from the European Federation of Pharmaceutical Industries and Associations), a Grant from AIMS-2-TRIALS (to Prof. D.G. Murphy), a Grant (to Prof. D.G Murphy) from NIHR Mental Health Biomedical Research Centre Infrastructure Support for Pilot Studies and a Grant (to Prof. D.G Murphy) from the Sackler Institute for Translational Neurodevelopment.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/19
Y1 - 2021/2/19
N2 - BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD.METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls.RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices.LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome.CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.
AB - BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD.METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls.RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices.LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome.CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.
KW - Autism spectrum disorder
KW - Executive functioning
KW - fMRI
KW - Serotonin
KW - Tianeptine
UR - http://www.scopus.com/inward/record.url?scp=85101242778&partnerID=8YFLogxK
U2 - 10.1186/s13229-021-00422-0
DO - 10.1186/s13229-021-00422-0
M3 - Article
C2 - 33608048
AN - SCOPUS:85101242778
SN - 2040-2392
VL - 12
SP - 14
JO - Molecular Autism
JF - Molecular Autism
IS - 1
M1 - 14
ER -