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Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine
Eileen Daly
King's College London
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3625-3467
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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-occuring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved in both 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 (phMRI) study, using a randomised double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during 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 inhibtion 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 if it improves clinical symptoms.
Keywords
autism spectrum disorder, executive functioning, tianeptine, serotonin, fMRI
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CURRENT STATUS: Under Revision
Version 2
Posted 07 Jan, 2021
No community comments so far
Review #1 received
Received 29 Dec, 2020
Editorial decision: Minor revision
On 29 Dec, 2020
Review #2 received
Received 25 Dec, 2020
Reviewer #2 agreed
On 14 Dec, 2020
Editor assigned
On 13 Dec, 2020
Reviewers invited
Invitations sent on 13 Dec, 2020
Reviewer #1 agreed
On 13 Dec, 2020
Submission checks complete
On 13 Dec, 2020
Editor invited
On 13 Dec, 2020
No comments provided
Review #2 received
Received 11 Nov, 2020
Editorial decision: Major revision
On 11 Nov, 2020
Reviewer #2 agreed
On 05 Nov, 2020
Review #1 received
Received 20 Oct, 2020
Reviewers invited
Invitations sent on 05 Oct, 2020
Reviewer #1 agreed
On 05 Oct, 2020
Editor assigned
On 28 Aug, 2020
Editor invited
On 27 Aug, 2020
Submission checks complete
On 24 Aug, 2020
First submitted
On 18 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular & Molecular Neuroscience
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This preprint is under consideration at Molecular Autism. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine
Eileen Daly
King's College London
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3625-3467
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 2
Posted 07 Jan, 2021
No community comments so far
Review #1 received
Received 29 Dec, 2020
Editorial decision: Minor revision
On 29 Dec, 2020
Review #2 received
Received 25 Dec, 2020
Reviewer #2 agreed
On 14 Dec, 2020
Editor assigned
On 13 Dec, 2020
Reviewers invited
Invitations sent on 13 Dec, 2020
Reviewer #1 agreed
On 13 Dec, 2020
Submission checks complete
On 13 Dec, 2020
Editor invited
On 13 Dec, 2020
No comments provided
Review #2 received
Received 11 Nov, 2020
Editorial decision: Major revision
On 11 Nov, 2020
Reviewer #2 agreed
On 05 Nov, 2020
Review #1 received
Received 20 Oct, 2020
Reviewers invited
Invitations sent on 05 Oct, 2020
Reviewer #1 agreed
On 05 Oct, 2020
Editor assigned
On 28 Aug, 2020
Editor invited
On 27 Aug, 2020
Submission checks complete
On 24 Aug, 2020
First submitted
On 18 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular & Molecular Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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-occuring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved in both 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 (phMRI) study, using a randomised double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during 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 inhibtion 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 if it improves clinical symptoms.
Figure 1
Figure 2
Figure 3