Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine

Abstract

BackgroundAutism 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) ‘normalizes’ differences in brain function during performance of EF tasks. 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. MethodWe conducted a pharmacological magnetic resonance imaging (phMRI) study 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. ResultsUnder placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibtion regions including inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in 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 ‘normalized’ during response inhibition in inferior frontal and premotor cortices.LimitationsOur sample only consisted of high functioning male adults. Therefore, our findings may not be generalizable to other autistic subgroups (e.g. children or women). ConclusionsOur findings provide the first evidence that tianeptine can ‘normalize’ atypical brain activation during EF in adults with ASD. 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.

Catecholaminergic and Cholinergic Neuromodulation in Autism Spectrum Disorder: A Comparison to Attention-Deficit Hyperactivity Disorder

“…Additionally, future pharmacological trials should consider the core deficits of ASD, as these deficits are currently not often assessed. Future studies should also investigate the neurobiological effects of these agents in ASD patients, as preliminarily done for propranolol and tianeptine (Narayanan et al 2010;Hegarty et al 2017;Wichers et al 2021). For example, the intraindividual variability of connectivity can be assessed to see how pharmacological agents may influence this potential underlying mechanism of ASD pathology (Falahpour et al 2016).…”

“…A recent fMRI study showed that tianeptine did not behaviorally affect sustained attention or inhibition/stopping in ASD patients, but the drug did normalize ECN activation during tasks (Wichers et al 2021). Overall, although some trials report beneficial effects of TCAs in ASD, most trials show little to no significant therapeutic effects of this class of medications.…”