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

Abstract

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.

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).…”

“…Another TCA, tianeptine, seems to decrease hyperactivity, irritability, inappropriate speech and inappropriate eye contact (Niederhofer et al, 2003). A recent fMRI study showed that tianeptine did not behaviorally affect sustained attention or inhibition/stopping in ASD, 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.…”

Brain Functional Alterations in Prepubertal Boys With Autism Spectrum Disorders

“…Many studies have reported the abnormal appearance of the cuneus in people with ASD. Based on fMRI, Wichers et al (2021) found that during sustained attention tasks, compared to controls, adults with ASD had decreased brain activation in the right cuneus. Guo detected that the decrease in ALFF was significant for ASD in adolescents in the right cuneus ( Guo et al, 2017 ).…”

Bridging the translational neuroscience gap: Development of the ‘shiftability’ paradigm and an exemplar protocol to capture psilocybin-elicited ‘shift’ in neurobiological mechanisms in autism

“…Using fMRI, we have consistently found this to be the case. For example, we have reported that fMRI response can be modulated with single dose drug challenges which target components of the serotonin system (citalopram and tianeptine) 2,3,8,9 , glutamate-GABA system (riluzole) 11 and endocannabinoid system (cannabidiol) 4,5 . We have also used EEG recordings during sensory stimulation to capture response to GABAB receptor agonist, arbaclofen.…”

“…We call this a "shiftability" paradigm. To date, our "shiftability" studies have demonstrated that the autistic brain responds differently when different neurochemical systems are perturbed by a single, low dose pharmacological challenge [2][3][4][5][6][7][8][9][10][11] .…”