Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK.
Mol Autism. 2021 Feb 19;12(1):14. doi: 10.1186/s13229-021-00422-0.
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.
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.
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.
We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome.
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.
自闭症谱系障碍（ASD）与执行功能（EF）缺陷有关，这些缺陷被认为是核心症状以及共病精神症状的原因。这些缺陷的生物学基础尚不清楚，但可能包括 5-羟色胺能系统，该系统既参与调节神经典型人群的 EF，也参与 ASD 的病理生理学。我们之前的研究表明，通过急性色氨酸耗竭（ATD）减少 5-羟色胺会使 EF 任务中大脑功能的差异向对照水平转移。然而，ATD 在临床上不易使用，因此我们需要采用替代方法来挑战 5-羟色胺系统。因此，我们研究了 5-羟色胺调节剂噻奈普汀对 ASD 中 EF 网络的作用。
我们进行了一项药物磁共振成像研究，采用随机双盲交叉设计，比较了 12.5 毫克噻奈普汀和安慰剂对 38 名成年男性（19 名 ASD 患者和 19 名匹配对照）在两项 EF 任务（反应抑制和持续注意）中的大脑激活的影响。
在安慰剂条件下，与对照组相比，ASD 个体在反应抑制区域（包括下额前皮质、前运动区域和小脑）的大脑激活存在异常。在持续注意期间，ASD 个体的右侧颞中回、右侧楔前叶和左侧楔前叶的大脑激活减少。在安慰剂条件下观察到的大多数病例对照之间的大脑功能差异在噻奈普汀给药后被消除。此外，在 ASD 个体中，在下额前皮质和前运动皮质的反应抑制期间，大脑功能差异明显向对照水平转移。
我们进行了一项使用单剂量噻奈普汀的试点研究，因此，我们不能对长期结果发表评论。
我们的研究结果首次提供了证据，表明噻奈普汀可以使 ASD 成人在执行 EF 时的异常大脑激活向对照水平转移。未来的研究应探讨在长期噻奈普汀治疗后，这种 ASD 生物学的转变是否持续，以及它是否改善临床症状。
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