Executive Function in Autism Spectrum Disorder: History, Theoretical Models, Empirical Findings, and Potential as an Endophenotype

Alexander Luria was one of the first researchers to introduce a model based on neurobiological processes (26) suggesting the broader engagement of various brain regions. In this model, frontal lobes were conceptualized as the regulatory area directing complex problem solving. Damage to the frontal lobes was associated with the frontal lobe syndrome (49), characterized by disinhibition, inability to follow a sequence of instructions, and repetitive motor movements.

Advancements in neuroimaging techniques have placed increasing focus on neuroanatomical localization of EF processes primarily within frontal cortical regions. Localization of cool EF processes has been associated primarily with the dorsolateral prefrontal cortex (PFC), while the top–down processes that regulate hot EFs are linked to the orbitofrontal or ventromedial prefrontal cortex. Some cognitive models also propose specific neuroanatomical correlates of EF. For example, for Stuss' model (87) it was proposed that the task setting and monitoring EFs are localized in the left and right lateral frontal cortex, respectively, while behavioral/emotional regulation corresponds with the localization of hot EFs in the orbitofrontal cortex. Energization is reported to be mediated by the superior medial prefrontal cortex, while metacognition is guided by the frontal poles (87).

The identification of these regional contributions, while valuable, does not encapsulate the broad cortical systems that are being recognized as significant in the neural processes that underlie EF processes (89). Building on the neuroanatomical localization of EF, connectivity models focus on neural circuitry between cortical regions and may present a more integrated approach in the study of EF.

Neuroimaging studies identified that discrete EFs are linked to broader brain networks including the areas within the prefrontal cortex. For example, set shifting was associated with activity of the lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule (52). Set switching task was associated with involvement of the prefrontal cortex and frontoparietal areas of the brain (52, 90). An extended brain network connectivity between dorsal and ventral brain networks was observed in fluency tasks including activation in the inferior frontal gyrus and left dorsolateral prefrontal cortex (34). A differentiation between dorsal and ventral brain networks was observed between phonemic and semantic fluency tasks, respectively (61). Similarly, extended brain network involvement is reported during completion of planning tasks including activation of the dorsolateral prefrontal cortex, the anterior and posterior cingulate areas, and the parietal cortex (91). Activation of frontal regions during working memory tasks included activation of the bilateral superior and middle frontal gyri, bilateral frontal polar regions, and precuneus gyrus (92).

At the neurochemical level of analysis, a number of neurotransmitters have been linked to EF processes. A comprehensive review (93) summarized the role of four neurotransmitter systems in EF. Dopamine (DA) was reported to influence cool EF constructs (set shifting, response inhibition) and to moderate hot EF reward processes. Norepinephrine (NA) circuits were associated with a number of EF cognitive processes (including response inhibition and set shifting likely due to influence of NA on arousal and attentional systems. Serotonin (5-hydroxytrypatamine [5-HT]) modulated response inhibition, through its action in the orbitofrontal cortex. Finally, the cholinergic system mediated set shifting and was proposed to also interact with a number of other neural circuits for a more complex integration of EF processes.

The role of γ-aminobutyric acid (GABA) is increasingly linked with mediating processes associated with neural circuitry in the prefrontal cortex. GABA is the primary inhibitory neurotransmitter in the mature brain, working with excitatory glutamate to create an excitation/inhibition (E/I) balance thought to reflect the activity of the cortex. More excitation is theorized to represent greater activity, while greater inhibition suggests decreased cortical activity (94). Increased GABA (compared to glutamate) within the lateral PFC has been associated with better ability to select between competing tasks (95). Improved working memory performance under increased memory load was associated with higher GABA concentration in the dorsolateral PFC. A recent study (pre-print) (47) attributed a key role to GABAergic genetic contributions to the common EF factor (45), using a large sample in a genome-wide association study (GWAS). This study highlighted the role of the excitatory/inhibitory balance in EF, especially the role of GABA-mediated inhibition.

The models described above reflect the divergent approaches taken in the study of EF in normative literature. In ASD, however, focus has been primarily on comparing diagnostic groups with autism and other cohorts on performance on discrete EF constructs. The executive dysfunction hypothesis discussed below sums a large part of empirical research of EF in ASD. It may reflect efforts to identify discriminating profiles between different groups. Novel approaches to the study of EF in ASD have focused on brain connectivity and neurotransmitter imbalance with limited evaluation of other EF models.