Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that affects 1 in 59 people worldwide (1). Individuals with ASD are characterized by social communication deficits, e.g., difficulties in the production and comprehension of nonverbal gestures, that manifest very early in their lives. Such deficits significantly impair their social and occupational functioning (2). In the past decade, researchers have attempted to identify critical components underlying lifelong social communication difficulties in ASD, one of which is the deficit in imitation.
Imitation, defined as the ability to simultaneously observe and replicate an action displayed by another person (3, 4), has been considered an important skill for early social and intellectual development (5). Research with typically developing individuals has revealed that imitative skills progressively develop from the imitation of simple actions to the imitation of complicated gestures in the first two years of life as a child continuously interacts with the environment (6). This developmental trajectory of imitation, however, has been found to be delayed in individuals with autism (7). Moreover, imitation is a form of social learning and imitation problem was found to be a significant predictor of communication development and intellectual outcomes in children with ASD (8, 9). This research collectively suggests that impaired imitation early in life contributes to behavioral manifestations in ASD.
It has been proposed that the mirror neuron system (MNS) supports the ability to imitate in humans. The MNS is a neural circuit involving interconnected brain regions that process information related to the perception and execution of biological motions (10, 11). Some of these brain regions, i.e., the pars opercularis of the inferior frontal gyrus, ventral premotor cortex and inferior parietal lobule (12), contain mirror neurons, which are neurons that “discharge both when individuals perform a given motor act and when individuals observe another person performing a motor act with a similar goal” (13, p.757). Other regions within the MNS do not contain mirror neurons. Instead, these regions support imitation by providing sensory/perceptual/affective inputs to frontal and parietal mirror neuron regions (14). Previous research has shown that the organization of the MNS is task-specific. For example, imitation of hand actions involves the frontoparietal regions with mirror neurons (i.e., inferior frontal gyrus pars opercularis, dorsal premotor cortex, supplementary motor area, precentral gyrus and inferior parietal lobule), as well as superior temporal sulcus and visual cortex for visual processing (14, 15). Imitation of facial expressions, which requires additional affective processing compared to hand action imitation, involves a more extensive activation of brain regions beyond the mirror neuron regions and visual regions. The core MNS regions include the inferior frontal gyrus (pars orbitalis, pars triangularis) coactivated with other cortical regions for face processing (i.e., fusiform face area) and visual attention/attentional control to face stimuli (i.e., middle occipital gyrus/median cingulate cortex), as well as subcortical regions for emotional processing (e.g., amygdala; 16).
Given that the MNS is a plausible neural correlate for imitation, individuals with ASD, who have been found to have impairments in imitation, have been hypothesized to show a dysfunctional MNS. A number of functional magnetic resonance imaging (fMRI) studies have been conducted to compare the activation patterns of the MNS in ASD individuals with age- and/or IQ-matched typically developing (TD) controls during the observation of biological motions. The visual stimuli used in these fMRI studies can largely be classified into two categories: (1) “cold” stimuli–biological motions without an emotional component, such as hand grasping (e.g., 2, 17 and 18) “hot” stimuli–biological motions that convey emotions, such as human faces expressing different emotions (19, 20). These fMRI studies, however, have presented inconsistent results. For example, in a study in which images of “cold” actions were presented to participants, greater activation in the right dorsal premotor cortex (a brain region with mirror neurons) was recorded in ASD participants than in TD participants (17). A similar action observation paradigm was adopted by Pokorny (18), although they did not find significant differences in brain activation within the MNS between the ASD and TD participants. With respect to the observation of “hot” stimuli, there have also been inconsistencies. For example, Kim, Choi (19) and Sato, Toichi (20) displayed both happy and fearful faces to participants with and without ASD. Kim, Choi (19) reported that ASD individuals exhibited a reduction in activation in some MNS regions (i.e., inferior frontal gyrus and amygdala) in the right brain only, while Sato, Toichi (20) reported reductions in bilateral activation in these regions. These contradictory results have led us to two important questions regarding MNS function in individuals with ASD: Is the MNS truly dysfunctional in individuals with ASD? If their MNS is dysfunctional, how can the previous contradictory findings be explained?
Summarizing the available data with meta-analytical methods would be helpful for us to answer these questions. To our knowledge, one relevant meta-analysis has been conducted. Rather than including all MNS studies regardless of the nature of stimuli (“cold” vs “hot” stimuli), this meta-analysis included only the data from “cold” action observation and imitation studies among adolescents and adults (mean age = 12-33) with and without ASD using the activation likelihood estimation (ALE) method (21). From the 13 included studies, the meta-analytic data revealed greater activation in the ASD than TD individuals at the right anterior inferior parietal lobule, a brain region with mirror neurons. This study appeared to provide some evidence that part of the MNS might be dysfunctional in individuals with ASD during “cold” action processing. However, whether there is a global deficit in both “cold” and “hot” action processing remains unclear. Additionally, having found that the complexity of the neural network required for different visual stimuli might account for the discrepancies in fluctuating behavioral performance in individuals with ASD (22, 23), and given that the observation/imitation of “hot” stimuli requires a more extensive MNS (10), it is reasonable to postulate that the nature (i.e., “cold” vs “hot”) of stimuli presented to trigger MNS activities may play a role in explaining the inconsistent results. Furthermore, provided that the gray matter volumes in frontal, parietal and occipital regions, where mirror neurons are situated, atypically decline in ASD compared to TD individuals starting from early adolescence (age 10-15) through adulthood (24), the age of participants across different studies may be another factor modulating the inconsistent results. An updated meta-analysis including all fMRI studies that investigated the MNS in ASD would thus be essential to draw conclusions regarding these unanswered questions.
This meta-analysis aimed to explore the differences in MNS activation patterns between TD and ASD individuals when they observe/imitate biological motions with/without emotional components. Effect-size signed differential mapping (ES-SDM), a mixed voxel-based meta-analytic method, was adopted (25) to synthesize the available fMRI data.
It was hypothesized that the MNS activation patterns were different in TD and ASD individuals; such differences in activation patterns would be modulated by the nature of the stimuli (i.e., biological motions with/without emotional components) and age (i.e., adolescent/adult). Meta-regressions, enabled by the ES-SDM, were also performed to explore clusters that exhibited statistically significant changes in activation across ages in ASD and TD individuals.