Mirror Neuron Activity Associated with Social Impairments but not Age in Autism Spectrum Disorder Peter G. Enticott, Hayley A. Kennedy, Nicole J. Rinehart, Bruce J. Tonge, John L. Bradshaw, John R. Taffe, Zafiris J. Daskalakis, and Paul B. Fitzgerald Background: The neurobiology of autism spectrum disorder (ASD) is not particularly well understood, and biomedical treatment ap- proaches are therefore extremely limited. A prominent explanatory model suggests that social-relating symptoms may arise from dysfunc- tion within the mirror neuron system, while a recent neuroimaging study suggests that these impairments in ASD might reduce with age. Methods: Participants with autism spectrum disorder (i.e., DSM-IV autistic disorder or Asperger’s disorder) (n = 34) and matched control subjects (n = 36) completed a transcranial magnetic stimulation study in which corticospinal excitability was assessed during the observa- tion of hand gestures. Results: Regression analyses revealed that the ASD group presented with significantly reduced corticospinal excitability during the observation of a transitive hand gesture (relative to observation of a static hand) (p  .05), which indicates reduced putative mirror neuron system activity within ventral premotor cortex/inferior frontal gyrus. Among the ASD group, there was also a negative association between putative mirror neuron activity and self-reported social-relating impairments, but there was no indication that mirror neuron impairments in ASD decrease with age. Conclusions: These data provide general support for the mirror neuron hypothesis of autism; researchers now must clarify the precise functional significance of mirror neurons to truly understand their role in the neuropathophysiology of ASD and to determine whether they should be used as targets for the treatment of ASD. Key Words: Asperger’s disorder, autism, electromyography, mirror neuron system, primary motor cortex, transcranial magnetic stimulation A utism spectrum disorder (ASD) is characterized by severe social, communicative, and behavioral impairments. The precise neuropathophysiology of ASD is unclear, but a re- cent account suggests that dysfunction of mirror neurons might underlie aspects of ASD, particularly with respect to social relating (1). Originally discovered via depth electrode recordings in ma- caque monkeys (2), mirror neurons are brain cells that become active not only when a behavior is performed but also when that same behavior is observed. Mirror neurons and mirror systems have since been established in humans using a range of techniques (e.g., functional magnetic resonance imaging [fMRI], electroencephalog- raphy [EEG], transcranial magnetic stimulation [TMS]) and in a range of modalities (e.g., behavior, sensation, pain, emotion) (3,4). Theo- retical accounts propose that mirror systems provide an embodied simulation that not only allows an understanding of the actions of others but also facilitates broader social cognitive processes, in- cluding empathy and understanding others’ mental and emotional states (5). It has been widely suggested that dysfunction of mirror neurons may underlie ASD (i.e., the broken mirror hypothesis) (6–8). Evi- dence for reduced activation of elements of the mirror system in autism comes from a range of noninvasive techniques, including fMRI (9), structural magnetic resonance imaging (10,11), EEG indi- ces of mu suppression (12–14), and TMS indices of corticospinal excitability during action observation (15). Stimuli used to elicit a mirror neuron response in these studies have been similarly varied but include static emotional facial expressions (9), static nonemo- tional facial expressions (16), and intransitive hand movements (12,13,15,17). Another study demonstrated that the observation of an action led to mirrored activity of a muscle that was soon to be used by the observed individual to complete a goal (e.g., activation of mouth-opening mylohyoid muscle when viewing an object grasped for the purpose of eating) but that this mirrored anticipa- tion was absent in ASD (18); this implies a deficit in linking or representing motor chains for understanding intention. While gen- erally supportive of reduced mirror system activity in ASD and links with social relating (9), these studies have nevertheless been char- acterized by small sample sizes, thereby limiting further analyses (e.g., regression). More recently, Bastiaansen et al. (19) used fMRI to investigate responses to facial expressions among adults with ASD; while there were no overall group differences, the authors found reductions in inferior frontal gyrus (IFG) activity for younger individuals with ASD (mean age: 22 years) and an age-related increase in IFG activity for the ASD group. These age patterns were not apparent among the control group. This is a particularly interesting and novel finding, as it suggests that individuals with ASD may outgrow any mirror neu- ron deficit by early-mid adulthood, raising questions about the importance of the mirror neuron system (MNS) among adults with ASD, many of whom nevertheless continue to experience pro- nounced social difficulties. Despite this evidence for a mirror neuron impairment, ASD is increasingly recognized, from clinical, genetic, and neurobiological perspectives, as a heterogeneous group of disorders. Accordingly, one neurobiological model, such as the mirror neuron account, is unlikely to provide an explanatory account that applies to all indi- From the Monash Alfred Psychiatry Research Centre (PGE, HAK, PBF), School of Psychology and Psychiatry, Monash University and the Alfred, Mel- bourne; and Centre for Developmental Psychiatry and Psychology (PGE, NJR, BJT, JLB, JRT), School of Psychology and Psychiatry, Monash Univer- sity, Clayton, Australia; and Centre for Addiction and Mental Health (ZJD), University of Toronto, Toronto, Canada. Address correspondence to Peter G. Enticott, Ph.D., Monash University and the Alfred, School of Psychology and Psychiatry, Monash Alfred Psychi- atry Research Centre, Level 1, Old Baker Building, The Alfred, Melbourne, Victoria, 3004, Australia; E-mail: peter.enticott@monash.edu. Received Jul 12, 2011; revised Aug 31, 2011; accepted Sep 1, 2011. BIOL PSYCHIATRY 2012;71:427– 433 0006-3223/$36.00 doi:10.1016/j.biopsych.2011.09.001 © 2012 Society of Biological Psychiatry