Modulating Temporoparietal Junction Mentalizing-Related Activity in Autism Spectrum Disorder using Transcranial Magnetic Stimulation

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Deficits in mentalizing, a high-order social cognitive process that allows individuals to build representations of others’ state of mind (e.g. emotions and motivation) and adjust their own behaviors accordingly, are hypothesized to underline the core social communication abnormalities that characterize autism spectrum disorder (ASD). Our pilot data outline a specialized mentalizing neural network that includes the temporo- parietal junction (TPJ, including the posterior superior temporal sulcus, pSTS), that can be modulated with repetitive transcranial magnetic stimulation (rTMS). These data show that the activity in the right TPJ/pSTS is specifically modulated by mentalizing processes, probed with a social-competitive fMRI Domino task, and that young adults diagnosed with either ASD or schizophrenia show decreased mentalizing related activity in this region compared to typically developed (TD) controls. However, this deficit is associated with social communication skills only in ASD. Thus, specifically modulating the underlying neural mechanisms of mentalizing with rTMS could be an effective intervention for this core deficit in ASD. With this proposal, we will delineate the mechanistic effects of inhibitory vs. excitatory rTMS of the right TPJ, specifically in modulating mentalizing task-related (MTR) neural activity in adults diagnosed with ASD (N=40) compared to matched TD (N=40) individuals ages 18-35 with IQ>80. All participants will be scheduled for four study sessions that include a baseline and three subsequent sessions that will each include two functional magnetic resonance imaging (fMRI) scans, one pre and one post an rTMS session. During each fMRI scan, participants will be engaged in intersocial, competitive Domino task that involves mentalizing. Our rTMS manipulation, administered in a double-blind, counterbalanced fashion, includes one session each of excitatory (intermittent theta-burst stimulation, iTBS), inhibitory (continuous TBS, cTBS), and sham sequences. The rTMS will be guided with individualized electric-field modeling calculated from a structural MRI scan collected on the baseline session. This robust design is necessary to identify the optimal rTMS sequence to engage the right TPJ and the mentalizing network in ASD because firm conclusions about how best to modulate this network cannot be drawn from the few known published reports. We expect to replicate our previous findings of a mentalizing network, with a right TPJ node, that will highlight deficits in ASD relative to TD participants. Also, we hypothesize that iTBS will result in increased, while cTBS in decreased MTR neural activity in the mentalizing network, with this being more pronounced in ASD, and sham resulting in no change. Understanding this mechanism will be the first and crucial step in validating rTMS of the right TPJ as a viable neural target to modulate neural circuit, and subsequently to modulate social-communication skills in ASD in future clinical studies. The significance of such a line of research should be considered in the context of the high prevalence of ASD and the dire need of developing effective interventions, especially for adults.