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Theta burst stimulation (TBS) is associated with the modulation of a range of clinical, cognitive, and behavioural outcomes, but specific neurobiological effects remain somewhat unclear. This systematic literature review investigated resting-state and task-based functional magnetic resonance imaging (fMRI) outcomes post-TBS in healthy human adults. Fifty studies that applied either continuous—or intermittent—(c/i) TBS, and adopted a pretest–posttest or sham-controlled design, were included. For resting-state outcomes following stimulation applied to motor, temporal, parietal, occipital, or cerebellar regions, functional connectivity generally decreased in response to cTBS and increased in response to iTBS, though there were some exceptions to this pattern of response. These findings are mostly consistent with the assumed long-term depression (LTD)/long-term potentiation (LTP)-like plasticity effects of cTBS and iTBS, respectively. Task-related outcomes following TBS were more variable. TBS applied to the prefrontal cortex, irrespective of task or state, also produced more variable responses, with no consistent patterns emerging. Individual participant and methodological factors are likely to contribute to the variability in responses to TBS. Future studies assessing the effects of TBS via fMRI must account for factors known to affect the TBS outcomes, both at the level of individual participants and of research methodology.

The mirror neuron system (MNS) has been theorized to play a neurobiological role in a number of social cognitive abilities and is commonly indexed putatively in humans via interpersonal motor resonance (IMR) and mu suppression. Although both indices are thought to measure similar neuronal populations (i.e., "mirror neurons"), it has been suggested that these methods are unrelated, and therefore, incompatible. However, prior studies reporting no relationships were typically conducted in small and underpowered samples. Thus, we aimed to investigate this potential association in a large sample of neurotypical adults (N = 116; 72 females). Participants underwent transcranial magnetic stimulation (TMS), electromyography (EMG), and electroencephalography (EEG) during the observation of videos of actors performing grasping actions in order to index IMR and mu suppression (in beta, lower alpha, and upper alpha bandwidths). A series of linear regressions revealed no associations between IMR and each of the mu suppression bandwidths. Supplementary Bayesian analyses provided further evidence in favor of the null (B01 = 8.85-8.93), providing further support for no association between the two indices of MNS activity. Our findings suggest that these two measures may indeed be unrelated indices that perhaps assess different neurophysiological aspects of the MNS. These results have important implications for future studies examining the MNS.

Theoretical perspectives suggest that the mirror neuron system (MNS) is an important neurobiological contributor to empathy, yet empirical support is mixed. Here, we adopt a summary model for empathy, consisting of motor, emotional, and cognitive components of empathy. This review provides an overview of existing empirical studies investigating the relationship between putative MNS activity and empathy in healthy populations. 52 studies were identified that investigated the association between the MNS and at least one domain of empathy, representing data from 1044 participants. Our results suggest that emotional and cognitive empathy are moderately correlated with MNS activity, however, these domains were mixed and varied across techniques used to acquire MNS activity (TMS, EEG, and fMRI). Few studies investigated motor empathy, and of those, no significant relationships were revealed. Overall, results provide preliminary evidence for a relationship between MNS activity and empathy. However, our findings highlight methodological variability in study design as an important factor in understanding this relationship. We discuss limitations regarding these methodological variations and important implications for clinical and community translations, as well as suggestions for future research.

BackgroundCorpus callosum anomalies are commonly noted in autism spectrum disorder (ASD). Given the complexity of its microstructural architecture, with crossing fibers projecting throughout, we applied fixel-based analysis to probe white matter micro- and macrostructure within this region. As ASD is a neurodevelopmental condition with noted abnormalities in brain growth, age was also investigated.MethodsData for participants with (N=54) and without (N=50) ASD, aged 5-34 years, were obtained from the Autism Brain Imaging Data Exchange-II (ABIDE-II). Within each site, indices of fiber density (FD), fiber cross-section (FC), and combined fiber density and cross-section (FDC) were compared between those groups.ResultsYoung adolescents with ASD (age = 11.19 ± 7.54) showed reduced macroscopic FC and FDC compared to age-matched neurotypical controls (age = 10.04 ± 4.40). Reduced FD and FDC was noted in a marginally older ASD (age 13.87 ± 3.15) cohort compared to matched controls (age = 13.85 ± 2.90). Among the oldest cohorts, a non-significant trend indicated reduced FD in older adolescents/young adults with ASD (age = 17.07 ± 3.56) compared to controls (age = 16.55 ± 2.95). There was a positive correlation between age and callosal mean FC and FDC in the youngest cohort. When stratified by diagnosis, this finding remained only for the ASD sample.ConclusionWhite matter aberration appears greatest among younger ASD cohorts. In older adolescents and young adults, less of the corpus callosum seems affected. This supports the suggestion that some early neuropathophysiological indicators in ASD may dissipate with age.

The right temporoparietal junction (rTPJ) is a multisensory integration hub that is increasingly utilized as a target of stimulation studies exploring its rich functional network roles and potential clinical applications. While transcranial direct current stimulation (tDCS) is frequently employed in such studies, there is still relatively little known regarding its local and network neurophysiological effects, particularly at important nonmotor sites such as the rTPJ. The current study applied either anodal, cathodal, or sham high-definition tDCS to the rTPJ of 53 healthy participants and used offline EEG to assess the impacts of stimulation on resting state (eyes open and eyes closed) band power and coherence. Temporoparietal and central region delta power was increased after anodal stimulation (the latter trend only), whereas cathodal stimulation increased frontal region delta and theta power. Increased coherence between right and left temporoparietal regions was also observed after anodal stimulation. All significant effects occurred in the eyes open condition. These findings are discussed with reference to domain general and mechanistic theories of rTPJ function. Low-frequency oscillatory activity may exert long-range inhibitory network influences that enable switching between and integration of endogenous/exogenous processing streams.NEW & NOTEWORTHY Through the novel use of high-definition transcranial direct current stimulation (tDCS) and EEG, we provide evidence that both anodal and cathodal stimulation of the right temporoparietal junction selectively modulate slow-wave power and coherence in distributed network regions of known relevance to proposed temporoparietal junction functionality. These results also provide direct evidence of the ability of tDCS to modulate oscillatory activity at a long-range network level, which may have explanatory power in terms of both neurophysiological and behavioral effects.

IntroductionThere are no well-established biomedical treatments for the core symptoms of autism spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve clinical and cognitive outcomes in ASD. We describe here the protocol for a funded multicentre randomised controlled clinical trial to investigate whether a course of rTMS to the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain activation in ASD, can improve social communication in adolescents and young adults with ASD.Methods and analysisThis study will evaluate the safety and efficacy of a 4-week course of intermittent theta burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (n=150, aged 14–40 years) will receive 20 sessions of either active iTBS (600 pulses) or sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, and neurophysiological assessments before and at multiple time points up to 6 months after iTBS. Safety will be assessed via a structured questionnaire and adverse event reporting. The study will be conducted from November 2020 to October 2024.Ethics and disseminationThe study was approved by the Human Research Ethics Committee of Monash Health (Melbourne, Australia) under Australia’s National Mutual Acceptance scheme. The trial will be conducted according to Good Clinical Practice, and findings will be written up for scholarly publication.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12620000890932).

BackgroundThere is evidence to suggest a disruption of gamma-aminobutyric acid (GABA) in autism spectrum disorder (ASD), but findings are mixed. Concurrent electroencephalography and transcranial magnetic stimulation (TMS-EEG) provides a novel method by which to probe GABA-mediated cortical inhibition.MethodsWith a particular focus on GABAB-ergic mechanisms, we investigated the N100 peak of the TMS evoked potential (TEP), as well as long interval cortical inhibition (LICIEEG) in adults with ASD (n = 23; 12 female) without intellectual disability, and a neurotypical comparison group (n =22; 12 female) matched for age, sex, and IQ. Seventy-five single-(spTMS) and 75 paired-(ppTMS; 100 ms inter-stimulus-interval) pulses were applied to the right primary motor cortex (M1), right temporoparietal junction (TPJ), and right dorsolateral prefrontal cortex (DLPFC) while EEG was recorded from 20 scalp electrodes. Additionally, electromyography (EMG) was used to investigate corticospinal inhibition following ppTMS to M1 (LICIEMG).ResultsThere were no group differences in the N100 amplitude or latency following spTMS. LICI outcomes following ppTMS, as measured by either EEG or EMG, also did not differ between groups. These findings were further supported by Bayesian analyses, which provided weak-moderate support for the null hypothesis.LimitationsData presented here reflect adults without intellectual disability, and the generalisability of these results is therefore limited.ConclusionsThe findings of this study argue against GABAB-ergic impairment in adults with ASD without intellectual disability, at least at the cortical regions examined. Further research investigating these mechanisms in ASD at various ages, with varying degrees of symptomatology, and at different brain sites is an important factor in understating the role of GABA in the neuropathophysiology of ASD.

Atypical white matter (WM) microstructure is commonly implicated in the neuropathophysiology of autism spectrum disorder (ASD). Fixel based analysis (FBA), at the cutting-edge of diffusion-weighted imaging, can account for crossing WM fibers and can provide indices of both WM micro- and macrostructure. We applied FBA to investigate WM structure between 25 (12 males, 13 females) adults with ASD and 24 (12 males, 12 females) matched controls. As the role of biological sex on the neuropathophysiology of ASD is of increasing interest, this was also explored. There were no significant differences in WM micro- or macrostructure between adults with ASD and matched healthy controls. When data were stratified by sex, females with ASD had reduced fiber density and cross-section (FDC), a combined metric comprised of micro- and macrostructural measures, in the corpus callosum, a finding not detected between the male sub-groups. We conclude that micro- and macrostructural WM aberrations are present in ASD, and may be influenced by biological sex.

Prior studies have demonstrated that aspects of social cognition can be modulated via temporoparietal junction (TPJ) transcranial direct current stimulation (tDCS). However, this technique lacks focality and electrophysiological effects or correlates are rarely examined. The present study investigated whether anodal and/or cathodal high-definition tDCS (HD-tDCS) would influence facial emotion processing performance relative to sham stimulation, and whether task performance changes were related to neurophysiological changes. Participants completed a facial emotion attribution tasks before and after rTPJ HD-tDCS, with event-related potentials (ERP) recorded during task performance. Anodal rTPJ HD-tDCS improved facial emotion processing performance for static depictions of fear (but not surprise). Stimulation condition influenced P300 latency, and also influenced the relationship between behavioural and electrophysiological (ERP) outcomes in several circumstances, findings which both support and challenge anodal-excitation/cathodal-inhibition accounts of tDCS effects. Results suggest that rTPJ anodal HD-tDCS can influence facial emotion recognition (i.e., affective mentalizing), and elucidate the nature and distribution of underlying neurophysiological processes. Stimulation effects, however, might depend on the intensity and salience/valence (negativity/threat) of the emotion, and these behavioural effects may not relate directly or simply to the ERPs assessed here.

Interpersonal motor resonance (IMR) is a common putative index of the mirror neuron system (MNS), a network containing specialised cells that fire during both action execution and observation. Visual content inputs to the MNS, however, it is unclear whether visual behaviours mediate the putative MNS response. We aimed to examine gaze effects on IMR during action observation. Neurotypical adults (N = 99; 60 female) underwent transcranial magnetic stimulation, electromyography, and eye-tracking during the observation of videos of actors performing grasping actions. IMR was measured as a percentage change in motor evoked potentials (MEPs) of the first dorsal interosseous muscle during action observation relative to baseline. MEP facilitation was observed during action observation, indicating IMR (65.43%, SE = 11.26%, P

Theoretical perspectives suggest that the mirror neuron system (MNS) is an important neurobiological contributor to empathy, yet empirical support is mixed. Here, we adopt a summary model for empathy, consisting of motor, emotional, and cognitive components of empathy. This review provides an overview of existing empirical studies investigating the relationship between putative MNS activity and empathy in healthy populations. 52 studies were identified that investigated the association between the MNS and at least one domain of empathy, representing data from 1044 participants. Our results suggest that emotional and cognitive empathy are moderately correlated with MNS activity, however, these domains were mixed and varied across techniques used to acquire MNS activity (TMS, EEG, and fMRI). Few studies investigated motor empathy, and of those, no significant relationships were revealed. Overall, results provide preliminary evidence for a relationship between MNS activity and empathy. However, our findings highlight methodological variability in study design as an important factor in understanding this relationship. We discuss limitations regarding these methodological variations and important implications for clinical and community translations, as well as suggestions for future research.

The temporoparietal junction (TPJ) is implicated in mental and emotional state attribution, processes associated with autism-relevant traits. Transcranial direct current stimulation (tDCS) to the TPJ can influence social-cognitive performance. However, associations with electrophysiology and autism-relevant traits remain relatively unexamined. This study had two aims: first, exploring links between Autism-Spectrum Quotient (AQ) scores and social-cognitive performance; second, examining interactions between AQ scores and high-definition-tDCS (HD-tDCS) applied to the right TPJ in terms of mental/emotional state attribution and neurophysiological outcomes. Fifty-three participants completed mental/emotional state attribution tasks before and after HD-tDCS. Pre-stimulation mental state attribution accuracy was reduced in participants with higher AQ Switching scores. Cathodal stimulation was associated with reduced emotion attribution performance in participants with higher AQ Switching and AQ Social scores (the latter at trend-level). Anodal stimulation more frequently interacted with AQ Social scores in terms of neurophysiology, in particular regarding reduced delta power in the left compared to right TPJ, and trend-level positive interactions with P100 and P300 latencies during the emotion recognition task. Elements of attention/switching (AQ Switching) may subserve or underpin elements of social cognition (AQ Social), and cathodal and anodal stimulation may have differing effects depending on trait levels in these domains. This study makes an important and original contribution in terms of increasing understanding of how such trait-level variation might interact with the effects of tDCS and also extending previous studies with regard to understanding potential roles of the rTPJ in both attention and social cognition and how autism-relevant traits might influence TPJ function.

The human mirror neuron system (MNS) is hypothesised to be crucial to social cognition. Given that key MNS-input regions such as the superior temporal sulcus are involved in biological motion processing, and mirror neuron activity in monkeys has been shown to vary with visual attention, aberrant MNS function may be partly attributable to atypical visual input. To examine the relationship between gaze pattern and interpersonal motor resonance (IMR; an index of putative MNS activity), healthy right-handed participants aged 18-40 (n = 26) viewed videos of transitive grasping actions or static hands, whilst the left primary motor cortex received transcranial magnetic stimulation (TMS). Motor-evoked potentials (MEPs) recorded in contralateral hand muscles were used to determine IMR. Participants also underwent eyetracking analysis to assess gaze patterns whilst viewing the same videos. No relationship was observed between predictive gaze (PG) and IMR. However, IMR was positively associated with fixation counts in areas of biological motion in the videos, and negatively associated with object areas. These findings are discussed with reference to visual influences on the MNS, and the possibility that MNS atypicalities might be influenced by visual processes such as aberrant gaze pattern.

Imaging and lesion studies have suggested numerous roles for the temporoparietal junction (TPJ), for example in attention and neglect, social cognition, and self/other processing. These studies cannot establish causal relationships, and the importance and relevance of (and interrelationships between) proposed roles remain controversial. This review examined studies that use noninvasive transcranial stimulation (NTS) to explore TPJ function. Of the 459 studies identified, 40 met selection criteria. The strengths and weaknesses of NTS-relevant parameters used are discussed, and methodological improvements suggested. These include the need for careful selection of stimulation sites and experimental tasks, and use of neuronavigation and concurrent functional activity measures. Without such improvements, overlapping and discrete functions of the TPJ will be difficult to disentangle. Nevertheless, the contributions of these studies to theoretical models of TPJ function are discussed, and the clinical relevance of TPJ stimulation explored. Some evidence exists for TPJ stimulation in the treatment of auditory hallucinations, tinnitus, and depersonalisation disorder. Further examination of the TPJ in conditions such as autism spectrum disorder is also warranted.