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First visual fMRI now shows ToM in ASD and ADHD

NEW study shows the fMRI evidence of Theory of Mind (ToM) in ASD, as well as in ASD+ADHD (55% of children and adolescents with the disorders meet both diagnostic criteria), as compared to Neurotypicals (Typically Developing Individuals).

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NEW study shows the fMRI evidence of Theory of Mind (ToM) in ASD, as well as in ASD+ADHD (55% of children and adolescents with the disorders meet both diagnostic criteria), as compared to Neurotypicals (Typically Developing Individuals).

Neural Correlates of Theory of Mind in Autism Spectrum Disorder, Attention-Deficit Hyperactivity Disorder, and the Comorbid Condition

Ilzarbe, D., Lukito, S., Moessnang, C., O’Daly, O. G., Lythgoe, D. J., Murphy, C. M., Ashwood, K., Stoencheva, V., Rubia, K., & Simonoff, E. (2020). Neural Correlates of Theory of Mind in Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, and the Comorbid Condition. Frontiers in psychiatry11, 544482. https://doi.org/10.3389/fpsyt.2020.544482

Abbreviations

  • ADHD, attention-deficit/hyperactivity disorder
  • ASD, autism spectrum disorder
  • FC, al connectivity
  • GD, goal directed movement
  • fMRI, al Magnetic Resonance Imaging
  • TD, typically developing controls
  • mPFC, medial prefrontal cortex
  • ToM, Theory of mind
  • TPJ, temporoparietal junction
  • rANG, right angular gyrus
  • RD, random movement
  • ROI, region-of-interest

INTRODUCTION

Autism spectrum disorder (ASD) is characterized by social communication difficulties and stereotypical/repetitive behaviors, while attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate symptoms of inattention, hyperactivity, and impulsivity (1). 

Despite the distinct presentations, up to 55% of children and adolescents with the disorders meet both diagnostic criteria (2, 3). 

Furthermore, reports of a co-occurrence of both disorders in adulthood may indicate its persistence (4–6). 

Reviews and meta-analyses suggest overlapping cognitive impairments in both disorders including the difficulties in theory of mind (ToM), i.e., the inference of others’ mental states or “mentalizing” (7–9), even though ToM deficits have been thought to be ASD-specific [e.g., (10–13)].

In ASD, mentalizing problems are conceptualized as a core symptom (11) or a consequence of diminished social motivation (14). 

The deficits in ASD are commonly associated with under-activation of temporo- and frontolimbic social brain networks, in medial and ventrolateral prefrontal, temporo-parietal cortices, and amygdala in children [e.g., (15, 16)] and adults [e.g., (17–19)], leading to the “hypo-intentionality” hypothesis of autism (20). 

However, over-activation of these regions has also been reported in children and adults with ASD (21–24). 

Reduced activation in the right temporoparietal junction (TPJ) and medial prefrontal cortex (mPFC), particularly, has been shown to correlate with increased autism severity scores (15, 17, 25).

During mentalizing, children and adults with ASD also showed reduced al connectivity (FC) (17, 20, 21, 26, 27) in the social brain network that is typically increased in TD controls (17, 28, 29). 

Such FC reduction in ASD has been reported between frontal, especially mPFC, and temporo-parietal regions, particularly on the right hemisphere (20, 26, 30), ventral premotor and sensorimotor areas (25), and among widespread seed regions in the network (21, 27). 

These findings, together with observation of reduced FC across other cognitive domains (31–33), have led to the theory of domain-general frontal-posterior under-connectivity in ASD (34).

In ADHD, social cognition, and mentalizing deficits are increasingly reported, mostly in children (35–39) but also in adults (40–43), albeit not as consistently as in ASD (8). 

For the adult age group particularly, recent studies have reported intact mentalizing in ADHD, who are instead impaired in empathy and in their ability for generating solutions for social problems (44, 45). 

In line with these findings, a review has suggested that social cognition deficits in ADHD are less severe and more heterogeneous than in ASD (8).

In the context of neuroimaging of ADHD, altered orbitofrontal and lateral fronto-striatal activation, which is typicaly linked to executive deficits (46–48), has been cited as possible mediator for the social cognition deficits in ADHD (49, 50), although, to our knowledge, no fMRI studies have explored neural correlates of ToM in ADHD. 

Importantly, it is unclear if social cognition and mentalizing deficits are intrinsic to ADHD (41) or reflect co-occuring ASD traits in the population (40).

Comparative fMRI studies involving people with ADHD alone, ASD alone, and/or combined ASD+ADHD could tease apart disorder-differentiating impairments in social brain regions. 

To date, these studies have been conducted exclusively in children and adolescents with the disorders (51–55). 

One al magnetic resonance imaging (fMRI) study has found ASD-specific inferior frontal gyrus under-activation relative to TD and ADHD during emotion identification (51). 

Furthermore, using resting-state fMRI, ASD-differentiating intrinsic FC impairments were observed in regions typically involved in mentalizing, with increased local (i.e., “degree centrality”) temporo-limbic FC in the ASD and ASD+ADHD groups relative to TD and ADHD, and shared precuneus over-connectivity across all clinical groups (55). Electroencephalography (EEG) biomarkers for face and eye-gaze processings such as N170 have also been found to be ASD-differentiating relative to ADHD (52–54). 

These findings suggest that the neural abnormalities underlying social cognition, based on a number of neural and electrophysiological correlates, might be specific to ASD and not ADHD

However, the hypothesis has not been tested during mentalizing specifically.

Therefore, we directly compare hemodynamic response and FC in brain regions during ToM relative to non-ToM conditions across individuals with ADHD, ASD, ASD+ADHD, and typical development. 

To address the lack of investigation of brain correlates of comorbidity in the adult population, this study focused on young adults using the Frith-Happé animated-triangle fMRI task that is frequently used for investigating ToM in ASD (21, 24, 27), which has also been shown to detect ToM deficits in ADHD, albeit in children (35). 

(Frith-Happé animated-triangle)

We aimed to investigate if ToM performance deficits are similar or different and are associated with similar or different neural correlates across the three clinical groups. 

Based on previous findings of neuroimaging (51), FC (55), and EEG (52–54), we hypothesized that abnormalities in the social brain network, e.g., under-activation in right TPJ and mPFC, and reduced fronto-posterior FC during ToM (21, 27, 34) would distinguish the ASD groups, with and without ADHD, from the group with ADHD alone, who would show no neuroal impairments.

DISCUSSION

To our knowledge, this is the first study to investigate brain activation and FC associated with ToM in young adult males with ASD, ADHD, ASD+ADHD, and TD. 

Despite comparable task performance, ASD adults with and without ADHD had increased activation relative to ADHD alone during mentalizing in a key temporo-parietal ToM region, which was trend-wise increased relative to TD in the ASD group without ADHD. In FC, during mentalizing, there were mixed patterns of findings with all clinical groups sharing the lack of increased average FC over all connectivity pairs when compared to TD, which was particularly significant when considering the individual FC pairs in posterior temporo-parietal regions. 

Furthermore, under-connectivity between right inferior frontal and posterior cingulate cortices was found in the ASD groups, with and without ADHD, while the decreasing FC in medial frontal cortex and left temporo-parietal junction with mentalizing was found only in the ADHD groups, with and without ASD.

Increased temporoparietal activation in rANG during mentalizing appears to differentiate adults with ASD, with or without ADHD, from those with ADHD alone, and at a trend- level from TD controls. 

Therefore, we show for the first time that this over-activation is ASD-specific relative to the ADHD. 

This finding was significant in whole-brain analyses of ToM > RD contrast, and either significant or at trend-level in ROI analyses of both mentalizing contrasts. 

Previous studies have shown reduced rANG activation in children and adults with ASD relative to controls (15, 17–19). 

However, some studies have also found over-activation in the social brain regions during mentalizing in children and adults with ASD relative to TD (21–24), typically concomitant with unimpaired mentalizing task performance. 

The present findings could reflect increased processing effort in ASD to perform mentalizing as well as the TD controls and ADHD group [e.g., (23, 24)]. 

Supporting this interpretation was the positive correlation between rANG activation and the increased prompts for describing ToM movement in ASD, and between rANG activation and RT for classifying ToM clips in TD controls.

Discrepancies of findings were observed across contrasts (ToM > GD vs. ToM > RD) and analysis types (e.g., whole brain vs. ROI). 

Specifically, the ToM > GD contrast, relative to ToM > RD in whole-brain and ROI analyses, reduced some brain activation differences to non-significance. 

Thus, GD motion seems to evoke temporoparietal activation at intermediate level between RD and ToM, which could express parametric modulation of right temporoparietal activation when observing interaction based on goal pursuit alone compared to interaction involving the attribution of mental states in others.

Overall, the clinical groups showed a lack of increased FC during ToM compared to TD controls. 

The under-connectivity between rANG and bilateral TPJ/STS in particular seemed in line with the findings of anterior and posterior TPJ dysconnectivity between ASD and ADHD during resting state (79). 

The right-lateralized local rANG-rTPJ/STS under-connectivity during ToM is interesting, given the strong evidence of a positive association between BOLD activation and local FC density during mentalizing (80). 

Specifically, the rANG activation in both ASD groups, with and without ADHD, exhibited opposite effect to what is expected from a reduced local temporoparietal connectivity between rANG and rTPJ. 

This supports the atypical brain hypothesis [e.g., (21–24, 27)], instead of the hypo-intentionality hypothesis of ASD (20), which now extends to the comorbid group.

The lack of increased connectivity in rIFG-PCC during ToM, was found in ASD and ASD+ADHD but not in ADHD or TD controls. 

As well as implicated during mentalizing, the rIFG is part of the mirroring networks and is implicated in action processing and social attention. 

The rIFG is hypothesized as a gateway into the mentalizing networks (81, 82), which include the PCC. 

Thus, the rIFG-PCC under-connectivity may reflect information transmission failures across the two networks (26, 30), which is ASD-differentiating.

Relative to TD controls, ADHD and ASD+ADHD showed decreasing FC between mPFC and lTPJ with increasing ToM. 

Functional coupling between mPFC and the temporal cortices occurs bilaterally during mentalizing [e.g., (28, 75, 82, 83)]. 

While it has not been discussed as much as the rTPJ in the context of mentalizing, the lTPJ is implicated in explicit ToM in metaanalytic connectivity modeling (84), and lesions in the region impaired spontaneous ToM in adults (85, 86). 

Those specific subdomains of ToM difficulties could perhaps be investigated further in ADHD.

FINDINGS

The findings of the study should be viewed with its strengths and limitations. 

Firstly, the sample size was relatively small, which may have reduced statistical power to detect small effects and increased probability of false positives. 

The inclusion of young adult males only enhanced the group homogeneity at the expense of the finding’s generalizability to other population groups, including female, children, and older adults with the conditions. 

The absence of correlations between primary ToM measures and brain activation and connectivity also constrained the interpretation of findings. 

There was limited variance of task performance across all participant groups, which could have reflected reduced symptom severity in non-clinically referred participants (87) or a lack of sensitivity of the simplistic animated-triangle fMRI task for detecting differences between groups. 

Finally, it is also possible that ToM impairments are present in ADHD in a subtle form that was undetectable by the animated triangle task. 

Future studies could investigate clinically referred participants, using more complex and naturalistic mentalizing tasks [e.g., (18, 26)].

SUMMARY

To summarize, despite evidence of reduced connectivity in all three clinical groups relative to TD controls during ToM, a differentially increased activation pattern was found in both ASD and comorbid groups relative to ADHD in right temporoparietal cortex, which is a key mentalizing region. 

  • Both ASD and comorbid groups also showed reduced right inferior frontal and posterior cingulate coupling, which may reflect an atypical information transmission to the mentalizing network.
  • In contrast, both ADHD and comorbid groups showed decreasing connectivity between medial prefrontal and left temporoparietal cortices with increasing ToM when compared to TD controls.
  • These findings denote a complex pattern of atypical brain underpinning mentalizing in these three conditions in young adult males, with some evidence of ASD- and ADHD-differentiating features and a combined neuroal atypicality in the comorbid group.
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