Dissecting neural correlates of theory of mind and executive functions in behavioral variant frontotemporal dementia

Abstract

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Keywords: Executive functions; Frontotemporal dementia; Magnetic resonance imaging; Reading the Mind in the Eyes Test; Social cognition; Theory of mind.

Fig. 1

Associations of gray matter volume (GMV) via voxel-based morphometry (VBM) (top four rows) with Reading the Mind in the Eyes Test (RMET) performance as a measure of social cognition (SC) and five different tests reflective of performance in executive functions (EF). Voxel based morphometry (VBM) results are thresholded at p < 0.005 FWE_TFCE. All results indicate positive associations of test performance with GMV with warmer colors indicating stronger associations. The two bottom rows highlight overlapping regions of VBM results [here additional liberal thresholds (i.e. p<0.05 FWE_TFCE) were applied for exploratory purposes]. Please note that colors of the last row’s illustrations are not reflective of individual tests, but highlight the number of overlapping results. Left side of the brain is shown on the left. RMET Reading the Mind in the Eyes Test; H5PT Hamasch-Five-Point Test, TMT Trail Making Test B/A; sFLU semantic Fluency; pFLU phonemic Fluency

Fig. 2

Associations of cortical thickness (CTH) with performance in the Reading the Mind in the Eyes Test (RMET) and five different tests reflective of executive function (EF). Results are thresholded at p < 0.005 FWE_TFCE. All results indicate a positive relationship of test performance. The color bar illustrates the level of significance (i.e. pFWE_TFCE). Bottom rows highlight overlapping regions of CTH results (please note that colors are not reflective of individual tests, but highlight the number of overlapping results only). The bottom row highlights the overlap of all six tests at a liberal threshold (p<0.05 FWE_TFCE) for exploratory purposes. Left side of the brain is shown on the left (i.e. when both hemispheres are shown). H5PT Hamasch-Five-Point Test, TMT Trail Making Test B/A; sFLU semantic Fluency; pFLU phonemic Fluency

Fig. 3

Associations of Reading the Mind in the Eyes (RMET) and executive function (EF) test performance with gray matter volume (GMV; top rows) and cortical thickness (CTH; bottom rows) after additional adjustment for the respective other test performance (i.e. RMET adjusted for sFLU and H5PT, combined and individually). Results are thresholded at p < 0.05 FWE_TFCE and p < 0.005 FWE_TFCE [voxel based morphometry (VBM) results for RMET only; indicated by warm yellow color]. Here, for better differentiation VBM results are illustrated with two separate monochromatic colormaps. All illustrated results indicate a positive relationship of test performance with GMV and CTH. For CTH results, the color bar illustrates the level of significance (i.e. pFWE_TFCE). Left side of the brain is shown on the left (i.e. in sections and when both hemispheres are shown). sFLU semantic fluency; H5PT Hamasch-Five-Point Test

Fig. 4

Radar chart illustrating the relationship of structural covariance networks (i.e. C1 – C12) with performance in the Reading the Mind in the Eyes Test (RMET) and executive function (EF) tests with the scale indicating spearman r correlation coefficients of partial correlation analyses adjusted for age and gender. Left side of the brain is shown on the left when both hemispheres are shown). H5PT Hamasch-Five-Point Test, TMT Trail Making Test B/A; sFLU semantic Fluency; pFLU phonemic Fluency. Please note that for the TMT lower values indicate better performance, therefore the correlation coefficients were inverted for illustrative purposes

Fig. 5

Term-based (i.e. “social”, “theory mind”, “executive”) Neurosynth meta-analyses with the corresponding overlap with voxel based morphometry (VBM) based brain structural correlates of the Reading the Mind in the Eyes Test (RMET) as determined in this study. Left side of the brain is shown on the left