Anterior temporal lobe degeneration produces widespread network-driven dysfunction

Abstract

The neural organization of semantic memory remains much debated. A 'distributed-only' view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.

Keywords: anterior temporal lobe; cognition; functional neuroimaging; semantic dementia; semantics.

Figure 1

Intrinsic ATL connectivity in the healthy brain. Group-level ATL-seeded intrinsic connectivity network maps are shown for HC1 (A), HC2 (B), and their overlap (C), generated with a joint height-extent threshold (P < 0.0001 for peak height and FWE-corrected P < 0.05 for spatial extent). Brain regions beyond the coverage of the optimized EPI protocol are shaded in B and C, and thus only labelled in A. Black circles in A signify the location of the ATL seeds. Amy = amygdala; aMCC = anterior midcingulate cortex; Calc = calcarine; dPI = dorsal posterior insula; FI = frontoinsula; Fus = fusiform; Hes = Heschl’s; Ling = lingual gyrus; lOcG = lateral occipital gyrus; MTG = middle temporal gyrus; OFC = orbitofrontal cortex; PCC = posterior cingulate cortex; pMCC = posterior midcingulate cortex; PCu = precuneus; PHG = parahippocampus; PoCG = postcentral gyrus; PrCG = precentral gyrus; rmPFC = rostral medial prefrontal cortex; STG = superior temporal gyrus.

Figure 2

Semantic variant PPA (svPPA) shows distributed reductions in intrinsic connectivity and local functional brain activity. Group difference maps (semantic variant PPA < HC3) from ATL-seeded intrinsic connectivity (A) and fractional ALFF (fALFF, B) analyses were generated with a joint height-extent threshold (P < 0.01 for peak height and P < 0.05 for spatial extent). The overlap between the intrinsic connectivity network (ICN) and fractional ALFF group-difference maps is shown in C with two statistical thresholds chosen to illustrate the convergence of the findings [P < 0.05 (light blue) or P < 0.01 (dark blue) for peak height, and P < 0.05 for spatial extent]. Overlap maps are also visualized on a rendered brain surface using mri3dX (http://www.cubric.cf.ac.uk/Documentation/mri3dX/), where atrophied regions from the semantic variant PPA < HC3 voxel-based morphometry analysis (Supplementary Fig. 2) are highlighted in yellow. Amy = amygdala; Calc = calcarine; dPI = dorsal posterior insula; FI = frontoinsula; Fus = fusiform; Hes = Heschl's; lOcG = lateral occipital gyrus; MTG = middle temporal gyrus; PCC = posterior cingulate cortex; PCu = precuneus; PHG = parahippocampus; PoCG = postcentral gyrus; PrCG = precentral gyrus; rmPFC = rostral medial prefrontal cortex; STG = superior temporal gyrus.

Figure 3

Local functional activity impairments correlate with semantic deficits. Set I (A, blue) and Set II (B, red) regions of interest were selected from the fractional ALFF semantic variant PPA < HC3 difference map. Mean fractional ALFF values from selected regions of interest were plotted against scores on a semantic processing [Peabody Picture Vocabulary Test (PPVT)]; (C and E) and emotion recognition (TASIT; D and F) task. Significant correlations (P < 0.017, Pearson correlation, Bonferroni-corrected for multiple comparisons) are plotted in black (C and F) and non-significant correlations are plotted in grey (D and E). ACC = anterior cingulate cortex; BOLD = blood oxygen level-dependent; Calc = calcarine; FI = frontoinsula; Fus = fusiform; MTG = middle temporal gyrus.

Figure 4

ATL subregion grey matter atrophy predicts fractional ALFF values within visual versus auditory processing regions. (A) Top: Coronal section through the ATL of the rhesus monkey, showing cytoarchitectural subdivisions [reprinted with permission from Fig. 1 in Morán et al., 1987)]. Tract tracing results suggested that auditory inputs predominate in the dorsolateral part of the temporopolar cortex (blue) whereas visual inputs become more prominent in the ventral ATL (red). TPa-p = temporopolar cortex, agranular periallocortical; TPdg = temporopolar cortex, dysgranular; TPg = temporopolar cortex, granular. Bottom: Human ATL coronal section illustrating parallel cytoarchitectural subdivisions, reprinted (left–right flipped for comparison) with permission from Fig. 9A in Ding et al. (2009). The authors commented (p. 621) that Area TAr is thought to be involved in higher order auditory processing (blue), whereas anterior areas 35, 36, and TE are thought to be involved in high order visual processing (red). TAr = the area rostral to area TA; TAp = the polysensory area in the dorsal bank of the STS; TEd, TEr = dorsal and ventral parts of area TE; TG = the area caps the tip of temporal pole; 35B, 36 = Area 35b and 36 based on Brodmann (Brodmann, 1909). Temporal areas TA and TE are based on Von Ecomono and Koskinas (Von Economo, 1929). Voxel-based regression analyses included (B) primary cortices (calcarine sulcus and Heschl’s gyrus) and (C) sensory association cortices (fusiform and superior temporal gyri). Consistent with connectivity-based predictions, distinct ATL clusters were identified whose grey matter volumes significantly correlated with fractional ALFF values in posterior visual (orange and red) and auditory (blue and purple) processing regions, thresholded at P < 0.01. In the right hemisphere model (A and B, right), more expansive clusters were identified at this threshold for auditory regressors (transparent purple) and were further thresholded at P < 0.005 (solid purple) to illustrate the region of peak significance. Results for left and right hemispheres are labelled in different colour tones.