Task-Free Functional Language Networks: Reproducibility and Clinical Application

Abstract

Intrinsic connectivity networks (ICNs) identified through task-free fMRI (tf-fMRI) offer the opportunity to investigate human brain circuits involved in language processes without requiring participants to perform challenging cognitive tasks. In this study, we assessed the ability of tf-fMRI to isolate reproducible networks critical for specific language functions and often damaged in primary progressive aphasia (PPA). First, we performed whole-brain seed-based correlation analyses on tf-fMRI data to identify ICNs anchored in regions known for articulatory, phonological, and semantic processes in healthy male and female controls (HCs). We then evaluated the reproducibility of these ICNs in an independent cohort of HCs, and recapitulated their functional relevance with a post hoc meta-analysis on task-based fMRI. Last, we investigated whether atrophy in these ICNs could inform the differential diagnosis of nonfluent/agrammatic, semantic, and logopenic PPA variants. The identified ICNs included a dorsal articulatory-phonological network involving inferior frontal and supramarginal regions; a ventral semantic network involving anterior middle temporal and angular gyri; a speech perception network involving superior temporal and sensorimotor regions; and a network between posterior inferior temporal and intraparietal regions likely linking visual, phonological, and attentional processes for written language. These ICNs were highly reproducible across independent groups and revealed areas consistent with those emerging from task-based meta-analysis. By comparing ICNs' spatial distribution in HCs with patients' atrophy patterns, we identified ICNs associated with each PPA variant. Our findings demonstrate the potential use of tf-fMRI to investigate the functional status of language networks in patients for whom activation studies can be methodologically challenging.SIGNIFICANCE STATEMENT We showed that a single, short, task-free fMRI acquisition is able to identify four reproducible and relatively segregated intrinsic left-dominant networks associated with articulatory, phonological, semantic, and multimodal orthography-to-phonology processes, in HCs. We also showed that these intrinsic networks relate to syndrome-specific atrophy patterns in primary progressive aphasia. Collectively, our results support the application of task-free fMRI in future research to study functionality of language circuits in patients for whom tasked-based activation studies might be methodologically challenging.

Keywords: functional connectivity; language networks; primary progressive aphasia; reproducibility; resting-state connectivity.

Figure 1.

Identification and reproducibility of the intrinsic language networks. The seeds used to build the networks are shown in a sagittal view of a standard brain in the MNI space (a). The resulting networks are displayed on a three-dimensional rendering of the Montreal Neurological Institute standard brain at p < 5 × 10⁻⁵ after FWE correction for multiple comparisons at peak level over the whole brain and k > 180 for cluster extent for HC1 (b) and HC2 (c). The significant voxels of each network were binarized and shown in blue (network seeded from the posterior ITG, pITG), yellow (network seeded from the Superior parietal temporal region, Spt), red (network seeded from the opercular IFG, opIFG), and green (network seeded from the anterior MTG, aMTG).

Figure 2.

Spatial distribution of the four task-free networks. Rendered left-hemisphere lateral views of the four ICNs identified through a statistical conjunction of the two groups. Maps were thresholded at the same statistical threshold used to identify the networks for each group separately, binarized and colored using the same color scheme in Figure 1 (blue for the network seeded from the pITG, yellow for the network seeded from the Spt, red for the network seeded from the opIFG, and green for the one seeded from the aMTG). The render at the center of the figure shows that the four networks cover almost the entire left hemisphere with a small degree of overlap.

Figure 3.

Characterization of PPA variants based on the similarity measure between the four ICNs derived from controls and the atrophy maps of PPA patients. The figure shows the similarity matrix obtained from combining the spatial organization of the four ICNs derived from controls and the atrophy maps of PPA patients. It shows a clear identification of nfvPPA/opIFG ICN (red frame), svPPA/aMTG ICN (green frame), and lvPPA/posterior networks (blue, green, and yellow frames) patients, as visible from the similarity values within each of these variants. The sparse representation of similarity values within the group of lvPPA patients, calls for high intersubject variability of the patients affected by this syndrome.

Figure 4.

Task-based derived networks identified through meta-analysis. a, Sagittal slices of the ICNs identified with tf-fMRI and already shown in Figure 2. b, Results of the meta-analysis on task-based fMRI studies using the following terms to create the functional maps: speech production (b–I), speech perception (b–II), semantic memory (b–III), and orthography (b–IV). The functional maps resulting from the meta-analysis using the abovementioned terms recapitulate on the cognitive functions associated to each of the tf-fMRI ICNs.