Altered effective connectivity within the language network in primary progressive aphasia

Abstract

Primary progressive aphasia (PPA) is a neurodegenerative dementia syndrome principally characterized by the gradual dissolution of language functions, especially in the early stages of disorder. In a previous functional neuroimaging study, PPA patients were found to activate core language areas similarly to control subjects when performing semantic and phonological processing tasks (Sonty et al., 2003). In the present study, functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) were used to study multiregional effective connectivity in early-stage PPA (n = 8) and control (n = 8) subjects performing semantic word matching and visual letter matching tasks. fMRI analysis showed semantic task-specific activations in the left inferior frontal (Broca's area) and posterior superior temporal (Wernicke's area) regions, in addition to other language regions, in both groups. Using a model language network consisting of six left hemisphere regions, the DCM analysis demonstrated reduced language-specific effective connectivity between Wernicke's and Broca's areas in the PPA patient group. Furthermore, this decrement in connectivity was predictive of semantic task accuracy. These results demonstrate for the first time that dysfunctional network interactions (effective connectivity), rather than hypoactivity within individual brain regions, may contribute to the emergence of language deficits seen in PPA.

Figures

Figure 1.

Task paradigm. Subjects were instructed to respond to matching stimuli (arrows) but not to nonmatching stimuli (crosses) for the SYN (semantic task) and LETTER (visual task) conditions.

Figure 2.

Task performance results. Reaction times (in milliseconds) (a) and percentage accuracy (b) for the PPA patients and control subjects for the SYN (semantic task) and LETTER (visual task) conditions, with significant differences (p < 0.05) between the two groups indicated by an asterisk. Error bars indicate SEM.

Figure 3.

fMRI results. Brain activations for control subjects and PPA patients specific for the semantic task (SYN–LETTERS contrast). Both groups showed similar left-lateralized patterns of activation in inferior frontal gyrus, temporoparietal cortex, and anterior cingulate/supplementary motor cortex (not pictured). Also shown is brain activation for PPA > controls for the SYN–LETTERS contrast in left premotor cortex. Activations shown are significant at p > 0.05, corrected.

Figure 4.

Subject-specific network regions of interest. Left hemisphere regions were selected based on suprathreshold activation for the main effect of SYN and/or the SYN > LETTER contrast. Consensus maxima were obtained for the group of control subjects (black dots), and individually obtained from each subject within 15 mm of the consensus maximum. Note: Adjoining dots for fusiform and superior temporal foci are separated by 20 mm in the x direction.

Figure 5.

Model network of interregional connections and experimental inputs. Chosen and alternate network models for DCM model comparison are shown. Regions were connected with stimulus inputs entering fusiform (FUS) and parietal (iPS) visual processing streams. Models assumed unidirectional inputs from FUS and iPS to all other regions. The red arrows and arrowheads highlight defining organizational features for each network model: Chosen Model, Inputs from all other regions converge onto sTS and iFG; Alternate Model 1, all other regions are bidirectionally connected; Alternate Model 2, posterior regions (iPL, sTS) send unidirectional input to anterior regions (PRE, iFG); and Alternate Model 3, regions are connected in separate streams between iPL and PRE, and between sTS and iFG. Alternate Model 4 is a fully interconnected network. Task-specific modulatory effects were assessed at every interregional connection for the chosen model. SYN, Semantic task input; LET, visual task input.

Figure 6.

Connections with significant task-specific modulation in controls (a) and PPA patients (b) (p < 0.05, corrected). Numerical values represent a subtraction between the SYN and LETTER modulatory effects at each connection.

Figure 7.

Significant reduction in task-specific modulation in PPA patients seen for the forward connection from posterior superior temporal sulcus (in the classical Wernicke's area) to inferior frontal gyrus (in the classical Broca's area); p < 0.05, corrected on two-sample t test comparisons. The value shown is the p value for the between-group comparison.

Figure 8.

Semantic task accuracy as a function of the modulation of the forward connection from Wernicke's area (posterior sTS) to Broca's area (iFG) by semantic task context in PPA patients (dots) (a) and control subjects (diamonds) (b). r2, Regression coefficient (significant at p < 0.05). No other connections were significant predictors of semantic task accuracy in either group.