Functional neural circuits that underlie developmental stuttering

Abstract

The aim of this study was to identify differences in functional and effective brain connectivity between persons who stutter (PWS) and typically developing (TD) fluent speakers, and to assess whether those differences can serve as biomarkers to distinguish PWS from TD controls. We acquired resting-state functional magnetic resonance imaging data in 44 PWS and 50 TD controls. We then used Independent Component Analysis (ICA) together with Hierarchical Partner Matching (HPM) to identify networks of robust, functionally connected brain regions that were highly reproducible across participants, and we assessed whether connectivity differed significantly across diagnostic groups. We then used Granger Causality (GC) to study the causal interactions (effective connectivity) between the regions that ICA and HPM identified. Finally, we used a kernel support vector machine to assess how well these measures of functional connectivity and granger causality discriminate PWS from TD controls. Functional connectivity was stronger in PWS compared with TD controls in the supplementary motor area (SMA) and primary motor cortices, but weaker in inferior frontal cortex (IFG, Broca's area), caudate, putamen, and thalamus. Additionally, causal influences were significantly weaker in PWS from the IFG to SMA, and from the basal ganglia to IFG through the thalamus, compared to TD controls. ICA and GC indices together yielded an accuracy of 92.7% in classifying PWS from TD controls. Our findings suggest the presence of dysfunctional circuits that support speech planning and timing cues for the initiation and execution of motor sequences in PWS. Our high accuracy of classification further suggests that these aberrant brain features may serve as robust biomarkers for PWS.

Fig 1. Activity in each of the 12 clusters of reproducible independent components.

The first three columns display the random-effect group activity maps detected from the 44 PWS. The first column is a coronal view, the second is a sagittal view, and the third is an axial view. The last three columns displays the group activity maps detected from the 50 TD controls. Each row displays one group activity map generated by applying a one-sample t-test to 1 of the 12 clusters of independent components. Any two group activity maps within the same row across the first three and second three columns are significantly similar to one another in their spatial configurations. PMC = primary motor cortex; SMA = supplementary motor cortex; IFG = inferior frontal gyrus; PSC = primary somatosensory cortex; ACC = anterior cingulate cortex; STG = superior temporal gyrus; IPL = inferior parietal lobule; PCC = posterior cingulate cortex.

Fig 2. Comparisons of neural connectivity between PWS and normal controls (PWS vs. controls).

The two sets of three columns display t-contrast maps comparing the group activity maps from the PWS and TD control participants. The images show that functional connectivity was greater in PWS compared with normal control participants in the SMA and PMC (shown in red), but their functional connectivity was weaker in the IFG, caudate, putamen, and thalamus (shown in blue). PMC = primary motor cortex; SMA = supplementary motor cortex; IFG = inferior frontal gyrus.

Fig 3. Correlation of z-score for Blood-Oxygen-Level-Dependent (BOLD) activity, an fMRI index of neural activity, in the independent component from the left Inferior Frontal Gyrus (IFG, Broca’s area) with the severity of stuttering symptoms in PWS (z-transformed total score in the ACES and OASES self-report measures).

BOLD correlated inversely with symptom severity, indicating that greater neural activity accompanied less severe symptoms across PWS participants.

Fig 4. Diagram showing the significant interregional causal connections as estimated by the Granger Causality Index (GCI) and the comparison of GCIs between the PWS and normal control participants (as shown by the corresponding z-score).

Red lines represent causal influences from region X to region Y. Yellow lines represent up causal influence from region X to region Y via the thalamus. The arrowhead shows the direction of each causal influence. The z-score indicates the group difference in GCIs between PWS and Controls. Only significant connections are shown.