Intrinsic connectivity network disruption in progressive supranuclear palsy

Abstract

Objective: Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.

Methods: Using task-free functional magnetic resonance imaging, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region that shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity.

Results: Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletomotor, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within corticosubcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores.

Interpretation: This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.

Copyright © 2012 American Neurological Association.

Figures

Figure 1. The dMT-associated ICN

The dMT was used as a seed ROI for voxel-wise task-free fMRI analyses in healthy young (HC1, upper row) and older (HC2, middle row) controls. Results are displayed at height threshold p

Figure 2. Network connectivity reductions in PSP

Examining the same dMT-associated ICN shown in Figure 1, we found connectivity reductions in PSP distributed throughout the network. Results are displayed at p

Figure 3. The broader PSP-related network in health and disease

Regions showing intrinsic connectivity to the dMT in the HC2 group were isolated (A, Supplementary Figure 1, Supplementary Table 2) and used to generate matrices representing the connectivity strength between each ROI pair for HC2 (B), HC3 (C), and PSP (D). Color bars in B–D indicate the Pearson correlation coefficients (r) derived for each node pair transformed to z-scores. In (E), the node pair matrix highlights those pairs showing significant connectivity reduction in PSP vs. HC3, corrected at the matrix level for false discovery rate to produce a p < 0.05 (z ≥ 2.21). The color bar indicates the z-scores derived from the two-sample t-test (PSP < HC3). Colored node pairs indicate significant reductions. aINS, anterior insula; BG, basal ganglia; cPONS, caudal pons; MFG, middle frontal gyrus; MTJ, mesothalamic junction; pMCC, posterior midcingulate cortex; PreCu, precuneus; rPONS, rostral pons; RSC, retrosplenial cortex; SMG, supramarginal gyrus. Other abbreviations as in Figures 1 & 2.

Figure 4. The matrix-derived dMT-associated ICN architecture and connectivity reductions in PSP

An edge-weighted force-directed algorithm was used to display the relationships among network nodes in the healthy brain (HC2 data). Heuristically, nodes clustered together represent more closely related subnetworks and nodes placed centrally within the overall graph have stronger, more numerous edges characteristic of central hubs. Node diameter represents node total flow, whereas edge thickness represents the correlation coefficient of the node pair connected by that edge transformed to z-scores. To overlay PSP-related deficits on the healthy brain graph, nodes were colored by the t-score resulting from the two-sample t-test for node total flow (PSP

Figure 5. Clinical Correlations to dMT-associated ICN Score

Scatterplots represent the relationships between mean network connectivity and CDR sum of boxes score, PSPRS, and downward saccade velocity. The dMT-associated ICN score was calculated as each subject’s mean beta value across all voxels within their dMT-associated ICN map, masked by the ICN as defined in HC2 subjects (see Methods). Circles represent PSP subjects; the one filled circle indicates an outlier excluded from the CDR and PSPRS correlation analyses but included in the downward saccade velocity correlation analysis, in which she was not an outlier. For comparison, the empty triangle represents the mean dMT-associated ICN score for matched control subjects (HC3).

Figure 6. Effect size comparison of dMT associated ICN reductions versus grey matter atrophy in patients with PSP-S compared to matched controls

Upper row: We compared voxel-wise PSP-S