Resting state functional connectivity of the striatum in Parkinson's disease

Abstract

Classical accounts of the pathophysiology of Parkinson's disease have emphasized degeneration of dopaminergic nigrostriatal neurons with consequent dysfunction of cortico-striatal-thalamic loops. In contrast, post-mortem studies indicate that pathological changes in Parkinson's disease (Lewy neurites and Lewy bodies) first appear primarily in the lower brainstem with subsequent progression to more rostral parts of the neuraxis. The nigrostriatal and histological perspectives are not incompatible, but they do emphasize different anatomical structures. To address the question of which brain structures are functionally most affected by Parkinson's disease, we performed a resting-state functional magnetic resonance imaging study focused on striatal functional connectivity. We contrasted 13 patients with advanced Parkinson's disease versus 19 age-matched control subjects, using methodology incorporating scrupulous attention to minimizing the effects of head motion during scanning. The principal finding in the Parkinson's disease group was markedly lower striatal correlations with thalamus, midbrain, pons and cerebellum. This result reinforces the importance of the brainstem in the pathophysiology of Parkinson's disease. Focally altered functional connectivity also was observed in sensori-motor and visual areas of the cerebral cortex, as well the supramarginal gyrus. Striatal functional connectivity with the brainstem was graded (posterior putamen > anterior putamen > caudate), in both patients with Parkinson's disease and control subjects, in a manner that corresponds to well-documented gradient of striatal dopaminergic function loss in Parkinson's disease. We hypothesize that this gradient provides a clue to the pathogenesis of Parkinson's disease.

Figure 1

Striatal seed regions of interest defined in a representative control subject. Region of interest boundaries were manually traced on T₁-weighted images using Analyze 8.5 as illustrated in the left and middle panels. The boundary between anterior and posterior putamen was taken to be the posterior aspect of the fornix. Brain left is shown on the image left. Six regions of interest were defined in each subject: left caudate (red), left anterior putamen (green), left posterior putamen (yellow), right caudate (dark blue), right anterior putamen (pink) and right posterior putamen (light blue). The right panel shows a 3D rendering of the same regions of interest generated using 3D Slicer (http://www.slicer.org).

Figure 2

Striatal functional connectivity [z(r) maps] averaged over subjects in the control (left) and Parkinson’s disease groups (right). Each row corresponds to a distinct striatal seed region of interest. Warm and cool colours represent positive and negative correlations. The underlying image is the study-specific atlas template (see ‘Materials and methods’ section). The Talairach atlas plane of section is indicated under each column. The z, y and x correspond, respectively, to axial, coronal and sagittal sections. Similar z(r) maps obtained with right hemisphere striatal seeds are shown in Supplementary Fig. 3. Arrows (control group left anterior putamen map) indicate the supramarginal gyrus bilaterally (Talairach coordinates: ±55.5, −42, +27); seeds centred on these coordinates were used to obtain the results shown Fig. 5. Letters identify local resting-state functional connectivity MRI peaks: a = sensori-motor cortex, b = fronto-polar cortex, c = anterior cingulate cortex, d = supramarginal gyrus, e = visual cortex, f = subgenual prefrontal cortex, g = thalamus, h = midbrain, i = pons and j = cerebellum. LaP = left anterior putamen; LC = left caudate; LpP = left posterior putamen; PD = Parkinson’s disease.

Figure 3

Random effects analysis contrasting the control versus Parkinson’s disease groups. The mapped quantity is the Gaussianized t-statistic (Z-score) thresholded at |Z| > 2.6. All illustrated clusters are significant at the P = 0.05 level (Supplementary material). Left caudate, left anterior putamen and left posterior putamen as in Fig. 2. Warm colours indicate more positive correlations in the control group. Cool colours indicate more negative correlations in the control group. Similar results obtained with right hemisphere striatal seeds are shown in Supplementary Fig. 4. LaP = left anterior putamen; LC = left caudate; LpP = left posterior putamen; PD = Parkinson's disease.

Figure 4

(A) Striatal functional connectivity with the extended brainstem. Fisher z-transformed correlations [z(r)] were evaluated in each individual by averaging over extended brainstem voxels showing a significant group effect (Fig. 3). Bar height indicates the group mean. Error bars indicate the standard error of the mean. Left caudate, left anterior putamen and left posterior putamen as in Figs 2 and 3. Right caudate, right anterior putamen and right posterior putamen indicate corresponding seed regions of interest in the right hemisphere. Note graded (caudate < anterior putamen < posterior putamen) extended brainstem correlations in both groups and systematically more negative correlations in the Parkinson’s disease group. (B) Individual striatum:extended brainstem functional connectivity [z(r)] averaged over all six striatal seeds versus UPDRS III scores in each patient; z(r) values are plotted relative to the mean obtained in the control group. LaP = left anterior putamen; LC = left caudate; LpP = left posterior putamen; PD = Parkinson's disease; RaP = right anterior putamen; RC = right caudate; RpP = right posterior putamen.

Figure 5

Group-averaged z(r) maps obtained with seed regions of interest in the supramarginal gyrus (supramarginal gyrus) of each hemisphere. The seeds were defined as 7-mm radius spheres centred on the paired posterior positive foci in the control group left anterior putamen result shown in Fig. 2 (z = 27). (A) Results obtained in the control group. Positive correlations correspond to the ventral attention network. Generally, symmetric maps and comparable results were obtained with supramarginal gyrus seeds in either hemisphere. (B) Results obtained in the Parkinson’s disease (PD) group. For the left supramarginal gyrus seed, reduced correlation magnitude in the Parkinson’s disease group without major difference in topography; for the right supramarginal gyrus seed, major reorganization in the Parkinson’s disease group. (C) Cluster-wise significant (P < 0.05) group contrast effects; conventions as in Fig. 3. Only the right supramarginal gyrus seed showed significant clusters in the control group versus the Parkinson’s disease group. (D) Left: (patient with Parkinson’s disease − control mean) supramarginal gyrus:caudate blood oxygen level-dependent correlation versus UPDRS III limb score asymmetry. Each hemisphere is plotted separately. Right: Right (Parkinson’s disease − control mean) − Left (Parkinson’s disease − control mean) supramarginal gyrus:caudate correlations versus UPDRS III limb score asymmetry.

Figure 6

Correlation histograms of group-averaged z(r) values compiled over all voxels in the brain. Selected subregions of the brain, shown at the right, are colour-coded: yellow = extended brainstem (EBS), green = combined sensori-motor (SM) and visual (Vis) areas and orange = prefrontal region of increased caudate correlations in the Parkinson’s disease group. The coloured partition of each histogram represents voxels in the corresponding subregion. The remaining voxels are grey. Abrupt partition boundaries (arrows) are a consequence of the thresholding procedure used to define the subregions. Histogram SDs (group means of SD measured in individuals) are indicated in inset text. Statistical significance of control minus Parkinson’s disease histogram SD (width) was assessed by permutation resampling. The posterior putamen histogram was significantly more narrow in the Parkinson’s disease group (P < 0.05 ÷ 3 comparisons). The anterior putamen histogram was narrower in the Parkinson’s disease group (P < 0.05 uncorrected). The caudate histogram was broader (not significant); left caudate, left anterior putamen and left posterior putamen are as in Figs 2–4. The bottom row shows control minus Parkinson’s disease difference histograms. Note the substantially similar difference histograms across striatal seed regions of interest. PD = Parkinson's disease.

Figure 7

Schematized version of Fig. 6. Extended brainstem (EBS, yellow), cortex subregion (blue) and remaining (grey) voxels are modelled as Gaussian distributions. Top (control group): putamen:extended brainstem correlations are more positive than putamen:cortex correlations; caudate:extended brainstem correlations are less positive than caudate:cortex correlations. Middle (Parkinson’s disease group): striatal:extended brainstem and striatal:cortex correlation are identically shifted in both caudate and putamen relative to the control group. This shift causes putamen:extended brainstem and putamen:cortex correlations to be centred on zero, narrowing the putamen histrogram, whereas the caudate distribution becomes broader. Bottom: histogram of control minus Parkinson’s disease differences is the same for caudate and putamen. PD = Parkinson's disease.