Functional connectivity of the cortico-subcortical sensorimotor loop is modulated by the severity of nigrostriatal dopaminergic denervation in Parkinson's Disease

Abstract

To assess if the severity of nigrostriatal innervation loss affects the functional connectivity (FC) of the sensorimotor cortico-striato-thalamic-cortical loop (CSTCL) in Parkinson's Disease (PD), Resting-State functional MRI and ¹⁸F-DOPA PET data, simultaneously acquired on a hybrid PET/MRI scanner, were retrospectively analyzed in 39 PD and 16 essential tremor patients. Correlations between posterior Putamen DOPA Uptake (pPDU) and the FC of the main CSTCL hubs were assessed separately in the two groups, analyzing the differences between the two groups by a group-by-pPDU interaction analysis of the resulting clusters' FC. Unlike in essential tremor, in PD patients pPDU correlated inversely with the FC of the thalamus with the sensorimotor cortices, and of the postcentral gyrus with the dorsal cerebellum, and directly with the FC of pre- and post-central gyri with both the superior and middle temporal gyri and the paracentral lobule, and of the caudate with the superior parietal cortex. The interaction analysis confirmed the significance of the difference between the two groups in these correlations. In PD patients, the post-central cortex FC, in the clusters correlating directly with pPDU, negatively correlated with both UPDRS motor examination score and Hoehn and Yahr stage, independent of the pPDU, suggesting that these FC changes contribute to motor impairment. In PD, nigrostriatal innervation loss correlates with a decrease in the FC within the sensorimotor network and between the sensorimotor network and the superior temporal cortices, possibly contributing to motor impairment, and with a strengthening of the thalamo-cortical FC, that may represent ineffective compensatory phenomena.

Fig. 1. Correlations of thalamic FC with pPDU.

Scatterplots for PD (red) and ET (blue) patients of the mean FC of the clusters (highlighted in the inserts on the right, the most affected side is at reader’s left) showing a significant inverse correlation of the thalamic FC (y axis) with pPDU (x axis) in PD patients. For the purposes of the graph, all clusters’ voxels were averaged as all the clusters from this contrast provided substantially overlapping patterns of correlation. FC of the thalamus on the MAS with bilateral rolandic cortices shows an inverse correlation with pPDU in PD patients, with no significant correlations in ET patients in the same regions. For demonstrative purposes, the FC maps at the level of the bilateral sensorimotor cortex of the PD patients at the extreme of the pPDU range are shown. A clear negative thalamic FC in the sensorimotor strips in the PD patient with the highest pPDU can be appreciated.

Fig. 2. Correlations of post-central cortex FC with pPDU.

Scatterplots for PD (red) and ET (blue) patients of the mean FC of the clusters (highlighted in the inserts on the right, the most affected side is at reader’s left) showing a significant correlation of the post-central cortex FC (y axis) with pPDU (x axis) in PD patients. For the purposes of the graph, for each contrast all clusters were averaged as they provided substantially overlapping patterns of correlation. The FC of the post-central cortex on the MAS with the superior/mid temporal gyri and the paracentral lobule shows a significant direct correlation with pPDU in PD patients, with no significant correlation in ET patients in the same regions (a). On the contrary, The FC between the post-central cortex homolateral to the MAS and both thalami and homolateral lobule 6 and crus 1 of the cerebellum decreases with increasing pPDU in PD patients, also in this case without a significant correlation in ET patients (b).

Fig. 3. Correlations of pre-central cortex FC with pPDU.

Scatterplots for PD (red) and ET (blue) patients of the mean FC of the clusters (highlighted in the inserts on the right, the most affected side is at reader’s left) showing a significant correlation of the pre-central cortex FC (y axis) with pPDU (x axis) in PD patients. For the purposes of the graph, for each contrast all clusters were averaged as they provided substantially overlapping patterns of correlation. The FC of the pre-central cortex on the MAS with the homolateral superior/mid temporal gyri and inferior occipital cortex shows a significant direct correlation with pPDU in PD patients, with no significant correlation in ET patients in the same regions (a). On the contrary, The FC of the pre-central cortex on the MAS with the thalami decreased with increasing pPDU in PD patients (b).

Fig. 4. Correlations of post-central cortex FC with pPDU.

Scatterplots for PD (red) and ET (blue) patients of the mean FC of the cluster (highlighted in the inserts on the right, the most affected side is at reader’s left) showing a significant correlation of the caudate FC (y axis) with pPDU (x axis) in PD patients. FC of the caudate on the MAS with the homolateral superior parietal cortex shows an inverse correlation with pPDU in PD patients, with no significant correlation in ET patients in the same regions.

Fig. 5. Correlations of post-central cortex FC with clinical scores.

Scatterplots of the Unified Parkinson’s Disease Rating Scale Motor Examination score (UPDRS-ME, a, p = 0.007) and Hoehn and Yahr stage (H&Y, b, p = 0.002) against the mean FC of the regions where the post-central cortex FC correlates with pPDU (highlighted in the inserts on the right, the most affected side is at reader’s left). For each graph, residuals from the linear regression analysis, following correction for age sex and motion parameters, are plotted. Regression line along with the 95% confidence intervals is superimposed.