Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease
Brain Imaging and Behavior
Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamocortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel
... ivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve declare that they have no conflict of interest. Informed Consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance. (Figure 3 , Suppl. Table 1) : Both groups showed functional connectivity overlap during both the resting-state and the task between the caudate seed and inferior prefrontal, anterior cingulate, and temporal brain regions including the insula, anterior entorhinal cortex, and temporopolar areas. Group similarities Group differences (Figure 4, Tables 3 and 4) : During the resting-state, PD showed more connectivity to thalamic and insula regions, and less connectivity to premotor, motor, and somatosensory regions than controls. During task processing, PD exhibited less connectivity to left temporoparietal regions than controls involving among other regions the supramarginal gyrus (SMG) (Figure 4.1) . For task>rest, and when using an uncorrected threshold of p<0.001, PD showed more extended caudate-prefrontal cortical connectivity (Table 3 ) and stronger caudate-precuneus connectivity relative to controls (Table 4 ). Putamen connectivity Group similarities (Figure 3 , Supplement Table 2 ): Both groups showed putamen connectivity to inferior prefrontal, insula, superior temporal and parietal regions during rest, with additional connectivity to premotor and dorsal frontal regions during task processing. (Figure 4, Tables 3 and 4) : During rest, PD showed less putamen connectivity to anterior prefrontal regions than controls (Table 3) . For task>rest, and using an uncorrected p-threshold, interactions indicated that PD, relative to controls, had weaker putamen-dorsal posterior cingulate cortex (dPCC) connectivity and stronger putamenmotor/premotor cortical connectivity (Table 4 ) (Figure 4.2) . Group differences Globus pallidus connectivity Group similarities (Figure 3, Supplementary Table 3) : Testing the functional connectivity of the globus pallidus in PD patients and controls, we found overlapping connectivity for both groups to inferior prefrontal, insula, and entorhinal cortical regions during both rest and task, with additional connectivity to superior and middle temporal regions during rest. Group differences (Figure 4 , Tables 3 and 4): During task processing, PD showed less pallidum-prefrontal cortical connectivity than controls, also including the subgenual cortex and temporopolar area (Table 3) . For task>rest, a significant interaction effect revealed that PD, relative to controls, exhibited weaker pallidum connectivity to inferior prefrontal, anterior cingulate, orbitofrontal, subgenual, and temporal cortices (infPFC), to visual association cortices (VAA) involving fusiform and occipital gyri, and to medial temporal regions including the parahippocampal gyrus, perirhinal and pitiform cortices (Table 4 ) (Figure 4.3) . Thalamus connectivity Group similarities (Figure 3, Supplementary Table 4) : Testing the functional connectivity of the thalamus in PD patients and controls, we found overlapping connectivity for both groups to insula, cingulate, and prefrontal cortices during rest and task. Müller-Oehring et al.