Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease

Introduction: Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in separate PD cohorts, indexing dopamine-dependent changes in large-scale brain network dynamics and its implications in clinical features. Methods: We pooled data from two cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) SPECT were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-PET imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. Results: In both cohorts, dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state (X2(1, N=79) = 5.82, p= 0.016) and a lower number of transitions (U(N=79) = 337.5, z = -2.06 p= .039) than controls. Significantly, worse motor scores (UPDRS-III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state (UPDRS-III: τb(N=63) = -.281; p =.003, DaT putamen: τb(N=63)=.213, p= .023, DaT caudate: τb(N=63)=.209, p= .025) and a low total number of transitions (UPDRS-III: τb(N=63)= -.308; p = .001, DaT putamen: τb(N=63)=.350, p<.001, DaT caudate: τb(N=63)=.251, p=.007). Additionally, worse motor performance was associated with a low number of bi-directional transitions between the GI and the lesser connected (LC) state (τb(N=63)= -.237; p =.019). These results could not be reproduced in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity or clinical measure were observed. Conclusion: In early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to depend on striatal dopamine availability. Notably, we obtained these results in only one cohort, but not in a replication sample. ### Competing Interest Statement AA reports no conflicts of interest. MH reports receiving research funding from the German Research Foundation (DFG). T. van Eimeren received honoraria, stipends or speaker fees from the Lundbeck Foundation, Gain Therapeutics, Orion Pharma, Lundbeck Pharma, Atheneum, and the International Movement Disorders Society. He receives materials from Life Molecular Imaging and Lilly Pharma. He owns stocks of the corporations NVIDIA, Microsoft and I.B.M. GRF serves as an editorial board member of Cortex, Neurological Research and Practice, NeuroImage: Clinical, Zeitschrift fuer Neuropsychologie, DGNeurologie, and Info Neurologie & Psychiatrie; receives royalties from the publication of the books Funktionelle MRT in Psychiatrie und Neurologie, Neurologische Differentialdiagnose, and SOP Neurologie; receives royalties from the publication of the neuropsychological tests KAS and Koepps; received honoraria for speaking engagements from Deutsche Gesellschaft fuer Neurologie (DGN) and Forum fuer medizinische Fortbildung FomF GmbH.