Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson’s disease

Li, Weihua; Lao–Kaim, Nicholas P; Roussakis, Andreas–Antonios; Martín-Bastida, Antonio; Valle‐Guzman, Natalie; Paul, Gesine; Soreq, Eyal; Daws, Richard E.; Foltynie, Tom; Barker, Roger A.; Hampshire, Adam; Piccini, Paola

doi:10.1016/j.nicl.2020.102409

Cited by 24 publications

(55 citation statements)

References 50 publications

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“…Thus, in a final step FC values between clusters of dopaminergic deficiency and cortical clusters were subjected to exploratory correlation analyses. In line with previous results, a close relationship between striatal dopaminergic integrity and functional coupling was traceable 41 . Yet, unlike results from Li et al 41 , our approach poses important advantages, insofar as that we could select study-specific dopamine-depleted structures as seeds instead of general presynaptic function.…”

Section: Discussionsupporting

confidence: 91%

“…In line with previous results, a close relationship between striatal dopaminergic integrity and functional coupling was traceable 41 . Yet, unlike results from Li et al 41 , our approach poses important advantages, insofar as that we could select study-specific dopamine-depleted structures as seeds instead of general presynaptic function. Furthermore, we demonstrated a correlation between striatocortical FC and reduced cortical FDG uptake 10 indicating cortical metabolic consequences of reduced coupling to subcortical areas such as the right caudate.…”

Section: Discussionsupporting

confidence: 91%

“…A solid body of literature describes aberrant temporal coupling within striatal structures and with widespread brain regions in PD patients 10 , 18 , 38 , 39 . To the best of our knowledge, the only two longitudinal studies published so far were restricted to one or two modalities and describe abnormal FC in posterior cortical areas 40 and widespread, progressive impairment in coupling of the basal ganglia within the sensorimotor network 41 . In the current study, reduced FC of the posterior putamen to sensorimotor areas at baseline 10 was not only replicable but also showed progression of hypoconnectivity to regions including the supplementary motor area, the precentral gyrus, and the parietotemporal area.…”

Section: Discussionmentioning

confidence: 99%

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Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Steidel

Ruppert

Greuel

et al. 2022

npj Parkinsons Dis.

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The prevailing network perspective of Parkinson’s disease (PD) emerges not least from the ascending neuropathology traceable in histological studies. However, whether longitudinal in vivo correlates of network degeneration in PD can be observed remains unresolved. Here, we applied a trimodal imaging protocol combining 18F-fluorodeoxyglucose (FDG)- and 18F-fluoro-L-Dopa- (FDOPA)-PET with resting-state functional MRI to assess longitudinal changes in midbrain metabolism, striatal dopamine depletion and striatocortical dysconnectivity in 17 well-characterized PD patients. Whole-brain (un)paired-t-tests with focus on midbrain or striatum were performed between visits and in relation to 14 healthy controls (HC) in PET modalities. Resulting clusters of FDOPA-PET comparisons provided volumes for seed-based functional connectivity (FC) analyses between visits and in relation to HC. FDG metabolism in the left midbrain decreased compared to baseline along with caudatal FDOPA-uptake. This caudate cluster exhibited a longitudinal FC decrease to sensorimotor and frontal areas. Compared to healthy subjects, dopamine-depleted putamina indicated stronger decline in striatocortical FC at follow-up with respect to baseline. Increasing nigrostriatal deficits and striatocortical decoupling were associated with deterioration in motor scores between visits in repeated-measures correlations. In summary, our results demonstrate the feasibility of in-vivo tracking of progressive network degeneration using a multimodal imaging approach. Specifically, our data suggest advancing striatal and widespread striatocortical dysfunction via an anterior-posterior gradient originating from a hypometabolic midbrain cluster within a well-characterized and only mild to moderately affected PD cohort during a relatively short period.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Steidel

Ruppert

Greuel

et al. 2022

npj Parkinsons Dis.

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“…Indeed, we found that negative modulation of a connection from SN to putamen was significantly larger during RND compared to SEQ in pwPD, and when compared to RND in controls. Similarly, a recent resting-state functional connectivity study showed that pwPD with greater dopaminergic deficits had decreased connectivity between midbrain and putamen ( Li et al, 2020 ). Thus, we speculate that during implicit learning of a motor sequence, the increased drive to recruit the dysfunctional endogenous nigro-striatal dopaminergic system is reflected by similar modulation of SN to putamen connectivity as in controls.…”

Section: Discussionmentioning

confidence: 93%

Motor Sequence Learning Deficits in Idiopathic Parkinson’s Disease Are Associated With Increased Substantia Nigra Activity

Tzvi

Bey

Nitschke

et al. 2021

Front. Aging Neurosci.

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Previous studies have shown that persons with Parkinson’s disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-thalamo-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however, unsuccessfully. Finally, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differences between the groups were found during sequence learning. We speculate that learning-specific SN recruitment leads to a relative increase in SN- > putamen connectivity, which returns to a pathological reduced state when no learning takes place.

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“…Previous studies of the relationship between nigrostriatal dopaminergic innervation and FC have focused on striatal FC. In particular, the correlation of the nigrostriatal innervation, sampled by the striatal TRODAT-1 binding potential 14 , 11 C-Altropane PET 13 , 11 C-PE2I 20 , or with 18 F-FP-CIT PET 12 , with the FC of the striatum has been previously studied in patients with nigrostriatal dopamine loss. Results showed in de-novo, drug-naive PD patients a direct correlation between the posterior putamen dopaminergic innervation and its FC with the dorsolateral frontal cortex contralateral to the MAS, and with the dorsal cerebellum bilaterally 12 .…”

Section: Discussionmentioning

confidence: 99%

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

Quarantelli

Quattrone

Sarica

et al. 2022

npj Parkinsons Dis.

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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.

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Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson’s disease

Cited by 24 publications

References 50 publications

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

Motor Sequence Learning Deficits in Idiopathic Parkinson’s Disease Are Associated With Increased Substantia Nigra Activity

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

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