Functional connectivity in the basal ganglia network differentiates PD patients from controls

Abstract

Objective: To examine functional connectivity within the basal ganglia network (BGN) in a group of cognitively normal patients with early Parkinson disease (PD) on and off medication compared to age-and sex-matched healthy controls (HC), and to validate the findings in a separate cohort of participants with PD.Methods: Participants were scanned with resting-state fMRI (RS-fMRI) at 3T field strength.Resting-state networks were isolated using independent component analysis. A BGN template was derived from 80 elderly HC participants. BGN maps were compared between 19 patients with PD on and off medication in the discovery group and 19 age-and sex-matched controls to identify a threshold for optimal group separation. The threshold was applied to 13 patients with PD (including 5 drug-naive) in the validation group to establish reproducibility of findings.Results: Participants with PD showed reduced functional connectivity with the BGN in a wide range of areas. Administration of medication significantly improved connectivity. Average BGN connectivity differentiated participants with PD from controls with 100% sensitivity and 89.5% specificity. The connectivity threshold was tested on the validation cohort and achieved 85% accuracy. Conclusions:We demonstrate that resting functional connectivity, measured with MRI using an observer-independent method, is reproducibly reduced in the BGN in cognitively intact patients with PD, and increases upon administration of dopaminergic medication. Our results hold promise for RS-fMRI connectivity as a biomarker in early PD. Classification of evidence:This study provides Class III evidence that average connectivity in the BGN as measured by RS-fMRI distinguishes patients with PD from age-and sex-matched controls. Functional changes in the basal ganglia (BG) lie at the heart of Parkinson disease (PD). fMRI employing motor tasks has identified abnormalities in BG and supplementary motor area. 1,2However, interpretation of those changes may be confounded by the fact that patients with PD have difficulty with performing motor tasks. Resting-state fMRI can overcome this problem by providing an index of activity across the whole brain while the participant is at rest. Independent component analysis (ICA) enables isolation of resting-state brain networks, where individual areas in a given network show tight functional connectivity.3 Recent studies demonstrated effectiveness of this technique in identifying changes in the default mode network 4,5 and sensorimotor network 6 in PD. Although ICA-derived BG network (BGN) has been reliably identified in other disease states, 7-9 to our knowledge, no study so far has investigated it in PD.

Increased connectivity between sensorimotor and attentional areas in Parkinson’s disease

“…Our study uses an unbiased, data-driven approach based on ICA that can emphasize broader changes in functional connectivity not restricted to a set of predefined seeds. Other important studies employing ICA [8,15,22,23] have been already published. The advantage of our analysis approach is that it evaluates connectivity changes in all neural networks not just in a preselected few (1 to maximum 5 networks) [8,15,22,23].…”

“…Previous studies experimented with different ICA dimensionalities and found that 50 is the minimum number of components necessary to separate known networks, in particular for separating the basal ganglia network from the sensorimotor and salience networks [23]. Another study suggested a minimum of 60 components in order to detect motor, language, and working memory networks [56].…”

“…The third hierarchical cluster (green lines) contained motor components (8,19,22,23) along with a basal ganglia component (component 15) which is known, from task-related fMRI studies [54,55], to be involved in motor and sensory processes. The basal ganglia network (component 15) seems to be mainly related to the prefrontal cortex (component 13) into a potential cortico-striato-thalamic circuit.…”

“…However, these studies have analyzed a limited number of networks: either a single network-sensorimotor [22] or basal ganglia [23], three networks involved in cognitive processing [8], or at most five networks-cognitive/visual [15]. Therefore, existing studies were mainly restricted to a small number of specific networks.…”

“…To the best of our knowledge, our study is the first to use a high number of ICA maps to investigate both intra-and internetworks connectivity in Parkinson's disease, in an effort to find rs-fMRI biomarkers for PD-an objective that remains challenging, even with the significant efforts made worldwide [8,23].…”