Basal ganglia circuits changes in Parkinson's disease patients

Abstract

Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson's disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects.

Figure 1. GCA results from the left SNc in the resting state

Brain regions receiving significant positive (hot color) or negative (cold color) influences from the left SNc in healthy controls (A), and PD patients (B) in the resting state (one-sample t-test, p < 0.05, FDR corrected). C: Brain regions having significant influences on the left SNc in healthy subjects in the resting state (one-sample t-test, p < 0.05, FDR corrected).

Figure 2. Differences between PD patients and controls, and between on and off state

A: Brain regions receiving significantly increased influences from the left SNc in healthy controls than in PD patients in the resting state (two-sample t-test, p < 0.05, FDR corrected). B: Brain regions receiving significantly increased influences from the left SNc in PD patients when on compared to off in the resting state (paired t-test, p < 0.05, FDR corrected).

Figure 3. The different pattern of connectivity in the SNc in healthy controls and PD patients in the resting state

Red/blue lines indicate positive/negative influences of the SNc with other brain regions. The arrows indicate the directionality of influences between the SNc and other regions. The dotted lines indicate decreased connectivity from the SNc to the corresponding brain regions in PD patients compared to healthy controls. Abbreviations: CMA, cingulate motor area; DLPFC, dorsolateral prefrontal cortex; DMN, default mode network; GPe, external globus pallidus; GPi, internal globus pallidus; M1, primary motor cortex; PMC, premotor cortex; SMA, supplementary motor area; SNc, substantia nigra pars compacta; STN, subthalamic nucleus; TL, temporal lobe. The question mark indicates uncertain brain region.