Abstract
Alterations to interactions between networked brain regions underlie cognitive impairment in many neurodegenerative diseases, providing an important physiological link between brain structure and cognitive function. Previous attempts to characterize the effects of Parkinson’s disease (PD) on network functioning using resting-state functional magnetic resonance imaging (rs-fMRI), however, have yielded inconsistent and contradictory results. Potential problems with prior work arise in the specifics of how the area targeted by the diseases (the basal ganglia) interacts with other brain regions. Specifically, current computational models point to the fact that the basal ganglia contributions should be captured with modulatory (i.e., second-order) rather than direct (i.e., first-order) functional connectivity measures. Following this hypothesis, a principled but manageable large-scale brain architecture, the Common Model of Cognition, was used to identify differences in basal ganglia connectivity in PD by analyzing resting-state fMRI data from 111 participants (70 patients with PD; 41 healthy controls) using Dynamic Causal Modeling (DCM). Specifically, the functional connectivity of the basal ganglia was modeled as two second-level, modulatory connections that control projections from sensory cortices to the prefrontal cortex, and from the hippocampus and medial temporal lobe to the prefrontal cortex. We then examined group differences between patients with PD and healthy controls in estimated modulatory effective connectivity in these connections. The Modulatory variant of the Common Model of Cognition outperformed the Direct model across all subjects. It was also found that these second-level modulatory connections had higher estimates of effective connectivity in the PD group compared to the control group, and that differences in effective connectivity were observed for all direct connections between the PD and control groups.We make the case that accounting for modulatory effective connectivity better captures the effects of PD on network functioning and influences the interpretation of the directionality of the between-group results. Limitations include that the PD group was scanned on dopaminergic medication, results were derived from a reasonable but small number of individuals and the ratio of PD to healthy control participants was relatively unbalanced. Future research will examine if the observed effect holds for individuals with PD scanned off their typical dopaminergic medications.
Highlights
Parkinson’s disease (PD) is a neurodegenerative syndrome that targets predominantly dopaminergic neurons in the substantia nigra pars compacta (SNc; Dauer and Przedborski, 2003; Jankovic, 2008)
The lack of effect could be explained by the lower signal-to-noise ratios that are observed in subcortical brain regions in high-density neuroimaging protocols as well as the peculiar BOLD activity of the basal ganglia, which typically spikes in response to reward-signaling events rather than showing sustained spontaneous activity (Delgado, 2007)
Since each region’s activity in Dynamic Causal Modeling (DCM) is affected by the oscillatory regressors as well as the activity of other regions, the lack of effect in the basal ganglia does not compromise the validity of our DCM analysis as long as the rest of the regions of interest (ROIs) show modulation by the oscillatory regressors
Summary
Parkinson’s disease (PD) is a neurodegenerative syndrome that targets predominantly dopaminergic neurons in the substantia nigra pars compacta (SNc; Dauer and Przedborski, 2003; Jankovic, 2008). The second is the Modulatory CMC, which incorporates additional assumptions that capture our modern understanding of the basal ganglia, the brain region associated with the CMC’s procedural memory component This model replaces the direct connection between the BG to the PFC with two second-level, modulatory connections that control projections from the MTL to the PFC and from the SENS to the PFC (see Figure 2A). Both implementations are in principle compatible with the tenets of the CMC (Laird et al, 2017), the use of modulatory connections reflects a contemporary functional interpretation of the role of the basal ganglia; according to this view, the basal ganglia do not directly manipulate the contents of working memory, but rather ‘‘gate’’ (Frank et al, 2004) or ‘‘route’’ (Stocco et al, 2010) information from other areas to the prefrontal cortex. This hypothesis follows from our knowledge that PD restricts the gating of cortical signals to the prefrontal cortex (Albin et al, 1989), which, in DCM, would be reflected in a lower or negative value of the BG modulatory connections
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