Investigating Focal Connectivity Deficits in Alzheimer's Disease Using Directional Brain Networks Derived from Resting-State fMRI

Abstract

Connectivity analysis of resting-state fMRI has been widely used to identify biomarkers of Alzheimer's disease (AD) based on brain network aberrations. However, it is not straightforward to interpret such connectivity results since our understanding of brain functioning relies on regional properties (activations and morphometric changes) more than connections. Further, from an interventional standpoint, it is easier to modulate the activity of regions (using brain stimulation, neurofeedback, etc.) rather than connections. Therefore, we employed a novel approach for identifying focal directed connectivity deficits in AD compared to healthy controls. In brief, we present a model of directed connectivity (using Granger causality) that characterizes the coupling among different regions in healthy controls and Alzheimer's disease. We then characterized group differences using a (between-subject) generative model of pathology, which generates latent connectivity variables that best explain the (within-subject) directed connectivity. Crucially, our generative model at the second (between-subject) level explains connectivity in terms of local or regionally specific abnormalities. This allows one to explain disconnections among multiple regions in terms of regionally specific pathology; thereby offering a target for therapeutic intervention. Two foci were identified, locus coeruleus in the brain stem and right orbitofrontal cortex. Corresponding disrupted connectivity network associated with the foci showed that the brainstem is the critical focus of disruption in AD. We further partitioned the aberrant connectomic network into four unique sub-networks, which likely leads to symptoms commonly observed in AD. Our findings suggest that fMRI studies of AD, which have been largely cortico-centric, could in future investigate the role of brain stem in AD.

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

“…Other methods such as Granger Causality can identify directional functional interactions, whereby activity in one region precedes activity in another. Using this method, one study identified the LC as the node of functional connectivity deficits in AD patients ( Zhao et al, 2017 ). These deficits were shown to culminate in the orbitofrontal cortex, taking multiple routes through the working memory, emotional memory, and language system circuits.…”

Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases—An Overview of Imaging Studies

“…The LC undergoes early and significant deterioration and recent imaging studies suggest LC functional dysconnectivity that involves brain regions other than the hippocampus in AD. A recent work employed Granger causality mapping to create a model of directed connectivity and characterized regional functional coupling in AD and healthy controls (Zhao S. et al, 2017 ). With group differences determined with a generative model of pathology, the authors identified the LC and right orbitofrontal cortex as the two foci of disruption in AD.…”

Mild cognitive impairment in de novo Parkinson's disease: A neuromelanin MRI study in locus coeruleus

“…Decreased volume, cell loss and aggregation of tau protein in the LC of Alzheimer's disease (AD) patients have been widely reported . Resting‐state functional MRI revealed that 2 foci, the LC and orbitofrontal cortex, were affected in AD . The connectivity between the LC and parahippocampal gyrus was reduced in patients with MCI due to AD compared with that in healthy controls .…”