Making the connection: Methods to infer functional connectivity in brain studies

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In Parkinson's disease (PD), a common neurodegenerative disorder, there is discordance between brain cell loss and clinical disability because substantial compensatory mechanisms occur in PD, minimizing overall impairment. Thus measures of altered brain activity in PD are a product of both disease and compensatory processes, and disentangling these effects, while vital for understanding the mechanisms of disability, remains a challenge. As there is increasing evidence that normal and diseased brain functioning differ by altered patterns of dynamic connectivity between brain regions, it is critical to develop models assessing connectivity  using current technologies available for non-invasively assessing PD subjects, i.e. fMRI and EEG. Our specific aims are to isolate disease effects from compensatory mechanisms and to determine the effects of medication (L-Dopa) in PD across 3 main domains: Connectivity, Spatial Extent of Activity, and Temporal Dynamics. This joint initiative between UBC, SFU and UNC represents a new collaboration between clinician-scientists treating and performing fMRI research in PD (Drs. McKeown and Huang); scientists with expertise in brain segmentation and shape analysis (Drs. Abugharbieh and Beg), as well as network modeling & statistical inference (Dr. Wang).  The proposed research consists of the following technical components: 1.) Extend the newly developed dynamic causal models (DCM) for brain effective connectivity; 2.) Provide quantitative analysis of the spatial characteristics of fMRI activation; 3.) Determine the sensitivity of network models to mis-specification of manually-drawn regions of interest; and 4.) Expand Blind Source Separation (BSS) methods to the EEG data to infer transient synchronization between brain areas. This cross-disciplinary research effort has significant impact because it will advance understanding of both disease progression and the compensatory changes, and the developed methods will be widely applicable to other brain diseases.  Also, the Canadian pharmaceutical industry would substantially benefit from a means to differentiate between neuroprotective and symptomatic effects of novel therapies.