We applied a multi-modal imaging approach to examine structural and functional alterations in the default-mode network (DMN) that are associated with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a transitional phase between healthy cognitive aging and dementia. Subjects included 10 patients with probable AD, 11 patients with aMCI, and 12 age- and education-matched normal controls (NC). Whole-brain resting-state functional, diffusion-weighted, and volumetric magnetic resonance imaging (MRI) data as well as 18F-fluorodeoxyglucose-based positron emission tomography (FDG-PET) data were acquired. We carried out resting-state functional MRI-based functional connectivity and diffusion MRI-based structural connectivity analyses using isthmus of the cingulate cortex (ICC) and the subjacent white matter as the seeds. Whole-brain group and region of interest-based analyses demonstrated that AD weakens the structural and functional connections between ICC and other regions within the DMN, consistent with regional reduction of metabolic activity and atrophy within the DMN. A progressive weakening trend of these connections was also observed from NC to aMCI and then AD, although significant differences between aMCI and the other two groups were not found. Overall, based on both FDG-PET and MRI results, the DMN appears to serve as a window to understanding structural and functional brain changes associated with AD and aMCI.

This fMRI/DWI integration study suggests that functional connectivity analysis might be a more sensitive and robust approach in understanding the connectivity between cortical regions, and can be used to improve DWI-based structural connectivity analysis.

Whereas resting state BOLD (blood oxygenation-level dependent) functional MRI (fMRI) has been widely used to assess functional connectivity between cortical regions, the laminar specificity of such measures is poorly understood. This study aims to determine (a) whether the resting state functional connectivity (rsFC) between two functionally related cortical regions varies with depth, (b) the relationship between layer-resolved tactile stimulus-evoked activation pattern and inter-layer rsFC pattern between two functionally distinct but related areas 3b and 1, and (c) the effects of spatial resolution on rsFC measures. We examined the inter-layer rsFC between somatosensory areas 3b and 1 of squirrel monkeys under anesthesia using tactile stimulus-driven and resting state BOLD acquisitions at sub-millimeter resolution. Consistent with previous observations in the areas 3b and 1, we detected robust stimulus-evoked BOLD activations with foci confined mainly to the upper layers (centered at 21% of the cortical depth). By carefully placing seeds in upper, middle and lower layers of areas 3b and 1, we observed strong rsFC between superficial and middle layers of these two areas. The layer-resolved activation patterns in areas 3b and 1 agree with their inter-layer rsFC patterns, and are consistent with the known anatomical connections between layers. In summary, using BOLD rsFC pattern we identified an inter-layer inter-areal microcircuit that shows strong intrinsic functional connections between superficial and middle layer somatosensory areas 3b and 1 of monkeys. RsFC can be used as a robust invasive tool to probe inter-layer cortico-cortical microcircuits.

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