Aging-Dependent Loss of Connectivity in Alzheimer's Model Mice with Rescue by mGluR5 Modulator.

Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD ( App NL-G-F /hMapt ), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.

Multimodal measures of spontaneous brain activity reveal both common and divergent patterns of cortical functional organization.

Large-scale functional networks have been characterized in both rodent and human brains, typically by analyzing fMRI-BOLD signals. However, the relationship between fMRI-BOLD and underlying neural activity is complex and incompletely understood, which poses challenges to interpreting network organization obtained using this technique. Additionally, most work has assumed a disjoint functional network organization (i.e., brain regions belong to one and only one network). Here, we employed wide-field Ca2+ imaging simultaneously with fMRI-BOLD in mice expressing GCaMP6f in excitatory neurons. We determined cortical networks discovered by each modality using a mixed-membership algorithm to test the hypothesis that functional networks are overlapping rather than disjoint. Our results show that multiple BOLD networks are detected via Ca2+ signals; there is considerable network overlap (both modalities); networks determined by low-frequency Ca2+ signals are only modestly more similar to BOLD networks; and, despite similarities, important differences are detected across modalities (e.g., brain region "network diversity"). In conclusion, Ca2+ imaging uncovered overlapping functional cortical organization in the mouse that reflected several, but not all, properties observed with fMRI-BOLD signals.

Ten simple rules for predictive modeling of individual differences in neuroimaging.

Establishing brain-behavior associations that map brain organization to phenotypic measures and generalize to novel individuals remains a challenge in neuroimaging. Predictive modeling approaches that define and validate models with independent datasets offer a solution to this problem. While these methods can detect novel and generalizable brain-behavior associations, they can be daunting, which has limited their use by the wider connectivity community. Here, we offer practical advice and examples based on functional magnetic resonance imaging (fMRI) functional connectivity data for implementing these approaches. We hope these ten rules will increase the use of predictive models with neuroimaging data.