Early altered directionality of resting brain network state transitions in the TgF344-AD rat model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in memory loss and cognitive decline. Synaptic dysfunction is an early hallmark of the disease whose effects on whole-brain functional architecture can be identified using resting-state functional MRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of AD's pathophysiology. Methods: Here, we obtained rsfMRI data in the TgF344-AD rat model at the pre- and early-plaque stages. This model recapitulates the major pathological and behavioral hallmarks of AD. We used co-activation pattern (CAP) analysis to investigate if and how the dynamic organization of intrinsic brain functional networks states, undetectable by earlier methods, is altered at these early stages. Results: We identified and characterized six intrinsic brain states as CAPs, their spatial and temporal features, and the transitions between the different states. At the pre-plaque stage, the TgF344-AD rats showed reduced co-activation of hub regions in the CAPs corresponding to the default mode-like and lateral cortical network. Default mode-like network activity segregated into two distinct brain states, with one state characterized by high co-activation of the basal forebrain. This basal forebrain co-activation was reduced in TgF344-AD animals mainly at the pre-plaque stage. Brain state transition probabilities were altered at the pre-plaque stage between states involving the default mode-like network, lateral cortical network, and basal forebrain regions. Additionally, while the directionality preference in the network-state transitions observed in the wild-type animals at the pre-plaque stage had diminished at the early-plaque stage, TgF344-AD animals continued to show directionality preference at both stages. Discussion: Our study enhances the understanding of intrinsic brain state dynamics and how they are impacted at the early stages of AD, providing a nuanced characterization of the early, functional impact of the disease's neurodegenerative process.

Comparison of Resting-State Functional MRI Methods for Characterizing Brain Dynamics.

Resting-state functional MRI (fMRI) exhibits time-varying patterns of functional connectivity. Several different analysis approaches have been developed for examining these resting-state dynamics including sliding window connectivity (SWC), phase synchrony (PS), co-activation pattern (CAP), and quasi-periodic patterns (QPP). Each of these approaches can be used to generate patterns of activity or inter-areal coordination which vary across time. The individual frames can then be clustered to produce temporal groupings commonly referred to as "brain states." Several recent publications have investigated brain state alterations in clinical populations, typically using a single method for quantifying frame-wise functional connectivity. This study directly compares the results of k-means clustering in conjunction with three of these resting-state dynamics methods (SWC, CAP, and PS) and quantifies the brain state dynamics across several metrics using high resolution data from the human connectome project. Additionally, these three dynamics methods are compared by examining how the brain state characterizations vary during the repeated sequences of brain states identified by a fourth dynamic analysis method, QPP. The results indicate that the SWC, PS, and CAP methods differ in the clusters and trajectories they produce. A clear illustration of these differences is given by how each one results in a very different clustering profile for the 24s sequences explicitly identified by the QPP algorithm. PS clustering is sensitive to QPPs with the mid-point of most QPP sequences grouped into the same single cluster. CAPs are also highly sensitive to QPPs, separating each phase of the QPP sequences into different sets of clusters. SWC (60s window) is less sensitive to QPPs. While the QPPs are slightly more likely to occur during specific SWC clusters, the SWC clustering does not vary during the 24s QPP sequences, the goal of this work is to improve both the practical and theoretical understanding of different resting-state dynamics methods, thereby enabling investigators to better conceptualize and implement these tools for characterizing functional brain networks.

Moving beyond the 'CAP' of the Iceberg: Intrinsic connectivity networks in fMRI are continuously engaging and overlapping.

Resting-state functional magnetic resonance imaging is currently the mainstay of functional neuroimaging and has allowed researchers to identify intrinsic connectivity networks (aka functional networks) at different spatial scales. However, little is known about the temporal profiles of these networks and whether it is best to model them as continuous phenomena in both space and time or, rather, as a set of temporally discrete events. Both categories have been supported by series of studies with promising findings. However, a critical question is whether focusing only on time points presumed to contain isolated neural events and disregarding the rest of the data is missing important information, potentially leading to misleading conclusions. In this work, we argue that brain networks identified within the spontaneous blood oxygenation level-dependent (BOLD) signal are not limited to temporally sparse burst moments and that these event present time points (EPTs) contain valuable but incomplete information about the underlying functional patterns. We focus on the default mode and show evidence that is consistent with its continuous presence in the BOLD signal, including during the event absent time points (EATs), i.e., time points that exhibit minimum activity and are the least likely to contain an event. Moreover, our findings suggest that EPTs may not contain all the available information about their corresponding networks. We observe distinct default mode connectivity patterns obtained from all time points (AllTPs), EPTs, and EATs. We show evidence of robust relationships with schizophrenia symptoms that are both common and unique to each of the sets of time points (AllTPs, EPTs, EATs), likely related to transient patterns of connectivity. Together, these findings indicate the importance of leveraging the full temporal data in functional studies, including those using event-detection approaches.

Time-resolved effective connectivity in task fMRI: Psychophysiological interactions of Co-Activation patterns.

Investigating context-dependent modulations of Functional Connectivity (FC) with functional magnetic resonance imaging is crucial to reveal the neurological underpinnings of cognitive processing. Most current analysis methods hypothesise sustained FC within the duration of a task, but this assumption has been shown too limiting by recent imaging studies. While several methods have been proposed to study functional dynamics during rest, task-based studies are yet to fully disentangle network modulations. Here, we propose a seed-based method to probe task-dependent modulations of brain activity by revealing Psychophysiological Interactions of Co-activation Patterns (PPI-CAPs). This point process-based approach temporally decomposes task-modulated connectivity into dynamic building blocks which cannot be captured by current methods, such as PPI or Dynamic Causal Modelling. Additionally, it identifies the occurrence of co-activation patterns at single frame resolution as opposed to window-based methods. In a naturalistic setting where participants watched a TV program, we retrieved several patterns of co-activation with a posterior cingulate cortex seed whose occurrence rates and polarity varied depending on the context; on the seed activity; or on an interaction between the two. Moreover, our method exposed the consistency in effective connectivity patterns across subjects and time, allowing us to uncover links between PPI-CAPs and specific stimuli contained in the video. Our study reveals that explicitly tracking connectivity pattern transients is paramount to advance our understanding of how different brain areas dynamically communicate when presented with a set of cues.