1166
Symposium
A comprehensive and pragmatic approach to examining the intrinsic organization and intercommunication of brain regions involves the utilization of resting-state functional magnetic resonance imaging (rsfMRI). Typically, rsfMRI data is analyzed by quantifying the extent of synchrony among functionally related regions, which is interpreted as a measure of functional connectivity (FC) between various brain areas. Significant research on rsfMRI networks has elucidated the relationship between patterns of intrinsic brain activity, functional connectivity, cognitive function, and behavior. However, the interpretation of FC networks derived from rsfMRI studies is constrained by the reliance of fMRI signals on hemodynamic changes as proxies for neural activity. Consequently, our inability to accurately interpret and physiologically decode the mechanisms underlying interareal fMRI ultimately limits the impact of this research.
Many key questions relating to the fundamental principles of rsfMRI connectivity remain unanswered but can be addressed in mechanistic studies that probe specific aspects of FC. Pre-clinical fMRI studies paired with additional recording modalities and manipulations have proven to be indispensable for adding to our understanding of the underlying mechanisms driving rsfMRI FC.
This symposium aims to present modern techniques and findings to the OHBM community regarding pre-clinical fMRI’s role in understanding the mechanism of rsfMRI. This topic is of broad interest and benefits cognitive neuroscientists and researchers focused on functional networks in both healthy and diseased brains. The presented results will highlight the nuances of neurovascular coupling which ultimately influences the interpretation of derived hemodynamic functional networks, their dynamics, and the neural underpinnings they represent.
1. Audience members should be able to compare and contrast the presented techniques (fMRI, optical imaging, optogenetics, hemogenetics), including the knowledge yielded from each technique’s use.
2. Audience members should have a thorough understanding of what functional connectivity is, and how it can be interpreted across techniques.
The target audience for this symposium will likely be individuals with varying levels of experience or expertise with functional connectivity and possibly method(s) that utilize functional connectivity. The first talk will attempt to provide any necessary background for anyone who is less knowledgeable about the topic, to better set up the following presentations.
Presentations
Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has revolutionized our understanding of the brain activity landscape, bridging circuit neuroscience in animal models with noninvasive brain mapping in humans. This immensely utilized technique, however, faces challenges such as acoustic noise, electromagnetic interference, motion artifacts, magnetic-field inhomogeneity, and limitations in sensitivity and specificity. A solution addressing these issues would be transformative for mapping functional connectivity. Here, we introduce Steady-state On-the-Ramp Detection of INduction-decay with Oversampling (SORDINO), an fMRI technique that maintains a constant total gradient amplitude while acquiring data during continuously changing gradient direction. When benchmarked against conventional fMRI on a 9.4T system, SORDINO is silent, sensitive, specific, and resistant to artifacts. SORDINO offers superior compatibility with concurrent multimodal experiments such as electrophysiology, electrochemistry, and optical imaging at cellular resolution. It also carries novel T1 contrast mechanisms distinct from BOLD. SORDINO facilitates brain-wide activity and connectivity mapping in awake, behaving mice, overcoming stress- and motion-related confounds that are among the most challenging barriers in conventional fMRI studies.
Presenter
Ian Shih, University of North Carolina Chapel Hill, NC
United States
The relationship between BOLD signal correlations and neuronal correlations has largely been studied by modelling the associations between fMRI and electrophysiological recordings. These studies, while critical for understanding this relationship, are confounded by the interdependence between different electrophysiological rhythms. In this presentation I will show recent work where we used optogenetic stimulation of the mouse DMN to causally investigate how nested rhythms impact large scale functional connectivity. This rhythmic stimulation is functionally distinct from canonical block design stimulation, resulting in propagation of the rhythm throughout the DMN with region specific phase differences that are envelope, but not carrier, frequency dependent. I will provide evidence for a neural origin of these phase differences and discuss how traditional functional connectivity calculations are affected by them. I will also provide evidence for resonant properties within the stimulated axonal network. These results shed light on the relationship between haemodynamic and electrophysiological correlations, and how distributed networks like the DMN respond to targeted neuromodulation.
In this study, we explored the neural basis of resting-state FC in mice by employing fMRI combined with optogenetic silencing, which suppresses excitatory neuron activity to enable the measurement of spontaneous causal interactions. Spontaneous connectivity patterns resemble the bilateral patterns of resting-state FC, contrasting with the predominantly ipsilateral connectivity observed during optogenetic activation. Additionally, spontaneous activity was found to propagate through polysynaptic structural pathways, whereas evoked activity was primarily restricted to monosynaptic pathways. This finding suggests that FC emerges from causal interactions driven by ongoing spontaneous neural activity.
Presenter
Hyun Seok Moon, Institute for Basic Science Seoul, Gyeonggi Province
Korea, Republic of
Hemogenetic fMRI is a new technique designed to translate molecular signaling events in the central nervous system into localized changes in BOLD fMRI signals, using genetically encoded reporter genes. The resulting MRI signals from reporter-expressing cells—referred to as artificial BOLD signals—can be distinguished from the brain’s intrinsic BOLD activity by administering a reporter-specific inhibitor. For the first-generation, calcium-sensitive hemogenetic fMRI reporters, we engineered nitric oxide synthases for targeting image contrast (NOSTIC) to convert intracellular calcium fluctuations into hemodynamic changes. Neuronal nitric oxide synthase (nNOS), in particular, is a calcium-activated enzyme that generates cell-permeable NO, thereby influencing local vascular dynamics. By utilizing advanced viral vector strategies to introduce these reporters, hemogenetic fMRI enables the investigation of circuit-specific brain activities that are difficult to capture using conventional BOLD-fMRI. In this presentation, I will detail the design of the NOSTIC reporter gene and demonstrate how it can be employed to analyze neural circuitry in rodent models. I will also discuss additional hemogenetic fMRI strategies that achieve cell-type specificity and target distinct molecular events, further expanding the utility of this innovative approach.
Presenter
Nan Li, UT Southwestern Dallas, TX
United States