Reconstructing the Hemodynamic Response Function via a Bimodal Transformer

The relationship between blood flow and neuronal activity is widely recognized, with blood flow frequently serving as a surrogate for neuronal activity in fMRI studies. At the microscopic level, neuronal activity has been shown to influence blood flow in nearby blood vessels. This study introduces the first predictive model that addresses this issue directly at the explicit neuronal population level. Using in vivo recordings in awake mice, we employ a novel spatiotemporal bimodal transformer architecture to infer current blood flow based on both historical blood flow and ongoing spontaneous neuronal activity. Our findings indicate that incorporating neuronal activity significantly enhances the model's ability to predict blood flow values. Through analysis of the model's behavior, we propose hypotheses regarding the largely unexplored nature of the hemodynamic response to neuronal activity

In Brain Multi-Photon Imaging of Vaterite Drug Delivery Cargoes loaded with Carbon Dots

Biocompatible fluorescent agents, such as phenylenediamine carbon dots (CDs), are key contributors to the theragnostic paradigm, enabling real-time in vivo imaging of drug delivery cargoes. This study explores the optical properties of these CDs, demonstrating their potential for two-photon fluorescence imaging in brain vessels. Using an open aperture z-scan technique, we measured the wavelength-dependent nonlinear absorption cross-section of the CDs, achieving a peak value near 50 GM. This suggests the potential use of phenylenediamine CDs for efficient multiphoton excitation in the 775 - 895 nm spectral range. Mesoporous vaterite nanoparticles were loaded with fluorescent CDs to examine the possibility of a simultaneous imaging and drug delivery platform. Efficient one and two-photon imaging of the CD-vaterite composites, uptaken by macrophage and genetically engineered C6-Glioma cells, was demonstrated. For an in vivo scenario, vaterite nanoparticles loaded with CDs were directly injected into the brain of a living mouse, and their flow was monitored in real-time within the blood vessels. The facile synthesis of phenylenediamine carbon dots, their significant nonlinear responses, and biological compatibility show a viable route for implementing drug tracking and sensing platforms in living systems

A Guide to Delineate the Logic of Neurovascular Signaling in the Brain

The neurovascular system may be viewed as a distributed nervous system within the brain. It transforms local neuronal activity into a change in the tone of smooth muscle that lines the walls of arterioles and microvessels. We review the current state of neurovascular coupling, with an emphasis on signaling molecules that convey information from neurons to neighboring vessels. At the level of neocortex, this coupling is mediated by: (i) a likely direct interaction with inhibitory neurons, (ii) indirect interaction, via astrocytes, with excitatory neurons, and (iii) fiber tracts from subcortical layers. Substantial evidence shows that control involves competition between signals that promote vasoconstriction versus vasodilation. Consistent with this picture is evidence that, under certain circumstances, increased neuronal activity can lead to vasoconstriction rather than vasodilation. This confounds naïve interpretations of functional brain images. We discuss experimental approaches to detect signaling molecules in vivo with the goal of formulating an empirical basis for the observed logic of neurovascular control

Brain capillary networks across species : a few simple organizational requirements are sufficient to reproduce both structure and function

Despite the key role of the capillaries in neurovascular function, a thorough characterization of cerebral capillary network properties is currently lacking. Here, we define a range of metrics (geometrical, topological, flow, mass transfer, and robustness) for quantification of structural differences between brain areas, organs, species, or patient populations and, in parallel, digitally generate synthetic networks that replicate the key organizational features of anatomical networks (isotropy, connectedness, space-filling nature, convexity of tissue domains, characteristic size). To reach these objectives, we first construct a database of the defined metrics for healthy capillary networks obtained from imaging of mouse and human brains. Results show that anatomical networks are topologically equivalent between the two species and that geometrical metrics only differ in scaling. Based on these results, we then devise a method which employs constrained Voronoi diagrams to generate 3D model synthetic cerebral capillary networks that are locally randomized but homogeneous at the network-scale. With appropriate choice of scaling, these networks have equivalent properties to the anatomical data, demonstrated by comparison of the defined metrics. The ability to synthetically replicate cerebral capillary networks opens a broad range of applications, ranging from systematic computational studies of structure-function relationships in healthy capillary networks to detailed analysis of pathological structural degeneration, or even to the development of templates for fabrication of 3D biomimetic vascular networks embedded in tissue-engineered constructs

Convergence among Non-Sister Dendritic Branches: An Activity-Controlled Mean to Strengthen Network Connectivity

The manner by which axons distribute synaptic connections along dendrites remains a fundamental unresolved issue in neuronal development and physiology. We found in vitro and in vivo indications that dendrites determine the density, location and strength of their synaptic inputs by controlling the distance of their branches from those of their neighbors. Such control occurs through collective branch convergence, a behavior promoted by AMPA and NMDA glutamate receptor activity. At hubs of convergence sites, the incidence of axo-dendritic contacts as well as clustering levels, pre- and post-synaptic protein content and secretion capacity of synaptic connections are higher than found elsewhere. This coupling between synaptic distribution and the pattern of dendritic overlapping results in ‘Economical Small World Network’, a network configuration that enables single axons to innervate multiple and remote dendrites using short wiring lengths. Thus, activity-mediated regulation of the proximity among dendritic branches serves to pattern and strengthen neuronal connectivity

Linking brain vascular physiology to hemodynamic response in ultra-high field MRI

Functional MRI using blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity via evoked cerebral blood volume (CBV) and oxygenation changes. Thus, its spatio-temporal characteristics are determined by vascular physiology and MRI parameters. In this paper, we focus on the spatial distribution and time course of the fMRI signal and their magnetic field strength dependence. Even though much is still unknown, the following consistent picture is emerging: a) For high spatial resolution imaging, fMRI contrast-to-noise increases supra-linearly with field strength. b) The location and spacing of penetrating arteries and ascending veins in the cortical tissue are not correlated to cortical columns, imposing limitations on achievable point-spread function (PSF) in fMRI. c) Baseline CBV distribution may vary over cortical layers biasing fMRI signal to layers with high CBV values. d) The largest CBV change is in the tissue microvasculature, less in surface arteries and even less in pial veins. e) Venous CBV changes are only relevant for longer stimuli, and oxygenation changes are largest in post-capillary blood vessels. f) The balloon effect (i.e. slow recovery of CBV to baseline) is located in the tissue, consistent with the fact that the post-stimulus undershoot has narrower spatial PSF than the positive BOLD response. g) The onset time following stimulation has been found to be shortest in middle/lower layers, both in optical imaging and high-resolution fMRI, but we argue and demonstrate with simulations that varying signal latencies can also be caused by vascular properties and, therefore, may potentially not be interpreted as neural latencies. With simulations, we illustrate the field strength dependency of fMRI signal transients, such as the adaptation during stimulation, initial dip and the post-stimulus undershoot. In sum, vascular structure and function impose limitations on the achievable PSF of fMRI and give rise to complex fMRI transients, which contain time-varying amount of excitatory and inhibitory neuronal information. Nevertheless, non-invasive fMRI at ultra-high magnetic fields not only provides high contrast-to-noise but also an unprecedented detailed view on cognitive processes in the human brain