Development of the multi-scale dynamic modeling techniques for multi-modal brain recordings



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Fundamental principles underlying computation in multi-scale brain networks illustrate how multiple brain areas and their coordinated activity give rise to complex cognitive functions. Whereas brain activity has been studied in the micro- to meso-scale in studying the connections between the dynamical patterns and the behaviors, the investigation of the neural population dynamics is mainly limited by the single-scale analysis. My goal is to develop a multi-scale dynamical model for the collective activity of neuronal populations. First, I introduced a bio-inspired deep learning approach, termed NeuroBondGraph Network (NBGNet), to capture cross-scale dynamics that can infer and map the neural data from multiple scales (Chapter 2). The NBGNet not only exhibits more than an 11-fold improvement in reconstruction accuracy, but also predicts synchronous neural activity and preserves correlated low-dimensional latent dynamics. I also show that the NBGNet robustly predicts held-out data across a long time scale (two weeks) without retraining. The effective connectivity defined from the presented model agrees with the established neuroanatomical hierarchy of motor control in the literature. I then introduced the m̲ulti-s̲cale n̲eural d̲ynamics n̲eural o̲rdinary d̲ifferential e̲quation (msDyNODE) to uncover multiscale brain communications governing cognitive behaviors (Chapter 3). I demonstrated that msDyNODE successfully captured multiscale activity using both simulations and electrophysiological experiments. The msDyNODE-derived casual interactions between recording channels and scales not only aligned well with the abstraction of the hierarchical anatomy of the mammalian nervous system but also exhibited behavioral dependences. This work offers a new approach for in depth mechanistic studies on the brain where simultaneous acquisition of multi-scale neural activity is available. While the traditional neuronal tracing method serves as gold standard to assess the neural connectivity, toxicity and the limited efficiency prevent it from serving as a reliable tool to validate the multi-scale connectivity. It has been demonstrated that dendritic spines increase or become bigger after long-term potentiation while decrease or become smaller after long-term depression. Thus, we hypothesized the existence of excitatory and inhibitory connectivity can be revealed by the dynamics of dendritic spines. Since the dendritic spines can be smaller than the Abbe diffraction limit (~200 nm), we need an in-vivo super-resolution microscopy to achieve our goal. As a super-resolution imaging method, stimulated emission depletion (STED) microscopy has unraveled fine intracellular structures and provided insights into nanoscale organizations in cells. Although image resolution can be further enhanced by continuously increasing the STED-beam power, the resulting photodamage and phototoxicity are major issues for real-world applications of STED microscopy. In Chapter 4, I demonstrated that, with 50% less STED-beam power, the STED image resolution can be improved up to 1.45-fold using the separation of photons by a lifetime tuning (SPLIT) scheme combined with a deep learning-based phasor analysis algorithm termed flimGANE (f̲luorescence l̲ifetime i̲m̲aging based on a g̲enerative a̲dversarial n̲e̲twork). This work offers a new approach for STED imaging in situations where only a limited photon budget is available. In summary, I emphasized that this is the first time we are able to infer the nonlinear multiscale interactions in the brain networks by our multi-scale dynamic modeling approach. This opens a window of opportunity that multi-scale connectivity can provide a mechanistic understanding of brain computations underlying behaviors or mental states.


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