Program Director/Principal Investigator (Last, First, Middle): Chen, Rong PROJECT DESCRIPTION A. BACKGROUND AND SIGNIFICANCE Real-time neural decoding centers on predicting behavior variables based on neural activity data, where the prediction is performed at a pace that reliably keeps up with the speed of the activity that is being monitored. Neuromodulation devices are becoming one of the most powerful tools for the treatment of brain disorders, enhancing neurocognitive performance, and demonstrating causality (Bergmann et al., 2016; Knotkova and Rasche, 2015). A precise neuromodulation system (Figure 1) integrates neural activity monitoring, real-time neural decoding, and neuromodulation. In precise neuromodulation, a decoding device predicts a behavior variable based on neural data streams in real-time. Based on the decoding results, neuromodulation parameters such as timing, frequency, duration, and amplitude are changed. Precise neuromodulation systems with closed-loop real-time feedback are superior to the fixed (open- loop) neuromodulation paradigm (Brocker et al., 2017; deBettencourt et al., 2015; Ezzyat et al., 2017). A recent direct brain stimulation study (Ezzyat et al., 2017) demonstrated significant advantages of precise neuromodulation over open-loop neuromodulation. Ezzyat et al. applied direct brain stimulation with decoding capability to patients with epilepsy to improve their memory. They found that stimulation increased memory function only if delivered when the decoding device indicated low encoding efficiency while stimulation decreased memory function if delivered when the decoding device indicated high encoding efficiency. An open-loop neuromodulation system with a fixed stimulation paradigm may not always facilitate memory function. Miniature cellular imaging (Ghosh et al., 2011; Kerr and Nimmerjahn, 2012; Scott et al., 2013) is one of the most powerful ways to study neural circuits. It enables us to investigate neural circuits during behaviors for an understanding of network architecture of behavior, cognition, and emotion. Miniature cellular imaging records neuronal activity at cellular and sub-second levels of spatial and temporal resolution in freely moving animals. Miniature cellular imaging has many advantages. First, compared with in vivo multi-electrode recording, miniature calcium imaging can probe all cells in the field of view, and visualize the spatial location of monitored cells (Kerr et al., 2005). Second, compared with magnetic resonance imaging, which measures brain activity at the macroscopic scale and with low temporal resolution, miniature cellular imaging provides high spatial and temporal resolution. Third, fiber photometry (Cui et al., 2014) lacks cellular-level resolution, while miniature cellular imaging allows concurrent tracking of neural calcium activities at cellular spatial resolution. Simultaneous neural activity monitoring and intetvention Stimulation Calcium imaging Real-time decoding system Figure 1 A precise neuromodulation system. Our project centers on developing RNDC-Lab. PHS 398 (Rev. 01 /18 Approved Through 03/31/2020) Page 26 Miniature cellular imaging with real- time decoding capability captures the central vision of brain science, (The brain initiative, 2014). Combined with optogenetics, it is a tremendous asset to studying neural mechanisms underlying normal and disease states, and leads to precise neuromodulation. However, developing such systems is a challenging task. A major obstacle is the analysis of the large imaging streams that are generated. The massive high-dimensional data streams that are generated include 0MB No. 0925-0001