Title: A causal inference approach of monosynapses from spike trains

Abstract: Neuroscientists have worked on the problem of estimating synaptic properties, such as connectivity and strength, from simultaneously recorded spike trains since the 1960s. Recent years have seen renewed interest in the problem, coinciding with rapid advances in the technology of high-density neural recordings and optogenetics, which can be used to calibrate causal hypotheses about functional connectivity. Here, a rigorous causal inference framework for pairwise excitatory and inhibitory monosynaptic effects between spike trains is developed. Causal interactions are identified by separating spike interactions in pairwise spike trains by their timescales. Fast algorithms for computing accurate estimates of associated quantities are also developed. Through the lens of this framework, the link between biophysical parameters and statistical definitions of causality between spike trains is examined across a spectrum of dynamical systems simulations. In an idealized setting, we demonstrate a correspondence between the synaptic causal metric developed here and the probabilities of causation developed by Tian and Pearl. Since the probabilities of causation are derived under distinct assumptions and include data from experimental randomization, this opens up the possibility of testing the synaptic inference framework's assumptions with juxtacellular or optogenetic stimulation. We simulate such an experiment with a biophysically detailed channelrhodopsin model and show that randomization is not achieved; strong confounding persists even with strong stimulations. A principal goal is to ask how carefully articulated causal assumptions might better inform the design of neural stimulation experiments and, in turn, support experimental tests of those assumptions.