In silico exploration of mouse brain dynamics by focal stimulation reflects the organization of functional networks and sensory processing

Resting-state functional networks such as the default mode network (DMN) dominate spontaneous brain dynamics. To date, the mechanisms linking brain structure and brain dynamics and functions in cognition, perception, and action remain unknown, mainly due to the uncontrolled and erratic nature of the resting state. Here we used a stimulation paradigm to probe the brain’s resting behavior, providing insights on state-space stability and multiplicity of network trajectories after stimulation. We performed explorations on a mouse model to map spatiotemporal brain dynamics as a function of the stimulation site. We demonstrated the emergence of known functional networks in brain responses. Several responses heavily relied on the DMN and were suggestive of the DMN playing a mechanistic role between functional networks. We probed the simulated brain responses to the stimulation of regions along the information processing chains of sensory systems from periphery up to primary sensory cortices. Moreover, we compared simulated dynamics against in vivo brain responses to optogenetic stimulation. Our results underwrite the importance of anatomical connectivity in the functional organization of brain networks and demonstrate how functionally differentiated information processing chains arise from the same system.

Supplementary Figure 3. In-strength indicates the incoming projections to a brain area. The hypothalamus receives the strongest input in the mouse brain model and the cerebellum the weakest. The isocortex is listed 9 out of 11 structures. The structures are ordered by their mean in-strength. This indicates that the subcortical structures are highly interdependent and the isocortex might be sensitive to subcortical input while it can be autonomous as well. For each structure (e.g., thalamus), 10 areas are listed in order of the highest in-strength.
Note that the cortical subplate is divided in seven areas. intrahemispheric connections were shorter than the connections between the isocortical hemispheres. This result confirms the report in Braitenberg and Schüz, 1998, Chapter 26, of a second peak in the histogram whose significance is obscured. The isocortical connections were outnumbered, thus their quantitative effect on the entire mouse, in panel A, is marginal. Time delays translate into shifts of transmitted local brain activity. The local activity in the network model of the mouse brain is assumed to primarily convey the natural frequency at each brain area (about 42 Hz). The time delays translate into a phase shift in local activity throughout its transmission. The number of bins is 119 with a bin width of 0.0889 mm in panel A and 17 bins of 0.3056 mm width in panel B. The number of bins in the histogram, n bins , was calculated according to n bins = exp(0.626 + 0.4 log (n -1)), with the number of connections n (Otnes and Enochson, 1972), which is listed in Table 2. Table 3 provides the statistics.

Supplementary
Supplementary Figure 6. Similarity matrices of the ss-DRNs reveal a consistent formation of spatially similar activity in the mouse brain. Each of the 512 brain areas is stimulated individually, and the 512 ss-DRNs are compared with each other resulting in one similarity matrix per connectivity parameter configuration. That is summarized in a similarity matrix for a given proportion of homogeneous short-range to heterogeneous longrange SCs (varied along rows) and for a given length of short-range connections (varied along the columns).
The similarity of ss-DRNs increases with warmer colors (yellow indicates the maximum correlation of two ss-DRNs). The stimulation sites (areas) are equally sorted for all similarity matrices. The color bar on the axes of the lower-left matrix (500 µm spatial range and 100% of short-range SC) displays the structures to which a brain area belongs (e.g., nucleus accumbens and fundus of the striatum are cerebral nuclei in the mouse model).
Though the results indicate clusters of DRNs, the organization of the similarity matrices was almost unchanged concerning the length of short-range SCs (similarity matrices along the columns). Long-range SC (see the row of 0% short-range SC) supported ss-DRNs that differ from those supported by the short-range SC (see the row of 100% short-range SC). However, both similarity matrices merge in the mix of short-and long-range SCs (see the similarity matrices along the rows).  (CN and GN). The upper limb, and especially the forelimb, connects through the CN, whereas the lower limb, and especially the hind limb, connects through the GN in the medulla. The nuclei of the medulla connect via the medial lemniscus to the contralateral thalamus (VPL), which has ipsilateral ramifications into the primary somatosensory cortex (S1). The sensory networks in panels A, B, D, E are based on textbook descriptions (e.g., Watson et al., 2011) and include the relevant structures given by the ABA. The sensory pathways can be described using the ABA.
However, the ABA needs refinements to distinguish lower and upper limb (especially hind and forelimb), see panel E. The ABA does not include a division of the barrel field of the primary somatosensory areas (compare panels C-D). The networks in panels A, B, D, E indicate information flows to areas that do not necessarily terminate in the primary sensory areas of the isocortex, such as the hypothalamic and midbrain targets of the retinal ganglion cells in panel A, and the midbrain nuclei related to whisker movements in panel D. These wellknown connections are usually not discussed regarding sensory processing in textbooks. As a result, visual and whisker system meet in the SuCo regarding eye and whisker movements. Note that the model is agnostic about the (sensory) information, meaning that nuclei may be activated, but the object of processing (information) is less defined. Meaning is attached by the vast amount of studies about the physiology of the nuclei. For instance, the hypothalamic nuclei play a role in the circadian timing system, and the nuclei in the midbrain (OT, PPT, OPT) receive input from the retina (see panel A). They are known to be involved in eye movement coordination and reflexes. The ABA includes the following areas involved in sensory processing. Brain areas and abbreviations are listed in Supplementary Table 1 and Supplementary Table 2 (Right) The similarity matrix between empirical and simulated patterns was thresholded and binarized using the threshold vector generated in Panel A. To highlight how similar the empirical and simulated patterns were, only