Phase-lags in large scale brain synchronization: Methodological considerations and in-silico analysis

Architecture of phase relationships among neural oscillations is central for their functional significance but has remained theoretically poorly understood. We use phenomenological model of delay-coupled oscillators with increasing degree of topological complexity to identify underlying principles by which the spatio-temporal structure of the brain governs the phase lags between oscillatory activity at distant regions. Phase relations and their regions of stability are derived and numerically confirmed for two oscillators and for networks with randomly distributed or clustered bimodal delays, as a first approximation for the brain structural connectivity. Besides in-phase, clustered delays can induce anti-phase synchronization for certain frequencies, while the sign of the lags is determined by the natural frequencies and by the inhomogeneous network interactions. For in-phase synchronization faster oscillators always phase lead, while stronger connected nodes lag behind the weaker during frequency depression, which consistently arises for in-silico results. If nodes are in anti-phase regime, then a distance π is added to the in-phase trends. The statistics of the phases is calculated from the phase locking values (PLV), as in many empirical studies, and we scrutinize the method’s impact. The choice of surrogates do not affects the mean of the observed phase lags, but higher significance levels that are generated by some surrogates, cause decreased variance and might fail to detect the generally weaker coherence of the interhemispheric links. These links are also affected by the non-stationary and intermittent synchronization, which causes multimodal phase lags that can be misleading if averaged. Taken together, the results describe quantitatively the impact of the spatio-temporal connectivity of the brain to the synchronization patterns between brain regions, and to uncover mechanisms through which the spatio-temporal structure of the brain renders phases to be distributed around 0 and π.Trial registration: South African Clinical Trials Register: http://www.sanctr.gov.za/SAClinicalbrnbspTrials/tabid/169/Default.aspx, then link to respiratory tract then link to tuberculosis, pulmonary; and TASK Applied Sciences Clinical Trials, AP-TB-201-16 (ALOPEXX): https://task.org.za/clinical-trials/.Author summary: Functional connectivity, and in particular, phase coupling between distant brain regions may be fundamental in regulating neuronal processing and communication. However, phase relationships between the nodes of the brain and how they are confined by its spatio-temporal structure, have been mostly overlooked. We use a model of oscillatory dynamics superimposed on the space-time structure defined by the connectome, and we analyze the possible regimes of synchronization. Limitations of data analysis are also considered and we show that the choice of the significance threshold for coherence does not essentially impact the statistics of the observed phase lags, although it is crucial for the right detection of statistically significant coherence. Analytical insights are obtained for networks with heterogeneous time-delays, based on the empirical data from the connectome, and these are confirmed by numerical simulations, which show in- or anti-phase synchronization depending on the frequency and the distribution of time-delays. Phase lags are shown to result from inhomogeneous network interactions, so that stronger connected nodes generally phase lag behind the weaker.