Background: The brain is continuously targeted by a wealth of stimuli with complex spatio-temporal patterns and has presumably evolved in order to cope with those inputs in an optimal way. Previous studies investigating the response capabilities of either single neurons or intact sensory systems to external stimulation demonstrated that stimuli temporal distribution is an important, if often overlooked, parameter. Results: In this study we investigated how cortical networks plated over micro-electrode arrays respond to different stimulation sequences in which inter-pulse intervals followed a 1/f β distribution, for different values of β ranging from 0 to ∞. Cross-correlation analysis revealed that network activity preferentially synchronizes with external input sequences featuring β closer to 1 and, in any case, never for regular (i.e. fixed-frequency) stimulation sequences. We then tested the interplay between different average stimulation frequencies (based on the intrinsic firing/bursting frequency of the network) for two selected values of β, i.e. 1 (scale free) and ∞ (regular). In general, we observed no preference for stimulation frequencies matching the endogenous rhythms of the network. Moreover, we found that in case of regular stimulation the capability of the network to follow the stimulation sequence was negatively correlated to the absolute stimulation frequency, whereas using scale-free stimulation cross-correlation between input and output sequences was independent from average input frequency. Conclusions: Our results point out that the preference for a scale-free distribution of the stimuli is observed also at network level and should be taken into account in designing more efficient protocols for neuromodulation purposes.
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