Neuromodulatory effects on brain traveling waves: Insights from combined pharmacology, pupillometry and fMRI

Brain activity fluctuates over time, and understanding the factors that influence such fluctuations is crucial for understanding the flexible nature of the brain and cognition. Recent work in animals and humans has revealed the presence of specific spatio-temporal patterns in global brain activity in the form of travelling waves that propagate over tens of seconds. In particular, it has been shown that activity propagates following a principal gradient from unimodal to transmodal regions. This activity propagation has been observed across experimental and analytic approaches, indicating its ubiquity and hinting towards a physiological relevance, but its functional meaning remains unclear. Given the prominent role of neuromodulatory systems in regulating brain activity and behavior, that neuromodulators affect neural gain and excitability, and that manipulation of neuromodulatory activity have been shown to affect indices of functional connectivity typically measured on slow time scales, I had previously hypothesized that neuromodulatory systems modulate the spatio-temporal propagation of brain activity in specific ways. In the talk I will present a series of studies aimed to directly assess how different neuromodulatory systems influences spatio-temporal patterns of brain activity in humans. Employing fMRI datasets that included pharmacological manipulations of different monoaminergic neuromodulators and placebo conditions, as well as pupillometric signatures of arousal-related neuromodulation, I investigated how neuromodulatory activity influenced different aspects of travelling wave activity as measured with fMRI in humans. Specifically, I assessed the effect of atomoxetine, which increases the levels of noradrenaline and dopamine in the brain (N = 36), and the effect of lysergic acid diethylamide (LSD), a serotoninergic agonist (N = 15). Furthermore, I examined travelling wave activity across resting state and task conditions. I found that different levels of neuromodulatory tone affect the speed of travelling wave propagation over the cortex, and that this was related to measures of functional network topology. I also examined temporal variations in pupil size as a signature of transient changes in neuromodulatory activity, and found that periods of travelling waves were characterized by larger pupil size. The results suggest that the overall levels of different arousal-related neuromodulatory systems affect travelling wave propagation, and that this modulated propagation shapes integrated functional connectivity features. Furthermore, pupil signatures indicated that instantaneous changes in neuromodulatory activity may act as time-specific regulators of travelling wave activity. The findings highlight specific effects of both prolonged and transient neuromodulatory influences on slow brain dynamics, suggesting a finely tuned regulation of brain communication at the slow time scales.