Temporal theta slow-wave activity (TTA-SW) in premature infants is a specific neurobiomarker of the early neurodevelopment of perisylvian networks observed as early as 24 weeks of gestational age (wGA). It is present at the turning point between non-sensory driven spontaneous networks and cortical network functioning. Despite its clinical importance, the underlying mechanisms responsible for this spontaneous nested activity and its functional role have not yet been determined. The coupling between neural oscillations at different timescales is a key feature of ongoing neural activity, the characteristics of which are determined by the network structure and dynamics. The underlying mechanisms of cross-frequency coupling (CFC) are associated with several putative functions in adults. In order to show that this generic mechanism is already in place early in the course of development, we analyzed electroencephalography recordings from sleeping preterm newborns (24-27 wGA). Employing cross-frequency phase-amplitude coupling analyses, we found that TTAs were orchestrated by the SWs defined by a precise temporal relationship. Notably, TTAs were synchronized to the SW trough, and were suppressed during the SW peak. Spontaneous endogenous TTA-SWs constitute one of the very early signatures of the developing temporal neural networks with key functions, such as language and communication. The presence of a fine-tuned relationship between the slow activity and the TTA in premature neonates emphasizes the complexity and relative maturity of the intimate mechanisms that shape the CFC, the disruption of which can have severe neurodevelopmental consequences.

The ability to extract rhythmic structure is important for the development of language, music and social communication. Although previous studies show infants’ brains entrain to the periodicities of auditory rhythms and even different metrical interpretations (e.g., groups of two vs. three beats) of ambiguous rhythms, whether the premature brain tracks beat and meter frequencies had not been explored previously. We used high-resolution electroencephalography, while premature infants (n = 19, five male, mean age 32 ± 2.59 wGA) heard two auditory rhythms in the incubators. We observed selective enhancement of the neural response at both beat and meter-related frequencies. Further, neural oscillations at the beat and duple (groups of 2) meter were phase aligned with the envelope of the auditory rhythmic stimuli. Comparing the relative power at beat and meter frequencies across stimuli and frequency revealed evidence for selective enhancement of duple meter. This suggests that even at this early stage of development, neural mechanisms for processing auditory rhythms beyond simple sensory coding are present. Our results add to a few recent neuroimaging studies demonstrating discriminative auditory abilities of premature neural networks. Specifically, our results demonstrate the early capacities of the immature neural circuits and networks to code both simple beat and beat grouping (i.e., hierarchical meter) regularities of auditory sequences. Considering the importance of rhythm processing for acquiring language and music, our findings indicate that even before birth, the premature brain is already learning this important aspect of the auditory world in a sophisticated and abstract way.Significant Statement:Processing auditory rhythm is of great neurodevelopmental importance. In an electroencephalography experiment in premature newborns, we found converging evidence that when presented with auditory rhythms the premature brain encodes multiple periodicities corresponding to beat and beat grouping (meter) frequencies, and even selectively enhances the neural response to meter compared to beat, as in human adults. We also found that the phase of low frequency neural oscillations align to the envelope of the auditory rhythms, and that this phenomenon becomes less precise at lower frequencies. These findings demonstrate the initial capacities of the developing brain to code auditory rhythm, and the importance of special care to the auditory environment of this vulnerable population during a highly dynamic period of neural development.

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