Central Autonomic Network and Heart Rate Variability in Premature Neonates

Abstract

Introduction: The Central Autonomic Network (CAN) is a hierarchy of brain structures that collectively influence cardiac autonomic input, mediating the majority of brain-heart interactions, but has never been studied in premature neonates. In this study, we use heart rate variability (HRV), which has been described as the "primary output" of the CAN, and resting-state functional MRI (rsfMRI) to characterize brain-heart relationships in premature neonates.

Methods: We studied premature neonates who underwent rsfMRI at term (37-week postmenstrual age or above) and had HRV data recorded during the same week of their MRI. HRV was derived from continuous electrocardiogram data during the week of the rsfMRI scan. For rsfMRI, a seed-based approach was used to define regions of interest (ROIs) pertinent to the CAN, and blood oxygen level-dependent signal was correlated between each ROI as a measure of functional connectivity. HRV was correlated with CAN connectivity (CANconn) for each region, and subgroup analysis was performed based on sex and clinical comorbidities.

Results: Forty-seven premature neonates were included in this study, with a mean gestational age at birth of 28.1 +/- 2.6 weeks. Term CANconn was found to be significantly correlated with HRV in approximately one-fifth of CAN connections. Two distinct patterns emerged among these HRV-CANconn relationships. In the first, increased HRV was associated with stronger CANconn of limbic regions. In the second pattern, stronger CANconn at the precuneus was associated with impaired HRV maturation. These patterns were especially pronounced in male premature neonates.

Conclusion: We report for the first time evidence of brain-heart relationships in premature neonates and an emerging CAN, most striking in male neonates, suggesting that the brain-heart axis may be more vulnerable in male premature neonates. Signatures in the heart rate may eventually become an important noninvasive tool to identify premature males at highest risk for neurodevelopmental impairment.

Keywords: Autonomic nervous system; Connectivity; Developing brain; Heart rate variability; Neonatal period.

Fig. 1.

a–d Three-dimensional models exhibiting whole brain atlas views with CAN ROIs are highlighted in color and are shown in a coronal view with labeled ROIs, a sagittal view, a superior axial view, and an inferior axial view.

Fig. 2.

Trajectory of average weekly HRV based on sex (females in yellow, males in green) and morbidity (low morbidity in light blue, high morbidity in purple) for each HRV metric: alpha 1 (a, b), alpha 2 (c, d), RMS1 (e, f), RMS2 (g, h), and LF/HF ratio (i, j).

Fig. 3.

Summary of all significant correlations between HRV and connectivity for all subjects, grouped by HRV metric. Pearson’s correlation coefficient and p value are reported. Columns with the correlation coefficient are shaded in the manner of a tricolor heat map where values fall on a spectrum between red and green based on their relation to the minimum (red), median (yellow), and maximum values (green). Green represents more positive R values, and red represents more negative R values.

Fig. 4.

Subgroup analysis focused on HRV-CAN_conn involving limbic regions in (a) and precuneus in (b). There are several additional columns for subgroup analysis of males, females, low-morbidity groups, and high-morbidity groups. Pearson’s correlation coefficient is reported for each group followed by the associated p value. For each subgroup, significant correlations with p value <0.05 are bolded. Columns with the correlation coefficient are shaded in the manner of a tricolor heat map where values fall on a spectrum between red and green based on their relation to the minimum (red), median (yellow), and maximum values (green). Green represents more positive R values, and red represents more negative R values.