Cortical motor activity modulates respiration and reduces apnoea in neonates
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eLife Assessment
Zandvoort and colleagues describe respiration-brain coupling in the context of apnoea in human newborns. The authors have addressed an important question and supported their claims with solid data. The rigor of the findings could perhaps be further strengthened with some relatively minor changes to the analysis methodology.
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Abstract
Abstract
Respiration is governed by a widespread network of cortical and subcortical structures. This complex communication between the brain and lungs is altered in pathological conditions. Apnoea – the cessation of respiration – is a common condition in infants, particularly those born prematurely. Apnoea in infants is believed to relate to immaturity of brainstem respiratory centres; involvement of the cortex in respiration in infants has yet to be explored. We investigated if cortical control of respiration occurs in newborn humans and whether it relates to apnoea. Using simultaneous electroencephalography (EEG) and impedance pneumography, we show that cortico-respiratory coupling is present in premature and term newborns (104 recordings from 68 infants; 34.5 ± 2.6 weeks post-menstrual age), identifying an interplay between breathing phase and EEG amplitude. We further shed light on the biological meaning by revealing that the strongest coupling occurs during inspiration and that cortical activity precedes respiration, with coupling strongest over frontocentral regions. These findings support the notion that the cortico-respiratory coupling observed here primarily constitutes communication between cortical motor areas and lung effectors. Moreover, we show that cortico-respiratory coupling is negatively correlated with the rate of apnoea, revealing novel mechanistic insight into this common and potentially life-threatening neonatal pathology.
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eLife Assessment
Zandvoort and colleagues describe respiration-brain coupling in the context of apnoea in human newborns. The authors have addressed an important question and supported their claims with solid data. The rigor of the findings could perhaps be further strengthened with some relatively minor changes to the analysis methodology.
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Reviewer #1 (Public review):
Summary:
The authors investigated the extent to which phase-amplitude coupling (PAC) of respiratory and electrophysiological brain activity recordings was related to episodes of life-threatening apnoea in human newborns.
Strengths:
I want to commend the authors for acquiring unique and illuminating data; the difficulty in recording and handling these data has to be appreciated. As far as I can tell, Zandvoort and colleagues are the first to provide robust evidence for respiration-brain coupling in newborns. Their creative use of the phase-slope index for peripheral-central interactions is innovative and credible. If proven to be robust, the authors' findings have important implications well beyond the field of brain-body research.
Weaknesses:
While the analyses were overall competently conducted and …
Reviewer #1 (Public review):
Summary:
The authors investigated the extent to which phase-amplitude coupling (PAC) of respiratory and electrophysiological brain activity recordings was related to episodes of life-threatening apnoea in human newborns.
Strengths:
I want to commend the authors for acquiring unique and illuminating data; the difficulty in recording and handling these data has to be appreciated. As far as I can tell, Zandvoort and colleagues are the first to provide robust evidence for respiration-brain coupling in newborns. Their creative use of the phase-slope index for peripheral-central interactions is innovative and credible. If proven to be robust, the authors' findings have important implications well beyond the field of brain-body research.
Weaknesses:
While the analyses were overall competently conducted and well-justified, I was not entirely convinced by a few methodological choices, specifically i) the computation of PAC surrogates, ii) details of the linear mixed-effects model, and iii) the electrode selection for linking phase-amplitude coupling to apnoea frequency.
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Reviewer #2 (Public review):
Summary:
The author's central hypothesis was that the strength of cortico-respiratory coupling in infants is negatively associated with apnoea rate. To prove this, they first investigated the existence of cortico-respiratory coupling in premature and term-born infants, the spatial localisation of the cortical activity and its relationship with the phase of the respiratory cycle, and the directionality of coupling.
Strengths:
The researchers used synchronised EEG and impedance pneumography to detect the phase amplitude coupling.
They have studied a wide range of gestations, from 28 weeks to 42 weeks, including males and females. Their exclusion criteria ensured that healthy babies were studied and potential confounders of impaired respiratory activity were avoided. Their sequential approach in addressing the …
Reviewer #2 (Public review):
Summary:
The author's central hypothesis was that the strength of cortico-respiratory coupling in infants is negatively associated with apnoea rate. To prove this, they first investigated the existence of cortico-respiratory coupling in premature and term-born infants, the spatial localisation of the cortical activity and its relationship with the phase of the respiratory cycle, and the directionality of coupling.
Strengths:
The researchers used synchronised EEG and impedance pneumography to detect the phase amplitude coupling.
They have studied a wide range of gestations, from 28 weeks to 42 weeks, including males and females. Their exclusion criteria ensured that healthy babies were studied and potential confounders of impaired respiratory activity were avoided. Their sequential approach in addressing the objectives was appropriate.
Weaknesses:
As a neonatal clinician and neuroscientist, I have commented based on my expertise. I have not commented on signal processing.
I did not identify any major weaknesses in the study. Some minor weaknesses include:
(1) Data relating to the cortical oscillations and the respiratory phase is given. However, whether this would lead to their hypothesis that the strength of cortico-respiratory coupling is negatively associated with apnoea rate is unclear. What preceding data enabled the authors to link the strength of coupling to the rate of apnoea?
(2) If we did not know of data showing the existence of cortico-respiratory coupling in newborn infants, then should it not be the first research question to examine?
(3) What are the characteristics of the infants who contributed data to establish the cortico-respiratory coupling (Figures 2 and 3)?
(4) Although it is the most plausible direction of the relationship, with neural activation driving respiratory muscle contraction, how can the authors prove this with their data? Given that they show coherence between signals, how do we know that the cortical signal precedes the respiratory muscle contraction?
(5) Apgar score is an ordinal variable. The authors should summarise this as median (range).
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Reviewer #3 (Public review):
Summary:
This is a strong and important report that presents a framework for understanding cortical contributions to neonatal respiration. Overall, the authors successfully achieved their goal of linking cortical activity to respiratory drive. Despite the correlational nature of this study, it is a crucial step in establishing a foundation for future work to elucidate the interaction between cortical activity and breathing.
Strengths:
(1) The introduction and use of workflows that establish correlational relationships between breathing and brain activity.
(2) The execution of these workflows in human neonates.
Weaknesses:
Interpretations related to causal inference, confounds of sleep and caffeine, and the spatial interpretation of EEG data need to be addressed to ensure that the data appropriately support …
Reviewer #3 (Public review):
Summary:
This is a strong and important report that presents a framework for understanding cortical contributions to neonatal respiration. Overall, the authors successfully achieved their goal of linking cortical activity to respiratory drive. Despite the correlational nature of this study, it is a crucial step in establishing a foundation for future work to elucidate the interaction between cortical activity and breathing.
Strengths:
(1) The introduction and use of workflows that establish correlational relationships between breathing and brain activity.
(2) The execution of these workflows in human neonates.
Weaknesses:
Interpretations related to causal inference, confounds of sleep and caffeine, and the spatial interpretation of EEG data need to be addressed to ensure that the data appropriately support the conclusions.
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Author response:
We would like to thank the reviewers for their helpful comments and critique of our manuscript. We plan to make the following revisions, which will improve the clarity of our manuscript and the robustness of our findings.
We will revise methodological details and interpretation throughout the manuscript. In particular, we will consider alternative methods for calculating surrogates. We intend to investigate the relationship between apnoea rate and phase-amplitude coupling at other electrodes as suggested by Reviewer 1, and we will revise the details of the linear-mixed effects models.
In relation to the comments raised by both Reviewers 2 and 3, we will carefully address the wording throughout the manuscript, including addressing the order of hypotheses, our interpretation of the directionality of the relationship …
Author response:
We would like to thank the reviewers for their helpful comments and critique of our manuscript. We plan to make the following revisions, which will improve the clarity of our manuscript and the robustness of our findings.
We will revise methodological details and interpretation throughout the manuscript. In particular, we will consider alternative methods for calculating surrogates. We intend to investigate the relationship between apnoea rate and phase-amplitude coupling at other electrodes as suggested by Reviewer 1, and we will revise the details of the linear-mixed effects models.
In relation to the comments raised by both Reviewers 2 and 3, we will carefully address the wording throughout the manuscript, including addressing the order of hypotheses, our interpretation of the directionality of the relationship between cortical and respiratory activity, and the connection between cortical-respiratory coupling and apnoea. We will further clarify the limitations of our recording setup and approach, in particular the limited EEG montage, and add further details with regards to sleep state and caffeine.
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