The brain beating and heart breathing: a unifying theory of the neuro- cardiac- respiratory control in infant and adult sudden unexpected deaths

Background: Sudden Infant Death Syndrome (SIDS) is characterized by the death of an infant that cannot be explained, despite a systematic case examination, including death scene investigation, autopsy and review of the clinical history. Nowadays, Sudden Unexpected Infant Death (SUID) is a wide-ranging concept used to describe any sudden and unexpected death, whether explained or unexplained, including SIDS, which occurs during the first year of life. Several differing and sometimes contradictory hypotheses of the underlying mechanisms of SIDS have been proposed. The most reliable seems to be the “triple risk hypothesis”. Based on this theory, unexpected infant deaths might arise as a consequence of the combination of three factors coming together: a vulnerable infant, a vulnerable phase of development and a final insult occurring in this window of vulnerability. Recently, a unified neuropathological theory contributes to describing SIDS. According to this, serotonergic neurons play a crucial homeostatic function in the cardiorespiratory brainstem centres. A high incidence of morphological abnormalities and biochemical defects of serotoninergic neurotransmission have been reported in the brainstem of SIDS victims. This brain region includes the main nuclei and structures that coordinate the vital activities, such as cardiovascular function and breathing, perinatal and after birth. Nevertheless, evidence suggests likely genomic complexity and a degree of overlap among SIDS, Sudden Intrauterine Death (SIUD), Sudden Cardiac Death (SCD) and Sudden Unexpected Death in Epilepsy (SUDEP). In SUDEP, which has clinical parallels with SIDS, alterations to medullary serotoninergic neural populations and autonomic dysregulation have been shown too. Molecular profiling of SUDEP cases and the investigation of genetic models have directed to the identification of putative SUDEP genes of which most are ion channel active along the neurocardiac, neuroautonomic, and neurorespiratory pathway. Concurrently, anomalous time- activation, transcription or regional expression of candidate neuro-cardiac-respiratory genes implicated for SUDEP, could be similarly involved in other unexpected sudden deaths. A small but significant proportion of infants who die suddenly and unexpectedly have been shown on postmortem genetic testing to have Developmental Serotonopathies, Cardiac Channelopathies and Autonomic Nervous System Dysregulation, with considerable implications for surviving and future family members. This has led to the demonstration that neuro-cardiac genes are expressed in both tissues (brain and heart) and recently in the respiratory system. Aim: Despite their decreasing incidence, SIDS and SUDEP are still important causes of death. There are many nuclei in the cardio and respiratory centres of the brain involved in unexpected and sudden deaths. Cardiac, sympathetic, and respiratory motor activities can be viewed as a unified rhythm controlled by brainstem neural circuits for effective and efficient gas exchange. We aim to describe abnormalities in these nuclei, in part because robust molecular or functional examination of these nuclei has not been carefully performed. We intend to perform detailed functional mapping of these brainstem nuclei. Specifically, the cardiorespiratory and cardioventilatory coupling can be understood as a unified vital rhythm controlled by brainstem neural circuits. By cardiorespiratory coupling, we mean the Respiratory Sinus Arrhythmia (RSA) that is characterized by a heart rate (HR) increasing during inspiration and an HR decrease during expiration. Conversely, Cardioventilatory coupling (CVC) is considered the influence of heartbeats and arterial pulse pressure on respiration with the tendency for the next inspiration to start at a preferred latency after the last heartbeat in expiration. We hypothesized that these two reflex systems are not separate, but constitute an integrated network. We defined this last concept as "unifying theory". By studying all the maps of the cardiorespiratory nuclei of the Literature, we integrated this concept into a reworking map of brainstem nuclei that could also explain the gasping and blocking cardiorespiratory of sudden deaths. The theory of a unique, unifying cardiorespiratory network, it has been recently demonstrated in some cases of arrhythmia, in some cases of SUDEP with striking systolic hypotensive changes and in some cases of SIDS too. Material and Methods: We investigated articles, reviews indexed in PubMed describing putative neuro-cardiac-respiratory genes and cardiorespiratory, and cardioventilatory coupling theories. Specifically, we evaluated cardiorespiratory brainstem nuclei and whole brains of fetal, infant and adult autopsies respectively to detect congenital errors in the cerebral development or malformations, but also to identify the “normal” or “dysplastic” brainstem centres. Results: Based on the Literature, we identified a brain-heart gene mapping and a scheme of cardiorespiratory brainstem nuclei network. Contemporary, we collected a large pool of fetal brain malformations and cardiorespiratory nuclei dysgenesis both in infants both in adult sudden deaths. We found dysgenesia, agenesia and hypoplasia of brainstem nuclei associated with SIDS cases, compared with post-mortem infant control cases. However, the arcuate nucleus showed insignificant inter-variations regarding adults autoptic cases. Discussion: Many intrinsic and extrinsic factors increase fetal, perinatal, infant, and adult sudden death susceptibility. The final common pathway for SIDS and SUDEP involves a failure to arouse and autoresuscitate in response to environmental challenge. The different risk factors, among these a prone position, can directly alter the function of cardiorespiratory nuclei and impair the ability of this network to coordinate cardiorespiratory–cardioventilatory coupling. Conclusions: Neuropathological analysis of the infant brainstem and neuro-cardiac-respiratory gene mapping represents a good tool to infer on the final events of SIDS and SUDEP, although nothing it is clear regarding the role of adult cardiorespiratory centres. An integrated study of postmortem neuropathology and molecular autopsies could help to understand the network of this beating-breathing-thinking unit.