arXiv subjects

Martin G. Frasch

Publications and source records attributed to Martin G. Frasch.

36 records · Page 2Linked to original sources

arXiv2021

The role of the vagus nerve during fetal development and its relationship with the environment

The autonomic nervous system (ANS) regulatory capacity begins before birth as the sympathetic and parasympathetic activity contributes significantly to the fetus' development. Several studies have shown how vagus nerve is involved in many vital processes during fetal, perinatal and postnatal life: from the regulation of inflammation through the anti-inflammatory cholinergic pathway, which may affect the functioning of each organ, to the production of hormones involved in bioenergetic metabolism. In addition, the vagus nerve has been recognized as the primary afferent pathway capable of transmitting information to the brain from every organ of the body. Therefore, this hypothesis paper aims to review the development of ANS during fetal and perinatal life, focusing particularly on the vagus nerve, to identify possible "critical windows" that could impact its maturation. These "critical windows" could help clinicians know when to monitor fetuses to effectively assess the developmental status of both ANS and specifically the vagus nerve. In addition, this paper will focus on which factors (i.e. fetal characteristics and behaviors, maternal lifestyle and pathologies, placental health and dysfunction, labor, incubator conditions, and drug exposure) may have an impact on the development of the vagus during the above-mentioned "critical window" and how. This analysis could help clinicians and stakeholders define precise guidelines for improving the management of fetuses and newborns, particularly to reduce the potential adverse environmental impacts on ANS development that may lead to persistent long-term consequences. Since the development of ANS and the vagus influence have been shown to be reflected in cardiac variability, this paper will rely in particular on studies using fetal heart rate variability (fHRV) to monitor the continued growth and health of both animal and human fetuses.

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arXiv2021

Heart rate variability code: Does it exist and can we hack it?

Heart rate variability (HRV) has been studied for over 50 years, yet an integrative concept is missing on what HRV's mathematical properties represent physiologically. Here I introduce the notion of HRV code as an attempt to address this challenge systematically. I review the existing evidence from physiological studies in various species to support this concept and propose experiments to help validate and expand this notion further.

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arXiv2021

Detection of Maternal and Fetal Stress from the Electrocardiogram with Self-Supervised Representation Learning

In the pregnant mother and her fetus, chronic prenatal stress results in entrainment of the fetal heartbeat by the maternal heartbeat, quantified by the fetal stress index (FSI). Deep learning (DL) is capable of pattern detection in complex medical data with high accuracy in noisy real-life environments, but little is known about DL's utility in non-invasive biometric monitoring during pregnancy. A recently established self-supervised learning (SSL) approach to DL provides emotional recognition from electrocardiogram (ECG). We hypothesized that SSL will identify chronically stressed mother-fetus dyads from the raw maternal abdominal electrocardiograms (aECG), containing fetal and maternal ECG. Chronically stressed mothers and controls matched at enrolment at 32 weeks of gestation were studied. We validated the chronic stress exposure by psychological inventory, maternal hair cortisol and FSI. We tested two variants of SSL architecture, one trained on the generic ECG features for emotional recognition obtained from public datasets and another transfer-learned on a subset of our data. Our DL models accurately detect the chronic stress exposure group (AUROC=0.982+/-0.002), the individual psychological stress score (R2=0.943+/-0.009) and FSI at 34 weeks of gestation (R2=0.946+/-0.013), as well as the maternal hair cortisol at birth reflecting chronic stress exposure (0.931+/-0.006). The best performance was achieved with the DL model trained on the public dataset and using maternal ECG alone. The present DL approach provides a novel source of physiological insights into complex multi-modal relationships between different regulatory systems exposed to chronic stress. The final DL model can be deployed in low-cost regular ECG biosensors as a simple, ubiquitous early stress detection and monitoring tool during pregnancy. This discovery should enable early behavioral interventions.

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arXiv2021

Update on the multimodal pathophysiological dataset of gradual cerebral ischemia in a cohort of juvenile pigs: auditory, sensory and high-frequency sensory evoked potentials

We expand from a spontaneous to an evoked potentials (EP) data set of brain electrical activities as electrocorticogram (ECoG) and electrothalamogram (EThG) in juvenile pig under various sedation, ischemia and recovery states. This EP data set includes three stimulation paradigms: auditory (AEP, 40 and 2000 Hz), sensory (SEP, left and right maxillary nerve) and high-frequency oscillations (HFO) SEP. This permits derivation of electroencephalogram (EEG) biomarkers of corticothalamic communication under these conditions. The data set is presented in full band sampled at 2000 Hz. We provide technical validation of the evoked responses for the states of sedation, ischemia and recovery. This extended data set now permits mutual inferences between spontaneous and evoked activities across the recorded modalities. Future studies on the dataset may contribute to the development of new brain monitoring technologies, which will facilitate the prevention of neurological injuries.

q-bio.NC↗

arXiv2020

Recording and manipulation of vagus nerve electrical activity in chronically instrumented unanesthetized near term fetal sheep

Background: The chronically instrumented pregnant sheep has been used as a model of human fetal development and responses to pathophysiologic stimuli. This is due to the unique amenability of the unanesthetized fetal sheep to the surgical placement and maintenance of catheters and electrodes, allowing repetitive blood sampling, substance injection, recording of bioelectrical activity, application of electric stimulation and in vivo organ imaging. Recently, there has been growing interest in pleiotropic effects of vagus nerve stimulation (VNS) on various organ systems such as innate immunity, metabolism, and appetite control. There is no approach to study this in utero and corresponding physiological understanding is scarce. New Method: Based on our previous presentation of a stable chronically instrumented unanesthetized fetal sheep model, here we describe the surgical instrumentation procedure allowing successful implantation of a cervical uni- or bilateral VNS probe with or without vagotomy. Results: In a cohort of 53 animals, we present the changes in blood gas, metabolic, and inflammatory markers during the postoperative period. We detail the design of a VNS probe which also allows recording from the nerve. We also present an example of vagus electroneurogram (VENG) recorded from the VNS probe and an analytical approach to the data. Comparison with Existing Methods: This method represents the first implementation of VENG/VNS in a large pregnant mammalian organism. Conclusions: This study describes a new surgical procedure allowing to record and manipulate chronically the vagus nerve activity in an animal model of human pregnancy.

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arXiv2020

Monitoring fetal electroencephalogram intrapartum: a systematic literature review

Background: Studies about the feasibility of monitoring fetal electroencephalogram (fEEG) during labor began in the early 1940s. By the 1970s, clear diagnostic and prognostic benefits from intrapartum fEEG monitoring were reported, but until today, this monitoring technology has remained a curiosity. Objectives: Our goal was to review the studies reporting the use of fEEG including the insights from interpreting fEEG patterns in response to uterine contractions during labor. We also used the most relevant information gathered from clinical studies to provide recommendations for enrollment in the unique environment of a labor and delivery unit. Data sources: PubMed. Eligibility criteria: The search strategy was: ("fetus"[MeSH Terms] OR "fetus"[All Fields] OR "fetal"[All Fields]) AND ("electroencephalography"[MeSH Terms] OR "electroencephalography"[All Fields] OR "eeg"[All Fields]) AND (Clinical Trial[ptyp] AND "humans"[MeSH Terms]). Because the landscape of fEEG research has been international, we included studies in English, French, German, and Russian. Results: From 256 screened studies, 40 studies were ultimately included in the qualitative analysis. We summarize and report features of fEEG which clearly show its potential to act as a direct biomarker of fetal brain health during delivery, ancillary to fetal heart rate monitoring. However, clinical prospective studies are needed to further establish the utility of fEEG monitoring intrapartum. We identified clinical study designs likely to succeed in bringing this intrapartum monitoring modality to the bedside. Limitations: Despite 80 years of studies in clinical cohorts and animal models, the field of research on intrapartum fEEG is still nascent and shows great promise to augment the currently practiced electronic fetal monitoring.

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arXiv2020

Early Biomarkers and Intervention Programs for the Infant Exposed to Prenatal Stress

Functional development of affective and reward circuits, cognition and response inhibition later in life exhibits vulnerability periods during gestation and early childhood. Extensive evidence supports the model that exposure to stressors in the gestational period and early postnatal life increases an individual's susceptibility to future impairments of functional development. Recent versions of this model integrate epigenetic mechanisms of the developmental response. Their understanding will guide the future treatment of the associated neuropsychiatric disorders. A combination of non-invasively obtainable physiological signals and epigenetic biomarkers related to the principal systems of the stress response, the Hypothalamic-Pituitary axis (HPA) and the Autonomic Nervous System (ANS), are emerging as the key predictors of neurodevelopmental outcomes. Such electrophysiological and epigenetic biomarkers can prove to timely identify children benefiting most from early intervention programs. Such programs should ameliorate future disorders in otherwise apparently healthy children. The recently developed Early Family-Centered Intervention Programs aim to influence the care and stimuli provided daily by the family and improving parent/child attachment, a key element for healthy socio-emotional adult life. Although frequently underestimated, such biomarker-guided early intervention strategy represents a crucial first step in the prevention of future neuropsychiatric problems and in reducing their personal and societal impact.

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arXiv2020

Impact of chronic fetal hypoxia and inflammation on cardiac pacemaker cell development

Chronic fetal hypoxia and infection are examples of adverse conditions during complicated pregnancy, which impact cardiac myogenesis and increase the lifetime risk of heart disease. However, the effects that chronic hypoxic or inflammatory environments exert on cardiac pacemaker cells are poorly understood. Here, we review the current evidence and novel avenues of bench-to-bed research in this field of perinatal cardiogenesis as well as its translational significance for early detection of future risk for cardiovascular disease.

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arXiv2020

Multimodal pathophysiological dataset of gradual cerebral ischemia in a cohort of juvenile pigs

Ischemic brain injuries are frequent and difficult to detect reliably or early. We present the multi-modal data set containing cardiovascular (blood pressure, blood flow, electrocardiogram) and brain electrical activities to derive electroencephalogram (EEG) biomarkers of corticothalamic communication under normal, sedation and hypoxic/ischemic conditions with ensuing recovery. We provide technical validation using EEGLAB. We also delineate the corresponding changes in the electrocardiogram (ECG)-derived heart rate variability (HRV) with the potential for future in-depth analyses of joint EEG-ECG dynamics. We review an open-source methodology to derive signatures of coupling between the ECoG and electrothalamogram (EThG) signals contained in the presented data set to better characterize the dynamics of thalamocortical communication during these clinically relevant states. The data set is presented in full band sampled at 2000 Hz, so the additional potential exists for insights from the full-band EEG and high-frequency oscillations under the bespoke experimental conditions. Future studies on the dataset may contribute to the development of new brain monitoring technologies, which will facilitate the prevention of neurological injuries.

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arXiv2019

Fetal cardiovascular decompensation during labor predicted from the individual heart rate: a prospective study in fetal sheep near term and the impact of low sampling rate

We present a novel computerized fetal heart rate intrapartum algorithm for early and individualized prediction of fetal cardiovascular decompensation, a key event in the causal chain leading to brain injury. This real-time machine learning algorithm performs well on noisy fetal heart rate data and requires ~2 hours to train on the individual fetal heart rate tracings in the first stage of labor; once trained, the algorithm predicts the event of fetal cardiovascular decompensation with 92% sensitivity. We show that the algorithm's performance suffers reducing sensitivity to 67% when the fetal heart rate is acquired at the sampling rate of 4 Hz used in ultrasound cardiotocographic monitors compared to the electrocardiogram(ECG)-derived signals as can be acquired from maternal abdominal ECG.

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arXiv2019

Microglial memory of early life stress and inflammation: susceptibility to neurodegeneration in adulthood

We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life-modifying interventions to steer developmental trajectories to their optimum?

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arXiv2019

Chronic stress may disrupt covariant fluctuations of vitamin D and cortisol plasma levels in pregnant sheep during the last trimester: a preliminary report

Psychosocial stress during pregnancy is a known contributor to preterm birth, but also has been increasingly appreciated as an in utero insult acting long-term on prenatal and postnatal neurodevelopmental trajectories. These events impact many information molecules, including both vitamin D and cortisol. Both have been linked to low birth premature babies. Cortisol tends to be further elevated in women, while vitamin D tends to be decreased from their normal levels during pregnancy. One facilitates labor in part by elevating placental CRH, the other by limiting CRH in placental tissue. Both are linked to managing adversity. Studies in large animal models with high resemblance to human physiology are sparse to model the changes induced by such stress exposure. Using an established pregnant sheep model of stress during human development, here we focused on measuring the changes in maternal Vitamin D and cortisol responses due to chronic inescapable stress mimicking daily challenges in the last trimester of human pregnancy. The present pilot data show that chronic maternal stress during pregnancy results in endocrine and metabolic chronic habituation paralleled by sensitization to acute stress challenges. Chronic stress appears to disrupt a physiological relationship between oscillations of vitamin D and cortisol. These speculations need to be explored in future studies.

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arXiv2019

Unexpected sawtooth artifact in beat-to-beat pulse transit time measured from patient monitor data

Object: It is increasingly popular to collect as much data as possible in the hospital setting from clinical monitors for research purposes. However, in this setup the data calibration issue is often not discussed and, rather, implicitly assumed, while the clinical monitors might not be designed for the data analysis purpose. We hypothesize that this calibration issue for a secondary analysis may become an important source of artifacts in patient monitor data. We test an off-the-shelf integrated photoplethysmography (PPG) and electrocardiogram (ECG) monitoring device for its ability to yield a reliable pulse transit time (PTT) signal. Approach: This is a retrospective clinical study using two databases: one containing 35 subjects who underwent laparoscopic cholecystectomy, another containing 22 subjects who underwent spontaneous breathing test in the intensive care unit. All data sets include recordings of PPG and ECG using a commonly deployed patient monitor. We calculated the PTT signal offline. Main Results: We report a novel constant oscillatory pattern in the PTT signal and identify this pattern as a sawtooth artifact. We apply an approach based on the de-shape method to visualize, quantify and validate this sawtooth artifact. Significance: The PPG and ECG signals not designed for the PTT evaluation may contain unwanted artifacts. The PTT signal should be calibrated before analysis to avoid erroneous interpretation of its physiological meaning.

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arXiv2019

Vagal contributions to fetal heart rate variability: an omics approach

Fetal heart rate variability (fHRV) is an important indicator of health and disease, yet its physiological origins, neural contributions in particular, are not well understood. We aimed to develop novel experimental and data analytical approaches to identify fHRV measures reflecting the vagus nerve contributions to fHRV. In near-term ovine fetuses, a comprehensive set of 46 fHRV measures was computed from fetal pre-cordial electrocardiogram recorded during surgery and 72 hours later without (n=24) and with intra-surgical bilateral cervical vagotomy (n=15). The fetal heart rate did not change due to vagotomy. We identify fHRV measures specific to the vagal modulation of fHRV: Multiscale time irreversibility asymmetry index (AsymI), Detrended fluctuation analysis (DFA) alpha1, Kullback-Leibler permutation entropy (KLPE) and Scale dependent Lyapunov exponent slope (SDLE alpha). We provide a systematic delineation of vagal contributions to fHRV across signal-analytical domains which should be relevant for the emerging field of bioelectronic medicine and the deciphering of the vagus code. Our findings also have clinical significance for in utero monitoring of fetal health during surgery.

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arXiv2019

Fetus: the radar of maternal stress, a cohort study

Objective: We hypothesized that prenatal stress (PS) exerts lasting impact on fetal heart rate (fHR). We sought to validate the presence of such PS signature in fHR by measuring coupling between maternal HR (mHR) and fHR. Study design: Prospective observational cohort study in stressed group (SG) mothers with controls matched for gestational age during screening at third trimester using Cohen Perceived Stress Scale (PSS) questionnaire with PSS-10 equal or above 19 classified as SG. Women with PSS-10 less than 19 served as control group (CG). Setting: Klinikum rechts der Isar of the Technical University of Munich. Population: Singleton 3rd trimester pregnant women. Methods: Transabdominal fetal electrocardiograms (fECG) were recorded. We deployed a signal processing algorithm termed bivariate phase-rectified signal averaging (BPRSA) to quantify coupling between mHR and fHR resulting in a fetal stress index (FSI). Maternal hair cortisol was measured at birth. Differences were assumed to be significant for p value less than 0.05. Main Outcome Measures: Differences for FSI between both groups. Results: We screened 1500 women enrolling 538 of which 16.5 % showed a PSS-10 score equal or above 19 at 34+0 weeks. Fifty five women eventually comprised the SG and n=55 served as CG. Median PSS was 22.0 (IQR 21.0-24.0) in the SG and 9.0 (6.0-12.0) in the CG, respectively. Maternal hair cortisol was higher in SG than CG at 86.6 (48.0-169.2) versus 53.0 (34.4-105.9) pg/mg. At 36+5 weeks, FSI was significantly higher in fetuses of stressed mothers when compared to controls [0.43 (0.18-0.85) versus 0.00 (-0.49-0.18)]. Conclusion: Our findings show a persistent effect of PS affecting fetuses in the last trimester.

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arXiv2018

Heart rate variability monitoring identifies asymptomatic toddlers exposed to Zika virus during pregnancy

Although Zika virus (ZIKV) seems to be prominently neurotropic, there are some reports of involvement of other organs, particularly the heart. Of special concern are those children exposed prenatally to ZIKV and born with no microcephaly or other congenital anomaly. Electrocardiogram (ECG) - derived heart rate variability (HRV) metrics represent an attractive, low cost, widely deployable tool for early identification of such children. We hypothesized that HRV in such children would yield a biomarker of fetal ZIKV exposure. We investigated the HRV properties of 21 infants aged 4 to 25 months from Brazil. The infants were divided in two groups, the ZIKV-exposed (n=13) and controls (n=8). Single channel ECG was recorded in each child at ~15 months of age and HRV was analyzed in 5 min segments to provide a comprehensive characterization of the degree of variability and complexity of the heart rate. Using a cubic Support Vector Machine (SVM) classifier we identified babies as Zika cases or controls with negative predictive value of 92% and positive predictive value of 86%. Our results show that HRV metrics can help differentiate between ZIKV-affected, yet asymptomatic, and non-ZIKV exposed babies. We identified the Grid Count as the best HRV measure in this study allowing such differentiation, regardless the presence of microcephaly. We show that it is feasible to measure HRV in infants and toddlers using a small non-invasive portable ECG device and that such approach may uncover memory of in utero exposure to ZIKV. This approach may be useful for future studies and low-cost screening tools involving this challenging to examine population.

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arXiv2017

Non-invasive biomarkers of fetal brain development reflecting prenatal stress: an integrative multi-scale multi-species perspective on data collection and analysis

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). The HPA axis is a dynamic system regulating homeostasis, especially the stress response, and is highly sensitive to adverse early life experiences. We review the evidence for the effects of PS on fetal programming of the HPA axis and the ANS. We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of these programming effects. Such approach would identify adverse postnatal brain developmental trajectories, a prerequisite for designing therapeutic interventions. The multiple scales include the biomarkers reflecting changes in the brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS. We conclude that studies into PS effects must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive biomarkers.

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arXiv2017

Efficient fetal-maternal ECG signal separation from two channel maternal abdominal ECG via diffusion-based channel selection

There is a need for affordable, widely deployable maternal-fetal ECG monitors to improve maternal and fetal health during pregnancy and delivery. Based on the diffusion-based channel selection, here we present the mathematical formalism and clinical validation of an algorithm capable of accurate separation of maternal and fetal ECG from a two channel signal acquired over maternal abdomen.

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