Biology subjects

Frasch, M. G.

Publications and source records attributed to Frasch, M. G..

7 recordsLinked to original sources

bioRxiv2026

Fetal Twin: a mechanistic computational model of fetal physiology for heart-rate-variability biomarker research

Fetal-monitoring biomarkers for neonatal hypoxic-ischemic brain injury face a structural gap: the mechanistic ground truth that would label a training set -- perfusion pressure, the moment of decompensation, the injury time course -- cannot be measured at scale or ethically in human pregnancy or labor, and generative synthetic data carry no mechanistic labels. We address this with a mechanistic computational model of the fetal cardiovascular, autonomic, and metabolic response to controlled hypoxic stress, and use it to test how beat detection and acquisition fidelity alter the interpretation of fetal-heart-rate-variability (HRV) biomarkers. The model integrates these systems forward in time across antepartum development (gestational-age growth scaling) and intrapartum stress (umbilical-cord occlusions), emitting synthetic monitoring signals (fetal heart rate, RR intervals) co-registered with model-computed latent labels (pH, base deficit, lactate, perfusion pressure, decompensation and injury states). In a fetal-sheep-derived autonomic-loop configuration we report three results. First, a phase-accumulator beat detector shows that the apparently physiologic baseline HRV of an earlier build was largely a detector artifact, and a noise-off control shows beat-to-beat variability requires an explicit stochastic driver rather than self-sustained autonomic oscillation. Second, a sampling-fidelity sweep yields a fidelity-matched selection rule: a deceleration-area biomarker is preserved at CTG-grade 4 Hz whereas RMSSD is corrupted there (inflated about 8-fold by timing quantization) and recovers only at fetal-ECG rates. Third, autonomic modulation alone does not reproduce the published RMSSD rise-then-collapse -- a negative result that motivates, but does not prove, an intrinsic sinoatrial-pacemaker contribution as a testable hypothesis. This is an in-silico, hypothesis-generating study: the model is not validated for individual fetal prediction, clinical risk estimation, or clinical decision-making. The model is implemented as Fetal Twin (engine fetaltwin), a source-available research instrument released under a noncommercial license, together with all figure configurations, so that these controlled experiments are reproducible. Key PointsO_LIProgress on fetal-monitoring biomarkers for neonatal brain-injury risk is constrained by a structural gap: the mechanistic ground truth that would label a training set -- perfusion pressure, the moment of cardiovascular decompensation, the time course of injury -- cannot be measured at scale or ethically during human pregnancy or labor. C_LIO_LIWe present Fetal Twin (source-available engine fetaltwin), a publicly available, noncommercially-licensed mechanistic testbed for fetal physiological development. It integrates the fetal cardiovascular, metabolic, and autonomic systems forward in time across antepartum development (gestational-age growth scaling) and intrapartum stress (umbilical-cord occlusions), and emits synthetic monitoring signals (fetal heart rate, RR intervals) co-registered with model-computed latent labels (pH, lactate, perfusion pressure, decompensation and injury states). C_LIO_LIThe names digital-twin connotation is deliberate but bounded: Fetal Twin is a mechanistic, population-level twin of fetal physiology used as a research instrument -- not a validated, patient-specific clinical digital twin or predictor. Its purpose is to interrogate what candidate biomarkers can and cannot mean, via in-silico controls impossible in vivo -- swapping the beat detector, turning a noise source off, ablating a reflex, or quantizing the signal to a monitors sampling grid. C_LIO_LIDemonstrations in a fetal-sheep-derived autonomic-loop configuration show that beat-to-beat HRV amplitude can be a numerical artifact of the beat detector, and that in this model class beat-to-beat variability requires an explicit stochastic driver -- it does not arise as a self-sustained oscillation of the deterministic autonomic loop. C_LIO_LIA further demonstration establishes a fidelity-matched biomarker-selection rule -- a deceleration-area biomarker survives CTG-grade 4 Hz sampling whereas RMSSD is corrupted at that rate and needs fetal-ECG timing -- and a negative result shows the published RMSSD "rise-then-collapse" is not reproducible from autonomic modulation in this model class, motivating (but not proving) an intrinsic-pacemaker hypothesis. C_LI

physiology↗

bioRxiv2026

Coordination-dynamics invariants from simultaneous vagus nerve electroneurogram and ECG: a Python pipeline applied to neonatal piglet endotoxaemia

HRV complexity metrics track the systemic cytokine response across mammalian inflammation models, but the dynamical mechanism translating molecular inflammation into HRV structure has remained unresolved, and no existing tool jointly extracts coordination-dynamics signatures from simultaneous vagus nerve electroneurogram (VENG) and ECG. We describe a modular open-source Python pipeline that (i) detects spectrally distinct latent states in 20 kHz whole-trunk VENG using a symmetric-Kullback-Leibler scan-statistic changepoint detector ported from earthquake seismology and verified against its R progenitor; (ii) places the inter-changepoint-interval series in the Haken-Kelso-Bunz coupled-oscillator framework, computes the Kuramoto order parameter R, fits the bistable potential V({varphi}) = -a cos{varphi} - b cos 2{varphi}, and maps each timepoint into the Arnold-tongue ({Omega}, K) plane; contrasts compound-action-potential band power between successive latent states; and (iii) couples the VENG analysis to a CIMVA HRV pipeline driven by a 5-algorithm Pro-MAC R-peak ensemble. Applied to a previously published two-animal neonatal piglet endotoxaemia cohort (Castel et al., 2020, 2024), the pipeline recovers known features of the (iv) preparation and surfaces three case-series observations that we frame as hypotheses for prospective replication: (1) a 6-8 s VENG state-switching period coincident with the HRV LF/HF spectral boundary; (2) qualitatively divergent coordination-dynamics trajectories under LPS versus LPS + VNS (Kuramoto R collapses from 0.69 to 0.12 without VNS, undergoes biphasic recovery to 0.99 with VNS, the two trajectories crossing at 60-75 min); (3) a regime-dependent empirical coupling between R and the HRV embedding scaling exponent eScalE (R {middle dot} eScalE {approx} 0.33 during moderate challenge, doubling to {approx}0.80 during VNS overshoot). Pre-specified null comparisons (Poisson and bootstrap surrogates) demonstrate that R and the critical-slowing-down indicators carry information beyond their most obvious null alternatives. With N = 2 animals no inferential statistics are possible, so these findings are reported as hypothesis-generating; the manuscript closes with a pre-registered prospective protocol designed specifically to falsify them. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/728499v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@5ad100org.highwire.dtl.DTLVardef@4f6bb2org.highwire.dtl.DTLVardef@27a58aorg.highwire.dtl.DTLVardef@e52e15_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIWe present an open-source Python pipeline that extracts coordination-dynamics invariants (Kuramoto phase coherence, Haken-Kelso-Bunz potential parameters, Arnold-tongue position, critical-slowing-down indicators) from simultaneously recorded vagus nerve electroneurogram (VENG) and ECG, starting from a spectral-KL scan-statistic changepoint detector ported from earthquake seismology. C_LIO_LIApplied to a previously published two-animal cohort (Castel et al., 2024), the pipeline reveals that VENG alternates between two spectrally distinct latent states at a baseline period of 6-8 s that coincides with the HRV low-frequency/high-frequency spectral boundary ([~]0.15 Hz). We propose the VENG latent-state oscillator as a candidate mechanistic generator of vagal LF HRV; this is a hypothesis motivated by the timescale match and is not established by the present data. C_LIO_LIIn this cohort, LPS endotoxaemia and vagus nerve stimulation drove qualitatively divergent trajectories in the coordination-dynamics phase space (Kuramoto R: 0.69 [->] 0.12 without VNS; biphasic to R [->] 0.99 with VNS at the IL-6/IL-8 cytokine peak). Because the design provides one animal per arm, these are case-series observations and not a between-arm statistical comparison. C_LIO_LIInter-changepoint-interval variance rose >100-fold roughly 15 min before overt state-switching collapse in the unmitigated animal. Bootstrap nulls drawn from the same animals pre-collapse ICI pool reject the same-distribution alternative ([§]2.6), motivating a critical-slowing-down early-warning hypothesis that requires prospective replication before any clinical use is warranted. C_LIO_LIThe pipeline surfaces a regime-dependent empirical coupling between VENG phase coherence (R) and HRV embedding scaling exponent (eScalE) in the VNS-treated animal: during moderate challenge R {middle dot} eScalE {approx} 0.33 (CV {approx} 0.20), during VNS-enhanced overshoot (45, 90, 105 min) the product doubles to {approx}0.80. The product is a post-hoc empirical construct, not a derived conservation law; we propose it as a falsification target for prospective cohorts ([§]6). C_LI

physiology↗

bioRxiv2024

Newborn reactions to maternal prenatal stress alter umbilical cord blood tRNA fragments targeting cholinergic transcripts

Maternal perceived prenatal stress (PPS) is a known risk factor for diverse developmental impairments in newborns, but the underlying molecular processes are incompletely understood. Here, we report that maternal PPS altered the birth profiles of blood transfer RNA fragments (tRFs), 16-50nt long non-random cleavage products of tRNAs, in a sex-dependent manner. Importantly, comparing stressed versus control maternal and umbilical cord blood serum presented alterations that were not limited to individual tRFs, but rather reflected selective changes in particular tRF families grouped by their mitochondrial or nuclear genome origin, parental tRNA coded amino acid, and cleavage type. tRF families that show stress- and sex-specific effects, revealed shared length and expression patterns which were strongest in the female newborns. Several of these tRFs carry complementary motifs to specific cholinergic mRNAs, suggesting possible translational regulation similar to microRNAs. Compatible with the cholinergic regulation of stress reactions, those "CholinotRFs" achieved an AUC of 95% when classifying female newborns according to maternal PPS. Moreover, we found altered catalytic activity of serum acetylcholinesterase, which was particularly elevated in male newborns, marking a second sex-specific effect. Our findings demonstrate an association of tRF families patterns with newborns sex-specific stress response to PPS and may lead to better diagnosis and therapeutic tools for these and other stressors.

molecular biology↗

bioRxiv2022

Factors determining success of the chronically instrumented unanesthetized fetal sheep model of human development: a retrospective cohort study

AimChronically instrumented non-anesthetized fetal sheep (CINAFS) have been the mainstay model of human fetal development for 60 years. As a large "two for one" animal model, with instrumentation of the ewe and her fetus, the model poses challenges to implement de novo and to maintain overtime at the highest standards of operating procedures to ensure its ongoing performance. A common, yet conventionally underreported issue researchers face is the rate of animal loss. Here, we investigate what determines the success of the pregnant sheep model. MethodsWe conducted a retrospective cohort study consisting of 82 experiments spanning the course of six years. Our team identified ten variables that we anticipated were likely to influence the experimental outcome, such as the time of year, animal size, and surgical complexity. ResultsThe single variable identified in this study as determining the successful outcome of the experiments is the experience level of the team. ConclusionThe CINAFS model offers enormous potential to further our understanding of human fetal development and to create interventional technologies. However, to improve the outcomes of CINAFS models, improved communication and training are needed. We discuss the implications of our findings for the successful implementation of this challenging yet scientifically advantageous animal model of human physiology. Key pointsO_LIThe fetal sheep model closely mirrors the physiology of human fetal development C_LIO_LIIn addition to its high translational potential, this model is known to have some generally not reported rate of experimental failure C_LIO_LIWe show that factors such as animal characteristics & surgical complexity do not influence the experimental outcomes C_LIO_LIInstead, the key factor in model experimental success is the level of the research teams experience C_LIO_LIThe key factors to improve the animal model outcomes are an intra- and inter-team communication C_LI

physiology↗

bioRxiv2021

Relationship between Deceleration Morphology and Phase Rectified Signal Averaging-based Parameters during Labor

During labor, uterine contractions trigger the response of the autonomic nervous system (ANS) of the fetus, producing sawtooth-like decelerations in the fetal heart rate (FHR) series. Under chronic hypoxia, ANS is known to regulate FHR differently with respect to healthy fetuses. In this study, we hypothesized that such different ANS regulation might also lead to a change in the FHR deceleration morphology. The hypothesis was tested in an animal model comprising 7 normoxic and 5 chronically hypoxic fetuses that underwent a protocol of umbilical cord occlusions (UCOs). Deceleration morphologies in the fetal inter-beat time interval (FRR) series were modeled using a trapezoid with four parameters, i.e., baseline b, deceleration depth a, UCO response time{tau} u and recovery time{tau} r. Comparing normoxic and hypoxic sheep, we found a clear difference for{tau} u (24.8 {+/-} 9.4 vs 39.8 {+/-} 9.7 s; p < 0.05), a (268.1 {+/-} 109.5 vs 373.0 {+/-} 46.0 ms; p < 0.1) and {Delta}{tau} ={tau} u -{tau} r (13.2 {+/-} 6.9 vs 23.9 {+/-} 7.5 s; p < 0.05). Therefore, the animal model supported the hypothesis that hypoxic fetuses have a longer response time{tau} u and larger asymmetry {Delta}{tau} as a response to UCOs. Assessing these morphological parameters during labor is challenging due to non-stationarity, phase desynchronization and noise. For this reason, in the second part of the study, we quantified whether acceleration capacity (AC), deceleration capacity (DC), and deceleration reserve (DR), computed through Phase-Rectified Signal Averaging (PRSA, known to be robust to noise), were correlated with the morphological parameters. DR and DC correlated with {Delta}{tau} and{tau} u for a wide range of the PRSA parameter T (max Pearsons correlation{rho} = 0.9, p < 0.05, and{rho} = 0.6, p < 0.1, respectively). In conclusion, deceleration morphologies have been found to differ between normoxic and hypoxic sheep fetuses during UCOs. The same difference can be assessed through PRSA based parameters, further motivating future investigations on the translational potential of this methodology on human data.

bioengineering↗

bioRxiv2018

First evidence that intrinsic fetal heart rate variability exists and is affected by chronic hypoxia

INTRODUCTIONIt is established that normal fetal HRV represents the integration of the autonomic nervous system, components due to fetal body and breathing movements, baroreflex and circadian processes. There is also some evidence of possible intrinsic pacemaker rhythms of the SA node affecting HRV in adult disease.\n\nHowever, whether intrinsic HRV (iHRV) exists in the fetal period and whether this is affected by chronic fetal hypoxia has never been tested. Here, we show iHRV in isolated hearts from fetal sheep in late gestation and significant effects on iHRV of pregnancy complicated by chronic fetal hypoxia.\n\nMETHODSChronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n=6) or hypoxia (10% inspired O2, n=9) for the last third of gestation (105-138 dG; term~145 dG) in bespoke isobaric chambers, as before. At 138dG, isolated hearts were studied under a Langendorff preparation. CIMVA software was used to calculate basal iHRV matrix indices across five signal-analytical domains from the systolic peaks within 15 min segments in each heart, as before. Data presented as Mean+SEM were compared by the Students t test for unpaired data.\n\nRESULTSThis level of maternal H yields fetal PaO2 values of 11.5{+/-}0.6 relative to controls of 20.9{+/-}0.5 mmHg. Hearts isolated from H pregnancy showed approximately 4-fold increases in the Grid transformation feature as well as the AND similarity index (sgridAND, informational domain) and a 4-fold reduction in the Scale dependent Lyapunov exponent slope (SDLEalpha, invariant domain). We also detected a 2-fold reduction in the Recurrence quantification analysis, the percentage of laminarity and recurrences and maximum diagonal line (pL, pR, dlmax, all from geometric domain) and (AsymI, energetic domain). For dlmax and sgridAND measures, this is also correlated to left ventricular end-diastolic pressure (LVEDP) across both groups.\n\nCONCLUSIONSThe isolated fetal hearts from the hypoxic pregnancy group exhibit a lower complexity in iHRV. This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it.\n\nSignificance StatementFetal heart rate variability (fHRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. Both, the heart, intrinsically, and extrinsic systems, such as the brain, are hypothesized to contribute to HRV. In a near-term fetal sheep model of human development, we identified fHRV components reflecting intrinsic contributions to fHRV. In addition, we show that these intrinsic fHRV components carry memory of chronic oxygen deprivation the fetus experienced during the last third of gestation.

physiology↗

bioRxiv2017

α7 nicotinic acetylcholine receptor signalling modulates the inflammatory and iron homeostasis in fetal brain microglia

Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on 7 nicotinic acetylcholine receptor (7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of 7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective 7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with 7nAChR agonistic stimulation. Conversely, antagonistic 7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated 7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of 7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and 7nAChR signaling in neurodevelopment.

neuroscience↗