Association between prenatal glucocorticoid exposure and adolescent neurodevelopment: An observational follow-up study.

INTRODUCTION: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long-lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8-9 years. This follow-up study aimed to examine whether these findings persisted into adolescence. MATERIAL AND METHODS: Prospective observational follow-up study involving twenty-one 14- to 15-year-old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty-five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention-deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus-pituitary-adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. RESULTS: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 versus references 105.9, mean difference -2.0, 95% confidence interval [CI]: -7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress-induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency-adjusted means: 16.0 Hz versus 17.8 Hz, mean difference -1.83 Hz, 95% CI: -3.21 to -0.45, p = 0.01). CONCLUSIONS: In 14- to 15-year-old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow-up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions.

Intake of eggs, choline, lutein, zeaxanthin, and DHA during pregnancy and their relationship to fetal neurodevelopment.

BACKGROUND: Maternal intake of eggs and nutrients contained within eggs during pregnancy have the potential to impact fetal neurodevelopment; however, this area is understudied. The purpose of this study was to determine whether maternal egg and choline intake and nutrient interactions between choline, lutein and zeaxanthin (L/Z), and DHA predict fetal neurodevelopment in a large cohort of pregnant women (n = 202). NCT02709239. METHODS: Food frequency questionnaires were used to assess egg and nutrient intake during pregnancy. Fetal neurodevelopment was measured using fetal biomagnetometry at 32 and 36wks gestation, and fetal autonomic indices (SDNN, RMSSD) and brain maturation indices (fABAS) were calculated. Generalized linear models tested the relationships between choline intake, egg intake, and nutrient interactions with fetal neurodevelopment. RESULTS: Maternal egg intake predicted RMSSD at 32wks and fABAS at 36wks. The interaction between choline and L/Z intake predicted fABAS at 32wks and 36wks and the interaction between choline intake, L/Z intake, and DHA predicted fABAS at 36wks. At 36wks, SDNN was predicted by L/Z intake and interactions between choline and L/Z, L/Z and DHA, and choline, L/Z, and DHA. CONCLUSION: Eggs and the nutrients contained within eggs showed synergistic associations with fetal neurodevelopment, and consumption should be encouraged among pregnant women.

Prenatal docosahexaenoic acid effect on maternal-infant DHA-equilibrium and fetal neurodevelopment: a randomized clinical trial.

INTRODUCTION: Maternal-infant equilibrium occurs when cord blood docosahexaenoic acid (DHA) is less than or equal to maternal DHA at delivery. Equilibrium may be an indicator of sufficient DHA for optimal fetal and infant neurodevelopment. The purpose of this study was to test the effect of maternal DHA supplementation on equilibrium status and fetal neurodevelopment. METHODS: Women enrolled between 12 and 20 weeks gestation and were randomized to 200 or 800 mg DHA/day until delivery. Maternal red blood cell (RBC) phospholipids were measured at enrollment, 32 weeks, delivery, and in cord blood at delivery. Fetal neurodevelopment was measured at 32 and 36 weeks gestation. Intent-to-treat analyses were conducted to test differences in equilibrium status by group. Fetal outcomes were assessed by equilibrium status and group. RESULTS: Three hundred women enrolled and 262 maternal-infant dyads provided blood samples at delivery. No maternal-infant dyads with maternal RBC-DHA ≤ 6.96% at delivery achieved equilibrium. The incidence of equilibrium was significantly higher in the 800 mg group. There was no effect of maternal group or equilibrium status on fetal neurodevelopment. CONCLUSION: The significance of maternal-infant DHA equilibrium remains unknown. Ongoing research will test the effect of treatment group, equilibrium, and nutrient status on infant behavior and brain function. IMPACT: Pregnant women who received a higher dose of docosahexaenoic acid (DHA) were more likely to achieve maternal-infant DHA equilibrium at delivery. Equilibrium status had no effect on fetal neurodevelopment in this sample. While DHA is crucial for early life neurodevelopment, the significance of achieving maternal-infant equilibrium above the lower threshold is uncertain. There is a lower threshold of maternal DHA status where maternal-infant DHA equilibrium never occurs. The lack of equilibrium associated with low maternal DHA status may indicate insufficient maternal status for optimal placental transfer.

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8- to 9-year-old children: A prospective observational study.

INTRODUCTION: Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. MATERIAL AND METHODS: Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+6  weeks of gestation) compared with 38 non-exposed, age-matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention-deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). RESULTS: There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relation between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses. CONCLUSIONS: Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment.

Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice.

Sepsis-induced myocardial depression (SIMD) is an early and frequent consequence of the infection-induced systemic inflammatory response syndrome. In homiotherms, variations in ambient temperature (Ta) outside the thermoneutral zone induce thermoregulatory responses mainly driven by a gradually increased sympathetic activity, which may affect disease severity. We hypothesized that thermoregulatory responses upon reduced Ta exposition aggravate SIMD in mice. Mice were kept at neutral Ta (30 ± 0.5 °C), moderately lowered Ta (26 ± 0.5 °C) or markedly lowered Ta (22 ± 0.5 °C), exposed to lipopolysaccharide- (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection) evoked shock and monitored for survival, cardiac autonomic nervous system function and left ventricular performance. Primary adult cardiomyocytes and heart tissue derived from treated mice were analyzed for inflammatory responses and signaling pathways of myocardial contractility. We show that a moderate reduction of Ta to 26 °C led to a 40% increased mortality of LPS-treated mice when compared to control mice and that a marked reduction of Ta to 22 °C resulted in an early mortality of all mice. Mice kept at 26 °C exhibited increased heart rate and altered indices of heart rate variability (HRV), indicating sympathovagal imbalance along with aggravated LPS-induced SIMD. This SIMD was associated with reduced myocardial ß-adrenergic receptor expression and suppressed adrenergic signaling, as well as with increased myocardial iNOS expression, nitrotyrosine formation and leukocyte invasion as well as enhanced apoptosis and appearance of contraction band necrosis in heart tissue. While ineffective separately, combined treatment with the ß2-adrenergic receptor (AR) antagonist ICI 118551 (10 ng/gbw) and the inducible nitric oxide synthase (iNOS) inhibitor 1400 W (5 µg/gbw) reversed the increase in LPS-induced mortality and aggravation of SIMD at reduced Ta. Thus, consequences of thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range increase the mortality from LPS-evoked shock and markedly prolong impaired myocardial function. These changes are mitigated by combined ß2-AR and iNOS inhibition.

Dependencies between maternal and fetal autonomic tone.

Background Disturbances in maternal physiology can cause changes in the fetal condition that may lead to impaired fetal development. Synchronous monitoring of cardiac autonomic tone via the assessment of the fetal and maternal heart rate (HR) and heart rate variability (HRV) may provide an appropriate diagnostic window. Methods Partial rank correlation coefficients between the maternal and fetal HR and HRV indices were calculated and verified by testing surrogate data in 315 magnetocardiographic (MCG) recordings from 141 healthy women pregnant with singleton fetuses [18+6 to 39+2 weeks gestational age (WGA)]. We assessed maternal self-perceived depression, anxiety and stress by means of the Depression, Anxiety, Stress Scales self-reporting instrument (DASS42G) questionnaire. Results The maternal HRV correlated positively with the fetal HRV, but negatively with the fetal HR. Correlation was |r|<0.2 in state-independent and gestational age (GA) <32 weeks, but |r|>0.2 in active sleep and GA ≥32 weeks. The DASS42G results correlated with the maternal HRV and HR, while the fetal HR and HRV were not influenced. Conclusion Correlations between maternal and fetal autonomic activation were statistically confirmed. They depend on the GA and active fetal state. As far as healthy subjects are concerned, maternal self-perceived stress, anxiety or depression is mirrored in maternal but not in fetal autonomic tone.

Autonomic outcome is better after endarterectomy than after stenting in patients with asymptomatic carotid stenosis.

OBJECTIVE: Carotid endarterectomy and stenting have comparable efficacy in stroke prevention in asymptomatic carotid stenosis. In patients with carotid stenosis, cardiac events have a more than threefold higher incidence than cerebrovascular events. Autonomic dysfunction predicts cardiovascular morbidity and mortality, and carotid stenosis interferes with baroreceptor and chemoreceptor function. We assessed the effect of elective carotid revascularization (endarterectomy vs stenting) on autonomic function as a major prognostic factor of cardiovascular health. METHODS: In 42 patients with ≥70% asymptomatic extracranial carotid stenosis, autonomic function was determined by analysis of heart rate variability (total band power [TP], high frequency band power [HF], low-frequency band power [LF], very low frequency band power [VLF]), baroreflex sensitivity (αHF, αLF), respiratory chemoreflex sensitivity (central apnea-hypopnea index), and cardiac chemoreflex sensitivity (hyperoxic TP, HF, LF, and VLF ratios) before and 30 days after revascularization. RESULTS: Patients with endarterectomy were older than patients with stenting (69 ± 7 vs 62 ± 7 years; P ≤ .008) but did not differ in gender distribution and preintervention autonomic function. Compared with stenting, postintervention heart rate variability was higher (ln TP, 6.7 [95% confidence interval (CI), 6.3-7.0] vs 6.1 [95% CI, 5.8-6.5; P ≤ .009]; ln HF, 4.5 [95% CI, 4.1-5.0] vs 4.0 [95% CI, 3.4-4.5; P ≤ .05]; ln VLF, 6.0 [95% CI, 5.7-6.4] vs 5.5 [95% CI, 5.2-5.9; P ≤ .02]); respiratory chemoreflex sensitivity (central apnea-hypopnea index, 5.5 [95% CI, 2.8-8.2] vs 10.0 [95% CI, 6.9-13.1; P ≤. 01]) and cardiac chemoreflex sensitivity (TP ratio, 1.2 [95% CI, 1.1-1.3] vs 1.0 [95% CI, 0.9-1.0; P ≤ .0001]; HF ratio, 1.4 [95% CI, 1.2-1.5] vs 0.9 [95% CI, 0.8-1.1; P ≤ .001]; LF ratio, 1.5 [95% CI, 1.3-1.6] vs 1.0 [95% CI, 0.8-1.1; P ≤ .0001]; VLF ratio, 1.2 [95% CI, 1.1-1.3) vs 1.0 [95% CI, 0.9-1.1; P ≤ .002]) were lower after endarterectomy. Postintervention baroreflex sensitivity did not differ after endarterectomy and stenting. CONCLUSIONS: Autonomic function was better after endarterectomy than after stenting. Better autonomic function after endarterectomy was based on restoration of chemoreceptor but not baroreceptor function and may improve cardiovascular long-term outcome.

Evaluation of standardized, computerized Dawes/Redman heart-rate analysis based on different recording methods and in relation to fetal beat-to-beat heart rate variability.

Dawes and Redman (DR) based their definition of short-term variation (STV) on the successive differences of mean inter-beat intervals dividing 1 min of cardiotocography recordings in 16 epochs of 3.75 s each. In contrast, heart rate variability (HRV) is based on the inter-beat intervals of discrete R peaks, also referred to as normal-to-normal (NN) intervals. Despite the historical achievements of DR in providing a robust method with the equipment available at the time to encourage the widespread use and creation of large databases, one must ask whether the STV (DR) parameter is reproducible using a different method of recording, and how much temporal information is actually lost by applying the averaging algorithm sketched above. We simultaneously performed both standard Oxford cardiotocography and transabdominal fetal electrocardiography recordings in 26 patients with low-risk singletons. In addition, we revisited our database of 418 standard fetal magnetocardiographic recordings, applying the DR algorithm to the fetal NN data and compared them to standard HRV parameters. The correlation between STV (DR) from cardiotocography and fetal electrocardiography was stronger that of either with short term fHRV from NN intervals. The methodological trade-off to gain STV as a robust parameter from heart rate traces of limited temporal resolution is accompanied by a loss of temporal information that, at the moment, only fetal magnetocardiography and, to a lesser extent, fetal electrocardiography may provide.

Study protocol: prediction of stroke associated infections by markers of autonomic control.

BACKGROUND: Infection is the most important complication after acute stroke. This is substantially based on a stroke-induced immunosuppression. Heart rate variability (HRV) represents the autonomic nervous system activity in connection with stroke-induced immunomodulation and infections. We demonstrated in a feasibility study that HRV indices obtained in patients without acute post-stroke infections can predict infections in the subsequent sub-acute phase. METHODS/DESIGN: The study PRED-SEP is a prospective observational study. Adult patients with acute ischemic infarction in the territory of the middle cerebral artery and severe neurological deficit (National Institutes of Health Stroke Scale: NIHSS ≥ 8) are recruited. Primary endpoint is the development of infections, secondary endpoints are SIRS and severe sepsis in the sub-acute phase (day 3-5) after stroke and the functional outcome after 3 months. Infection is defined according to the PANTHERIS study and comprises pneumonia, urinary tract infection and infections without determined focus. SIRS and severe sepsis are defined according to German Sepsis Society guidelines. Functional outcome is measured by lethality and neurological scores (modified Rankin Scale, Barthel Index). Prognostic factors are HRV risk indices calculated from selected intervals of 24 h ECG measurements within 48 hours after symptom onset. It is planned to recruit 240 patients.HRV risk indices (predictors) will be calculated according to standards and procedures previously developed and published by the authors. The predictive effects of HRV indices on infections will be estimated by fitting logistic regression models and estimating odds ratios with 95% confidence intervals. A prespecified modelling procedure will be applied to estimate unadjusted and confounder adjusted odds ratios. Secondary endpoints will be analysed in the same way. The functional outcome scales will be dichotomized. The association between HRV indices and pro- and anti-inflammatory markers will be quantified by calculating the appropriate correlation coefficients according to scale (Person or Spearman). DISCUSSION: Since a general prophylactic antibiotic treatment after stroke is not recommended, results of this study could have essential implications for an early identification and hence, timely appropriate treating of stroke-induced infections. TRIAL REGISTRATION: Prädiktoren für die Sepsis - Pred Sep, German Clinical Trials Register: DRKS00003392.

Fetal development of complex autonomic control evaluated from multiscale heart rate patterns.

Development of the fetal autonomic nervous system's integrative capacity in relation to gestational age and emerging behavioral pattern is reflected in fetal heart rate patterns. Conventional indices of vagal and sympathetic rhythms cannot sufficiently reflect their complex interrelationship. Universal behavioral indices of developing complex systems may provide additional information regarding the maturating complex autonomic control. We investigated fetal magnetocardiographic recordings undertaken at 10-min intervals in active (n = 248) and quiet (n = 111) states between 22 and 39 wk gestational age. Standard deviation of heartbeat intervals, skewness, contribution of particular rhythms to the total power, and multiscale entropy were analyzed. The multiscale entropy methodology was validated for 10-min data sets. Age dependence was analyzed by linear regression. In the quiet state, contribution of sympathovagal rhythms and their complexity over a range of corresponding short scales increased with rising age, and skewness shifted from negative to positive values. In the active state, age dependencies were weaker. Skewness as the strongest parameter shifted in the same direction. Fluctuation amplitude and the complexity of scales associated with sympathovagal rhythms increased. We conclude that in the quiet state, stable complex organized rhythms develop. In the active state, however, increasing behavioral variability due to multiple internal coordinations, such as movement-related heart rate accelerations, and external influences develop. Hence, the state-selective assessment in association with developmental indices used herein may substantially improve evaluation of maturation age and early detection and interpretation of developmental problems in prenatal diagnosis.

Heart rate variability as a marker and predictor of inflammation, nosocomial infection, and sepsis - A systematic review.

PURPOSE: The autonomic nervous system interacts with the immune system via the inflammatory response. Heart rate variability (HRV), a marker of autonomic activity, is associated with inflammation, and nosocomial infections/sepsis, and has clinical implications for the monitoring of at-risk patients. Due to the vagal tone's influence on anti-inflammatory immune response, this association may predominately be reflected by vagally-mediated HRV indices. However, HRV's predictive significance on inflammation/infection remains unclear. METHODS: 843 studies examining the associations/prognostic value of HRV indices on inflammation, and nosocomial infection/sepsis were screened in this systematic review. According to inclusion and exclusion criteria, 68 associative studies and 14 prediction studies were included. RESULTS: HRV and pro-inflammatory state were consistently associated in healthy subjects and patient groups. Pro-inflammatory state was related to reduced total power HRV including vagally- and non-vagally-mediated HRV indices. Similar, compared to controls, HRV reductions were observed during nosocomial infections/sepsis. Only limited evidence supports the predictive value of HRV in the development of nosocomial infections/sepsis. Reduced very low frequency power HRV showed the highest predictive value in adults, even with different clinical conditions. In neonates, an increased heart rate characteristic score, combining reduced total power HRV, decreased complexity, and vagally-dominated asymmetry, predicted sepsis. CONCLUSIONS: Pro-inflammatory state is related to an overall reduction in HRV rather than a singular reduction in vagally-mediated HRV indices, reflecting the complex autonomic-regulatory changes occurring during inflammation. The potential benefit of using continuous HRV monitoring for detecting nosocomial infection-related states, and the implications for clinical outcome, need further clarification.

Development of integrative autonomic nervous system function: an investigation based on time correlation in fetal heart rate patterns.

OBJECTIVE: To describe the development of the integrative capacity of the fetal autonomic nervous system (ANS) according to gestational age and emerging behavioral states, assuming that developing integrative ANS functions are reflected in increasing autocorrelation of fetal heart rate and fetal heart rate variability markers. METHODS: Magnetocardiograms of 114 healthy fetuses (21-40 weeks of gestation) were recorded. Level of fetal activity (quiet/active sleep) was estimated according to characteristic heart rate patterns. Autocorrelation functions of (i) fetal heart rate and (ii) time patterns of SDNN (standard deviation of normal-to-normal intervals) and RMSSD (root mean square of successive differences in normal-to-normal intervals) were calculated and autocorrelation was determined over different time scales. Age and activity related changes were examined using linear regression and non-parametric tests. RESULTS: During pregnancy, autocorrelation increased in fetal heart rate signals and time patterns of SDNN and RMSSD. Short-time correlation (0-20 s) changed between 21 and 31 gestational weeks. Long-time correlation (75-300 s) accelerated later in pregnancy and did not increase in quiet heart rate patterns. Strong state-dependent changes were found with time patterns of SDNN. CONCLUSIONS: Emerging integrative ANS functions are reflected in increasing autocorrelation of fetal heart rate fluctuations over increasing time scales. The period from 21 to 31 gestational weeks seems to be critical to ANS development. Increasing long-time correlation is specific to active sleep states.

The Relationship between Gestational Diabetes Metabolic Control and Fetal Autonomic Regulation, Movement and Birth Weight.

(1) Background: Maternal metabolic control in gestational diabetes is suggested to influence fetal autonomic control and movement activity, which may have fetal outcome implications. We aimed to analyze the relationship between maternal metabolic control, fetal autonomic heart rate regulation, activity and birth weight. (2) Methods: Prospective noninterventional longitudinal cohort monitoring study accompanying 19 patients with specialist clinical care for gestational diabetes. Monthly fetal magnetocardiography with electro-physiologically-based beat-to-beat heart rate recording for analysis of heart rate variability (HRV) and the 'fetal movement index' (FMI) was performed. Data were compared to 167 healthy pregnant women retrieved from our pre-existing study database. (3) Results: Fetal vagal tone was increased with gestational diabetes compared to controls, whereas sympathetic tone and FMI did not differ. Within the diabetic population, sympathetic activation was associated with higher maternal blood-glucose levels. Maternal blood-glucose levels correlated positively with birth weight z scores. FMI showed no correlation with birth weight but attenuated the positive correlation between maternal blood-glucose levels and birth weight. (4) Conclusion: Fetal autonomic control is altered by gestational diabetes and maternal blood-glucose level, even if metabolic adjustment and outcome is comparable to healthy controls.

Can fetal heart rate variability obtained from cardiotocography provide the same diagnostic value like from electrophysiological interbeat intervals?

OBJECTIVE: Fetal heart rate variability (HRV) is widely used for monitoring fetal developmental disturbances. Only expensive fetal magnetocardiography (fMCG) allows the precise recording of the individual fetal heart beat intervals uncovering also highly frequent vagal modulation. In contrast, transabdominal fetal electrocardiography (fECG) suffers from noise overlaying the fetal cardiac signal. Cardiotocography (CTG) is the clinical method of choice, however, based on Doppler ultrasound, improper to resolve single beats concisely. The present work addresses the transferability of established electrophysiological HRV indices to CTG recordings during the fetal maturation period of 20-40 weeks of gestation (WGA). APPROACH: We compared (a) HRV indices obtained from fMCG, CTG and fECG of short-term amplitude fluctuations (sAMPs) and long-term amplitude fluctuations (lAMPs) and complexity, and (b) their diagnostic value for identifying maturational age, fetal growth restriction (FGR) and small for gestational age (SGA). We used the functional brain age score (fABAS) and categories of long- and short-term regulation and complexity. MAIN RESULTS: Integrating all substudies, we found: (a) indices related to long-term regulation, and with modified meaning and values of short-term regulation and sympathovagal balance (SVB) according to electrophysiological HRV standards can be obtained from CTG. (b) Models using HRV indices calculated from CTG allow the identification of maturational age and discriminate FGR from controls with almost similar precision as electrophysiological means. (c) A modified set of HRV parameters containing short- and long-term regulation and long-term/short-term ratio appeared to be most suitable to describe autonomic developmental state when CTG data is used. SIGNIFICANCE: Whereas the predominantly vagally modulated beat-to-beat precise high frequencies of HRV are not assessable from CTG, we identified relevant related HRV indices and categories for CTG recordings with diagnostic potential. They require further evaluation and confirmation with respect to any issues of fetal developmental and perinatal problems in subsequent studies. This methodology significantly extends the measures of established CTG devices. Novelty and significance HRV indices provide predestinated diagnostic markers of autonomic control in fetuses. However, the established CTG does not provide the temporal precision of electrophysiological recordings. Beat-to-beat related, mainly vagally modulated behavior is not exactly represented in CTG. However, a set of CTG-specific HRV indices that are mainly comparable to established electrophysiological HRV parameters obtained by magnetocardiography or electrocardiography provided almost similar predictive value for fetal maturational age and were helpful in characterizing FGR. These results require validation in the monitoring of further fetal developmental disturbances. We recommend a corresponding extension of CTG methodology.

Drug effect on EEG connectivity assessed by linear and nonlinear couplings.

Quantitative analysis of human electroencephalogram (EEG) is a valuable method for evaluating psychopharmacological agents. Although the effects of different drug classes on EEG spectra are already known, interactions between brain locations remain unclear. In this work, cross mutual information function and appropriate surrogate data were applied to assess linear and nonlinear couplings between EEG signals. The main goal was to evaluate the pharmacological effects of alprazolam on brain connectivity during wakefulness in healthy volunteers using a cross-over, placebo-controlled design. Eighty-five pairs of EEG leads were selected for the analysis, and connectivity was evaluated inside anterior, central, and posterior zones of the scalp. Connectivity between these zones and interhemispheric connectivity were also measured. Results showed that alprazolam induced significant changes in EEG connectivity in terms of information transfer in comparison with placebo. Trends were opposite depending on the statistical characteristics: decreases in linear connectivity and increases in nonlinear couplings. These effects were generally spread over the entire scalp. Linear changes were negatively correlated, and nonlinear changes were positively correlated with drug plasma concentrations; the latter showed higher correlation coefficients. The use of both linear and nonlinear approaches revealed the importance of assessing changes in EEG connectivity as this can provide interesting information about psychopharmacological effects.

Central sleep apnea indicates autonomic dysfunction in asymptomatic carotid stenosis: a potential marker of cerebrovascular and cardiovascular risk.

STUDY OBJECTIVES: Arteriosclerosis related stenosis in the carotid bulb causes autonomic imbalance, likely due to carotid chemoreceptor and baroreceptor dysfunction. The latter are associated with increased cerebrovascular and cardiovascular mortality. Chemoreceptor and baroreceptor dysfunction is also involved in the origin of central sleep apnea syndrome (CSA) in different clinical entities. We hypothesized that CSA is associated with stenosis of the internal carotid artery (ICA). The mechanism of this association is an autonomic imbalance induced by stenosis-mediated chemoreceptor and baroreceptor dysfunction. DESIGN: Cross-sectional prospective study. SETTING: University-based tertiary referral sleep clinic and research center. PATIENTS: Fifty-nine patients with various degrees of asymptomatic extracranial ICA (elCA) (n = 49) and intracranial ICA (ilCA) stenosis (n = 10) were investigated. INTERVENTIONS: Polysomnography to detect CSA and analysis of spontaneous heart rate variability (HRV) to detect autonomic imbalance. MEASUREMENTS AND RESULTS: CSA occurred in 39% of the patients with elCA stenosis but was absent in patients with ilCA stenosis. CSA was present in patients with severe elCA stenosis of > or = 70% on one side. Independent predictors for CSA were severity of stenosis, asymmetric distribution of stenosis between both elCA and autonomic imbalance, namely a decrease of parasympathetic tone. The specific constellation of HRV-parameters indicated increased chemoreceptor sensitivity and impaired baroreflex sensitivity. CONCLUSIONS: CSA indicates autonomic dysfunction in patients with asymptomatic elCA stenosis. Detection of CSA may help to identify asymptomatic patients with an increased risk of cerebrovascular or cardiovascular events who particularly benefit from carotid revascularization.

Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy.

Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.

Heart rate variability categories of fluctuation amplitude and complexity: diagnostic markers of fetal development and its disturbances.

OBJECTIVE: In fetal diagnosis the myriad and diversity of heart rate variability (HRV) indices prevents a comparable routine evaluation of disturbances in fetal development and well-being. The work aims at the extraction of a small set of HRV key indices that could help to establish a universal, overarching tool to screen for any disturbance. APPROACH: HRV indices were organized in categories of short-term (prefix s) and long-term (prefix l) amplitude fluctuations (AMP), complexity (COMP), and patterns (PATTERN) and common representatives for each category were extracted. This procedure was done with respect to the diagnostic value in the evaluation of the maturation age throughout the second and complete third trimester of pregnancy as well as to potential differences associated with maternal life-style factors (physical exercise, smoking), nutrient intervention (docosahexaenoic acid (DHA) supplementation), and complications of pregnancy (gestational diabetes mellitus (GDM), intra-uterine growth restriction (IUGR)). MAIN RESULTS: We found a comprehensive minimal set that includes [lAMP: short term variation (STV), initially introduced in cardiotocography, sAMP: heart rate increase across one interbeat interval of phase rectified averaged signal - acceleration capacity (ACst1), lCOMP: scale 4 multi-scale entropy (MSE4), PATTERN: skewness] for the maturation age prediction, and partly overlapping [lAMP: STV, sAMP: ACst1, sCOMP: Lempel Ziv complexity (LZC)] for the discrimination of the deviations. SIGNIFICANCE: The minimal set of category-based HRV representatives allows for a screening of fetal development and well-being. These results are an important step towards a universal and comparable diagnostic tool for the early identification of developmental disturbances. Novelty & Significance Fetal development and its disturbances have been reported to be associated with a multiplicity of HRV indices. Furthermore, these HRV indices change with maturation. We propose the abstraction of HRV categories defined by short- and long-term fluctuation amplitude, complexity, and pattern indices that cover all relevant aspects of maturational age, behavioral influences and a series of pathological disturbances. The study data are provided by multiple centers. Our approach is an important step towards the goal of a standardized diagnostic tool for early identification of fetal developmental disturbances with respect to the reduction of serious complications in the later life.

Very Low Frequency Heart Rate Variability Predicts the Development of Post-Stroke Infections.

Stroke-induced immunodepression is a major risk factor for severe infectious complications in the immediate post-stroke period. We investigated the predictive value of heart rate variability (HRV) to identify patients at risk of post-stroke infection, systemic inflammatory response syndrome, or severe sepsis during the post-acute interval from days 3 to 5 after stroke onset. A prospective, observational monocentric cohort study was conducted in a university hospital stroke unit of patients with ischemic infarction in the territory of the middle cerebral artery without an ongoing infection at admission. Standard HRV indices were processed from Holter ECG. Recording started within the first day after the onset of stroke. Infection (primary endpoint: pneumonia, urinary tract, unknown localization) was assessed between days 3 and 5. The predictive value of HRV adjusted for clinical data was analyzed by logistic regression models and area under the receiver operating characteristic curve (AUC). From 287 eligible patients, data of 89 patients without event before completion of 24-h Holter ECG were appropriate for prediction of infection (34 events). HRV was significantly associated with incident infection even after adjusting for clinical covariates. Very low frequency (VLF) band power adjusted for both, the National Institutes of Health Stroke Scale (NIHSS) at admission and diabetes predicted infection with AUC = 0.80 (cross-validation AUC = 0.74). A model with clinical data (diabetes, NIHSS at admission, involvement of the insular cortex) performed similarly well (AUC = 0.78, cross-validation AUC = 0.71). Very low frequency HRV, an index of integrative autonomic-humoral control, predicts the development of infectious complications in the immediate post-stroke period. However, the additional predictive value of VLF band power over clinical risk factors such as stroke severity and insular involvement was marginal. The continuous HRV monitoring starting immediately after admission might probably increase the predictive performance of VLF band power. That needs to be clarified in further investigations.

Autonomic dysfunction predicts both 1- and 2-month mortality in middle-aged patients with multiple organ dysfunction syndrome.

OBJECTIVE: Multiple organ dysfunction syndrome (MODS) is a disease entity that carries a high mortality rate. It is characterized by a sequential failure of several organ systems after a trigger event, most commonly sepsis. There is increasing evidence that autonomic dysfunction may substantially contribute to the development of MODS. We recently characterized the spectrum of autonomic dysfunction by using heart rate variability in critically ill MODS patients and were able to show that autonomic dysfunction predicts 28-day mortality in MODS. The aim of the present study was evaluate whether autonomic dysfunction is also a predictor of 180-day and 365-day mortalities. DESIGN: Prospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university center. PATIENTS: Ninety consecutively admitted score-defined MODS patients. INTERVENTIONS: We assessed heart rate variability as a marker of autonomic dysfunction. The patients were followed for 180- and 365-day mortalities. MEASUREMENTS AND MAIN RESULTS: We prospectively used the heart rate variability variable lnVLF, which predicted 28-day mortality best in the entire cohort of patients, for analysis of longer term mortality. The variable lnVLF was found to be useful for risk prediction for about 60 days, and then the survival curves became nearly parallel. CONCLUSIONS: Autonomic function of critically ill MODS patients is blunted, and this attenuation has prognostic implications not merely concerning 28-day mortality but also concerning longer term (about 2-month) mortality.