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Identifying the hemodynamic range that best supports cerebral perfusion using near infrared spectroscopy (NIRS) autoregulation monitoring is a potential physiologic marker for neonatal hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia. However, an optimal autoregulation monitoring algorithm has not been identified for neonatal clinical medicine. We tested whether the hemoglobin volume phase (HVP), hemoglobin volume (HVx), and pressure passivity index (PPI) identify changes in autoregulation that are associated with brain injury on MRI or death. The HVP measures the phase difference between a NIRS metric of cerebral blood volume, the total hemoglobin (THb), and mean arterial blood pressure (MAP) at the frequency of maximum coherence. The HVx is the correlation coefficient between MAP and THb. The PPI is the percentage of coherent MAP-DHb (difference between oxygenated and deoxygenated hemoglobin, a marker of cerebral blood flow) epochs in a chosen time period. Neonates cooled for HIE were prospectively enrolled in an observational study in two neonatal intensive care units. In analyses adjusted for study site and encephalopathy level, all indices detected relationships between poor autoregulation in the first 6 h after rewarming with a higher injury score on MRI. Only HVx and PPI during hypothermia and the PPI during rewarming identified autoregulatory dysfunction associated with a poor outcome independent of study site and encephalopathy level. Our findings suggest that the accuracy of mathematical autoregulation algorithms in detecting the risk of brain injury or death may depend on temperature and postnatal age. Extending autoregulation monitoring beyond the standard 72 h of therapeutic hypothermia may serve as a method to provide personalized care by assessing the need for and efficacy of future therapies after the hypothermia treatment phase.

Recent evidence favors a network concept in tuberous sclerosis (TSC) with seizure generation and propagation related to changes in global and regional connectivity between multiple, anatomically distant tubers. Direct exploration of network dynamics in TSC has been made possible through intracranial sampling with stereoelectroencephalography (sEEG). The objective of this study is to define epileptic networks in TSC using quantitative analysis of sEEG recordings. We also discuss the impact of the definition of these epileptic networks on surgical decision-making. Intracranial sEEG recordings were obtained from four pediatric patients who presented with medically refractory epilepsy secondary to TSC and subjected to quantitative signal analysis methods. Cortical connectivity was quantified by calculating pairwise coherence between all contacts and constructing an association matrix. The global coherence, defined as the ratio of the largest eigenvalue to the sum of all the eigenvalues, was calculated for each frequency band (delta, theta, alpha, beta, gamma). Spatial distribution of the connectivity was identified by plotting the leading principal component (product of the largest eigenvalue and its corresponding eigenvector). Four pediatric subjects with TSC underwent invasive intracranial monitoring with sEEG, comprising 31 depth electrodes and 250 contacts, for localization of the epileptogenic focus and guidance of subsequent surgical intervention. Quantitative connectivity analysis revealed a change in global coherence during the ictal period in the beta/low gamma (14–30 Hz) and high gamma (31–80 Hz) bands. Our results corroborate findings from existing literature, which implicate higher frequencies as a driver of synchrony and desynchrony. Coordinated high-frequency activity in the beta/low gamma and high gamma bands among spatially distant sEEG define the ictal period in TSC. This time-dependent change in global coherence demonstrates evidence for intra-tuberal and inter-tuberal connectivity in TSC. This observation has surgical implications. It suggests that targeting multiple tubers has a higher chance of seizure control as there is a higher chance of disrupting the epileptic network. The use of laser interstitial thermal therapy (LITT) allowed us to target multiple disparately located tubers in a minimally invasive manner with good seizure control outcomes.

OBJECTIVE: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. STUDY DESIGN: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. RESULTS: Sixty-two patients were included. Elevated Tau levels on days 2–3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03–1.09; aOR: 1.04, 95% CI: 1.01–1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). CONCLUSIONS: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.

BACKGROUND Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU. METHODS We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed. RESULTS The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics. CONCLUSIONS Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age. IMPACT Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought.

The objective was to examine the discriminatory ability of electroencephalogram (EEG) delta power in neonates with hypoxic-ischemic encephalopathy (HIE) with well-defined outcomes. Prolonged continuous EEG recordings from term neonates with HIE during therapeutic hypothermia enrolled in a prospective observational study were examined. Adverse outcome was defined as death or severe brain injury by magnetic resonance imaging (MRI); favorable outcome was defined as normal or mild injury by MRI. Neonates were stratified by Sarnat grade of encephalopathy at admission. EEG was partitioned into 10-minute nonoverlapping artifact- and seizure-free epochs. Delta power was calculated and compared between the groups using receiver operating characteristic (ROC) analyses and Wilcoxon rank-sum tests. An area under the ROC curve >0.7 with P

To determine whether ventilator-related fluctuations in cerebral blood volume (CBV) are associated with cerebral pressure passivity. In a prospective study of newborns undergoing positive-pressure ventilation, we calculated coherence between continuous mean arterial pressure (MAP) and cerebral near-infrared spectroscopy hemoglobin difference (HbD). Significant HbD–MAP coherence indicated cerebral pressure passivity. CBV changes were measured as the spectral power of total hemoglobin (SHbT) at the ventilator frequency. A regression model tested whether SHbT predicts cerebral pressure passivity and/or death/brain injury, controlling for birth gestational age and other factors. We studied 68 subjects with prematurity (n = 19), congenital heart disease (n = 11), and hypoxic–ischemic encephalopathy (n = 38). SHbT, sedative use, and pCO2 were positively associated, and circulating hemoglobin negatively associated, with cerebral pressure passivity (p

Delivery of the newborn occurs either vaginally or via caesarean section. It is not known whether the mode of delivery and exposure to labor affects early autonomic nervous system (ANS) function, as measured by heart rate variability (HRV), or cortical electroencephalogram (EEG) activity. The objective of the study was to determine if autonomic function in newborns differs by mode of delivery. Simultaneous recording of EEG and electrocardiogram were collected in low-risk term newborns at

Purpose To compare early changes in autonomic nervous system (ANS) tone between newborns with complex congenital heart disease (CHD) and newborns without CHD. Methods We performed a case–control study of heart rate variability (HRV) in newborns with complex CHD [transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS)] and low-risk control newborns without CHD. Cases with CHD were admitted following birth to a pediatric cardiac intensive care unit and had archived continuous ECG data. Control infants were prospectively enrolled at birth. ECG data in cases and controls were analyzed for HRV in the time and frequency domains at 24 h of age. We analyzed the following HRV metrics: alpha short (αs), alpha long (αL), root mean square short and long (RMSs and RMSL), low-frequency (LF) power, normalized LF (nLF), high-frequency (HF) power, and normalized HF (nHF). We used ANOVA to compare HRV metrics between groups and to control for medication exposures. Results HRV data from 57 infants with CHD (TGA, n = 33 and HLHS, n = 24) and from 29 controls were analyzed. The HRV metrics αS, RMSL, LF, and nLF were significantly lower in infants with CHD than in the controls. Due to the effect of normalization, nHF was higher in CHD infants (P

The mature cerebral cortex has a topographically organized influence on reflex autonomic centers of the brainstem and diencephalon and sympathetic activation coming primarily from the right hemisphere and parasympathetic activation from the left. In the term newborn, the maturational status of this central autonomic system remains poorly understood. Sixteen term newborns admitted to Children’s National with unilateral middle cerebral artery (MCA) strokes (n = 8 left, n = 8 right) had archived continuous electrocardiograph (EKG) signals available. We compared stroke laterality and severity with indices of autonomic function, as measured by heart rate variability. We performed both time- and frequency-domain analyses on the R–R interval (RRi) over 24h of continuous EKG data at around 7 days of age. Right MCA stroke significantly increased sympathetic tone, while left MCA stroke increased parasympathetic tone. Regardless of laterality, stroke severity was associated inversely with sympathetic tone and positively with parasympathetic tone. Surprisingly, injury to either insular region had no significant autonomic effect. Phenobarbital blood levels were positively associated with sympathetic tone and inversely related to parasympathetic tone. Based on these findings, it is difficult to reconcile the functional topography of the central autonomic system in term newborns with that currently proposed for the normal mature brain. Further investigation is clearly needed.

Brain injury is a serious and common complication of critical congenital heart disease (CHD). Impaired autonomic development (assessed by heart rate variability (HRV)) is associated with brain injury in other high-risk neonatal populations.To determine whether impaired early neonatal HRV is associated with pre-operative brain injury in CHD.In infants with critical CHD, we evaluated HRV during the first 24 h of cardiac ICU (CICU) admission using time-domain (RMS 1, RMS 2, and alpha 1) and frequency-domain metrics (LF, nLF, HF, nHF). Pre-operative brain magnetic resonance imaging (MRI) was scored for injury using an established system. Spearman's correlation coefficient was used to determine the association between HRV and pre-operative brain injury.We enrolled 34 infants with median birth gestational age of 38.8 weeks (IQR 38.1-39.1). Median postnatal age at pre-operative brain MRI was 2 days (IQR 1-3 days). Thirteen infants had MRI evidence of brain injury. RMS 1 and RMS 2 were inversely correlated with pre-operative brain injury.Time-domain metrics of autonomic function measured within the first 24 h of admission to the CICU are associated with pre-operative brain injury, and may perform better than frequency-domain metrics under non-stationary conditions such as critical illness.Autonomic dysfunction, measured by heart rate variability (HRV), in early transition is associated with pre-operative brain injury in neonates with critical congenital heart disease. These data extend our earlier findings by providing further evidence for (i) autonomic dysfunction in infants with CHD, and (ii) an association between autonomic dysfunction and brain injury in critically ill neonates. These data support the notion that further investigation of HRV as a biomarker for brain injury risk is warranted in infants with critical CHD.

Near-infrared spectroscopy (NIRS)-based measures of cerebral autoregulation (CAR) can potentially identify neonates with hypoxic–ischemic encephalopathy (HIE) who are at greatest risk of irreversible brain injury. However, modest predictive abilities have precluded previously described metrics from entering clinical care. We previously validated a novel autoregulation metric in a piglet model of induced hypotension called the hemoglobin volume phase index (HVP). The objective of this study was to evaluate the clinical ability of the HVP to predict adverse outcomes neonates with HIE. This is a prospective study of neonates with HIE who underwent therapeutic hypothermia (TH) at a level 4 neonatal intensive care unit (NICU). Continuous cerebral NIRS and mean arterial blood pressure (MAP) from indwelling arterial catheters were measured during TH and through rewarming. Multivariate autoregressive process was used to calculate the coherence between MAP and the sum total of the oxy- and deoxygenated Hb densities (HbT), a surrogate measure of cerebral blood volume (CBV). The HVP was calculated as the cosine-transformed phase shift at the frequency of maximal MAP-HbT coherence. Brain injury was assessed by neonatal magnetic resonance imaging (MRI), and developmental outcomes were assessed by the Bayley Scales of Infant Development (BSID-III) at 15–30 months. The ability of the HVP to predict (a) death or severe brain injury by MRI and (b) death or significant developmental delay was assessed using logistic regression analyses. In total, 50 neonates with moderate or severe HIE were monitored. Median HVP was higher, representing more dysfunctional autoregulation, in infants who had adverse outcomes. After adjusting for sex and encephalopathy grade at presentation, HVP at 21–24 and 24–27 h of life predicted death or brain injury by MRI (21–24 h: OR 8.8, p = 0.037; 24–27 h: OR 31, p = 0.011) and death or developmental delay at 15–30 months (21–24 h: OR 11.8, p = 0.05; 24–27 h: OR 15, p = 0.035). Based on this pilot study of neonates with HIE, HVP merits further study as an indicator of death or severe brain injury on neonatal MRI and neurodevelopmental delay in early childhood. Larger studies are warranted for further clinical validation of the HVP to evaluate cerebral autoregulation following HIE.

PURPOSE: The mature central autonomic network includes connectivity between autonomic nervous system brainstem centers and the cerebral cortex. The study objective was to evaluate the regional connectivity between the cerebral cortex and brainstem autonomic centers in term newborns by measuring coherence between high-density electroencephalography and heart rate variability as measured by electrocardiography. METHODS: Low-risk term newborns with birth gestational age 39–40 weeks were prospectively enrolled and studied using time-synced electroencephalography and electrocardiography for up to 60 minutes before discharge from the birth hospital. The cortico-autonomic nervous system association was analyzed using coherence between electroencephalography-delta power and heart rate variability. Heart rate variability measured parasympathetic tone (root mean square of successive differences of heart rate) and sympathetic tone (standard deviation of heart rate). RESULTS: One hundred and twenty-nine low-risk term infants were included. High coherence delta(-)root mean square of successive differences was found in central, bi-temporal, and occipital brain regions with less robust coherence delta-standard deviation in the central region and bi-temporal areas. CONCLUSIONS: Our findings describe a topography of cortico-autonomic connectivity present at term in low-risk newborns, which was more robust to parasympathetic than sympathetic brainstem centers and was independent of newborn state.

BackgroundAuditory steady-state responses (ASSRs) are ongoing evoked brain responses to continuous auditory stimuli that play a role for auditory processing of complex sounds and speech perception. Transient auditory event-related responses (AERRs) have previously been recorded using fetal magnetoencephalography (fMEG) but involve different neurological pathways. Previous studies in children and adults demonstrated that the cortical components of the ASSR are significantly affected by state of consciousness and by maturational changes in neonates and young infants. To our knowledge, this is the first study to investigate ASSRs in human fetuses.Methods47 fMEG sessions were conducted with 24 healthy pregnant women in three gestational age groups (30–32 weeks, 33–35 weeks and 36–39 weeks). The stimulation consisted of amplitude-modulated (AM) tones with a duration of one second, a carrier frequency (CF) of 500 Hz and a modulation frequency (MF) of 27 Hz or 42 Hz. Both tones were presented in a random order with equal probability adding up to 80–100 repetitions per tone. The ASSR across trials was quantified by assessing phase synchrony in the cortical signals at the stimulation frequency.Results and ConclusionTen out of 47 recordings were excluded due to technical problems or maternal movements. Analysis of the included 37 fetal recordings revealed a statistically significant response for the phase coherence between trials for the MF of 27 Hz but not for 42 Hz. An exploratory subgroup analysis moreover suggested an advantage in detectability for fetal behavioral state 2F (active asleep) compared to 1F (quiet asleep) detected using fetal heart rate. In conclusion, with the present study it was possible to detect human fetal ASSRs for the first time. These findings warrant further investigations of the developing fetal brain.

We studied the effect of EKG sampling rate on heart rate variability (HRV) analysis. We acquired EKG from four term hypoxic-ischemic encephalopathic infants undergoing therapeutic hypothermia. The EKG signal was acquired continuously for 4 days from the cardiorespiratory monitor through the analog port. The following HRV metrics were calculated: normalized low-frequency (nLF), normalized high-frequency (nHF), low-frequency (LF), high-frequency (HF), short-term detrended fluctuation analysis (DFA) exponent (α s ), long-term DFA exponent (α L ), root mean square (RMS) short (RMSS), and RMS long (RMSL). In addition, heart rate was used. These metrics were calculated for EKG acquired at 1 KHz (served as reference, EKGref) as well as from EKGs downsampled at 500 Hz (EKG 500 ), 250 Hz (EKG 250 ), and 125 Hz (EKG 125 ). The bedside monitors were simultaneously sending the EKG to a data warehouse, storing the EKG (EKG DWH ) at 250 Hz. All HRV metrics were also calculated for the EKG DWH . The comparison between HRV metrics calculated from EKG ref and downsampled EKG (EKG 500 , EKG 250 , EKG 125 ) was made with intraclass correlation coefficient (r). The comparisons of HRV metrics between EKG 250 and EKG DWH were also made with ICC. Our results show that HRV calculated with EKG ref and from downsampled EKG were highly correlated (r>0.8 for all comparisons, P 250 and EKG DWH were also significantly correlated (r=0.7, P DWH signal and caution must be exercised in interpreting the HF power calculated from this EKG.

In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation.We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30-33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks).One hundred infants, median (Q1-Q3) birth GA of 31.9 (28.7-33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities.Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA.Heart rate variability can evaluate the maturation of the autonomic nervous system. Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu. The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages. Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU. Modern NICU advances appear to support autonomic development in the preterm infant.

An alternative analysis approach, namely, orthogonal detrended fluctuation analysis (ODFA), is proposed to quantify the long-range correlation exponent. This method uses an orthogonal polynomial to attenuate any trends and quantify the (auto-) correlations in the data. The method is tested using numerically simulated data with long-range correlation. A matrix formalism of this approach is also proposed. Furthermore, the extension to high-order polynomial detrending is discussed. The proposed approach quantifies the long-range exponent with an error rate of about 8% for short datasets (3000 samples) and an error rate of about 1% for long datasets (100 000 samples). ODFA can find applications that involve processing long datasets as well as in real-time processing.

Background Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV). Materials and Methods HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis. Results HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] Conclusion Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach.

Introduction: The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. Methods: We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. Results: Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO2), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. Conclusion: Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO2 and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.

BackgroundDecreased heart rate variability (HRV) is a measure of autonomic dysfunction and brain injury in newborns with hypoxic ischemic encephalopathy (HIE). This study aimed to characterize the relationship between HRV and brain injury pattern using magnetic resonance imaging (MRI) in newborns with HIE undergoing therapeutic hypothermia.MethodsHRV metrics were quantified in the time domain (αS, αL, and root mean square at short (RMSS) and long (RMSL) timescales) and frequency domain (relative low-(LF) and high-frequency (HF) power) over 24-27 h of life. The brain injury pattern shown by MRI was classified as no injury, pure cortical/white matter injury, mixed watershed/mild basal ganglia injury, predominant basal ganglia or global injury, and death. HRV metrics were compared across brain injury pattern groups using a random-effects mixed model.ResultsData from 74 infants were analyzed. Brain injury pattern was significantly associated with the degree of HRV suppression. Specifically, negative associations were observed between the pattern of brain injury and RMSS (estimate -0.224, SE 0.082, P=0.006), RMSL (estimate -0.189, SE 0.082, P=0.021), and LF power (estimate -0.044, SE 0.016, P=0.006).ConclusionDegree of HRV depression is related to the pattern of brain injury. HRV monitoring may provide insights into the pattern of brain injury at the bedside.

OBJECTIVE To determine whether measures of heart rate variability are related to changes in temperature during rewarming after therapeutic hypothermia for hypoxic-ischemic encephalopathy. DESIGN Prospective observational study. SETTING Level 4 neonatal ICU in a free-standing academic children's hospital. PATIENTS Forty-four infants with moderate to severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. INTERVENTIONS Continuous electrocardiogram data from 2 hours prior to rewarming through 2 hours after completion of rewarming (up to 10 hr) were analyzed. MEASUREMENTS AND MAIN RESULTS Median beat-to-beat interval and measures of heart rate variability were quantified including beat-to-beat interval SD, low and high frequency relative spectral power, detrended fluctuation analysis short and long α exponents (αS and αL), and root mean square short and long time scales. The relationships between heart rate variability measures and esophageal/axillary temperatures were evaluated. Heart rate variability measures low frequency, αS, and root mean square short and long time scales were negatively associated, whereas αL was positively associated, with temperature (p < 0.01). These findings signify an overall decrease in heart rate variability as temperature increased toward normothermia. CONCLUSIONS Measures of heart rate variability are temperature dependent in the range of therapeutic hypothermia to normothermia. Core body temperature needs to be considered when evaluating heart rate variability metrics as potential physiologic biomarkers of illness severity in hypoxic-ischemic encephalopathy infants undergoing therapeutic hypothermia.

Central topography of autonomic nervous system (ANS) function has yet to be fully deciphered. In adults it has been shown to lateralize sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. We examined functional topography of central ANS in newborn subjects utilizing spectral analysis of heart rate variability (HRV), an established measure of ANS function. We studied newborns with hypoxic-ischemic encephalopathy participating in a prospective study undergoing a therapeutic hypothermia protocol. We included subjects with continuous heart rate data over the first 3 h of normothermia (post rewarming) and brain magnetic resonance imaging, which was reviewed and scored according to a 4 region scheme. HRV was evaluated by spectral analysis in the low-frequency (0.05 to 0.25 Hz) and high-frequency (0.3 to 1 Hz) ranges. The relationship between injured brain regions and HRV was studied using multiple regressions. Forty eight newborns were included. When examined in isolation, right hemisphere injury had a significant negative effect on HRV (−0.088; 95% CI: −0.225,−0.008). The combination of posterior fossa region injury with right hemispheric injury or left hemispheric injury demonstrated significant positive (0.299; 95% CI: 0.065, 0.518) and negative (−0.475; 95% CI: −0.852, −0.128) influences on HRV, respectively. The association between brain injury location and HRV in the high-frequency range did not reach significance. Our data support the notion that lateralized cerebral modulation of the ANS, specifically of its sympathetic component, is present in the term newborn, and suggest complex modulation of these tracts by components of the posterior fossa.

Objectives The ability of the premature brain to extract and use oxygen has not been studied adequately. This study aimed to determine factors that influence fractional tissue oxygen extraction (FTOE) of the brain in premature infants using near-infrared spectroscopy (NIRS) and pulse oximetry. Study Design We prospectively studied FTOE in very low birth weight (BW) infants (< 1,500 g and ≤ 34 weeks' gestation). Factors affecting FTOE and its variability were examined using bivariate and linear regression models. FTOE variability was measured on two scales: short scales (3-20 seconds) and long scales (20-150 seconds). Results We examined 147 simultaneous NIRS and pulse oximetry recordings that were collected from 72 premature infants (gestational age [GA] = 28 weeks and BW = 1,036 g). In regression models, average FTOE correlated negatively with hemoglobin (Hb) and increased significantly in patients with severe intraventricular hemorrhage/periventricular leukomalacia. Both FTOE short- and long-scale variabilities correlated negatively with GA and positively with postnatal age (PNA). Moreover, FTOE long-scale variability was significantly reduced in infants supported with invasive ventilation. Conclusions In premature infants, cerebral oxygen extraction increased with reduced Hb and severe brain injury. Variability in oxygen extraction showed differential changes with GA and PNAs and was affected by invasive ventilation.

Background Cerebral pressure passivity (CPP) in sick newborns can be detected by evaluating coupling between mean arterial pressure (MAP) and cerebral blood flow measured by NIRS hemoglobin difference (HbD). However, continuous MAP monitoring requires invasive catheterization with its inherent risks. We tested whether heart rate (HR) could serve as a reliable surrogate for MAP in the detection of CPP in sick newborns. Methods Continuous measurements of MAP, HR, and HbD were made and partitioned into 10-minute epochs. Spectral coherence (COH) was computed between MAP and HbD (COHMAP-HbD) to detect CPP, between HR and HbD (COHHR-HbD) for comparison, and between MAP and HR (COHMAP-HR) to quantify baroreflex function (BRF). The agreement between COHMAP-HbD and COHHR-HbD was assessed using ROC analysis. Results We found poor agreement between COHMAP-HbD and COHHR-HbD in left hemisphere (area under the ROC curve (AUC) 0.68) and right hemisphere (AUC 0.71). Baroreflex failure (COHMAP-HR not significant) was present in 79% of epochs. Confining comparison to epochs with intact BRF showed an AUC of 0.85 for both hemispheres. Conclusions In these sick newborns, HR was an unreliable surrogate for MAP required for the detection of CPP. This is likely due to the prevalence of BRF failure in these infants.

Background There is no current method for continuous quantification of neurovascular coupling (NVC) in spontaneous brain activity. To fill this void, we propose a novel method to quantify NVC using electroencephalogram (EEG) and near-infrared spectroscopy (NIRS) data. New method Since EEG and NIRS measure physiologic changes occurring at different time scales, we bring them into a common dynamical time frame (DTF). To achieve this, we partition both signals into one-second epochs and calculate the standard deviation of the EEG and the average value of the NIRS for each epoch. We then quantify the NVC by calculating spectral coherence between the two signals in the DTF. The resulting NVC will have a low resolution with all of its content localized below 1 Hz. Results After validating this framework on simulated data, we applied this approach to EEG and NIRS signals collected from four term infants undergoing therapeutic hypothermia for neonatal encephalopathy. Two of these infants showed no evidence of structural brain injury, and the other two died during the course of the therapy. The intact survivors showed emergence of NVC during hypothermia and/or after rewarming. In contrast, the two critically ill infants, who subsequently died, lacked this feature. Comparison with existing methods Existing methods quantify NVC by averaging neurovascular signals based on certain events (for example seizure) in the EEG activity, whereas our approach quantifies coupling between spontaneous background EEG and NIRS. Conclusion Real-time continuous monitoring of NVC may be a promising physiologic signal for cerebral monitoring in future.

Background Premature infants are vulnerable to destructive brain injury and disturbed neurological development. Prematurity may alter maturation of the central autonomic nervous system (ANS). Aims To compare ANS function (using heart rate variability; HRV) between preterm infants with normal neuroimaging at term equivalent age and low-risk term controls. Study design, subjects. We performed a case-control study of preterm infants born ≤28 weeks gestational age that had normal brain imaging and archived continuous EKG data at term equivalent age. We documented other factors thought to influence ANS maturation (e.g. infection, ventilation days, and postnatal steroids). Controls were low-risk term gestational age newborns from uncomplicated pregnancies/deliveries. We characterized HRV metrics using frequency-(Welch periodogram) and time-domain (detrended fluctuation) analyses. Sympathetic tone was characterized by α1, root mean square analysis (RMS1 and RMS2), low-frequency (LF) power, and normalized LF (nLF) and parasympathetic tone was characterized by high-frequency (HF) power and normalized HF (nHF). α2 characterized ultraslow changes in heart rate. We used ANCOVA to compare HRV metrics between groups. Outcome measures, results. HRV from 26 preterm infants were compared to 55 controls. Analyzed HRV data for preterm infants were recorded at median (range) gestational age of 39 (36–39) weeks and for controls at 39 (37–41) weeks gestational age. α1, RMS2, LF and HF were significantly higher in control infants and remained significant after controlling for infection, ventilator days, and postnatal steroids (P Conclusions Autonomic maturation is impaired in a premature extrauterine environment. In the absence of destructive brain injury, our data suggest an important role for disturbed programming in this impaired autonomic development.

Background Near infrared spectroscopy (NIRS) derived hemoglobin difference (HbD: oxygenated [HbO2] – reduced hemoglobin [Hb]) and total hemoglobin (HbT: HbO2+Hb) have been used as surrogate measures of cerebral blood flow and volume, respectively. Statistically, a lack of HbD-blood pressure (BP) or negative HbT-BP association is regarded as a state of intact cerebral pressure autoregulation (CPA). In contrast, a co-variation of HbD/HbT and systemic blood pressure (BP) in the same direction is thought of as a failure of CPA. If the quality of one (NIRS/BP) or both signals is compromised, the reliability of the results may be adversely affected. In this work, we develop an analytic approach to assess the quality of the NIRS signals. New method Given that cardiac pulses cause hemodynamic changes that are transmitted through the peripheral vasculature, cerebral NIRS signals should exhibit cyclical changes at the pulse frequency. Therefore, we propose that an association between HbD/HbT and electrocardiogram (EKG) signals would be an indicator of NIRS quality. We demonstrate the application of this approach with data collected from six newborns undergoing therapeutic hypothermia for neonatal encephalopathy. Results We observed an intermittent lack of association between NIRS signals and EKG data over the course of several hours of continuous records, indicating a loss in the strength in NIRS signals. Comparison with existing method Existing CPA characterization suffers from Type-II error which the current preprocessing approach can mitigate. Conclusions The proposed approach will allow for real-time assessment of NIRS signal quality that is essential for accurate CPA monitoring.

Objective To evaluate whether infants with hypoxic-ischemic encephalopathy and evidence of autonomic dysfunction have aberrant physiological responses to care events that could contribute to evolving brain injury. Study design Continuous tracings of heart rate (HR), blood pressure (BP), cerebral near infrared spectroscopy, and video electroencephalogram data were recorded from newborn infants with hypoxic-ischemic encephalopathy who were treated with hypothermia. Videos between 16 and 24 hours of age identified 99 distinct care events, including stimulating events (diaper changes, painful procedures), and vagal stimuli (endotracheal tube manipulations, pupil examinations). Pre-event HR variability was used to stratify patients into groups with impaired versus intact autonomic nervous system (ANS) function. Postevent physiological responses were compared between groups with the nearest mean classification approach. Results Infants with intact ANS had increases in HR/BP after stimulating events, whereas those with impaired ANS showed no change or decreased HR/BP. With vagal stimuli, the HR decreased in infants with intact ANS but changed minimally in those with impaired ANS. A pupil examination in infants with an intact ANS led to a stable or increased BP, whereas the BP decreased in the group with an impaired ANS. Near infrared spectroscopy measures of cerebral blood flow/blood volume increased after diaper changes in infants with an impaired ANS, but were stable or decreased in those with an intact ANS. Conclusion HR variability metrics identified infants with impaired ANS function at risk for maladaptive responses to care events. These data support the potential use of HR variability as a real-time, continuous physiological biomarker to guide neuroprotective care in high-risk newborns.

Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury.

Cardiac rhythm is an essential component of fetal cardiac evaluation. The Monica AN24 is a fetal heart rate monitor that may provide a quick, inexpensive modality for obtaining a noninvasive fetal electrocardiogram (fECG) in a clinical setting. The fECG device has the ability to acquire fECG signals and allow calculation of fetal cardiac time intervals between 16- and 42-week gestational age (GA). We aimed to demonstrate the feasibility of fECG acquisition in a busy fetal cardiology clinic using the Monica fetal heart rate monitor. This is a prospective observational pilot study of fECG acquired from fetuses referred for fetal echocardiography. Recordings were performed for 5–15 min. Maternal signals were attenuated and fECG averaged. fECG and fetal cardiac time intervals (PR, QRS, RR, and QT) were evaluated by two cardiologists independently and inter-observer reliability was assessed using intraclass coefficient (ICC). Sixty fECGs were collected from 50 mothers (mean GA 28.1 ± 6.1). Adequate signal-averaged waveforms were obtained in 20 studies with 259 cardiac cycles. Waveforms could not be obtained between 26 and 30 weeks. Fetal cardiac time intervals were measured and were reproducible for PR (ICC = 0.89; CI 0.77–0.94), QRS (ICC = 0.79; CI 0.51–0.91), and RR (ICC = 0.77; CI 0.53–0.88). QT ICC was poor due to suboptimal T-wave tracings. Acquisition of fECG and measurement of fetal cardiac time intervals is feasible in a clinical setting between 19- and 42-week GA, though tracings are difficult to obtain, especially between 26 and 30 weeks. There was high reliability in fetal cardiac time intervals measurements, except for QT. The device may be useful for assessing atrioventricular/intraventricular conduction in fetuses from 20 to 26 and >30 weeks. Techniques to improve signal acquisition, namely T-wave amplification, are ongoing.

Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide-spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program.

Characterization of heart rate using detrended fluctuation analysis (DFA) is impeded by respiratory oscillations. In particular, the short-term exponent measured from 15 to 30 beats is compromised in the DFA. We reconstruct respiratory signal from electrocardiograms and attenuate the respiratory oscillation in the heart rate using a frequency-dependent subtraction approach. We validate this method by applying it to an electrocardiogram signal simulated using a coupled differential equation with the respiratory oscillation modelled using a sine function. The exponent estimated using the proposed approach agreed with the exponent incorporated in the model within a narrow range. In contrast, the exponent obtained from the raw data deviated from the expected value. Furthermore, the exponents obtained for the raw heart rate are smaller than the exponents obtained for the respiration oscillation attenuated heart rate. We apply this approach to heart rate measured from 12 preterm infants that were being treated for prematurity related complications. As observed in the simulated data, we show that compared to the raw heart rate, the respiratory oscillation attenuated heart rate shows higher short-term exponent (p < 0.001).

Background Patent ductus arteriosus (PDA) is a common complication of prematurity and a risk factor for poor outcome. Infants undergoing surgical PDA ligation are at highest risk for neurodevelopmental injury. Autonomic dysfunction has been described in premature infants with PDA. Aim To interrogate the autonomic nervous system by analysis of advanced heart rate variability (HRV) metrics before and after surgical closure of the PDA. Study Design Prospective, observational study. Subjects Twenty-seven infants born before 28 weeks' gestation were included in this study. Methods Continuous electrocardiogram data were sampled at a rate of 125 Hz for a total of 6 hours before and 6 hours after 30 hours of surgical closure. HRV was determined by detrended fluctuation analysis to calculate the short and long root mean square (RMSL and RMSS) and α components at two time scales (long and short). Results Gestational age (GA) was positively associated with RMSL, RMSS, and αS and was negatively associated with αL. There was no difference between RMSs, RMSL, αS, or αL before and after surgery; however, median heart rate was lower after surgery (p Conclusion Advancing GA is highly associated with increasing HRV; however, surgical ligation does not affect HRV in the postoperative period.

article Objective: Cerebral mapping of central autonomic nervous system (ANS) 1 function in mature animals and humans lateralizes sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. Spectral analysis of heart rate variability (HRV) 2 is an established measure of ANS function. We examined whether such lateralization is present in the term newborn. Methods: We retrospectively reviewed records of infants N36 weeks of gestation diagnosed with hypoxic ische- mic encephalopathy (HIE). 3 We included infants with neonatal EEG and regional injury on brain MRI, which was scored using a schema. We extracted ECG signals from the EEG recording, but excluded periods of electrographic seizureactivitytoeliminatepossibleseizureinfluenceonHRV.HRVwasevaluatedbyspectralanalysisinthehigh frequency (HF 4 ;0 .3-1 Hz) and low frequency (LF 5 ;0 .05-0.25 Hz) ranges, and the LF/HF ratio was examined to assess sympatho-vagal balance. The relation between the injured brain regions and HRV was studied using mul- tiple linear regression models. Results: We studied 40 neonates with HIE. Injury to the right cerebral cortex (p = 0.009) and right cerebellum (p = 0.041) predicted a decreased LF/HF ratio. Injury to the left cerebral cortex (p = 0.035) and left cerebellum (p = 0.041) was associated with an increased LF/HF ratio. The association between brain injury location and the individual LF or HF spectral powers of brain injury did not reach significance. Conclusions: Our data suggest that a functional lateralization for cerebral autonomic influence is established by term gestation. © 2014 Elsevier Ireland Ltd. All rights reserved.