Central Autonomic Network and heart rate variability in premature neonates.

INTRODUCTION: The Central Autonomic Network (CAN) is a hierarchy of brain structures that collectively influence cardiac autonomic input, mediating the majority of brain-heart interactions, but has never been studied in premature neonates. In this study, we use heart rate variability (HRV), which has been described as the "primary output" of the CAN, and resting state functional MRI to characterize brain-heart relationships in premature neonates. METHODS: We studied premature neonates who underwent resting state functional MRI (rsfMRI) at term, (37-weeks postmenstrual age [PMA] or above) and had HRV data recorded during the same week of their MRI. HRV was derived from continuous electrocardiogram data during the week of the rsfMRI scan. For rsfMRI, a seed-based approach was used to define regions of interest (ROI) pertinent to the CAN, and blood oxygen level-dependent signal was correlated between each ROI as a measure of functional connectivity. HRV was correlated with CAN connectivity (CANconn) for each region, and sub-group analysis was performed based on sex and clinical comorbidities. RESULTS: Forty-seven premature neonates were included in this study, with a mean gestational age at birth of 28.1 +/- 2.6 weeks. Term CANconn was found to be significantly correlated with HRV in approximately one-fifth of CAN connections. Two distinct patterns emerged among these HRV-CANconn relationships. In the first, increased HRV was associated with stronger CANconn of limbic regions. In the second pattern, stronger CANconn at the precuneus was associated with impaired HRV maturation. These patterns were especially pronounced in male premature neonates. CONCLUSION: We report for the first time evidence of brain-heart relationships in premature neonates and an emerging CAN, most striking in male neonates, suggesting that the brain-heart axis may be more vulnerable in male premature neonates. Signatures in the heart rate may eventually become an important non-invasive tool to identify premature males at highest risk for neurodevelopmental impairment.

Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy.

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.

Autonomic markers of extubation readiness in premature infants.

BACKGROUND: In premature infants, extubation failure is common and difficult to predict. Heart rate variability (HRV) is a marker of autonomic tone. Our aim is to test the hypothesis that autonomic impairment is associated with extubation readiness. METHODS: Retrospective study of 89 infants <28 weeks. HRV metrics 24 h prior to extubation were compared for those with and without extubation success within 72 h. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric, and a predictive model was created. RESULTS: Seventy-three percent were successfully extubated. The success group had significantly lower oxygen requirement, higher sympathetic HRV metrics, and a lower parasympathetic HRV metric. α1 (measure of autocorrelation, related to sympathetic tone) was the best predictor of success-area under the curve (AUC) of .73 (p = 0.001), and incorporated into a predictive model had an AUC of 0.81 (p < 0.0001)-sensitivity of 81% and specificity of 78%. CONCLUSIONS: Extubation success is associated with HRV. We show an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α1, a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model. IMPACT: This article depicts autonomic markers predictive of extubation success. We depict an autonomic imbalance in those who fail extubation with heightened parasympathetic and blunted sympathetic signal. We describe a predictive model for extubation success with a sensitivity of 81% and specificity of 78%.

Clinical Study of Continuous Non-Invasive Blood Pressure Monitoring in Neonates.

The continuous monitoring of arterial blood pressure (BP) is vital for assessing and treating cardiovascular instability in a sick infant. Currently, invasive catheters are inserted into an artery to monitor critically-ill infants. Catheterization requires skill, is time consuming, prone to complications, and often painful. Herein, we report on the feasibility and accuracy of a non-invasive, wearable device that is easy to place and operate and continuously monitors BP without the need for external calibration. The device uses capacitive sensors to acquire pulse waveform measurements from the wrist and/or foot of preterm and term infants. Systolic, diastolic, and mean arterial pressures are inferred from the recorded pulse waveform data using algorithms trained using artificial neural network (ANN) techniques. The sensor-derived, continuous, non-invasive BP data were compared with corresponding invasive arterial line (IAL) data from 81 infants with a wide variety of pathologies to conclude that inferred BP values meet FDA-level accuracy requirements for these critically ill, yet normotensive term and preterm infants.

The Utility of Cerebral Autoregulation Indices in Detecting Severe Brain Injury Varies by Cooling Treatment Phase in Neonates with Hypoxic-Ischemic Encephalopathy.

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.

In infants with congenital heart disease autonomic dysfunction is associated with pre-operative brain injury.

BACKGROUND: 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. OBJECTIVE: To determine whether impaired early neonatal HRV is associated with pre-operative brain injury in CHD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: 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.

Autonomic development in preterm infants is associated with morbidity of prematurity.

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.

Autonomic nervous system maturation in the premature extrauterine milieu.

BACKGROUND: In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation. METHODS: 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). RESULTS: 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. CONCLUSION: 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. IMPACT: 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.

Cerebral cortical autonomic connectivity in low-risk term newborns.

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 of 39-40 weeks were prospectively enrolled and studied using time-synced electroencephalography and electrocardiography for up to 60 min before discharge from the birth hospital. The ccortical autonomicc nervous system association was analyzed using coherence between electroencephalography-delta power and heart rate variability. Heart rate variability measured the 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, bitemporal, and occipital brain regions, with less robust coherence delta-standard deviation in the central region and bitemporal areas. CONCLUSIONS: Our findings describe a topography of ccortical autonomicc connectivity present at term in low-risk newborns, which was more robust to parasympathetic than sympathetic brainstem centers and was independent of newborn state.

Exploratory Assessment of the Relationship Between Hemoglobin Volume Phase Index, Magnetic Resonance Imaging, and Functional Outcome in Neonates with Hypoxic-Ischemic Encephalopathy.

BACKGROUND/OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Heart rate variability is depressed in the early transitional period for newborns with complex congenital heart disease.

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 < 0.0001), although absolute HF was lower (P = 0.0461). After adjusting for medications, αS and nLF remained lower and nHF higher in newborns with CHD (P < 0.0005). CONCLUSIONS: Infants with complex CHD have depressed autonomic balance in the early postnatal period, which may complicate the fetal-neonatal transition.

Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia.

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.

The effect of unilateral stroke on autonomic function in the term newborn.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Autonomic Dysfunction in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia Impairs Physiological Responses to Routine Care Events.

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.

Pattern of brain injury and depressed heart rate variability in newborns with hypoxic ischemic encephalopathy.

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.

Effect of Temperature on Heart Rate Variability in Neonatal ICU Patients With Hypoxic-Ischemic Encephalopathy.

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.

Baroreflex dysfunction in sick newborns makes heart rate an unreliable surrogate for blood pressure changes.

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 near infra-red spectroscopy 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-min 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.

Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease.

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.

Brain Maturity and Variation of Oxygen Extraction in Premature Infants.

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.