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.

Prediction of outcome of hypoxic-ischemic encephalopathy in newborns undergoing therapeutic hypothermia using heart rate variability.

OBJECTIVE: To assess the use of continuous heart rate variability (HRV) as a predictor of brain injury severity in newborns with moderate to severe HIE that undergo therapeutic hypothermia. STUDY DESIGN: Two cohorts of newborns (n1 = 55, n2 = 41) with moderate to severe hypoxic-ischemic encephalopathy previously treated with therapeutic hypothermia. HRV was characterized by root mean square in the short time scales (RMSS) during therapeutic hypothermia and through completion of rewarming. A logistic regression and Naïve Bayes models were developed to predict the MRI outcome of the infants using RMSS. The encephalopathy grade and gender were used as control variables. RESULTS: For both cohorts, the predicted outcomes were compared with the observed outcomes. Our algorithms were able to predict the outcomes with an area under the receiver operating characteristic curve of about 0.8. CONCLUSIONS: HRV assessed by RMSS can predict severity of brain injury in newborns with HIE.

Cerebral autoregulation monitoring using the cerebral oximetry index after neonatal cardiac surgery: A single-center retrospective cohort study.

OBJECTIVE: To investigate whether cerebral autoregulation is impaired after neonatal cardiac surgery and whether changes in autoregulation metrics are associated with different congenital heart defects or the incidence of postoperative neurologic events. METHODS: This is a retrospective observational study of neonates undergoing monitoring during the first 72 hours after cardiac surgery. Archived data were processed to calculate the cerebral oximetry index (COx) and derived metrics. Acute neurologic events were identified by an electronic medical record review. The Skillings-Mack test and the Wilcoxon signed-rank test were used to analyze the evolution of autoregulation metrics over time; the Mann-Whitney U test was used for comparison between groups. RESULTS: We included 28 neonates, 7 (25%) with hypoplastic left heart syndrome and 21 (75%) with transposition of the great arteries. Overall, the median percentage of time spent with impaired autoregulation, defined as percentage of time with a COx >0.3, was 31.6% (interquartile range, 21.1%-38.3%). No differences in autoregulation metrics between different cardiac defects subgroups were observed. Seven patients (25%) experienced a postoperative acute neurologic event. Compared to the neonates without an acute neurologic event, those with an acute neurologic event had a higher COx (0.16 vs 0.07; P = .035), a higher percentage of time with a COx >0.3 (39.4% vs 29.2%; P = .017), and a higher percentage of time with a mean arterial pressure below the lower limit of autoregulation (13.3% vs 6.9%; P = .048). CONCLUSIONS: COx monitoring after cardiac surgery allowed for the detection of impaired cerebral autoregulation, which was more frequent in neonates with postoperative acute neurologic events.

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.

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%.

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.

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.

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.

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.

Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy.

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50-60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

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.

A pilot study: Auditory steady-state responses (ASSR) can be measured in human fetuses using fetal magnetoencephalography (fMEG).

BACKGROUND: Auditory 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. METHODS: 47 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 CONCLUSION: Ten 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, this pilot study is the first description of a method to detect human ASSRs in fetuses. The findings warrant further investigations of the developing fetal brain.

Prognostic Value of Continuous Electroencephalogram Delta Power in Neonates With Hypoxic-Ischemic Encephalopathy.

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 <.05 was considered a significant separation between groups. The favorable outcome group (n = 67) had higher delta power than the adverse outcome group (n = 28) across the majority of time periods from 9 to 90 hours of life. Delta power discriminated outcome groups for neonates with moderate encephalopathy (63 favorable and 14 adverse outcome) earlier in cooling (9-42 hours of life) than neonates with severe encephalopathy (21-42 hours of life). Outcome groups were differentiated after 81 hours of life in neonates with moderate and severe encephalopathy. Delta power can distinguish cooled HIE neonates with adverse outcome independently of the encephalopathy grade at presentation. Delta power may be a real-time continuous biomarker of evolving encephalopathy and brain injury/death in neonates with HIE.

The effect of labor and delivery mode on electrocortical and brainstem autonomic function during neonatal transition.

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 <72 hours of age to measure HRV, the asymmetry index, and EEG power. Newborns were compared by delivery type: vaginal delivery (VD), cesarean section (CS) after labor (L-CS), or elective CS (E-CS). Quantile Regression controlled for gestational age, postnatal age, and percent active states. One hundred and eighteen newborns were studied at 25.2 (11.4) hours of age. Sixty-two (52.5%) were born by VD, 22 by L-CS (18.6%), and 34 by E-CS (28.8%). HRV metrics didn't differ by delivery mode. Asymmetry index was higher in L-CS compared to VD and E-CS (P = 0.03). On EEG, L-CS newborns showed lower relative gamma power compared to VD and E-CS (P = 0.005). The study found that overall ANS tone is not altered by mode of delivery in low-risk term newborns.

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.

Anodal tDCS modulates cortical activity and synchronization in Parkinson's disease depending on motor processing.

BACKGROUND: Transcranial direct current stimulation (tDCS) may alleviate motor symptoms in Parkinson's disease (PD). However, the neurophysiological effects of tDCS on cortical activation, synchronization, and the relation to clinical motor symptoms and motor integration need characterization. OBJECTIVE: We aimed to explore the effect of tDCS over the left sensorimotor area on clinical motor outcome, right hand fine motor performance as well as cortical activity and synchronization in the high beta range. METHODS: In this double-blind randomized sham-controlled clinico-neurophysiological study we investigated ten idiopathic PD patients and eleven matched healthy controls (HC) on two days during an isometric precision grip task and at rest before and after 'verum' and 'sham' anodal tDCS (20 min; 1 mA; anode [C3], cathode [Fp2]). We measured clinical outcome, fine motor performance, and analysed both cortical frequency domain activity and corticocortical imaginary coherence. RESULTS: tDCS improved PD motor symptoms. Neurophysiological features indicated a motor-task-specific modulation of activity and coherence from 22 to 27 Hz after 'verum' stimulation in PD. Activity was significantly reduced over the left sensorimotor and right frontotemporal area. Before stimulation, PD patients showed reduced coherence over the left sensorimotor area during motor task compared to HC, and this increased after 'verum' stimulation in the motor task. The activity and synchronization modulation were neither observed at rest, after sham stimulation nor in healthy controls. CONCLUSION: Verum tDCS modulated the PD cortical network specifically during fine motor integration. Cortical oscillatory features were not in general deregulated in PD, but depended on motor processing.

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.

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.