Global and intertuberal epileptic networks in tuberous sclerosis based on stereoelectroencephalographic (sEEG) findings: a quantitative EEG analysis in pediatric subjects and surgical implications.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis.

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] < 0.7). The pattern of HRV change was significantly associated with the clinical severity of NEC (stage II vs. stage III). 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.

The Impact of Surgical Patent Ductus Arteriosus Closure on Autonomic Function in Premature Infants.

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 < 0.01). Conclusion Advancing GA is highly associated with increasing HRV; however, surgical ligation does not affect HRV in the postoperative period.

Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

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.

Association of brain functional connectivity with neurodevelopmental outcomes in healthy full-term newborns.

OBJECTIVE: To study the association between neurodevelopmental outcomes and functional brain connectivity (FBC) in healthy term infants. METHODS: This is a retrospective study of prospectively collected High-density electroencephalography (HD-EEG) from newborns within 72 hours from birth. Developmental assessments were performed at two years of age using the Bayley Scales of Infant Development-III (BSID-III) measuring cognitive, language, motor, and socio-emotional scores. The FBC was calculated using phase synchronization analysis of source signals in delta, theta, alpha, beta, and gamma frequency bands and its association with neurodevelopmental score was assessed with stepwise regression. RESULTS: 47/163 had both HD-EEG and BSID-III scores. The FBC of frontal region was associated with cognitive score in the theta band (corrected p, regression coefficients range: p < 0.01, 1.66-1.735). Language scores were significantly associated with connectivity in all frequency bands, predominantly in the left hemisphere (p < 0.01, -2.74-2.40). The FBC of frontal and occipital brain regions of both hemispheres was related to motor score and socio-emotional development in theta, alpha, and gamma frequency bands (p < 0.01, -2.16-2.97). CONCLUSIONS: Functional connectivity of higher-order processing is already present at term age. SIGNIFICANCE: The FBC might be used to guide interventions for optimizing subsequent neurodevelopment even in low-risk newborns.

Functional brain network properties of healthy full-term newborns quantified by scalp and source-reconstructed EEG.

OBJECTIVE: Identifying the functional brain network properties of term low-risk newborns using high-density EEG (HD-EEG) and comparing these properties with those of established functional magnetic resonance image (fMRI) - based networks. METHODS: HD-EEG was collected from 113 low-risk term newborns before delivery hospital discharge and within 72 hours of birth. Functional brain networks were reconstructed using coherence at the scalp and source levels in delta, theta, alpha, beta, and gamma frequency bands. These networks were characterized for the global and local network architecture. RESULTS: Source-level networks in all the frequency bands identified the presence of the efficient small world (small-world propensity (SWP) > 0.6) architecture with four distinct modules linked by hub regions and rich-club (coefficient > 1) topology. The modular regions included primary, association, limbic, paralimbic, and subcortical regions, which have been demonstrated in fMRI studies. In contrast, scalp-level networks did not display consistent small world architecture (SWP < 0.6), and also identified only 2-3 modules in each frequency band.The modular regions of the scalp-network primarily included frontal and occipital regions. CONCLUSIONS: Our findings show that EEG sources in low-risk newborns corroborate fMRI-based connectivity results. SIGNIFICANCE: EEG source analysis characterizes functional connectivity at the bedside of low-risk newborn infants soon after birth.

Removal of interference from fetal MEG by frequency dependent subtraction.

Fetal magnetoencephalography (fMEG) recordings are contaminated by maternal and fetal magnetocardiography (MCG) signals and by other biological and environmental interference. Currently, all methods for the attenuation of these signals are based on a time-domain approach. We have developed and tested a frequency dependent procedure for removal of MCG and other interference from the fMEG recordings. The method uses a set of reference channels and performs subtraction of interference in the frequency domain (SUBTR). The interference-free frequency domain signals are converted back to the time domain. We compare the performance of the frequency dependent approach with our present approach for MCG attenuation based on orthogonal projection (OP). SUBTR has an advantage over OP and similar template approaches because it removes not only the MCG but also other small amplitude biological interference, avoids the difficulties with inaccurate determination of the OP operator, provides more consistent and stable fMEG results, does not cause signal redistribution, and if references are selected judiciously, it does not reduce fMEG signal amplitude. SUBTR was found to perform well in simulations and on real fMEG recordings, and has a potential to improve the detection of fetal brain signals. The SUBTR removes interference without the need for a model of the individual interference sources. The method may be of interest for any sensor array noise reduction application where signal-free reference channels are available.

Cortical representation of different motor rhythms during bimanual movements.

The cortical control of bimanual and unimanual movements involves complex facilitatory and inhibitory interhemispheric interactions. We analysed the part of the cortical network directly related to the motor output by corticomuscular (64 channel EEG-EMG) and cortico-cortical (EEG-EEG) coherence and delays at the frequency of a voluntarily maintained unimanual and bimanual rhythm and in the 15-30-Hz band during isometric contractions. Voluntary rhythms of each hand showed coherence with lateral cortical areas in both hemispheres and occasionally in the frontal midline region (60-80 % of the recordings and 10-30 %, respectively). They were always coherent between both hands, and this coherence was positively correlated with the interhemispheric coherence (p < 0.01). Unilateral movements were represented mainly in the contralateral cortex (60-80 vs. 10-30 % ipsilateral, p < 0.01). Ipsilateral coherence was more common in left-hand movements, paralleled by more left-right muscle coherence. Partial corticomuscular coherence most often disappeared (p < 0.05) when the contralateral cortex was the predictor, indicating a mainly indirect connection of ipsilateral/frontomesial representations with the muscle via contralateral cortex. Interhemispheric delays had a bimodal distribution (1-10 and 15-30 ms) indicating direct and subcortical routes. Corticomuscular delays (mainly 12-25 ms) indicated fast corticospinal projections and musculocortical feedback. The 15-30-Hz corticomuscular coherence during isometric contractions (60-70 % of recordings) was strictly contralaterally represented without any peripheral left-right coherence. Thus, bilateral cortical areas generate voluntary unimanual and bimanual rhythmic movements. Interhemispheric interactions as detected by EEG-EEG coherence contribute to bimanual synchronization. This is distinct from the unilateral cortical representation of the 15-30-Hz motor rhythm during isometric movements.

Electroencephalogram in low-risk term newborns predicts neurodevelopmental metrics at age two years.

OBJECTIVE: To determine whether neurodevelopmental biomarkers at 2 years of age are already present in the newborns' EEG at birth. METHODS: Low-risk term newborns were enrolled and studied utilizing EEG prior to discharge from the birth hospital. A 14-channel EEG montage (scalp-level) and source signals were calculated using the EEG. Their spectral power was calculated for each of the five frequency bands. Cognitive, language and motor skills were assessed using the Bayley Scales of Infant Development-III at age 2 years. The relationship between the spectral power in each frequency band and neurodevelopmental scores were quantified using the Spearman's r. The role of gender, gestational age (GA) and delivery mode, if found significant (P < 0.05), were controlled by analyzing partial correlation. RESULTS: We studied 47 newborns and found a significant association between gender, and delivery mode with EEG power. Scalp- and source-level spectral powers were positively associated with cognitive and language scores. At the source level, significant associations were identified in the parietal and occipital regions. CONCLUSIONS: Electrophysiological biomarkers of neurodevelopment at age 2 years are already present at birth in low-risk term infants. SIGNIFICANCE: Low-risk newborns' EEG utility as a screening tool to optimize neurodevelopmental outcome warrants further evaluation.

Change in EEG Activity is Associated with a Decrease in Tinnitus Awareness after rTMS.

OBJECTIVE: To examine how 1Hz and 10Hz rTMS temporarily influence ratings of tinnitus loudness, annoyance, and awareness. The thalamocortical dysrhythmia (TCD) model of tinnitus was tested by examining changes in spectral power and coherence of resting state EEGs from baseline to each phase of treatment and correlating these data with change in tinnitus. METHODS: Nineteen participants completed a double-blind, placebo (sham rTMS) controlled, within-subjects study with crossover between the two active rTMS treatment conditions. An imposed order effect, sham rTMS first, eliminated drift of active treatment into the placebo condition. The primary outcome measures were analogue ratings of tinnitus loudness, annoyance, and awareness, assessed repeatedly at baseline and during treatment, and 64 channel, resting state EEGs collected at baseline and the end of each treatment phase. Active rTMS consisted of 1800 pulses at 110% of motor threshold over temporal cortex delivered at 1Hz and 10Hz over four days. The research design also examined the effect of rTMS immediately following stimulation, regression to the mean in tinnitus ratings made over multiple days, and differences between treatment responders and non-responders. RESULTS: There was no immediate effect of rTMS on tinnitus during a single rTMS session. Regression to the mean in tinnitus ratings occurred over three days of baseline and four days of treatment (both sham and active rTMS). After accounting for regression to the mean in the statistical model, 1Hz rTMS led to a significant decrease in tinnitus awareness from baseline and 10Hz rTMS trended in the same direction, whereas sham rTMS showed little change from baseline other than regression to the mean. Changes from baseline in spectral power of the resting state EEG provided partial support for predictions based on TCD model of tinnitus for active 1 and 10Hz rTMS but not sham rTMS. However, only an increase in beta coherence correlated significantly with a decrease in tinnitus awareness. Changes in the EEG were robust in treatment responders but absent among non-responders and during sham rTMS. CONCLUSIONS: A positive response to rTMS for tinnitus is associated with an rTMS-induced change in beta coherence of the EEG. Increased beta coherence may be a biomarker of the rTMS effect; a "top-down" modulation of the EEG that promotes habituation to tinnitus. Participants whose tinnitus did not improve after rTMS did not show any changes in the EEG.

Detrended fluctuation analysis using orthogonal polynomials.

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.

Identifying an optimal epoch length for spectral analysis of heart rate of critically-ill infants.

BACKGROUND AND OBJECTIVE: To identify the optimal epoch length for power spectral analysis of cardiac beat-to-beat intervals (BBi) in critically ill newborns. MATERIALS AND METHOD: BBi of 49 term newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy with well-defined outcomes (good outcome (n = 28): no or mild brain injury and adverse outcome (n = 21): moderate or severe brain injury or death) served as test population. A power spectrum of BBi was calculated with an autoregressive model in three different epoch lengths: 2 min, 5 min, and 10 min. Spectral power was quantified in three different frequency bands: very low-frequency (0.016-0.04 Hz), low-frequency (0.05-0.25 Hz), and high-frequency (0.3-1 Hz). In each frequency band, the absolute power and the normalized power were calculated. Furthermore, standard deviation (SDNN) of BBi was calculated. These metrics were compared between the outcome groups with a receiver operator characteristic (ROC) analysis in 3-h windows. The ROC curve area >0.7 was regarded as a significant separation. RESULTS: The absolute spectral powers in all three epoch lengths in all three frequency bands and SDNN distinguished the two outcome groups consistently for most time points. The spectral metrics calculated with a 2-min epoch length performed as well as the five- and 10-min epoch lengths (paired t-test P < 0.05). CONCLUSION: Spectral analysis of BBi in 2-min epoch shows a similar discriminatory power as longer epoch lengths. A shorter epoch also has clinical advantages for translation into a continuous real-time bedside monitor of heart rate variability in the intensive care unit.

Effect of EKG Sampling Rate on Heart Rate Variability Analysis.

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 (αs), long-term DFA exponent (αL), 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 (EKG500), 250 Hz (EKG250), and 125 Hz (EKG125). The bedside monitors were simultaneously sending the EKG to a data warehouse, storing the EKG (EKGDWH) at 250 Hz. All HRV metrics were also calculated for the EKGDWH. The comparison between HRV metrics calculated from EKGref and downsampled EKG (EKG500, EKG250, EKG125) was made with intraclass correlation coefficient (r). The comparisons of HRV metrics between EKG250 and EKGDWH were also made with ICC. Our results show that HRV calculated with EKGref and from downsampled EKG were highly correlated (r>0.8 for all comparisons, P<; 0.001). HRV metrics from EKG250 and EKGDWH were also significantly correlated (r=0.7, P<; 0.001) for all metrics except for HF (r=0.276). These data show that HF power is compromised in the EKGDWH signal and caution must be exercised in interpreting the HF power calculated from this EKG.

An objective assessment of fetal and neonatal auditory evoked responses.

OBJECTIVE: We propose to use cross-correlation function to determine significant fetal and neonatal evoked responses (ERs). METHODS: We quantify ERs by cross-correlation between the stimulus time series and the recorded brain signals. The statistical significance of the correlation is calculated by surrogate analysis. For validation of our approach we investigated a model which mimics the generation of ERs. The model assumes a fixed latency of the ER and contains two parameters, epsilon and lambda. Whether or not the system responds to a given stimulus is controlled by epsilon. The amount to which the system is excited from the base line (background activity) is governed by lambda. We demonstrate the technique by applying it to auditory evoked responses from four fetuses (21 records) between 27 and 39 weeks of gestational age and four neonates (eight records). RESULTS: The method correctly identified the ER and the latency incorporated in the model. A combined analysis of fetuses and neonates data resulted in a significant negative correlation between age and latency. CONCLUSIONS: The analysis of ER, especially for fetal and newborn recordings, should be based on advanced data analysis including the assessment of the significance of responses. The negative correlation between age and latency indicates the neurological maturation. SIGNIFICANCE: The proposed method can be used to objectively assess the ER in fetuses and neonates.

Cortical representation of rhythmic foot movements.

The cortex is involved in rhythmic hand movements. The cortical contribution to rhythmic motor patterns of the feet, however, has never been evaluated in humans. In this study we investigated EEG activity related to rhythmic stepping and tapping movements in 10 healthy subjects. Subjects performed self-paced fast bilateral anti-phase, in-phase and unilateral rhythmic foot movements as well as an isometric cocontraction of the calf muscles, while being seated as relaxed as possible. Surface EMG from the anterior tibial muscles was recorded in parallel with a 64 channel EEG. Power spectra, corticomuscular coherence and corticomuscular delay were calculated. All subjects showed corticomuscular coherence at the stepping frequencies in the central midline region that extended further to the frontal mesial area. The magnitude and the topography of this coherence were equal for the right and left anterior tibial muscle and all movement conditions. During cocontraction there was coherence in the 15-30 Hz range which was refined to the central midline area. EEG-EMG delays were significant in 9 subjects with values between 14 and 26 ms, EMG-EEG feedback was only found in 6 subjects with delays between 25 and 40 ms. We conclude that rhythmic motor patterns of the feet are represented in the cortex, transmitted to the muscles with delays compatible with fast corticospinal transmission and fed back to the cortex. A similar cortical contribution may be important also for gait control in humans.

Differentiating phase shift and delay in narrow band coherent signals.

OBJECTIVE: Differentiating between a fixed activation pattern (phase shift) and conduction time (time delay) in rhythmic signals has important physiological implications but is methodologically difficult. METHODS: Delay was estimated by the maximising coherence method and phase spectra calculated between (i) a narrow band-pass filtered AR2 process and its delayed copy for different phase shifts, (ii) the surface EMGs from two antagonistic forearm muscles with reciprocal alternating activity, and (iii) EEG and EMG data from 11 recordings in five Parkinsonian tremor patients. RESULTS: Estimated delays between the versions of the AR2 process resembled the real delay and were not significantly biased by the phase-shifts. The reciprocal alternating pattern of muscle activation was shown to be a pure phase-shift without any time delay. The phase between tremor-coherent cortical electrodes and EMG showed opposite signs and differed by 3pi/4-pi between the antagonistic muscles. Bidirectional delays between contralateral cortex and EMG did not differ between the antagonists and were in keeping with fast corticospinal transmission and feedback to the cortex for both muscles. CONCLUSIONS: Phase shifts and delays reflect different mechanisms in tremor related oscillatory interactions. SIGNIFICANCE: The maximising coherence method can differentiate between them.

Assessing cardiac and neurological maturation during the intrauterine period.

The world's first magnetoencephalography (MEG) system specifically designed for fetal and newborn assessment has been installed at the University of Arkansas for Medical Sciences. This noninvasive system called SARA (SQUID Array for Reproductive Assessment) consists of 151 primary superconducting sensors that detect biomagnetic fields from the human body. Since the installation of SARA, significant progress has been made toward the ultimate goal of developing a clinical neurological assessment tool for the developing fetus. Using appropriate analysis techniques, cardiac and brain signals are recorded and studied to gain new understanding of fetal maturation. It is clear from our investigations that a combination of assessment protocols including both fetal heart and brain activity is necessary for the development of a comprehensive new method of fetal neurological testing. We plan to implement such a test protocol for fetuses at high risk for neurological impairment due to certain maternal risk factors and/or fetal diagnostic findings.

Ensuring signal quality of cerebral near infrared spectroscopy during continuous longterm monitoring.

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.

Early maturation of sinus rhythm dynamics in high-risk fetuses.

OBJECTIVE: The purpose of this study was to compare cardiac dynamics of high-risk and low-risk fetuses using beat to beat variability. STUDY DESIGN: This study obtained 214 fetal magnetocardiography recordings from a group of high-risk fetuses with maternal conditions associated with placental insufficiency with the risk of developing intrauterine growth restriction or were already diagnosed with intrauterine growth restriction. For purpose of comparison, another 136 recordings were obtained from low-risk fetuses. The cardiac beat-to-beat intervals computed as RR intervals were analyzed from both groups using the mean and median interval, standard deviation of normal-to-normal intervals, root mean square of the successive differences, and the fraction of the normal-to-normal intervals (pNNx) that differ by more than the chosen tolerance level of 'x' milliseconds from the previous normal-to-normal intervals. Tests for significance between high-risk and low-risk fetuses were calculated using an independent samples t test within the following gestational age groups, 27-30 weeks, 31-35 weeks, and 36-40 weeks. RESULTS: The root mean square of the successive differences, and the pNNx showed a significant difference between the low-risk and high-risk fetuses in the 31-35-week and the 36-40-week divisions. In the 31-35-week age division, low-risk fetuses had significantly lower root mean square of the successive differences, and pNN values than the high risk, but in the 36-40-week division, the low-risk fetuses had significantly higher root mean square of the successive differences, and pNN values. CONCLUSION: Cardiac dynamics for fetuses of mothers at risk for placental insufficiency mature quicker than fetuses not at risk for placental insufficiency.