Automatic detection of burst synchrony in preterm infants

\u3cp\u3eElectroencephalographic characteristics are useful in assessment of the functional status of specific neuronal connections relative to postmenstrual age. Interhemispheric burst synchrony (IBS) is a measure of the functional connectivity between the hemispheres in the maturing preterm brain. An algorithm was developed to assess IBS and was used in a prospective, longitudinal EEG study on 18 very preterm infants (< 32 weeks gestational age) with normal follow-up at 2 years of age. The preterm infants underwent weekly 4-hour multi-channel EEG recordings, resulting in n = 77 EEGs. After automated detection of bursts, the algorithm defines the start and end of interhemispheric synchronous burst activity, based on selection criteria found in literature. The algorithm was designed to emulate visual inspection, providing objective results in an automated manner. This approach may be applied in clinical use and open novel avenues to automated analysis in EEG monitoring and, moreover, it may facilitate assessment of the functional status of interhemispheric connections. As such, assessment of low interhemispheric synchrony may be associated with brain injury.\u3c/p\u3

Functional connectivity in preterm infants derived from EEG coherence analysis

Objective : To quantify the neuronal connectivity in preterm infants between homologous channels of both hemispheres. Methods : EEG coherence analysis was performed on serial EEG recordings collected from preterm infants with normal neurological follow-up. The coherence spectrum was divided in frequency bands: dnewborn(0–2 Hz), ¿newborn(2–6 Hz), anewborn(6–13 Hz), ßnewborn(13–30 Hz). Coherence values were evaluated as a function of gestational age (GA) and postnatal maturation. Results : All spectra show two clear peaks in the dnewborn and ¿newborn-band, corresponding to the delta and theta EEG waves observed in preterm infants. In the dnewborn-band the peak magnitude coherence decreases with GA and postnatal maturation for all channels. In the ¿newborn-band, the peak magnitude coherence decreases with GA for all channels, but increases with postnatal maturation for the frontal polar channels. In the ßnewborn-band a modest magnitude coherence peak was observed in the occipital channels, which decreases with GA. Conclusions : Interhemispherical connectivity develops analogously with electrocortical maturation: signal intensities at low frequencies decrease with GA and postnatal maturation, but increase at high frequencies with postnatal maturation. In addition, peak magnitude coherence is a clear trend indicator for brain maturation. Significance : Coherence analysis can aid in the clinical assessment of the functional connectivity of the infant brain with maturation

Comparison of ECG-based physiological markers for hypoxia in a preterm ovine model

BACKGROUND:\u3cbr/\u3eCurrent methods for assessing perinatal hypoxic conditions did not improve infant outcomes. Various waveform-based and interval-based ECG markers have been suggested, but not directly compared. We compare performance of ECG markers in a standardized ovine model for fetal hypoxia.\u3cbr/\u3eMETHODS:\u3cbr/\u3eSixty-nine fetal sheep of 0.7 gestation had ECG recorded 4 h before, during, and 4 h after a 25-min period of umbilical cord occlusion (UCO), leading to severe hypoxia. Various ECG markers were calculated, among which were heart rate (HR), HR-corrected ventricular depolarization/repolarization interval (QTc), and ST-segment analysis (STAN) episodic and baseline rise markers, analogue to clinical STAN device alarms. Performance of interval- and waveform-based ECG markers was assessed by correlating predicted and actual hypoxic/normoxic state.\u3cbr/\u3eRESULTS:\u3cbr/\u3eOf the markers studied, HR and QTc demonstrated high sensitivity (≥86%), specificity (≥96%), and positive predictive value (PPV) (≥86%) and detected hypoxia in ≥90% of fetuses at 4 min after UCO. In contrast, STAN episodic and baseline rise markers displayed low sensitivity (≤20%) and could not detect severe fetal hypoxia in 65 and 28% of the animals, respectively.\u3cbr/\u3eCONCLUSION:\u3cbr/\u3eInterval-based HR and QTc markers could assess the presence of severe hypoxia. Waveform-based STAN episodic and baseline rise markers were ineffective as markers for hypoxia

Multipotent adult progenitor cells for hypoxic-ischemic injury in the preterm brain

\u3cp\u3eBackground: Preterm infants are at risk for hypoxic-ischemic encephalopathy. No therapy exists to treat this brain injury and subsequent long-term sequelae. We have previously shown in a well-established pre-clinical model of global hypoxia-ischemia (HI) that mesenchymal stem cells are a promising candidate for the treatment of hypoxic-ischemic brain injury. In the current study, we investigated the neuroprotective capacity of multipotent adult progenitor cells (MAPC\u3csup\u3e®\u3c/sup\u3e), which are adherent bone marrow-derived cells of an earlier developmental stage than mesenchymal stem cells and exhibiting more potent anti-inflammatory and regenerative properties. Methods: Instrumented preterm sheep fetuses were subjected to global hypoxia-ischemia by 25 min of umbilical cord occlusion at a gestational age of 106 (term ~147) days. During a 7-day reperfusion period, vital parameters (e.g., blood pressure and heart rate; baroreceptor reflex) and (amplitude-integrated) electroencephalogram were recorded. At the end of the experiment, the preterm brain was studied by histology. Results: Systemic administration of MAPC therapy reduced the number and duration of seizures and prevented decrease in baroreflex sensitivity after global HI. In addition, MAPC cells prevented HI-induced microglial proliferation in the preterm brain. These anti-inflammatory effects were associated with MAPC-induced prevention of hypomyelination after global HI. Besides attenuation of the cerebral inflammatory response, our findings showed that MAPC cells modulated the peripheral splenic inflammatory response, which has been implicated in the etiology of hypoxic-ischemic injury in the preterm brain. Conclusions: In a pre-clinical animal model MAPC cell therapy improved the functional and structural outcome of the preterm brain after global HI. Future studies should establish the mechanism and long-term therapeutic effects of neuroprotection established by MAPC cells in the developing preterm brain exposed to HI. Our study may form the basis for future clinical trials, which will evaluate whether MAPC therapy is capable of reducing neurological sequelae in preterm infants with hypoxic-ischemic encephalopathy.\u3c/p\u3

Why -aVF can be used in STAN as a proxy for scalp electrode-derived signal:reply to comments by Kjellmer et al

\u3cp\u3eThe conclusion of our recent paper that performance of the STAN device in clinical practice is potentially limited by high false-negative and high false-positive STAN-event rates and loss of ST waveform assessment capacity during severe hypoxemia, evoked comments by Kjellmer, Lindecrantz and Rosén. These comments can be summarized as follows: 1) STAN analysis is based on a unipolar lead but the authors used a negative aVF lead, and they did not validate this methodology; 2) The fetuses used in the study were too young to display the signals that the authors were trying to detect. In response to these comments we now provide both a theoretical and an experimental underpinning of our approach. In an in vivo experiment in human we placed several electrodes over the head (simulating different places of a scalp electrode), simultaneously recorded Einthoven lead I and II, and constructed -aVF from these two frontal leads. Irrespective of scalp electrode placement, the correlation between any of unipolar scalp electrode-derived signals and constructed-aVF was excellent (≥ 0.92). In response to the second comment we refer to a study which demonstrated that umbilical cord occlusion resulted in rapid increase in T/QRS ratio that coincided with initial hypertension and bradycardia at all gestational ages which were tested from 0.6-0.8 gestation. The animals of our study were in this gestational range and, hence, our experimental setup can be used to assess STAN's quality to detect fetal hypoxia. In conclusion, we have clearly demonstrated the appropriateness of using-aVF as a proxy for a scalp electrode-derived signal in STAN in these preterm lambs. Investigation why STAN could not detect relevant ST-changes and instead produced erroneous alarms in our experimental setup is hampered by the fact that the exact STAN algorithm (signal processing and analysis) is not in the public domain.\u3c/p\u3

ST waveform analysis for monitoring hypoxic distress in fetal sheep after prolonged umbilical cord occlusion

\u3cp\u3eIntroduction The inconclusive clinical results for ST-waveform analysis (STAN) in detecting fetal hypoxemia may be caused by the signal processing of the STAN-device itself. We assessed the performance of a clinical STAN device in signal processing and in detecting hypoxemia in a fetal sheep model exposed to prolonged umbilical cord occlusion (UCO). Methods Eight fetal lambs were exposed to 25 minutes of UCO. ECG recordings were analyzed during a baseline period and during UCO. STAN-event rates and timing of episodic T/QRS rise, baseline T/QRS rise and the occurrence of biphasic ST-waveforms, as well as signal loss, were assessed. Results During baseline conditions of normoxemia, a median of 40 (IQR, 25–70) STAN-events per minute were detected, compared to 10 (IQR, 2–22) during UCO. During UCO STAN-events were detected in five subjects within 10 minutes and in six subjects after 18 minutes, respectively. Two subjects did not generate any STAN-event during UCO. Biphasic ST event rate was reduced during UCO (median 0, IQR 0–5), compared to baseline (median 32, IQR, 6–55). ST-waveforms could not be assessed in 62% of the recording time during UCO, despite a good quality of the ECG signal. Conclusions The STAN device showed limitations in detecting hypoxemia in fetal sheep after prolonged UCO. The STAN device produced high false positive event rates during baseline and did not detect T/QRS changes adequately after prolonged fetal hypoxemia. During 14% of baseline and 62% of the UCO period, the STAN-device could not process the ECG signal, despite its good quality. Resolving these issues may improve the clinical performance of the STAN device.\u3c/p\u3

Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia

\u3cp\u3eHypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6) MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE. \u3c/p\u3