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Objective: To evaluate the utility of a fully automated deep learning -based quantitative measure of EEG background, Brain State of the Newborn (BSN), for early prediction of clinical outcome at four years of age., Methods: The EEG monitoring data from eighty consecutive newborns was analyzed using the automatically computed BSN trend. BSN levels during the first days of life (a of total 5427 hours) were compared to four clinical outcome categories: favorable, cerebral palsy (CP), CP with epilepsy, and death. The time dependent changes in BSN-based prediction for different outcomes were assessed by positive/negative predictive value (PPV/NPV) and by estimating the area under the receiver operating characteristic curve (AUC)., Results: The BSN values were closely aligned with four visually determined EEG categories (p < 0·001), as well as with respect to clinical milestones of EEG recovery in perinatal Hypoxic Ischemic Encephalopathy (HIE; p < 0·003). Favorable outcome was related to a rapid recovery of the BSN trend, while worse outcomes related to a slow BSN recovery. Outcome predictions with BSN were accurate from 6 to 48 hours of age: For the favorable outcome, the AUC ranged from 95 to 99% (peak at 12 hours), and for the poor outcome the AUC ranged from 96 to 99% (peak at 12 hours). The optimal BSN levels for each PPV/NPV estimate changed substantially during the first 48 hours, ranging from 20 to 80., Conclusions: We show that the BSN provides an automated, objective, and continuous measure of brain activity in newborns., Significance: The BSN trend discloses the dynamic nature that exists in both cerebral recovery and outcome prediction, supports individualized patient care, rapid stratification and early prognosis., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: This study evaluated the accuracy of neonatal amplitude-integrated electroencephalography (aEEG) brain monitoring for predicting development of postneonatal epilepsy after perinatal hypoxic ischemic encephalopathy (HIE)., Methods: We studied a population-based cohort of 85 consecutive neonates with moderate-to-severe HIE that had aEEG started <12 hours postnatally. We marked electrographic seizures and graded each hour of the aEEG background as inactive, burst-suppression, or continuous without or with sleep cycling. These aEEG parameters were compared to outcome at 4-years age (deceased, epilepsy, cerebral palsy without epilepsy, favorable), which was available for 80 children., Results: At group level, total seizure burden (p = 0.003), maximum hourly seizure burden (p = 0.007), and aEEG background recovery (p < 0.001) were all significantly associated with outcome. At individual level six children developed epilepsy, and the most accurate predictors for later epilepsy were inactive aEEG at 24 hours (accuracy 97%, positive predictive value 100%, two false negatives) and inactive aEEG at the onset of seizures (accuracy 97%, sensitivity of 100%, one false positive)., Conclusions: At individual level aEEG background recovery was a better predictor for later epilepsy than neonatal seizures, although both were associated with epilepsy at group level., Significance: Poor aEEG background recovery predicts development of epilepsy after perinatal HIE at individual level., Competing Interests: Conflict of interest statement None of the authors has any conflict of interest to disclose., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: We assessed in extremely preterm born (EPB) children whether secondary somatosensory cortex (SII) responses recorded with magnetoencephalography (MEG) at term-equivalent age (TEA) correlate with neurodevelopmental outcome at age 6 years. Secondly, we assessed whether SII responses differ between 6-year-old EPB and term-born (TB) children., Methods: 39 EPB children underwent MEG with tactile stimulation at TEA. At age 6 years, 32 EPB and 26 TB children underwent MEG including a sensorimotor task requiring attention and motor inhibition. SII responses to tactile stimulation were modeled with equivalent current dipoles. Neurological outcome, motor competence, and general cognitive ability were prospectively evaluated at age 6 years., Results: Unilaterally absent SII response at TEA was associated with abnormal motor competence in 6-year-old EPB children (p = 0.03). At age 6 years, SII responses were bilaterally detectable in most EPB (88%) and TB (92%) children (group comparison, p = 0.69). Motor inhibition was associated with decreased SII peak latencies in TB children, but EPB children lacked this effect (p = 0.02)., Conclusions: Unilateral absence of an SII response at TEA predicted poorer motor outcome in EPB children., Significance: Neurophysiological methods may provide new means for outcome prognostication in EPB children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Somatosensory evoked potentials (SEPs) offer an additional bedside tool for outcome prediction after perinatal asphyxia., Aims: To assess the reliability of SEPs recorded with bifrontoparietal amplitude-integrated electroencephalography (aEEG) brain monitoring setup for outcome prediction in asphyxiated newborns undergoing therapeutic hypothermia., Study Design: Retrospective observational single-center study., Subjects: 27 consecutive asphyxiated full- or near-term newborns (25 under hypothermia) that underwent median nerve aEEG-SEPs as part of their clinical evaluation at the neonatal intensive care unit of Helsinki University Hospital., Outcome Measures: aEEG-SEP classification (present, absent or unreliable) was compared to classification of SEPs recorded with a full EEG montage (EEG-SEP), and outcome determined from medical records at approximately 12-months-age. Unfavorable outcome included death, cerebral palsy, or severe epilepsy., Results: The aEEG-SEP and EEG-SEP classifications were concordant in 21 of the 22 newborns with both recordings available. All five newborns with bilaterally absent aEEG-SEPs had absent EEG-SEPs and the four with outcome information available had an unfavorable outcome (one was lost to follow-up). Of the newborns with aEEG-SEPs present, all with follow-up exams available had bilaterally present EEG-SEPs and a favorable outcome (one was lost to follow-up). One newborn with unilaterally absent aEEG-SEP at 25 h of age had bilaterally present EEG-SEPs on the next day, and a favorable outcome., Conclusions: aEEG-SEPs recorded during therapeutic hypothermia on the first postnatal days are reliable for assessing brain injury severity. Adding SEP into routine aEEG brain monitoring offers an additional tool for very early outcome prediction after birth asphyxia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the accuracy of hypoxic ischemic encephalopathy (HIE) grade, and neonatal neurophysiological and neuroimaging measures for predicting development of infantile spasms syndrome (IS) or other postneonatal, infantile onset epilepsy after perinatal HIE., Methods: We examined a population-based cohort of 92 consequent infants with moderate-to-severe HIE. The HIE grade and neonatal neuroimaging (MRI) and neurophysiology (EEG and somatosensory evoked potentials, SEPs) findings were compared to the development of IS or other epilepsy within the first year of life., Results: Out of 74 surviving infants with follow-up information, five developed IS and one developed a focal onset epilepsy. They all had recovered from severe HIE. All survivors with inactive neonatal EEG (recorded within the first few postnatal days, n = 4) or the most severe type of brain injury in MRI (n = 3) developed epilepsy (positive predictive value, PPV 100 %). Bilaterally absent SEPs had 100 % sensitivity and 75 % PPV for epilepsy. A combination of absent SEPs and a poor MRI finding (combined deep and cortical gray matter injury) resulted in higher PPV (86 %) without lowering sensitivity (100 %). Follow-up EEGs showed recurrent epileptiform activity already between 1- and 2-months age in those that developed epilepsy, distinguishing them from those surviving without epilepsy., Conclusions: Poor neonatal neuroimaging and neurophysiological findings provide accurate prediction for development of infantile onset epilepsy after HIE. Of the neonates with severe HIE, the ones with severe neonatal MRI and neurophysiological abnormalities need frequent follow-up, including repeated EEGs, for early detection of IS., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: The unspecific symptoms of neonatal stroke still challenge its bedside diagnosis. We studied the accuracy of routine electroencephalography (EEG) and simultaneously recorded somatosensory evoked potentials (EEG-SEP) for diagnosis and outcome prediction of neonatal stroke., Methods: We evaluated EEG and EEG-SEPs from a hospital cohort of 174 near-term neonates with suspected seizures or encephalopathy, 32 of whom were diagnosed with acute ischemic or hemorrhagic stroke in MRI. EEG was scored for background activity and seizures. SEPs were classified as present or absent. Developmental outcome of stroke survivors was evaluated from medical records at 8- to 18-months age., Results: The combination of continuous EEG and uni- or bilaterally absent SEP (n = 10) was exclusively seen in neonates with a middle cerebral artery (MCA) stroke (specificity 100%). Moreover, 80% of the neonates with this finding developed with cerebral palsy. Bilaterally present SEPs did not exclude stroke, but predicted favorable neuromotor outcome in stroke survivors (positive predictive value 95%)., Conclusions: Absent SEP combined with continuous EEG background in near-term neonates indicates an MCA stroke and a high risk for cerebral palsy., Significance: EEG-SEP offers a bedside method for diagnostic screening and a reliable prediction of neuromotor outcome in neonates suspected of having a stroke., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the reliability of recording cortical somatosensory evoked potentials (SEPs) in asphyxiated newborns using the 4-electrode setup applied in routine long-term amplitude-integrated EEG (aEEG) brain monitoring and to assess the number of averages needed for reliably detecting the cortical responses., Methods: We evaluated median nerve SEPs in 50 asphyxiated full-term newborns. The SEP interpretation (present or absent) from the original recordings with 21-electrodes and approximately 600 trials served as the reference. This was compared to SEP classification (absent, present, or unreliable) based on a reduced (300 or 150) number of averages, and to classification based on only four electrodes (F3, P3, F4, P4)., Results: Compared to the original classification, cortical SEPs were uniformly interpreted as present or absent in all 50 newborns with the 4-electrode setup and 600 averages. Reducing number of averages to 300 still resulted in correct SEP interpretation in 49/50 newborns with 21-electrode setup, and 46/50 newborns with 4-electrode setup., Conclusions: Evaluation of early cortical neonatal SEPs is reliable from the 4-electrode setup commonly used in aEEG monitoring. SEP is discernible in most newborns with 300 averages., Significance: Adding SEP into routine aEEG monitoring offers an additional tool for early neonatal neurophysiological evaluation.

Background: Children born preterm are prone to motor problems. Research on their motor performance has, however, rarely been integrated with sensory processing., Aim: To examine sensory-motor performance in children born extremely preterm (EPT)., Method: In a longitudinal prospective cohort study, 49 EPT (born <28 gestational weeks; 32 boys and 17 girls) and 33 term-born (16 boys and 17 girls) children were assessed with six individual subtests from the Sensory Integration and Praxis Tests at the age of 7.0 to 7.3 years., Results: The rate of test z-scores indicating dysfunction [from -2 standard deviations (SD) to < -1 SD for mild and < -2 SD for moderate-to-severe] was significantly higher in EPT children than in term-born children in all the subtests. When comparing mean performance adjusted for gender and mother's education, EPT children performed worse than term-born children in Design Copying (z-score difference - 0.83; 95% confidence interval -1.32 to -0.34), Motor Accuracy (-0.82; -1.26 to -0.38), Postural Praxis (-0.95; -1.45 to -0.45), Manual Form Perception (-0.59; -1.12 to -0.06), and Finger Identification (-0.88; -1.45 to -0.31). Additional adjustment for Full-Scale Intelligence Quotient rendered difference in Manual Form Perception non-significant., Conclusion: Seven-year-old EPT children perform worse than their term-born peers in tests for visual-motor, somatosensory, and motor planning performance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To evaluate the added value of somatosensory (SEPs) and visual evoked potentials (VEPs) recorded simultaneously with routine EEG in early outcome prediction of newborns with hypoxic-ischemic encephalopathy under modern intensive care., Methods: We simultaneously recorded multichannel EEG, median nerve SEPs, and flash VEPs during the first few postnatal days in 50 term newborns with hypoxic-ischemic encephalopathy. EEG background was scored into five grades and the worst two grades were considered to indicate poor cerebral recovery. Evoked potentials were classified as absent or present. Clinical outcome was determined from the medical records at a median age of 21months. Unfavorable outcome included cerebral palsy, severe mental retardation, severe epilepsy, or death., Results: The accuracy of outcome prediction was 98% with SEPs compared to 90% with EEG. EEG alone always predicted unfavorable outcome when it was inactive (n=9), and favorable outcome when it was normal or only mildly abnormal (n=17). However, newborns with moderate or severe EEG background abnormality could have either favorable or unfavorable outcome, which was correctly predicted by SEP in all but one newborn (accuracy in this subgroup 96%). Absent VEPs were always associated with an inactive EEG, and an unfavorable outcome. However, presence of VEPs did not guarantee a favorable outcome., Conclusions: SEPs accurately predict clinical outcomes in newborns with hypoxic-ischemic encephalopathy and improve the EEG-based prediction particularly in those newborns with severely or moderately abnormal EEG findings., Significance: SEPs should be added to routine EEG recordings for early bedside assessment of newborns with hypoxic-ischemic encephalopathy., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Prior studies on extremely preterm infants have reported long-term prognostic value of absent secondary somatosensory cortex (SII) responses in magnetoencephalography (MEG) at term. The present work (i) further examines the potential added value of SII responses in neonatal neurological evaluation of preterm infants, and (ii) tests whether SII responses are detectable in routine neonatal electroencephalogram complemented with median nerve stimulation (EEG-SEP)., Methods: Altogether 29 infants born <28 gestational weeks underwent MEG, MRI, and neonatal neurological examination at term age, and Hempel neurological examination at 2-years corrected age. Term-age EEG-SEP was available for seven infants., Results: While in neonatal neurological examination severely abnormal finding predicted unfavorable outcome in 2/2 infants, outcome was unfavorable also in 3/9 (33%) moderately abnormal and in 5/18 (28%) mildly abnormal/normal infants. Of these eight infants four had unilaterally absent SII responses in MEG, compared with only two of the 24 infants with favorable outcome. Furthermore, SII responses (when present in MEG) were also usually detectable in EEG-SEP., Conclusions: Complementing clinical EEG recording with SEP holds promise for valuable extension of neonatal neurophysiological assessment., Significance: Multimodal study of EEG and sensory evoked responses is informative, safe, and cheap, and it can be readily performed at bedside., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Animal experiments have suggested that the quality of the early intermittent brain activity is important for shaping neuronal connectivity during developmental phase that corresponds to early prematurity. This is a pilot study aiming to assess whether spontaneous activity transients (SAT) in the early preterm babies are affected by drugs that are routinely used in neonatal intensive care., Methods: We collected retrospectively seventeen EEG recordings (15 babies, conceptional age 26-33weeks, no brain lesions) that were divided into groups according to drug administration at the time of EEG: phenobarbital, fentanyl, theophylline, and controls. SATs were extracted from the EEG for further analysis with several advanced time-series analysis paradigms., Results: The visual appearance of SATs was unaffected by drugs. Phenobarbital reduced the total power of the SAT events. Both fentanyl and phenobarbital reduced the length of SATs, and enhanced the oscillations at higher frequencies. Theophylline reduced the oscillatory activity at middle frequencies during SAT, but enhanced oscillations at higher frequencies during time-period prior to SAT., Conclusions: Our findings suggest, that (i) all drugs examined affect brain activity in ways that are not seen in the visual EEG interpretation, and that (ii) both acute and long term (i.e. developmental) effects of these drugs on brain may warrant more attention as a part of optimizing preterm neurological care., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine interhemispheric differences and effect of postmenstrual age (PMA), height, and gender on somatosensory evoked magnetic fields (SEFs) from the primary (SI) and secondary (SII) somatosensory cortices in healthy newborns., Methods: We recorded SEFs to stimulation of the contralateral index finger (right in 46 and left in 12) healthy fullterm newborns and analyzed the magnetic responses with equivalent current dipoles., Results: Activity from both the SI and SII was consistently detectable in the contralateral hemisphere of the newborns during quiet sleep. No significant interhemispheric differences existed in SI or SII response peak latencies, source strengths, or location (n=8, quiet sleep). SI or SII response peak latency or source strength were not significantly affected by PMA, height, or gender., Conclusions: During the neonatal period (PMA 37-44 weeks), activity from the contralateral SI and SII can be reliably evaluated with MEG. The somatosensory responses are similar in the left and right hemispheres and no corrections for exact PMA, height, or gender are necessary for interpreting the results. However, the evaluation should be conducted in quiet sleep., Significance: The reproducibility of the magnetic SI and SII responses suggests clinical applicability of the presented MEG method., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Increased survival of extremely low birth weight infants has led to a need for new prognostic methods to predict possible future neurological impairment. We investigated the early development of the somatosensory system by recording the somatosensory evoked magnetic fields (SEFs) during natural sleep at fullterm age in 16 very prematurely born infants and 16 healthy newborns born at term. The purpose was to determine possible changes in the function of the somatosensory cortex in the prematurely born infants by comparing the latency, strength, location and morphology of the SEFs with those of healthy fullterm newborns. We recorded reliable SEFs in all patients and controls. The equivalent current dipole (ECD) strength of the first cortical response, M60, was significantly lower in the patients. Otherwise, the general morphology and latency of the SEFs were similar in the two groups of babies. The similar response latencies in the two groups indicate normally developed conduction in the somatosensory system of the prematurely born infants. The attenuated ECD strength may reflect weaker synchrony in firing or a smaller number of the cortical neurons activated by the somatosensory stimulation. At the individual level, in four of the preterm infants, a later M200 response was not present or could not be modeled: all of them had lesions of the underlying hemisphere depicted by ultrasound and magnetic resonance imaging.

Objective: To develop an electrode cap with high number of electrodes for recording very small preterm babies, to assess the physiological stress imposed by the application of this cap on babies, and to estimate what added information could be potentially obtained with more electrodes in this age group., Methods: We recruited eleven extremely small preterm babies (conceptional age 25-29 weeks) to record their EEG with a custom-tailored high-density EEG cap (20 channels), coupled with a Full-band EEG amplifier. Physiological stress caused by the cap placement was assessed by recording heart rate and arterial oxygen saturation before and during EEG cap placement, as well as before and during a routine care procedure of the given baby. The quality of novel information obtained with this system was assessed by comparing the full signal to a set of EEG signals where we deliberately distorted and omitted major signal components to make it appear as in the conventional EEG systems., Results: The changes in heart rate or oxygen saturation caused by the cap placement are fully comparable to the changes seen after any normal care procedure in the same baby. Our recordings did also reveal that brain activity in the small premies is highly focal, and often confined to only one or two electrodes. Hence it cannot be pertinently localized with the currently used low number of recording electrodes. Moreover, recordings from babies with focal intracerebral hemorrhages showed that changes after vascular insults are clearly more prominent and hence easier to detect visually from multichannel recordings., Conclusions: Recording of high-fidelity EEG (high-density caps and FbEEG system) is practical in the incubator environment, and the application of a proper EEG cap is not more stressful to the baby than a routine care procedure. Moreover, these achievable amendments in the recording system seem to disclose major physiological and pathological signal components in the as yet poorly explored patient group., Significance: Introduction of a technically feasible and physically gentle enough EEG recording system will enable further development of clinical neurophysiological understanding, as well as the design of pertinent brain monitors, which is urgently needed in these patients.

The main objective of this study was to characterize the cellular phenotypes in the repair tissue of full-thickness defects of articular cartilage by histologic and molecular biologic techniques. Healing of the defects in the articular cartilage of the knee joints of 12 rabbits was analyzed at days 3, 7, 14, 28 and 50 using histology and Northern analysis of mRNA levels for type I, II and III collagens and osteonectin. The cellular source of each mRNA was determined by in situ hybridization. Two novel cDNA clones for rabbit type II and III collagen mRNAs were constructed to obtain species-specific hybridization probes. The repair tissue of full-thickness defects consisted of two types of tissue. At the bottom of the defect, bone-derived cells with high levels of type I collagen and osteonectin mRNA were actively producing new osteoid, while superficially a slow transition from a fibrin clot into undifferentiated mesenchyme with cells containing type III collagen mRNA was observed. This tissue subsequently became fibrocartilaginous, with small groups of cells turning on the transcription of the type II collagen gene and acquiring a phenotype typical for hyaline cartilage. The data suggest that small clusters of cells in the repair tissue of full-thickness articular cartilage defects are capable of turning on an apparently correct chondrocytic phenotype. The low transcription level of the type II collagen gene suggests, however, that insufficient amounts of fundamentally important regulatory factors or progenitor cells are present in the repair tissue. In the future, such factors should be administrable into the joint by novel therapeutic means.

The extracellular proteins types I and III collagen are abundantly expressed during development. Here, the patterns of the pro alpha 1(I), pro alpha 2(I), and pro alpha 1(III) collagen mRNAs are systematically examined from 7.5 to 17.5 days of development (E7.5 to E17.5) in the mouse using in situ hybridization with specific riboprobes. Coordinated expression of pro alpha 1(I) and pro alpha 2(I) collagen mRNA was found throughout development in all regions examined. Widespread type I collagen expression starting at E8.5 occurred in embryonic mesoderm, sclerotomes, dermatomes, and in the forming connective tissues. After E14.5, regions of ossification showed highest levels of type I collagen expression. Pro alpha 1(III) collagen expression was specific to and coordinated with patterns of type I collagen expression in many fibroblast-containing tissues. No expression of type III collagen occurred in osteoblasts. This comprehensive study of the transcripts of abundantly expressed structural proteins should provide a basis for comparison of other key extracellular matrix molecules and serve as a reference for studies on the patterns of activities of various promoter/enhancer-reporter gene constructions of type I and III collagen genes in transgenic mice.

Studies on the function of extracellular matrix components of cartilages and on chondrocyte-specific regulatory mechanisms will benefit from approaches in which transgenic mice and cell cultures will complement each other. We therefore established and extensively characterized primary cultures of mouse chondrocytes isolated from rib growth plates of newborn mice harboring a transgene in which type II collagen gene regulatory sequences were driving expression of an E. coli beta-galactosidase reporter gene. Primary chondrocytes expressed a fully differentiated phenotype in monolayer culture, producing mRNAs for the collagen types II, IX and X, and for the transgene. Transgenic cells also synthesized high levels of E. coli beta-galactosidase, easily quantifiable and also detectable in individual cells by X-gal staining. When chondrocytes were isolated from transgenic mice in which beta-galactosidase was fused to the product of the neomycin resistance gene, they displayed resistance to G418. After one to two weeks in culture, chondrocytes progressively lost expression of the transgenes, in parallel with that of cartilage-specific genes, and started expressing high levels of type I collagen RNA. The use of transgenic chondrocytes allowed us to easily score phenotypic changes by assaying beta-galactosidase activity and neomycin resistance. Cultures of mouse chondrocytes, such as those reported here, should also help characterize biochemically the phenotypes of other transgenic mice in studies of genetic diseases of cartilages and of mechanisms involved in chondrogenesis.