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Background and ObjectivesSeizures are common during neonatal encephalopathy (NE), but the contribution of seizure burden (SB) to outcomes remains controversial. This study aims to examine the relationship between electrographic SB and neurologic outcomes after NE.MethodsThis prospective cohort study recruited newborns ≥36 weeks postmenstrual age around 6 hours of life between August 2014 and November 2019 from a neonatal intensive care unit (NICU). Participants underwent continuous electroencephalography for at least 48 hours, brain MRI within 3–5 days of life, and structured follow-up at 18 months. Electrographic seizures were identified by board-certified neurophysiologists and quantified as total SB and maximum hourly SB. A medication exposure score was calculated based on all antiseizure medications given during NICU admission. Brain MRI injury severity was classified based on basal ganglia and watershed scores. Developmental outcomes were measured using the Bayley Scales of Infant Development, Third Edition. Multivariable regression analyses were performed, adjusting for significant potential confounders.ResultsOf 108 enrolled infants, 98 had continuous EEG (cEEG) and MRI data collected, of which 5 were lost to follow-up, and 6 died before age 18 months. All infants with moderate-severe encephalopathy completed therapeutic hypothermia. cEEG-confirmed neonatal seizures occurred in 21 (24%) newborns, with a total SB mean of 12.5 ± 36.4 minutes and a maximum hourly SB mean of 4 ± 10 min/h. After adjusting for MRI brain injury severity and medication exposure, total SB was significantly associated with lower cognitive (−0.21, 95% CI −0.33 to −0.08,p= 0.002) and language (−0.25, 95% CI −0.39 to −0.11,p= 0.001) scores at 18 months. Total SB of 60 minutes was associated with 15-point decline in language scores and 70 minutes for cognitive scores. However, SB was not significantly associated with epilepsy, neuromotor score, or cerebral palsy (p> 0.1).DiscussionHigher SB during NE was independently associated with worse cognitive and language scores at 18 months, even after adjusting for exposure to antiseizure medications and severity of brain injury. These observations support the hypothesis that neonatal seizures occurring during NE independently contribute to long-term outcomes.

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).We studied a population-based cohort of 85 consecutive neonates with moderate-to-severe HIE that had aEEG started12 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.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).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.Poor aEEG background recovery predicts development of epilepsy after perinatal HIE at individual level.

ObjectiveTo examine whether fast ripples (FRs) are an accurate marker of the epileptogenic zone, we analyzed overnight stereo-EEG recordings from 43 patients and hypothesized that FR resection ratio, maximal FR rate, and FR distribution predict postsurgical seizure outcome.MethodsWe detected FRs automatically from an overnight recording edited for artifacts and visually from a 5-minute period of slow-wave sleep. We examined primarily the accuracy of removing ≥50% of total FR events or of channels with FRs to predict postsurgical seizure outcome (Engel class I = good, classes II–IV = poor) according to the whole-night and 5-minute analysis approaches. Secondarily, we examined the association of low overall FR rates or absence or incomplete resection of 1 dominant FR area with poor outcome.ResultsThe accuracy of outcome prediction was highest (81%, 95% confidence interval [CI] 67%–92%) with the use of the FR event resection ratio and whole-night recording (vs 72%, 95% CI 56%–85%, for the visual 5-minute approach). Absence of channels with FR rates >6/min (p = 0.001) and absence or incomplete resection of 1 dominant FR area (p < 0.001) were associated with poor outcome.ConclusionsFRs are accurate in predicting epilepsy surgery outcome at the individual level when overnight recordings are used. Absence of channels with high FR rates or absence of 1 dominant FR area is a poor prognostic factor that may reflect suboptimal spatial sampling of the epileptogenic zone or multifocality, rather than an inherently low sensitivity of FRs.Classification of evidenceThis study provides Class II evidence that FRs are accurate in predicting epilepsy surgery outcome.

The conventional assessment of preterm somatosensory functions using averaged cortical responses to electrical stimulation ignores the characteristic components of preterm somatosensory evoked responses (SERs). Our study aimed to systematically evaluate the occurrence and development of SERs after tactile stimulus in preterm infants. We analysed SERs performed during 45 electroencephalograms (EEGs) from 29 infants at the mean post-menstrual age of 30.7 weeks. Altogether 2,087 SERs were identified visually at single trial level from unfiltered signals capturing also their slowest components. We observed salient SERs with a high amplitude slow component at a high success rate after hand (95%) and foot (83%) stimuli. There was a clear developmental change in both the slow wave and the higher frequency components of the SERs. Infants with intraventricular haemorrhage (IVH; eleven infants) had initially normal SERs, but those with bilateral IVH later showed a developmental decrease in the ipsilateral SER occurrence after 30 weeks of post-menstrual age. Our study shows that tactile stimulus applied at bedside elicits salient SERs with a large slow component and an overriding fast oscillation, which are specific to the preterm period. Prior experimental research indicates that such SERs allow studying both subplate and cortical functions. Our present findings further suggest that they might offer a window to the emergence of neurodevelopmental sequalae after major structural brain lesions and, hence, an additional tool for both research and clinical neurophysiological evaluation of infants before term age.

Objective To develop and validate an automated method for bedside monitoring of sleep state fluctuations in neonatal intensive care units. Methods A deep learning-based algorithm was designed and trained using 53 EEG recordings from a long-term (a)EEG monitoring in 30 near-term neonates. The results were validated using an external dataset from 30 polysomnography recordings. In addition to training and validating a single EEG channel quiet sleep, we constructed Sleep State Trend (SST), a bedside-ready means for visualising classifier outputs. Results The accuracy of quiet sleep detection in the training data was 90%, and the accuracy was comparable (85-86 %) in all bipolar derivations available from the 4-electrode recordings. The algorithm generalised well to an external dataset, showing 81% overall accuracy despite different signal derivations. SST allowed an intuitive, clear visualisation of the classifier output. Conclusions Fluctuations in sleep states can be detected at high fidelity from a single EEG channel, and the results can be visualised as a transparent and intuitive trend in the bedside monitors. Significance The Sleep State Trend (SST) may provide caregivers a real-time view of sleep state fluctuations and its cyclicity.

To determine whether interhemispheric difference in sleep spindles in infants with perinatal unilateral brain injury could link to a pathological network reorganization that underpins the development of unilateral cerebral palsy (CP).This was a multicentre retrospective study of 40 infants (19 females, 21 males) with unilateral brain injury. Sleep spindles were detected and quantified with an automated algorithm from electroencephalograph records performed at 2 months to 5 months of age. The clinical outcomes after 18 months were compared to spindle power asymmetry (SPA) between hemispheres in different brain regions.We found a significantly increased SPA in infants who later developed unilateral CP (n=13, with the most robust interhemispheric difference seen in the central spindles. The best individual-level prediction of unilateral CP was seen in the centro-occipital spindles with an overall accuracy of 93%. An empiric cut-off level for SPA at 0.65 gave a positive predictive value of 100% and a negative predictive value of 93% for later development of unilateral CP.Our data suggest that automated analysis of interhemispheric SPA provides a potential biomarker of unilateral CP at a very early age. This holds promise for guiding the early diagnostic process in infants with a perinatally identified brain injury.Unilateral perinatal brain injury may affect the development of electroencephalogram (EEG) sleep spindles. Interhemispheric asymmetry in sleep spindles can be quantified with automated EEG analysis. Spindle power asymmetry can be a potential biomarker of unilateral cerebral palsy.

Electroencephalogram (EEG) monitoring is recommended as routine in newborn neurocritical care to facilitate early therapeutic decisions and outcome predictions. EEG's larger-scale implementation is, however, hindered by the shortage of expertise needed for the interpretation of spontaneous cortical activity, the EEG background. We developed an automated algorithm that transforms EEG recordings to quantified interpretations of EEG background and provides simple intuitive visualisations in patient monitors.In this method-development and proof-of-concept study, we collected visually classified EEGs from infants recovering from birth asphyxia or stroke. We used unsupervised learning methods to explore latent EEG characteristics, which guided the supervised training of a deep learning-based classifier. We assessed the classifier performance using cross-validation and an external validation dataset. We constructed a novel measure of cortical function, brain state of the newborn (BSN), from the novel EEG background classifier and a previously published sleep-state classifier. We estimated clinical utility of the BSN by identification of two key items in newborn brain monitoring, the onset of continuous cortical activity and sleep-wake cycling, compared with the visual interpretation of the raw EEG signal and the amplitude-integrated (aEEG) trend.We collected 2561 h of EEG from 39 infants (gestational age 35·0-42·1 weeks; postnatal age 0-7 days). The external validation dataset included 105 h of EEG from 31 full-term infants. The overall accuracy of the EEG background classifier was 92% in the whole cohort (95% CI 91-96; range 85-100 for individual infants). BSN trend values were closely related to the onset of continuous EEG activity or sleep-wake cycling, and BSN levels showed robust difference between aEEG categories. The temporal evolution of the BSN trends showed early diverging trajectories in infants with severely abnormal outcomes.The BSN trend can be implemented in bedside patient monitors as an EEG interpretation that is intuitive, transparent, and clinically explainable. A quantitative trend measure of brain function might harmonise practices across medical centres, enable wider use of brain monitoring in neurocritical care, and might facilitate clinical intervention trials.European Training Networks Funding Scheme, the Academy of Finland, Finnish Pediatric Foundation (Lastentautiensäätiö), Aivosäätiö, Sigrid Juselius Foundation, HUS Children's Hospital, HUS Diagnostic Center, National Health and Medical Research Council of Australia.

Objective: We assessed in extremely preterm born (EPB) children whether secondary somatosensory cor-tex (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. (c) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO2), arterial pO2 levels, and supplemental oxygen (FiO2) would associate with later neuroanatomic changes. Methods SpO2, arterial blood gases, and FiO2 from 73 ELGANs (GA 26.4 ± 1.2; BW 867 ± 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58). Results The ELGANs with later WM abnormalities exhibited lower SpO2 and pO2 levels, and higher FiO2 need during the first 3 days than those with normal WM. They also had higher pCO2 values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO2 and pO2 levels and lower FiO2 need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment. Conclusions Low oxygen levels and high FiO2 need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets. Impact This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants.

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. (C) 2019 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.

Correction: Volume88, Page158-158 DOI10.1016/j.seizure.2021.04.001 PublishedMAY 2021 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.

Highlights • Neonatal SEPs can be reliably detected using the 4-electrode aEEG monitoring setup. • SEP is discernible in most fullterm newborns with 300 averages. • Recording SEPs jointly with aEEG facilitates SEP assessment after birth asphyxia., 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.

Idiopathic toe walking is a relatively common developmental condition often leading to secondary problems such as pain and muscle contractures in the lower extremities. The cause of idiopathic toe walking is unknown, which hinders the development of treatment strategies. To test whether children with idiopathic toe walking have functional alterations in their spinal motor circuits, we studied the properties of the soleus H-reflex and its modulation with vibration in 26 idiopathic toe walkers and 16 typically developing children. At the group level, the H-reflex properties did not differ, but at the individual level, in 7 of 25 idiopathic toe walkers, some of the H-reflex parameters fell out of normal limits of typically developing children. However, the H-reflex was suppressed by vibration to the Achilles tendon similarly in both the idiopathic toe walkers and typically developing children. In conclusion, idiopathic toe walking in some children can be associated with functional alterations in their spinal motor circuits.

Opioid exposure during pregnancy is a potential risk factor for the developing central nervous system of the fetus. We studied evoked responses in buprenorphine-exposed newborns who displayed neonatal abstinence syndrome (NAS) to elucidate the possible alterations in functioning of the somatosensory and auditory systems.We compared somatosensory (SEFs) and auditory evoked magnetic fields (AEFs), recorded with magnetoencephalography (MEG), of 11 prenatally buprenorphine-exposed newborns with those of 12 healthy newborns. Peak latencies, source strength and location of SEFs or AEFs were recorded.AEFs were present in all buprenorphine-exposed newborns without significant differences from those of healthy newborns. In contrast, though no group level differences in SEFs existed, at individual level the response deviated from the typical neonatal morphology in four buprenorphine-exposed newborns.Although buprenorphine exposure during pregnancy does not seem to cause constant deficiencies in somatosensory or auditory processing, in some newborns the typical development of somatosensory networks may be - at least transiently - disrupted.

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 hypoxicischemic 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 21 months. 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. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Children born extremely preterm may have difficulties in response inhibition, but the neural basis of such problems is unknown. We recorded magnetoencephalography (MEG) during a somatosensory Go/NoGo task in six-year-old children born extremely preterm (EPT; n = 22) and in children born full term (FT; n = 21). The children received tactile stimuli randomly to their left little (target) and index (non-target) finger and were instructed to squeeze a soft toy with the opposite hand every time they felt a stimulus on the little finger. Behaviorally, the EPT children performed worse than the FT children, both in responding to the target finger stimulation and in refraining from responding to the non-target finger stimulation. In MEG, after the non-target finger stimulation (i.e., during the response inhibition), the sensorimotor alpha and beta oscillation levels in the contralateral-to-squeeze hemisphere were elevated in the FT children when compared with a condition with corresponding stimulation but no task (instead the children were listening to a story and not attending to the fingers). This NoGo task effect was absent in the EPT children. Further, in the sensorimotor cortex contralateral to the tactile stimulation, the post-stimulus suppression was less pronounced in the EPT than FT children. We suggest that the missing NoGo task effect and lower suppression of sensorimotor oscillations are markers of deficient functioning of the sensorimotor networks in the EPT children.

Cerebral palsy (CP) is characterized by difficulty in control of movement and posture due to brain damage during early development. In addition, tactile discrimination deficits are prevalent in CP. To study the function of somatosensory and motor systems in CP, we compared the reactivity of sensorimotor cortical oscillations to median nerve stimulation in 12 hemiplegic CP children vs. 12 typically developing children using magnetoencephalography. We also determined the primary cortical somatosensory and motor representation areas of the affected hand in the CP children using somatosensory‐evoked magnetic fields and navigated transcranial magnetic stimulation, respectively. We hypothesized that the reactivity of the sensorimotor oscillations in alpha (10 Hz) and beta (20 Hz) bands would be altered in CP and that the beta‐band reactivity would depend on the individual pattern of motor representation. Accordingly, in children with CP, suppression and rebound of both oscillations after stimulation of the contralateral hand were smaller in the lesioned than intact hemisphere. Furthermore, in two of the three children with CP having ipsilateral motor representation, the beta‐ but not alpha‐band modulations were absent in both hemispheres after affected hand stimulation suggesting abnormal sensorimotor network interactions in these individuals. The results are consistent with widespread alterations in information processing in the sensorimotor system and complement current understanding of sensorimotor network development after early brain insults. Precise knowledge of the functional sensorimotor network organization may be useful in tailoring individual rehabilitation for people with CP. Hum Brain Mapp 35:4105–4117, 2014. © 2014 Wiley Periodicals, Inc.

Aim Treatment with therapeutic hypothermia has challenged the use of amplitude-integrated electroencephalography in predicting outcomes after perinatal asphyxia. In this study, we assessed the feasibility and gain of somatosensory evoked potentials (SEP) during hypothermia. Methods This retrospective study comprised neonates from 35 + 6 to 42 + 2 gestational weeks and treated for asphyxia or hypoxic-ischaemic encephalopathy at Helsinki University Hospital between 14 February 2007 and 23 December 2009. This period was partly before the introduction of routine therapeutic hypothermia, which enabled us to include normothermic neonates who would these days receive hypothermia treatment. We analysed SEPs from 47 asphyxiated neonates and compared the results between 23 normothermic and 24 hypothermic neonates. Results Our data showed that hypothermia led to SEP latencies lengthening by a few milliseconds, but the essential gain for predicting outcomes by SEPs was preserved during hypothermia. Of the 24 hypothermic neonates, bilaterally absent SEPs were associated with poor outcome in 2/2 neonates, normal SEPs were associated with good outcomes in 13/15 neonates and 5/7 neonates with unilaterally absent or grossly delayed SEPs had a poor outcome. Conclusion Our findings indicated that SEPs were a reliable tool for evaluating the somatosensory system in asphyxiated neonates in both normothermic and hypothermic conditions.

highlights In 46 healthy newborns, activity from both the primary (SI) and secondary somatosensory cortices (SII) was detectable with magnetoencephalography to tactile stimulation of the contralateral index finger dur- ing quiet sleep (QS). No significant interhemispheric differences in the responses from SI or SII existed. Within the neonatal period (postmenstrual age (PMA) between 37 and 44 weeks) PMA, height, or gen- der did not significantly affect the latency or strength of the somatosensory evoked magnetic fields (SEFs). abstract 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 hemi- spheres 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.

Summary Magnetoencephalography (MEG) is a noninvasive method to study brain activity. In the previous decade the advantages of MEG — good temporal resolution combined with good spatial resolution allowing separation of activated brain areas — have been successfully used in gaining new information about the neonatal brain functioning. In this review, we discuss the findings from studies of spontaneous magnetoencephalogram and evoked responses to somatosensory, auditory, and visual stimulation. Our group has shown that stimulation of the upper limb in neonates evokes a response sequence reflecting activation of both primary (S I ) and secondary somatosensory (S II ) cortices. Like in mature brains, the earliest cortical response to median nerve stimulation reflects the arrival of afferent information to S I . However, source modeling of the subsequent activation from S I suggests immature cortical functioning in neonates. Another feature typical for neonates is that the S II response is prominent in quiet sleep, unlike in adults in whom it diminishes in sleep. Interestingly, in very prematurely-born infants, we found alterations of the somatosensory responses at both group and individual levels. MEG provides a novel way to look at brain activity in neonates and can be used to increase knowledge of the development of brain processing and its disturbances.

Aim In individuals with cerebral palsy (CP), cerebral insults during early development may induce profound reorganization of the motor representation. This study determined the extent of alterations in cortical somatosensory functions in adolescents with hemiplegic CP with subcortical brain lesions. Method We recorded somatosensory evoked magnetic fields in response to hand area stimulation from eight adolescents with hemiplegic CP (five females and three males; mean age 14y 6mo, SD 2y 3mo) and eight age- and sex-matched healthy comparison adolescents (mean age 15y 4mo, SD 2y 4mo). All participants in the CP group had purely subcortical brain lesions in magnetic resonance images. Results The somatosensory representation of the affected limb was contralateral (i.e. ipsilesional), but detailed inspection of the evoked responses showed alterations bilaterally. In the primary somatosensory cortex, the representation areas of digits II and V were in both hemispheres closer to each other in participants with CP than in comparison participants [ANOVA main effect group F1,14=5.58; p=0.03]. In addition, the morphology of median nerve evoked fields was altered in the participants with CP. Interpretation In hemiplegic CP, modification of the somatosensory cortical network extends beyond what would be expected based on the unilateral symptoms and the anatomical lesion. Further understanding of the functional alterations in the sensorimotor networks may aid in developing more precisely designed rehabilitation strategies.

Introduction Differential diagnostics and outcome prediction in newborns presenting with seizures or encephalopathy remain difficult in the bedside. The objectives of the present study were (i) to determine the accuracy of simultaneously recorded EEG and somatosensory evoked potentials (SEPs) in differentiating between hypoxic-ischemic encephalopathy (HIE) and stroke as the underlying etiology of neonatal seizures or encephalopathy and (ii) to determine the accuracy of EEG and SEPs and their combination for predicting outcome in newborns with HIE or stroke. Methods The study comprised of 133 newborns (gestational age > 34 weeks) that underwent a clinically indicated EEG and simultaneous SEPs in the acute phase of their illness. 102 of the newborns had HIE and 31 had stroke. EEG background was scored as continuous (sleep stages identifiable and EEG continuous at least in active sleep or awake state) or discontinuous (sleep stages not identifiable and EEG not continuous at any time during the recording). The SEPs were classified as bilaterally absent, unilaterally absent, or bilaterally present. Outcome was evaluated from medical records at approximately 1–1.5 years age. Death, cerebral palsy, severe mental retardation, and epilepsy were considered as unfavorable outcomes. Normal or mildly abnormal development (e.g. mild motor or language delay) were considered as favorable outcomes. Results The combinations of EEG and SEP abnormalities were indicative of etiology (HIE vs stroke) and predictive of outcome. If the EEG was discontinuous, the etiology was always HIE (33 newborns) regardless of SEPs. Furthermore, if the EEG was continuous, but SEPs were uni- (9 newborns) or bilaterally (1 newborn) absent, the etiology was always stroke. Normal SEPs and continuous EEG occurred in 69 newborns with HIE and 21 newborns with stroke, and hence in these newborns the distinction between the etiologies could not be made with the present EEG-SEP criteria. This combination was, however, highly predictive of a favorable outcome regardless of the etiology: The outcome was favorable in 67/69 of those HIE and 20/21 of those with stroke. On the contrary, bi- or unilaterally absent SEPs were associated with poor outcome in all newborns with HIE (22/22) and all but two newborns with stroke (8/10). Furthermore, in newborns with HIE, even if the EEG was discontinuous but SEPs were bilaterally present, the outcome was likely to be favorable (8/11 newborns). Conclusion EEG-SEP is useful in bedside differential diagnostics between HIE and stroke in newborns presenting with seizures or general signs of encephalopathy. Furthermore, EEG-SEP is accurate in outcome prediction in both etiologies.

Objective:To assess the role of single and repeated auditory brain stem response (ABR) in predicting mortality and severe neurological injury among children having bacterial meningitis (BM) in Luanda, Angola.Methods:The morphology of ABR traces of 221 children (aged 2 months to 12 years) from admission day was analyzed and compared with age-matched normative data. Absence and delay of traces were compared with mortality and mortality or severe neurological injury in subgroup analyses. Outcome was also evaluated with repeated ABR of 166 children based on presence or absence of responses at 80 dB nHL (normal hearing level) stimulation level.Results:Individually, the absence of typical ABR waveform did not signify poor outcome. At the group level, latencies and interpeak latencies (IPLs) were significantly prolonged among patients with BM in comparison with controls, and the prolongation correlated with higher mortality or severe neurological sequelae.Conclusions:We confirmed the effect of BM on neural conduction time in auditory pathway. However, ABR in similar settings seems not useful for individual prognostication, although at the group level, delayed latencies, IPLs, or both associated with poorer outcome.

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.

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).Altogether 29 infants born28 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.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.Complementing clinical EEG recording with SEP holds promise for valuable extension of neonatal neurophysiological assessment.Multimodal study of EEG and sensory evoked responses is informative, safe, and cheap, and it can be readily performed at bedside.

Objective Despite the frequency and importance of sensorimotor deficits after perinatal stroke (PS), the correlation between brain damage and severity of hemiparesis remains unclear. We aimed to investigate inter-relations between stroke topography, (re)organization of motor and sensory pathways, and clinical grade of hemiparesis in children with PS. Methods Seven children (3 boys; age 12–18 years) with mild to profound upper limb impairment (MACS I-V) after left-sided PS were enrolled. 3T structural MRI scans were reviewed to define vascular origin and extent of the infarction. Information about gestational age, delivery, and type of presentation, were collected from patient records. Navigated transcranial magnetic stimulation (nTMS) was used to map cortical hand muscle representations. The integrity of thalamocortical pathways was evaluated with somatosensory evoked magnetic fields to electrical median nerve stimulation and tractography based on regions of interest defined by neuroradiologist. Asymmetry of tract volume (TV), tract mean fractional anisotropy and mean diffusivity (MD) were estimated. Somatosensory responses were assessed by Semmes-Weinstein monofilaments. Results In two children with unilateral truncal middle cerebral artery (MCA) infarctions, moderate to severe hemiparesis (MACS II-III; sensory deficits in one) was associated with ipsilateral motor and contralateral somatosensory representation of the paretic hand. In a child with proximal MCA stroke, profound hemiplegia with sensory impairment (MACS V) was found in relation to purely contralateral motor and somatosensory projections, distinguished by decreased ipsilesional thalamocortical TV and increased MD in comparison to other subjects. While MEG showed contralateral somatosensory representation in four children with periventricular venous infarctions, who had less severe hemiparesis (MACS I-II, no sensory deficits), nTMS revealed bilateral motor representation. Conclusion Distinct (re)organization patterns after different subtypes of PS are demonstrated by modern neuroimaging techniques, which complement structural MRI in the prediction of severity of hemiparesis after PS.

Higher cortical function during sensory processing can be examined by recording specific somatosensory-evoked magnetic fields (SEFs) with magnetoencephalography (MEG). We evaluated whether, in extremely low-gestational-age (ELGA) infants, abnormalities in MEG-recorded SEFs at term age are associated with adverse neurodevelopment at 2 y of corrected age.SEFs to tactile stimulation of the index finger were recorded at term age in 30 ELGA infants (26.5 ± 1.2 wk, birth weight: 884 g ± 181 g). Neurodevelopment was evaluated at 2 y of corrected age. Controls were 11 healthy term infants.In nine of the ELGA infants (30.0%), SEFs were categorized as abnormal on the basis of lack of response from secondary somatosensory cortex (SII). At 2 y, these infants had a significantly worse mean developmental quotient and locomotor subscale on the Griffiths Mental Development Scales than the ELGA infants with normal responses. Mild white matter abnormalities in magnetic resonance imaging at term age were detected in 21% of infants, but these abnormalities were not associated with adverse neurodevelopment.Abnormal SII responses at term predict adverse neuromotor development at 2 y of corrected age. This adverse development may not be foreseen with conventional neuroimaging methods, suggesting a role for evaluating SII responses in the developmental risk assessment of ELGA infants.

We addressed the neural organization of speech versus nonspeech sound processing by investigating preattentive cortical auditory processing of changes in five features of a consonant–vowel syllable (consonant, vowel, sound duration, frequency, and intensity) and their acoustically matched nonspeech counterparts in a simultaneous EEG–MEG recording of mismatch negativity (MMN/MMNm). Overall, speech–sound processing was enhanced compared to nonspeech sound processing. This effect was strongest for changes which affect word meaning (consonant, vowel, and vowel duration) in the left and for the vowel identity change in the right hemisphere also. Furthermore, in the right hemisphere, speech–sound frequency and intensity changes were processed faster than their nonspeech counterparts, and there was a trend for speech-enhancement in frequency processing. In summary, the results support the proposed existence of long-term memory traces for speech sounds in the auditory cortices, and indicate at least partly distinct neural substrates for speech and nonspeech sound processing.

In individuals with cerebral palsy (CP), cerebral insults during early development may induce profound reorganization of the motor representation. This study determined the extent of alterations in cortical somatosensory functions in adolescents with hemiplegic CP with subcortical brain lesions.We recorded somatosensory evoked magnetic fields in response to hand area stimulation from eight adolescents with hemiplegic CP (five females and three males; mean age 14y 6mo, SD 2y 3mo) and eight age- and sex-matched healthy comparison adolescents (mean age 15y 4mo, SD 2y 4mo). All participants in the CP group had purely subcortical brain lesions in magnetic resonance images.The somatosensory representation of the affected limb was contralateral (i.e. ipsilesional), but detailed inspection of the evoked responses showed alterations bilaterally. In the primary somatosensory cortex, the representation areas of digits II and V were in both hemispheres closer to each other in participants with CP than in comparison participants [ANOVA main effect group F(1,14) =5.58; p=0.03]. In addition, the morphology of median nerve evoked fields was altered in the participants with CP.In hemiplegic CP, modification of the somatosensory cortical network extends beyond what would be expected based on the unilateral symptoms and the anatomical lesion. Further understanding of the functional alterations in the sensorimotor networks may aid in developing more precisely designed rehabilitation strategies.

The spatiotemporal dynamics of the neural processing of spoken morphologically complex words are still an open issue. In the current study, we investigated the time course and neural sources of spoken inflected and derived words using simultaneously recorded electroencephalography (EEG) and magnetoencephalography (MEG) responses. Ten participants (native speakers) listened to inflected, derived, and monomorphemic Finnish words and judged their acceptability. EEG and MEG responses were time-locked to both the stimulus onset and the critical point (suffix onset for complex words, uniqueness point for monomorphemic words). The ERP results showed that inflected words elicited a larger left-lateralized negativity than derived and monomorphemic words approximately 200 ms after the critical point. Source modeling of MEG responses showed one bilateral source in the superior temporal area ∼100 ms after the critical point, with derived words eliciting stronger source amplitudes than inflected and monomorphemic words in the right hemisphere. Source modeling also showed two sources in the temporal cortex approximately 200 ms after the critical point. There, inflected words showed a more systematic pattern in source locations and elicited temporally distinct source activity in comparison to the derived word condition. The current results provide electrophysiological evidence for at least partially distinct cortical processing of spoken inflected and derived words. In general, the results support models of morphological processing stating that during the recognition of inflected words, the constituent morphemes are accessed separately. With regard to derived words, stem and suffix morphemes might be at least initially activated along with the whole word representation.

Objective To evaluate the maturation of tactile processing by recording somatosensory evoked magnetic fields (SEFs) from healthy human subjects. Methods SEFs to tactile stimulation of the left index finger were measured from the contralateral somatosensory cortex with magnetoencephalography (MEG) in five age groups: newborns, 6- and 12–18-month-olds, 1.6–6-year-olds, and adults. The waveforms of the measured signals and equivalent current dipoles (ECDs) were analyzed in awake and sleep states in order to separate the effects of age and vigilance state on SEFs. Results There was an orderly, systematic change in the measured and ECD source waveforms of the initial cortical responses with age. The broad U-shaped response in newborns (M60) shifted to a W-shaped response with emergence of a notch by 6 months of age. The adult-type response with M30 and M50 components was present by 2 years. The ECDs of M60 and M30 were oriented anteriorly and that of M50 posteriorly. These maturational changes were independent of vigilance state. Conclusions The most significant maturation of short latency cortical responses to tactile stimulation takes place during the first 2 years of life. Significance The maturational changes of somatosensory processing can noninvasively be evaluated with MEG already in infancy.

Methods: An electrophysiological parameter measured by Magnetoencephalography was used to quantify an Intra-Cortical Connectivity (ICC) index focused on the primary somatosensory cortical areas (S1). Twenty one patients affected by mild (Extended Disability Scale Score, EDSS, mean 1,7 range 0-3,5) relapsing-remitting multiple sclerosis (RR-MS) in the remitting phase without clinically evident sensory impairment were evaluated. Three dimensional magnetic resonance imaging (3D-MRI) was used to quantify the lesion load, discriminating black hole (BH) and non-BH portions, normalized by individual brain volumes. Results: When matched with a control population, MS patients showed a reduced ICC, combined with the complete loss of the finger-dependent functional specialization in left S1 cortex. No association was found between ICC impairment and disease duration, or prolongation of the central sensory conduction time, evidence of spinal cord lesions and disease modifying therapy. The ICC index slightly correlated with the lesion load. Conclusion:A local index of intra-cortical connectivity in a circumscribed brain primary area was altered in mildly disabled RR-MS patients, also in absence of any impairment of central sensory conduction. It is concluded that the diffuse damage influencing the multi-nodal network subtending complex cerebral functions also affects intrinsic cortical connectivity. S1 ICC is proposed as a highly sensitive and simple-to-test functional index for the evaluation of the widespread cerebral damage in RR-MS.