Analysis of infant cortical synchrony is constrained by the number of recording electrodes and the recording montage

Objective: To assess how the recording montage in the neonatal EEG influences the detection of cortical source signals and their phase interactions. Methods: Scalp EEG was simulated by forward modeling 20-200 simultaneously active sources covering the cortical surface of a realistic neonatal head model. We assessed systematically how the number of scalp electrodes (11-85), analysis montage, or the size of cortical sources affect the detection of cortical phase synchrony. Statistical metrics were developed for quantifying the resolution and reliability of the montages. Results: The findings converge to show that an increase in the number of recording electrodes leads to a systematic improvement in the detection of true cortical phase synchrony. While there is always a ceiling effect with respect to discernible cortical details, we show that the average and Laplacian montages exhibit superior specificity and sensitivity as compared to other conventional montages. Conclusions: Reliability in assessing true neonatal cortical synchrony is directly related to the choice of EEG recording and analysis configurations. Because of the high conductivity of the neonatal skull, the conventional neonatal EEG recordings are spatially far too sparse for pertinent studies, and this loss of information cannot be recovered by re-montaging during analysis. Significance: Future neonatal EEG studies will need prospective planning of recording configuration to allow analysis of spatial details required by each study question. Our findings also advice about the level of details in brain synchrony that can be studied with existing datasets or by using conventional EEG recordings. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.Peer reviewe

Studying connectivity in the neonatal EEG

In humans the few months surrounding birth comprise a developmentally critical period characterised by the growth of major neuronal networks as well as their initial tuning towards more functionally mature large-scale constellations. Proper wiring in the neonatal brain, especially during the last trimester of pregnancy and the first weeks of postnatal life, relies on the brain’s endogenous activity and remains critical throughout one’s life. Structural or functional abnormalities at the stage of early network formation may result in a neurological disorder later during maturation. Functional connectivity measures based on an infant electroencephalographic (EEG) time series may be used to monitor these processes. A neonatal EEG is temporally discrete and consists of events (e.g., spontaneous activity transients (SATs)) and the intervals between them (inter-SATs). During early maturation, communication between areas of the brain may be transmitted through two distinct mechanisms: synchronisation between neuronal oscillations and event co-occurrences. In this study, we proposed a novel algorithm capable of assessing the coupling on both of these levels. Our analysis of real data from preterm neonates using the proposed algorithm demonstrated its ability to effectively detect functional connectivity disruptions caused by brain lesions. Our results also suggest that SAT synchronisation represents the dominant means through which inter-areal cooperation occurs in an immature brain. Structural disturbances of the neuronal pathways in the brain carry a frequency selective effect on the functional connectivity decreasing at the event level. Next, we used mathematical models and computational simulations combined with real EEG data to analyse the propagation of electrical neuronal activity within the neonatal head. Our results show that the conductivity of the neonatal skull is much higher than that found in adults. This leads to greater focal spread of cortical signals towards the scalp and requires high-density electrode meshes for quality monitoring of neonatal brain activity. Additionally, we show that the specific structure of the neonatal skull fontanel does not represent a special pathway for the spread of electrical activity because of the overall high conductivity of the skull. Finally, we demonstrated that the choice of EEG recording montage may strongly affect the fidelity of non-redundant neuronal information registration as well as the output of functional connectivity analysis. Our simulations suggest that high-density EEG electrode arrays combined with mathematical transformations, such as the global average or current source density (CSD), provide more spatially accurate details about the underlying cortical activity and may yield results more robust against volume conduction effects. Furthermore, we provide clear instruction regarding how to optimise recording montages for different numbers of sensors.Lähikuukaudet ennen ja jälkeen syntymää ovat ihmisillä hermoston kehityksen kannalta kriittisiä vaiheita, joita luonnehtii mittavien hermostollisten verkostojen kasvu sekä niiden alustava virittäytyminen toiminnallisesti kypsiksi suuren mittakaavan yhteenliittymiksi. Vastasyntyneen aivojen koko loppuelämään vaikuttavien hermoverkostojen muodostuminen määräytyy ensimmäisten syntymän jälkeisten viikkojen mutta erityisesti raskauden viimeisen kolmanneksen aikaisen aivojen sisäsyntyisen aktiivisuuden mukaan. Rakenteelliset tai toiminnalliset epämuodostumat näiden varhaisten hermoverkostojen muodostumisvaiheessa voi johtaa neurologisiin häiriöihin myöhemmässä kypsymisessä. Varhaisen kehityksen vaiheita voidaan valvoa vastasyntyneillä mittaamalla hermoyhteyksien toiminnallista liittyvyyttä aivosähkökäyrien (EEG) aikasarjojen avuilla. Vastasyntyneen aivosähkökäyrä on ajallisesti epäjatkuva ja koostuu lyhytkestoisista spontaanin aktiivisuuden tapahtumista, SATeista (Spontaneous Activity Transients) sekä niiden välisistä ajanhetkistä, inter-SATeista. Varhaisessa hermostollisessa kypsymisessä aivoalueiden välinen yhteydenpito voi tapahtua kahdella eri mekanismilla: hermostollisten oskillaatioiden välisellä synkronisaatioilla ja tapahtumien samanaikaisuudella. Tässä tutkimuksessa me kehitimme uuden matemaattisen mallin, algoritmin, jolla voi arvioida näiden kahden mekanismin välistä kytkeytymistä. Vastasyntyneiden keskosten mittausdataan pohjautuva analyysimme osoitti, että kehittämämme algoritmi on toimiva väline aivovaurioiden aiheuttamien toiminnallisten liittyvyyskatkoksien havaitsemisessa. Tuloksemme osoittavat myös, että SAT-synkronisaatio on aivoalueiden pääasiallisin yhteydenpitokeino kypsymättömissä vastasyntyneen aivoissa. Hermostollisten yhteyksien rakenteelliset epämuodostumat heikentävät toiminnallista liittyvyyttä taajuuskohtaisesti tapahtumatasolla. Seuraavaksi me käytimme matemaattisia malleja ja tietokonesimulaatioita yhdistettynä varsinaiseen EEG-mittausdataan analysoidaksemme sähköisen hermostollisen aktiivisuuden leviämistä vastasyntyneen päässä. Tulostemme mukaan vastasyntyneen kallon sähkönjohtavuus on paljon korkeampi kuin aikuisilla ihmisillä. Tämä aiheuttaa aivokuoren signaalien suurempaa paikallista leviämistä päänahkaa kohti, minkä takia vastasyntyneen aivoaktiivisuuden luotettava rekisteröinti vaatii enemmän ja tiheämmin mittauselektrodeja kuin aikuisilla. Lisäksi todistimme, että vastasyntyneen kallon aukileet eivät muodosta erityistä reittiä sähköisen aktiivisuuden leviämiselle, kallon suuren johtavuuden takia. Lopuksi osoitimme, että EEG-mittausasetelman valinta voi vahvasti vaikuttaa ei-päällekkäisen hermostollisen datan mittaustarkkuuteen ja sitä seuraaviin liittyvyysanalyyseihin. Simulaatiomme mukaan suuritiheyksinen EEG-mittauselektrodiasetelma yhdistettynä matemaattisiin muunnoksiin, kuten virtalähdetiheyden (Current Source Density) globaalikeskiarvoon, tarjoavat spatiaalisesti tarkkoja yksityiskohtia alla sijaitsevasta aivokuoren aktiivisuudesta ja voi erottaa selkeästi sekundääristen virtatihentymien osuuden. Lisäksi laadimme selkeät ohjeet kuinka optimoida mittausasetelma eri elektrodimäärille

Cortical Cross-Frequency Coupling Is Affected by in utero Exposure to Antidepressant Medication

Up to five percent of human infants are exposed to maternal antidepressant medication by serotonin reuptake inhibitors (SRI) during pregnancy, yet the SRI effects on infants' early neurodevelopment are not fully understood. Here, we studied how maternal SRI medication affects cortical frequency-specific and cross-frequency interactions estimated, respectively, by phase-phase correlations (PPC) and phase-amplitude coupling (PAC) in electroencephalographic (EEG) recordings. We examined the cortical activity in infants after fetal exposure to SRIs relative to a control group of infants without medical history of any kind. Our findings show that the sleep-related dynamics of PPC networks are selectively affected by in utero SRI exposure, however, those alterations do not correlate to later neurocognitive development as tested by neuropsychological evaluation at two years of age. In turn, phase-amplitude coupling was found to be suppressed in SRI infants across multiple distributed cortical regions and these effects were linked to their neurocognitive outcomes. Our results are compatible with the overall notion that in utero drug exposures may cause subtle, yet measurable changes in the brain structure and function. Our present findings are based on the measures of local and inter-areal neuronal interactions in the cortex which can be readily used across species, as well as between different scales of inspection: from the whole animals to in vitro preparations. Therefore, this work opens a framework to explore the cellular and molecular mechanisms underlying neurodevelopmental SRI effects at all translational levels.Peer reviewe

Cortical responses to tactile stimuli in preterm infants

Abstract 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.Peer reviewe

A Bedside Method for Measuring Effects of a Sedative Drug on Cerebral Function in Newborn Infants

Background: Data on the cerebral effects of analgesic and sedative drugs are needed for the development of safe and effective treatments during neonatal intensive care. Electroencephalography (EEG) is an objective, but interpreter-dependent method for monitoring cortical activity. Quantitative computerized analyses might reveal EEG changes otherwise not detectable. Methods: EEG registrations were retrospectively collected from 21 infants (mean 38.7 gestational weeks; range 27–42) who received dexmedetomidine during neonatal care. The registrations were transformed into computational features and analyzed visually, and with two computational measures quantifying relative and absolute changes in power (range EEG; rEEG) and cortico-cortical synchrony (activation synchrony index; ASI), respectively. Results: The visual assessment did not reveal any drug effects. In rEEG analyses, a negative correlation was found between the baseline and the referential frontal (rho = 0.612, p = 0.006) and parietal (rho = −0.489, p = 0.035) derivations. The change in ASI was negatively correlated to baseline values in the interhemispheric (rho = −0.753; p = 0.001) and frontal comparisons (rho = −0.496; p = 0.038). Conclusion: Cerebral effects of dexmedetomidine as determined by EEG in newborn infants are related to cortical activity prior to DEX administration, indicating that higher brain activity levels (higher rEEG) during baseline links to a more pronounced reduction by DEX. The computational measurements indicate drug effects on both overall cortical activity and cortico-cortical communication. These effects were not evident in visual analysis

A Bedside Method for Measuring Effects of a Sedative Drug on Cerebral Function in Newborn Infants

Background: Data on the cerebral effects of analgesic and sedative drugs are needed for the development of safe and effective treatments during neonatal intensive care. Electroencephalography (EEG) is an objective, but interpreter-dependent method for monitoring cortical activity. Quantitative computerized analyses might reveal EEG changes otherwise not detectable. Methods: EEG registrations were retrospectively collected from 21 infants (mean 38.7 gestational weeks; range 27–42) who received dexmedetomidine during neonatal care. The registrations were transformed into computational features and analyzed visually, and with two computational measures quantifying relative and absolute changes in power (range EEG; rEEG) and cortico-cortical synchrony (activation synchrony index; ASI), respectively. Results: The visual assessment did not reveal any drug effects. In rEEG analyses, a negative correlation was found between the baseline and the referential frontal (rho = 0.612, p = 0.006) and parietal (rho = −0.489, p = 0.035) derivations. The change in ASI was negatively correlated to baseline values in the interhemispheric (rho = −0.753; p = 0.001) and frontal comparisons (rho = −0.496; p = 0.038). Conclusion: Cerebral effects of dexmedetomidine as determined by EEG in newborn infants are related to cortical activity prior to DEX administration, indicating that higher brain activity levels (higher rEEG) during baseline links to a more pronounced reduction by DEX. The computational measurements indicate drug effects on both overall cortical activity and cortico-cortical communication. These effects were not evident in visual analysis

Phase-based cortical synchrony is affected by prematurity

Peer reviewe

Functional connectivity of intrinsic cognitive networks during resting state and task performance in preadolescent children

Earlier studies on adults have shown that functional connectivity (FC) of brain networks can vary depending on the brain state and cognitive challenge. Network connectivity has been investigated quite extensively in children in resting state, much less during tasks and is largely unexplored between these brain states. Here we used functional magnetic resonance imaging and independent component analysis to investigate the functional architecture of large-scale brain networks in 16 children (aged 7-11 years, 11 males) and 16 young adults (aged 22-29 years, 10 males) during resting state and visual working memory tasks. We identified the major neurocognitive intrinsic connectivity networks (ICNs) in both groups. Children had stronger FC than adults within the cingulo-opercular network in resting state, during task performance, and after controlling for performance differences. During tasks, children had stronger FC than adults also within the default mode (DMN) and right frontoparietal (rFPN) networks, and between the anterior DMN and the frontopolar network, whereas adults had stronger coupling between the anterior DMN and rFPN. Furthermore, children compared to adults modulated the FC strength regarding the rFPN differently between the brain states. The FC within the anterior DMN correlated with age and performance in children so that the younger they were, the stronger was the FC, and the stronger the FC within this network, the slower they performed the tasks. The group differences in the network connectivity reported here, and the observed correlations with task performance, provide insight into the normative development of the preadolescent brain and link maturation of functional connectivity with improving cognitive performance.Peer reviewe

A protocol for the analysis of DTI data collected from young children

Analysis of scalar maps obtained by diffusion tensor imaging (DTI) produce valuable information about the microstructure of the brain white matter. The DTI scanning of child populations, compared with adult groups, requires specifically designed data acquisition protocols that take into consideration the trade-off between the scanning time, diffusion strength, number of diffusion directions, and the applied analysis techniques. Furthermore, inadequate normalization of DTI images and non-robust tensor reconstruction have profound effects on data analyses and may produce biased statistical results. Here, we present an acquisition sequence that was specifically designed for pediatric populations, and describe the analysis steps of the DTI data collected from extremely preterm-born young school-aged children and their age- and gender-matched controls. The protocol utilizes multiple software packages to address the effects of artifacts and to produce robust tensor estimation. The computation of a population-specific template and the nonlinear registration of tensorial images with this template were implemented to improve alignment of brain images from the children.Peer reviewe

Cortical networks show characteristic recruitment patterns after somatosensory stimulation by pneumatically evoked repetitive hand movements husin newborn infants

Controlled assessment of functional cortical networks is an unmet need in the clinical research of noncooperative subjects, such as infants. We developed an automated, pneumatic stimulation method to actuate naturalistic movements of an infant's hand, as well as an analysis pipeline for assessing the elicited electroencephalography (EEG) responses and related cortical networks. Twenty newborn infants with perinatal asphyxia were recruited, including 7 with mild-to-moderate hypoxic-ischemic encephalopathy (HIE). Statistically significant corticokinematic coherence (CKC) was observed between repetitive hand movements and EEG in all infants, peaking near the contralateral sensorimotor cortex. CKC was robust to common sources of recording artifacts and to changes in vigilance state. A wide recruitment of cortical networks was observed with directed phase transfer entropy, also including areas ipsilateral to the stimulation. The extent of such recruited cortical networks was quantified using a novel metric, Spreading Index, which showed a decrease in 4 (57%) of the infants with HIE. CKC measurement is noninvasive and easy to perform, even in noncooperative subjects. The stimulation and analysis pipeline can be fully automated, including the statistical evaluation of the cortical responses. Therefore, the CKC paradigm holds great promise as a scientific and clinical tool for controlled assessment of functional cortical networks.Peer reviewe