Rhythm in the Premature Neonate Brain: Very Early Processing of Auditory Beat and Meter.

The ability to extract rhythmic structure is important for the development of language, music, and social communication. Although previous studies show infants' brains entrain to the periodicities of auditory rhythms and even different metrical interpretations (e.g., groups of two vs three beats) of ambiguous rhythms, whether the premature brain tracks beat and meter frequencies has not been explored previously. We used high-resolution electroencephalography while premature infants (n = 19, 5 male; mean age, 32 ± 2.59 weeks gestational age) heard two auditory rhythms in the incubators. We observed selective enhancement of the neural response at both beat- and meter-related frequencies. Further, neural oscillations at the beat and duple (groups of 2) meter were phase aligned with the envelope of the auditory rhythmic stimuli. Comparing the relative power at beat and meter frequencies across stimuli and frequency revealed evidence for selective enhancement of duple meter. This suggests that even at this early stage of development, neural mechanisms for processing auditory rhythms beyond simple sensory coding are present. Our results add to a few previous neuroimaging studies demonstrating discriminative auditory abilities of premature neural networks. Specifically, our results demonstrate the early capacities of the immature neural circuits and networks to code both simple beat and beat grouping (i.e., hierarchical meter) regularities of auditory sequences. Considering the importance of rhythm processing for acquiring language and music, our findings indicate that even before birth, the premature brain is already learning this important aspect of the auditory world in a sophisticated and abstract way.SIGNIFICANCE STATEMENT Processing auditory rhythm is of great neurodevelopmental importance. In an electroencephalography experiment in premature newborns, we found converging evidence that when presented with auditory rhythms, the premature brain encodes multiple periodicities corresponding to beat and beat grouping (meter) frequencies, and even selectively enhances the neural response to meter compared with beat, as in human adults. We also found that the phase of low-frequency neural oscillations aligns to the envelope of the auditory rhythms and that this phenomenon becomes less precise at lower frequencies. These findings demonstrate the initial capacities of the developing brain to code auditory rhythm and the importance of special care to the auditory environment of this vulnerable population during a highly dynamic period of neural development.

Neural oscillations suggest periodicity encoding during auditory beat processing in the premature brain.

When exposed to rhythmic patterns with temporal regularity, adults exhibit an inherent ability to extract and anticipate an underlying sequence of regularly spaced beats, which is internally constructed, as beats are experienced even when no events occur at beat positions (e.g., in the case of rests). Perception of rhythm and synchronization to periodicity is indispensable for development of cognitive functions, social interaction, and adaptive behavior. We evaluated neural oscillatory activity in premature newborns (n = 19, mean age, 32 ± 2.59 weeks gestational age) during exposure to an auditory rhythmic sequence, aiming to identify early traces of periodicity encoding and rhythm processing through entrainment of neural oscillations at this stage of neurodevelopment. The rhythmic sequence elicited a systematic modulation of alpha power, synchronized to expected beat locations coinciding with both tones and rests, and independent of whether the beat was preceded by tone or rest. In addition, the periodic alpha-band fluctuations reached maximal power slightly before the corresponding beat onset times. Together, our results show neural encoding of periodicity in the premature brain involving neural oscillations in the alpha range that are much faster than the beat tempo, through alignment of alpha power to the beat tempo, consistent with observations in adults on predictive processing of temporal regularities in auditory rhythms. RESEARCH HIGHLIGHTS: In response to the presented rhythmic pattern, systematic modulations of alpha power showed that the premature brain extracted the temporal regularity of the underlying beat. In contrast to evoked potentials, which are greatly reduced when there is no sounds event, the modulation of alpha power occurred for beats coinciding with both tones and rests in a predictive way. The findings provide the first evidence for the neural coding of periodicity in auditory rhythm perception before the age of term.

The frontal sharp transient in newborns: An endogenous neurobiomarker concomitant to the physiological and critical transitional period around delivery?

The frontal sharp transient (FST) consists of transient electrical activity recorded around the transitional period from the in to ex utero environment. Although its positive predictive value is assumed, nothing is known about its functionality or origin. The objectives were (i) to define its characteristics and (ii) to develop functional hypothesis. The 128-channels high-resolution electroencephalograms of 20 healthy newborns (37.1-41.6 weeks) were studied. The morphological and time-frequency characteristics of 418 FSTs were analyzed. The source localization of the FSTs was obtained using a finite element head model (5 layers and fontanels) and various source localization methods (distributed and dipolar). The characteristics (duration, slopes, and amplitude) and the localization of FSTs were not modulated by the huge developmental neuronal processes that occur during the very last period of gestation. The sources were located beneath the ventral median part of the frontal lobe around the interhemispheric fissure, suggesting that the olfactory bulbs and orbitofrontal cortex, essential in olfaction and the mother-infant attachment relationship, are likely candidates for the generation of FSTs. FSTs may contribute to the implementation of the functionalities of brain structures involved in the higher-order processing necessary for survival ahead of delivery, with a genetic fingerprint.

Detection of regularities in auditory sequences before and at term-age in human neonates.

During the last trimester of gestation, fetuses and preterm neonates begin to respond to sensory stimulation and to discover the structure of their environment. Yet, neuronal migration is still ongoing. This late migration notably concerns the supra-granular layers neurons, which are believed to play a critical role in encoding predictions and detecting regularities. In order to gain a deeper understanding of how the brain processes and perceives regularities during this stage of development, we conducted a study in which we recorded event-related potentials (ERP) in 31-wGA preterm and full-term neonates exposed to alternating auditory sequences (e.g. "ba ga ba ga ba"), when the regularity of these sequences was violated by a repetition (e.g., ``ba ga ba ga ga''). We compared the ERPs in this case to those obtained when violating a simple repetition pattern ("ga ga ga ga ga" vs. "ga ga ga ga ba"). Our results indicated that both preterm and full-term neonates were able to detect violations of regularity in both types of sequences, indicating that as early as 31 weeks gestational age, human neonates are sensitive to the conditional statistics between successive auditory elements. Full-term neonates showed an early and similar mismatch response (MMR) in the repetition and alternating sequences. In contrast, 31-wGA neonates exhibited a two-component MMR. The first component which was only observed for simple sequences with repetition, corresponded to sensory adaptation. It was followed much later by a deviance-detection component that was observed for both alternation and repetition sequences. This pattern confirms that MMRs detected at the scalp may correspond to a dual cortical process and shows that deviance detection computed by higher-level regions accelerates dramatically with brain maturation during the last weeks of gestation to become indistinguishable from bottom-up sensory adaptation at term.

Assessing the effects of head modelling errors and measurement noise on EEG source localization accuracy in preterm newborns: A single-subject study.

The accuracy of electroencephalogram (EEG) source localization is compromised because of head modelling errors. In this study, we investigated the effect of inaccuracy in the conductivity of head tissues and head model structural deficiencies on the accuracy of EEG source analysis in premature neonates. A series of EEG forward and inverse simulations was performed by introducing structural deficiencies into the reference head models to generate test models, which were then used to investigate head modelling errors caused by cerebrospinal fluid (CSF) exclusion, lack of grey matter (GM)-white matter (WM) distinction, fontanel exclusion and inaccuracy in skull conductivity. The modelling errors were computed between forward and inverse solutions obtained using the reference and test models generated for each deficiency. Our results showed that the exclusion of CSF from the head model had a strong widespread effect on the accuracy of the EEG source localization with position errors lower than 4.17 mm. The GM and WM distinction also caused strong localization errors (up to 3.5 mm). The exclusion of fontanels from the head model also strongly affected the accuracy of the EEG source localization for sources located beneath the fontanels with a maximum localization error of 4.37 mm. Similarly, inaccuracies in the skull conductivity caused errors in EEG forward and inverse modelling in sources beneath cranial bones. Our results indicate that the accuracy of EEG source imaging in premature neonates can be largely improved by using head models, which include not only the brain, skull and scalp but also the CSF, GM, WM and fontanels.

The prognostic value of neonatal conventional-EEG monitoring in hypoxic-ischemic encephalopathy during therapeutic hypothermia.

AIM: To determine the prognostic value of conventional electroencephalography (EEG) monitoring in neonatal hypoxic-ischemic encephalopathy (HIE). METHOD: In this multicentre retrospective study, 95 full-term neonates (mean of 39.3wks gestational age [SD  1.4], 36 [38%] females, 59 [62%] males) with HIE (2013-2016) undergoing therapeutic hypothermia were divided between favourable or adverse outcomes. Background EEG activity (French classification scale: 0-1-2-3-4-5) and epileptic seizure burden (epileptic seizure scale: 0-1-2) were graded for seven 6-hour periods. Conventional EEG monitoring was investigated by principal component analysis (PCA), with clustering methods to extract prognostic biomarkers of development at 2 years and infant death. RESULTS: Eighty-one per cent of infants with an adverse outcome had a French classification scale equal to or greater than 3 after H48 (100% at H6-12). The H6-12 epileptic seizure scale was equal to or greater than 1 for 39%, increased to 52% at H30-36 and then remained equal to or greater than 1 for 39% after H48. Forty-five per cent of infants with a favourable outcome had a H6-12 French classification scale equal to or greater than 3, which dropped to 5% after H48; 13% had a H6-12 epileptic seizure scale equal to or greater than 1 but no seizures after H48. Clustering methods based on PCA showed the high efficiency (96%) of conventional EEG monitoring for outcome prediction and allowed the definition of three prognostic EEG biomarkers: H6-78 French classification scale mean, H6-78 French classification scale slope, and H30-78 epileptic seizure scale mean. INTERPRETATION: Early lability and recovery of physiological features is prognostic of a favourable outcome. Seizure onset from the second day should also be considered to accurately predict neurodevelopment in HIE and support the importance of conventional EEG monitoring in HIE in infants cooled with therapeutic hypothermia. WHAT THIS PAPER ADDS: Comprehensive analysis showed the high prognostic efficiency (96%) of conventional electroencephalography (EEG) monitoring. Prognostic EEG biomarkers consist of the grade of background EEG activity, its evolution, and the mean seizure burden. Persistent seizures (H48) without an improvement in background EEG activity were consistently associated with an adverse outcome.

Evolution of cross-frequency coupling between endogenous oscillations over the temporal cortex in very premature neonates.

Temporal theta activity in coalescence with slow-wave (TTA-SW) is one of the first neurobiomarkers of the neurodevelopment of perisylvian networks in the electroencephalography (EEG). Dynamic changes in the microstructure and activity within neural networks are reflected in the EEG. Slow oscillation slope can reflect synaptic strength, and cross-frequency coupling (CFC), associated with several putative functions in adults, can reflect neural communication. Here, we investigated the evolution of CFC, in terms of SW theta phase-amplitude coupling (PAC), during the course of very early development between 25 and 32 weeks of gestational age in 23 premature neonates. We used high-resolution EEG and dipole models as spatial filters to extract the source waveforms corresponding to TTA-SW. We also carried out nonlinear phase-dependent correlation measurements to examine whether the characteristics of the SW slopes are associated with TTA-SW coupling. We show that neurodevelopment leads to temporal accumulation of the SW theta PAC toward the trough of SW. Steepness of the negative going slope of SW determined the degree of this coupling. Systematic modulation of SW-TTA CFC during development is a signature of the complex development of local cortico-cortical perisylvian networks and distant thalamo-cortical neural circuits driving this nested activity over the perisylvian networks.

Performance Analysis of Optically Pumped 4He Magnetometers vs. Conventional SQUIDs: From Adult to Infant Head Models.

Optically pumped magnetometers (OPMs) are new, room-temperature alternatives to superconducting quantum interference devices (SQUIDs) for measuring the brain's magnetic fields. The most used OPM in MagnetoEncephaloGraphy (MEG) are based on alkali atoms operating in the spin-exchange relaxation-free (SERF) regime. These sensors do not require cooling but have to be heated. Another kind of OPM, based on the parametric resonance of 4He atoms are operated at room temperature, suppressing the heat dissipation issue. They also have an advantageous bandwidth and dynamic range more suitable for MEG recordings. We quantitatively assessed the improvement (relative to a SQUID magnetometers array) in recording the magnetic field with a wearable 4He OPM-MEG system through data simulations. The OPM array and magnetoencephalography forward models were based on anatomical MRI data from an adult, a nine-year-old child, and 10 infants aged between one month and two years. Our simulations showed that a 4He OPMs array offers markedly better spatial specificity than a SQUID magnetometers array in various key performance areas (e.g., signal power, information content, and spatial resolution). Our results are also discussed regarding previous simulation results obtained for alkali OPM.

Neurovascular coupling in the developing neonatal brain at rest.

The neonatal brain is an extremely dynamic organization undergoing essential development in terms of connectivity and function. Several functional imaging investigations of the developing brain have found neurovascular coupling (NVC) patterns that contrast with those observed in adults. These discrepancies are partly due to that NVC is still developing in the neonatal brain. To characterize the vascular response to spontaneous neuronal activations, a multiscale multimodal noninvasive approach combining simultaneous electrical, hemodynamic, and metabolic recordings has been developed for preterm infants. Our results demonstrate that the immature vascular network does not adopt a unique strategy to respond to spontaneous cortical activations. NVC takes on different forms in the same preterm infant during the same recording session in response to very similar types of neural activation. This includes (a) positive stereotyped hemodynamic responses (increases in HbO, decreases in HbR together with increases in rCBF and rCMRO2), (b) negative hemodynamic responses (increases in HbR, decreases in HbO together with decreases in rCBF and rCMRO2), and (c) Increases and decreases in both HbO-HbR and rCMRO2 together with no changes in rCBF. Age-related NVC maturation is demonstrated in preterm infants, which can contribute to a better understanding/prevention of cerebral hemodynamic risks in these infants.

The intimate relationship between coalescent generators in very premature human newborn brains: Quantifying the coupling of nested endogenous oscillations.

Temporal theta slow-wave activity (TTA-SW) in premature infants is a specific neurobiomarker of the early neurodevelopment of perisylvian networks observed as early as 24 weeks of gestational age (wGA). It is present at the turning point between non-sensory driven spontaneous networks and cortical network functioning. Despite its clinical importance, the underlying mechanisms responsible for this spontaneous nested activity and its functional role have not yet been determined. The coupling between neural oscillations at different timescales is a key feature of ongoing neural activity, the characteristics of which are determined by the network structure and dynamics. The underlying mechanisms of cross-frequency coupling (CFC) are associated with several putative functions in adults. In order to show that this generic mechanism is already in place early in the course of development, we analyzed electroencephalography recordings from sleeping preterm newborns (24-27 wGA). Employing cross-frequency phase-amplitude coupling analyses, we found that TTAs were orchestrated by the SWs defined by a precise temporal relationship. Notably, TTAs were synchronized to the SW trough, and were suppressed during the SW peak. Spontaneous endogenous TTA-SWs constitute one of the very early signatures of the developing temporal neural networks with key functions, such as language and communication. The presence of a fine-tuned relationship between the slow activity and the TTA in premature neonates emphasizes the complexity and relative maturity of the intimate mechanisms that shape the CFC, the disruption of which can have severe neurodevelopmental consequences.

Preterm Modulation of Connectivity by Endogenous Generators: The Theta Temporal Activities in Coalescence with Slow Waves.

The neuronal activity of the preterm brain is characterized by various endogenous activities whose roles in neurodevelopmental maturation processes have not been fully elucidated. The preterm EEG is characterized by discontinuities composed of short bursts of activity with dominant low frequencies. One of the earliest endogenous activities is the theta temporal activity in coalescence with slow waves (TTA-SW), which appears at 24 to 32 weeks of gestational age (wGA). The present study investigated the influence of TTA-SW on the spatial organization of the early preterm brain network. To achieve this objective, High-Density EEG data were recorded from preterm infants (29-32 wGA) and functional connectivity (FC) was estimated from the scalp EEG. TTA-SW, particularly in the theta band, induced increased FC between left temporal and left frontal areas and between left temporal and parietal areas with TTA-SW at the left temporal region, while FC was limited to the right temporal regions in the case of TTA-SW at the right temporal region. Regardless of the lateralization of TTA-SW, long-range FCs were observed between left frontal to left parietal areas, suggesting that these regions, together with the temporal region, provide a basis for coherent neuronal activation across distal cortical regions. TTA-SW dynamic features showed that brief phases of TTA-SW had an impact on both local and whole brain network organization, supporting the importance of TTA-SW as a biomarker of brain development.

Functional Maps at the Onset of Auditory Inputs in Very Early Preterm Human Neonates.

During the last trimester of human gestation, neurons reach their final destination and establish long- and short-distance connections. Due to the difficulties obtaining functional data at this age, the characteristics of the functional architecture at the onset of sensory thalamocortical connectivity in humans remain largely unknown. In particular, it is unknown to what extent responses evoked by an external stimulus are general or already sensitive to certain stimuli. In the present study, we recorded high-density event-related potentials (ERPs) in 19 neonates, tested ten weeks before term (28-32 weeks gestational age (wGA), that is, at an average age of 30 wGA) by means of a syllable discrimination task (i.e., a phonetic change: ba vs. ga; and a voice change: male vs. female voice). We first observed that the syllables elicited 4 peaks with distinct topographies implying a progression of the sensory input along a processing hierarchy; second, repetition induced a decrease in the amplitude (repetition suppression) of these peaks, but their latencies and topographies remained stable; and third, a change of stimulus generated mismatch responses, which were more precisely time-locked to event onset in the case of a phonetic change than in the case of a voice change. A hierarchical and parallel functional architecture is therefore able to process environmental sounds in a timely precise fashion, well before term birth. This elaborate functional architecture at the onset of extrinsic neural activity suggests that specialized areas weakly dependent on the environment are present in the perisylvian region as part of the genetic endowment of the human species.

Effect of confounding variables on hemodynamic response function estimation using averaging and deconvolution analysis: An event-related NIRS study.

Slow and rapid event-related designs are used in fMRI and functional near-infrared spectroscopy (fNIRS) experiments to temporally characterize the brain hemodynamic response to discrete events. Conventional averaging (CA) and the deconvolution method (DM) are the two techniques commonly used to estimate the Hemodynamic Response Function (HRF) profile in event-related designs. In this study, we conducted a series of simulations using synthetic and real NIRS data to examine the effect of the main confounding factors, including event sequence timing parameters, different types of noise, signal-to-noise ratio (SNR), temporal autocorrelation and temporal filtering on the performance of these techniques in slow and rapid event-related designs. We also compared systematic errors in the estimates of the fitted HRF amplitude, latency and duration for both techniques. We further compared the performance of deconvolution methods based on Finite Impulse Response (FIR) basis functions and gamma basis sets. Our results demonstrate that DM was much less sensitive to confounding factors than CA. Event timing was the main parameter largely affecting the accuracy of CA. In slow event-related designs, deconvolution methods provided similar results to those obtained by CA. In rapid event-related designs, our results showed that DM outperformed CA for all SNR, especially above -5 dB regardless of the event sequence timing and the dynamics of background NIRS activity. Our results also show that periodic low-frequency systemic hemodynamic fluctuations as well as phase-locked noise can markedly obscure hemodynamic evoked responses. Temporal autocorrelation also affected the performance of both techniques by inducing distortions in the time profile of the estimated hemodynamic response with inflated t-statistics, especially at low SNRs. We also found that high-pass temporal filtering could substantially affect the performance of both techniques by removing the low-frequency components of HRF profiles. Our results emphasize the importance of characterization of event timing, background noise and SNR when estimating HRF profiles using CA and DM in event-related designs.

Cortical light scattering during interictal epileptic spikes in frontal lobe epilepsy in children: A fast optical signal and electroencephalographic study.

OBJECTIVE: Interictal epileptic spikes (IES) represent a signature of the transient synchronous and excessive discharge of a large ensemble of cortical heterogeneous neurons. Epilepsy cannot be reduced to a hypersynchronous activation of neurons whose functioning is impaired, resulting on electroencephalogram (EEG) in epileptic seizures or IES. The complex pathophysiological mechanisms require a global approach to the interactions between neural synaptic and nonsynaptic, vascular, and metabolic systems. In the present study, we focused on the interaction between synaptic and nonsynaptic mechanisms through the simultaneous noninvasive multimodal multiscale recording of high-density EEG (HD-EEG; synaptic) and fast optical signal (FOS; nonsynaptic), which evaluate rapid changes in light scattering related to changes in membrane configuration occurring during neuronal activation of IES. METHODS: To evaluate changes in light scattering occurring around IES, three children with frontal IES were simultaneously recorded with HD-EEG and FOS. To evaluate change in synchronization, time-frequency representation analysis of the HD-EEG was performed simultaneously around the IES. To independently evaluate our multimodal method, a control experiment with somatosensory stimuli was designed and applied to five healthy volunteers. RESULTS: Alternating increase-decrease-increase in optical signals occurred 200 ms before to 180 ms after the IES peak. These changes started before any changes in EEG signal. In addition, time-frequency domain EEG analysis revealed alternating decrease-increase-decrease in the EEG spectral power concomitantly with changes in the optical signal during IES. These results suggest a relationship between (de)synchronization and neuronal volume changes in frontal lobe epilepsy during IES. SIGNIFICANCE: These changes in the neuronal environment around IES in frontal lobe epilepsy observed in children, as they have been in rats, raise new questions about the synaptic/nonsynaptic mechanisms that propel the neurons to hypersynchronization, as occurs during IES. We further demonstrate that this noninvasive multiscale multimodal approach is suitable for studying the pathophysiology of the IES in patients.

Shedding light on interictal epileptic spikes: An in vivo study using fast optical signal and electrocorticography.

OBJECTIVE: Interictal epileptic spikes (IESs), apart from being a key marker of epileptic neuronal networks, constitute a nice model of the widespread endogenous phenomenon of neuronal hypersynchronization. Many questions concerning the mechanisms that drive neurons to hypersynchronize remain unresolved, but synaptic as well as nonsynaptic events are likely to be involved. In this study, changes in optical properties of neural tissues were observed in rats with penicillin-induced IES using fast optical signal (FOS) concomitantly with electrocorticography (ECoG). METHODS: In this study, near-infrared optical imaging was used with ECoG to investigate variations in the optical properties of cortical tissue directly associated with neuronal activity in 15 rats. FOS changes correspond to variations of scattered light from neuronal tissue when neurons are activated. To independently evaluate our method, a control experiment on somatosensory was designed and applied to seven different rats. Time-frequency analysis was also used to track variations of (de)synchronization concomitantly with changes in optical signals during IES. RESULTS: FOS responses revealed that changes in optical signals occurred 320 msec before to 370 msec after the IES peak. These changes started before any changes in ECoG signal. In addition, time-frequency domain electrocorticography revealed an alternating decrease-increase-decrease in the ECoG spectral power (pointing to desynchronization-synchronization-desynchronization), which occurred concomitantly with an increase-decrease-increase in relative optical signal during the IES. These results suggest a relationship between (de)synchronization and optical changes. SIGNIFICANCE: These changes in the neuronal environment around IESs raise new questions about the mechanisms that induce changes in optical properties of neural tissues before the IES, which may provide suitable conditions for neuronal synchronization during IESs. FOS-ECoG constitutes a multimodal approach and opens new avenues to study the mechanisms of neuronal synchronization in the pathologic brain, which has clinical implications, at least in epilepsy.

Hemodynamic Changes Associated with Interictal Spikes Induced by Acute Models of Focal Epilepsy in Rats: A Simultaneous Electrocorticography and Near-Infrared Spectroscopy Study.

Interictal spikes can be generated by blocking GABAA receptor-mediated inhibition. The nature of the hemodynamic activities associated with interictal spikes in acute models of focal epilepsy based on GABA deactivation has not been determined. We analyzed systemic changes in hemodynamic signals associated with interictal spikes generated by acute models of focal epilepsy. Simultaneous ElectroCorticoGraphy (ECoG) and Near-InfraRed Spectroscopy (NIRS) recordings were obtained in vivo from adult Sprague-Dawley rat brain during semi-periodic focal interictal spikes induced by local cortical application of low doses of Penicillin G (PG) and Bicuculline Methiodide (BM) as GABA deactivation agents. The Finite Impulse Response deconvolution technique was used to estimate the profile of hemodynamic changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) concentrations associated with interictal ECoG spikes in each rat. Our results show that, in both acute models of focal epilepsy, the hemodynamic changes associated with interictal spikes were characterized by pre-spike and post-spike primary NIRS responses, and recovery periods with slight differences in amplitude and latency. The pre-spike period starting at least 2 s prior to the onset of ECoG spikes was characterized by a significant decrease in HbO concomitant with an increase in HbR with respect to baseline. The post-spike primary NIRS response exhibited the expected changes described according to the classical view of neurovascular coupling, i.e., a significant increase in HbO and a significant decrease in HbR in response to interictal spikes. The recovery period was characterized by a decreased HbO signal and an increased HbR signal, followed by a return to baseline. Compared to the BM epilepsy model, the PG model was more stable and showed lower variability in the shape, amplitude and latency of the components of spike-related hemodynamic changes. Our findings support a prominent role for pre-spike hemodynamic changes in the initiation of interictal spikes. The mechanism of interactions between neuronal and vascular networks during the pre-spike period constitutes a complex process, resulting in increased sensitivity of the epileptogenic focus to induce neuronal spiking.

Effects of uncertainty in head tissue conductivity and complexity on EEG forward modeling in neonates.

In this study, we investigated the impact of uncertainty in head tissue conductivities and inherent geometrical complexities including fontanels in neonates. Based on MR and CT coregistered images, we created a realistic neonatal head model consisting of scalp, skull, fontanels, cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM). Using computer simulations, we investigated the effects of exclusion of CSF and fontanels, discrimination between GM and WM, and uncertainty in conductivity of neonatal head tissues on EEG forward modeling. We found that exclusion of CSF from the head model induced the strongest widespread effect on the EEG forward solution. Discrimination between GM and white matter also induced a strong widespread effect, but which was less intense than that of CSF exclusion. The results also showed that exclusion of the fontanels from the neonatal head model locally affected areas beneath the fontanels, but this effect was much less pronounced than those of exclusion of CSF and GM/WM discrimination. Changes in GM/WM conductivities by 25% with respect to reference values induced considerable effects in EEG forward solution, but this effect was more pronounced for GM conductivity. Similarly, changes in skull conductivity induced effects in the EEG forward modeling in areas covered by the cranial bones. The least intense effect on EEG was caused by changes in conductivity of the fontanels. Our findings clearly emphasize the impact of uncertainty in conductivity and deficiencies in head tissue compartments on modeling research and localization of brain electrical activity in neonates. Hum Brain Mapp 37:3604-3622, 2016. © 2016 Wiley Periodicals, Inc.

Syllabic discrimination in premature human infants prior to complete formation of cortical layers.

The ontogeny of linguistic functions in the human brain remains elusive. Although some auditory capacities are described before term, whether and how such immature cortical circuits might process speech are unknown. Here we used functional optical imaging to evaluate the cerebral responses to syllables at the earliest age at which cortical responses to external stimuli can be recorded in humans (28- to 32-wk gestational age). At this age, the cortical organization in layers is not completed. Many neurons are still located in the subplate and in the process of migrating to their final location. Nevertheless, we observed several points of similarity with the adult linguistic network. First, whereas syllables elicited larger right than left responses, the posterior temporal region escaped this general pattern, showing faster and more sustained responses over the left than over the right hemisphere. Second, discrimination responses to a change of phoneme (ba vs. ga) and a change of human voice (male vs. female) were already present and involved inferior frontal areas, even in the youngest infants (29-wk gestational age). Third, whereas both types of changes elicited responses in the right frontal region, the left frontal region only reacted to a change of phoneme. These results demonstrate a sophisticated organization of perisylvian areas at the very onset of cortical circuitry, 3 mo before term. They emphasize the influence of innate factors on regions involved in linguistic processing and social communication in humans.

Temporal resolvability analysis of macroscopic morphological development in neonatal cerebral magnetic resonance images.

OBJECTIVES: Reliable gradation of neonatal brain development is important for clinical investigation of neurological disorders. A prerequisite for such quantification of development is knowledge about temporal resolvability. METHODS: We hypothesized 2-week interval as the temporal resolvability of age-related templates to study macroscopic morphological brain development in the early weeks after birth. Therefore, we constructed two templates for the gestational age (GA) ranges of 39 to 40 and 41 to 42 weeks using T1-weighted magnetic resonance (MR) images. Then, we compared the spatial variation of anatomical landmarks and the average and the maximal length of spatial deformation in 30 subjects normalized to the two templates along x, y, and z directions. RESULTS: Multivariate analysis of variance (MANOVA) revealed significant difference between spatial variations of the above macroscopic features in the two age ranges. Furthermore, quantitative analysis of feature scattering yielded the same result even in features for which the null hypothesis was not rejected by MANOVA. Moreover, the same procedure was reiterated on two sets of subjects with the closer age range of 1 week (40 and 41 week's GA) and no significant difference could be detected. CONCLUSIONS: The results strengthen the hypothesis that 2-week is the temporal resolvability of age-related templates for macroscopic morphological studies of the developing brain in the early weeks after birth.

Negative central activity in extremely preterm newborns: EEG characterization and relationship with brain injuries and neurodevelopmental outcome.

OBJECTIVE: To characterize Negative Central Activity (NCA), an overlooked electroencephalographic activity of preterm newborns and investigate its relationship with brain injuries, dysfunction, and neurodevelopmental outcome. METHODS: 109 preterm infants (23-28 weeks) were retrospectively included. NCA were selected at the negative peak on EEG. Individual averaged NCA were automatically characterized. Brain structural data were collected from cranial ultrasounds (cUS). The neurodevelopmental outcome at two years of age was assessed by the Denver Developmental Screening Test-II. RESULTS: Thirty-six (33%) children showed NCA: 6,721 NCA were selected, a median of 75 (interquartile range, 25/157.3) per EEG. NCA showed a triphasic morphology, with a mean amplitude and duration of the negative component of 24.6-40.0 µV and 222.7-257.3 ms. The presence of NCA on EEG was associated with higher intraventricular haemorrhage (IVH) grade on the first (P = 0.016) and worst neonatal cUS (P < 0.001) and poorer neurodevelopmental outcome (P < 0.001). CONCLUSIONS: NCA is an abnormal EEG feature of extremely preterm newborns that may correspond to the functional neural impact of a vascular pathology. SIGNIFICANCE: The NCA relationships with an adverse outcome and the presence/severity of IVH argue for considering NCA in the assessment of pathological processes in the developing brain network and for early outcome prediction.