In animal models, spontaneous bursts of synchronized neuronal activity (known as spindle bursts) play an instructive role in key developmental processes that set early cortical circuits, including neuronal differentiation and synaptogenesis (Hanganu-Opatz, 2010; Khazipov and Luhmann, 2006). Experimental disruption of the normal occurrence and propagation of this early spontaneous activity leads to permanent loss of healthy cortical organization, such as segregation into ocular dominance columns (Xu et al., 2011) and whisker barrels (Tolner et al., 2012) in the primary visual and somatosensory cortices respectively.

Neural activity recorded in human infants during the preterm period with electroencephalography (EEG) is also characterized by intermittent high amplitude bursts known as Spontaneous Activity Transients (SATs) (Khazipov and Luhmann, 2006; André et al., 2010; Tolonen et al., 2007). SATs appear to have a crucial role in early human brain development, as their occurrence is positively correlated to brain growth during the preterm period (Benders et al., 2015). The most common of these events is the delta brush, a transient pattern characterised by a slow delta wave (0.3–1.5 Hz) with superimposed fast frequency alpha-beta spindles (8–25 Hz) (André et al., 2010; Whitehead et al., 2017). Delta brushes appear from 28 to 30 weeks PMA (Boylan et al., 2008; Lamblin et al., 1999; Niedermeyer, 2005; Vecchierini et al., 2007), have a peak incidence at 32–35 weeks PMA (André et al., 2010; Boylan et al., 2008; Lamblin et al., 1999; D'Allest and Andre, 2002; Hahn and Tharp, 2005) and disappear between 38–42 weeks PMA (Boylan et al., 2008; Hahn and Tharp, 2005). They initially have a diffuse or predominantly peri-central distribution in infants <32 weeks PMA (Lamblin et al., 1999; Boylan, 2007; Volpe, 1995), progressing to have a more temporal and occipital (but rarely frontal) topography in late preterm infants (Tolonen et al., 2007; D'Allest and Andre, 2002; Hahn and Tharp, 2005; Volpe, 1995; Watanabe et al., 1999). As with spindle bursts in animal models, delta brushes can also be elicited by external stimuli (Chipaux et al., 2013; Colonnese et al., 2010; Fabrizi et al., 2011; Milh et al., 2007) with their topographies coarsely overlying the primary sensory cortices of the relevant stimulus modality, suggesting that the activation of specific cortical regions appears on the scalp surface as different delta brush distributions.

As delta brushes are the hallmark of the preterm EEG, reviewing their incidence and morphology is an important part of the clinical neurophysiological assessment of hospitalised infants (Whitehead et al., 2017). Preterm infants with a greater incidence of delta brushes are more likely to develop normally (Biagioni et al., 1994), while diminished occurrence or atypical morphology is seen in infants with major brain lesions such as periventricular leukomalacia who later develop cerebral palsy (André et al., 2010; Watanabe et al., 1999; Conde et al., 2005; Kidokoro et al., 2006; Okumura et al., 1999; Okumura et al., 2002; Tich et al., 2007). As delta brushes should disappear at term equivalent age, the number of events can also be used to determine the severity of EEG dysmaturity, which is defined by the presence of patterns that are at least 2 weeks immature relative to an infant’s PMA ([André et al., 2010; Hahn and Tharp, 2005; Holmes and Lombroso, 1993; American Clinical Neurophysiology Society Critical Care Monitoring Committee et al., 2013) and which is associated with adverse cognitive outcome if persistent over serial recordings (Okumura et al., 2002; Holmes and Lombroso, 1993; Hayakawa et al., 1997; Lombroso, 1985).

Despite their common occurrence, developmental importance and clinical significance, existing animal and human studies are insufficient to build a model of the role of these electrophysiological events in humans, in particular because of the lack of information about their neuro-anatomical source. Whilst delta brushes can be readily identified with EEG, the localization of their source within the brain cannot be easily inferred just from the electrical potentials recorded at the scalp surface (Darvas et al., 2004). To overcome this intrinsic limitation of EEG recording, we used simultaneous EEG-fMRI to combine the temporal sensitivity of EEG with the whole brain spatial specificity of functional Magnetic Resonance Imaging (fMRI). Here, we provide the first evidence that spontaneous patterns of delta brush activity in the period preceding normal birth are associated with significant hemodynamic activity clearly localized to distinct regions within the developing cortex. We show that the most common event in the late preterm period (posterior-temporal delta brushes) are reflective of activity in the insular cortices and temporal pole. These findings provide the first evidence of a direct link between spontaneous neural and hemodynamic activity in early human life and provide a new understanding of how they relate to regional cortical function during this critical period.

Simultaneous EEG-fMRI data were successfully acquired in a group of 10 infants in their late preterm period (median PMA at data collection 35 + 1 weeks, range 32 + 2 to 36 + 2 weeks; five female) during natural sleep over a median of 7.5 min (range: 3.5–10.5 min). All the infants in the study sample were clinically well at the time of study and were reported as having normal brain appearances on their structural MR images. An optimized pre-processing and analysis pipeline which incorporated an age-specific hemodynamic response function (HRF) and template brain was used for the fMRI data (detailed in the supplementary methods) (Allievi et al., 2016; Arichi et al., 2012; Arichi et al., 2010; Serag et al., 2012). Due to the confounding effects of head motion on both EEG and fMRI data, several additional steps were also taken to specifically address this issue in both the initial pre-processing and analysis phase (see supplementary methods).

In line with the literature (André et al., 2010; Whitehead et al., 2017), delta brushes occurred frequently (median: 4.4/minute; range: 1.9–6.7) and with varying scalp distributions (23 in total; Figure 1 and Supplementary file 2). Nevertheless, right and left posterior-temporal delta brushes were consistently present in 10/10 and in 9/10 subjects respectively and could be associated with significant clusters of positive BOLD activity (p<0.05 with family wise error correction) in the ipsilateral insular cortex (Figure 2 and Figure 2—figure supplement 1). This result provides the first evidence that the insulae represent major locations of occurrence for these developmentally required neuronal events during our specific study window in the late preterm period. Although there are rapid changes occurring across the whole brain in human preterm development, the timing and trajectory of maturation has been shown to differ between regions (Makropoulos et al., 2016). In agreement with the idea that bursting neural activity is directly linked to brain maturation, the insular cortices in humans enter a crucial phase of their development during our study period (32–36 weeks PMA): (i) their volumetric growth trajectories (and those of the adjacent temporal lobes) accelerate (Makropoulos et al., 2016) and (ii) they establish an early pattern of dense functional and structural connectivity, which allows them to assume a prominent role as cortical hubs during infancy (Ball et al., 2014; Gao et al., 2011). As a result, the mature insulae have connections to almost all other regions of the brain, enabling them to play a versatile role in a wide range of functions including sensory and pain perception, multi-sensory integration, emotion, and cognition (Nieuwenhuys, 2012). Similarly, in primates and rodents, the insulae have a dense network of connections and play a key integrative function in sensory and behavioural processes (Butti and Hof, 2010; Mars et al., 2013; Miranda-Dominguez et al., 2014; Zingg et al., 2014). Their anatomical maturity is also more advanced in comparison to the surrounding cortex in early life (Huang et al., 2008; Kroenke et al., 2007). However, there are currently no animal developmental studies that directly address the relationship between bursting activity and maturation of this particular brain region.

Figure 1

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Figure 2 with 2 supplements see all

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The importance of the preterm period for insular development in humans is further emphasized by studies showing that the degree of prematurity at birth, recreational drug use in pregnancy and late onset intra-uterine growth restriction adversely affects both insular volume and thalamo-insular connectivity at term equivalent age (Ball et al., 2012; Batalle et al., 2016; Egaña-Ugrinovic et al., 2014; Grewen et al., 2015; Salzwedel et al., 2015), with the latter being significantly correlated with cognitive outcome at 2 years of age (Ball et al., 2015). Furthermore, insular dysfunction and poor growth have been implicated in a range of psychiatric conditions, including neurodevelopmental difficulties such as autism spectrum and attention deficit hyperactivity disorders which have greater prevalence in preterm born children (Hatton et al., 2012; Johnson and Marlow, 2011).

In addition to the insulae, right-sided posterior-temporal delta brushes were associated with significant clusters of hemodynamic activity in the right superior temporal lobe and pole (Figure 2). This finding is of particular significance as these are regions where the subplate, a transient structure which is thought to play a fundamental role in the generation of spindle burst activity in animals (Tolner et al., 2012), can be qualitatively appreciated on high resolution MR images and histology (Figure 2—figure supplement 2) (Kostović et al., 2014). In human development, the subplate follows a similar trajectory to delta brush activity, reaching maximal thickness in the middle of the third trimester before disappearing in most of the brain by term equivalent age (Kostović et al., 2014). The present results therefore support a link between these functional and structural developmental features in humans.

Source localizing spontaneous delta brushes to the insulae and temporal pole does not necessary imply that this activity starts here. Spindle bursts in animals are recorded from the cortical plate (Yang et al., 2013), but are thought to be driven by spontaneous activity from the periphery (whisker pad [Yang et al., 2009], spinal cord [Inácio et al., 2016], retina [Hanganu et al., 2006] and cochlea [Johnson et al., 2011]); as well as from central pattern generators (CPGs) such as the primary motor cortex, brainstem and thalamus within the somatomotor system (for review see [Luhmann et al., 2016]). It is therefore possible that other neuronal events in these centers may also precede the occurrence of delta brushes in humans, but cannot be detected with EEG and fMRI. In this instance, activity would then be amplified by the subplate resulting in measurable electrical-hemodynamic events in the cortex. Nevertheless, it is unlikely that the insular activation we observed here resulted directly from activity in the sensory periphery as the insulae are not involved in the primary processing of visual (Lee et al., 2012), auditory (Baldoli et al., 2015) or somatosensory stimuli (Allievi et al., 2016; Arichi et al., 2010).

Bilateral and unilateral parietal, occipital and mid-temporal, but rarely frontal, delta brushes were also sporadically recorded in individual subjects, suggesting the presence of other less active sources of spontaneous activity at this developmental stage (Figure 3 and Supplementary file 2). In addition to the ipsilateral primary clusters, other areas of BOLD activity were also frequently seen in the anatomical homologue in the opposite hemisphere and occasionally in association areas of the cortex (supplementary motor area (SMA), anterior cingulate, precuneus) or deeper structures of the brain (thalamus and basal ganglia) (Supplementary file 3). Delta brushes with topographies other than posterior-temporal are more frequent earlier on in development compared to the age window studied here (Lamblin et al., 1999; Boylan, 2007; Volpe, 1995) and may represent activity from other developing brain regions which follow a different maturational trajectory. However precise localization of the sources of these events and others that were not recorded in our study group will require further work in a larger study population which spans other age ranges when these regions may be more active. Such longitudinal work may also allow an exploration of whether key features of spindle burst activity in animals are also present in humans during maturation, such as increasing propagation of neuronal activity in local and neighbouring networks (Yang et al., 2013) and regional differences in oscillatory patterns (Yang et al., 2009), as well as association of these events to the presence of the transient subplate layer.

Figure 3

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Despite the apparent absence of a tight neurovascular coupling in perinatal rodent models (Kozberg et al., 2016; Zehendner et al., 2013), we demonstrated for the first time in human infants, a clear association between a direct measure of neural (EEG) and positive functional hemodynamic activity (fMRI). Whilst in rodents, neurovascular coupling matures postnatally together with the development of long-range connectivity patterns (Kozberg et al., 2016), in humans this connectivity can be readily identified by the late preterm period, thus suggesting that neuronal and hemodynamic activity are already closely linked by this time (Allievi et al., 2016; Doria et al., 2010; White et al., 2012). This relationship is developmentally regulated across the neonatal period resulting in changing hemodynamic responses (Arichi et al., 2012) and is validated by the presence of localised positive BOLD activation in the primary auditory and somatosensory cortices following sound and passive motor stimulation respectively (Allievi et al., 2016; Arichi et al., 2010; Baldoli et al., 2015; Erberich et al., 2003).

Spontaneous activity is a fundamental feature of developing neural circuits well before the establishment of cortical layers (Luhmann et al., 2016) and refinement through experience dependent mechanisms (Khazipov and Luhmann, 2006). Our findings provide the first evidence that the most common of these neuronal events in the late preterm period are seen in the posterior temporal regions and are largely generated by the insulae and subplate. As these events are known to have an instructive function in cortical maturation in rodents (Hanganu-Opatz, 2010; Khazipov and Luhmann, 2006; Rakic and Komuro, 1995), our results suggest that these structures may play a key developmental role as a major location of these bursting events in early human life.

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Author details

1. Tomoki Arichi

   1. Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
   2. Department of Bioengineering, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing, Data acquisition

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3550-1644

2. Kimberley Whitehead

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Formal analysis, Writing—review and editing, Data acquisition

   Competing interests

   No competing interests declared

3. Giovanni Barone

   1. Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
   2. Department of Pediatrics, Catholic University of Sacred Heart, Rome, Italy

   Contribution

   Formal analysis, Writing—review and editing, Data aquisition

   Competing interests

   No competing interests declared

4. Ronit Pressler

   Clinical Neurosciences, UCL-Institute of Child Health, London, United Kingdom

   Contribution

   Formal analysis, Writing—review and editing

   Competing interests

   No competing interests declared

5. Francesco Padormo

   1. Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
   2. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States

   Contribution

   Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

6. A David Edwards

   1. Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, United Kingdom
   2. Department of Bioengineering, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Funding acquisition, Writing—review and editing

   For correspondence

   ad.edwards@kcl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4801-7066

7. Lorenzo Fabrizi

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing, Data acquisition

   For correspondence

   l.fabrizi@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9582-0727

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