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Localization of spontaneous bursting neuronal activity ...
Localization of spontaneous bursting neuronal activity in the preterm human brain with simultaneous EEG-fMRI

Electroencephalographic recordings from the developing human brain are characterized by spontaneous neuronal bursts, the most common of which is the delta brush. Although similar events in animal models are known to occur in areas of immature cortex and drive their development, their origin in humans has not yet been identified. Here, we use simultaneous EEG-fMRI to localise the source of delta brush events in 10 preterm infants aged 32–36 postmenstrual weeks. The most frequent patterns were left and right posterior-temporal delta brushes which were associated in the left hemisphere with ipsilateral BOLD activation in the insula only; and in the right hemisphere in both the insular and temporal cortices. This direct measure of neural and hemodynamic activity shows that the insula, one of the most densely connected hubs in the developing cortex, is a major source of the transient bursting events that are critical for brain maturation.

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.


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