Delayed Functional Networks Development and Altered Fast Oscillation Dynamics in a Rat Model of Cortical Malformation.

Min-Jee Kim,Mi-Sun Yum,Tae-Sung Ko,Youngheun Jo,Minyoung Lee,Woo-Hyun Shim,Eun-Jin Kim

doi:10.3389/fnins.2020.00711

Min-Jee Kim, Mi-Sun Yum + Show 5 more

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https://doi.org/10.3389/fnins.2020.00711

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Abstract

Malformations of cortical development (MCD) is associated with a wide range of developmental delay and drug resistant epilepsy in children. By using resting-state functional magnetic resonance imaging (RS-fMRI) and event-related spectral perturbation (ERSP) of cortical electroencephalography (EEG) data, we tried to investigate the neural changes of spatiotemporal functional connectivity (FC) and fast oscillation (FO) dynamics in a rat model of methylazoxymethanol (MAM)-induced MCD. A total of 28 infant rats with prenatal exposure to MAM and those of age matched 28 controls with prenatal saline exposure were used. RS-fMRI were acquired at postnatal day 15 (P15) and 29 (P29), and correlation coefficient analysis of eleven region of interests (ROI) was done to find the differences of functional networks between four groups. Two hour-cortical EEGs were also recorded at P15 and P29 and the ERSP of gamma (30–80 Hz) and ripples (80–200 Hz) were analyzed. The rats with MCD showed significantly delayed development of superior colliculus-brainstem network compared to control rats at P15. In contrast to marked maturation of default mode network (DMN) in controls from P15 to P29, there was no clear development in MCD rats. The MCD rats showed significantly higher cortical gamma and ripples-ERSP at P15 and lower cortical ripples-ERSP at P29 than those of control rats. This study demonstrated delayed development of FC and altered cortical FO dynamics in rats with malformed brain. The results should be further investigated in terms of the epileptogenesis and cognitive dysfunction in patients with MCD.

Highlights

Malformations of cortical development (MCD) is a group of disorders that has disruption at any step of human brain development including cell proliferation, neuronal migration, or post-migrational cortical organization and connectivity (Barkovich et al, 2012; Guerrini and Dobyns, 2014)
When we compare the functional connectivity (FC) of postnatal day 15 (P15) and P29 in each group, control rats showed a significant increase in aCg/pCg-auditory cortex (Au) FC (Figure 2G, t = −4.97, p = 0.038) and V1/V2/PPC-Au FC (Figure 2G, t = −6.13, p = 0.026) and MCD rats showed a significant increase in superior colliculus (SC)-brainstem FC (Figure 2H, t = −5.4, p = 0.033) from P15 to P29
Malformations of cortical development are commonly associated with refractory epilepsy and cognitive impairment in children, yet the brain network alteration and developmental electrophysiological changes of this structurally abnormal brain are not clearly defined

Summary

Introduction

Malformations of cortical development (MCD) is a group of disorders that has disruption at any step of human brain development including cell proliferation, neuronal migration, or post-migrational cortical organization and connectivity (Barkovich et al, 2012; Guerrini and Dobyns, 2014). Near 90% of patients with epilepsy caused by MCD has been reported to be drug-resistant (Guerrini and Dobyns, 2014). Prenatal exposure of MAM disrupts cell migration resulting the malformations mostly in the hippocampal CA1 and CA2 region, to a lesser extent in the striatum, thalamus, hypothalamus, and cerebral cortex, which are similar to MCDs in human patients (Spatz and Laqueur, 1968; Singh, 1977; Luhmann, 2016). MAM-treated rats had behavioral alteration even at infancy which is consistent with cognitive impairment in patients with MCD (Lucas et al, 2011; Kim et al, 2017)

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