Hubs in the human fetal brain network

“From these matrices, measures of network centrality, degree and betweenness centrality (BC), were computed for every region by means of graph theoretical analysis, using the brain connectivity toolbox for Matlab (Rubinov and Sporns, 2010).”

“…the ventral and dorsal precuneus, posterior and anterior cingulate gyrus, ventromedial frontal cortex, and interior parietal brain regions (Zuo et al., 2012; Tomasi and Volkow, 2011), brain areas with considerable overlap with sub regions of the default mode network (DMN) (Greicius et al., 2003).”

“The CONN-fMRI Toolbox (Whitfield-Gabrieli and Nieto Castanon, 2012) was used to compute functional connectivity (FC) matrices.”

“The anatomical component correction (aCompCor) method of estimating and removing noise (Behzadi et al., 2007; Chai et al., 2012) was applied.”

“Given prior assertions that the centrality of hubs increase their susceptibility to insults (Crossley et al., 2014; Aerts et al., 2016; Bullmore and Sporns, 2012), and given prior reports of the importance of the cerebellum for early development, our results provide new data suggesting the…”

“…notion, the origins of neurodevelopmental disorders are increasingly attributed to alterations occurring during the prenatal period (Di Martino et al., 2014; Paneth et al., 2005; Rosenbaum et al., 2007) despite onsets in symptomatology between the 3rd and 20th years of life (Paus et al., 2008).”

“Insight into hub emergence before birth may be of great importance, since the fetal period is a critical time in brain development (Rice and Barone, 2000; Keunen et al., 2017) in which seemingly small disturbances, insults or exposures can produce lifelong changes in neurological and mental…”

“Advances in neuroimaging and network analyses have revealed the existence of sets of highly connected regions, often called “hubs”, that are critically important for enabling efficient neuronal signaling and communication [1, 2].”

“Moreover, alterations in cerebellar structure and function are frequently implicated in major developmental neuropsychological disorders, such as ADHD and autism (Seidman et al., 2005; Castellanos et al., 2002; Wang et al., 2014; Stoodley, 2014), and are assumed to develop prenatally.”

“A spatially constrained group level clustering approach (Craddock et al., 2012) was used to parcellate the preterm template brain at 32 weeks of gestation (Serag et al., 2012) into spatially contiguous, similarly sized ROIs.”

“This possible explanation for the simultaneous emergence of hubs and myelination in the same area is supported by the recent demonstration that neuronal activity regulates changes in myelin-forming cells within an active circuit in the mouse brain (Gibson et al., 2014).”

“Additionally, all isolated cortical hubs are located in areas marked as earliest to myelinate by Glasser and Van Essen (Glasser and Van Essen, 2011).”

“There is accumulating evidence available for altered hub topology in psychiatric disorders, such as autism and schizophrenia (Crossley et al., 2014; Bassett et al., 2008; Itahashi et al., 2014; van den Heuvel et al., 2013).”

“…found in the ventral and dorsal precuneus, posterior and anterior cingulate gyrus, ventromedial frontal cortex, and interior parietal brain regions (Zuo et al., 2012; Tomasi and Volkow, 2011), brain areas with considerable overlap with sub regions of the default mode network (DMN) (Greicius et…”

“Given prior assertions that the centrality of hubs increase their susceptibility to insults (Crossley et al., 2014; Aerts et al., 2016; Bullmore and Sporns, 2012), and given prior reports of the importance of the cerebellum for early development, our results provide new data suggesting the…”

“Advances in neuroimaging and network analyses have revealed the existence of sets of highly connected regions, often called “hubs”, that are critically important for enabling efficient neuronal signaling and communication (van den Heuvel and Sporns, 2013; Sporns et al., 2007).”

“In line with this, abnormal hub organization has been implicated in several neurological and psychiatric brain disorders (Bullmore and Sporns, 2012; Bassett and Bullmore, 2009).”

“Moreover, alterations in cerebellar structure and function are frequently implicated in major developmental neuropsychological disorders, such as ADHD and autism (Seidman et al., 2005; Castellanos et al., 2002; Wang et al., 2014; Stoodley, 2014), and are assumed to develop prenatally.”

“Hubs were also identified in the primary visual area and motor area, which are both areas that are reported to myelinate early in development (Deoni et al., 2011; Glasser and Van Essen, 2011; Dubois et al., 2014).”

“Since research has shown sex differences in brain connectivity maturation over development in childhood/adolescence (De Bellis et al., 2001; Satterthwaite et al., 2015) and even in infancy (Gao et al., 2015), this has potential to influence our results.”

“Moreover, alterations in cerebellar structure and function are frequently implicated in major developmental neuropsychological disorders, such as ADHD and autism [56-59], and are assumed to develop prenatally.”

“There is accumulating evidence available for altered hub topology in psychiatric disorders, such as autism and schizophrenia [6, 63-65].”

“Developmental studies in the first year of life have shown that functional hubs are already observable in infancy and are, while not fully mature, transitioning to an adult configuration [10-14].”

“Consistent with prior reports in infants [11, 14], we have identified visual and motor regions as functional connectivity hubs.”

“Accumulating research has emphasized the importance of this region in the early developing brain (Volpe, 2009).”

“Hubs were also identified in the primary visual area and motor area, which are both areas that are reported to myelinate early in development [42, 43, 49].”

“25) [39], we adjusted the threshold to T = 0 (i.”

“Recent work has also revealed that the fetal cerebellum may be particularly sensitive to premature birth (Limperopoulos et al., 2005; Pierson and Al Sufiani, 2016) and prenatal exposure to maternal psychological stress (Ulupinar and Yucel, 2005;).”

“Next, it identifies the most representative clusters of voxels using a normalized cut algorithm [35] and performs group AC CE PT ED M AN US CR IP T”

“The cerebellum may be of particular importance for the fetal brain network, as cerebellar growth is known to be exceptionally rapid over the third trimester of pregnancy and unparalleled by any other brain structure during this period (Limperopoulos et al., 2005).”

“Furthermore, our observation of hubs in the fusiform gyrus was also observed in two other studies examining hubs in health term newborns [10] and preterm infants [13].”

“These studies have revealed the existence of hubs and demonstrate that hubs are highly connected, an observation suggesting a functional rich-club organization is present in the brain network in very early life (van den Heuvel et al., 2015; Ball et al., 2014).”

“Consistent with this notion, the origins of neurodevelopmental disorders are increasingly attributed to alterations occurring during the prenatal period [21-23] despite onsets in symptomatology between the 3 and 20 years of life [24].”

“Since research has shown sex differences in brain connectivity maturation over development in childhood/adolescence (De Bellis et al., 2001; Satterthwaite et al., 2015) and even in infancy (Gao et al., 2015), this has potential to influence our results.”

“Subsequent within-segment preprocessing steps included reorientation, realignment and normalization to an average 32 week gestational age fetal anatomical template (Serag et al., 2012) using SPM8 (Statistical Parametric Mapping 8 from the Wellcome Trust Centre for Neuroimaging, 2009).”

“Moreover, alterations in cerebellar structure and function are frequently implicated in major developmental neuropsychological disorders, such as ADHD and autism (Seidman et al., 2005; Castellanos et al., 2002; Wang et al., 2014; Stoodley, 2014), and are assumed to develop prenatally.”

“Consistent with prior reports in infants (Fransson et al., 2011; Gao et al., 2011), we have identified visual and motor regions as functional connectivity hubs.”

“This finding is in line with Hwang et al. (2013), who reported that lesioning functional hubs significantly reduced efficiency compared with lesioning random nodes across all age groups studied (10–12, 13–17, and 18–20 years of age).”

“This finding is in line with reports of cross-hemispheric connectivity increases with advancing age in the fetal brain (Thomason et al., 2013).”

“Additionally, fetal fMRI studies have postulated the importance of PCC connectivity for the fetal brain network [15, 17].”

“…into hub emergence before birth may be of great importance, since the fetal period is a critical time in brain development (Rice and Barone, 2000; Keunen et al., 2017) in which seemingly small disturbances, insults or exposures can produce lifelong changes in neurological and mental functioning.”

“Since network metrics computed with graph theoretical analyses can vary with different thresholds (Drakesmith et al., 2015), our next step was to test the influence of different thresholds (T) on our results.”

“There is accumulating evidence available for altered hub topology in psychiatric disorders, such as autism and schizophrenia (Crossley et al., 2014; Bassett et al., 2008; Itahashi et al., 2014; van den Heuvel et al., 2013).”

“Additionally, the observation of multiple hubs in the cerebellum could be related to the finding that myelination starts in this region [42, 46-48].”

“The question remains, however, whether functional hub configuration of the brain emerges before birth, as networks already begin to form in utero (Thomason et al., 2014, 2013, 2015; Schöpf et al., 2012).”

“Moreover, animal models have shown that spontaneous bursts of synchronized neuronal activity, or spindle bursts, play an instructive role in key developmental processes that set early cortical circuits (Hanganu-Opatz, 2010).”

“18 and mother contribute to changes in image signal intensity that is difficult to separate from signals of interest [28, 66].”

“The question remains, however, whether functional hub configuration of the brain emerges before birth, as networks already begin to form in utero (Thomason et al., 2014, 2013, 2015; Schöpf et al., 2012).”

“Interestingly, a recent study in preterm human infants found that spontaneous bursting neuronal activity was mostly found in the insula and temporal cortices [52], two areas that have been identified as hubs in the developing brain [see discussion in 53].”

“Furthermore, our observation of hubs in the fusiform gyrus was also observed in two other studies examining hubs in health term newborns [10] and preterm infants [13].”

“Motion in the fetus and mother contribute to changes in image signal intensity that is difficult to separate from signals of interest (van den Heuvel and Thomason, 2016; Ferrazzi et al., 2014).”

“…deprivation from a variety of hormones (i.e., IGF-1, estrogens, progesterone and thyroid hormones) that are normally provided during (late) pregnancy (Berger and Soder, 2015; Elitt and Rosenberg, 2014), make generalizing the results from these studies to normal fetal hub development challenging.”

“Recent work has also revealed that the fetal cerebellum may be particularly sensitive to premature birth (Limperopoulos et al., 2005; Pierson and Al Sufiani, 2016) and prenatal exposure to maternal psychological stress (Ulupinar and Yucel, 2005;).”

“…deprivation from a variety of hormones (i.e., IGF-1, estrogens, progesterone and thyroid hormones) that are normally provided during (late) pregnancy (Berger and Soder, 2015; Elitt and Rosenberg, 2014), make generalizing the results from these studies to normal fetal hub development challenging.”

“Interestingly, a recent study in preterm human infants found that spontaneous bursting neuronal activity was mostly found in the insula and temporal cortices (Arichi et al., 2017), two areas that have been identified as hubs in the developing brain (see discussion in Thomason, 2018).”

“…notion, the origins of neurodevelopmental disorders are increasingly attributed to alterations occurring during the prenatal period (Di Martino et al., 2014; Paneth et al., 2005; Rosenbaum et al., 2007) despite onsets in symptomatology between the 3rd and 20th years of life (Paus et al., 2008).”

“Yet, caution should be exercised because all studies, but one (van den Heuvel et al., 2018), were based on small sample sizes which is a strong bias during FC analysis.”

“Both the temporal lobe (97) and the insular cortex (76, 98) were found to be already highly connected before birth.”

“Pycluster (Craddock et al., 2012) was used to generate 197 spatially contiguous, similarly sized regions of interest (ROI) in a spatially normalized fetal atlas space, that have been previously described (van den Heuvel et al., 2018), and are available for download at www. brainnexus.com.”