Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy

Lugo‐Candelas, Claudia; Cha, Jiook; Hong, Susie N.; Bastidas, Vanessa; Weissman, Myrna M.; Fifer, William P.; Myers, Michael; Talati, Ardesheer; Bansal, Ravi; Peterson, Bradley S.; Monk, Catherine; Gingrich, Jay A.; Posner, Jonathan

doi:10.1001/jamapediatrics.2017.5227

Cited by 102 publications

(84 citation statements)

References 51 publications

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“…Associations between prenatal SSRI exposure and brain function and structure during early infancy are also emerging (Jha et al, 2016;Lugo-Candelas et al, 2018;Podrebarac et al, 2017). Lugo-Candelas et al (2018) reported that infants exposed to SSRIs in utero had concomitant increases in amygdala and insula volume correlated with increases in white-matter connectivity relative to infants of untreated depressed mothers and control infants (Lugo-Candelas et al, 2018). Jha et al (2016) reported widespread microstructure reduction in prenatally SSRI-exposed compared to control infants, while Videman et al (2016), using electroencephalography, demonstrated alterations of connectivity patterns associated with prenatal exposure to SSRIs.…”

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confidence: 99%

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants

Rotem-Kohavi

Williams²,

Müller

et al. 2019

Depress Anxiety

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Background: Prenatal maternal depression (PMD) and selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood. Methods:We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state functional magnetic resonance imaging at postnatal Day 6. At 6 months, temperament was assessed using Infant Behavioral Questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time series to assess group differences in modularity, and connector and provincial hubs.Results: Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl's gyrus relative to the depressed-only group. PLSR showed that newborns' hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups.Conclusions: Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age. K E Y W O R D Sdepression, fMRI, infant, prenatal exposure, SSRIs

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confidence: 99%

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants

Rotem-Kohavi

Williams²,

Müller

et al. 2019

Depress Anxiety

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“…Nevertheless, our results provide a potential molecular mechanism for findings of altered brain connectivity in humans after exposure to maternal SSRI use [25][26][27] or depressive symptoms during gestation [29][30][31] . As outlined in the introduction, human studies often observe similar neurodevelopmental outcomes in children exposed to SSRIs as in children exposed to unmedicated depression, evoking questions about the source of the effects.…”

Section: Myelination Of Axons By Oligodendrocytes Plays a Critical Romentioning

confidence: 78%

“…Prenatal SSRI exposure is associated with altered white and gray matter architecture 24 and connectivity [25][26][27] in babies. Even though the SSRI-exposed group is usually compared to a control group exposed to unmedicated depressive symptoms of the mother [25][26][27] , it remains possible that the intensity or nature of the underlying depressive symptoms differs between these groups and partially mediates the observed effects 28 . It is known that the severity of antenatal depressive symptoms correlates to connectivity in brain networks involved in emotion regulation in infants 29 .…”

Section: Introductionmentioning

confidence: 99%

“…Several studies report sex differences 30 , with girls showing stronger associations of prenatal exposure to depressive symptoms with functional connectivity in emotion-regulation networks 31 , right amygdala volume 32 , and cortical thickness 33 than boys. Overall, prenatal exposure to SSRIs and maternal depression affect the developing brain in overlapping-but potentially also in distinct brain regions 34 , with a key role for corticolimbic structures such as the prefrontal cortex and the amygdala 25,35,36 .…”

Section: Introductionmentioning

confidence: 99%

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Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats

Ramsteijn

Verkaik-Schakel

Houwing

et al. 2020

Preprint

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Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin−associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.

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“…Human brain imaging outcomes suggest both structural and functional abnormalities in the perinatally-exposed population. Compared to controls or infants with depressed mothers, neonates with SSRI-treated mothers displayed increased gray matter volume and white matter connectivity in the amygdala and insula (Lugo-Candelas et al, 2018). Functional neuroimaging studies observed con-nectivity increases in infants' auditory resting-state network following prenatal SSRI exposure (Rotem-Kohavi et al, 2019) and reduced interhemispheric connectivity in EEG studies (Videman et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic and Calcium Response of Offspring to Somatosensory Stimuli

Rahn¹,

Maloney²,

Brier³

et al. 2019

eNeuro

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Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (HbO 2)] and neuronal calcium responses (Thy1-GCaMP6f fluorescence). Significant alterations in both cortical HbO 2 and calcium response amplitude were seen in the cortex ipsilateral to the stimulated paw in FLX as compared to controls. The cortical regions of largest difference in activation between FLX and controls also were consistent between HbO 2 and calcium contrasts at the end of stimulation. Taken together, these results suggest a global loss of response signal amplitude in FLX versus controls. These findings indicate that perinatal SSRI exposure has long-term consequences on somatosensory cortical responses.

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Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy

Cited by 102 publications

References 51 publications

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants

Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic and Calcium Response of Offspring to Somatosensory Stimuli

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