1. Introduction
There is considerable evidence that prenatal exposure to maternal depression is associated with less favorable child outcomes, with varying directions of effects depending on the timing of the exposure, as well as the outcome measured [
1,
2,
3,
4]. Antenatal depression is a common disorder with prevalence estimates of 7.4 to 12.8% in western societies [
5], and is highly comorbid with anxiety [
6]. Higher levels of depression and anxiety in pregnancy have been linked to more “difficult” temperament, and more emotional and behavioral problems in children, also when postnatal confounding factors were taken into account [
4,
7,
8,
9,
10].
The potential biological mechanisms mediating these associations have only recently started to be unraveled [
11], with an emphasis on the insult-sensitive fetal brain [
12,
13]. Neonates prenatally exposed to maternal depression show altered functional connectivity, as well as lower fractional anisotropy and axonal diffusivity between the amygdala and the left temporal cortex and insula, the bilateral anterior cingulate, medial orbitofrontal and ventromedial prefrontal cortices [
13,
14]. Studies in children in early to late childhood report that prenatal exposure to maternal depression is associated with cortical thinning, primarily in the right superior, medial orbital, and frontal pole regions of the prefrontal cortex, as well as in temporal brain regions [
15,
16,
17], and an increased volume of the amygdala [
18].
These studies suggest that antenatal depression during pregnancy independently contributes to offspring brain development, but the observational study designs are hampered by potential confounding factors, that are both associated with antenatal depression and offspring neurodevelopment, such as maternal smoking in pregnancy [
19,
20]. The highest level of evidence can be obtained only by performing experimental studies in humans that include biological substrates, which, to the best of our knowledge, has not been done yet [
2]. We aimed to address this gap in the literature, by conducting an explorative brain Magnetic Resonance Imaging (MRI) study, in children born to mothers who had participated in a pilot Randomized Controlled Trial (RCT) on the effectiveness of Cognitive Behavioral Therapy (CBT) for depression during their pregnancy [
21]. We hypothesized that treatment of maternal antenatal depression would ameliorate the assumed effects on the offspring’s brain (micro-)structure observed in prior observational studies in children prenatally exposed to maternal depression.
4. Discussion
We performed a longitudinal brain MRI study in 6-year-old children, built on a prior pilot RCT comparing Cognitive Behavioral Therapy (CBT) and Treatment as Usual (TAU) for maternal antenatal depression. We found no robust evidence for a treatment effect of CBT for antenatal depression on (micro)structural brain characteristics in 6-year-old offspring. Results from exploratory analyses (refraining from adjusting the results for multiple testing), indicated that children born to women receiving CBT for antenatal depression exhibited a cluster with increased gray matter concentration in the right medial temporal lobe, as well as a thicker lateral occipital cortex and lingual gyrus in the right hemisphere, compared to the TAU group. An unexpected finding was smaller FC along white matter tracts corresponding to the Fornix, the Stria Terminalis and the Optical Tract in the children from the CBT group. Although none of the results survived correction for multiple testing, and the sample size was extremely small, most trends we observed in exploratory analyses were in the hypothesized direction. Antenatal CBT for depression thus may possibly ameliorate offspring brain (micro)structural outcomes, but substantially larger studies are warranted to confirm our preliminary conclusions that CBT for antenatal depression affects brain development in children.
Growing evidence suggests that the origins of neurodevelopmental disorders can be traced back to the intrauterine period of life, during sensitive periods of cellular proliferation, differentiation and maturation [
4]. In animal models, changes in brain morphology have been observed in offspring of mothers exposed to prenatal stress, such as expanded dimensions of the lateral nucleus of the amygdala [
34], and reduced spine density and dendritic complexity in the prefrontal cortex [
35] in prenatally stressed animals. In our exploratory analyses, we observed higher gray matter concentration in the CBT group, compared to the TAU group in the right medial temporal lobe. This is in line with earlier studies showing associations between prenatal stress, anxiety, and depression with decreased gray matter volume and cortical thinning, in (among other regions), the temporal lobe [
15,
16,
36,
37]. The medial temporal lobe is part of multiple brain networks that have been shown to play an important role in processes related to auditory language processing and language learning in children [
38,
39]. Also, there was a trend towards a thicker lateral occipital cortex and lingual gyrus in the right hemisphere in the CBT group. Cortical thinning in regions associated with cognitive performance has been a consistent finding in studies investigating the effect of prenatal exposure to maternal stress, depression, anxiety or cortisol on neurodevelopment [
15,
17,
40]. Although the observed differences were small, and not robust after correction for multiple testing, our results imply that treatment of depression in pregnancy may potentially modify the negative direction of the associations described between prenatal exposure to maternal depression and an offspring’s cortical thickness [
15,
16,
41]. In literature, there is some evidence for a dose-response effect of prenatal stress and anxiety on child neurodevelopment [
8,
42]. We therefore additionally examined whether improvement of symptom scores in depression or anxiety directly after treatment correlated with cortical thickness of the lateral occipital cortex and lingual gyrus in the right hemisphere, as well as across the whole brain. We did not find evidence for any statistically significant correlation. The slopes in most figures showed small positive tendencies in the CBT group for depression and anxiety improvement and cortical thickness, potentially indicating a subtle dose-response trend between absolute improvement in depression and anxiety symptom score, and increased cortical thickness of the offspring brain, although this clearly requires replication in larger study samples. We found no differences in volumes of the amygdala, hippocampus, and cerebellum between the CBT and TAU groups. We had expected to find volumetric differences of mainly the amygdala, a structure that plays a pivotal role in emotional behavior, and is closely associated with stress reactivity and vulnerability for depressive disorder [
43,
44,
45]. In one study of similar size (
n = 19), children exposed to clinically relevant maternal depressive symptoms during pregnancy showed increased amygdala responses to negative emotional faces, compared to control children [
46]. Moreover, higher amygdala volume has been linked to prenatal depression and maternal cortisol levels in earlier studies [
18,
47].
Nevertheless, our findings correspond with a large observational study that examined the association between prenatal depressive symptoms and child brain morphology at the age of six years, and could not detect an association with amygdala volume either [
17].
An unexpected finding in contrast to our hypothesis was smaller white matter FC in children from the CBT group along the tracts of the Fornix, the Stria Terminalis and the Optical tract. The Stria Terminalis is involved in a range of behaviors that are implicated in psychiatric disease, including the stress response [
48], extended duration fear states [
49] and social behavior [
50]. Our results therefore imply that untreated antenatal depression may lead to increased white matter fiber FC in white matter tracts in the offspring that play a role in the development of psychopathology in later life. As far as we are aware, fixel-based analysis has not yet been studied in a developmental context which complicates comparisons with prior study results, in which fractional anisotropy (FA) is commonly used as an estimate for white matter microstructure. FA indicates the coherence of brain fiber organization, although this has shown to be only a crude derivative of actual individual fiber anisotropy [
51]. A prior study reported lower FA in the amygdala of neonates prenatally exposed to high maternal depressive symptoms. [
14]. However, in a similar study, infants born to mothers with higher prenatal maternal depressive symptoms, showed greater functional connectivity of the amygdala with other brain regions, mimicking patterns of connectivity observed in adolescents and adults with major depressive disorder [
13]. Another study found a
positive association between white matter integrity (defined as increased FA) in neonates and prenatal exposure to maternal depressive symptoms, although this was restricted to the uncinate fasciculus in boys [
52]. The authors propose that their results, which at a first glance seem counter-intuitive, may actually be indicative of accelerated brain maturation after prenatal depression exposure, with potentially increased risk for psychopathology in later life [
53]. Although speculative, smaller white matter FC of the Fornix and Stria Terminalis in children of mothers treated for antenatal depression may indicate lower functional connectivity and hence a lower response to stress, but this evidently requires further examination in future studies. As far as we are aware, the effects of prenatal depression on Optic Tract white matter integrity have not been studied, but greater FA in the left optic radiation has been associated with bipolar disorders in an earlier study, indicating that microstructural alterations in this particular tract may correlate to certain psychopathologic disorders [
54].
This study has some important limitations that need to be considered when interpreting the results. The most important limitation is that of the small sample size, indicating very low power to detect relevant effect sizes. Therefore, the results from this study should be interpreted with great caution. Only 14.8% of all women and their children were willing to participate in the current MRI study. This highlights the major challenge of performing long-term follow-ups of intervention studies for antenatal depression that include biological assessments in children. Nevertheless, these studies are vital, as they are currently lacking, and can provide unique evidence on whether psychological treatment for depression during pregnancy may affect offspring brain development [
2]. We emphasize that our results should be considered as explorative, and can be used for the design of sufficiently powered future trials. Also, the analyses were performed without the inclusion of covariates, since the CBT and TAU groups were reasonably balanced in terms of mother and child characteristics. Because of the relatively broad age range of children, we compared our unadjusted results with the results including child age as an additional covariate. This did not substantially alter our results, and therefore the unadjusted results were reported. However, we cannot rule out that confounding has occurred due to (unmeasured) postnatal experiences as a result of improved maternal mood in pregnancy, such as better mother-infant attachment, or more positive parenting [
55]. This may be reflected by the observation that women from the TAU group more often used antidepressant medication during the follow-up, which potentially has impacted the outcomes through parenting by a more depressed mother. Nevertheless, despite the higher rate of antidepressant use in the TAU group, symptom scores of maternal depression and anxiety during the follow-up were about similar in both groups, indicating that differences in exposure to postnatal maternal mood complaints and associated behavioral parental changes between the two groups has been limited.
Finally, it should be noted that the responders had a higher income, and were more highly educated compared to non-responders. They also reported lower scores of depression and anxiety at baseline, and a smaller reduction in symptoms after treatment. The less apparent effectiveness of treatment in the responders compared to the non-responders may have led to an underestimation of the true effects of antenatal depression treatment on offspring brain morphology and connectivity.