Our study is the first to analyze the natural history of prenatal ventricle enlargement in early childhood. We found that children with prenatally diagnosed MVM demonstrated persistent enlargement of lateral ventricle volume through 2 years of age. MVM children as a group also tended to score lower on the fine motor and expressive language subscales of the Mullen Scale of Early Learning. Maximal prenatal atrial width was also highly correlated with lateral ventricle volumes at both 1 and 2 years of age. Taken together, our results indicate that prenatal lateral ventricle structure may be a biomarker of abnormal postnatal brain development.
Previous studies have found developmental delays in patients with MVM (13
). Bloom and colleagues (1997) utilized the standardized Bayley Scales of Infant Development and found reductions in the MVM group for both the Psychomotor Development Index (PDI) and the Mental Development Index (MDI) around 22 months of age (33
). Beeghly et al (2010) also found similar deficits in children with MVM for motor tasks as measured by PDI scores without exhibiting deficits in cognitive function or adaptive learning (34
). In this study, we have demonstrated that our cohort displayed reductions in fine motor skills, as well as mild deficits in expressive language abilities. Our findings support previous research, however, long-term follow-up assessments of these children are necessary to characterize persistent neurodevelopmental effects of prenatally enlarged ventricles.
We found that lateral ventricle enlargement is associated with increases in total brain volume and both gray and white matter volumes. The fetuses with MVM are typically identified in mid-2nd
trimester (18–20 weeks), a point in development when neurogenesis and migration are not yet complete (35
), thus enlargement of the ventricle may partially precede the majority of gray and white matter development. The increased white and gray matter volumes in MVM children suggest that the increased brain size and tissue volumes could be a consequence of prenatal ventricle enlargement. Importantly, we found a similar pattern of lateral ventricle enlargement and associated increases in gray matter volumes on neonatal MRI in boys (but not girls) at genetic high risk for schizophrenia (36
Little is known about determinates of prenatal lateral ventricle volume. Inflation of the lateral ventricles occurs early in development before the generation of the choroid plexuses. Studies in zebrafish show that a Na+
ATPase ion pump generates osmotic gradients in the ventricular lumen and is responsible for inflation and maintaining proper intraventricular pressure throughout development (37
). Aberrant modulation of intraventricular pressure after neurulation could be responsible for ventricular enlargement. After neural tube closure and inflation, it has been hypothesized that neuroepithelial cells constituting the walls of the lateral ventricle secrete embryonic cerebrospinal fluid (eCSF) (37
). eCSF is different from adult CSF as it contains over 200 different proteins including proteoglycans, growth factors and extracellular matrix proteins, believed to support early neuronal survival (38
). In rat embryos, early disruption of proteoglycan synthesis causes changes in eCSF osmolality that result in enlargement of the ventricles (40
During early gestation, eCSF growth factors support the primary population of cortical progenitor neurons located along the walls of the lateral ventricle (41
). Increased surface area of the lateral ventricle walls in MVM may result in a larger number of progenitor neurons and corresponding increase in the production of neurons and glia. Studies have found a correlation between ventricle size and the amount of neuronal cell proliferation within the corresponding periventricular region (42
). The thickness of the subventricular zone has been shown to predict sites of gyral and sulcal formation in macaques (41
The movement of eCSF has also been implicated in regulating cortical development. Sawamoto and colleagues (2006) demonstrated that the flow of eCSF within the lateral ventricle influences migration of neuroblasts to the olfactory bulb in mice (43
). An abnormally enlarged lateral ventricle could potentially have abnormal eCSF flow altering migration of neurons and downstream cortical development.
Increased lateral ventricle size has also been associated with an increased risk of neurodevelopmental disorders. In schizophrenia, enlarged lateral ventricle size is reported in 77% of studies and it is considered one of the more consistent findings on MRI and it tends to be present early in the course of the illness (44
). As noted above, we found lateral ventricle enlargement in males at high risk for schizophrenia in the neonatal period (36
). Many transgenic mouse models utilized to investigate the neurobiology of schizophrenia and other neurodevelopmental disorders do display enlarged lateral ventricles. For example, Disrupted in schizoprhrenia-1 (DISC1) dominant negative transgenic mice have enlarged lateral ventricle size as well as behavioral abnormalities characteristic of schizophrenia including hyperactivity, anhedonia and disturbances in sensory-motor gating. (47
). Inducible hDISC1 transgenic mouse models have also been shown to demonstrate gender-specific behavioral phenotypes associated with mood disorders, such as elevated aggression, depression-like symptoms in female mice and increased responses to stimulants in males (48
). Type III-NRG1 heterozygous mutants displayed increased lateral ventricle size as well as other behavioral characteristics of schizophrenia such as deficits in sensorimotor gating and memory impairment (49
). Interestingly, a recent study found that first-episode patients with schizophrenia who had combinations of risk alleles in NRG1 and DISC1 had 48% larger lateral ventricle volumes than those with no risk alleles (50
Our study has several limitations. The number of subjects with MRI scans was limited by those who declined to participate in the scanning as well as unsuccessful scans at follow-up visits. Attrition in the MVM group led to a smaller sample size at 2 years of age. The majority of our MVM cohort (mean atrial width = 1.05 cm) falls at the low end of the range (1.0–1.5 cm) that is clinically considered prenatal MVM. Outcome studies indicate that atrial widths of 1.2 cm or greater are more often associated with poorer neurodevelopmental outcomes than widths between 1.0–1.2 cm (51
, 52). It is important to note that prenatal atrial widths in the 1.0–1.2 range in this study are associated with significant enlargement of the lateral ventricles at both 1 and 2 years of age and associated alterations of total white and gray matter, as well as mild reductions in fine motor and expressive language scores.
In summary, we found that children with prenatal MVM have persistently enlarged lateral ventricle volume through 2 years of age. In concordance with our previous findings (23
), we also found associated gray and white matter changes in children with MVM. While overall developmental scores were similar to controls, children with MVM exhibited reductions in fine motor and expressive language skills. Our study indicates that prenatal ventricle size is highly associated with enlarged lateral ventricle volume at both 1 and 2 years and that the overall relative size of the fetal lateral ventricle appears to be conserved during the early postnatal period and beyond. Thus, enlargement of lateral ventricles appear to be structural markers of altered fetal brain development. Future long-term follow-up studies are needed to determine if prenatal MVM is associated with high risk of neuropsychiatric disorders.