6. Sex Differences in Brain Pathologies
Disparities in the incidence of many brain pathologies have been reported between males and females. The neurobiological basis of this heterogeneity might suggest a potential role of underlying morphological/functional brain sex differences. Male infants were shown to be affected by birth asphyxia about 3 times more than female infants (Gupta SK et al., 2014). On the other hand, a higher proportion of severe hypoxic-ischemic encephalopathy was reported among females (Simiyu IN et al., 2017) (Table 1). Of neonates surviving hypoxia-ischemia, term, and preterm males display about 30% higher incidence of cerebral palsy and more severe motor deficits than females (Bona E et al., 1998; Jarvis S et al., 2005). Moreover, a lower mortality rate of females from respiratory illnesses suggests that females might be more resistant to hypoxia than males (Mage ST et al., 2006).
Furthermore, several studies have reported a higher incidence of neonatal seizures in males than in females (And V and Nair PMC, 2014; Nishiyama M et al., 2020; Rehman Malik A et al., 2013). The exception is the study by Eghbalian et al. which reported two times higher prevalence of neonatal seizure in females than in males (Eghbalian F et al., 2015). A higher incidence of hypoxic-ischemic encephalopathy in males might contribute to male-dominance of neonatal seizures the most common cause of seizures in the first 48 hours of life (Digra SK et al., 2007; Nemati H et al., 2018). Another brain pathology showing a sex bias is neural tube defects (NTDs). Spina bifida, the most common type of NTDs displays a higher prevalence in males according to some studies (Liu J et al., 2018; Sahmat et al., 2017), with other clinical studies reporting the opposite results (Deak KL et al., 2008; Janerich DT, 1975; Lary JN et al., 1996). In addition, anencephaly and encephalocele, other types of NTDs, were shown with marked preponderance among females (Liu J et al., 2018; Deak KL et al., 2008; Janerich DT, 1975; Roigers SC et al., 1973). The greater susceptibility to NTDs of one gender over the other could be explained by the interaction between genetic and environmental factors (Deak KL et al., 2008; Teicher MH et al., 2003), and the presence of sex differences in some specific aspects of the neurulation process (Brook FA et al., 1994). This will require further elucidation in future studies.
A series of studies have reported the development of brain tumors in children < 1 year with a higher incidence rate in male infants. The most common histological diagnoses were primitive neuroectodermal tumors, ependymoma, and choroid plexus tumors (Ghodsi SM et al., 2015; Jaing TH et al., 2011) . As brain tumors are characterized by significant incidence variation across age groups, males are more likely to develop brain tumors than females at all ages (Le Rhum E and Weller M, 2020). This might be partly explained by the potential sex-specific genetic factors and biology (Le Rhum E and Weller M, 2020). Several neuropsychological disorders reportedly demonstrate gender biases. While symptoms of schizophrenia typically manifest in late adolescence and early adulthood (Le Rhum E and Weller M, 2020), the precursors to schizophrenia onset may emerge as early as infancy. Structural brain abnormalities in male neonates have been linked more closely to genetic risk for schizophrenia (Shi F et al., 2012). Male infants with schizophrenic parents were reported to exhibit significantly larger volumes of intracranial cerebrospinal fluid (CSF) and lateral ventricles (Gilmore JH et al., 2018), as well as a reduced number of subcortical-cortical fibers (Shi F et al., 2012).. This suggests the possibility of new lines of evidence regarding the existence of early brain alterations in neonates with a genetic risk of schizophrenia during the very early neonatal period.
Autism spectrum disorder (ASD) is among the most common neurodevelopmental disorders with a greater incidence in male infants (Ozonoff S et al., 2011; Limperopoulous C et al., 2008). Many studies have illustrated the neuro-developmental consequences of fetal exposure to stress, partly explaining the sex difference incidence in ASD, in addition to the genetic influence which is a key factor in the vulnerability to ASD (Ozonoff S et al., 2011; Davis EP et al., 2014). Several hypotheses were formulated to explain the developmental mechanisms underlying this male bias, including genetic and pre- and perinatal hormonal mechanisms (Lai MC et al., 2015). Finally, women are impacted by major depressive disorder (MDD) approximately twice as frequently as men (Acosta H et al., 2020). Polygenic risk scores for MDD (PRS-MDD) have the capability to predict its risk by assessing the cumulative presence of specific risk alleles in single nucleotide polymorphisms (SNPs) associated with MDD. A study by Acosta et al, (2020) showed that higher PRS-MDD is associated with smaller bilateral caudate volumes in females compared to male infants (Acosta H et al., 2020).
Easson et al, (2023) have conducted a study employing pulsed arterial spin labeling MRI to measure the total cerebral blood flow in adolescents and young adults born with congenital heart disease (CHD). Their findings indicated significantly lower global and regional cerebral blood flow (CBF) in post pubertal females with CHD compared to female controls. In contrast, male youth with CHD did not exhibit significant differences in CBF relative to their control counterparts. The authors propose that the observed sex differences in CBF during post puberty may be linked to sex-specific hormonal changes, particularly estrogen, accompanying puberty, ultimately influencing neuronal oxygenation demands (Easson K et al., 2023). It is noteworthy to add that previous studies on neurological disorders have also reported sex difference at birth with high prevalence in males than females of neural tube defects and neonatal seizures (Talebian A et al., 2015). It has been shown that autism spectrum disorder affects more boys than girls (Kuzniewicz, M.W et al., 2014), while girls are more susceptible to major depressive disorder than girls (Acosta H et al., 2020). However, numerous research studies on the normal brain development of neonates and infants have revealed diverse trends between boys and girls, involving aspects such as volume, microstructures, or connectivity. Despite these findings, a few meta-analysis review papers have asserted the absence of sex difference in brain development. For instance, A review focusing on the hippocampus noted that observed volume differences between boys and girls vanished when adjusted for total brain volume (Tan A et al., 2016). Another systemic meta-analysis review suggests that the recorded volumetric differences in the amygdala, while subtle, are not statistically significant due to biases in statistical analysis (Marwha D et al., 2017). A review study by Eliot et al (2021) suggested that sex differences in brain size and lateralization are essentially obscured by genetic, epigenetic, and experiential factors (Mitchell TN et al., 2003).
7. Limitations, Conclusion, and Future Perspectives
In this review, we have attempted to provide a synopsis of the literature on sexual differences in infants’ brains. We primarily focus on MRI-DTI and MRI 3D-T1W findings because this advanced, noninvasive, and repeated modality allows for accurate and reproducible measures in neonates, whether or not sedation is required. While most research studies indicate sexual differences in brain development, a few meta-analyses review papers suggest that these changes may result from biases in statistical analysis, genetic factors, or experimental design. Although the limited sample size remains a major constraint in investigations of neonatal brain development, reproducible studies on normal and pathological brain structure development, along with findings from various modalities, converge to the conclusion that sexual differences persist in brain GM and WM development and structural connectivity up to certain age. We highlighted key structural differences between healthy male and female neonatal and infant brains and reviewed common neurological and neuropsychological disorders with specific sex predilections. A growing body of evidence supports the presence of differences in various attributes and regions of the neonatal/infantile brain. Male infants often exhibited greater brain volume, cortical surface area, faster total volume growth, and more GM and WM, along with larger frontal and temporal volumes. On the other hand, female infants have been shown to exhibit greater left parietal and right temporal volumes, higher leftward asymmetry in the occipital and prefrontal regions, a higher ratio of CC to the whole brain, and other regional differences, including a more complex Broca’s area. These dissimilarities may partly explain sex differences in behaviors and emotional functions. Once again, this review underscores that although subtle gender differences may be observed, they should be considered when investigating brain development. It is crucial to account for sex differences in statistical analyses and their associations with behavior and biological correlates.
Further work is needed to explore in vivo brain development in early fetal life. Given the scarcity of literature addressing early brain sexual differences, further research on brain sex differences in neonates and infants is essential to support efforts in optimizing the management of neurological diseases in a sex-specific manner. This is especially important considering the noted male and female predominance in many common neurological, neurodevelopmental, and psychiatric disorders.
Figure 1: Systematic review flowchart showing the step-by-step procedure of identification screening, eligibility and inclusion of studies.
Table 1. Studies reported sex differences regarding brain disorders.
Abbreviation: ADOS: Autism Diagnostic Observation Schedule; APGAR score: Appearance, Pulse, Grimace, Activity, and Respiration score; ASD: Autism spectrum disorder; CSF: Cerebrospinal fluid; CT: computerized tomography; cUS: Cranial ultrasonography; DTI: diffusion tensor imaging; EEG: electroencephalogram; MDD: Major depressive disorder; MRI 3DT1W: Magnetic resonance imaging 3-dimensional T1-weighted; MRI 3DT2W: Magnetic resonance imaging 3-dimentional T2-weighted; N/A: not available.
Authors’ contributions: S.-M.N and M.-I.K conceived the concept and idea of the present review. Z. S, M. R, S.-M.N, and M.-I.K worked on the study design strategy and selected the topics to be discussed. Z. S, M. R, D.M, and R.-H.N did literature searches and screened titles and abstracts for relevance. Z. S, M. R, D. M, R.-H.N abstracted the data from the eligible full-text articles. Z. S, M.R, and D. M analyzed and interpreted the data and drafted the manuscript. S.- M.N, M.-I.M, and N.P. critically revised the manuscript. All authors have read and approved the final draft.
Funding: Not funded.
Institutional Review Board Statement: Not applicable
Informed Consent Statement: Not applicable
Data Availability Statement: Not applicable
Conflicts of interest: None.