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.