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\begin{document}

\title{Insight into Brain Sex Differences of Typically Developed In-fants: A
Systematic Review}



\author[1]{Zahraa Saker}%
\author[2]{Mahdi Rizk}%
\author[3]{Diana Merie}%
\author[4]{Rami Nabha}%
\author[5]{Nicole Pariseau}%
\author[5]{Sanaa Nabha}%
\author[6]{Malek Makki}%
\affil[1]{Al Rassoul Al-Aazam Hospital}%
\affil[2]{Modern University for Business and Science}%
\affil[3]{Lebanese University}%
\affil[4]{University of Oradea}%
\affil[5]{University of Michigan}%
\affil[6]{University of Picardy Jules Verne}%


\vspace{-1em}



  
  \date{June 11, 2024}


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\selectlanguage{english}
\begin{abstract}
The human brain encodes gender differences. This fact has been gradually
expanded from the realm of the hypothalamus and sexual behavior to the
whole brain with its different lobes, structures, and functions, by the
influence of the constantly advancing neuroscientific and imag-ing
research. However, less is known about sex differences in the brains of
neonates and infants, despite their relevance to various sex-linked
diseases that develop early in life. In this review, we provide a
synopsis of the literature evidence on sex differences in the brains of
neonates and infants at the morphological, structural, and network
levels. We also briefly overview the pre-sent evidence on the sex bias
in some brain disorders affecting infants and neonates.%
\end{abstract}%



\sloppy


Insight into Brain Sex Differences of Typically Developed Infants: A
Systematic Review

\textbf{Abstract} \textbf{:}The human brain encodes gender differences.
This fact has been gradually expanded from the realm of the hypothalamus
and sexual behavior to the whole brain with its different lobes,
structures, and functions, by the influence of the constantly advancing
neuroscientific and imaging research. However, less is known about sex
differences in the brains of neonates and infants, despite their
relevance to various sex-linked diseases that develop early in life. In
this review, we provide a synopsis of the literature evidence on sex
differences in the brains of neonates and infants at the morphological,
structural, and network levels. We also briefly overview the present
evidence on the sex bias in some brain disorders affecting infants and
neonates.

\textbf{1. Introduction: A Historical Perspective}

The degree to which sex differences extend to human brain anatomy has
been investigated in many studies. The first postmortem studies on brain
sex differences have reported larger and more asymmetrical male than
female brains (Swaab DF and Horfman MA, 1984). During that period, brain
sexual differences in neuroscience were exclusively restricted to the
hypothalamus, sex hormones, and sexual behavior (Siva NL and Boulant JA,
1986; Levine S, 1966). Later, a surge of research focused on the
influence of sex hormones on different brain regions such as the
amygdala, hypothalamus, and hippocampus (Siva NL and Boulant JA, 1986),
as well as brain sensory motor and cognitive functions including memory,
emotion, navigation, and pain perception in healthy and diseased
condition (Kimura D et al., 1996). By the 20\textsuperscript{th}century,
the development of neuroimaging techniques (MRI, PET, TMS, EEG) has
extensively advanced our understanding of the differences between male
and female brains during normal development, from childhood, through
adolescence, to adulthood. Neuroimaging highlighted the differences in
behaviors, cognitive and emotional functions, and pointed out the risk
and consequences of various neurological and psychological disorders
(Arnold AP et al., 2017). Analyzing such differences has a wide range of
implications, from studying fundamental neuroscience to practical
guidelines in the diagnosis, prognosis, and treatment of brain
disorders. As research continues to deepen our knowledge of biological
sex differences, a newly emerging field is intended to address the
diagnostic and clinical needs of both sexes: sex-based biology and
medicine. The overall purpose of this review paper is to combine the
findings from neuroscience, neuroimaging, brain research,
neurobehavioral, neonatology, and neurodevelopment studies covering all
aspects of neonate brain development from volumetric, to microstructure
and functional connectivity. We aim to provide the investigators with a
global and precise overview on this topic to help the exploration of sex
differences in normal brain development. This review research allows for
a better understanding of the pathophysiology of brain abnormalities
observed in various sex-linked diseases such as neural tube defects,
neonatal seizures, autism spectrum disorder (ASD), and brain tumor, that
develop early in life.

\textbf{2. Materials and Methods}

Using the ``Preferred Reporting Items for Systematic Reviews and
Meta-Analyses'' (PRISMA) 2009 guidelines, a comprehensive search
independently using two databases, namely OVID/Medline and PubMed, was
performed for the keywords: ``sexual dimorphism'', ``sex differences ``,
``gender difference'', ''brain'', ``infants'', and ``neonates''.
Keywords were combined using the Boolean operators OR and AND. The
search strategy was as follows: (``sexual dimorphism'' OR ``sex
differences'' OR ``gender differences'') AND (brain) and (``infants'' OR
``neonates''). All the keywords were used as exploded medical subject
headings (MeSH) for the OVID/Medline and Pubmed. This study addressed
studies published in peer-reviewed journals from 1945 p to 31 October
2022. All duplicates were excluded in addition to abstracts, case
reports, non-English articles, reviews, commentaries, and editorials.
All English studies published in any year about sexual differences in
neonates' and infants' brains were included. Bibliography lists from all
eligible articles were also hand-searched to identify additional papers
potentially relevant for inclusion. No date restrictions had been set
for the articles to be retrieved from the search. A total of 568 records
were found in the literature related to brain sex differences. Of these,
208 studies did not meet our eligibility criteria and were excluded.
Finally, a total of 36 full-text studies were included in our systematic
review (Figure 1).

\textbf{3. Brain Morphology}

\textbf{3.1. Brain morphometric volume}

The most agreed-upon brain sexual difference is that both infant and
adolescent males have larger total brain volume than females. A
post-mortem study of mature neonates has shown that there is no
significant difference in mean brain weight between males and females
(Lenroot RK et al., 2007). Other studies reported that total brain
volume (TBV), intracranial volume (ICV), and intracranial cavity (ICC)
were larger in male than female infants (Knickmeyer RC et al, 2008;
Knickmeyer RC et al, 2018; Wang S et al., 2018). Additionally, sex was
found to be a significant factor in determining the total surface area
of the brain, with a larger cortical surface area (Li G et al., 2013;
Jha SC et al., 2018) and brain width in male than female infants by
roughly 5\% (Baibakov SE and Fedorov VP, 2010). Furthermore, Villa et
al. have demonstrated a faster TBV growth rate in male than female
infants during the perinatal period (Villa LM et al., 2021), with
consistent results in infancy (Holland D. et al., 2014). In addition,
morphometric analysis of infants' ventricles showed that male infants
demonstrated 4.5\% greater anterior-posterior size of lateral
ventricles, and 24.2\% greater height of the fourth ventricle compared
to female infants (Baibakov SE and Fedorov VP, 2010). On the other hand,
larger lateral ventricles (Gilmore JH et al., 2004), and a 16.9\%
increase in the fourth ventricle length were reported in female compared
to male infants (Baibakov SE and Fedorov VP, 2010)..

\textbf{3.2. Gray and white matters}

Stronger growth of gray matter (GM) compared to white matter (WM) was
observed during the early postnatal period and the first year of life in
both sexes (Knickmeyer, R.C. et al. 2008; Gilmore JH et al., 2007),. It
was described that male compared to female infants had about 10.2\% more
GM volume, 6.4\% more WM volume, and 7.8\% more subcortical GM volume
(Gilmore JH et al., 2007; Dean DC et al., 2018). This suggests that
larger cortical GM can be considered as the main contributor to a larger
brain volume in males (Reiss AL. et al, 1996). In contrast, in
prematurely born infants, Benavides et al. have shown greater GM volume
in females but greater WM volume in males (Benavides A et al., 2019).
The data recorded in neonates suggest that brain WM and GM maturation is
a continuous process and does not stop in infancy but continues at a
different rate in boys and girls.

The growth of the brain GM is concurrent with the development of several
cognitive and motor functions. However, abnormalities in early brain
development have been implicated in neurodevelopmental disorders, such
as overgrowth of GM volumes in children who are at high risk of autism
(Hazlett HC et al., 2019), and increased cortical GM volume in male
infants at high genetic risk of schizophrenia (Gilmore JH et al., 2010).

\textbf{3.3. Brain lobes}

Cerebral lobes show different growth rates during the first weeks of
life in both sexes (Gilmore JH et al., 2018). The fastest growth rate is
exhibited by the frontal lobe (4.44 ml/week), followed by the parietal
lobes (2.93 ml/week), temporal lobes (2.29 ml/week), occipital lobes
(2.40 ml/week), and lastly the limbic regions (0.58 ml/week) (Nishida M
et al., 2006). The frontal and temporal lobes continue their growth
during the first two years after birth with significant growth of the
frontal lobe over the temporal lobes (Matsuzawa J et al., 2001). A
significant sex difference was found in the total volume of frontal and
temporal lobes in infants where 2-5 weeks-old males had greater volumes,
while females of the same age had greater volumes of the left parietal
and right temporal lobes (Lehtola SJ et al., 2019). Moreover, male
infants showed a greater length of the right parietal and right
occipital lobes by 12.2\% and 16.4\% respectively compared to female
infants (Baibakov SE and Fedorov VP, 2010). Gilmore et al. reported
significant differences in the growth pattern of the cortical lobes with
the occipital and parietal regions growing significantly faster than the
prefrontal region (Gilmore JH et al., 2007) Furthermore, this study
demonstrated that the brains of neonate females present more asymmetry
in both regions compared to males (Gilmore JH et al., 2007).

\textbf{3.4. Gyrification}

The sulcal and gyral patterns start to form during the third trimester
of pregnancy (White T et al., 2010), and continue to develop in the
first 2 years of life in parallel with the increase in brain size (Li G
et al. 2013). As the volume of the cortical hemispheres increases by
88\% during infancy (Knickmeyer RC et al., 2008), the thickness of the
cerebral cortex increases by 31\% (Lyall AE et al., 2015), 42\% in
sulcal depth (Meng Y et al., 2014), and expands by about 80\% in surface
area (Li G et al., 2013; Lyall AE et al., 2015),, particularly during
the first postnatal year. In neonates, inter-individual variability of
cortical folding was investigated, and significant sex differences were
detected in the superior temporal gyrus, inferior frontal gyrus, and
cingulate cortex (Duan D et al., 2019). Male infants showed greater GM
volumes in the fusiform gyrus, superior, middle, and inferior temporal
gyrus, Heschl's gyrus, left medial frontal gyrus, left superior frontal
gyrus, as well as left precentral and postcentral gyri (Knickmeyer RC et
al., 2014). However, females demonstrated higher GM volumes in bilateral
superior and middle frontal gyri, precentral gyri, inferior and middle
temporal gyri, and medial frontal gyri (superior), as well as the left
superior temporal gyrus. These possibly explain the enhanced social
interactive capacities and visual preference, along with better
self-regulation in newborn girls than boys (Knickmeyer RC et al., 2014).
It is worth mentioning that some differences in gyrification present
only in children and adults are primarily located in regions associated
with social cognition (Mutlu AK et al., 2018). Furthermore, at birth,
males' cortical thickness of the left fusiform gyrus was remarkably
greater than that of females (Lyall AE et al., 2015). Kim et al (2016)
observed higher cortical shape complexity in the middle cingulate and
parieto-occipital sulcal regions in male infants, but a more complex
Broca's area in females (Kim SH et al., 2016). In the other hand, the
authors reported no sex differences in the right anterior superior
temporal gyrus after birth until 2 years of age (Kim SH et al., 2016).
Moreover, males displayed significantly faster expansion rates of the
surface areas of many gyri in the left hemisphere compared to females
i.e., precentral gyrus, superior frontal gyrus, middle frontal gyrus,
olfactory gyrus, insula, superior parietal gyrus, and the right
calcarine gyrus (Lyall AE et al., 2015). Variation in cortical
gyrification emerges as a potentially useful marker for normal
development, as structural abnormalities in cortical folding were
evident in certain neuropsychological disorders such as ASD and
schizophrenia (Yang DY et al., 2016). An investigation using T2W fetal
MRI aimed to assess the timing of sulcal emergence and its temporal
variability. The study identified a trend indicating that females
exhibited a significantly earlier sulcal emergence than males in the
right superior-temporal-sulcus. In addition, a larger temporal
variability of sulcal emergence timing was found in male fetuses in the
right intraparietal sulcus, while the right precentral sulcus showed
lower variability in males. These findings are attributed to the
influence of various cellular and molecular processes, including sex
hormones and sex-biased gene expression (Yun HJ et al., 2022).

\textbf{3.5. Hemispheric asymmetry}

The human brain exhibits hemispheric asymmetry as early as 20 weeks of
gestation (Bisiacchi P and Cainelli E, 2022). In line with studies
across the infancy period, leftward asymmetry was found in the volume of
the hemispheric brain, the occipital lobe, prefrontal lobe, parietal
lobe volumes, and lateral ventricles (Gilmore JH et al., 2007; Choe MS,
et al., 2013; Hering-Hanit R et al., 2001). On the other hand, rightward
asymmetry was documented in the volume of the temporal lobe (Lehtola SJ
et al., 2019) indicating the formation of specialized neuronal circuits
during the earliest period of brain development (Dean DC et al., 2018).

Significant sex differences in asymmetry were found in the occipital and
prefrontal lobes where female infants showed a more pronounced leftward
asymmetry in both regions (Gilmore DH et al., 2007). Hemispheric
asymmetries of the mean depth of the sulcal pits also exhibited sexual
differences. Males, but not females, showed considerably greater mean
sulcal pit depth in the right hemisphere than that of the left
hemisphere at 1 and 2 years of age (Meng Y et al., 2015)\textbf{.} In
their 2022 study, Alexopoulos et al. employed functional Near Infrared
Spectroscopy --(fNIRS) to examine sex differences in the neural
processing of speech and non-speech (reversed) stimuli in infants during
the first days after birth. They found that girls exhibited significant
oxyhemoglobin changes exclusively within the left hemisphere in response
to speech stimuli. In contrast, boys demonstrated simultaneous neural
activations in both hemispheres, with a larger and more significant
fronto-temporal cluster observed in the right hemisphere (Alexopoulos J
et al., 2022). In a separate investigation utilizing T2W MRI, Lu et al.
(2019) explored the lateral ventricle volume (LVV) of normally developed
infants. The results indicated a significantly larger total LVV for
males (13,093.25 \selectlanguage{ngerman}± 5972.09 mm\textsuperscript{3}\textsubscript{,} 95 \%
confidence interval) compared to females (11,092.70 ± 4647.55
mm\textsuperscript{3}). The authors observed a left-ward asymmetry of
LVV (Left \textgreater{} Right) in both male and female infants. These
findings align with prior research on neonates, demonstrating larger
total brain volume, hippocampus and thalamus in males compared to
females (Lu Z et al., 2019).

\textbf{4. Brain Structures}

\textbf{4.1. Hippocampus}

It has been shown that the hippocampus is asymmetric in children and
adults without any sex effect (Jack CR et al., 1989; Szabo CA et al.,
2001) In line with these findings, Thompson et al. have not found a sex
difference in hippocampus symmetry neither in preterm nor in full-term
neonates taking into consideration that hippocampal asymmetry develops
during the gestational period and maintains into adulthood (Thompson DK
et al., 2008; Thompson et al., 2009). This asymmetry has been suggested
to be more pronounced in male children from 1 to 15 years old, than in
their female counterparts (Pfulger T et al., 1999). It has been
suggested that this sex-difference asymmetry is due to the influence of
sex hormones, particularly testosterone (Lenroot RK and Giedd JN, 2010).

\textbf{4.2. Amygdala}

Several studies have reported morphological and functional sex
differences in the amygdala. The effect of sex differences in the human
amygdala affect the formation of emotional memory, sexual behavior, and
psychological disorders (Hamann S, 2005). Namely, altered amygdalar
function in autism is four times more frequent in males compared to
females and has been linked to the greater prevalence of depression in
women. (Hamann S, 2005). In neonates with maternal psychological
distress, the volume of the left amygdala was smaller in male than that
in females (Lehtola SJ et al., 2020). This could be explained by
sex-different adaptation to cortisol levels, which leads to postnatal
amygdalar enlargement in females (Buss C et al., 2020).

\textbf{4.3. Hypothalamus}

The hypothalamus is another sexually dimorphic brain structure that have
been studied in neonates. Between 36 and 43 weeks of gestational age,
males exhibited a larger left thalamic volume than females, but this
difference disappeared after controlling for ICV (Giu A et al., 2013).
The sexually dimorphic nucleus of the preoptic area of the hypothalamus
is more than twice as large in young adult males compared to females and
contains about twice as many cells in men (Swaab DF and Fliers E; 1985),
. However, the distinction in sex-related characteristics becomes
noticeable only between the ages of 4 years and puberty. At a younger
age, it appears that the total number of cells and the rate of growth
are comparable between the two sexes (Swaab DF and Hofman MA, 1988).

\textbf{4.4. Corpus callosum}

The corpus callosum (CC) is the main interhemispheric commissure that
arises in the brains of placental mammals (Tomasch J, 1954). The CC is
formed in the 20\textsuperscript{th} week of gestation (Tanaka-Arakawa
MM et al., 2015), and grows in both anterior and posterior directions,
with a more prominent anterior growth (Jovanov-Milosevic N et al.,
2009). It mainly grows by fiber addition during gestation and in the
early postnatal period, and it undergoes significant development during
the first two years of life by progressive increase of layer of myelin
sheaths that continues into young adulthood (Deoni SC et al., 2011). CC
is the first human brain structure to be called ``sexually dimorphic''
(Eliot L et al., 2021). Nevertheless, CC sex-related differences are
still a matter of debate (Mitchell TN et al., 2003; Schmithorst VJ et
al., 2017). Studying the development of CC in different age subgroups
revealed a significantly higher ratio of CC to the whole brain in
females than in males (Tanaka-Arakawa MM et al., 2015). A slightly
larger CC area was reported in female infants when compared to
age-matched boys without significant sex differences (Vanucci RV et al.,
2017). However, other studies have revealed a significant larger CC area
in male infants between birth and the 14\textsuperscript{th} month of
age. The anteroposterior CC length was found to be longer in males, but
the bulbosity index was similar in both sexes (Clarke S et al., 1989;
Schmied A et al., 2020). A greater height of CC in male infants was
recognized (Hwang SJ et al., 2004) suggesting a different pattern of
spatial arrangement of the CC axons between the sexes, and indicating
faster growth of CC inferior-superior regions in males than in females
(Oka SJ et al., 1999). Vannucci et al. have revealed a significant
expansion in CC mainly in the splenium, genu, and body of CC, n infants,
with a greater splenium length-height ratio observed only in female
infants (Vanucci RC et al., 2017). Moreover, female infants exhibited
well-developed regions of CC except for the isthmus (Makki MI and
Hagmann C, 2017). The development of CC in female infants could be due
to the influence of maternal factors during brain development (Chang CL
et al., 2018) i.e. prenatal testosterone that enhances axonal pruning.
Additionally, a significantly larger thickness of splenium in female
neonate infants was observed (Hwang SJ et al., 2004) in line with the
findings reported on human fetus (Achiron S et al., 2001; de Lacoste MC
et al., 1986). In a recent volumetric MRI study employing 3D-T1W
imaging, Lewis et al (2022) partitioned the mid-sagittal acquisition of
the neonatal CC into 25 equal length segments. The findings revealed a
significantly greater exponent in the allometric relationship (log
regression) in female neonates compared to their male counterparts. This
greater growth in females, surpassing that in males, is considered
normal due to the processes of exuberance and pruning involved in the
development of the cortex and connectivity (Lewis JD et al., 2022). The
differences in size, shape, and thickness of the CC sub-regions may
reflect the differences in the functional connectivity between the two
hemispheres that later underlie gender differences in verbal abilities,
integration of sensory and motor information between the two
hemispheres, as well as spatial orientation and attention.

\textbf{5. Neural Networks}

\textbf{5.1. Corticospinal tracts}

The corticospinal tract (CST) is the primary neural pathway for
voluntary motor activities, especially fine movements (Jang SH, 2014).
Simultaneous with the dynamic postnatal development of the brain is a
similarly significant maturation of the CST, facilitated by rapid
myelination (Dubois J et al., 2009; Liu Y et al., 2010). Although the
lateralization in the entire CST microstructure was absent, it was
detected in the spatial parts of the segmented CST such as the
CST-cerebral peduncle and CST-posterior limb of the internal capsule
(Saadani-Makki F et al., 2019). Previous studies have suggested a
correlation between the early organization and WM maturation of CST and
the development of later functional lateralization (Dubois J et al.,
2009).

Rightward asymmetry at the levels of CST-cerebral peduncle and
CST-posterior limb of the internal capsule were observed in male infants
but not in females. However, female infants only displayed a CST
asymmetry at the level of the posterior limb of the internal capsule,
supporting the existence of different organization between the sexes
(alignment, direction, and fiber crossing) and stronger coherence of
these fibers in the right side of CST (Saadani-Makki F et al., 2019).
Leftward asymmetry in the CST-cerebral peduncle and CST-posterior limb
of the internal capsule was also reported in preterm neonates scanned at
term equivalent age (Liu Y, et al., 2010). The sex-related spatial
microstructure differences of CST that can be detected after birth are
of great interest for a better understanding of the developmental
changes in the motor pathway which can later predict early possible
motor dysfunctions.

\textbf{5.2. Thalamocortical tracts}

The thalamocortical tracts (TCT) are the major subcortical projections
into sensory areas and the associative brain regions such as the frontal
cortex (Krsnik Z et al., 2017). These tracts undergo initial growth,
pathfinding, and target selection under the control of a variety of
signaling molecules and complex cellular and molecular interactions
(Molnar Z et al., 2012). Thus, the microstructural changes of TCT are
observable during the early development of the human brain (Aeby A.,
2009). The thalamus-salience and the thalamus-sensorimotor networks have
been found in neonates, but obviously the thalamus-default mode networks
and the thalamus-medial visual were not evident until 1 year of age
(Alcauter S et al., 2014). These findings highlight the critical role of
the thalamus-relayed sensory information for proper functioning during
early life. Nevertheless, little is known about the sex effects on the
thalamocortical tracts in neonates and infants. Although, a DTI study
reported that neonate girls have asymmetric TCT pathway (higher
diffusion indices on the right compared to the left), no TCT asymmetry
can be found in neonate boys (Saadani-Makki F et al., 2021). When both
genders were combined, the right asymmetric TCT was still significant
with higher diffusion indices in the right compared to the left,
providing insight into faster WM maturation in the left hemisphere
compared to the right around 38 weeks of GA (Saadani-Makki F et al.,
2021).On the other hand, analyses of diffusion MR tractography failed to
identify any TCT hemispheric asymmetry during brain development (Goodyer
IM et al., 2017), which might be due to incomplete myelin development of
the fetus' brain. A recent resting-state functional MRI (rs-fMRI)
investigation on a large cohort of neonates and infants explored the
early sex difference in functional connectivity and the biological
correlation with language development, and executive function.
Noteworthy sex differences in the longitudinal trajectories of
functional connectivity change were identified in temporal areas from
birth to 2 years of age, specifically in the right fusiform gyrus in
neonates, the right inferior-temporal gyrus in 1-year-olds, and the
right superior temporal gyrus in 2- year-olds. These sex differences in
functional connectivity were found to be associated with behavioral
scores collected throughout infancy and early childhood. The observed
variations in sex differences underscore the substantial variability in
early life, mirroring the rapid structural brain growth and functional
reorganization that correlates with genes on the X-chromosome (Fenke SJ
et al., 2023).

\textbf{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)\textbf{,} with other clinical studies
reporting the opposite results (Deak KL et al., 2008; Janerich DT, 1975;
Lary JN et al., 1996)\textbf{.} 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 \textless{} 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) \textbf{.} 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).

\textbf{7.} \textbf{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.

\textbf{Figure 1:} Systematic review flowchart showing the step-by-step
procedure of identification screening, eligibility and inclusion of
studies.

\textbf{Table 1.} Studies reported sex differences regarding brain
disorders.

\textbf{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.

\textbf{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.

\textbf{Funding:} Not funded.

\textbf{Institutional Review Board Statement:} Not applicable

\textbf{Informed Consent Statement:} Not applicable

\textbf{Data Availability Statement:} Not applicable

\textbf{Conflicts of interest:} None.

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