Introduction

Worldwide, more than 250 million children fail to reach their developmental potential with respect to age-appropriate height and/or weight (i.e., are stunted, underweight, and/or wasted)¹. Many of these children live in low and middle income settings (LMICs), where they experience adverse health, family, and environmental factors that affect their physical development². Many of these environmental and psychosocial factors also impact early brain development^3,4, placing these children at risk for cognitive deficits and reduced academic success and achievement. Stunted children are less likely to be enrolled in school and are more likely to leave early⁵; and often have lower overall intelligence quotients (IQ) as well as specific deficits in motor skills, reading, language, reasoning, and social-emotional functioning⁶. Unfortunately, no longitudinal neuroimaging study has investigated the impact of these specific family and socioeconomic factors on measures of brain growth in children in these settings, which may underlie and precede these later cognitive and academic concerns.

Methods

497 longitudinal brain imaging scans were acquired of 156 children (76 female) in Uttar Pradesh (UP), India, on a Philips Achieva 3T MRI scanner equipped with 12-channel head RF array. Children enrolled at ~6, 9, 12 or 15 months of age, and followed until they were 18, 21, 24, or 27 months, with imaging performed every 6 months. T1w anatomical IR-SPGR were acquired, as well as anthropometry, socioeconomic, and demographic data for each child. For volumetric analysis, whole-brain white and gray matter (WM and GM), and regional thalamus, hippocampus, amygdala, and caudate nucleus volumes were calculated^7,8. Mixed effects models were used to calculate individual trajectories of brain development and physical growth (linear growth and weight gain). Mean male and female brain growth trajectories, normalized for child head circumference were also calculated. And models were used to systematically investigate the impact of gender, height and weight for age (HAZ and WAZ), family income, family size, maternal education, use of a flush or open pit toilet, and electricity access on patterns of brain growth.

Results

There were no significant male-female group differences in child health indicators, such as birth weight (p=0.43), gestation weeks completed (p=0.67), stunting or wasting occurrence (p=0.26 and 0.07), parent age at child birth (p>0.8), parent education levels (p>0.25), family caste (p=0.64) or Kuppuswamy SES score (p=0.8). From the individual measures of weight gain, linear growth, and brain volume development (Fig, 1), we found significant associations between rate of brain growth and child weight gain for white and gray matter (WM: r2=0.22, p<0.00001 ; GM: r2=0.08, p=0.003 ) but not linear growth rate (WM: r2=0.003, p=0.5; GM: r2=0.002, p=0.57 ). Individual and group mean male and female WM and GM growth trajectories (Fig. 2) reveal a significant male-female difference in growth rate and total volume present at 6m and persisting throughout childhood even when controlling for child head size. These results are mirrored on a regional level (Fig. 2), where we find that girls have significantly smaller and slower developing thalamus, hippocampus, and amygdala than boys with or without normalizing for head size, however, no male-female difference was found in right or left hemisphere caudate nucleus. These results differ significantly from data collected in higher income settings, which do not show such a pronounced gender effect until later in childhood9. Investigating environmental factors associated with overall increased or decreased anatomical values (Tables 1 and 2), we find that being male and having higher WAZ are significantly associated with increased whole-brain and regional WM and GM volumes. Higher maternal education was significantly associated with whole-brain WM volume, as well as amygdala, and hippocampal GM volume. Increased HAZ was associated with increased hippocampal and left amygdala volume, and improved sanitation (access to a flush toilet) was associated with whole-brain gray matter volume.

Discussion

Results here present the first findings of brain growth trends in LMIC children. While the impact of malnutrition (underweight), sanitation, and overall SES on brain development was expected, developmental differences between boys and girls was surprising. Within India, gender disparities in infant nutrition, healthcare seeking, and other metrics of child health have been well reported¹⁰. In UP, the girl-to-boy ratio of 0.9 is amongst the lowest in the world, and the proportion of female to male newborns receiving healthcare is approximately 1:2. These gender disparities persist across all facets of life, with nearly twice as many girls as boys between 7-14 years of age not attending school. Within our cohort, we note that mothers were more than twice as likely to be illiterate as fathers (odds ratio = 2.5; p = 0.003). These early health inequalities may underpin observed neurodevelopmental differences: reduced infant nutrition and breastfeeding may impact WAZ, which we find consistently impacts neurodevelopment. Emphasizing a potential generation effect, as shown throughout maternal education is significantly associated with regional brain volumes and structural organization and integrity. Thus, girls may be born into a disadvantaged generational cycle that promotes worsened neurodevelopmental outcomes and sets the stage to impact their future offspring.

Acknowledgements

No acknowledgement found.

References

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