Research Summary

Are Elevated Brain RNI Values Associated with Excessive Weight Gain in Adolescent Girls?

Kate Young

Key Highlights:

  • Restricted normalized isotropic (RNI) values were associated with age but not BMI in weight-stable youth; however, among youth with variable weight gain, RNI and BMI showed positive bidirectional associations.
  • In girls, higher RNI values were strongly associated with greater BMI increases during a 2-year period.
  • These findings suggest that RNI may be a sensitive neuroimaging biomarker for detecting neuroinflammatory changes related to excessive weight gain.
  • RNI alterations may precede or reflect obesity-related neurodevelopmental changes, with potential sex-specific trajectories during adolescence.

In a longitudinal cohort study of 3110 adolescents from the Adolescent Brain Cognitive Development (ABCD) Study, Shana Adise, PhD, an investigator in the division of endocrinology, diabetes and metabolism at Children’s Hospital Los Angeles and her research team found that restricted normalized isotropic (RNI) values—an MRI-derived index of brain microstructure—were linked to age in youth with stable, healthy weight but not to BMI. However, among those with variable weight gain, including transitions to overweight or obesity, RNI values demonstrated significant bidirectional associations with BMI. In girls, elevated RNI values were robustly associated with greater increases in BMI over a 2-year follow-up period, suggesting a potential neurobiological pathway linking brain microstructure to unhealthy weight gain.

The growing prevalence of childhood obesity has prompted greater interest in the neurodevelopmental implications of excess weight. Prior research suggests a possible association between altered brain structure and cognition, potentially mediated by neuroinflammation. However, previous studies have not clarified whether microstructural brain changes precede weight gain or are its consequence, particularly in the context of normative development and sex-specific factors such as puberty. This study sought to isolate these associations by examining only children who began with a healthy weight.

Researchers analyzed baseline and 2-year follow-up data from the ABCD Study, focusing on youths aged 9 to 10 years with a BMI below the 85th percentile at baseline. Using restriction spectrum imaging (RSI), they quantified RNI values in subcortical brain regions associated with appetite control. Weight trajectories were classified into two groups: healthy-weight, weight-stable (HW-WS) and healthy-weight, non-stable (HW-NS). Linear mixed-effects models assessed relationships among age, BMI, puberty, and RNI, stratified by sex.

In HW-WS youths, RNI values increased with age but showed no association with BMI, indicating RNI may reflect normal neurodevelopmental processes such as synaptic pruning. Among those with variable weight gain, however, RNI values were positively and bidirectionally associated with BMI across several subcortical regions, including the putamen, pallidum, hippocampus, and thalamus. These associations were particularly robust in girls, where elevated RNI values predicted greater future weight gain. This sex-specific pattern suggests that neuroinflammatory processes may disproportionately affect female adolescents during periods of rapid developmental change.

Despite these compelling findings, several limitations must be acknowledged. The study did not include direct markers of neuroinflammation or adiposity, and BMI was used as a proxy for weight gain without assessing body composition. Pubertal status was assessed via self-report, which may lack accuracy, and peripheral markers of systemic inflammation were not available. Consequently, the mechanistic pathways underlying RNI changes remain speculative.

“This study provides additional support for the idea that neurobiological factors, such as potential neuroinflammation, may underlay and/or promote weight gain due to potential dysregulated appetitive control and its associated cognitive and metabolic consequences,” the study authors concluded. “Future mechanistic studies are needed to determine the specific cellular changes underlying these associations.”

Reference:
Adise S, Li ZA, Ottino-González J, Morys F, Chiarelli PA, Hershey T. Distinct patterns of weight gain, age, and subcortical microstructure in early adolescence. JAMA Netw Open. 2025;8(7):e2522211. Published 2025 Jul 1. doi:10.1001/jamanetworkopen.2025.22211