Restriction spectrum imaging (RSI) ( 37, 38 ) separates the diffusion-weighted MRI signal into distinct components originating in intracellular and extracellular water, which respectively correspond to restricted and hindered diffusion ( 38 ) ( Fig. 1 ). This distinction can be used to estimate the degree of cellularity in specific brain structures.

We use an MRI technique to probe nucleus accumbens (NAcc) tissue microstructure and predict waist circumference after 1 y.

We find that increased cell density in the NAcc is strongly associated with obesity in a large cohort of children and predicts future weight gain independent of waist circumference at baseline.

These results extend animal studies showing a vicious cycle in which diet-induced neuroinflammation leads to disruption of the brains reward circuitry and subsequently promotes further unhealthy eating and weight gain.

Abstract The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life.

Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens NAcc) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear.

Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity.

More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain.

In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y.

These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.

Obesity is associated with negative consequences on an individuals mental health ( 3 5 ), physical health ( 6 8 ), and on mortality rates ( 1 ).

Children and adolescents with obesity have more than a fivefold likelihood of becoming obese adults ( 9 ) and are likely to have a more substantial obesity-related disease burden ( 10 ).

Obesity is defined by an excessive amount of fat accumulation and has traditionally been quantified using body mass index (BMI) ( 11 ) or BMI scores adjusted for age and sex in children ( 12 ).

However, BMI differences in thinner individuals are largely attributable to differences in fat-free mass ( 13 ), and, conversely, BMI has been suggested to be a poor indicator of severe adiposity ( 14 16 ).

Recent guidelines have suggested that waist circumference may be a better estimate of visceral adiposity in children within a normal BMI range (e.g., 17, 18 ).

Consistent with this, waist circumference has been shown to estimate body fat more accurately than BMI ( 19 ) and waist-to-hip ratio (WHR) ( 20 ).

Further, studies have shown waist circumference to outperform BMI in predicting fat gain ( 21 ) and obesity-related health risks in children ( 22, 23 ), which may be more informative for understanding susceptibility for future health outcomes, such as subclinical inflammation, metabolic dysfunction, and cardiovascular disease ( 24, 25 ).

Despite the long-term costs and consequences associated with childhood obesity, the neurobiological mechanisms that underlie early weight gain remain unclear.

Previous work has implicated the brains mesolimbic dopaminergic systemin particular, the nucleus accumbens (NAcc)in promoting unhealthy eating and other reward-motivated behaviors ( 26 28 ).

For example, in adults, individual differences in NAcc blood oxygen level-dependent (BOLD) responses to food cues have been positively associated with ad libitum snack consumption ( 29 ), weight gain ( 30 ), diet failure ( 31 ), and BMI ( 32 ).

Not only have similar associations been observed in children and adolescents ( 33, 34 ), but the role of this circuitry may disproportionately affect susceptibility to unhealthy behaviors in youth.

Regional and circuit-based changes involving the NAcc appear to precede the maturation of control-related prefrontal circuitry during development ( 35 ), which may lead to an overreliance on reward circuitry in driving behavior ( 36 ).

This imbalance may contribute to and enhance vulnerability for developing unhealthy eating behaviors early in life, thereby increasing risk for obesity during adolescence as well as during adulthood.

Beyond correlational support for associations between obesity-related measures (e.g., BMI, waist circumference) and brain structure and function, a greater understanding of the cytoarchitecture in key regions within the developing mesolimbic system may yield novel insight into the mechanisms underlying disproportionate weight gain in youth.

Recent developments in diffusion magnetic resonance imaging (dMRI) methodology afford the opportunity to probe the tissue microstructure of deep gray nuclei by providing metrics that directly relate to cell and neurite density.

This distinction can be used to estimate the degree of cellularity in specific brain structures.

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