The roots of addiction risk may lie in how young brains function long before substance use begins, according to a new study from Weill Cornell Medicine. The investigators found that children with a family history of substance use disorder (SUD) already showed distinctive patterns of brain activity that differ between boys and girls, which may reflect separate predispositions for addiction. The research , published Nov. 21, in Nature Mental Health, analyzed brain scans from nearly 1,900 children ages 9 to 11 participating in the National Institutes of Health's Adolescent Brain Cognitive Development (ABCD) Study .
"These findings may help explain why boys and girls often follow different paths toward substance use and addiction," said senior author Dr. Amy Kuceyeski, professor of mathematics and neuroscience in the Department of Radiology and the Feil Family Brain & Mind Research Institute at Weill Cornell. "Understanding those pathways could eventually help guide how we tailor prevention and treatment for each group."
Tracking Neural Energy Shifts
To explore these neural differences, the researchers used a computational approach called "network control theory" to measure how the brain transitions between different patterns of activity during rest. "When you lie in an MRI scanner, your brain isn't idle; it cycles through recurring patterns of activation," said first author Louisa Schilling, doctoral candidate in the Computational Connectomics Laboratory at Weill Cornell. "Network control theory lets us calculate how much effort the brain expends to shift between these patterns." This transition energy indicates the brain's flexibility, or its ability to shift from inward, self-reflective thought to external focus.
Disruptions in this process have been observed in people with heavy alcohol use and cocaine use disorder, and when under the influence of psychedelics.
Opposing Patterns in Boys and Girls
The study found that girls with a family history of SUD displayed higher transition energy in the brain's default-mode network, which is associated with introspection. Compared with girls without such a family history, this elevated energy suggests their brains may work harder to shift gears from internal-focused thinking.
"That may mean greater difficulty disengaging from negative internal states like stress or rumination," Schilling said. "Such inflexibility could set the stage for later risk, when substances are used as a way to escape or self-soothe."
In contrast, boys with a family history showed lower transition energy in attention networks that control focus and response to external cues. "Their brains seem to require less effort to switch states, which might sound good, but it may lead to unrestrained behavior," Dr. Kuceyeski said. "They may be more reactive to their environment and more drawn to rewarding or stimulating experiences."
Put simply, she said, "Girls may have a harder time stepping on the brakes, while boys may find it easier to step on the gas when it comes to risky behaviors and addiction." Since the brain differences appeared before any substance use, they may indicate inherited or early-life environmental vulnerability rather than the effects of drugs.
Toward More Personalized Prevention
The researchers emphasize the need to analyze data from boys and girls separately, since averaging results across both groups masked the contrasts. Separate analyses revealed distinct patterns, underscoring the importance of sex as a biological variable in brain and behavioral research.
The findings mirror what clinicians see in adults: women are more likely to use substances to relieve distress and progress more quickly to dependence, while men are more likely to seek substances to feel euphoria or excitement. Identifying early neural vulnerabilities in adolescence could help guide prevention before substance abuse begins.
"Recognizing that boys and girls may travel different neural roads toward the same disorder can help tailor how we intervene," Dr. Kuceyeski said. "For example, programs for girls might focus on coping with internal stress, while for boys the emphasis might be on attention and impulse control."
