Introduction

The widespread prevalence and devastating consequences of substance use constitute an international public health concern.¹ While the adverse outcomes associated with substance use typically emerge in late adolescence and/or young adulthood, they are often set in motion earlier. As earlier onset of substance use is a potent predictor of later problematic use,^2,3,4,5 it is critical to understand risk factors and mechanisms contributing to initial substance experimentation.

Neuroimaging studies have revealed that substance involvement (eg, initiation, use, escalating or problematic use, or substance use disorder [SUD]) is associated with lower gray matter volume, thinner cortex, and less white matter integrity.^6,7,8,9,10 While these patterns are often observed globally, some associations are regionally potentiated (eg, hippocampus^11,12,13 or dorsolateral prefrontal cortex [dlPFC]^6,7,14). With few exceptions,^15,16,17,18 these findings have emerged from cross-sectional studies and are largely speculated to be substance-induced.^19,20,21,22

Some longitudinal magnetic resonance imaging (MRI) studies are consistent with substance-induced brain differences^6,9; however, converging evidence from longitudinal and genetically informed studies suggests that these differences may also reflect predisposing risk for substance involvement arising from genetic and environmental exposures.^{7,14,15,18,23} For instance, lower volume and thinner dlPFC of substance-naive children predicts future alcohol involvement,^7,10,18 family history of alcohol use disorder is associated with thinner frontal cortices in substance-naive youths,²⁴ and low-drinking twin and nontwin siblings of high-drinking individuals have similarly smaller dlPFC and insula volumes as their heavy drinking counterparts.⁷ Similar associations have been observed for other substances (eg, cannabis).^23,25 These findings suggest that neuroanatomical correlates of substance involvement may, at least partially, reflect predisposing risk factors, in addition to direct consequences of use. This broadly aligns with genetically informed models hypothesizing that neurobiological correlates of addiction may reflect both causes and consequences,²⁶ as well as with developmental theories (eg, dual-systems or maturational imbalance models) highlighting brain development as a predispositional factor for substance involvement.^27,28

We examined associations between brain structure and substance use initiation in children enrolled in the ongoing Adolescent Brain and Cognitive Development (ABCD) Study.²⁹ We first tested whether baseline neuroanatomical variability was associated with any substance use initiation occurring before or up to 3 years following initial neuroimaging scans. We then tested whether any observed associations were present when excluding children who reported substance use initiation before the baseline neuroimaging session (ie, in a substance-naive subsample). Evidence that neuroanatomical variability in substance-naive youths predicts future substance use initiation would suggest that these correlates may represent predispositional risk factors for substance involvement. While neuroanatomical features associated with substance involvement are largely shared across different substances, substance-specific effects have also been found.⁸ Thus, we also examined neuroanatomical correlates of the 3 most commonly used substances in early adolescence: alcohol, nicotine, and cannabis. Broadly, we hypothesized that neuroanatomical features associated with substance use initiation would be evident even before use began, consistent with their conceptualization as putative predispositional risk factors. Specifically, we hypothesized that substance use initiation would be characterized by smaller global neuroanatomical indices, and that these differences would be particularly pronounced in regions previously identified as putative predispositional risk markers (ie, dlPFC and insula).

Methods

Participants

The ABCD Study²⁹ is a longitudinal study of complex behavior and biological development from middle childhood to young adulthood. A total of 11 875 children aged 8.9 to 11 years at baseline (born 2005-2009) were recruited from 22 US research sites. Parents or caregivers provided written informed consent and children provided assent to a research protocol approved by the institutional review board at each site.³⁰ Race and ethnicity were reported by parent or caregiver and were assessed to characterize the sociodemographic variability of our sample. Baseline neuroimaging data were drawn from ABCD data release 3.0; all other data were drawn from release 5.0. Final analytic samples after missing data exclusion (eMethods in Supplement 2) were 6556 to 9804 participants (Table). This study followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

Table. Sample Demographics by Substance Use Initiation Endorsement in Current Analytic Adolescent Brain Cognitive Development Sample by 3-Year Follow-Up.

Substance Use Initiation

Annual in-person (ie, baseline and follow-ups at 1 year, 2 years, and 3 years) and midyear phone interviews (at 6 months, 18 months, and 30 months) assessed substance use. Participants endorsing use at any assessment from baseline to follow-up 3 (ie, lifetime use) were included in substance use initiation groups. Alcohol (808 participants) and nicotine (34 participants) use endorsed solely in the context of religious ceremonies were coded as missing to restrict comparisons to use outside these settings.

Alcohol use initiation (3123 participants) was defined as sipping or full drinks of alcohol (eMethods in Supplement 2). Nicotine use initiation (431 participants) was defined as use of nicotine products in any form or route of administration. Cannabis use initiation (212 participants) was defined as use of cannabis in any form or route of administration except synthetic cannabis or cannabis-infused alcoholic drinks, which were included under any substance use. Any substance use initiation (3460 participants) was defined as alcohol, nicotine, or cannabis use initiation or any other illicit substance use (213 participants). Substance-naive participants (6344 participants) endorsed no substance use from baseline to follow-up 3 with nonmissing data for follow-up 3 to protect against misclassification of participants whose follow-up 3 status was unknown (1065 participants). eTable 1 in Supplement 1 lists study release variables.

Structural Magnetic Resonance Imaging

Baseline structural MRI data, obtained via 3T MRI scanners and harmonized across 3 MRI vendor platforms, were available for 11 556 of 11 875 participants following FreeSurfer processing and quality control protocols (eMethods in Supplement 2). In total, 297 imaging-derived phenotypes (IDPs) were examined in the current study, including global IDPs (ie, whole brain volume, total intracranial volume, total cortical volume, total cortical surface area, mean cortical thickness, mean cortical sulcal depth, and total subcortical gray matter volume; k = 7); bilateral volume of 9 subcortical structures (ie, accumbens, amygdala, caudate, cerebellar cortex, cerebellar white matter, globus pallidus, hippocampus, putamen, and thalamus; total k = 18); and total volume, mean thickness, total surface area, and mean sulcal depth of 34 bilateral cortical regions according to the Desikan-Killiany atlas³¹ (total k = 68/metric).

Statistical Analysis

A series of independent linear mixed-effect regressions wherein IDPs were regressed on substance use initiation groups were conducted using the lme4 version 1.1-30 package in R version 4.2.1 (R Project for Statistical Computing).^32,33 Variables were z-scored before analyses, and listwise deletion was used for missing data. Primary analyses contrasted any substance use initiation (3460 participants) vs no initiation (6344 participants); secondary analyses considered alcohol (3123 participants), nicotine (431 participants), and cannabis (212 participants) use initiation independently and contrasted them against no substance initiation (6344 participants). Fixed-effect covariates in all analyses were baseline age and age-squared, sex, pubertal status, familial relationship (ie, sibling, twin, or triplet), and MRI scanner model (eTable 2 in Supplement 1; eMethods and eFigure 1 in Supplement 2). Random intercepts were modeled for effects of family nested within data collection sites (eMethods in Supplement 2). For regional brain association models, the global metric was also included as a covariate (eg, mean cortical thickness for regional thickness) (eMethods in Supplement 2). Although sociodemographic characteristics are associated with both neuroanatomical development and substance use outcomes,^{34,35,36,37,38,39} these variables were not included as covariates as they may plausibly influence observed associations in meaningful ways, in which case, exploring these as putative mechanisms contributing to associations (a research question beyond the scope of the current study) would be more appropriate than controlling for them.

Multiple testing corrections were applied first using Bonferroni correction to all tests conducted as part of the study to prioritize especially robust results (P = .05/1188 = 4.21 × 10⁻⁵). Additional 5% false discovery rate (FDR) corrections were applied across all tests examining associations between IDPs and any substance use initiation (primary analysis; k = 297 tests), and all secondary tests of associations between IDPs and alcohol, nicotine, and cannabis use initiation (k = 891 tests), to highlight results not surviving the more stringent Bonferroni correction (eMethods in Supplement 2).

Post Hoc Analyses

As prenatal substance exposure is associated with substance use initiation⁴⁰ and brain structure,^41,42 we conducted post hoc analyses of FDR-significant associations controlling for prenatal substance exposures (eMethods in Supplement 2). Additionally, as a large portion of participants initiated substance use before the baseline study session (2257 participants), we examined whether FDR-significant associations remained when restricting substance use initiation groups to only participants endorsing initiation following the baseline assessment (1203 participants for any substance; 933 participants for alcohol; 322 participants for nicotine; and 201 participants for cannabis) to test whether IDP correlates were present before initiation (eMethods in Supplement 2). Finally, both restriction of analytic samples to postbaseline substance use initiation and inclusion of prenatal exposure as a covariate were incorporated in post hoc tests to examine associations that might reflect predispositional variability independent of prenatal substance exposure. Data were analyzed from February to September 2024.

Results

Among our full analytic sample of 9804 participants (5160 boys [52.6%]; mean [SD] baseline age, 9.9 [0.6] years; 213 Asian [2.2%], 1474 Black [15.0%], 514 Hispanic/Latino [5.2%], 29 American Indian [0.3%], 10 Pacific Islander [0.1%], 7463 White [76.1%], and 75 reporting other or unknown race or declining to respond [0.7%]), 3460 ABCD participants initiated substance use before age 15 with 3123 (90.2%) of these reporting alcohol use initiation and considerable overlap among initiation of alcohol, nicotine, and cannabis use (Table, eResults, eFigure 2 in Supplement 2).

Eight IDPs were associated with any early substance use initiation after Bonferroni correction (eTables 3-4 in Supplement 1). Any substance use initiation was associated with larger global neuroanatomical indices (k = 5), including whole brain (β = 0.05; 95% CI, 0.03 to 0.06; P = 2.80 × 10⁻⁸), total intracranial (β = 0.04; 95% CI, 0.02 to 0.05; P = 3.49 × 10⁻⁶), cortical (β = 0.05; 95% CI, 0.03 to 0.07; P = 4.31 × 10⁻⁸), and subcortical volumes (β = 0.05; 95% CI, 0.03 to 0.07; P = 4.39 × 10⁻⁸), as well as greater total cortical surface area (β = 0.04; 95% CI, 0.03 to 0.06; P = 6.05 × 10⁻⁷) (Figure 1). Regionally (k = 3), thinner right rostral middle frontal gyrus (β = −0.03; 95% CI, −0.02 to −0.05; P = 6.99 × 10⁻⁶), thicker left lingual gyrus (β = 0.03; 95% CI, 0.02 to 0.05; P = 2.65 × 10⁻⁵), and larger right lateral occipital gyrus volume (β = 0.04; 95% CI, 0.02 to 0.05; P = 1.12 × 10⁻⁵) were associated with any substance use initiation (Figure 2A and Figure 3).⁴³ An additional 36 regional IDPs were also associated with any substance use initiation using FDR correction (Figure 2A, Figure 3; eFigure 3 in Supplement 2; eTable 3 in Supplement 1). Of all regional associations (ie, 3 Bonferroni-significant plus 36 FDR-significant associations; k = 39), the majority were with cortical thickness (22 of 39 [56.4%]). Notably, any substance use initiation was characterized by thinner cortex in all frontal regions (k = 9), but thicker cortex in all other lobes (occipital k = 6, parietal k = 1, and temporal k = 6). Any substance use initiation was also associated with larger regional brain volumes (subcortical k = 3, and cortical k = 7), deeper regional sulci (k = 3), and differences in regional cortical surface area (k = 4).

Figure 1. Global Brain Metric Associations With Early Substance Use Initiation in the Adolescent Brain Cognitive Development (ABCD) Study.

_{Standardized regression coefficients with 95% CIs for associations between global metrics and substance use initiation.}

Figure 2. Manhattan Plots of Regional Neuroanatomical Associations With Early Substance Use Initiation in the Adolescent Brain Cognitive Development (ABCD) Study.

_{This figure plots –log10-transformed false discovery rate (FDR)–corrected P values (PFDR) from mixed-effect regressions for all regional association analyses grouped within neuroanatomical metrics for each substance (ie, cortical and subcortical volume, thickness, surface area, and sulcal depth). P values are aggregated and color coded by cortical lobes and subcortical regions with darker colors reflecting left (L) hemisphere and lighter colors reflecting right (R) hemisphere for each region (eg, dark red indicates L frontal lobe and lighter red indicates R frontal lobe). Although often considered separate from frontal, parietal, and temporal lobes, and located at their junction, for simplicity the insular cortex is plotted here along with temporal regions. Dashed blue line reflects PFDR < .05. For any substance and alcohol use (A, B), labeled regions reflect associations that are Bonferroni-significant for all study comparisons (P < .05 / 1188=4.21 × 10−5). For nicotine and cannabis use (C, D), labeled regions reflect FDR-significant associations.}

Figure 3. Regional Cortical Volume and Thickness Associations With Early Substance Use Initiation in the Adolescent Brain Cognitive Development (ABCD) Study.

_{Cortical volume and thickness patterning of associations with any substance use initiation are plotted as t statistics (red indicates a positive association and blue indicates a negative association) according to the Desikan–Killiany cortical atlas.31 Regions with bold yellow outlines were Bonferroni-significant for all study comparisons, and those with bold black outlines exhibited false discovery rate (FDR)–significant associations (eTable 3 in Supplement 1). Regional brain plots were constructed using the ggseg package in R.43}

Secondary analyses compared the 3 most used substances (alcohol, nicotine, and cannabis) with no substance use. Unsurprisingly, given the preponderance of alcohol use initiation in this sample, alcohol findings largely recapitulated those observed for any substance use. Thirteen associations with alcohol use initiation remained significant after Bonferroni correction. In addition to identifying the same global and regional IDPs that were associated with any substance use initiation described previously (k = 8), the following additional IDPs (k = 5) were also significant after Bonferroni correction: greater left lateral occipital volume (β = 0.04; 95% CI, 0.02 to 0.05; P = 2.57 x 10⁻⁵) and bilateral parahippocampal gyri cortical thickness (right, β = 0.04; 95% CI, 0.02 to 0.06; P = 2.52 x 10⁻⁵; left, β = 0.04; 95% CI, 0.02 to 0.06; P = 3.25 x 10⁻⁵) and less bilateral superior frontal gyri cortical thickness (right, β = −0.03; 95% CI, −0.02 to −0.04; P = 2.34 x 10⁻⁵; left, β = −0.03; 95% CI, −0.01 to −0.04; P = 2.47 x 10⁻⁵) (Figure 2B, Figure 4; eTables 5-6 in Supplement 1). Following FDR correction, nicotine use was associated with lower right superior frontal gyrus volume (β = −0.03; 95% CI, −0.01 to −0.05; P = .002) and deeper left lateral orbitofrontal cortex sulci (β = 0.05; 95% CI, 0.02 to 0.07; P = 2.68 x 10⁻⁴), and cannabis use was associated with thinner left precentral gyrus (β = −0.03; 95% CI, −0.01 to −0.05; P = 3.26 x 10⁻⁴) and lower right inferior parietal gyrus (β = −0.03; 95% CI, −0.02 to −0.05; P = 4.13 x 10⁻⁴) and right caudate volumes (β = −0.03; 95% CI, −0.01 to −0.05; P = .002) (Figure 2C-D; eFigure 4 in Supplement 2; eTables 7-10 in Supplement 1). These associations were not robust to Bonferroni correction.

Figure 4. Regional Cortical Volume and Thickness Associations With Early Alcohol Use Initiation in the Adolescent Brain Cognitive Development (ABCD) Study.

_{Cortical volume and thickness patterning of associations with alcohol use initiation are plotted as t statistics (red indicates a positive association and blue indicates a negative association) according to the Desikan–Killiany cortical atlas.31 Regions with bold yellow outlines were Bonferroni-significant for all study comparisons, and those with bold black outlines exhibited false discovery rate (FDR)–significant associations (eTable 5 in Supplement 1). Regional brain plots were constructed using the ggseg package in R.43}

Results were largely consistent in models including a separate random effect of site (eTable 11 in Supplement 1). All FDR- and Bonferroni-significant associations remained significant when including prenatal exposure as a covariate in post hoc analyses (eTables 3, 5, 7, and 9 in Supplement 1). Most Bonferroni-significant associations (14 of 21 [66.7%]) remained significant when removing participants who endorsed substance initiation before the baseline neuroimaging session, as well as most global (eg, whole brain) and subcortical (eg, globus pallidus) volume associations and many cortical thickness findings (eg, right rostral middle frontal gyrus for alcohol) (eTables 3 and 5 in Supplement 1). All FDR-significant results for nicotine and cannabis use initiation remained significant when excluding participants endorsing baseline nicotine and cannabis use (eTables 7 and 9 in Supplement 1). eTable 12 in Supplement 1 summarizes all post hoc analyses. All effect sizes in the full sample were highly correlated with those from the sample that excluded baseline initiation (median [IQR] r, 0.79 [0.76-0.85]) (eResults, eFigure 5 in Supplement 2).

Discussion

Early substance use initiation is associated with escalating use, use of multiple substances, SUD development, and other adverse life outcomes (eg, lower educational attainment and elevated psychopathology).^44,45,46,47 We identified neuroanatomical features associated with early substance use initiation (ie, being aged <15 years), most of which are evident before any substance exposure. The direction of association between cortical thickness and substance use initiation was regionally specific; the cortical mantle was thinner in prefrontal regions, but thicker in temporal, occipital, and parietal regions among youths who initiated substance use. While age is associated with cortical thickness broadly across brain regions,⁴⁸ our data suggest that regionally specific differences, rather than global age-related trends, may confer vulnerability to substance use initiation. SUDs and in particular alcohol use disorder have been characterized by broad reductions in cortical thickness in multiple brain regions with largest effects found in the frontal cortex.^8,20 That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure^8,20,49 and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk.^15,26

This finding has important implications for brain-based theoretical models of addiction. The stage-based neurobiological model of addiction speculates that predominantly substance-induced variability in frontal regions contributes to later stages of addiction wherein compulsive use and craving develop following repeated drug pairings and related disruption of prefrontal afferent regulation of subcortical reward and stress-related circuitry.⁵⁰ Our findings suggest that structural differences in the prefrontal cortex may predispositionally contribute to initial stages of substance involvement. Neurodevelopmental theories postulate that typical asynchronous regional brain maturation (ie, rapid subcortical development and later prefrontal development) leaves adolescents vulnerable to substance involvement by promoting emotional saliency in the context of underdeveloped cognitive control.^51,52 Our findings of thinner frontal cortex alongside larger subcortical volumes at baseline (mean [SD] age, 9.9 [0.6] years) being associated with early substance use initiation are challenging to interpret with respect to these theories. Total cortical thickness peaks at age 1.7 years and steadily declines throughout life with limited evidence of regionally specific trajectories.⁵³ By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.⁵³ Our data cannot yet determine at what developmental point(s) substance-related variability in brain structure arose (eg, whether thinner prefrontal cortices are attributable to less thickness developing through infancy and/or arise from greater pruning in later childhood). Large-scale longitudinal studies (eg, the Healthy Brain and Child Development Study⁵⁴) tracking neurodevelopment and substance exposure or involvement from the neonatal period to young adulthood are necessary to address the origins of these differences.

Unlike negative associations between whole and regional brain volumes with adult substance use and SUDs,^8,55,56 and contrary to our hypotheses, we found that greater global and regional cortical volumes were associated with early substance use initiation; greater subcortical volumes and total surface area were as well. However, it is important to consider that, while related to subsequent stages of substance involvement, there are considerable phenotypic differences between initiation in youths and problematic use in adults that may be associated with brain feature dissimilarities. Such differences could plausibly reflect opposing effects of predisposition and exposure-related changes or differences in developmental trajectories. Associations observed in the current study may be capturing variability related to exploration and risk-taking that has variable impact on progression of use.⁵⁷ Notably, larger globus pallidus volume, here associated with substance use initiation and in other ABCD studies associated with sensation seeking,⁵⁸ has been linked to both occasional use and SUDs in adults,²⁰ highlighting a plausibly stable risk feature from precocious use and experimentation to later problematic use. Moreover, greater cortical surface area has been shown to be genetically correlated with alcohol use and sensation seeking in independent samples^25,59 and related to family history of substance problems in ABCD,⁶⁰ supporting the interpretation that greater surface area may reflect the influence of preexisting risk factors. Importantly, our findings are not incompatible with brain volume and/or surface area declines that may arise from substance exposure and/or differences in later brain development conferring risk for substance involvement progression.

Limitations

This study had limitations. First, while our study was sufficiently powered to detect expected small effects for any substance and alcohol use initiation,⁶¹ less frequently endorsed individual substances may not have had adequate power (ie, 80% power for |β| > 0.04 at P < .005 for nicotine and cannabis). Although small effects suggest that these findings are not clinically informative for an individual, they do inform and challenge current theoretical models of addiction. Currently, there is limited variability in substance use involvement within released ABCD Study data, which restricted our investigation to associations with substance use initiation. It is possible that later, more problematic substance involvement phenotypes or multivariate approaches (eg, whole brain network analysis⁶²) would yield larger effects. Such multivariate models could serve as omnibus tests to reduce multiple testing burden with subsequent post hoc univariate testing.

Second, while additional ABCD Study neuroimaging scans are available, relatively few substance-naive participants at baseline initiated before the next scan (417 participants), precluding well-powered models examining neuroanatomical changes associated with substance use initiation (ie, potential exposure effects). As this sample continues to age and substance involvement becomes more common and variable, evaluating cooccurring trajectories of substance involvement and neuroanatomy will be valuable. Although such investigations cannot determine whether changes in neural phenotypes reflect a consequence of substance exposure or developmental predisposition that cooccurs, genetically informed study designs may be leveraged to test the plausibility of both.^15,26

Third, most of the sample had complete data, missingness was not associated with primary outcomes, and we accounted for several known familial, pregnancy-related, and child-related confounding variables. However, unmeasured confounders and undetected systemic differences in missing data may have influenced associations. While sociodemographic, environmental, and genetic variables were not included as covariates, these are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them. Furthermore, given substantial heritability estimates of neuroanatomy⁶³ and evidence of family history of substance use problems as a risk factor for thinner frontal cortices,^24,64 genetically informed studies are needed to examine genetic influences on substance-related neuroanatomical variability and evaluate the plausibility of environmental causality, including through possible sociodemographic differences.

Conclusions

In this cohort study of 9804 children, we identified neuroanatomical features associated with substance use initiation that were present before substance exposure. Convergent with evidence from genetically informed (eg, discordant twin or sibling)^7,14,23 and other longitudinal research,^7,10,18 our data increasingly place interpretations that substance-related variability solely arises from substance exposure on a procrustean bed. Ultimately, a greater understanding of the links between brain structure and substance involvement may uncover predispositional risk factors that provide insight into the early causes of SUDs and clinically informative mechanisms through which myriad adverse health outcomes associated with substance involvement emerge.

Summary

The study investigated the relationship between brain structure and substance use initiation in children, utilizing data from the Adolescent Brain and Cognitive Development (ABCD) Study. Researchers examined whether baseline neuroanatomical variability predicted subsequent substance use initiation, controlling for various demographic and developmental factors. The analysis focused on identifying neuroanatomical correlates that may represent predispositional risk factors for substance involvement, independent of direct consequences of substance use.

Methods

The ABCD Study, a large-scale longitudinal study of child development, provided the data. The sample included over 11,000 children aged 8.9 to 11 years at baseline. Substance use initiation was assessed through annual in-person and mid-year phone interviews. Structural MRI data were processed using FreeSurfer, yielding numerous imaging-derived phenotypes (IDPs) for analysis. Statistical analysis involved linear mixed-effects regression, controlling for relevant covariates such as age, sex, and pubertal status. Multiple testing corrections were employed using both Bonferroni and false discovery rate (FDR) methods. Post hoc analyses addressed potential confounding variables like prenatal substance exposure and baseline substance use.

Results

Analyses revealed significant associations between several brain structural measures and substance use initiation. Larger global brain indices (e.g., whole brain volume, total cortical volume) were associated with any early substance use initiation. Regionally, thinner right rostral middle frontal gyrus and thicker left lingual gyrus were observed in those who initiated substance use. These associations largely persisted even after excluding individuals who reported substance use before baseline neuroimaging, suggesting a predispositional component. Specific substance analyses demonstrated similar patterns for alcohol use initiation, with additional associations found for nicotine and cannabis. Post hoc analyses controlling for prenatal substance exposure confirmed the majority of the findings.

Discussion

The findings challenge the prevailing view that neuroanatomical differences observed in substance users are solely attributable to the neurotoxic effects of substance use. The presence of structural brain differences before substance initiation indicates a potential predispositional role of brain structure in substance use initiation, which may need to be incorporated into neurobiological models of addiction. The study's limitations include potential power issues for less frequently used substances, and the inability to definitively disentangle predispositional factors from consequences of substance use based on the study design. Future research, such as genetically-informed studies, is recommended to fully clarify these complex relationships.

Conclusions

This study provides evidence that neuroanatomical features associated with substance use initiation are evident even before exposure, suggesting a possible predispositional risk. This has implications for understanding the etiology of substance use disorders and calls for further research to fully elucidate the complex interplay between brain development, genetics, environment, and substance use.

Summary

This study investigated the relationship between brain structure and the initiation of substance use in children participating in the Adolescent Brain and Cognitive Development (ABCD) Study. Researchers examined whether baseline neuroanatomical variations predicted substance use initiation within three years of the initial brain scans, both in the full sample and a subsample of substance-naive children. The goal was to determine if observed brain characteristics represented predispositional risk factors rather than solely consequences of substance use. Analyses focused on the three most common substances among early adolescents: alcohol, nicotine, and cannabis.

Methods

The ABCD Study, a longitudinal study of child development, provided the data. The sample included over 11,000 children aged 8.9 to 11 years at baseline. Substance use was assessed through annual in-person and mid-year phone interviews. Baseline structural MRI data, processed using FreeSurfer, yielded 297 imaging-derived phenotypes (IDPs) for analysis, including global and regional brain metrics. Statistical analysis involved linear mixed-effect regressions, controlling for relevant covariates such as age, sex, pubertal status, and familial relationships. Multiple testing corrections were applied using Bonferroni and false discovery rate (FDR) methods. Post-hoc analyses addressed potential confounding factors like prenatal substance exposure and pre-baseline substance use.

Results

Analyses revealed significant associations between various brain structures and any early substance use initiation. Larger global brain indices (whole brain, intracranial, cortical, and subcortical volumes, and cortical surface area) were associated with early substance initiation. Regionally, thinner right rostral middle frontal gyrus, thicker left lingual gyrus, and larger right lateral occipital gyrus were also associated with initiation. These associations largely persisted even after excluding participants who had already initiated substance use before the baseline scan, suggesting a predispositional element. Alcohol use initiation findings mirrored those for any substance use, with additional associations involving the parahippocampal and superior frontal gyri. Nicotine and cannabis use initiation showed fewer significant associations.

Discussion

The findings challenge the assumption that observed neuroanatomical differences are solely consequences of substance use. The presence of these brain structural differences before substance use initiation suggests they may represent predispositional risk factors. This has implications for existing models of addiction, implying a possible role for pre-existing brain structural variability in the initiation of substance use, in addition to the effects of substance exposure itself. The study's findings also challenge the asynchronous brain maturation model that suggests the relative immaturity of prefrontal regions in adolescence is a predispositional factor.

Limitations

The study acknowledged limitations including potentially insufficient power for analyses of less frequently used substances (nicotine and cannabis), limited variability in substance use in the available data, and the possibility of unmeasured confounders. The researchers also noted the need for future research employing genetically informed designs to clarify the interplay between genetics, environment, and neuroanatomical development in relation to substance use initiation.

Conclusions

This study provides evidence suggesting that neuroanatomical features may be predispositional risk factors for early substance use initiation, highlighting a more nuanced understanding of the complex relationship between brain structure, development and substance use. Further research, particularly longitudinal studies with genetically informed designs, is needed to fully elucidate these complex relationships and to identify potential targets for prevention and intervention strategies.

Summary

A study examined the relationship between brain structure and the initiation of substance use in children. Researchers looked at whether differences in brain anatomy before substance use predicted who would later start using substances. The study used data from the Adolescent Brain and Cognitive Development (ABCD) Study, a large, ongoing research project.

Methods

The ABCD Study included over 11,000 children aged 8.9 to 11 years. Researchers used data from brain scans (MRI) and interviews about substance use. They compared children who had started using substances (alcohol, nicotine, cannabis, or other drugs) by age 15 to those who hadn't. The analysis adjusted for factors like age, sex, and puberty stage to focus on the brain structure-substance use link.

Results

Several brain features were associated with early substance use initiation. Children who started using substances earlier had larger overall brain volumes and surface area. However, the thickness of their cortex (the brain's outer layer) was thinner in the prefrontal areas (related to decision-making and control) but thicker in other areas. These differences were seen before the children had started using substances, suggesting they could be risk factors. The patterns were similar for alcohol, nicotine, and cannabis.

Discussion

The findings challenge the idea that all brain differences seen in substance users are solely caused by drug use. It suggests some brain features might make some individuals more vulnerable to starting substance use early. The study's results have implications for understanding how addiction develops and potential risk factors. More research is needed to fully understand the timeline of brain changes and their connection to substance use.

Limitations

The study's limitations include the possibility of insufficient power to detect effects for less common substances, the limited variability in substance use in the ABCD data, and the potential for unmeasured factors influencing the results. More research, including genetically-informed studies, is needed to clarify these relationships.

Conclusions

This large study found that brain differences are present before children start using substances, potentially identifying predispositional risk factors for early substance use initiation. Further research is necessary to confirm these findings and explore the complex interplay between brain development, genetics, and the initiation of substance use.

Summary

Scientists studied kids to see if brain differences were linked to starting to use drugs or alcohol before age 15. They used brain scans and asked kids about their drug and alcohol use.

The Study

The study looked at many kids' brain scans. Some kids started using drugs or alcohol before their brain scans, and some did not. The scientists wanted to know if the kids' brains were different before they started using these things. They checked for differences in the size and shape of different brain parts.

What They Found

The scientists found that some brain differences were linked to whether a child started using drugs or alcohol. Kids who started using these substances earlier often had slightly bigger brains overall. Some parts of the brain were also a bit different. For example, some parts of the brain were thinner, while other parts were thicker. This was true even for kids who hadn't yet started using drugs or alcohol, suggesting these differences might make it more likely that a child will use drugs or alcohol in the future.

What it Means

This study shows that some kids' brains might be different in ways that could make them more likely to start using drugs or alcohol. More research is needed to understand exactly why these brain differences are there and how they are connected to drug and alcohol use.