Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.

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Magnetic resonance imaging (MRI) continues to drive many important neuroscientific advances. However, progress in uncovering reproducible associations between individual differences in brain structure/function and behavioral phenotypes (e.g., cognition, mental health) may have been undermined by typical neuroimaging sample sizes (median N=25)1,2. Leveraging the Adolescent Brain Cognitive Development (ABCD) Study3 (N=11,878), we estimated the effect sizes and reproducibility of these brain wide associations studies (BWAS) as a function of sample size. The very largest, replicable brain wide associations for univariate and multivariate methods were r=0.14 and r=0.34, respectively. In smaller samples, typical for brain wide association studies, irreproducible, inflated effect sizes were ubiquitous, no matter the method (univariate, multivariate). Until sample sizes started to approach consortium levels, BWAS were underpowered and statistical errors assured. Multiple factors contribute to replication failures4,5,6; here, we show that the pairing of small brain behavioral phenotype effect sizes with sampling variability is a key element in widespread BWAS replication failure. Brain behavioral phenotype associations stabilize and become more reproducible with sample sizes of N>2,000. While investigator initiated brain behavior research continues to generate hypotheses and propel innovation, large consortia are needed to usher in a new era of reproducible human brain wide association studies.

Background Connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) is compromised in multiple psychiatric disorders, many of which emerge during adolescence. To identify what extent the deviations in amygdala-vmPFC maturation contribute to the onset of psychiatric disorders, it is essential to characterize amygdala-vmPFC connectivity changes during typical development. Methods Using an accelerated cohort longitudinal design (1–3 time points, 10–25 years, N=246), we characterized developmental changes of amygdala-vmPFC subregion functional and structural connectivity using resting state fMRI and diffusion-weighted imaging. Results Functional connectivity between the centromedial amygdala and rostral anterior cingulate (rACC), anterior vmPFC, and subgenual cingulate significantly decreased from late childhood to early adulthood in males and females. Age associated decreases were also observed between the basolateral amygdala and rACC. Importantly, these findings were replicated in a separate cohort (10–22 years, N=327). Similarly, structural connectivity, as measured by quantitative anisotropy, significantly decreased with age in the same regions. Functional connectivity between the centromedial amygdala and rACC was associated with structural connectivity in these same regions during early adulthood (ages 22–25). Finally, a novel time-varying coefficient analysis showed that increased centromedial amygdala-rACC functional connectivity was associated with greater anxiety and depression symptoms during early adulthood, while increased structural connectivity in centromedial amygdala-anterior vmPFC white matter was associated with greater anxiety/depression during late childhood. Conclusions Specific developmental periods of functional and structural connectivity between amygdala-prefrontal systems may contribute to the emergence of anxiety and depressive symptoms, and may play a critical role in the emergence of psychiatric disorders in adolescence.

Adolescence marks a time of unique neurocognitive development, in which executive functions reach adult levels of maturation. While many core facets of executive function may reach maturation in childhood, these processes continue to be refined and stabilized during adolescence. We propose that this is mediated, in part, by interactions between the hippocampus and pre-frontal cortex. Specifically, we propose that development of this circuit refines adolescents’ ability to extract relevant information from prior experience to support task-relevant behavior. In support of this model, we review evidence for protracted structural and functional development both within and across the hippocampus and prefrontal cortex. We describe emerging research demonstrating the refinement of adolescents’ ability to integrate prior experiences to support goal-oriented behavior, which parallel hippocampal-prefrontal integration. Finally, we speculate that the development of this circuit is mediated by increases in dopaminergic neuromodulation present in adolescence, which may underlie memory processing, plasticity, and circuit integration. This model provides a novel characterization of how memory and executive systems integrate throughout adolescence to support adaptive behavior.