A Scalable fMRI Estimate of Basal Ganglia Brain Tissue Iron for Use in Developmental and Translational Neuroscience

ABSTRACT Dopaminergic (DA) function and basal ganglia neurobiology are central to reward learning, motivation, and cognitive control, and dysregulation of these systems contributes to neuropsychiatric conditions that emerge during development. Adolescence is marked by profound reorganization of DAergic basal ganglia circuitry, yet direct in vivo assessment of the DA system remains limited in youth. Brain tissue iron is a developmentally sensitive marker of DA-related neurobiology that can be measured non-invasively via magnetic resonance imaging (MRI). Iron is an essential co-factor for DA synthesis and a foundational metabolic resource that supports cellular metabolism, myelination, and energetic demands of the basal ganglia. T2*-weighted echo-planar imaging (EPI), collected during functional MRI (fMRI), is sensitive to magnetic susceptibility of non-heme brain iron. Leveraging this property, we demonstrate the validity and broad applicability of an iron-sensitive metric that can be derived from conventional single-echo fMRI: ΔR2*. In a longitudinal developmental dataset (N = 151; age range 12–31), ΔR2* showed high reliability, strong longitudinal stability, and validity via robust convergence with established quantitative relaxometry-based iron measures (R2* and R2’). Critically, ΔR2* can be retrospectively estimated from extant fMRI data and derived in large-scale consortium data repositories, demonstrated here in the Adolescent Brain and Cognitive Development (ABCD) baseline cohort (N = 8,366; ages 9–11). We show that ΔR2* captures known age-related increases in basal ganglia iron, highlighting neurodevelopmental sensitivity at population-scale. Together, these findings establish ΔR2* as a reliable, widely accessible marker of basal ganglia iron, enabling scalable investigation of lifespan trajectories and neuropsychiatric risk in existing and future datasets. Competing Interest Statement The authors have declared no competing interest. Footnotes Funding: Collection and distribution of the ABCD data were supported by National Institutes of Health (NIH) funding U01DA041048; U01DA050989; U01DA051016; U01DA041022; U01DA051018; U01DA051037; U01DA050987; U01DA041174; U01DA041106; U01DA041117; U01DA041028; U01DA041134; U01DA050988; U01DA051039; U01DA041156; U01DA041025; U01DA041120; U01DA051038; U01DA041148; U01DA041093; U01DA041089; U24DA041123; U24DA041147 This work was supported by the National Institute of Mental Health (R00MH127293 for H.S.T, C.H., and B. Larsen; 5RO1MH080243-07 for A.C.P., F.J.C., A.O., and B. Luna), the National Institute on Drug Abuse (NIDA; K23DA057486 to B.T.C.), the Brain and Behavior Research Foundation (BBRF; to A.C.P. and B.T.C.), the Jacobs Foundation (B.T.C.), and the Staunton Farm Foundation (A.C.P., F.J.C., B.Luna). Declaration of Interests: The authors declare no competing interests.