Multivariate and regional age-related change in basal ganglia iron in neonates.

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in resting-state functional magnetic resonance imaging (rsfMRI), associated with dopaminergic processing. We used data from the Developing Human Connectome Project (n = 464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [range: 24.29-42.29] but found positive associations with postnatal age [range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA < 35 wk) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

Brain tissue iron neurophysiology and its relationship with the cognitive effects of dopaminergic modulation in children with and without ADHD.

Children with attention-deficit/hyperactivity disorder (ADHD) exhibit impairments in response inhibition. These impairments are ameliorated by modulating dopamine (DA) via the administration of rewards or stimulant medication like methylphenidate (MPH). It is currently unclear whether intrinsic DA availability impacts these effects of dopaminergic modulation on response inhibition. Thus, we estimated intrinsic DA availability using magnetic resonance-based assessments of basal ganglia and thalamic tissue iron in 36 medication-naïve children with ADHD and 29 typically developing (TD) children (8-12 y) who underwent fMRI scans and completed standard and rewarded go/no-go tasks. Children with ADHD additionally participated in a double-blind, randomized, placebo-controlled, crossover MPH challenge. Using linear regressions covarying for age and sex, we determined there were no group differences in brain tissue iron. We additionally found that higher putamen tissue iron was associated with worse response inhibition performance in all participants. Crucially, we observed that higher putamen and caudate tissue iron was associated with greater responsivity to MPH, as measured by improved task performance, in participants with ADHD. These results begin to clarify the role of subcortical brain tissue iron, a measure associated with intrinsic DA availability, in the cognitive effects of reward- and MPH-related dopaminergic modulation in children with ADHD and TD children.

Subcortical brain iron deposition in individuals with schizophrenia.

Subcortical structures play a critical role the pathophysiology and treatment of schizophrenia (SZ), yet underlying neurophysiological processes, in vivo, remain largely unexplored. Brain tissue iron, which can be measured with magnetic resonance-based methods, is a crucial component of a variety of neuronal functions including neurotransmitter synthesis. Here we used a proxy measure of tissue iron to examine basal ganglia and thalamic structures in an adult cohort of individuals with chronic SZ. A publicly available dataset of 72 individuals with SZ between ages 18 and 65, and a matched sample of 74 healthy control (HC) participants were included. A novel method that calculated the inverse-normalized T2*-weighted contrast (1/nT2*) was used to estimate brain iron within the basal ganglia and thalamus. Between group, age- and sex-related differences in 1/nT2* were examined, in addition to correlations with measures of psychopathology and cognition. Individuals with SZ showed greater 1/nT2* (iron index) compared to HCs in the thalamus (p < 0.01, FWE corrected). Age-related 1/nT2* accumulation was noted in regions of the basal ganglia, coinciding with prior work, and prominent sex-differences were noted in the caudate and thalamus (p < 0.01, FWE corrected). No significant relationship was observed between 1/nT2* and measures of neurocognition or psychopathology. Overall, our findings characterize a non-invasive proxy measure of tissue iron in SZ and highlight thalamic iron accumulation as a potential marker of illness.

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment­resistant schizophrenia.

RATIONALE: Though numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ's efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ's unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning. OBJECTIVE: In a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2'), which demonstrates utility as a proxy measure for elements of DA functioning. METHODS: Participants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2' in relation to CLZ response (% reduction of psychotic symptoms). RESULTS: We first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2' across CLZ treatment. CONCLUSION: Overall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment.