Adolescent-to-adult gains in cognitive flexibility are adaptively supported by reward sensitivity, exploration, and neural variability.

Cognitive flexibility exhibits dynamic changes throughout development, with different forms of flexibility showing dissociable developmental trajectories. In this review, we propose that an adolescent-specific mode of flexibility in the face of changing environmental contingencies supports the emergence of adolescent-to-adult gains in cognitive shifting efficiency. We first describe how cognitive shifting abilities monotonically improve from childhood to adulthood, accompanied by increases in brain state flexibility, neural variability, and excitatory/inhibitory balance. We next summarize evidence supporting the existence of a dopamine-driven, adolescent peak in flexible behavior that results in reward seeking, undirected exploration, and environmental sampling. We propose a neurodevelopmental framework that relates these adolescent behaviors to the refinement of neural phenotypes relevant to mature cognitive flexibility, and thus highlight the importance of the adolescent period in fostering healthy neurocognitive trajectories.

Aperiodic EEG and 7T MRSI evidence for maturation of E/I balance supporting the development of working memory through adolescence.

Adolescence has been hypothesized to be a critical period for the development of human association cortex and higher-order cognition. A defining feature of critical period development is a shift in the excitation: inhibition (E/I) balance of neural circuitry, however how changes in E/I may enhance cortical circuit function to support maturational improvements in cognitive capacities is not known. Harnessing ultra-high field 7 T MR spectroscopy and EEG in a large, longitudinal cohort of youth (N = 164, ages 10-32 years old, 347 neuroimaging sessions), we delineate biologically specific associations between age-related changes in excitatory glutamate and inhibitory GABA neurotransmitters and EEG-derived measures of aperiodic neural activity reflective of E/I balance in prefrontal association cortex. Specifically, we find that developmental increases in E/I balance reflected in glutamate:GABA balance are linked to changes in E/I balance assessed by the suppression of prefrontal aperiodic activity, which in turn facilitates robust improvements in working memory. These findings indicate a role for E/I-engendered changes in prefrontal signaling mechanisms in the maturation of cognitive maintenance. More broadly, this multi-modal imaging study provides evidence that human association cortex undergoes physiological changes consistent with critical period plasticity during adolescence.

Adolescent neurocognitive development and decision-making abilities regarding gender-affirming care.

Recently, politicians and legislative bodies have cited neurodevelopmental literature to argue that brain immaturity undermines decision-making regarding gender-affirming care (GAC) in youth. Here, we review this literature as it applies to adolescents' ability to make decisions regarding GAC. The research shows that while adolescence is a time of peak risk-taking behavior that may lead to impulsive decisions, neurocognitive systems supporting adult-level decisions are available given deliberative processes that minimize influence of short-term rewards and peers. Since GAC decisions occur over an extended period and with support from adult caregivers and clinicians, adolescents can engage adult-level decision-making in this context. We also weigh the benefits of providing GAC access during adolescence and consider the significant costs of blocking or delaying GAC. Transgender and non-binary (TNB) adolescents face significant mental health challenges, many of which are mitigated by GAC access. Further, initiating the GAC process during adolescence, which we define as beginning at pubertal onset, leads to better long-term mental health outcomes than waiting until adulthood. Taken together, existing research indicates that many adolescents can make informed decisions regarding gender-affirming care, and that this care is critical for the well-being of TNB youth. We highlight relevant considerations for policy makers, researchers, and clinicians.

Differential Item Functioning in Reports of Delinquent Behavior Between Black and White Youth: Evidence of Measurement Bias in Self-Reports of Arrest in the Adolescent Brain Cognitive Development Study.

Youth self-reports are a mainstay of delinquency assessment; however, making valid inferences about delinquency using these assessments requires equivalent measurement across groups of theoretical interest. We examined whether a brief 10-item delinquency measure exhibited measurement invariance across non-Hispanic White (n = 6,064) and Black (n = 1,666) youth (ages 10-11 years old) in the Adolescent Brain Cognitive Developmentsm Study (ABCD Study®). We detected differential item functioning (DIF) in two items. Black youth were more likely to report being arrested or picked up by police than White youth with the same score on the latent delinquency trait. Although multiple covariates (income, urgency, and callous-unemotional traits) reduced mean-level difference in overall delinquency, they were generally unrelated to the DIF in the Arrest item. However, the DIF in the Arrest item was reduced in size and no longer significant after adjusting for neighborhood safety. Results illustrate the importance of considering measurement invariance when using self-reported delinquency scores to draw inferences about group differences, and the utility of measurement invariance analyses for helping to identify mechanisms that contribute to group differences generally.

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.

A canonical trajectory of executive function maturation from adolescence to adulthood.

Theories of human neurobehavioral development suggest executive functions mature from childhood through adolescence, underlying adolescent risk-taking and the emergence of psychopathology. Investigations with relatively small datasets or narrow subsets of measures have identified general executive function development, but the specific maturational timing and independence of potential executive function subcomponents remain unknown. Integrating four independent datasets (N = 10,766; 8-35 years old) with twenty-three measures from seventeen tasks, we provide a precise charting, multi-assessment investigation, and replication of executive function development from adolescence to adulthood. Across assessments and datasets, executive functions follow a canonical non-linear trajectory, with rapid and statistically significant development in late childhood to mid-adolescence (10-15 years old), before stabilizing to adult-levels in late adolescence (18-20 years old). Age effects are well captured by domain-general processes that generate reproducible developmental templates across assessments and datasets. Results provide a canonical trajectory of executive function maturation that demarcates the boundaries of adolescence and can be integrated into future studies.

Motor synchronization and impulsivity in pediatric borderline personality disorder with and without attention-deficit hyperactivity disorder: an eye-tracking study of saccade, blink and pupil behavior.

Shifting motor actions from reflexively reacting to an environmental stimulus to predicting it allows for smooth synchronization of behavior with the outside world. This shift relies on the identification of patterns within the stimulus - knowing when a stimulus is predictable and when it is not - and launching motor actions accordingly. Failure to identify predictable stimuli results in movement delays whereas failure to recognize unpredictable stimuli results in early movements with incomplete information that can result in errors. Here we used a metronome task, combined with video-based eye-tracking, to quantify temporal predictive learning and performance to regularly paced visual targets at 5 different interstimulus intervals (ISIs). We compared these results to the random task where the timing of the target was randomized at each target step. We completed these tasks in female pediatric psychiatry patients (age range: 11-18 years) with borderline personality disorder (BPD) symptoms, with (n = 22) and without (n = 23) a comorbid attention-deficit hyperactivity disorder (ADHD) diagnosis, against controls (n = 35). Compared to controls, BPD and ADHD/BPD cohorts showed no differences in their predictive saccade performance to metronome targets, however, when targets were random ADHD/BPD participants made significantly more anticipatory saccades (i.e., guesses of target arrival). The ADHD/BPD group also significantly increased their blink rate and pupil size when initiating movements to predictable versus unpredictable targets, likely a reflection of increased neural effort for motor synchronization. BPD and ADHD/BPD groups showed increased sympathetic tone evidenced by larger pupil sizes than controls. Together, these results support normal temporal motor prediction in BPD with and without ADHD, reduced response inhibition in BPD with comorbid ADHD, and increased pupil sizes in BPD patients. Further these results emphasize the importance of controlling for comorbid ADHD when querying BPD pathology.

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.

Age-related differences in transient gamma band activity during working memory maintenance through adolescence.

Adolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65 Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, the developmental decrease during the delay period was more dramatic, resulting in an increase in event spiking from fixation to delay in adolescence but not adulthood. While average power of the transient gamma events was found to mediate age-related differences in total gamma power in the fixation and delay periods, the number of gamma events was related to total power in only the delay period, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.

Puberty contributes to adolescent development of fronto-striatal functional connectivity supporting inhibitory control.

Adolescence is defined by puberty and represents a period characterized by neural circuitry maturation (e.g., fronto-striatal systems) facilitating cognitive improvements. Though studies have characterized age-related changes, the extent to which puberty influences maturation of fronto-striatal networks is less known. Here, we combine two longitudinal datasets to characterize the role of puberty in the development of fronto-striatal resting-state functional connectivity (rsFC) and its relationship to inhibitory control in 106 10-18-year-olds. Beyond age effects, we found that puberty was related to decreases in rsFC between the caudate and the anterior vmPFC, rostral and ventral ACC, and v/dlPFC, as well as with rsFC increases between the dlPFC and nucleus accumbens (NAcc) across males and females. Stronger caudate rsFC with the dlPFC and vlPFC during early puberty was associated with worse inhibitory control and slower correct responses, respectively, whereas by late puberty, stronger vlPFC rsFC with the dorsal striatum was associated with faster correct responses. Taken together, our findings suggest that certain fronto-striatal connections are associated with pubertal maturation beyond age effects, which, in turn are related to inhibitory control. We discuss implications of puberty-related fronto-striatal maturation to further our understanding of pubertal effects related to adolescent cognitive and affective neurodevelopment.

Genetic variation in the dopamine system is associated with mixed-strategy decision-making in patients with Parkinson's disease.

Decision-making during mixed-strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed-strategy decision-making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty-six PD patients (ages 49-85, Hoehn and Yahr Stages 1-3) and 22 healthy controls (ages 54-75) competed in a mixed-strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed-strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within-subject, multi-centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val158 Met), rs6277 (C957T) and rs907094 (encoding DARPP-32). PD and control participants displayed comparable mixed-strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow-up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD.

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.

Contributions of dopamine-related basal ganglia neurophysiology to the developmental effects of incentives on inhibitory control.

Inhibitory control can be less reliable in adolescence, however, in the presence of rewards, adolescents' performance often improves to adult levels. Dopamine is known to play a role in signaling rewards and supporting cognition, but its role in the enhancing effects of reward on adolescent cognition and inhibitory control remains unknown. Here, we assessed the contribution of basal ganglia dopamine-related neurophysiology using longitudinal MR-based assessments of tissue iron in rewarded inhibitory control, using an antisaccade task. In line with prior work, we show that neutral performance improves with age, and incentives enhance performance in adolescents to that of adults. We find that basal ganglia tissue iron is associated with individual differences in the magnitude of this reward boost, which is strongest in those with high levels of tissue iron, predominantly in adolescence. Our results provide novel evidence that basal ganglia neurophysiology supports developmental effects of rewards on cognition, which can inform neurodevelopmental models of the role of dopamine in reward processing during adolescence.

Dopamine-related striatal neurophysiology is associated with specialization of frontostriatal reward circuitry through adolescence.

Characterizing developmental changes in frontostriatal circuitry is critical to understanding adolescent development and can clarify neurobiological mechanisms underlying increased reward sensitivity and risk-taking and the emergence of psychopathology during this period. However, the role of striatal neurobiology in the development of frontostriatal circuitry through human adolescence remains largely unknown. We examined background connectivity during a reward-guided decision-making task ("reward-state"), in addition to resting-state, and assessed the association between age-related changes in frontostriatal connectivity and age-related changes in reward learning and risk-taking through adolescence. Further, we examined the contribution of dopaminergic processes to changes in frontostriatal circuitry and decision-making using MR-based assessments of striatal tissue-iron as a correlate of dopamine-related neurobiology. Connectivity between the nucleus accumbens (NAcc) and ventral anterior cingulate, subgenual cingulate, and orbitofrontal cortices decreased through adolescence into adulthood, and decreases in reward-state connectivity were associated with improvements reward-guided decision-making as well as with decreases in risk-taking. Finally, NAcc tissue-iron mediated age-related changes and was associated with variability in connectivity, and developmental increases in NAcc R2' corresponded with developmental decreases in connectivity. Our results provide evidence that dopamine-related striatal properties contribute to the specialization of frontostriatal circuitry, potentially underlying changes in risk-taking and reward sensitivity into adulthood.

Impulsivity and Emotional Dysregulation Predict Choice Behavior During a Mixed-Strategy Game in Adolescents With Borderline Personality Disorder.

Impulsivity and emotional dysregulation are two core features of borderline personality disorder (BPD), and the neural mechanisms recruited during mixed-strategy interactions overlap with frontolimbic networks that have been implicated in BPD. We investigated strategic choice patterns during the classic two-player game, Matching Pennies, where the most efficient strategy is to choose each option randomly from trial-to-trial to avoid exploitation by one's opponent. Twenty-seven female adolescents with BPD (mean age: 16 years) and twenty-seven age-matched female controls (mean age: 16 years) participated in an experiment that explored the relationship between strategic choice behavior and impulsivity in both groups and emotional dysregulation in BPD. Relative to controls, BPD participants showed marginally fewer reinforcement learning biases, particularly decreased lose-shift biases, increased variability in reaction times (coefficient of variation; CV), and a greater percentage of anticipatory decisions. A subset of BPD participants with high levels of impulsivity showed higher overall reward rates, and greater modulation of reaction times by outcome, particularly following loss trials, relative to control and BPD participants with lower levels of impulsivity. Additionally, BPD participants with higher levels of emotional dysregulation showed marginally increased reward rate and increased entropy in choice patterns. Together, our preliminary results suggest that impulsivity and emotional dysregulation may contribute to variability in mixed-strategy decision-making in female adolescents with BPD.

A novel fMRI paradigm to dissociate the behavioral and neural components of mixed-strategy decision making from non-strategic decisions in humans.

During competitive interactions, such as predator-prey or team sports, the outcome of one's actions is dependent on both their own choices and those of their opponents. Success in these rivalries requires that individuals choose dynamically and unpredictably, often adopting a mixed strategy. Understanding the neural basis of strategic decision making is complicated by the fact that it recruits various cognitive processes that are often shared with non-strategic forms of decision making, such as value estimation, working memory, response inhibition, response selection, and reward processes. Although researchers have explored neural activity within key brain regions during mixed-strategy games, how brain activity differs in the context of strategic interactions versus non-strategic choices is not well understood. We developed a novel behavioral paradigm to dissociate choice behavior during mixed-strategy interactions from non-strategic choices, and we used task-based functional magnetic resonance imaging (fMRI) to contrast brain activation. In a block design, participants competed in the classic mixed-strategy game, "matching pennies," against a dynamic computer opponent designed to exploit predictability in players' response patterns. Results were contrasted with a non-strategic task that had comparable sensory input, motor output, and reward rate; thus, differences in behavior and brain activation reflect strategic processes. The mixed-strategy game was associated with activation of a distributed cortico-striatal network compared to the non-strategic task. We propose that choosing in mixed-strategy contexts requires additional cognitive demands present to a lesser degree during the control task, illustrating the strength of this design in probing function of cognitive systems beyond core sensory, motor, and reward processes.