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.

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.

Gestational and postnatal age associations for striatal tissue iron deposition in early infancy.

Striatal development is crucial for later motor, cognitive, and reward behavior, but age-related change in striatal physiology during the neonatal period remains understudied. An MRI-based measure of tissue iron deposition, T2*, is a non-invasive way to probe striatal physiology neonatally, linked to dopaminergic processing and cognition in children and adults. Striatal subregions have distinct functions that may come online at different time periods in early life. To identify if there are critical periods before or after birth, we measured if striatal iron accrued with gestational age at birth [range= 34.57-41.85 weeks] or postnatal age at scan [range= 5-64 days], using MRI to probe the T2* signal in N = 83 neonates in three striatal subregions. We found iron increased with postnatal age in the pallidum and putamen but not the caudate. No significant relationship between iron and gestational age was observed. Using a subset of infants scanned at preschool age (N = 26), we show distributions of iron shift between time points. In infants, the pallidum had the least iron of the three regions but had the most by preschool age. Together, this provides evidence of distinct change for striatal subregions, a possible differentiation between motor and cognitive systems, identifying a mechanism that may impact future trajectories.

Striatal dopamine supports reward expectation and learning: A simultaneous PET/fMRI study.

Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing underlying reward learning behaviors, based on the computation of reward prediction errors. However, competing evidence supports human dopamine signaling in the basal ganglia as also contributing to the generation of higher order learning heuristics. Here, we present data from a large (N = 81, 18-30yo), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with [11C]Raclopride (RAC), assessing striatal dopamine (DA) D2/3 receptor binding, during performance of a probabilistic reward learning task. Both fMRI activation and PET DA measures showed ventral striatum involvement for signaling rewards. However, greater DA release was uniquely associated with learning strategies (i.e., learning rates) that were more task-optimal within the best fitting reinforcement learning model. This DA response was associated with BOLD activation of a network of regions including anterior cingulate cortex, medial prefrontal cortex, thalamus and posterior parietal cortex, primarily during expectation, rather than prediction error, task epochs. Together, these data provide novel, human in vivo evidence that striatal dopaminergic signaling interacts with a network of cortical regions to generate task-optimal learning strategies, rather than representing reward outcomes in isolation.

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.

Dorsolateral Prefrontal Cortex Glutamate/Gamma-Aminobutyric Acid (GABA) Alterations in Clinical High Risk and First-Episode Schizophrenia: A Preliminary 7-T Magnetic Resonance Spectroscopy Imaging Study.

Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the three groups. Furthermore, HC had higher Glu/GABA in rDLPFC compared to lDLPFC (R > L), whereas the opposite relationship (R < L) was observed in the DLPFC Glu/GABA of FES patients. Altogether, these findings indicate that GABA/Cre and Glu/GABA DLPFC alterations are present before illness manifestation and worsen in FES patients, thus representing a putative early pathophysiological biomarker for SCZ and related psychotic disorders.

Pubertal development underlies optimization of inhibitory control through specialization of ventrolateral prefrontal cortex.

Inhibitory control improves into young adulthood after specialization of relevant brain systems during adolescence. However, the biological mechanisms supporting this unique transition are not well understood. Given that adolescence is defined by puberty, we examined relative contributions of chronological age and pubertal maturation to inhibitory control development. 105 8-19-year-olds completed 1-5 longitudinal visits (227 visits total) in which pubertal development was assessed via self-reported Tanner stage and inhibitory control was assessed with an in-scanner antisaccade task. As expected, percentage and latency of correct antisaccade responses improved with age and pubertal stage. When controlling for pubertal stage, chronological age was distinctly associated with correct response rate. In contrast, pubertal stage was uniquely associated with antisaccade latency even when controlling for age. Chronological age was associated with fMRI task activation in several regions including the right dorsolateral prefrontal cortex, while puberty was associated with right ventrolateral prefrontal cortex (VLPFC) activation. Furthermore, task-related connectivity between VLPFC and cingulate was associated with both pubertal stage and response latency. These results suggest that while age-related developmental processes may support maturation of brain systems underlying the ability to inhibit a response, puberty may play a larger role in the effectiveness of generating cognitive control responses.

Development of frontal GABA and glutamate supports excitation/inhibition balance from adolescence into adulthood.

Animal and human postmortem studies provide evidence for changes in gamma-aminobutyric acid (GABA) and glutamate in prefrontal cortex (PFC) during adolescence, suggesting shifts in excitation and inhibition balance consistent with critical period plasticity. However, how GABA and glutamate change through adolescence and how the balance of these inhibitory and excitatory neurotransmitters changes is not well understood in vivo in humans. High field (7 Tesla) Magnetic Resonance Spectroscopic Imaging was used to investigate age-related changes in the balance of GABA/creatine (Cr) and glutamate/Cr in multiple developmentally-relevant regions of frontal cortex in 144 10-30-year-olds. Results indicated a homogenous pattern of age-related Glu/Cr decreases across regions, while age-related changes in GABA/Cr were heterogenous, with a mix of stable and decreasing age effects. Importantly, balance between glutamate/Cr and GABA/Cr in areas of frontal cortex increased through adolescence, suggesting the presence of critical period plasticity in frontal cortex at this significant time of development when adult trajectories are established.

A longitudinal investigation of GABA, glutamate, and glutamine across the insula during antipsychotic treatment of first-episode schizophrenia.

Individuals with first-episode schizophrenia (FES) typically present with acute psychotic symptoms. Though antipsychotic drugs are the mainstay for treatment, the neurobiology underlying successful treatment remains largely elusive. Recent evidence from functional connectivity studies highlights the insula as a key structure in the neural mechanism of response. However, molecular contributions to response across insular regions remain largely unknown. We used 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to measure glutamate (Glu), Glutamine (Gln), and GABA from anterior and posterior regions of the insula across antipsychotic treatment. A total of 36 participants were examined, including 15 individuals with FES and moderate to severe psychosis who were scanned at two time points, while starting and after 6 weeks of antipsychotic treatment. Symptoms were carefully monitored across the study period to characterize treatment response. GABA, Glu, and Gln levels were calculated relative to creatine in anterior and posterior insular regions, bilaterally. In relation to psychotic symptom reduction, we observed a significant increase in Glu across all insular regions with (p < 0.001), but no corresponding changes in Gln or GABA. In group analyses, the FES cohort showed lower levels of Glu (p < 0.001) and GABA (p = 0.02) at baseline. Finally, in exploratory analyses, treatment remitters demonstrated a normalization of lower insular Glu levels across treatment, unlike non-remitters. Overall, these findings contribute to our understating of molecular changes associated with antipsychotic response and demonstrate abnormalities specific to the insula in FES.

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.

Relationship between plasma clozapine/N-desmethylclozapine and changes in basal forebrain-dorsolateral prefrontal cortex coupling in treatment-resistant schizophrenia.

Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite, N-desmethylclozapine (NDMC), to an inverse relationship with cognition via putative action on the cholinergic system. However, neuroimaging correlates of CLZ/NDMC remain unknown. Here, we examined changes in basal forebrain functional connectivity with the dorsolateral prefrontal cortex, and secondly, cognition in relation to the CLZ/NDMC ratio. A cohort of nineteen chronically ill participants with treatment-resistant schizophrenia (TRS) undergoing 12 weeks of CLZ treatment were included. Measures of cognition and plasma CLZ/NDMC ratios were obtained in addition to resting-state functional neuroimaging scans, captured at baseline and after 12 weeks of CLZ treatment. We observed a significant correlation between basal forebrain-DLPFC connectivity and CLZ/NDMC ratios across CLZ treatment (p = 0.02). Consistent with previous findings, we also demonstrate a positive relationship between CLZ/NDMC ratio and working memory (p = 0.03). These findings may reflect the action of CLZ and NDMC on the muscarinic cholinergic system, highlighting a possible neural correlate of cognition across treatment.

An evolutionary gap in primate default mode network organization.

The human default mode network (DMN) is engaged at rest and in cognitive states such as self-directed thoughts. Interconnected homologous cortical areas in primates constitute a network considered as the equivalent. Here, based on a cross-species comparison of the DMN between humans and non-hominoid primates (macaques, marmosets, and mouse lemurs), we report major dissimilarities in connectivity profiles. Most importantly, the medial prefrontal cortex (mPFC) of non-hominoid primates is poorly engaged with the posterior cingulate cortex (PCC), though strong correlated activity between the human PCC and the mPFC is a key feature of the human DMN. Instead, a fronto-temporal resting-state network involving the mPFC was detected consistently across non-hominoid primate species. These common functional features shared between non-hominoid primates but not with humans suggest a substantial gap in the organization of the primate's DMN and its associated cognitive functions.

Stroke Risk Factors, Subtype, and Outcomes in a Multi-Ethnic Stroke Population.

Aim We aim to describe differences in stroke risk factors, subtypes and outcomes in a multi-ethnic Irish Stroke population. Gaining an insight into prevalent risk factors and subtypes in ethnic groups may help target prevention efforts. Methods We retrospectively identified patients originally not of Irish ethnicity (ONIE) admitted to the acute stroke unit between 2016 and 2018 through surname recognition (N=44). Country of origin was confirmed on chart review. The presumed native Irish (PNI) patients admitted over the same time frame were used as a comparison group (N=437). Data was collected on stroke subtype, comorbidities, outcomes and socioeconomic factors. Results Patients ONIE made up 9.1% of all stroke unit admissions. Male gender was more common accounting for 33 of 44 (75%) patients ONIE and 251 of 437 (57.4%) PNI (p = 0.02). Overall ONIE were younger than PNI patients (mean age 57.5 [SD 13.0] vs 69.6yr [SD 13.2], p <0.001). Patients ONIE also recorded higher rates of intracranial haemorrhage(ICH) (N = 15 [34.1%] vs N=51 [11.7%], p <0.01). Conclusion Our study demonstrates that stroke patients ONIE have a different stroke subtype and demographic profile compared to Irish patients. Patients ONIE are more likely to be young, male with higher rates of ICH.

Reproducible brain-wide association studies require thousands of individuals.

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.

Context-specific abnormalities of the central executive network in first-episode psychosis: relationship with cognition.

BACKGROUND: Cognitive impairments, which contribute to the profound functional deficits observed in psychotic disorders, have found to be associated with abnormalities in trial-level cognitive control. However, neural tasks operate within the context of sustained cognitive states, which can be assessed with 'background connectivity' following the removal of task effects. To date, little is known about the integrity of brain processes supporting the maintenance of a cognitive state in individuals with psychotic disorders. Thus, here we examine background connectivity during executive processing in a cohort of participants with first-episode psychosis (FEP). METHODS: The following fMRI study examined background connectivity of the dorsolateral prefrontal cortex (DLPFC), during working memory engagement in a group of 43 patients with FEP, relative to 35 healthy controls (HC). Findings were also examined in relation to measures of executive function. RESULTS: The FEP group relative to HC showed significantly lower background DLPFC connectivity with bilateral superior parietal lobule (SPL) and left inferior parietal lobule. Background connectivity between DLPFC and SPL was also positively associated with overall cognition across all subjects and in our FEP group. In comparison, resting-state frontoparietal connectivity did not differ between groups and was not significantly associated with overall cognition, suggesting that psychosis-related alterations in executive networks only emerged during states of goal-oriented behavior. CONCLUSIONS: These results provide novel evidence indicating while frontoparietal connectivity at rest appears intact in psychosis, when engaged during a cognitive state, it is impaired possibly undermining cognitive control capacities in FEP.

Hippocampal-Prefrontal Connectivity Prior to the COVID-19 Pandemic Predicts Stress Reactivity.

BACKGROUND: By adolescence, foundational cognitive and affective neurobehavioral processes specialize based on environmental demands, such as stress, to determine the basis of adult trajectories. The ongoing COVID-19 pandemic has increased stress for everyone, particularly adolescents who face unique stressors such as restrictions in socialization and education. However, variability in brain processes supporting stress reactivity is not well understood. Here, we leverage pre-pandemic brain development studies to identify how maturity of prefrontal connectivity with the amygdala and hippocampus (HPC) is associated with response to COVID-19. We hypothesized that age-related changes in connectivity of affective and cognitive brain systems may underlie the emotional response of adolescents during the pandemic. METHODS: In this study, 10- to 31-year-old participants (n = 111) completed resting-state functional magnetic resonance imaging scans prior to the pandemic and then completed a questionnaire 9 months into the pandemic measuring worry, COVID-related stress, sadness, perceived stress, and positive affect. Associations between pairwise functional connectivity of HPC/amygdala subregions with prefrontal cortex subdivisions and affective reactivity during the pandemic were examined. RESULTS: Regression analyses indicated that both worry and COVID-19-related stress increased with age (false discovery rate-corrected p < .05). Furthermore, greater connectivity between the anterior ventromedial prefrontal cortex and posterior HPC was associated with greater worry and COVID-19-related stress (p < .05 corrected), which was primarily driven by individuals younger than 18 years. CONCLUSIONS: Taken together, our results indicate that increases in stress reactivity to the COVID-19 pandemic across the transition to adulthood are driven by maturation of posterior HPC-ventromedial prefrontal cortex coupling, which integrates stress response and emotional memory processing.

Auditory cues facilitate object movement processing in human extrastriate visual cortex during simulated self-motion: A pilot study.

Visual segregation of moving objects is a considerable computational challenge when the observer moves through space. Recent psychophysical studies suggest that directionally congruent, moving auditory cues can substantially improve parsing object motion in such settings, but the exact brain mechanisms and visual processing stages that mediate these effects are still incompletely known. Here, we utilized multivariate pattern analyses (MVPA) of MRI-informed magnetoencephalography (MEG) source estimates to examine how crossmodal auditory cues facilitate motion detection during the observer's self-motion. During MEG recordings, participants identified a target object that moved either forward or backward within a visual scene that included nine identically textured objects simulating forward observer translation. Auditory motion cues 1) improved the behavioral accuracy of target localization, 2) significantly modulated the MEG source activity in the areas V2 and human middle temporal complex (hMT+), and 3) increased the accuracy at which the target movement direction could be decoded from hMT+ activity using MVPA. The increase of decoding accuracy by auditory cues in hMT+ was significant also when superior temporal activations in or near auditory cortices were regressed out from the hMT+ source activity to control for source estimation biases caused by point spread. Taken together, these results suggest that parsing object motion from self-motion-induced optic flow in the human extrastriate visual cortex can be facilitated by crossmodal influences from auditory system.