Finnegan J. Calabro

Adolescence is a critical period of development marked by improvements in cognitive control driven by maturation of executive brain systems. Neural mechanisms supporting inhibitory control—the ability to suppress a prepotent response in favor of generating a goal-directed response—mature into adulthood in parallel with refinements in frequency-specific neural oscillations and broadband spontaneous activity, supporting more accurate and reliable performance on response inhibition tasks, such as the antisaccade oculomotor task. Prior work has established that the maturation of neural circuitry contributes to age-related decreases in spontaneous activity, supporting higher-fidelity transmission of task-relevant activity, such as frequency-specific neural oscillations, which are crucial for antisaccade performance. Using longitudinal electroencephalography (EEG) data from 146 participants (72 F, ages 10-34, 253 total sessions) collected while participants performed an antisaccade task, we sought to understand the interplay between frontal oscillatory and spontaneous activity during cognitive processing and how it supports developmental improvements in inhibitory control. We found that spontaneous activity decreased developmentally during the preparation of an inhibitory response, and that this was associated with reduced trial-to-trial variability in response latency, indicating that reductions in spontaneous activity may increase the reliability of inhibitory control processing. Furthermore, performance-related decreases in broadband spontaneous activity were associated with the suppression of preparatory high-beta oscillations in an age-dependent manner, such that this relationship became more pronounced through development. Together, these results illustrate how developmental enhancements in the coordination of frequency-specific oscillations and spontaneous activity during inhibitory response preparation support developmental improvements in inhibitory control, providing a potential mechanism through which inhibitory control becomes more accurate and reliable from adolescence into adulthood.

Background: Adolescence is marked by improvements in inhibitory control along with brain maturational processes affecting function and structure of cortical circuitry. Preliminary evidence shows a developmental decrease of local neuronal inputs, suggesting a weakening of local connectivity supporting circuit refinement and mature behavior. Microstructural changes in gray matter, arising from processes such as synaptic pruning and myelination, may support this refinement, though it remains unknown how microstructural features interact with the reconfiguration of functional circuitry, or how this unfolds in vivo in normative development to support mature cognitive functioning. Methods: In this study, 175 participants ages 10-26 (93F; 17.32±4.82yo) completed an anti-saccade task, a developmentally-validated measure of inhibitory control, as well as a 3T MRI scan involving a multi-shell diffusion weighted imaging acquisition, multi-echo resting state fMRI, and structural (T1w, T2w) scans. We computed measures of neurite density (NDI) in gray matter using neurite orientation dispersion and density imaging, local functional connectivity with surface-based and volumetric regional homogeneity (ReHo), and intracortical myelin using T1w/T2w ratio. Generalized additive models examined non-linear age-related trends across a number of cortical and subcortical regions implicated in inhibitory control, as well as associations with anti-saccade performance. Results: We found that NDI significantly increased with age in all regions while ReHo decreased. Greater NDI was associated with more accurate anti-saccade performance and lower ReHo, which remained after residualizing NDI for T1w/T2w ratio, suggesting that microstructural reorganization beyond myelination may underlie functional specialization throughout adolescence. Lower ReHo, specifically in young adolescents, also resulted in better anti-saccade performance. Finally, an interaction between ReHo and NDI, rather than either measure alone, best predicted inhibitory control performance, such that the maturity of neurite density had the greatest effect when local connectivity was high, suggesting immaturity. Conclusions: Our results suggest that the joint maturation of microstructural elements and associated specialization of local functional circuitry interact to support the emergence of stable adult-level inhibitory control.

Despite growing evidence from magnetic resonance spectroscopy studies of glutamatergic and GABAergic abnormalities in schizophrenia, in vivo characterization of subcortical neurometabolites at ultra-high field and their longitudinal change across antipsychotic treatment remains limited. Ultra-high-field 7-Tesla (7 T) magnetic resonance spectroscopic imaging (MRSI) enables simultaneous multivoxel quantification of neurometabolites across subcortical regions implicated in schizophrenia, including the thalamus and dorsal caudate. Here, we leveraged 7 T MRSI to characterize subcortical neurometabolite profiles in 91 healthy individuals and 29 individuals with early-phase schizophrenia spectrum disorders (SSD) scanned while presenting with moderate to severe psychosis and following eight weeks of antipsychotic treatment. Primary analyses revealed lateralized alterations in glutamate (Glu) and GABA. In the caudate, Glu and Glx were elevated in the right hemisphere, while GABA was elevated on the right and reduced on the left, a dissociation observed in both the caudate and thalamus. Left thalamic Glx was also elevated, and Glu–GABA coupling was disrupted in the right thalamus. In secondary analyses, thalamic NAAG was markedly reduced in the left hemisphere, with elevation observed in the right thalamus, in addition to left-lateralized thalamic and caudate NAA reduction and elevated caudate GPC.Cho. In exploratory treatment-response analyses, non-remitters showed lower left thalamic and caudate NAA and GABA at baseline, with thalamic Glu declining below healthy control levels at follow-up only in non-remitters. Right thalamic NAAG elevation was restricted to the longer illness group. Collectively, these findings implicate an asymmetric disruption of astroglial–neuronal balance within subcortical regions in early-phase SSD, and across antipsychotic treatment.

Adolescent brain maturation involves structural changes effecting a shift in excitation/inhibition (E/I) balance, yet the functional implications of these changes remain unclear. One implication is a shift with respect to criticality. Adult brains, at rest, operate near a critical phase transition – at the boundary between an active, excitation-dominant phase, and an absorbing, inhibition-dominant phase. Special properties emerge when neural systems are balanced at criticality, including maximal susceptibility to perturbation, dynamic range, and information transmission. Thus, a clear picture of how adolescent brain maturation affects E/I balance and criticality is needed to understand how maturational processes shape cognition. Here, we leverage the dynamical properties of longitudinally-collected resting-state EEG recordings during N = 310 sessions from 169 healthy human participants ranging in age from 10 to 33 years old to quantify E/I and proximity to criticality. We find that adult brains operate closer to criticality, including spectrally-widespread increases in long-range temporal correlations and amplitude bistability. We also find band-specific changes in excitation versus inhibition whereby the mechanisms driving low-frequency (θ to α) oscillations shift towards lower E/I–possibly because of increasing inhibition–while the mechanisms driving high-frequency (γ) oscillations shift towards higher E/I, possibly because of decreasing inhibition. Opening eyes shifts brains towards lower E/I, and these state-dependent shifts are larger in adults. We simulate developmental effects with a neural mass model of coupled excitatory and inhibitory neurons providing a parsimonious account of how changes in brain dynamics could arise as a function of changes in local connectivity of excitatory and inhibitory neurons. Results indicate developmental movement towards criticality, and greater adaptability to state-specific demands, through adolescence to adulthood, reflecting changes in E/I balance with implications for cognitive development.

Anhedonia emerges in adolescence, has putative substrates in neural reward and dopamine systems, and is a hallmark of poor course in depression. Psychoneuroimmunology models suggest altered immune and reward systems may jointly underlie its development. When dopamine availability (rather than function) is considered, immune activation may be understood as a moderator amplifying how lower dopamine levels translate into motivational deficits. This cross-sectional study analyzed data from 55 youth with current depression (Mage=21.4 years; Female=75%). Plasma was assayed for relative quantification of 92 immune proteins, followed by dimensionality reduction via principal component (PC) analysis, forming five PC scores. Dopamine availability was indexed by basal ganglia tissue iron, quantified by MRI R2', a measure detectable in youth. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS), thought to capture overall anhedonia, and Positive Valence Systems Scale (PVSS), which provides overall, anticipatory, and consummatory anhedonia scores. PC1 scores-whose loadings indicated broadly distributed immune protein elevations consistent with general immune activation-moderated the relationship between basal ganglia dopamine availability and anhedonia: At higher PC1 levels, lower dopamine availability was linked to greater overall anhedonia (as measured by SHAPS) and anticipatory anhedonia, but not to consummatory anhedonia. Lower PC2 scores were associated with greater PVSS overall and consummatory anhedonia. Analyses examining individual basal ganglia regions suggest potential differences in dopaminergic-immune interactions across these regions, with effects most consistently observed in the putamen. Findings highlight nuanced neuroimmune pathways underlying anhedonia components in youth and support inflammation-based models of depression emphasizing dopaminergic-immune interplay.

Brain functional, structural, and neurochemical maturation has been found to support the specialization of executive systems through adolescence that will lead to adult level processing. Importantly, animal models and initial EEG studies in humans indicate developmental improvements in neural processing of complex information that would be evident in changes in temporal dynamics, which are not well-understood. Intrinsic neural timescales (INTs), or the temporal windows over which neural populations integrate inputs, have been proposed to reflect circuit-level properties such as excitatory-inhibitory (E/I) balance, myelination, and functional properties supporting complex information processing such as in executive functioning. Here, we used a multimodal, cross-species approach to investigate how INTs develop across adolescence to support cognitive specialization. In parallel analyses using a large longitudinal human EEG cohort, adolescent intracranial sEEG recordings, and macaque local field potentials, we observed robust reductions in INTs through adolescence, particularly in frontal and parietal association cortices. These developmental reductions were shaped by local circuit physiology, as evidenced by associations between shorter INTs and both lower aperiodic exponents, indicative of increased E/I balance, and reduced spectral offsets, suggesting lower aggregate spiking. We also found structural contributions via developmental interactions between age and deep layer intracortical myelination which predicted shorter INTs, suggesting that long-range circuitry may play a key role in shaping spontaneous temporal dynamics. Functionally, shorter INTs in adolescence were linked to improved working memory accuracy and reduced response time variability, indicating a behavioral advantage of refined temporal integration windows through development. Together, these findings establish INTs as a conserved, biologically grounded signature of adolescent brain maturation, providing a mechanistic framework for how structural and physiological refinements reorganize temporal processing to support increasingly efficient cognitive function.

Non-invasive brain imaging has played a critical role in establishing our understanding of the neural properties that contribute to the emergence of psychiatric disorders. However, characterizing core neurobiological mechanisms of psychiatric symptomatology requires greater structural, functional, and neurochemical specificity than is typically obtainable with standard field strength MRI acquisitions (e.g., 3T). Ultra-high field (UHF) imaging at 7 Tesla (7T) provides the opportunity to identify neurobiological systems that confer risk, determine etiology, and characterize disease progression and treatment outcomes of major mental illnesses. Increases in scanner availability, regulatory approval, and sequence availability have made the application of UHF to clinical cohorts more feasible than ever before, yet the application of UHF approaches to the study of mental health remains nascent. In this technical review, we describe core neuroimaging methodologies which benefit from UHF acquisition, including high resolution structural and functional imaging, single (¹H) and multi-nuclear (e.g., ³¹P) MR spectroscopy, and quantitative MR techniques for assessing brain tissue iron and myelin. We discuss advantages provided by 7T MRI, including higher signal- and contrast-to-noise ratio, enhanced spatial resolution, increased test-retest reliability, and molecular and neurochemical specificity, and how these have begun to uncover mechanisms of psychiatric disorders. Finally, we consider current limitations of UHF in its application to clinical cohorts, and point to ongoing work that aims to overcome technical hurdles through the continued development of UHF hardware, software, and protocols.

Summary: Cognitive abilities of primates, including humans, continue to improve through adolescence ^1,2 . While a range of changes in brain structure and connectivity have been documented ^3,4 , how they affect neuronal activity that ultimately determines performance of cognitive functions remains unknown. Here, we conducted a multilevel longitudinal study of monkey adolescent neurocognitive development. The developmental trajectory of neural activity in the prefrontal cortex accounted remarkably well for working memory improvements. While complex aspects of activity changed progressively during adolescence, such as the rotation of stimulus representation in multidimensional neuronal space, which has been implicated in cognitive flexibility, even simpler attributes, such as the baseline firing rate in the period preceding a stimulus appearance had predictive power over behavior. Unexpectedly, decreases in brain volume and thickness, which are widely thought to underlie cognitive changes in humans ⁵ did not predict well the trajectory of neural activity or cognitive performance changes. Whole brain cortical volume in particular, exhibited an increase and reached a local maximum in late adolescence, at a time of rapid behavioral improvement. Maturation of long-distance white matter tracts linking the frontal lobe with areas of the association cortex and subcortical regions best predicted changes in neuronal activity and behavior. Our results provide evidence that optimization of neural activity depending on widely distributed circuitry effects cognitive development in adolescence.