Spontaneous cortical dynamics from the first years to the golden years.

In the largest and most expansive lifespan magnetoencephalography (MEG) study to date (n = 434, 6 to 84 y), we provide critical data on the normative trajectory of resting-state spontaneous activity and its temporal dynamics. We perform cutting-edge analyses to examine age and sex effects on whole-brain, spatially-resolved relative and absolute power maps, and find significant age effects in all spectral bands in both types of maps. Specifically, lower frequencies showed a negative correlation with age, while higher frequencies positively correlated with age. These correlations were further probed with hierarchical regressions, which revealed significant nonlinear trajectories in key brain regions. Sex effects were found in absolute but not relative power maps, highlighting key differences between outcome indices that are generally used interchangeably. Our rigorous and innovative approach provides multispectral maps indicating the unique trajectory of spontaneous neural activity across the lifespan, and illuminates key methodological considerations with the widely used relative/absolute power maps of spontaneous cortical dynamics.

Effects of endogenous testosterone on oscillatory activity during verbal working memory in youth.

Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6-14 years-old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole-brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone-related effects in theta (4-7 Hz) and alpha (8-14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left-lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex-specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.

Developmental differences in functional organization of multispectral networks.

Assessing brain connectivity during rest has become a widely used approach to identify changes in functional brain organization during development. Generally, previous works have demonstrated that brain activity shifts from more local to more distributed processing from childhood into adolescence. However, the majority of those works have been based on functional magnetic resonance imaging measures, whereas multispectral functional connectivity, as measured using magnetoencephalography (MEG), has been far less characterized. In our study, we examined spontaneous cortical activity during eyes-closed rest using MEG in 101 typically developing youth (9-15 years old; 51 females, 50 males). Multispectral MEG images were computed, and connectivity was estimated in the canonical delta, theta, alpha, beta, and gamma bands using the imaginary part of the phase coherence, which was computed between 200 brain regions defined by the Schaefer cortical atlas. Delta and alpha connectivity matrices formed more communities as a function of increasing age. Connectivity weights predominantly decreased with age in both frequency bands; delta-band differences largely implicated limbic cortical regions and alpha band differences in attention and cognitive networks. These results are consistent with previous work, indicating the functional organization of the brain becomes more segregated across development, and highlight spectral specificity across different canonical networks.

Developmental and aging resting functional magnetic resonance imaging brain state adaptations in adolescents and adults: A large N (>47K) study.

The brain's functional architecture and organization undergo continual development and modification throughout adolescence. While it is well known that multiple factors govern brain maturation, the constantly evolving patterns of time-resolved functional connectivity are still unclear and understudied. We systematically evaluated over 47,000 youth and adult brains to bridge this gap, highlighting replicable time-resolved developmental and aging functional brain patterns. The largest difference between the two life stages was captured in a brain state that indicated coherent strengthening and modularization of functional coupling within the auditory, visual, and motor subdomains, supplemented by anticorrelation with other subdomains in adults. This distinctive pattern, which we replicated in independent data, was consistently less modular or absent in children and presented a negative association with age in adults, thus indicating an overall inverted U-shaped trajectory. This indicates greater synchrony, strengthening, modularization, and integration of the brain's functional connections beyond adolescence, and gradual decline of this pattern during the healthy aging process. We also found evidence that the developmental changes may also bring along a departure from the canonical static functional connectivity pattern in favor of more efficient and modularized utilization of the vast brain interconnections. State-based statistical summary measures presented robust and significant group differences that also showed significant age-related associations. The findings reported in this article support the idea of gradual developmental and aging brain state adaptation processes in different phases of life and warrant future research via lifespan studies to further authenticate the projected time-resolved brain state trajectories.

Denoising brain networks using a fixed mathematical phase change in independent component analysis of magnitude-only fMRI data.

Brain networks extracted by independent component analysis (ICA) from magnitude-only fMRI data are usually denoised using various amplitude-based thresholds. By contrast, spatial source phase (SSP) or the phase information of ICA brain networks extracted from complex-valued fMRI data, has provided a simple yet effective way to perform the denoising using a fixed phase change. In this work, we extend the approach to magnitude-only fMRI data to avoid testing various amplitude thresholds for denoising magnitude maps extracted by ICA, as most studies do not save the complex-valued data. The main idea is to generate a mathematical SSP map for a magnitude map using a mapping framework, and the mapping framework is built using complex-valued fMRI data with a known SSP map. Here we leverage the fact that the phase map derived from phase fMRI data has similar phase information to the SSP map. After verifying the use of the magnitude data of complex-valued fMRI, this framework is generalized to work with magnitude-only data, allowing use of our approach even without the availability of the corresponding phase fMRI datasets. We test the proposed method using both simulated and experimental fMRI data including complex-valued data from University of New Mexico and magnitude-only data from Human Connectome Project. The results provide evidence that the mathematical SSP denoising with a fixed phase change is effective for denoising spatial maps from magnitude-only fMRI data in terms of retaining more BOLD-related activity and fewer unwanted voxels, compared with amplitude-based thresholding. The proposed method provides a unified and efficient SSP approach to denoise ICA brain networks in fMRI data.

Developmental changes in endogenous testosterone have sexually-dimorphic effects on spontaneous cortical dynamics.

The transition from childhood to adolescence is associated with an influx of sex hormones, which not only facilitates physical and behavioral changes, but also dramatic changes in neural circuitry. While previous work has shown that pubertal hormones modulate structural and functional brain development, few of these studies have focused on the impact that such hormones have on spontaneous cortical activity, and whether these effects are modulated by sex during this critical developmental window. Herein, we examined the effect of endogenous testosterone on spontaneous cortical activity in 71 typically-developing youth (ages 10-17 years; 32 male). Participants completed a resting-state magnetoencephalographic (MEG) recording, structural MRI, and provided a saliva sample for hormone analysis. MEG data were source-reconstructed and the power within five canonical frequency bands (delta, theta, alpha, beta, and gamma) was computed. The resulting power spectral density maps were analyzed via vertex-wise ANCOVAs to identify spatially specific effects of testosterone and sex by testosterone interactions, while covarying out age. We found robust sex differences in the modulatory effects of testosterone on spontaneous delta, beta, and gamma activity. These interactions were largely confined to frontal cortices and exhibited a stark switch in the directionality of the correlation from the low (delta) to high frequencies (beta/gamma). For example, in the delta band, greater testosterone related to lower relative power in prefrontal cortices in boys, while the reverse pattern was found for girls. These data suggest testosterone levels are uniquely related to the development of spontaneous cortical dynamics during adolescence, and such levels are associated with different developmental patterns in males and females within regions implicated in executive functioning.

Dehydroepiandrosterone mediates associations between trauma-related symptoms and anterior pituitary volume in children and adolescents.

INTRODUCTION: The anterior pituitary gland (PG) is a potential locus of hypothalamic-pituitary-adrenal (HPA) axis responsivity to early life stress, with documented associations between dehydroepiandrosterone (DHEA) levels and anterior PG volumes. In adults, elevated anxiety/depressive symptoms are related to diminished DHEA levels, and studies have shown a positive relationship between DHEA and anterior pituitary volumes. However, specific links between responses to stress, DHEA levels, and anterior pituitary volume have not been established in developmental samples. METHODS: High-resolution T1-weighted MRI scans were collected from 137 healthy youth (9-17 years; Mage = 12.99 (SD = 1.87); 49% female; 85% White, 4% Indigenous, 1% Asian, 4% Black, 4% multiracial, 2% not reported). The anterior and posterior PGs were manually traced by trained raters. We examined the mediating effects of salivary DHEA on trauma-related symptoms (i.e., anxiety, depression, and posttraumatic) and PG volumes as well as an alternative model examining mediating effects of PG volume on DHEA and trauma-related symptoms. RESULTS: DHEA mediated the association between anxiety symptoms and anterior PG volume. Specifically, higher anxiety symptoms related to lower DHEA levels, which in turn were related to smaller anterior PG. CONCLUSIONS: These results shed light on the neurobiological sequelae of elevated anxiety in youth and are consistent with adult findings showing suppressed levels of DHEA in those with greater comorbid anxiety and depression. Specifically, adolescents with greater subclinical anxiety may exhibit diminished levels of DHEA during the pubertal window, which may be associated with disruptions in anterior PG growth.

Developmental trajectory of MEG resting-state oscillatory activity in children and adolescents: a longitudinal reliability study.

Neural oscillations may be sensitive to aspects of brain maturation such as myelination and synaptic density changes. Better characterization of developmental trajectories and reliability is necessary for understanding typical and atypical neurodevelopment. Here, we examined reliability in 110 typically developing children and adolescents (aged 9-17 years) across 2.25 years. From 10 min of magnetoencephalography resting-state data, normalized source spectral power and intraclass correlation coefficients were calculated. We found sex-specific differences in global normalized power, with males showing age-related decreases in delta and theta, along with age-related increases in beta and gamma. Females had fewer significant age-related changes. Structural magnetic resonance imaging revealed that males had more total gray, subcortical gray, and cortical white matter volume. There were significant age-related changes in total gray matter volume with sex-specific and frequency-specific correlations to normalized power. In males, increased total gray matter volume correlated with increased theta and alpha, along with decreased gamma. Split-half reliability was excellent in all frequency bands and source regions. Test-retest reliability ranged from good (alpha) to fair (theta) to poor (remaining bands). While resting-state neural oscillations can have fingerprint-like quality in adults, we show here that neural oscillations continue to evolve in children and adolescents due to brain maturation and neurodevelopmental change.

Trauma moderates the development of the oscillatory dynamics serving working memory in a sex-specific manner.

Working memory, the ability to hold items in memory stores for further manipulation, is a higher order cognitive process that supports many aspects of daily life. Childhood trauma has been associated with altered cognitive development including particular deficits in verbal working memory (VWM), but the neural underpinnings remain poorly understood. Magnetoencephalography (MEG) studies of VWM have reliably shown decreased alpha activity in left-lateralized language regions during encoding, and increased alpha activity in parieto-occipital cortices during the maintenance phase. In this study, we examined whether childhood trauma affects behavioral performance and the oscillatory dynamics serving VWM using MEG in a cohort of 9- to 15-year-old youth. All participants completed a modified version of the UCLA Trauma History Profile and then performed a VWM task during MEG. Our findings indicated a sex-by-age-by-trauma three-way interaction, whereby younger females experiencing higher levels of trauma had the lowest d' accuracy scores and the strongest positive correlations with age (i.e. older performed better). Likewise, females with higher levels of childhood trauma exhibited altered age-related alpha changes during the maintenance phase within the right temporal and parietal cortices. These findings suggest that trauma exposure may alter the developmental trajectory of neural oscillations serving VWM processing in a sex-specific way.

Transdiagnostic indicators predict developmental changes in cognitive control resting-state networks.

Over the past decade, transdiagnostic indicators in relation to neurobiological processes have provided extensive insight into youth's risk for psychopathology. During development, exposure to childhood trauma and dysregulation (i.e., so-called AAA symptomology: anxiety, aggression, and attention problems) puts individuals at a disproportionate risk for developing psychopathology and altered network-level neural functioning. Evidence for the latter has emerged from resting-state fMRI studies linking mental health symptoms and aberrations in functional networks (e.g., cognitive control (CCN), default mode networks (DMN)) in youth, although few of these investigations have used longitudinal designs. Herein, we leveraged a three-year longitudinal study to identify whether traumatic exposures and concomitant dysregulation trigger changes in the developmental trajectories of resting-state functional networks involved in cognitive control (N = 190; 91 females; time 1 Mage = 11.81). Findings from latent growth curve analyses revealed that greater trauma exposure predicted increasing connectivity between the CCN and DMN across time. Greater levels of dysregulation predicted reductions in within-network connectivity in the CCN. These findings presented in typically developing youth corroborate connectivity patterns reported in clinical populations, suggesting there is predictive utility in using transdiagnostic indicators to forecast alterations in resting-state networks implicated in psychopathology.

Longitudinal changes in the neural oscillatory dynamics underlying abstract reasoning in children and adolescents.

Fluid reasoning is the ability to problem solve in the absence of prior knowledge and is commonly conceptualized as "non-verbal" intelligence. Importantly, fluid reasoning abilities rapidly develop throughout childhood and adolescence. Although numerous studies have characterized the neural underpinnings of fluid reasoning in adults, there is a paucity of research detailing the developmental trajectory of this neural processing. Herein, we examine longitudinal changes in the neural oscillatory dynamics underlying fluid intelligence in a sample of typically developing youths. A total of 34 participants age 10 to 16 years-old completed an abstract reasoning task during magnetoencephalography (MEG) on two occasions set one year apart. We found robust longitudinal optimization in theta, beta, and gamma oscillatory activity across years of the study across a distributed network commonly implicated in fluid reasoning abilities. More specifically, activity tended to decrease longitudinally in additional, compensatory areas such as the right lateral prefrontal cortex and increase in areas commonly utilized in mature adult samples (e.g., left frontal and parietal cortices). Importantly, shifts in neural activity were associated with improvements in task performance from one year to the next. Overall, the data suggest a longitudinal shift in performance that is accompanied by a reconfiguration of the functional oscillatory dynamics serving fluid reasoning during this important period of development.

Detecting abnormal connectivity in schizophrenia via a joint directed acyclic graph estimation model.

Functional connectivity (FC) between brain region has been widely studied and linked with cognition and behavior of an individual. FC is usually defined as the correlation or partial correlation of fMRI blood oxygen level-dependent (BOLD) signals between two brain regions. Although FC has been effective to understand brain organization, it cannot reveal the direction of interactions. Many directed acyclic graph (DAG) based methods have been applied to study the directed interactions but their performance was limited by the small sample size while high dimensionality of the available data. By enforcing group regularization and utilizing samples from both case and control groups, we propose a joint DAG model to estimate the directed FC. We first demonstrate that the proposed model is efficient and accurate through a series of simulation studies. We then apply it to the case-control study of schizophrenia (SZ) with data collected from the MIND Clinical Imaging Consortium (MCIC). We have successfully identified decreased functional integration, disrupted hub structures and characteristic edges (CtEs) in SZ patients. Those findings have been confirmed by previous studies with some identified to be potential markers for SZ patients. A comparison of the results between the directed FC and undirected FC showed substantial differences in the selected features. In addition, we used the identified features based on directed FC for the classification of SZ patients and achieved better accuracy than using undirected FC or raw features, demonstrating the advantage of using directed FC for brain network analysis.

Eyes-closed versus eyes-open differences in spontaneous neural dynamics during development.

BACKGROUND: Assessing brain activity during rest has become a widely used approach in developmental neuroscience. Extant literature has measured resting brain activity both during eyes-open and eyes-closed conditions, but the difference between these conditions has not yet been well characterized. Studies, limited to fMRI and EEG, have suggested that eyes-open versus -closed conditions may differentially impact neural activity, especially in visual cortices. METHODS: Spontaneous cortical activity was recorded using MEG from 108 typically developing youth (9-15 years-old; 55 female) during separate sessions of eyes-open and eyes-closed rest. MEG source images were computed, and the strength of spontaneous neural activity was estimated in the canonical delta, theta, alpha, beta, and gamma bands, respectively. Power spectral density maps for eyes-open were subtracted from eyes-closed rest, and then submitted to vertex-wise regression models to identify spatially specific differences between conditions and as a function of age and sex. RESULTS: Relative alpha power was weaker in the eyes-open compared to -closed condition, but otherwise eyes-open was stronger in all frequency bands, with differences concentrated in the occipital cortex. Relative theta power became stronger in the eyes-open compared to the eyes-closed condition with increasing age in frontal cortex. No differences were observed between males and females. CONCLUSIONS: The differences in relative power from eyes-closed to -open conditions are consistent with changes observed in task-based visual sensory responses. Age differences occurred in relatively late developing frontal regions, consistent with canonical attention regions, suggesting that these differences could be reflective of developmental changes in attention processes during puberty. Taken together, resting-state paradigms using eyes-open versus -closed produce distinct results and, in fact, can help pinpoint sensory related brain activity.

The development of sensorimotor cortical oscillations is mediated by pubertal testosterone.

Puberty is a period of substantial hormonal fluctuations, and pubertal hormones can modulate structural and functional changes in the developing brain. Many previous studies have characterized the neural oscillatory responses serving movement, which include a beta event-related desynchronization (ERD) preceding movement onset, gamma and theta responses coinciding with movement execution, and a post-movement beta-rebound (PMBR) response following movement offset. While a few studies have investigated the developmental trajectories of these neural oscillations serving motor control, the impact of pubertal hormone levels on the maturation of these dynamics has not yet been examined. Since the timing and tempo of puberty varies greatly between individuals, pubertal hormones may uniquely impact the maturation of motor cortical oscillations distinct from other developmental metrics, such as age. In the current study we quantified these oscillations using magnetoencephalography (MEG) and utilized chronological age and measures of endogenous testosterone as indices of development during the transition from childhood to adolescence in 69 youths. Mediation analyses revealed complex maturation patterns for the beta ERD, in which testosterone predicted both spontaneous baseline and ERD power through direct and indirect effects. Age, but not pubertal hormones, predicted motor-related theta, and no relationships between oscillatory responses and developmental metrics were found for gamma or PMBR responses. These findings provide novel insight into how pubertal hormones affect motor-related oscillations, and highlight the continued development of motor cortical dynamics throughout the pubertal period.

Individual differences in amygdala volumes predict changes in functional connectivity between subcortical and cognitive control networks throughout adolescence.

Adolescence is a critical period of structural and functional neural maturation among regions serving the cognitive control of emotion. Evidence suggests that this process is guided by developmental changes in amygdala and striatum structure and shifts in functional connectivity between subcortical (SC) and cognitive control (CC) networks. Herein, we investigate the extent to which such developmental shifts in structure and function reciprocally predict one another over time. 179 youth (9-15 years-old) completed annual MRI scans for three years. Amygdala and striatum volumes and connectivity within and between SC and CC resting state networks were measured for each year. We tested for reciprocal predictability of within-person and between-person changes in structure and function using random-intercept cross-lagged panel models. Within-person shifts in amygdala volumes in a given year significantly and specifically predicted deviations in SC-CC connectivity in the following year, such that an increase in volume was associated with decreased SC-CC connectivity the following year. Deviations in connectivity did not predict changes in amygdala volumes over time. Conversely, broader group-level shifts in SC-CC connectivity were predictive of subsequent deviations in striatal volumes. We did not see any cross-predictability among amygdala or striatum volumes and within-network connectivity measures. Within-person shifts in amygdala structure year-to-year robustly predicted weaker SC-CC connectivity in subsequent years, whereas broader increases in SC-CC connectivity predicted smaller striatal volumes over time. These specific structure function relationships may contribute to the development of emotional control across adolescence.

Left amygdala structure mediates longitudinal associations between exposure to threat and long-term psychiatric symptomatology in youth.

Traumatic experiences during childhood can have profound effects on stress sensitive brain structures (e.g., amygdala and hippocampus) and the emergence of psychiatric symptoms. Recent theoretical and empirical work has delineated dimensions of trauma (i.e., threat and deprivation) as having distinct neural and behavioral effects, although there are few longitudinal examinations. A sample of 243 children and adolescents were followed for three time points, with each assessment approximately 1 year apart (ages 9-15 years at Time 1; 120 males). Participants or their caregiver reported on youths' threat exposure, perceived stress (Time 1), underwent a T1-weighted structural high-resolution MRI scan (Time 2), and documented their subsequent psychiatric symptoms later in development (Time 3). The primary findings indicate that left amygdala volume, in particular, mediated the longitudinal association between threat exposure and subsequent internalizing and externalizing symptomatology. Greater threat exposure related to reduced left amygdala volume, which in turn differentially predicted internalizing and externalizing symptoms. Decreased bilateral hippocampal volume was related to subsequently elevated internalizing symptoms. These findings suggest that the left amygdala is highly threat-sensitive and that stress-related alterations may partially explain elevated psychopathology in stress-exposed adolescents. Uncovering potential subclinical and/or preclinical predictive biomarkers is essential to understanding the emergence, progression, and eventual targeted treatment of psychopathology following trauma exposure.

The impact of pubertal DHEA on the development of visuospatial oscillatory dynamics.

The adolescent brain undergoes tremendous structural and functional changes throughout puberty. Previous research has demonstrated that pubertal hormones can modulate sexually dimorphic changes in cortical development, as well as age-related maturation of the neural activity underlying cognitive processes. However, the precise impact of pubertal hormones on these functional changes in the developing human brain remains poorly understood. In the current study, we quantified the neural oscillatory activity serving visuospatial processing using magnetoencephalography, and utilized measures of dehydroepiandrosterone (DHEA) as an index of development during the transition from childhood to adolescence (i.e., puberty). Within a sample of typically developing youth (ages 9-15), a novel association between pubertal DHEA and theta oscillatory activity indicated that less mature children exhibited stronger neural responses in higher-order prefrontal cortices during the visuospatial task. Theta coherence between bilateral prefrontal regions also increased with increasing DHEA, such that network-level theta activity became more distributed with more maturity. Additionally, significant DHEA-by-sex interactions in the gamma range were centered on cortical regions relevant for attention processing. These findings suggest that pubertal DHEA may modulate the development of neural oscillatory activity serving visuospatial processing and attention functions during the pubertal period.

Rice NIN-LIKE PROTEIN 3 modulates nitrogen use efficiency and grain yield under nitrate-sufficient conditions.

Nitrogen (N) is an essential macronutrient for crop growth and yield. Improving the N use efficiency (NUE) of crops is important to agriculture. However, the molecular mechanisms underlying NUE regulation remain largely elusive. Here we report that the OsNLP3 (NIN-like protein 3) regulates NUE and grain yield in rice under N sufficient conditions. OsNLP3 transcript level is significantly induced by N starvation and its protein nucleocytosolic shuttling is specifically regulated by nitrate. Loss-of-function of OsNLP3 reduces plant growth, grain yield, and NUE under sufficient nitrate conditions, whereas under low nitrate or different ammonium conditions, osnlp3 mutants show no clear difference from the wild type. Importantly, under sufficient N conditions in the field, OsNLP3 overexpression lines display improved grain yield and NUE compared with the wild type. OsNLP3 orchestrates the expression of multiple N uptake and assimilation genes by directly binding to the nitrate-responsive cis-elements in their promoters. Overall, our study demonstrates that OsNLP3, together with OsNLP1 and OsNLP4, plays overlapping and differential roles in N acquisition and NUE, and modulates NUE and the grain yield increase promoted by N fertilizer. Therefore, OsNLP3 is a promising candidate gene for the genetic improvement of grain yield and NUE in rice.

Efficient and stretchable organic light-emitting devices based on spontaneously formed disordered wrinkles.

We propose a facile, scalable strategy to introduce spontaneously formed disordered wrinkles into organic light-emitting devices (OLEDs) to enhance light extraction and realize stretchability of the devices. The luminance and current efficiency of the wrinkled OLEDs are improved by 37% and 18%, respectively, compared to the planar device. Meanwhile, broadband light scattering induced by the disordered wrinkles results in angle-stable electroluminescent spectra at wide viewing angles for the wrinkled OLEDs. The disordered wrinkles enable the OLEDs to be stretchable and withstand hundreds of stretching-releasing cycles at strain between 0% and 5%. This study provides a simple method to realize stretchable OLEDs with high efficiency.

Reliability of the NIH toolbox cognitive battery in children and adolescents: a 3-year longitudinal examination.

BACKGROUND: The Cognitive Battery of the National Institutes of Health Toolbox (NIH-TB) is a collection of assessments that have been adapted and normed for administration across the lifespan and is increasingly used in large-scale population-level research. However, despite increasing adoption in longitudinal investigations of neurocognitive development, and growing recommendations that the Toolbox be used in clinical applications, little is known about the long-term temporal stability of the NIH-TB, particularly in youth. METHODS: The present study examined the long-term temporal reliability of the NIH-TB in a large cohort of youth (9-15 years-old) recruited across two data collection sites. Participants were invited to complete testing annually for 3 years. RESULTS: Reliability was generally low-to-moderate, with intraclass correlation coefficients ranging between 0.31 and 0.76 for the full sample. There were multiple significant differences between sites, with one site generally exhibiting stronger temporal stability than the other. CONCLUSIONS: Reliability of the NIH-TB Cognitive Battery was lower than expected given early work examining shorter test-retest intervals. Moreover, there were very few instances of tests meeting stability requirements for use in research; none of the tests exhibited adequate reliability for use in clinical applications. Reliability is paramount to establishing the validity of the tool, thus the constructs assessed by the NIH-TB may vary over time in youth. We recommend further refinement of the NIH-TB Cognitive Battery and its norming procedures for children before further adoption as a neuropsychological assessment. We also urge researchers who have already employed the NIH-TB in their studies to interpret their results with caution.