Neural responding during uncertain threat anticipation in pediatric anxiety.

Excessive fear responses to uncertain threat are a key feature of anxiety disorders (ADs), though most mechanistic work considers adults. As ADs onset in childhood and confer risk for later psychopathology, we sought to identify conditions of uncertain threat that distinguish 8-17-year-old youth with AD (n = 19) from those without AD (n = 33), and assess test-retest reliability of such responses in a companion sample of healthy adults across three sites (n = 19). In an adapted uncertainty of threat paradigm, visual cues parametrically signaled threat of aversive stimuli (fear faces) in 25 % increments (0 %, 25 %, 50 %, 100 %), while participants underwent functional magnetic resonance imaging (fMRI). We compared neural response elicited by cues signaling different degrees of probability regarding the subsequent delivery of fear faces. Overall, youth displayed greater engagement of bilateral inferior parietal cortex, fusiform gyrus, and lingual gyrus during uncertain threat anticipation in general. Relative to healthy youth, AD youth exhibited greater activation in ventrolateral prefrontal cortex (vlPFC)/BA47 during uncertain threat anticipation in general. Further, AD differed from healthy youth in scaling of ventral striatum/sgACC activation with threat probability and attenuated flexibility of responding during parametric uncertain threat. Complementing these results, significant, albeit modest, cross-site test-retest reliability in these regions was observed in an independent sample of healthy adults. While preliminary due to a small sample size, these findings suggest that during uncertainty of threat, AD youth engage vlPFC regions known to be involved in fear regulation, response inhibition, and cognitive control. Findings highlight the potential of isolating neural correlates of threat anticipation to guide treatment development and translational work in youth.

Striatal Activity to Reward Anticipation as a Moderator of the Association Between Early Behavioral Inhibition and Changes in Anxiety and Depressive Symptoms From Adolescence to Adulthood.

Importance: The early childhood temperament of behavioral inhibition (BI), characterized by inhibited and fearful behaviors, has been associated with heightened risk for anxiety and depression across the lifespan. Although several neurocognitive correlates underlying vulnerability to the development of anxiety among inhibited children have been identified, little is known about the neurocognitive correlates underlying vulnerability to the development of depression. Objective: To examine whether blunted striatal activation to reward anticipation, a well-documented neurocognitive vulnerability marker of depression, moderates the association between early BI and the developmental changes in depression and anxiety from adolescence to adulthood. Design, Setting, and Participants: Participants in this prospective longitudinal study were recruited at age 4 months between 1989 and 1993 in the US. Follow-up assessments extended into 2018 (age 26 years). Data were analyzed between September 2021 to March 2022. Main Outcomes and Measures: BI was measured through an observation paradigm in infancy (ages 14 and 24 months). Neural activity to anticipated rewards during a monetary incentive delay task was measured using functional magnetic resonance imaging in adolescence (between ages 15-18 years; 83 individuals had usable data). Anxiety and depressive symptoms were self-reported across adolescence to young adulthood (ages 15 and 26 years; n = 108). A latent change score model, accounting for the interdependence between anxiety and depression, tested the moderating role of striatal activity to reward anticipation in the association between early BI and changes in anxiety and depressive symptoms. A region of interest approach limited statistical tests to regions within the striatum (ie, nucleus accumbens, caudate head, caudate body, putamen). Results: Of 165 participants, 84 (50.1%) were female and 162 (98%) were White. Preliminary analyses revealed significant increases in anxiety and depressive symptoms across ages 15 to 26 years, as well as individual variation in the magnitude of changes. Main analyses showed that reduced activity in the nucleus accumbens to reward anticipation moderated the association between early BI and increases in depressive (ß = -0.32; b = -4.23; 95% CI, -7.70 to -0.76; P = .02), and more depressive symptoms at age 26 years (ß = -0.47; b = -5.09; 95% CI, -7.74 to -2.43; P < .001). However, there were no significant interactions associated with latent changes in anxiety across age nor anxiety at age 26 years. Activity in the caudate and putamen did not moderate these associations. Conclusions and Relevance: Blunted reward sensitivity in the ventral striatum may be a developmental risk factor connecting an inhibited childhood temperament and depression over the transition to adulthood. Future studies should examine the efficacy of prevention programs, which target maladaptive reward processing and motivational deficits among anxious youths, in reducing risks for later depression.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Shared and Anxiety-Specific Pediatric Psychopathology Dimensions Manifest Distributed Neural Correlates.

BACKGROUND: Imaging research has not yet delivered reliable psychiatric biomarkers. One challenge, particularly among youth, is high comorbidity. This challenge might be met through canonical correlation analysis designed to model mutual dependencies between symptom dimensions and neural measures. We mapped the multivariate associations that intrinsic functional connectivity manifests with pediatric symptoms of anxiety, irritability, and attention-deficit/hyperactivity disorder (ADHD) as common, impactful, co-occurring problems. We evaluate the replicability of such latent dimensions in an independent sample. METHODS: We obtained ratings of anxiety, irritability, and ADHD, and 10 minutes of resting-state functional magnetic resonance imaging data, from two independent cohorts. Both cohorts (discovery: n = 182; replication: n = 326) included treatment-seeking youth with anxiety disorders, with disruptive mood dysregulation disorder, with ADHD, or without psychopathology. Functional connectivity was modeled as partial correlations among 216 brain areas. Using canonical correlation analysis and independent component analysis jointly we sought maximally correlated, maximally interpretable latent dimensions of brain connectivity and clinical symptoms. RESULTS: We identified seven canonical variates in the discovery and five in the replication cohort. Of these canonical variates, three exhibited similarities across datasets: two variates consistently captured shared aspects of irritability, ADHD, and anxiety, while the third was specific to anxiety. Across cohorts, canonical variates did not relate to specific resting-state networks but comprised edges interconnecting established networks within and across both hemispheres. CONCLUSIONS: Findings revealed two replicable types of clinical variates, one related to multiple symptom dimensions and a second relatively specific to anxiety. Both types involved a multitude of broadly distributed, weak brain connections as opposed to strong connections encompassing known resting-state networks.

Levels of early-childhood behavioral inhibition predict distinct neurodevelopmental pathways to pediatric anxiety.

BACKGROUND: Anxiety symptoms gradually emerge during childhood and adolescence. Individual differences in behavioral inhibition (BI), an early-childhood temperament, may shape developmental paths through which these symptoms arise. Cross-sectional research suggests that level of early-childhood BI moderates associations between later anxiety symptoms and threat-related amygdala-prefrontal cortex (PFC) circuitry function. However, no study has characterized these associations longitudinally. Here, we tested whether level of early-childhood BI predicts distinct evolving associations between amygdala-PFC function and anxiety symptoms across development. METHODS: Eighty-seven children previously assessed for BI level in early childhood provided data at ages 10 and/or 13 years, consisting of assessments of anxiety and an fMRI-based dot-probe task (including threat, happy, and neutral stimuli). Using linear-mixed-effects models, we investigated longitudinal changes in associations between anxiety symptoms and threat-related amygdala-PFC connectivity, as a function of early-childhood BI. RESULTS: In children with a history of high early-childhood BI, anxiety symptoms became, with age, more negatively associated with right amygdala-left dorsolateral-PFC connectivity when attention was to be maintained on threat. In contrast, with age, low-BI children showed an increasingly positive anxiety-connectivity association during the same task condition. Behaviorally, at age 10, anxiety symptoms did not relate to fluctuations in attention bias (attention bias variability, ABV) in either group; by age 13, low-BI children showed a negative anxiety-ABV association, whereas high-BI children showed a positive anxiety-ABV association. CONCLUSIONS: Early-childhood BI levels predict distinct neurodevelopmental pathways to pediatric anxiety symptoms. These pathways involve distinct relations among brain function, behavior, and anxiety symptoms, which may inform diagnosis and treatment.

Bidirectional Associations Between Stress and Reward Processing in Children and Adolescents: A Longitudinal Neuroimaging Study.

BACKGROUND: Aberrations in both neural reward processing and stress reactivity are associated with increased risk for mental illness; yet, how these two factors relate to each other remains unclear. Several studies suggest that stress exposure impacts reward function, thus increasing risk for psychopathology. However, the alternative hypothesis, in which reward dysfunction impacts stress reactivity, has been rarely examined. The current study aimed to test both hypotheses using a longitudinal design. METHODS: Participants were 38 children (23 girls; 61%) from a prospective cohort study. A standard stress-exposure measure was collected at 7 years of age. Children performed a well-validated imaging reward paradigm at age 10, and a standardized acute psychological stress laboratory protocol was administered both at age 10 and at age 13. Structural equation modeling was used to examine bidirectional associations between stress and neural response to reward anticipation. RESULTS: Higher exposure to stressful life events at age 7 predicted lower neural response to reward anticipation in regions of the basal ganglia at age 10, which included ventral caudate, nucleus accumbens, putamen, and globus pallidus. Lower response to reward anticipation in medial prefrontal and anterior cingulate cortex predicted higher stress reactivity at age 13. CONCLUSIONS: Our findings provide support for bidirectional associations between stress and reward processing, in that stress may impact reward anticipation, but also in that reduced reward anticipation may increase susceptibility to stress.

Pubertal maturation and sex effects on the default-mode network connectivity implicated in mood dysregulation.

This study examines the effects of puberty and sex on the intrinsic functional connectivity (iFC) of brain networks, with a focus on the default-mode network (DMN). Consistently implicated in depressive disorders, the DMN's function may interact with puberty and sex in the development of these disorders, whose onsets peak in adolescence, and which show strong sex disproportionality (females > males). The main question concerns how the DMN evolves with puberty as a function of sex. These effects are expected to involve within- and between-network iFC, particularly, the salience and the central-executive networks, consistent with the Triple-Network Model. Resting-state scans of an adolescent community sample (n = 304, male/female: 157/147; mean/std age: 14.6/0.41 years), from the IMAGEN database, were analyzed using the AFNI software suite and a data reduction strategy for the effects of puberty and sex. Three midline regions (medial prefrontal, pregenual anterior cingulate, and posterior cingulate), within the DMN and consistently implicated in mood disorders, were selected as seeds. Within- and between-network clusters of the DMN iFC changed with pubertal maturation differently in boys and girls (puberty-X-sex). Specifically, pubertal maturation predicted weaker iFC in girls and stronger iFC in boys. Finally, iFC was stronger in boys than girls independently of puberty. Brain-behavior associations indicated that lower connectivity of the anterior cingulate seed predicted higher internalizing symptoms at 2-year follow-up. In conclusion, weaker iFC of the anterior DMN may signal disconnections among circuits supporting mood regulation, conferring risk for internalizing disorders.

Altered Uncinate Fasciculus Microstructure in Childhood Anxiety Disorders in Boys But Not Girls.

OBJECTIVE: Anxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders. METHODS: FA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects. RESULTS: Tract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts. CONCLUSIONS: These findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.

Is the encoding of Reward Prediction Error reliable during development?

Reward Prediction Errors (RPEs), defined as the difference between the expected and received outcomes, are integral to reinforcement learning models and play an important role in development and psychopathology. In humans, RPE encoding can be estimated using fMRI recordings, however, a basic measurement property of RPE signals, their test-retest reliability across different time scales, remains an open question. In this paper, we examine the 3-month and 3-year reliability of RPE encoding in youth (mean age at baseline = 10.6 ±â€¯0.3 years), a period of developmental transitions in reward processing. We show that RPE encoding is differentially distributed between the positive values being encoded predominantly in the striatum and negative RPEs primarily encoded in the insula. The encoding of negative RPE values is highly reliable in the right insula, across both the long and the short time intervals. Insula reliability for RPE encoding is the most robust finding, while other regions, such as the striatum, are less consistent. Striatal reliability appeared significant as well once covarying for factors, which were possibly confounding the signal to noise ratio. By contrast, task activation during feedback in the striatum is highly reliable across both time intervals. These results demonstrate the valence-dependent differential encoding of RPE signals between the insula and striatum, and the consistency of RPE signals or lack thereof, during childhood and into adolescence. Characterizing the regions where the RPE signal in BOLD fMRI is a reliable marker is key for estimating reward-processing alterations in longitudinal designs, such as developmental or treatment studies.

The Integration of Functional Brain Activity from Adolescence to Adulthood.

Age-related changes in human functional neuroanatomy are poorly understood. This is partly due to the limits of interpretation of standard fMRI. These limits relate to age-related variation in noise levels in data from different subjects, and the common use of standard adult brain parcellations for developmental studies. Here we used an emerging MRI approach called multiecho (ME)-fMRI to characterize functional brain changes with age. ME-fMRI acquires blood oxygenation level-dependent (BOLD) signals while also quantifying susceptibility-weighted transverse relaxation time (T2*) signal decay. This approach newly enables reliable detection of BOLD signal components at the subject level as opposed to solely at the group-average level. In turn, it supports more robust characterization of the variability in functional brain organization across individuals. We hypothesized that BOLD components in the resting state are not stable with age, and would decrease in number from adolescence to adulthood. This runs counter to the current assumptions in neurodevelopmental analyses of brain connectivity that the number of BOLD signal components is a random effect. From resting-state ME-fMRI of 51 healthy subjects of both sexes, between 8.3 and 46.2 years of age, we found a highly significant (r = -0.55, p ≪ 0.001) exponential decrease in the number of BOLD components with age. The number of BOLD components were halved from adolescence to the fifth decade of life, stabilizing in middle adulthood. The regions driving this change were dorsolateral prefrontal cortices, parietal cortex, and cerebellum. The functional network of these regions centered on the cerebellum. We conclude that an age-related decrease in BOLD component number concurs with the hypothesis of neurodevelopmental integration of functional brain activity. We show evidence that the cerebellum may play a key role in this process.SIGNIFICANCE STATEMENT Human brain development is ongoing from childhood to at least 30 years of age. Functional MRI (fMRI) is key for characterizing changes in brain function that accompany development. However, developmental fMRI studies have relied on reference maps of adult brain organization in the analysis of data from younger subjects. This approach may limit the characterization of functional activity patterns that are particular to children and adolescents. Here we used an emerging fMRI approach called multi-echo fMRI that is not susceptible to such biases when analyzing the variation in functional brain organization over development. We hypothesized an integration of the components of brain activity over development, and found that the number of components decreases exponentially, halving from 8 to 35 years of age. The brain regions most affected underlie executive function and coordination. In summary, we show major changes in the organization and integration of functional networks over development into adulthood, with both methodological and neurobiological implications for future lifespan and disease studies on brain connectivity.

Implementing a Novel Guideline to Prevent Hospital-Acquired Pressure Ulcers in a Trauma Population: A Patient-Safety Approach.

BACKGROUND: The development of hospital-acquired pressure ulcers (HAPUs) is a common complication associated with immobilization and prolonged hospitalization in trauma patients. Our semi-annual Trauma Quality Improvement Program report identified HAPUs as an outlier complication. We used a hospital-wide initiative to reduce the incidence of HAPUs among our trauma patient population. Our study aimed to determine whether the implemented measures would decrease HAPUs incidence rates. STUDY DESIGN: We reviewed adult trauma patients during a 3-year period. The novel care-based platform and preventive measures for reducing HAPUs included the following components: pressure-reducing beds; improved and protocolized nutritional support; mandatory 2-hour change of posture; turning clocks; early surgical intervention; spot checks by our wound care nurse; and education to patients and caregivers. Paired-sample t-test and chi-square analyses were used, with significance defined as p < 0.05. RESULTS: A total of 9,755 patients were admitted to our trauma services in the study period. Of these, HAPUs developed in 89 patients (mean age 57.9 years and 48 [54%] were female). The Injury Severity Score ranged from 1 to 75, with a mean of 20 in patients with HAPUs compared with 8 in patients without HAPUs during the same study period. The incidence of HAPUs at our institution was initially 1.36%, which decreased to 0.98% in year 2 and to 0.39% in year 3 (p = 0.002). CONCLUSIONS: The novel 7-step care-based process changes, acquisition of specialized equipment, and educational initiatives implemented were associated with a significant decrease in the incidence rates of HAPUs.

Neural responses to reward in childhood: relations to early behavioral inhibition and social anxiety.

Behavioral inhibition (BI) is an early temperamental profile characterized by negative reactivity to novelty, withdrawal from social situations, and increased risk for social anxiety. Previous research associated BI assessed in early childhood to striatal hypersensitivity in mid-to-late adolescence. The present study examined this association among 10 year-olds, characterized with BI at ages 24 and 36 months on measures of temperamental reactivity. Participants (n = 40) were studied at age 10 using a reward processing task during functional magnetic resonance imaging (fMRI). Child- and maternal-report of social anxiety symptoms was collected at ages 10 and 13. Findings indicate greater caudate activation and stronger striatal connectivity in high, compared to low, behaviorally inhibited children. Caudate activation related to social anxiety symptoms at both ages. These findings suggest that enhanced striatal responsivity reliably manifests among high behaviorally inhibited children as early as age 10. This may reflect hyper-sensitivity to reward or excessive motivation to avoid errors.

Prevalence and ethnic/racial disparities in the distribution of pediatric injuries in South Florida: implications for the development of community prevention programs.

BACKGROUND: The state of Florida continues to report significant gender, ethnic and racial disparities in trauma incidence, access to care and outcomes in the adult population. Our objective was to assess pediatric injury profiles and ethnic/racial disparities of specific injuries in a Regional Trauma Center (TC) in South Florida. METHODS: Retrospective data from November 2011 to December 2015 were obtained from the Level 2 TC registry for children ≤21 years old. Demographic, injury pattern, geographic area, injury scores and treatment data were analyzed. RESULTS: One thousand six hundred ten patients, ages 0-21 years were cared for at the TC from 2011 to 2015.73% were males. Mean age = 15.7 years. Mortality was 2.3%. Using zip code data and using geographic mapping, we identified two main clusters where injuries were occurring. A multinomial regression analysis demonstrated that Hispanics had higher risks of falls (RR 10.4, 95% CI 2.7-29), motorcycle accidents (RR 3.7, 95% CI 1.7-8.2) and motor vehicle accidents (RR 6.4, 95% CI 3.6-11.4). Black/African American children had higher risks of gunshot wounds and resultant mortality (p < 0.01). CONCLUSION: There were racial, ethnic and gender disparities in the patterns of injury and outcomes among the youth attended at our TC. Geographic mapping allowed us the identification of the zones in South Florida where injuries were occurring. Understanding the differences and using geographic mapping to identify regions of higher prevalence will complement planning for prevention programs.

Altered striatal intrinsic functional connectivity in pediatric anxiety.

Anxiety disorders are among the most common psychiatric disorders of adolescence. Behavioral and task-based imaging studies implicate altered reward system function, including striatal dysfunction, in adolescent anxiety. However, no study has yet examined alterations of the striatal intrinsic functional connectivity in adolescent anxiety disorders. The current study examines striatal intrinsic functional connectivity (iFC), using six bilateral striatal seeds, among 35 adolescents with anxiety disorders and 36 healthy comparisons. Anxiety is associated with abnormally low iFC within the striatum (e.g., between nucleus accumbens and caudate nucleus), and between the striatum and prefrontal regions, including subgenual anterior cingulate cortex, posterior insula and supplementary motor area. The current findings extend prior behavioral and task-based imaging research, and provide novel data implicating decreased striatal iFC in adolescent anxiety. Alterations of striatal neurocircuitry identified in this study may contribute to the perturbations in the processing of motivational, emotional, interoceptive, and motor information seen in pediatric anxiety disorders. This pattern of the striatal iFC perturbations can guide future research on specific mechanisms underlying anxiety.

Early Childhood Behavioral Inhibition Predicts Cortical Thickness in Adulthood.

OBJECTIVE: Behavioral inhibition (BI) during early childhood predicts risk for anxiety disorders and altered cognitive control in adolescence. Although BI has been linked to variation in brain function through adulthood, few studies have examined relations between early childhood BI and adult brain structure. METHOD: The relation between early childhood BI and cortical thickness in adulthood was examined in a cohort of individuals followed since early childhood (N = 53, mean age 20.5 years). Analyses tested whether anxiety and/or cognitive control during adolescence moderated relations between BI and cortical thickness. Cognitive control was measured with the Eriksen Flanker Task. Initial analyses examined cortical thickness in regions of interest previously implicated in BI, anxiety disorders, and cognitive control: dorsal anterior cingulate (dACC), anterior insula (aI), and subgenual anterior cingulate (sgACC); and volumes of the amygdala and hippocampus. Exploratory analyses examined relations across the prefrontal cortex. RESULTS: BI during early childhood related to thinner dACC in adulthood. Neither anxiety nor cognitive control moderated this relation. A stronger congruency effect on the Eriksen Flanker Task during adolescence independently related to thinner dACC in adulthood. Higher anxiety during adolescence related to thicker cortex in the right ventrolateral prefrontal cortex (VLPFC) in adulthood among those with low BI as children. CONCLUSION: Temperament in early childhood and the interaction between temperament and later anxiety relate to adult brain structure. These results are consistent with prior work associating BI and anxiety with functional brain variability in the dACC and VLPFC.

Robust resting state fMRI processing for studies on typical brain development based on multi-echo EPI acquisition.

Several methodological challenges affect the study of typical brain development based on resting state blood oxygenation level dependent (BOLD) functional MRI (fMRI). One such challenge is mitigating artifacts such as those from head motion, known to be more substantial in younger subjects than older subjects. Other challenges include controlling for potential age-dependence in cerebrospinal fluid (CSF) volume affecting anatomical-functional coregistration; in vascular density affecting BOLD contrast-to-noise; and in CSF pulsation creating time series artifacts. Historically, these confounds have been approached through incorporating artifact-specific temporal and/or spatial filtering into preprocessing pipelines. However, such paths often come with new confounds or limitations. In this study we take the approach of a bottom-up revision of fMRI methodology based on acquisition of multi-echo fMRI and comprehensive utilization of the information in the TE-domain to enhance several aspects of fMRI analysis in the context of a developmental study. We show in a cohort of 25 healthy subjects, aged 9 to 43 years, that the analysis of multi-echo fMRI data eliminates a number of arbitrary processing steps such as bandpass filtering and spatial smoothing, while enabling procedures such as [Formula: see text] mapping, BOLD contrast normalization and signal dropout recovery, precise anatomical-functional coregistration based on [Formula: see text] measurements, automatic denoising through removing subject motion, scanner-related signal drifts and physiology, as well as statistical inference for seed-based connectivity. These enhancements are of both theoretical significance and practical benefit in the study of typical brain development.

Age-related changes in the intrinsic functional connectivity of the human ventral vs. dorsal striatum from childhood to middle age.

The striatum codes motivated behavior. Delineating age-related differences within striatal circuitry can provide insights into neural mechanisms underlying ontogenic behavioral changes and vulnerabilities to mental disorders. To this end, a dual ventral/dorsal model of striatal function was examined using resting state intrinsic functional connectivity (iFC) imaging in 106 healthy individuals, ages 9-44. Broadly, the dorsal striatum (DS) is connected to prefrontal and parietal cortices and contributes to cognitive processes; the ventral striatum (VS) is connected to medial orbitofrontal and anterior cingulate cortices, and contributes to affective valuation and motivation. Findings revealed patterns of age-related changes that differed between VS and DS iFCs. We found an age-related increase in DS iFC with posterior cingulate cortex (pCC) that stabilized after the mid-twenties, but a decrease in VS iFC with anterior insula (aIns) and dorsal anterior cingulate cortex (dACC) that persisted into mid-adulthood. These distinct developmental trajectories of VS vs. DS iFC might underlie adolescents' unique behavioral patterns and vulnerabilities to psychopathology, and also speaks to changes in motivational networks that extend well past 25 years old.

Role of contingency in striatal response to incentive in adolescents with anxiety.

This study examines the effect of contingency on reward function in anxiety. We define contingency as the aspect of a situation in which the outcome is determined by one's action-that is, when there is a direct link between one's action and the outcome of the action. Past findings in adolescents with anxiety or at risk for anxiety have revealed hypersensitive behavioral and neural responses to higher value rewards with correct performance. This hypersensitivity to highly valued (salient) actions suggests that the value of actions is determined not only by outcome magnitude, but also by the degree to which the outcome is contingent on correct performance. Thus, contingency and incentive value might each modulate reward responses in unique ways in anxiety. Using fMRI with a monetary reward task, striatal response to cue anticipation is compared in 18 clinically anxious and 20 healthy adolescents. This task manipulates orthogonally reward contingency and incentive value. Findings suggest that contingency modulates the neural response to incentive magnitude differently in the two groups. Specifically, during the contingent condition, right-striatal response tracks incentive value in anxious, but not healthy, adolescents. During the noncontingent condition, striatal response is bilaterally stronger to low than to high incentive in anxious adolescents, while healthy adolescents exhibit the expected opposite pattern. Both contingency and reward magnitude differentiate striatal activation in anxious versus healthy adolescents. These findings may reflect exaggerated concern about performance and/or alterations of striatal coding of reward value in anxious adolescents. Abnormalities in reward function in anxiety may have treatment implications.

Alterations in amygdala functional connectivity reflect early temperament.

Behavioral inhibition (BI) is a temperament identified early in life that is associated with increased risk for anxiety disorders. Amygdala hyperresponsivity, found both in behaviorally inhibited and anxious individuals, suggests that amygdala dysfunction may represent a marker of anxiety risk. However, broader amygdala networks have not been examined in individuals with a history of childhood BI. This study uses resting state fMRI to assess amygdala intrinsic functional connectivity (iFC) in 38 healthy young adults (19 with a history of BI, 19 with no history of BI) selected from a longitudinal study. Centromedial, basolateral, and superficial amygdala iFCs were compared between groups and examined in relation to self-report measures of anxiety. Group differences were observed in amygdala iFC with prefrontal cortex, striatum, anterior insula, and cerebellum. Adults characterized with BI in childhood endorsed greater state anxiety prior to entering the scanner, which was associated with several of the group differences. Findings support enduring effects of BI on amygdala circuitry, even in the absence of current psychopathology.