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.

Looking for the negative: Depressive symptoms in adolescent girls are associated with sustained attention to a potentially critical judge during in vivo social evaluation.

Attention biases toward negative stimuli are implicated in the development and maintenance of depression. However, research is needed to understand how depression affects attention biases as they unfold in a dynamic social environment, particularly during adolescence when depression rates significantly increase due to enhanced reactivity to social stress. To examine attention biases in a live, socially evaluative environment, 26 adolescent girls from the community gave a speech in front of a potentially critical judge and a positive judge while wearing mobile eye tracking glasses. Girls' depressive symptoms were measured using the Moods and Feelings Questionnaire. Across the sample, girls looked at the positive judge more frequently and for longer periods of time compared with the potentially critical judge. In contrast, higher depressive symptoms were associated with looking at the potentially critical judge for longer periods of time. When directly comparing attention to the potentially critical judge relative to the positive judge, dysphoric girls looked at the potentially critical judge more frequently and for longer periods of time compared with the positive judge. Findings suggest that adolescent depressive symptoms are related to sustained attention toward potentially critical evaluation at the exclusion of positive evaluation. This novel approach allowed for an in vivo examination of attention biases as they unfold during social evaluation, which begins to illuminate the interpersonal significance of attention biases. If replicated and extended longitudinally, this research could be used to identify adolescents at high risk for future depression and potentially be leveraged clinically in attention bias modification treatment.

Adolescent Gaze-Directed Attention During Parent-Child conflict: The Effects of Depressive Symptoms and Parent-Child Relationship Quality.

Although dysfunctions in attention have been implicated in the development and maintenance of depression in adults, findings from studies of depressed adolescents have been inconsistent. While some research has shown that youth with depressive symptoms exhibit increased attention to negative stimuli, other findings demonstrated attentional avoidance. Additionally, given the increase in parent-child conflict during adolescence, parent-child relationship quality may be an important moderating factor in the association between depressive symptoms and attention. To examine how depressive symptoms and parent-child relationship quality during adolescence influence attention, 25 mother-daughter pairs (girls ages 11-16) completed a conflict discussion task while wearing mobile eye-tracking glasses. Results suggest that girls with low positive parent-child relationship quality and greater depressive symptoms may have difficulty disengaging from their mother during negative interactions, which may exacerbate depressive symptoms. Therefore, the parent-child relationship should be further considered in treatments that target maladaptive attention patterns in youth with depressive symptoms.

Attention to Peer Feedback Through the Eyes of Adolescents with a History of Anxiety and Healthy Adolescents.

During adolescence, youth may experience heightened attention bias to socially relevant stimuli; however, it is unclear if attention bias toward social threat may be exacerbated for adolescents with a history of anxiety. This study evaluated attentional bias during the Chatroom-Interact task with 25 adolescents with a history of anxiety (18F, Mage = 13.6) and 22 healthy adolescents (13F, Mage = 13.8). In this task, participants received feedback from fictional, virtual peers who either chose them (acceptance) or rejected them (rejection). Overall, participants were faster to orient toward and spent longer time dwelling on their own picture after both rejection and acceptance compared to non-feedback cues. Social feedback was associated with greater pupillary reactivity, an index of cognitive and emotional neural processing, compared to non-feedback cues. During acceptance feedback (but not during rejection feedback), anxious youth displayed greater pupil response compared to healthy youth, suggesting that positive feedback from peers may differentially influence youth with a history of an anxiety disorder.

Incidental threat during visuospatial working memory in adolescent anxiety: an emotional memory-guided saccade task.

BACKGROUND: Pediatric anxiety disorders are among the most common psychiatric mental illnesses in children and adolescents, and are associated with abnormal cognitive control in emotional, particularly threat, contexts. In a series of studies using eye movement saccade tasks, we reported anxiety-related alterations in the interplay of inhibitory control with incentives, or with emotional distractors. The present study extends these findings to working memory (WM), and queries the interaction of spatial WM with emotional stimuli in pediatric clinical anxiety. METHODS: Participants were 33 children/adolescents diagnosed with an anxiety disorder, and 22 age-matched healthy comparison youths. Participants completed a novel eye movement task, an affective variant of the memory-guided saccade task. This task assessed the influence of incidental threat on spatial WM processes during high and low cognitive load. RESULTS: Healthy but not anxious children/adolescents showed slowed saccade latencies during incidental threat in low-load but not high-load WM conditions. No other group effects emerged on saccade latency or accuracy. CONCLUSIONS: The current data suggest a differential pattern of how emotion interacts with cognitive control in healthy youth relative to anxious youth. These findings extend data from inhibitory processes, reported previously, to spatial WM in pediatric anxiety.

Modeling sensitivity to social threat in adolescent girls: A psychoneurometric approach.

The Research Domain Criteria (RDoC) project's success rests on the assumption that constructs and data can be integrated across units of analysis and developmental stages. We adopted a psychoneurometric approach to establish biobehavioral liability models of sensitivity to social threat, a key component of potential threat that is particularly salient to the development of adolescent affective psychopathology. Models were derived from measures across four units of analysis in a community sample (n = 129) of 11- to 13-year-old girls oversampled for shy/fearful temperament. To test the ecological validity of derived factors, they were then related to real-world socioaffective processes in peer interactions over a 16-day ecological momentary assessment (EMA) protocol. Our results indicate that measures (i.e., amygdala reactivity to negative social feedback, eye-tracking bias toward social threat, parent- and adolescent-reports of social threat sensitivity) formed unit-specific factors, rather than one unified factor. These findings suggest that these factors were largely unrelated. Amygdala response to social punishment and attention bias toward threatening faces predicted real-world experiences with peers, suggesting that vigilance toward potentially threatening social information could be a mechanism through which vulnerable youth come to experience their peer interactions more negatively. We discuss measurement challenges confronting efforts to quantify developmentally sensitive RDoC constructs across units of analysis. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

"Don't judge me!": Links between in vivo attention bias toward a potentially critical judge and fronto-amygdala functional connectivity during rejection in adolescent girls.

During adolescence, increases in social sensitivity, such as heightened attentional processing of social feedback, may be supported by developmental changes in neural circuitry involved in emotion regulation and cognitive control, including fronto-amygdala circuitry. Less negative fronto-amygdala circuitry during social threat processing may contribute to heightened attention to social threat in the environment. However, "real-world" implications of altered fronto-amygdala circuitry remain largely unknown. In this study, we used multiple novel methods, including an in vivo attention bias task implemented using mobile eye-tracking glasses and socially interactive fMRI task, to examine how functional connectivity between the amygdala and prefrontal cortex (PFC) during rejection and acceptance feedback from peers is associated with heightened attention towards potentially critical social evaluation in a real-world environment. Participants were 77 early adolescent girls (ages 11-13) oversampled for shy/fearful temperament. Results support the reliability of this in vivo attention task. Further, girls with more positive functional connectivity between the right amygdala and anterior PFC during both rejection and acceptance feedback attended more to potentially critical social evaluation during the attention task. Findings could suggest that dysfunction in prefrontal regulation of the amygdala's response to salient social feedback supports heightened sensitivity to socially evaluative threat during adolescence.

Validating a mobile eye tracking measure of integrated attention bias and interpretation bias in youth.

INTRODUCTION: This study sought to validate a real-world speech task designed to assess attention and interpretation bias in an integrated and ecologically valid manner. METHODS: Thirty adolescent girls gave a speech in front of an emotionally ambiguous judge and a positive judge while wearing mobile eye tracking glasses to assess how long they looked at each judge (i.e., attention bias). They also reported their interpretations of the ambiguous judge and distress associated with the task (i.e., interpretation bias). RESULTS: These task-based measures correlated with self-report of interpretation bias and mother-report of attentional control, demonstrating convergent validity. They did not correlate with frustration or high intensity pleasure, indicating discriminant validity. Task-based measures of interpretation bias also showed predictive and incremental validity in relation to child distress during the speech. DISCUSSION: This proof-of-concept study demonstrates the initial validity of a novel task designed to assess attention and interpretation bias as they manifest in real-world social interactions.

Using a Smartphone App and Clinician Portal to Enhance Brief Cognitive Behavioral Therapy for Childhood Anxiety Disorders.

Cognitive behavioral therapy (CBT) is an efficacious treatment for child anxiety disorders, but 40%-50% of youth do not respond fully to treatment, and time commitments for standard CBT can be prohibitive for some families and lead to long waiting lists for trained CBT therapists in the community. SmartCAT 2.0 is an adjunctive mobile health program designed to improve and shorten CBT treatment for anxiety disorders in youth by providing them with the opportunity to practice CBT skills outside of session using an interactive and gamified interface. It consists of an app and an integrated clinician portal connected to the app for secure 2-way communication with the therapist. The goal of the present study was to evaluate SmartCAT 2.0 in an open trial to establish usability, feasibility, acceptability, and preliminary efficacy of brief (8 sessions) CBT combined with SmartCAT. We also explored changes in CBT skills targeted by the app. Participants were 34 youth (ages 9-14) who met DSM-5 criteria for generalized, separation, and/or social anxiety disorder. Results demonstrated strong feasibility and usability of the app/portal and high satisfaction with the intervention. Youth used the app an average of 12 times between each therapy session (M = 5.8 mins per day). At posttreatment, 67% of youth no longer met diagnostic criteria for an anxiety disorder, with this percentage increasing to 86% at 2-month follow-up. Youth showed reduced symptom severity over time across raters and also improved from pre- to posttreatment in CBT skills targeted by the app, demonstrating better emotion identification and thought challenging and reductions in avoidance. Findings support the feasibility of combining brief CBT with SmartCAT. Although not a controlled trial, when benchmarked against the literature, the current findings suggest that SmartCAT may enhance the utility of brief CBT for childhood anxiety disorders.

An integrative review of the vigilance-avoidance model in pediatric anxiety disorders: Are we looking in the wrong place?

Enduring cognitive models of anxiety posit that negative biases in information processing are implicated in the etiology, maintenance, and recurrence of anxiety disorders in youth and adults. Specifically, the vigilance-avoidance model of attention is an influential hypothesis proposed to explain anxious individuals' attentional patterns. The vigilance-avoidance model posits that anxious individuals, relative to nonanxious individuals, initially orient more quickly to threatening stimuli and then later avoid threatening stimuli. However, a large body of empirical research examining attentional mechanisms in anxious individuals uses paradigms that do not allow the measurement of the time course of attention. Furthermore, existing reviews that examine the time course of attention only include studies with adults. We systematically review in depth the literature that compares anxious and non-anxious children that takes advantage of research designs that allow the examination of the time course of attention. Across studies, there is not robust support for the vigilance-avoidance model in samples of anxious youth. Future research examining attention biases across time should employ tasks that more directly measure multiple stages of attention, in order to assess if vigilance-avoidance patterns emerge based on sample characteristics or task variables, and to inform intervention efforts.

A Longitudinal Follow-up Study Examining Adolescent Depressive Symptoms as a Function of Prior Anxiety Treatment.

OBJECTIVE: Children who are fearful and anxious are at heightened risk for developing depression in adolescence. Treating anxiety disorders in pre-/early adolescence may be one mechanism through which depressive symptoms later in adolescence can be prevented. We hypothesized that anxious youth who responded positively to cognitive-behavioral therapy (CBT) for anxiety would show reduced onset of depressive symptoms 2 years later compared to treatment nonresponders, and that this effect would be specific to youth treated with CBT compared to an active supportive comparison treatment. METHOD: Participants were 80 adolescents ages 11 to 17 years who had previously completed a randomized trial comparing predictors of treatment response to CBT and child-centered therapy (CCT). Youth met DSM-IV criteria for generalized, separation, and/or social anxiety disorder at the time of treatment. The present study was a prospective naturalistic 2-year follow-up examining trajectories toward depression, in which participants were reassessed for depressive symptoms 2 years after anxiety treatment. Treatment response was defined as a 35% reduction in independent evaluator-rated anxiety severity on the Pediatric Anxiety Rating Scale after treatment. RESULTS: As hypothesized, lower levels of depressive symptoms were observed in anxious youth who responded to CBT for anxiety (ß = -0.807, p = .004) but not CCT (ß = 0.254, p = .505). Sensitivity analyses showed that the effects were driven by girls. CONCLUSION: Findings suggest that CBT for anxiety is a promising approach to preventing adolescent depressive symptomatology, especially among girls. The results highlight the need for better early screening for anxiety and better dissemination of CBT programs targeting anxiety in youth.

The role of day-to-day emotions, sleep, and social interactions in pediatric anxiety treatment.

Do day-to-day emotions, social interactions, and sleep play a role in determining which anxious youth respond to supportive child-centered therapy (CCT) versus cognitive behavioral therapy (CBT)? We explored whether measures of day-to-day functioning (captured through ecological momentary assessment, sleep diary, and actigraphy), along with clinical and demographic measures, were predictors or moderators of treatment outcome in 114 anxious youth randomized to CCT or CBT. We statistically combined individual moderators into a single, optimal composite moderator to characterize subgroups for which CCT or CBT may be preferable. The strongest predictors of better outcome included: (a) experiencing higher positive affect when with one's mother and (b) fewer self-reported problems with sleep duration. The composite moderator indicated that youth for whom CBT was indicated had: (a) more day-to-day sleep problems related to sleep quality, efficiency, and waking, (b) day-to-day negative events related to interpersonal concerns, (c) more DSM-IV anxiety diagnoses, and (d) college-educated parents. These findings illustrate the value of both day-to-day functioning characteristics and more traditional sociodemographic and clinical characteristics in identifying optimal anxiety treatment assignment. Future studies will need to enhance the practicality of real-time measures for use in clinical decision making and evaluate additional anxiety treatments.

Anxiety and Gender Influence Reward-Related Processes in Children and Adolescents.

OBJECTIVE: This study examined the effects of pediatric anxiety and its interaction with gender on reward processes. Based on the purported greater sensitivity to risk in females than males and the propensity for risk aversion in anxiety, clinical anxiety and female gender were hypothesized to act synergistically in reducing reward sensitivity and increasing risk aversion in a pediatric population. METHODS: This hypothesis was tested in two separate experiments using two independent samples. Both experiments compared clinically anxious with typically developing (TD) youth, 8-18 years. Experiment 1 used a decision-making task, the Wheel of Fortune task (WOF), to examine risk taking as a function of varying levels of risk and reward in 36 anxious and 61 TD youths. Experiment 2 used an incentive delay task, the Piñata task, to examine sensitivity to reward and motivation to work for a reward in 38 anxious and 30 TD youth. Percent bet, reaction time, and accuracy were analyzed as a function of gender and diagnostic group. RESULTS: As hypothesized, anxiety was associated with reduced risk taking and sensitivity to reward. However, contrary to prediction, this effect was seen in males and not in females. These findings are consistent across both experiments. In experiment 1 (WOF), betting rate (i.e., risk taking) was significantly lower in anxious than in TD males (F[1;53] = 7.07, p = 0.01), whereas anxious females did not differ from TD females (F[1,42] = 1.2, p = 0.28). In experiment 2 (Piñata), anxiety impaired performance accuracy in males (F[1;36] = 8.39; p < 0.01) but not females (F[1;28] = 0.6; p = 0.445). CONCLUSIONS: Anxiety affected reward function differently in males and females. Contrary to hypothesis, anxious females behaved similarly to TD females on both tasks. However, anxious males were significantly more risk averse and less accurate than TD males. These findings suggest that therapeutic interventions for anxiety, which use manipulations of reward processes, should consider gender for optimal outcome.

Age and Social Context Modulate the Effect of Anxiety on Risk-taking in Pediatric Samples.

Although risk-taking has been studied from a developmental perspective, no study has examined how anxiety, age, risk-valence and social context interact to modulate decision-making in youths. This study probes this question using a risk-taking task, the Stunt Task, in clinically anxious children (n = 17, 10 F, age = 8.3-12.1 years), healthy children (n = 13, 4 F, age = 9.3-12.2 years), clinically anxious adolescents (n = 18, 6 F, age = 12.3-17.7 years), and healthy adolescents (n =14, 10 F, age = 12.5-17.3 years). Social context was manipulated: in one condition, participants were led to believe that a group of peers were observing and judging their performance (peer-judge), while, in the other condition, they were led to believe that peers were not observing them (control). Only anxious children showed an influence of social context on their risk-taking behavior. Specifically, anxious children bet significantly less and had slower reaction times (RT) during the peer-judge than control condition. However, across social conditions, risk-valence modulated RT differently in function of age and diagnosis. Anxious children were slower on the positive-valence risky trial, whereas anxious adolescents were slower on the negative-valence risky trials relative to their respective healthy peers. In conclusion, clinically anxious children were the only group that was sensitive (risk-averse) to the effect of a negative peer-judge context. The negative peer-judge context did not affect risky decision-making in adolescents, whether they were anxious or healthy. Future work using a stronger aversive social context might be more effective at influencing risky behavior in this age group.

From anxious youth to depressed adolescents: Prospective prediction of 2-year depression symptoms via attentional bias measures.

Anxious youth are at heightened risk for subsequent development of depression; however, little is known regarding which anxious youth are at the highest prospective risk. Biased attentional patterns (e.g., vigilance and avoidance of negative cues) are implicated as key mechanisms in both anxiety and depression. Aberrant attentional patterns may disrupt opportunities to effectively engage with, and learn from, threatening aspects of the environment during development and/or treatment, compounding risk over time. Sixty-seven anxious youth (ages 9-14; 36 female) completed a dot-probe task to assess baseline attentional patterns provoked by fearful-neutral face pairs. The time course of attentional patterns both during and after threat was assessed via eye-tracking and pupilometry. Self-reported depressive and anxiety symptoms were assessed 2 years after the conclusion of a larger psychotherapy treatment trial. Eye-tracking patterns indicating threat avoidance predicted greater 2-year depression scores, over and above baseline and posttreatment symptoms. Sustained, postthreat pupillary avoidance (reflecting preferential neural engagement with the neutral relative to the previously threatening location) predicted additional variance in depression scores, suggesting sustained avoidance in the wake of threat further exacerbated risk. Identical eye-tracking and pupil indices were not predictive of anxiety at 2 years. These biobehavioral markers imply that avoidant attentional processing in the context of anxiety may be a gateway to depression across a key maturational window. Excessive avoidance of threat could interfere with acquisition of adaptive emotion regulation skills during development, culminating in the broad behavioral deactivation that typifies depression. Prevention efforts explicitly targeting avoidant attentional patterns may be warranted.

Mobile technology boosts the effectiveness of psychotherapy and behavioral interventions: a meta-analysis.

We conducted a meta-analysis on the effects of mobile technology on treatment outcome for psychotherapy and other behavioral interventions. Our search of the literature resulted in 26 empirical articles describing 25 clinical trials testing the benefits of smartphone applications, personal digital assistants (PDAs), or text messaging systems either to supplement treatment or substitute for direct contact with a clinician. Overall, mobile technology use was associated with superior treatment outcome across all study designs and control conditions, effect size (ES) = .34, p < .0001. For the subset of 10 studies that looked specifically at the added benefit of mobile technology using a rigorous "Treatment" versus "Treatment + Mobile" design, effect sizes were only slightly more modest (ES = .27) and still significant (p < .05). Overall, the results support the role of mobile technology for the delivery of psychotherapy and other behavioral interventions.

Emotional and Nonemotional Conflict Processing in Pediatric and Adult Anxiety Disorders.

OBJECTIVE: Perturbations in emotional conflict adaptation, an implicit regulatory process, have been observed in adult anxiety disorders. However, findings remain inconsistent and restricted to adults. The current study compares conflict adaptation in youth and adults, with and without anxiety disorders. We predicted conflict adaptation would be present in the healthy but not the anxious groups. METHODS: In a clinic setting, 111 participants (27 healthy youth, 22 anxious youth, 41 healthy adults, and 21 anxious adults) completed emotional and nonemotional conflict tasks. Groups did not differ (all p's >0.1) on intelligence quotient (IQ), gender, and socioeconomic status; age did not differ between healthy and anxious subjects in either age cohort. Separate four way mixed-design analyses of variance were conducted to test hypotheses regarding the influence of diagnosis, age group, and task type on accuracy (percent correct) and reaction time (RT) for conflict adaptation (incongruent trials preceded by incongruent vs. congruent trials) and conflict detection (incongruent vs. congruent trials). RESULTS: Measures of conflict adaptation did not interact with diagnosis or age. There was a significant main effect of conflict adaptation across the overall sample in the expected direction for accuracy, but not RT. The well-replicated conflict detection effect also did emerge across tasks, with slower RT and lower accuracy for incongruent than for congruent trials. These effects were greater for the emotional than for nonemotional tasks. Finally, there were age differences in accuracy-based conflict detection specific to the emotional task, for which the size of the effect was larger for youth than for adults. CONCLUSIONS: The current study of youth and adults did not replicate prior behavioral findings of failure to engage conflict adaptation in anxiety disorders. Therefore, more work is needed before widely adopting conflict adaptation paradigms as a standard neurocognitive marker for anxiety disorders.

Oxytocin and vasopressin modulate risk-taking.

The modulation of risk-taking is critical for adaptive and optimal behavior. This study examined how oxytocin (OT) and arginine vasopressin (AVP) influence risk-taking in function of three parameters: sex, risk-valence, and social context. Twenty-nine healthy adults (14 males) completed a risk-taking task, the Stunt task, both in a social-stress (evaluation by unfamiliar peers) and non-social context, in three separate drug treatment sessions. During each session, one of three drugs, OT, AVP, or placebo (PLC), was administered intra-nasally. OT and AVP relative to PLC reduced betting-rate (risk-averse effect). This risk-averse effect was further qualified: AVP reduced risk-taking in the positive risk-valence (high win-probability), and regardless of social context or sex. In contrast, OT reduced risk-taking in the negative risk-valence (low win-probability), and only in the social-stress context and men. The reduction in risk-taking might serve a role in defensive behavior. These findings extend the role of these neuromodulators to behaviors beyond the social realm. How the behavioral modulation of risk-taking maps onto the function of the neural targets of OT and AVP may be the next step in this line of research.

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.

Low rate of non-attenders to primary care providers in Israel - a retrospective longitudinal study.

BACKGROUND: A model that combines reactive and anticipatory care within routine consultations has become recognized as a cost-effective means of providing preventive health care, challenging the need of the periodic health examination. As such, opportunistic screening may be preferable to organized screening. Provision of comprehensive preventive healthcare within the primary care system depends on regular attendance of the general population to primary care physicians (PCPs). OBJECTIVES: To assess the proportion of patients who do not visit a PCP even once during a four-year period, and to describe the characteristics of this population. METHODS: An observational study, based on electronic medical records of 421,012 individuals who were members of one district of Clalit Health Services, the largest health maintenance organization in Israel. RESULTS: The average annual number of visits to PCPs was 7.6 ± 8.7 to 8.3 ± 9.0 (median 5, 25%-75% interval 1-11) and 9.5 ± 10.0 to10.2 ± 10.4 (median 6, 25%-75% interval 1-14) including visits to direct access consultants) in the four years of the study. During the first year of the study 87.2% of the population visited a PCP. During the four year study period, only 1.5% did not visit a PCP even once. In a multivariate analysis having fewer chronic diseases (for each additional chronic disease the OR, 95% CI was 0.40 (0.38¬0.42)), being a new immigrant (OR, 95% CI 2.46 (2.32¬2.62)), and being male (OR, 95% CI 1.66 (1.58¬1.75)) were the strongest predictors of being a non-attender to a PCP for four consecutive years. CONCLUSIONS: The rate of nonattendance to PCPs in Israel is low. Other than new immigrant status, none of the characteristics identified for nonattendance suggest increased need for healthcare services.