Secondary analyses of sex differences in attention improvements across three clinical trials of a digital therapeutic in children, adolescents, and adults with ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. Inattentive symptoms, often predominant in girls with ADHD, represent a key driver of impairment and often persist into adulthood. AKL-T01 is a regulated digital therapeutic targeting inattention. We examined potential sex differences in the efficacy of AKL-T01 in three separate trials for 1) children, 2) adolescents, and 3) adults. METHODS: We conducted secondary analyses of clinical outcomes by sex in three AKL-T01 randomized clinical trials in ADHD (n1 = 180 children 30.6% female, M(SD) age = 9.71 (1.32); n2 = 146 adolescents; 41.1% female, M(SD) age = 14.34 (1.26); n3 = 153 adults; 69.9% female, M(SD) age = 39.86 (12.84)). Active treatment participants used AKL-T01 for 25 min/day over 4-6 weeks. Primary outcomes included change in attention on the Test of Variables of Attention (TOVA) and symptom change on the clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of robust linear regressions of TOVA and ADHD-RS change scores by sex, adjusting for baseline scores. RESULTS: In children, girls demonstrated greater improvement in objective attention relative to boys following AKL-T01 (TOVA Attentional Composite Score; Cohen's d = .36 and Reaction Time Mean Half; Cohen's d = .54), but no significant sex differences in ADHD rating scale change. We did not observe significant sex differences in outcomes in the adolescent or adult trials. Limitations include binary sex categorization and slight study design variation across the three samples. CONCLUSION: AKL-T01 might notably improve attentional functioning in girls with ADHD relative to boys. Objective attention measures may be particularly important in the assessment of attentional improvement in childhood, given known gender biases in ADHD symptom reporting. We emphasize the importance of considering sex and gender-specific factors in ADHD treatment evaluation. TRIAL REGISTRATIONS: STARS ADHD CHILD: ClinicalTrials.gov ID NCT03649074; STARS ADHD ADOLESCENT: ClinicalTrials.gov ID NCT04897074; STARS ADHD ADULT: ClinicalTrials.gov ID NCT05183919.

Preliminary Efficacy of a Digital Intervention for Adolescent Depression: Randomized Controlled Trial.

BACKGROUND: Adolescent depression is a significant public health concern; however, access to effective mental health care is limited. Digital therapeutics (DTx) can improve access to evidence-based interventions; however, their efficacy in adolescents is sparsely documented. OBJECTIVE: This study aims to examine the efficacy of a mobile app DTx versus an active control as an adjunct treatment for adolescent depression symptoms. METHODS: An internet-based open-label randomized control trial was conducted nationwide with a partial crossover design, and 168 adolescents aged 13 to 21 years with symptoms of depression were recruited between November 2020 and September 2021. Participants were randomized (1:1) to the cognitive behavioral therapy-based treatment app (Spark) or to a psychoeducational control app (control), which they would use for a duration of 5 weeks. The primary outcome was a between-group (Spark vs control) difference in the change in depression symptoms from baseline to postintervention, as measured by the Patient Health Questionnaire-8 (PHQ-8) using a linear mixed-effects analysis. The PHQ-8 ranges from 0 to 24, with scores of 5 to 9 indicating mild depression symptoms, scores of 10 to 14 indicating moderate symptoms, scores of 15 to 19 indicating moderately severe symptoms, and scores of 20 to 24 indicating severe symptoms. A minimal clinically important difference (5-point reduction between baseline and postintervention) in the Spark arm and group differences in remission and treatment response rates based on the PHQ-8 at postintervention were also investigated. RESULTS: A total of 160 participants were randomized, 80 in the Spark arm (mean age 16.89, SD 2.5 y) and 80 in the control arm (mean age 16.79, SD 2.59 y). Data from 121 participants (Spark: n=63; control: n=58) with moderate to severe (PHQ-8≥10) symptoms at baseline were included in the primary analyses following a modified intention-to-treat principle. A linear mixed-effect analysis revealed a nonsignificant difference between the study arms in depression symptom change over the intervention period. The Spark arm met a minimal clinically important difference threshold (mean -5.08, 95% CI -6.72 to -3.42). The remission rate in the Spark arm was significantly higher than that in the control arm (11/63, 17% vs 2/58, 3%; χ21=6.2; P=.01; false discovery rate-adjusted P=.03). The treatment response rates were not significantly different between the study arms (P=.07; false discovery rate-adjusted P=.16). Post hoc analyses including participants with mild to severe (PHQ-8 score ≥5) symptoms at baseline revealed promising evidence that Spark is effective in those with mild to severe symptoms. CONCLUSIONS: There is initial evidence that a self-guided, cognitive behavioral therapy-based DTx intervention may effectively treat mild to severe depression symptoms in adolescents. DTx may improve access to mental health care for adolescents or serve as an important adjunct to the standard of care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04524598; https://clinicaltrials.gov/study/NCT04524598.

Developmental changes in brain function linked with addiction-like social media use two years later.

Addiction-like social media use (ASMU) is widely reported among adolescents and is associated with depression and other negative health outcomes. We aimed to identify developmental trajectories of neural social feedback processing that are linked to higher levels of ASMU in later adolescence. Within a longitudinal design, 103 adolescents completed a social incentive delay task during 1-3 fMRI scans (6-9th grade), and a 4th self-report assessment of ASMU and depressive symptoms ∼2 years later (10-11th grade). We assessed ASMU effects on brain responsivity to positive social feedback across puberty and relationships between brain responsivity development, ASMU symptoms, and depressive symptoms while considering gender effects. Findings demonstrate decreasing responsivity, across puberty, in the ventral media prefrontal cortex, medial prefrontal cortex, posterior cingulate cortex, and right inferior frontal gyrus associated with higher ASMU symptoms over 2 years later. Significant moderated mediation models suggest that these pubertal decreases in brain responsivity are associated with increased ASMU symptoms which, among adolescent girls (but not boys), is in turn associated with increased depressive symptoms. Results suggest initial hyperresponsivity to positive social feedback, before puberty onset, and decreases in this response across development, may be risk factors for ASMU in later adolescence.

Comparing the multivariate relationships of conceptual adversity models and structural brain development in adolescent girls: A registered report.

Adverse experiences throughout development confer risk for a multitude of negative long-term outcomes, but the processes via which these experiences are neurobiologically embedded are still unclear. Adolescence provides an opportunity to understand how these experiences impact the brain's rapidly changing structure. Two models are central to current adversity conceptualizations: a cumulative risk model, where all types of experiences are combined to represent accumulating stress, and a dimensional model, where certain features of experience (e.g., threat or deprivation) exert unique neurophysiological influence. In this registered report, we extended upon previous research by using a form of representational similarity analysis to examine whether the dimensional and cumulative risk models of adversity predict cortical thinning in frontoparietal and frontotemporal networks and volumetric changes in subcortical regions throughout adolescence. Drawing from a longitudinal sample of 179 adolescent girls (ages 10-13 years at the first wave) from Lane County, Oregon, United States, and up to four waves of follow-up data, we found that operationalizing adversity by similarity in threat and deprivation provided better prediction of brain development than similarity in overall adversity. However, these dimensions do not exhibit unique associations with developmental changes in the hypothesized brain changes. These results underscore the significance of carefully defining adversity and considering its impact on the entire brain. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Telomere Erosion and Depressive Symptoms Across Development Following Institutional Care.

OBJECTIVE: A large literature has identified exposure to early caregiving adversities as a potent risk for developing affective psychopathology, with depression, in particular, increasing across childhood into adolescence. Evidence suggests telomere erosion, a marker of biological aging, may underlie associations between adverse early-life experiences and later depressive behavior; yet, little is understood about this association during development. METHOD: The current accelerated longitudinal study examined concurrent telomere length and depressive symptoms concurrently, 2 and 4 years later, from the preschool period through adolescence among children exposed (n =116) and not exposed (n = 242) to early previous institutional (PI) care. RESULTS: PI care was associated with shorter telomeres on average and with quadratic age-related growth in depressive symptoms, indicating a steeper association between PI care and depressive symptoms in younger age groups that leveled off in adolescence. Contrary to studies in adult samples, telomere length was not associated with depressive symptoms, and it did not predict future symptoms. CONCLUSION: These findings indicate that early caregiving disruptions increase the risk for both accelerated biological aging and depressive symptoms, although these variables did not correlate with each other during this age range.

Acculturative Orientations Among Hispanic/Latinx Caregivers in the ABCD Study: Associations With Caregiver and Youth Mental Health and Youth Brain Function.

Background: Population-based neuroscience offers opportunities to examine important but understudied sociocultural factors such as acculturation. Acculturation refers to the extent to which an individual retains their cultural heritage and/or adopts the receiving society's culture and is particularly salient among Hispanic/Latinx immigrants. Specific acculturative orientations have been linked to vulnerability to substance use, depression, and suicide and are known to influence family dynamics between caregivers and their children. Methods: Using data from first- and second-generation Hispanic/Latinx caregivers in the Adolescent Brain Cognitive Development (ABCD) Study (N = 1057), we examined how caregivers' acculturative orientation affects their mental health, as well as the mental health and brain function of their children. Neuroimaging analyses focused on regions associated with self- and affiliation-based social processing (ventromedial prefrontal cortex, insula, and temporoparietal junction). Results: We identified 2 profiles of caregiver acculturation: bicultural (retains heritage culture while adopting U.S. culture) and detached (discards heritage culture and rejects U.S. culture). Bicultural caregivers exhibited fewer internalizing and externalizing problems than detached caregivers; furthermore, youth exhibited similar internalizing effects across caregiver profiles. In addition, youth with bicultural caregivers displayed increased resting-state brain activity (i.e., fractional amplitude of low-frequency fluctuations and regional homogeneity) in the left insula, which has been linked to psychopathology; however, differences in long-range functional connectivity were not significant. Conclusions: Caregiver acculturation is an important familial factor that has been linked to significant differences in youth mental health and insula activity. Future work should examine sociocultural and neurodevelopmental changes across adolescence to assess health outcomes and determine whether localized, corticolimbic brain effects are ultimately translated into long-range connectivity differences.

Methods for decoding cortical gradients of functional connectivity.

Macroscale gradients have emerged as a central principle for understanding functional brain organization. Previous studies have demonstrated that a principal gradient of connectivity in the human brain exists, with unimodal primary sensorimotor regions situated at one end and transmodal regions associated with the default mode network and representative of abstract functioning at the other. The functional significance and interpretation of macroscale gradients remains a central topic of discussion in the neuroimaging community, with some studies demonstrating that gradients may be described using meta-analytic functional decoding techniques. However, additional methodological development is necessary to fully leverage available meta-analytic methods and resources and quantitatively evaluate their relative performance. Here, we conducted a comprehensive series of analyses to investigate and improve the framework of data-driven, meta-analytic methods, thereby establishing a principled approach for gradient segmentation and functional decoding. We found that a two-segment solution determined by a k-means segmentation approach and an LDA-based meta-analysis combined with the NeuroQuery database was the optimal combination of methods for decoding functional connectivity gradients. Finally, we proposed a method for decoding additional components of the gradient decomposition. The current work aims to provide recommendations on best practices and flexible methods for gradient-based functional decoding of fMRI data.

A CBT-based mobile intervention as an adjunct treatment for adolescents with symptoms of depression: a virtual randomized controlled feasibility trial.

Background: High rates of adolescent depression demand for more effective, accessible treatment options. A virtual randomized controlled trial was used to assess the feasibility and acceptability of a 5-week, self-guided, cognitive behavioral therapy (CBT)-based mobile application, Spark, compared to a psychoeducational mobile application (Active Control) as an adjunct treatment for adolescents with depression during the COVID-19 pandemic. Methods: A community sample aged 13-21, with self-reported symptoms of depression, was recruited nationwide. Participants were randomly assigned to use either Spark or Active Control (NSpark = 35; NActive Control = 25). Questionnaires, including the PHQ-8 measuring depression symptoms, completed before, during, and immediately following completion of the intervention, evaluated depressive symptoms, usability, engagement, and participant safety. App engagement data were also analyzed. Results: 60 eligible adolescents (female = 47) were enrolled in 2 months. 35.6% of those expressing interest were consented and all enrolled. Study retention was high (85%). Spark users rated the app as usable (System Usability Scalemean = 80.67) and engaging (User Engagement Scale-Short Formmean = 3.62). Median daily use was 29%, and 23% completed all levels. There was a significant negative relationship between behavioral activations completed and change in PHQ-8. Efficacy analyses revealed a significant main effect of time, F = 40.60, p < .001, associated with decreased PHQ-8 scores over time. There was no significant Group × Time interaction (F = 0.13, p = .72) though the numeric decrease in PHQ-8 was greater for Spark (4.69 vs. 3.56). No serious adverse events or adverse device effects were reported for Spark users. Two serious adverse events reported in the Active Control group were addressed per our safety protocol. Conclusion: Recruitment, enrollment, and retention rates demonstrated study feasibility by being comparable or better than other mental health apps. Spark was highly acceptable relative to published norms. The study's novel safety protocol efficiently detected and managed adverse events. The lack of significant difference in depression symptom reduction between Spark and Active Control may be explained by study design and study design factors. Procedures established during this feasibility study will be leveraged for subsequent powered clinical trials evaluating app efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04524598.

Cascading bidirectional influences of digital media use and mental health in adolescence.

A substantial portion of critical adolescent development is occurring within digital environments. However, certain individual differences may lead adolescents to use digital media in diverse ways. In this chapter we suggest that the way teens use digital media influences how digital media affects their mental health. Further, we propose a model in which these influences, in the context of ongoing development, may have feedback effects on how digital media is subsequently used, thus resulting in a self-perpetuating cycle. Our model suggests that certain developmental risk/protective factors and maladaptive/adaptive digital media behaviors likely perpetuate each other in a cyclical manner each serving to maintain and/or escalate the other. We discuss existing evidence of these processes in psychosocial, identity, incentive processing, and physical health development. Future research focusing on individual differences and self-reinforcing digital media behaviors that manifest these feedback loops may portray a more complete picture of cascading digital media influences across adolescent development.

Developmental Changes in Habenular and Striatal Social Reinforcement Responsivity Across Adolescence Linked With Substance Use.

BACKGROUND: Habenula (HB) function is implicated in substance use disorders and is involved in inhibiting dopamine release in the ventral striatum (VS). While blunted VS reward responsivity is implicated in risk for later substance use, links between HB reinforcement processing and progression of use have not, to our knowledge, been examined among adolescents. In the present study, we longitudinally assessed HB and VS responsivity to social rewards and punishments across adolescence and examined associations with substance use. METHODS: Within a longitudinal design, 170 adolescents (53.5% female) completed 1 to 3 functional magnetic resonance imaging scans across 6th to 9th grade and reported yearly substance use across 6th to 11th grade. We examined VS and HB responsivity to social reinforcement during a social incentive delay task in which adolescents received social rewards (smiling faces) and punishments (scowling faces). RESULTS: We observed increased VS responsivity to social rewards (vs. reward omissions) and increased VS, but decreased HB, responsivity to social punishment avoidance versus receipt. However, contrary to hypotheses, the HB displayed increased responsivity to social rewards (vs. reward omissions). Further, adolescents reporting regular substance use displayed longitudinally declining HB responsivity to social rewards (vs. reward omissions), whereas adolescents reporting no substance use displayed longitudinally increasing HB responsivity. In contrast, whereas VS responsivity to punishment avoidance versus receipt increased longitudinally among regular substance users, it stayed relatively stable among nonusers. CONCLUSIONS: These results suggest that differential HB and VS social reinforcement processing trajectories across adolescence are associated with substance use.

Associations between multi-method latent factors of puberty and brain structure in adolescent girls.

Pubertal processes are associated with structural brain development, but studies have produced inconsistent findings that may relate to different measurements of puberty. Measuring both hormones and physical characteristics is important for capturing variation in neurobiological development. The current study explored associations between cortical thickness and latent factors from multi-method pubertal data in 174 early adolescent girls aged 10-13 years in the Transitions in Adolescent Girls (TAG) Study. Our multi-method approach used self-reported physical characteristics and hormone levels (dehydroepiandrosterone (DHEA), testosterone (T), and estradiol (E2) from saliva) to estimate an overall pubertal factor and for each process of adrenarche and gonadarche. There were negative associations between the overall puberty factor representing later stage and thickness in the posterior cortex, including the occipital cortices and extending laterally to the parietal lobe. However, the multi-method latent factor had weaker cortical associations when examining the adnearcheal process alone, suggesting physical characteristics and hormones capture different aspects of neurobiological development during adrenarche. Controlling for age weakened some of these associations. These findings show that associations between pubertal stage and cortical thickness differ depending on the measurement method and the pubertal process, and both should be considered in future confirmatory studies on the developing brain.

Behavioral and Neural Trajectories of Risk Taking for Peer and Parent in Adolescence.

One feature of adolescence is a rise in risk-taking behaviors, whereby the consequences of adolescents' risky action often impact their immediate surrounding such as their peers and parents (vicarious risk taking). Yet, little is known about how vicarious risk taking develops, particularly depending on who the risk affects and the type of risky behavior. In a 3-wave longitudinal fMRI study, 173 adolescents completed 1-3 years of a risky decision-making task where they took risks to win money for their best friend and parent (n with behavioral and fMRI data ranges from 139-144 and 100-116 participants, respectively, per wave). Results of this preregistered study suggest that adolescents did not differentially take adaptive (sensitivity to the expected value of reward during risk taking) and general (decision-making when the expected values of risk taking and staying safe are equivalent) risks for their best friend and parent from sixth to ninth grade. At the neural level, preregistered ROI analyses revealed no differences in the ventral striatum and ventromedial pFC during general nor adaptive risk taking for best friend versus parent over time. Furthermore, exploratory longitudinal whole-brain analyses revealed subthreshold differences between best friend and parent trajectories within regulatory regions during general vicarious risk taking and social-cognitive regions during adaptive vicarious risk taking. Our findings demonstrate that brain regions implicated in cognitive control and social-cognitive processes may distinguish behaviors involving peers and parents over time.

Association of Habitual Checking Behaviors on Social Media With Longitudinal Functional Brain Development.

Importance: Social media platforms provide adolescents with unprecedented opportunities for social interactions during a critical developmental period when the brain is especially sensitive to social feedback. Objective: To explore how adolescents' frequency of checking behaviors on social media platforms is associated with longitudinal changes in functional brain development across adolescence. Design, Setting, and Participants: A 3-year longitudinal cohort study of functional magnetic resonance imaging (fMRI) among sixth- and seventh-grade students recruited from 3 public middle schools in rural North Carolina. Exposures: At wave 1, participants reported the frequency at which they checked Facebook, Instagram, and Snapchat. Main Outcome or Measure: Neural responses to the Social Incentive Delay task when anticipating receiving social feedback, measured annually using fMRI for 3 years. Participants saw a cue that indicated whether the social feedback (adolescent faces with emotional expressions) would be a reward, punishment, or neutral; after a delay, a target appeared and students responded by pressing a button as quickly as possible; a display of social feedback depended on trial type and reaction time. Results: Of 178 participants recruited at age 12 years, 169 participants (mean [SD] age, 12.89 [0.58] years; range, 11.93-14.52 years; 91 [53.8%] female; 38 [22.5%] Black, 60 [35.5%] Latinx, 50 [29.6%] White, 15 [8.9%] multiracial) met the inclusion criteria. Participants with habitual social media checking behaviors showed lower neural sensitivity to social anticipation at age 12 years compared with those with nonhabitual checking behaviors in the left amygdala, posterior insula (PI), and ventral striatum (VS; ß, -0.22; 95% CI, -0.33 to -0.11), right amygdala (ß, -0.19; 95% CI, -0.30 to -0.08), right anterior insula (AI; ß, -0.23; 95% CI, -0.37 to -0.09), and left dorsolateral prefrontal cortex (DLPFC; ß, -0.29; 95% CI, -0.44 to -0.14). Among those with habitual checking behaviors, there were longitudinal increases in the left amygdala/PI/VS (ß, 0.11; 95% CI, 0.04 to 0.18), right amygdala (ß, 0.09; 95% CI, 0.02 to 0.16), right AI (ß, 0.15; 95% CI, 0.02 to 0.20), and left DLPFC (ß, 0.19; 95% CI, 0.05 to 0.25) during social anticipation, whereas among those with nonhabitual checking behaviors, longitudinal decreases were seen in the left amygdala/PI/VS (ß, -0.12; 95% CI, -0.19 to -0.06), right amygdala (ß, -0.10; 95% CI, -0.17 to -0.03), right AI (ß, -0.13; 95% CI, -0.22 to -0.04), and left DLPFC (ß, -0.10, 95% CI, -0.22 to -0.03). Conclusions and Relevance: The results of this cohort study suggest that social media checking behaviors in early adolescence may be associated with changes in the brain's sensitivity to social rewards and punishments. Further research examining long-term associations between social media use, adolescent neural development, and psychological adjustment is needed to understand the effects of a ubiquitous influence on development for today's adolescents.

Longitudinal Change in Adolescent Depression and Anxiety Symptoms from before to during the COVID-19 Pandemic.

This study aimed to examine changes in depression and anxiety symptoms from before to during the first 6 months of the COVID-19 pandemic in a sample of 1,339 adolescents (9-18 years old, 59% female) from three countries. We also examined if age, race/ethnicity, disease burden, or strictness of government restrictions moderated change in symptoms. Data from 12 longitudinal studies (10 U.S., 1 Netherlands, 1 Peru) were combined. Linear mixed effect models showed that depression, but not anxiety, symptoms increased significantly (median increase = 28%). The most negative mental health impacts were reported by multiracial adolescents and those under 'lockdown' restrictions. Policy makers need to consider these impacts by investing in ways to support adolescents' mental health during the pandemic.

The Link Between Neuroticism and Everyday Cognitive Failures is Mediated by Self-Reported Mindfulness Among College Students.

Neuroticism has been linked to an increased likelihood of cognitive failures, including episodes of inattentiveness, forgetfulness, or accidents causing difficulties in successfully executing everyday tasks and impacting health and quality of life. Cognitive failures associated with trait neuroticism can prompt some negative psychological outcomes and risky behaviors. Accumulating evidence shows that augmenting mindfulness can benefit cognitive health and general well-being. However, little is known regarding potential cognitive-behavioral pathways through which individual differences in trait neuroticism could influence the propensity to cognitive failures. Using a sample of 1003 undergraduate college students (females: n = 779) consisting of self-reported questionnaire data, we conducted correlational and mediational analyses to investigate the interrelationship between neuroticism, mindfulness, and cognitive failures. Higher neuroticism scores (females: r = -0.388, males: r = -0.390) and higher cognitive failures scores (females: r = -0.339, males: r = -0.407, p < .001) were significantly correlated with lower self-reported mindfulness scores. Mindfulness significantly mediated the relationship between neuroticism and cognitive failures (ß = 0.50, 95%, CI: 0.37, 0.65). These findings indicate that higher mindfulness may help ameliorate negative effects of neuroticism on everyday cognitive failures. Future research will determine how college students may benefit from positive impact of mindfulness to improve their psychological and physical health.

Meaningful engagement: A crossfunctional framework for digital therapeutics.

Digital mental health interventions, or digital therapeutics, have the potential to transform the field of mental health. They provide the opportunity for increased accessibility, reduced stigma, and daily integration with patient's lives. However, as the burgeoning field continues to expand, there is a growing concern regarding the level and type of engagement users have with these technologies. Unlike many traditional technology products that have optimized their user experience to maximize the amount of time users spend within the product, such engagement within a digital therapeutic is not sufficient if users are not experiencing an improvement in clinical outcomes. In fact, a primary challenge within digital therapeutics is user engagement. Digital therapeutics are only effective if users sufficiently engage with them and, we argue, only if users meaningfully engage with the product. Therefore, we propose a 4-step framework to assess meaningful engagement within digital therapeutics: (1) Define the measure of value (2) Operationalize meaningful engagement for your digital therapeutic (3) Implement solutions to increase meaningful engagement (4) Iteratively evaluate the solution's impact on meaningful engagement and clinical outcomes. We provide recommendations to the common challenges associated with each step. We specifically emphasize a cross-functional approach to assessing meaningful engagement and use an adolescent-focused example throughout to further highlight developmental considerations one should consider depending on their target users.

Convergent gray matter alterations across drugs of abuse and network-level implications: A meta-analysis of structural MRI studies.

BACKGROUND: Neuroimaging studies often consider brain alterations linked with substance abuse within the context of individual drugs (e.g., nicotine), while neurobiological theories of addiction emphasize common brain network-level alterations across drug classes. Using emergent meta-analytic techniques, we identified common structural brain alterations across drugs and characterized the functionally-connected networks with which such structurally altered regions interact. METHODS: We identified 82 articles characterizing gray matter (GM) volume differences for substance users vs. controls. Using the anatomical likelihood estimation algorithm, we identified convergent GM reductions across drug classes. Next, we performed resting-state and meta-analytic functional connectivity analyses using each structurally altered region as a seed and computed whole-brain functional connectivity profiles as the union of both maps. We characterized an "extended network" by identifying brain areas demonstrating the highest degree of functional coupling with structurally impacted regions. Finally, hierarchical clustering was performed leveraging extended network nodes' functional connectivity profiles to delineate subnetworks. RESULTS: Across drug classes, we identified medial frontal/ventromedial prefrontal, and multiple regions in anterior cingulate (ACC) and insula as regions displaying convergent GM reductions among users. Overlap of these regions' functional connectivity profiles identified ACC, inferior frontal, PCC, insula, superior temporal, and putamen as regions of an impacted extended network. Hierarchical clustering revealed 3 subnetworks closely corresponding to default mode (PCC, angular), salience (dACC, caudate), and executive control networks (dlPFC and parietal). CONCLUSIONS: These outcomes suggest that substance-related structural brain alterations likely have implications for the functioning of canonical large-scale networks and the perpetuation of substance use and neurocognitive alterations.

The association of amygdala-insula functional connectivity and adolescent e-cigarette use via sleep problems and depressive symptoms.

BACKGROUND: Adolescent electronic cigarette (e-cigarette) use remains high. Elucidating contributing factors may enhance prevention strategies. Neurobiologically, amygdala-insula resting-state functional connectivity (rsFC) has been linked with aspects of sleep, affect, and substance use (SU). As such, we hypothesized that amygdala's rsFC with the insula would be associated with e-cigarette use via sleep problems and/or depression levels. METHODS: An adolescent sample (N = 146) completed a rs-fMRI scan at time 1 and self-reports at time 2 (∼15 months later). Given consistent associations between mental health outcomes and the rsFC of the laterobasal amygdala (lbAMY) with the anterior insula, we utilized a seed region (lbAMY) to region of interest (ROI) analysis approach to characterize brain-behavior relationships. Two serial mediation models tested the interrelations between amygdala's rsFC with distinct anterior insula subregions (i.e., ventral insula [vI], dorsal insula [dI]), sleep problems, depression levels, and days of e-cigarette use. RESULTS: An indirect effect was observed when considering the lbAMY's rsFC with the vI. Greater rsFC predicted more sleep problems, more sleep problems were linked with greater depressive symptoms, and greater depressive symptoms were associated with more e-cigarette use (indirect effect = 0.08, CI [0.01,0.21]). Indicative of a neurobiological dissociation, a similar indirect effect linking these variables was not observed when considering the lbAMY's rsFC with the dI (indirect effect = 0.03, CI [-0.001,0.10]). CONCLUSIONS: These outcomes highlight functional interactions between the amygdala and insula as a neurobiological contributor to sleep problems, depressive symptoms, and ultimately SU thereby suggesting potential intervention points to reduce teen e-cigarette use.

Age-related change in task-evoked amygdala-prefrontal circuitry: A multiverse approach with an accelerated longitudinal cohort aged 4-22 years.

The amygdala and its connections with medial prefrontal cortex (mPFC) play central roles in the development of emotional processes. While several studies have suggested that this circuitry exhibits functional changes across the first two decades of life, findings have been mixed - perhaps resulting from differences in analytic choices across studies. Here we used multiverse analyses to examine the robustness of task-based amygdala-mPFC function findings to analytic choices within the context of an accelerated longitudinal design (4-22 years-old; N = 98; 183 scans; 1-3 scans/participant). Participants recruited from the greater Los Angeles area completed an event-related emotional face (fear, neutral) task. Parallel analyses varying in preprocessing and modeling choices found that age-related change estimates for amygdala reactivity were more robust than task-evoked amygdala-mPFC functional connectivity to varied analytical choices. Specification curves indicated evidence for age-related decreases in amygdala reactivity to faces, though within-participant changes in amygdala reactivity could not be differentiated from between-participant differences. In contrast, amygdala-mPFC functional connectivity results varied across methods much more, and evidence for age-related change in amygdala-mPFC connectivity was not consistent. Generalized psychophysiological interaction (gPPI) measurements of connectivity were especially sensitive to whether a deconvolution step was applied. Our findings demonstrate the importance of assessing the robustness of findings to analysis choices, although the age-related changes in our current work cannot be overinterpreted given low test-retest reliability. Together, these findings highlight both the challenges in estimating developmental change in longitudinal cohorts and the value of multiverse approaches in developmental neuroimaging for assessing robustness of results.

Risky decision-making strategies mediate the relationship between amygdala activity and real-world financial savings among individuals from lower income households: A pilot study.

Lower financial savings among individuals experiencing adverse social determinants of health (SDoH) increases vulnerabilities during times of crisis. SDoH including low socioeconomic status (low-SES) influence cognitive abilities as well as health and life outcomes that may perpetuate poverty and disparities. Despite evidence suggesting a role for financial growth in minimizing SDoH-related disparities and vulnerabilities, neurobiological mechanisms linked with financial behavior remain to be elucidated. As such, we examined the relationships between brain activity during decision-making (DM), laboratory-based task performance, and money savings behavior. Participants (N = 24, 14 females) from low-SES households (income<$20,000/year) underwent fMRI scanning while performing the Balloon Analogue Risk Task (BART), a DM paradigm probing risky- and strategic-DM processes. Participants also completed self-report instruments characterizing relevant personality characteristics and then engaged in a community outreach financial program where amount of money saved was tracked over a 6-month period. Regarding BART-related brain activity, we observed expected activity in regions implicated in reward and emotional processing including the amygdala. Regarding brain-behavior relationships, we found that laboratory-based BART performance mediated the impact of amygdala activity on real-world behavior. That is, elevated amygdala activity was linked with BART strategic-DM which, in turn, was linked with more money saved after 6 months. In exploratory analyses, this mediation was moderated by emotion-related personality characteristics such that, only individuals reporting lower alexithymia demonstrated a relationship between amygdala activity and savings. These outcomes suggest that DM-related amygdala activity and/or emotion-related personality characteristics may provide utility as an endophenotypic marker of individual's financial savings behavior.