Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Leptin's Inverse Association with Brain Morphology and Depressive Symptoms - A Discovery and Confirmatory Study Across Two Independent Samples.

BACKGROUND: Major Depressive Disorder (MDD) has a complex, bi-directional relationship with metabolic dysfunction, yet the neural correlates of this association are not well understood. METHOD: In this cross-sectional investigation, we employed a two-step 'discovery and confirmatory' strategy, utilizing two independent samples (Sample 1: 288 participants, Sample 2: 196 participants) to examine the association between circulating indicators of metabolic health (leptin and adiponectin) and brain structures in individuals with MDD. RESULTS: We found a replicable inverse correlation between leptin levels and cortical surface area within essential brain areas responsible for emotion regulation, such as the left posterior cingulate cortex, right pars orbitalis, right superior temporal gyrus, and right insula (standardized beta coefficient (SBC) ranged: -0.27 to -0.49, puncorrected <0.05). Notably, this relationship was independent of C-Reactive Protein levels. We also identified a significant interaction effect of leptin levels and diagnosis on the cortical surface area of the right superior temporal gyrus (SBC = 0.26 in sample 1, SBC = 0.30 in sample 2, puncorrected < 0.05). We also observed a positive correlation between leptin levels and atypical depressive symptoms in both MDD groups (r = 0.14 in sample 1, r = 0.29 in sample 2, puncorrected < 0.05). CONCLUSION: The inverse association between leptin and cortical surface area in brain regions that are important for emotion processing and leptin's association with sleep disturbances supports the hypothesis that metabolic processes may be related to emotion regulation. However, the molecular mechanisms through which leptin might exert these effects should be explored further.

Could neurofeedback improve therapist-patient communication? Considering the potential for neuroscience informed examinations of the psychotherapeutic relationship.

Empathic communication between a patient and therapist is an essential component of psychotherapy. However, finding objective neural markers of the quality of the psychotherapeutic relationship have been elusive. Here we conceptualize how a neuroscience-informed approach involving real-time neurofeedback, facilitated via existing functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) technologies, could provide objective information for facilitating therapeutic rapport. We propose several neurofeedback-assisted psychotherapy (NF-AP) approaches that could be studied as a way to optimize the experience of the individual patient and therapist across the spectrum of psychotherapeutic treatment. Finally, we consider how the possible strengths of these approaches are balanced by their current limitations and discuss the future prospects of NF-AP.

Screen media activity in youth: A critical review of mental health and neuroscience findings.

This review has two primary objectives: (1) to offer a balanced examination of recent findings on the relationship between screen media activity (SMA) in young individuals and outcomes such as sleep patterns, mood disturbances, anxiety-related concerns, and cognitive processes; and (2) to introduce a novel multi-level system model that integrates these findings, resolves contradictions in the literature, and guides future studies in examining key covariates affecting the SMA-mental health relationship. Key findings include: (1) Several meta-analyses reveal a significant association between SMA and mental health issues, particularly anxiety and depression, including specific negative effects linked to prolonged screen time; (2) substantial evidence indicates that SMA has both immediate and long-term impacts on sleep duration and quality; (3) the relationship between SMA and cognitive functioning is complex, with mixed findings showing both positive and negative associations; and (4) the multifaceted relationship between SMA and various aspects of adolescent life is influenced by a wide range of environmental and contextual factors. SMA in youth is best understood within a complex system encompassing individual, caregiver, school, peer, and environmental factors, as framed by Bronfenbrenner's ecological systems theory, which identifies five interrelated systems (microsystem, mesosystem, exosystem, macrosystem, and chronosystem) that influence development across both proximal and distal levels of the environment. This model provides a framework for future research to examine these interactions, considering moderating factors, and to develop targeted interventions that can mitigate potential adverse effects of SMA on mental well-being.

The unique face of anxious depression: Increased sustained threat circuitry response during fear acquisition.

Background: Sensitivity to threat with dysregulation of fear learning is thought to contribute to the development of psychiatric disorders, including anxiety disorders (AD) and major depressive disorder (MDD). However, fewer studies have examined fear learning in MDD than in AD. Nearly half of individuals with MDD have an AD and the comorbid diagnosis has worse outcomes. The current study used propensity matching to examine the hypothesis that AD+MDD shows greater neural correlates of fear learning than MDD, suggesting that the co-occurrence of AD+MDD is exemplified by exaggerated defense related processes. Methods: 195 individuals with MDD (N = 65) or AD+MDD (N=130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Results: MDD and AD+MDD showed significantly different patterns of activation for [CSplus-CSminus] in the medial amygdala (ηp2=0.009), anterior insula (ηp2=0.01), dorsolateral prefrontal cortex (ηp2=0.002), dorsal anterior cingulate cortex (ηp2=0.01), mid-cingulate cortex (ηp2=0.01) and posterior cingulate cortex (ηp2=0.02). These differences were driven by greater activation to the CS+ in late conditioning phases in ADD+MDD relative to MDD. Conclusions: AD+MDD showed a pattern of increased sustained activation in regions identified with fear learning. Effects were consistently driven by the threat condition, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, and self-relevant processing.These findings help to elucidate the fear signaling mechanisms involved in the pathophysiology of comorbid anxiety and depression, thereby highlighting promising treatment targets for this prevalent treatment group.

Cognitive control as a potential neural mechanism of protective role of spirituality in anxiety disorders among American Indian people: An ERP study.

Research suggests that traditional cultural factors are protective against mental health conditions in American Indian (AI) populations. This study aims to determine if cognitive control is a neurocognitive mechanism of the protective role of spirituality in AI people with generalized anxiety disorder (GAD). Participants self-identified as AI (n = 52) and included individuals with GAD (n = 16) and without GAD (n = 36). Electroencephalography was collected during a stop-signal task to probe cognitive control using the P3 event-related potential. Higher levels of spirituality attenuated the processing efficiency disruption among individuals with GAD as indicated by P3 amplitudes closer to that of individuals without GAD.

Interoception in Fear Learning and Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric condition characterized by sustained symptoms, including reexperiencing, hyperarousal, avoidance, and mood alterations, following exposure to a traumatic event. Although symptom presentations in PTSD are heterogeneous and incompletely understood, they likely involve interactions between neural circuits involved in memory and fear learning and multiple body systems involved in threat processing. PTSD differs from other psychiatric conditions in that it is a temporally specific disorder, triggered by a traumatic event that elicits heightened physiological arousal, and fear. Fear conditioning and fear extinction learning have been studied extensively in relation to PTSD, because of their central role in the development and maintenance of threat-related associations. Interoception, the process by which organisms sense, interpret, and integrate their internal body signals, may contribute to disrupted fear learning and to the varied symptom presentations of PTSD in humans. In this review, the authors discuss how interoceptive signals may serve as unconditioned responses to trauma that subsequently serve as conditioned stimuli, trigger avoidance and higher-order conditioning of other stimuli associated with these interoceptive signals, and constitute an important aspect of the fear learning context, thus influencing the specificity versus generalization of fear acquisition, consolidation, and extinction. The authors conclude by identifying avenues for future research to enhance understanding of PTSD and the role of interoceptive signals in fear learning and in the development, maintenance, and treatment of PTSD.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

Striatal hypoactivation during monetary loss anticipation in individuals with substance use disorders in a heterogenous urban American Indian sample.

Research suggests that disproportionate exposure to risk factors places American Indian (AI) peoples at higher risk for substance use disorders (SUD). Although SUD is linked to striatal prioritization of drug rewards over other appetitive stimuli, there are gaps in the literature related to the investigation of aversive valuation processing, and inclusion of AI samples. To address these gaps, this study compared striatal anticipatory gain and loss processing between AI-identified with SUD (SUD+; n = 52) and without SUD (SUD-; n = 35) groups from the Tulsa 1000 study who completed a monetary incentive delay (MID) task during functional magnetic resonance imaging. Results indicated that striatal activations in the nucleus accumbens (NAcc), caudate, and putamen were greatest for anticipating gains (ps < 0.001) but showed no group differences. In contrast to gains, the SUD+ exhibited lower NAcc (p = .01, d =0.53) and putamen (p = .04, d =0.40) activation to anticipating large losses than the comparison group. Within SUD+ , lower striatal responses during loss anticipations were associated with slower MID reaction times (NAcc: r = -0.43; putamen: r = -0.35) during loss trials. This is among the first imaging studies to examine underlying neural mechanisms associated with SUD within AIs. Attenuated loss processing provides initial evidence of a potential mechanism wherein blunted prediction of aversive consequences may be a defining feature of SUD that can inform future prevention and intervention targets.

Neural processes of inhibitory control in American Indian peoples are associated with reduced mental health problems.

American Indians (AI) experience disproportionately high prevalence of suicide and substance use disorders (SUD). However, accounting for risk burden (e.g. historical trauma and discrimination), the likelihood of mental health disorders or SUD is similar or decreased compared with the broader population. Such findings have spurred psychological research examining the protective factors, but no studies have investigated its potential neural mechanisms. Inhibitory control is one of the potential neurobehavioral construct with demonstrated protective effects, but has not been examined in neuroimaging studies with AI populations specifically. We examined the incidence of suicidal thoughts and behaviors (STB) and SUD among AI (n = 76) and propensity matched (sex, age, income, IQ proxy and trauma exposure) non-Hispanic White (NHW) participants (n = 76). Among the AI sample, functional magnetic resonance imaging (fMRI) data recorded during the stop-signal task (SST) was examined in relation to STB and SUDs. AIs relative to NHW subjects displayed lower incidence of STB. AIs with no reported STBs showed greater activity in executive control regions during the SST compared with AI who endorsed STB. AI without SUD demonstrated lower activity relative to those individual reporting SUD. Results are consistent with a growing body of literature demonstrating the high level of risk burden driving disparate prevalence of mental health concerns in AI. Furthermore, differential activation during inhibitory control processing in AI individuals without STB may represent a neural mechanism of protective effects against mental health problems in AI. Future research is needed to elucidate sociocultural factors contributing protection against mental health outcomes in AIs and further delineate neural mechanisms with respect to specific concerns (e.g. SUD vs STB).

A machine learning analysis of risk and protective factors of suicidal thoughts and behaviors in college students.

OBJECTIVE: To identify robust and reproducible factors associated with suicidal thoughts and behaviors (STBs) in college students. METHODS: 356 first-year university students completed a large battery of demographic and clinically-relevant self-report measures during the first semester of college and end-of-year (n = 228). Suicide Behaviors Questionnaire-Revised (SBQ-R) assessed STBs. A machine learning (ML) pipeline using stacking and nested cross-validation examined correlates of SBQ-R scores. RESULTS: 9.6% of students were identified at significant STBs risk by the SBQ-R. The ML algorithm explained 28.3% of variance (95%CI: 28-28.5%) in baseline SBQ-R scores, with depression severity, social isolation, meaning and purpose in life, and positive affect among the most important factors. There was a significant reduction in STBs at end-of-year with only 1.8% of students identified at significant risk. CONCLUSION: Analyses replicated known factors associated with STBs during the first semester of college and identified novel, potentially modifiable factors including positive affect and social connectedness.

A randomized clinical trial of behavioral activation and exposure-based therapy for adults with generalized anxiety disorder.

Objective: Exposure-based therapy (EXP) and behavioral activation (BA) are empirically-supported behavioral intervention techniques that target avoidance and approach behavior to alleviate symptoms. Although EXP is an established treatment for generalized anxiety disorder (GAD), the effectiveness of BA for GAD has not been directly tested or compared with that of EXP. This study examined the efficacy of EXP and BA for adults with GAD. Method: In a randomized clinical trial (clinicaltrials.gov: NCT02807480) with partial blinding in Tulsa, OK, 102 adults with GAD were allocated to manualized, 10-session EXP or BA between April 2016-April 2021. Primary analyses were intention-to-treat and included the 94 (46 EXP, 48 BA) participants who started treatment. The GAD-7 self-report scale was the primary outcome measure. Results: Similar GAD-7 declines were observed at post-treatment for EXP (d=-0.97 [95% CI -1.40 to -0.53]) and BA (d=-1.14 [95% CI -1.57 to -0.70]), and were maintained through 6-month follow-up (EXP: d=-2.13, BA: d=-1.98). Compared to EXP, BA yielded more rapid declines in anxiety and depression scores during therapy (d=0.75-0.77), as well as lower anxiety and depression scores (d=0.13-0.14) and greater participant-rated improvement (d=0.64) at post-treatment. Bayesian analyses indicated 74-99% probability of greater change in BA than EXP at post-treatment. Conclusions: BA and EXP are both effective in treating GAD, and BA may confer greater benefit during treatment. Future research is warranted to inform personalized treatment approaches.

Striatal reactivity during emotion and reward relates to approach-avoidance conflict behaviour and is altered in adults with anxiety or depression.

BACKGROUND: We have previously reported activation in reward, salience and executive control regions during functional MRI (fMRI) using an approach-avoidance conflict (AAC) decision-making task with healthy adults. Further investigations into how anxiety and depressive disorders relate to differences in neural responses during AAC can inform their understanding and treatment. We tested the hypothesis that people with anxiety or depression have altered neural activation during AAC. METHODS: We compared 118 treatment-seeking adults with anxiety or depression and 58 healthy adults using linear mixed-effects models to examine group-level differences in neural activation (fMRI) during AAC decision-making. Correlational analyses examined relationships between behavioural and neural measures. RESULTS: Adults with anxiety or depression had greater striatal engagement when reacting to affective stimuli (p = 0.008, d = 0.31) regardless of valence, and weaker striatal engagement during reward feedback (p = 0.046, d = -0.27) regardless of the presence of monetary reward. They also had blunted amygdala activity during decision-making (p = 0.023, d = -0.32) regardless of the presence of conflict. Across groups, approach behaviour during conflict decision-making was inversely correlated with striatal activation during affective stimuli (p < 0.001, r = -0.28) and positively related to striatal activation during reward feedback (p < 0.001, r = 0.27). LIMITATIONS: Our transdiagnostic approach did not allow for comparisons between specific anxiety disorders, and our cross-sectional approach did not allow for causal inference. CONCLUSION: Anxiety and depression were associated with altered neural responses to AAC. Findings were consistent with the role of the striatum in action selection and reward responsivity, and they point toward striatal reactivity as a future treatment target. Blunting of amygdala activity in anxiety or depression may indicate a compensatory response to inhibit affective salience and maintain approach.

Active coping strategies and less pre-pandemic alcohol use relate to college student mental health during the COVID-19 pandemic.

Objective: To further delineate risk and resilience factors contributing to trajectories of mental health symptoms experienced by college students through the pandemic. Participants: n = 183 college students (67.2% female). Methods: Linear mixed models examined time effects on depression and anxiety. Propensity-matched subgroups exhibiting "increased" versus "low and stable" depression symptoms from before to after the pandemic-onset were compared on pre-pandemic demographic and psychological factors and COVID-related experiences and coping strategies. Results: Students experienced worsening of mental health symptoms throughout the pandemic, particularly during Fall 2020 compared with Fall 2019 (Depression scale d = -0.43 [95% CI: -0.65 to -0.21]). The propensity-matched subgroup exhibiting relative resilience ("low and stable" symptoms) reported less alcohol use prior to the pandemic, greater use of active coping strategies, and less of an impact on their college progress. Conclusions: Results point to several potential targets of screening and intervention to decrease residual impacts of the pandemic.

C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder.

Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated with gray matter volume in depression. This study examined whether the inflammatory mediator, C-reactive protein (CRP) and the putative neuroprotective index, KynA/QA, were associated with white matter integrity in MDD, and secondly, whether any such associations were independent of each other or whether the effect of CRP was mediated by KynA/QA. One hundred and sixty-six participants in the Tulsa 1000 study with a DSM-V diagnosis of MDD completed diffusion tensor imaging and provided a serum sample for the quantification of CRP, KynA, and QA. Correlational tractography was performed using DSI Studio to map the specific white matter pathways that correlated with CRP and KynA/QA. CRP was negatively related to KynA/QA (standardized beta coefficient, SBC = -0.35 with standard error, Std.E = 0.13, p < 0.01) after controlling for nine possible confounders, i.e., age, sex, body mass index (BMI), medication status, lifetime alcohol use, severity of depression, severity of anxiety, length of illness, and smoking status. Higher concentrations of CRP were associated with decreased white matter integrity (fractional anisotropy, FA) of the bilateral cingulum and fornix after controlling for the nine potential confounders (SBC = -0.43, Std.E = 0.13, p = 0.002). Greater serum KynA/QA was associated with increased white matter integrity of the bilateral fornix, bilateral superior thalamic radiations, corpus callosum, and bilateral cingulum bundles after controlling for the same possible confounders (SBC = 0.26, Std.E = 0.09, p = 0.005). The relationship between CRP and FA was not mediated by KynA/QA. Exploratory analyses also showed that KynA/QA but not CRP was associated with self-reported positive affect, attentiveness, and fatigue measured with the PANASX (SBCs = 0.17-0.23). Taken together, these results are consistent with the hypothesis that within a subgroup of MDD patients, a higher level of systemic inflammation alters the balance of KP metabolism but also raise the possibility that CRP and neuroactive KP metabolites represent independent molecular mechanisms underlying white matter alterations in MDD.

Behavioral and neural responses during fear conditioning and extinction in a large transdiagnostic sample.

BACKGROUND: Dysregulation of fear learning has been associated with psychiatric disorders that have altered positive and negative valence domain function. While amygdala-insula-prefrontal circuitry is considered important for fear learning, there have been inconsistencies in neural findings in healthy and clinical human samples. This study aimed to delineate the neural substrates and behavioral responses during fear learning in a large, transdiagnostic sample with predominantly depressive and/or anxious dysfunction. METHODS: Two-hundred and eighty-two individuals (52 healthy participants; 230 participants with depression and/or anxiety-related problems) from the Tulsa 1000 study, an ongoing, naturalistic longitudinal study based on a dimensional psychopathological framework, completed a Pavlovian fear learning task during functional magnetic resonance imaging. Linear mixed-effects analyses examined condition-by-time effects on brain activation (CS+, CS- across familiarization, conditioning, and extinction trials). A data-driven latent profile analysis (LPA) examined distinct patterns of behavioral and neural responses to threat across fear conditioning and extinction, while logistic regression analyses evaluated cognitive-affective predictors of latent profiles. RESULTS: Whole-brain analyses revealed a condition-by-time interaction in the anterior insula, postcentral gyrus, superior temporal gyrus, middle frontal gyrus, and cerebellum but not amygdala. The LPA identified distinct latent profiles across subjective and neural levels of measurement. Anterior insula profiles were characterized by marginal differences in age and state anxiety. CONCLUSIONS: Our findings demonstrate that human fear learning recruits a distributed network of regions involved in interoceptive, cognitive, motivational, and psychomotor processes. Data-driven analyses identified distinct profiles of subjective and neural responses during fear learning that transcended clinical diagnoses, but no robust relationships to demographic or cognitive-affective variable were identified.

Limits to the generalizability of resting-state functional magnetic resonance imaging studies of youth: An examination of ABCD Study® baseline data.

This study examined how resting-state functional magnetic resonance imaging (rs-fMRI) data quality and availability relate to clinical and sociodemographic variables within the Adolescent Brain Cognitive Development Study. A sample of participants with an adequate sample of quality baseline rs-fMRI data containing low average motion (framewise displacement ≤ 0.15; low-noise; n = 4,356) was compared to a sample of participants without an adequate sample of quality data and/or containing high average motion (higher-noise; n = 7,437) using Chi-squared analyses and t-tests. A linear mixed model examined relationships between clinical and sociodemographic characteristics and average head motion in the sample with low-noise data. Relative to the sample with higher-noise data, the low-noise sample included more females, youth identified by parents as non-Hispanic white, and youth with married parents, higher parent education, and greater household incomes (ORs = 1.32-1.42). Youth in the low-noise sample were also older and had higher neurocognitive skills, lower BMIs, and fewer externalizing and neurodevelopmental problems (ds = 0.12-0.30). Within the low-noise sample, several clinical and demographic characteristics related to motion. Thus, participants with low-noise rs-fMRI data may be less representative of the general population and motion may remain a confound in this sample. Future rs-fMRI studies of youth should consider these limitations in the design and analysis stages in order to optimize the representativeness and clinical relevance of analyses and results.

Self-regulation of the posterior cingulate cortex with real-time fMRI neurofeedback augmented mindfulness training in healthy adolescents: A nonrandomized feasibility study.

Mindfulness training (MT) promotes the development of one's ability to observe and attend to internal and external experiences with objectivity and nonjudgment with evidence to improve psychological well-being. Real-time functional MRI neurofeedback (rtfMRI-nf) is a noninvasive method of modulating activity of a brain region or circuit. The posterior cingulate cortex (PCC) has been hypothesized to be an important hub instantiating a mindful state. This nonrandomized, single-arm study examined the feasibility and tolerability of training typically developing adolescents to self-regulate the posterior cingulate cortex (PCC) using rtfMRI-nf during MT. Thirty-four adolescents (mean age: 15 years; 14 females) completed the neurofeedback augmented mindfulness training task, including Focus-on-Breath (MT), Describe (self-referential thinking), and Rest conditions, across three neurofeedback and two non-neurofeedback runs (Observe, Transfer). Self-report assessments demonstrated the feasibility and tolerability of the task. Neurofeedback runs differed significantly from non-neurofeedback runs for the Focus-on-Breath versus Describe contrast, characterized by decreased activity in the PCC during the Focus-on-Breath condition (z = -2.38 to -6.27). MT neurofeedback neural representation further involved the medial prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, posterior insula, hippocampus, and amygdala. State awareness of physical sensations increased following rtfMRI-nf and was maintained at 1-week follow-up (Cohens' d = 0.69). Findings demonstrate feasibility and tolerability of rtfMRI-nf in healthy adolescents, replicates the role of PCC in MT, and demonstrate a potential neuromodulatory mechanism to leverage and streamline the learning of mindfulness practice. ( ClinicalTrials.gov identifier #NCT04053582; August 12, 2019).