The unique face of comorbid anxiety and depression: Increased frontal, insula and cingulate cortex response during Pavlovian fear-conditioning.

BACKGROUND: Dysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes. METHODS: 195 individuals with MDD (N = 65) or AnxMDD (N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) were compared to stimuli not paired with threat (CS-). RESULTS: MDD and AnxMDD showed significantly different patterns of activation for CS+ vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; ηp2 = 0.02), dorsolateral prefrontal cortex (ηp2 = 0.01) and dorsal anterior/mid cingulate cortex (ηp2 = 0.01). These differences were driven by greater activation to the CS+ in AnxMDD versus MDD. LIMITATIONS: Limitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants. CONCLUSIONS: AnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group.

Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder.

A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2-ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. Sensitivity analyses excluding covariates yielded similar results. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) remained significant and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. NLRC4 and MFN2 were positively correlated with serum C-reactive protein concentrations, while ASC trended significant. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.

Blunted stimulus-preceding negativity during reward anticipation in major depressive disorder.

BACKGROUND: Reward processing dysfunction is a core characteristic of major depressive disorder (MDD), yet event-related potential (ERP) research in MDD has predominantly focused on reward receipt as opposed to anticipation. The stimulus-preceding negativity (SPN) ERP reflects anticipatory brain processing. This study examines whether individuals with MDD exhibit deficits during reward anticipation as evidenced by altered SPN amplitude. METHODS: We assessed prefeedback-SPN amplitudes during a monetary incentive delay (MID) task in individuals with MDD (n = 142, 99 with comorbid anxiety disorders [MDD + ANX]) compared to Controls (n = 37). A mixed analysis of variance was performed on prefeedback-SPN amplitude and behavioral measures, with group (MDD, MDD + ANX, Control) as the between-subjects factor, and feedback (gain, loss) and electrode (F3, F4, Fz, C3, C4, Cz, P3, P4, Pz) as within-subjects factors. RESULTS: A group main effect revealed faster reaction times for the Control group than MDD and MDD + ANX groups. A group x feedback interaction indicated that the MDD subgroup had smaller prefeedback-SPN amplitudes than MDD + ANX and Control groups when anticipating gain feedback. Additionally, individuals with current MDD, irrespective of past MDD and comorbid anxiety, exhibited smaller SPN amplitudes than Controls prior to gain feedback. LIMITATIONS: The MID paradigm, designed for functional magnetic resonance imaging (fMRI) data acquisition, lacks optimization for ERP analysis. Moreover, the clinical groups included more females than the Control group. CONCLUSIONS: Reduced resource allocation to reward anticipation may differentiate MDD from MDD + ANX and Control groups. Further investigation of the neural mechanisms of distinct MDD phenotypes is warranted.

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 2 Independent Samples.

BACKGROUND: Major depressive disorder has a complex, bidirectional relationship with metabolic dysfunction, but the neural correlates of this association are not well understood. METHODS: In this cross-sectional investigation, we used a 2-step discovery and confirmatory strategy utilizing 2 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 major depressive disorder. 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 range: -0.27 to -0.49, puncorrected < .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 (standardized beta coefficient = 0.26 in sample 1, standardized beta coefficient = 0.30 in sample 2, puncorrected < .05). We also observed a positive correlation between leptin levels and atypical depressive symptoms in both major depressive disorder groups (r = 0.14 in sample 1, r = 0.29 in sample 2, puncorrected < .05). CONCLUSIONS: The inverse association between leptin and cortical surface area in brain regions that are important for emotion processing and leptin's association with atypical depressive symptoms support the hypothesis that metabolic processes may be related to emotion regulation. However, the molecular mechanisms through which leptin may 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.

Exploring the role of neuronal-enriched extracellular vesicle miR-93 and interoception in major depressive disorder.

Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain neuronal-enriched extracellular vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMRI) to identify the contribution of gene regulatory pathways, in particular micro-RNA (miR) 93, to interoceptive dysfunction in MDD. Individuals with MDD (n = 41) and healthy comparisons (HC; n = 35) provided blood samples and completed an interoceptive attention task during fMRI. EVs were separated from plasma using a precipitation method. NEEVs were enriched by magnetic streptavidin bead immunocapture utilizing a neural adhesion marker (L1CAM/CD171) biotinylated antibody. The origin of NEEVs was validated with two other neuronal markers - neuronal cell adhesion molecule (NCAM) and ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3). NEEV specificities were confirmed by flow cytometry, western blot, particle size analyzer, and transmission electron microscopy. NEEV small RNAs were purified and sequenced. Results showed that: (1) MDD exhibited lower NEEV miR-93 expression than HC; (2) within MDD but not HC, those individuals with the lowest NEEV miR-93 expression had the highest serum concentrations of interleukin (IL)-1 receptor antagonist, IL-6, tumor necrosis factor, and leptin; and (3) within HC but not MDD, those participants with the highest miR-93 expression showed the strongest bilateral dorsal mid-insula activation during interoceptive versus exteroceptive attention. Since miR-93 is regulated by stress and affects epigenetic modulation by chromatin re-organization, these results suggest that healthy individuals but not MDD participants show an adaptive epigenetic regulation of insular function during interoceptive processing. Future investigations will need to delineate how specific internal and external environmental conditions contribute to miR-93 expression in MDD and what molecular mechanisms alter brain responsivity to body-relevant signals.

Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder.

A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in the endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2-ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. ASC and MFN2 were positively correlated with serum C-reactive protein concentrations. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.

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.

Elevated serum leptin is associated with attenuated reward anticipation in major depressive disorder independent of peripheral C-reactive protein levels.

Major depressive disorder (MDD) is associated with immunologic and metabolic alterations linked to central processing dysfunctions, including attenuated reward processing. This study investigated the associations between inflammation, metabolic hormones (leptin, insulin, adiponectin), and reward-related brain processing in MDD patients with high (MDD-High) and low (MDD-Low) C-reactive protein (CRP) levels compared to healthy comparison subjects (HC). Participants completed a blood draw and a monetary incentive delay task during functional magnetic resonance imaging. Although groups did not differ in insulin or adiponectin concentrations, both MDD-High (Wilcoxon p = 0.004, d = 0.65) and MDD-Low (Wilcoxon p = 0.046, d = 0.53) showed higher leptin concentrations than HC but did not differ from each other. Across MDD participants, higher leptin levels were associated with lower brain activation during reward anticipation in the left insula (r = - 0.30, p = 0.004) and left dorsolateral putamen (r = -- 0.24, p = 0.025). In contrast, within HC, higher leptin concentrations were associated with higher activation during reward anticipation in the same regions (insula: r = 0.40, p = 0.007; putamen: r = 0.37, p = 0.014). Depression may be characterized by elevated pro-inflammatory signaling via leptin concentrations through alternate inflammatory pathways distinct to CRP.

Exploring the role of neuronal-enriched extracellular vesicle miR-93 and interoception in major depressive disorder.

Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain Neuronal-Enriched Extracellular Vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMRI) to identify the contribution of gene regulatory pathways, in particular micro-RNA (miR) 93, to interoceptive dysfunction in MDD. Individuals with MDD (n = 44) and healthy comparisons (HC; n = 35) provided blood samples and completed an interoceptive attention task during fMRI. EVs were separated from plasma using a precipitation method. NEEVs were enriched by magnetic streptavidin bead immunocapture utilizing a neural adhesion marker (CD171) biotinylated antibody. NEEV specificities were confirmed by ow cytometry, western blot, particle size analyzer, and transmission electron microscopy. NEEV small RNAs were purified and sequenced. Results showed that: (1) MDD exhibited lower NEEV miR-93 expression than HC; (2) within MDD but not HC, those individuals with the lowest NEEV miR-93 expression had the highest serum concentrations of interleukin (IL)-1 receptor antagonist, IL-6, tumor necrosis factor, and leptin; and (3) within HC but not MDD, those participants with the highest miR-93 expression showed the strongest bilateral dorsal mid-insula activation. Since miR-93 is regulated by stress and affects epigenetic modulation by chromatin reorganization, these results suggest that healthy individuals but not MDD participants show an adaptive epigenetic regulation of insular function during interoceptive processing. Future investigations will need to delineate how specific internal and external environmental conditions contribute to miR-93 expression in MDD and what molecular mechanisms alter brain responsivity to body-relevant signals.

Elevated decision uncertainty and reduced avoidance drives in depression, anxiety and substance use disorders during approach-avoidance conflict: a replication study.

BACKGROUND: Decision-making under approach-avoidance conflict (AAC; e.g., sacrificing quality of life to avoid feared outcomes) may be affected in multiple psychiatric disorders. Recently, we used a computational (active inference) model to characterize information processing differences during AAC in individuals with depression, anxiety and/or substance use disorders. Individuals with psychiatric disorders exhibited increased decision uncertainty (DU) and reduced sensitivity to unpleasant stimuli. This preregistered study aimed to determine the replicability of this processing dysfunction. METHODS: A new sample of participants completed the AAC task. Individual-level computational parameter estimates, reflecting decision uncertainty and sensitivity to unpleasant stimuli ("emotion conflict"; EC), were obtained and compared between groups. Subsequent analyses combining the prior and current samples allowed assessment of narrower disorder categories. RESULTS: The sample in the present study included 480 participants: 97 healthy controls, 175 individuals with substance use disorders and 208 individuals with depression and/or anxiety disorders. Individuals with substance use disorders showed higher DU and lower EC values than healthy controls. The EC values were lower in females, but not males, with depression and/or anxiety disorders than in healthy controls. However, the previously observed difference in DU between participants with depression and/or anxiety disorders and healthy controls did not replicate. Analyses of specific disorders in the combined samples indicated that effects were common across different substance use disorders and affective disorders. LIMITATIONS: There were differences, although with small effect size, in age and baseline intellectual functioning between the previous and current sample, which may have affected replication of DU differences in participants with depression and/or anxiety disorders. CONCLUSION: The now robust evidence base for these clinical group differences motivates specific questions that should be addressed in future research: can DU and EC become behavioural treatment targets, and can we identify neural substrates of DU and EC that could be used to measure severity of dysfunction or as neuromodulatory treatment targets?

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).