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BACKGROUND: Efforts to identify risk and resilience factors for anxiety severity and course during the COVID-19 pandemic have focused primarily on demographic rather than psychological variables. Intolerance of uncertainty (IU), a transdiagnostic risk factor for anxiety, may be a particularly relevant vulnerability factor. METHOD: N = 641 adults with pre-pandemic anxiety data reported their anxiety, IU, and other pandemic and mental health-related variables at least once and up to four times during the COVID-19 pandemic, with assessments beginning in May 2020 through March 2021. RESULTS: In preregistered analyses using latent growth models, higher IU at the first pandemic timepoint predicted more severe anxiety, but also a sharper decline in anxiety, across timepoints. This finding was robust to the addition of pre-pandemic anxiety and demographic predictors as covariates (in the full sample) as well as pre-pandemic depression severity (in participants for whom pre-pandemic depression data were available). Younger age, lower self/parent education, and self-reported history of COVID-19 illness at the first pandemic timepoint predicted more severe anxiety across timepoints with strong model fit, but did not predict anxiety trajectory. CONCLUSIONS: IU prospectively predicted more severe anxiety but a sharper decrease in anxiety over time during the pandemic, including after adjustment for covariates. IU therefore appears to have unique and specific predictive utility with respect to anxiety in the context of the COVID-19 pandemic.
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Affect-biased attention is the phenomenon of prioritizing attention to emotionally salient stimuli and away from goal-directed stimuli. It is thought that affect-biased attention to emotional stimuli is a driving factor in the development of depression. This effect has been well-studied in adults, but research shows that this is also true during adolescence, when the severity of depressive symptoms are correlated with the magnitude of affect-biased attention to negative emotional stimuli. Prior studies have shown that trainings to modify affect-biased attention may ameliorate depression in adults, but this research has also been stymied by concerns about reliability and replicability. This study describes a clinical application of augmented reality-guided EEG-based attention modification ("AttentionCARE") for adolescents who are at highest risk for future depressive disorders (i.e., daughters of depressed mothers). Our results (n = 10) indicated that the AttentionCARE protocol can reliably and accurately provide neurofeedback about adolescent attention to negative emotional distractors that detract from attention to a primary task. Through several within and cross-study replications, our work addresses concerns about the lack of reliability and reproducibility in brain-computer interface applications, offering insights for future interventions to modify affect-biased attention in high-risk adolescents.
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Music and ketamine are both known to affect therapeutic outcomes, but few studies have investigated their co-administration. This scoping review describes the existing literature on the joint use of music and ketamine-or esketamine (the S(+) enantiomer of ketamine)-in humans. The review considers that extant studies have explored the intersection of ketamine/esketamine and music in healthy volunteers and in patients of various age groups, at different dosages, through different treatment processes, and have varied the sequence of playing music relative to ketamine/esketamine administration. Studies investigating the use of music during ketamine anesthesia are also included in the review because anesthesia and sedation were the early drivers of ketamine use. Studies pertaining to recreational ketamine use were omitted. The review was limited to articles published in the English language but not restricted by publication year. To the best of our knowledge, this scoping review is the first comprehensive exploration of the interplay between music and ketamine/esketamine and offers valuable insights to researchers interested in designing future studies.
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Ketamina , Musicoterapia , Humanos , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/uso terapêutico , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Depressão/tratamento farmacológico , Depressão/terapia , Manejo da DorRESUMO
INTRODUCTION: In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment's effects on implicit self-associations and their relation to symptom improvement. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30-40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial. RESULTS: The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: ß = -0.201; p = 0.049). DISCUSSION: Our findings suggest that changing implicit self-worth during a post-ketamine 'plasticity window' is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention's impact on implicit cognition, as this mechanism appears linked to the intervention's enduring clinical benefits.
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Background: Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research. Methods: One hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery-Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison. Results: We found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery-Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery-Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point. Conclusions: Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.
Rapidly acting pharmacological agents, such as subanesthetic ketamine, have offered the promise of a breakthrough in the way that depression is managed. However, to build on this potential, we still have much to learn about ketamine's mechanisms of action, particularly possible psychological mechanisms of action. Here, Aepfelbacher et al. conducted secondary analyses from a randomized controlled trial in depression. The authors found that a ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression improvements over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.
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This secondary analysis of a randomized clinical trial examines whether automated self-association training can prolong the antidepressant effect of a single infusion of ketamine beyond 1 month in patients with treatment-resistant depression.
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Ketamina , Humanos , Ketamina/uso terapêutico , Depressão/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Administração IntravenosaRESUMO
Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.
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Depressão , Ketamina , Adulto , Animais , Humanos , Imagem de Tensor de Difusão , Ketamina/farmacologia , Ketamina/uso terapêutico , Córtex Cerebral , Plasticidade NeuronalRESUMO
Compulsive behaviors (CBs) have been linked to orbitofrontal cortex (OFC) function in animal and human studies. However, brain regions function not in isolation but as components of widely distributed brain networks-such as those indexed via resting-state functional connectivity (RSFC). Sixty-nine individuals with CB disorders were randomized to receive a single session of neuromodulation targeting the left OFC-intermittent theta-burst stimulation (iTBS) or continuous TBS (cTBS)-followed immediately by computer-based behavioral "habit override" training. OFC seeds were used to quantify RSFC following iTBS and following cTBS. Relative to cTBS, iTBS showed increased RSFC between right OFC (Brodmann's area 47) and other areas, including dorsomedial prefrontal cortex (dmPFC), occipital cortex, and a priori dorsal and ventral striatal regions. RSFC connectivity effects were correlated with OFC/frontopolar target engagement and with subjective difficulty during habit-override training. Findings help reveal neural network-level impacts of neuromodulation paired with a specific behavioral context, informing mechanistic intervention development.
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OBJECTIVE: Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [ß]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (ß=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: ß=0.015, 95% CI=0.003, 0.03; t=2.35, df=568). CONCLUSIONS: After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.
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Transtorno Depressivo Resistente a Tratamento , Ketamina , Adulto , Humanos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Ketamina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego , Resultado do TratamentoRESUMO
Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.
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Transtorno Bipolar , Ketamina , Humanos , Ketamina/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Bipolar/tratamento farmacológico , Antidepressivos/uso terapêutico , Administração Intravenosa , Resultado do TratamentoRESUMO
Biases in attention to emotional stimuli (i.e., affect-biased attention) contribute to the development and mainte-nance of depression and anxiety and may be a promising target for intervention. Past attempts to therapeutically modify affect-biased attention have been unsatisfactory due to issues with reliability and precision. Electroencephalogram (EEG)-derived steady-state visual evoked potentials (SSVEPS) provide a temporally-sensitive biological index of attention to competing visual stimuli at the level of neuronal populations in the visual cortex. SSVEPS can potentially be used to quantify whether affective distractors vs. task-relevant stimuli have "won" the competition for attention at a trial-by-trial level during neuro-feedback sessions. This study piloted a protocol for a SSVEP-based neurofeedback training to modify affect-biased attention using a portable augmented-reality (AR) EEG interface. During neurofeedback sessions with five healthy participants, signifi-cantly greater attention was given to the task-relevant stimulus (a Gabor patch) than to affective distractors (negative emotional expressions) across SSVEP indices (p<0.000l). SSVEP indices exhibited excellent internal consistency as evidenced by a maximum Guttman split-half coefficient of 0.97 when comparing even to odd trials. Further testing is required, but findings suggest several SSVEP neurofeedback calculation methods most deserving of additional investigation and support ongoing efforts to develop and implement a SSVEP-guided AR-based neurofeedback training to modify affect-biased attention in adolescent girls at high risk for depression.
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Viés de Atenção , Realidade Aumentada , Neurorretroalimentação , Adolescente , Potenciais Evocados Visuais , Feminino , Humanos , Reprodutibilidade dos TestesRESUMO
There are known disparities in the burden of illness and access/quality of care for African, Latino/a, Asian, and Native American (ALANA) patients diagnosed with depressive disorders, which may occur because of health inequities. Racial stress and trauma (RST), or the significant fear and distress that can be imparted from exposure to racism, is one such inequity linked to the development of depression. The current review summarizes past research examining the association between racism, RST, and depression, as well as avenues in which RST becomes biologically embedded in ALANA individuals. We describe multimodal research that supports vigilance as a potential mediator of the association between RST and depression and consider the nuanced role that vigilance plays during experiences with racism. Finally, we describe methodological advances in the assessment of vigilance evoked by RST and the clinical implications that may be generated by future improvements. In each of these areas, we present examples of how ongoing and future research can be leveraged to provide support for psychosocial programs that facilitate autonomous community healing and resilience, increase calls for public policy changes, and support clinical interventions that lessen the burden of racism on ALANA communities.
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Depressive symptomology has been linked to low-grade peripheral inflammatory markers (PIMs), specifically C-reactive protein (CRP) and white blood cell count (WBC). However, such associations may be affected by multiple moderators (including race/ethnicity), though few well-powered and racially diverse studies have examined this. We examined 31 moderators of PIM-depression relationships in a large racially diverse cohort (n = 21,570). We also examined if associations between PIM and depression severity were dependent on clinical cutpoints for moderate depressive symptoms and elevated CRP. We found several positive moderators of PIM-depression relationships for both WBC and CRP: ongoing medication use (antidepressant, statin, or any prescription drug), presence of sleep concerns, and poor health status (ß's = 0.06-0.21, p's < 0.05). For both WBC and CRP, individuals of non-Hispanic White race/ethnicity were found to have stronger PIM-depression associations overall relative to minoritized groups (B's = 0.14 to 1.01, p's < 0.05). For CRP, stronger PIM-depression relationships existed for individuals with moderate (or greater) depression severity or elevated CRP (B's = 0.27 to 0.49, p's < 0.05). Thus, a wide range of moderators appears to affect PIM-depression associations. These results could help identify participants with strong coupling of PIM-depression severity, to guide future research and personalized treatments for depression and to indicate gaps in the applicability of widely referenced theoretical models among racial/ethnic minoritized groups.
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Antidepressivos , Depressão , Antidepressivos/uso terapêutico , Biomarcadores , Proteína C-Reativa/metabolismo , Depressão/tratamento farmacológico , Humanos , População BrancaRESUMO
BACKGROUND: Both low-grade elevation in peripheral inflammatory markers (e.g., white blood count (WBC) and C-reactive protein (CRP)) and physical illness (both chronic and acute) have been associated with depressive symptomology. However, it is unclear if low-grade elevation in inflammatory markers mediates relationships between physical illness and depression or if physical illness positively moderates relationships between inflammatory markers and depression. METHODS: In a well-powered, racially diverse cohort (n = 21,525) from NHANES datasets, we examined if inflammatory markers (CRP and WBC) and physical illnesses (acute and chronic) were independently associated with depression severity. We also examined if associations between physical illness and depression severity were mediated by inflammatory markers and if physical illness moderated associations between inflammatory markers and depression. RESULTS: We found that both inflammatory markers and physical illness were associated with depression severity, even after considering a wide range of potential confounders (e.g., age, gender, body mass index). Inflammatory markers mediated a marginal portion (<5%; p < 0.001) of potential effects of physical illness on depression severity. In moderation analyses, associations between inflammatory markers and depression severity were significantly stronger in participants with chronic physical illness than those without. This moderating effect was not present for acute physical illness. CONCLUSIONS: Inflammatory markers and physical illness appear independently linked to depression severity and, in individuals with chronic physical illness, inflammatory markers are more tightly connected to depressive symptomology. Such findings could help guide future individualized treatment research for depression based on both inflammatory marker level and physical illness burden.
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Doença Aguda , Doença Crônica , Depressão , Inflamação , Doença Aguda/epidemiologia , Biomarcadores , Proteína C-Reativa/metabolismo , Doença Crônica/epidemiologia , Depressão/epidemiologia , Humanos , Inflamação/epidemiologia , Inquéritos NutricionaisRESUMO
Patients with disorders of compulsivity show impairments in goal-directed behavior, which have been linked to orbitofrontal cortex (OFC) dysfunction. We recently showed that continuous theta burst stimulation (cTBS), which reduces OFC activity, had a beneficial effect on compulsive behaviors both immediately and at 1 week follow-up compared with inhibitory TBS (iTBS). In this same sample, we investigated whether two behavioral measures of goal-directed control (devaluation success on a habit override task; model-based planning on the two-step task) were also affected by acute modulation of OFC activity. Overall, model-based planning and devaluation success were significantly related to each other and (for devaluation success) to symptoms in our transdiagnostic clinical sample. These measures were moderately to highly stable across time. In individuals with low levels of model-based planning, active cTBS improved devaluation success. Analogous to previously reported clinical effects, this effect was specific to cTBS and not iTBS. Overall, results suggested that measures of goal directed behavior are reliable but less affected by cTBS than clinical self-report. Future research should continue to examine longitudinal changes in behavioral measures to determine their temporal relationship with symptom improvement after treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Objetivos , Estimulação Magnética Transcraniana , Método Duplo-Cego , Humanos , Motivação , Córtex Pré-Frontal , Estimulação Magnética Transcraniana/métodosRESUMO
BACKGROUND: Depressive disorders are linked to dysfunction in reward-related behaviors and corticostriatal reward circuitry. Low-grade dysregulation of the immune system, e.g., elevations in plasma interleukin 6 (IL-6) and tumor necrosis factor α, have been thought to affect corticostriatal reward circuitry. Little is presently known about the degree to which these relationships generalize to patients with treatment-resistant depression (TRD) and/or childhood trauma history. METHODS: Resting-state functional connectivity between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) regions and plasma inflammatory marker levels (IL-6, tumor necrosis factor α) were measured in 74 adults with TRD. Regression analyses examined associations of inflammatory markers with VS-vmPFC connectivity and the moderating effects of self-reported childhood trauma on these associations, with exploratory analyses examining trauma subtypes. RESULTS: IL-6 was negatively associated with VS-vmPFC connectivity (specifically for the left VS). Childhood trauma moderated the relationships between tumor necrosis factor α and VS-vmPFC connectivity (specifically for the right VS) such that greater childhood trauma severity (particularly emotional neglect) was associated with stronger cytokine-connectivity associations. CONCLUSIONS: This study independently extends previously reported associations between IL-6 and reductions in corticostriatal connectivity to a high-priority clinical population of treatment-seeking patients with TRD and further suggests that childhood trauma moderates specific associations between cytokines and corticostriatal connectivity. These findings suggest that associations between elevated plasma cytokine levels and reduced corticostriatal connectivity are a potential pathophysiological mechanism generalizable to patients with TRD and that such associations may be affected by trauma severity.
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The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.
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Transtornos de Ansiedade , Encéfalo , Adulto , Ansiedade , Transtornos de Ansiedade/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
BACKGROUND: Evidence supports raised circulating levels of inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor (TNFα), among clinically depressed adults, although preliminary findings in adolescents are mixed. Independently, meta-analyses identify correlations between childhood trauma and elevated cytokine levels in adulthood. Here, we examine the possible role of individual differences in exposure to childhood trauma in contributing to variability in cytokine levels in depressed adolescents. METHODS: 52 depressed adolescents and 20 healthy adolescents completed measures of childhood trauma and provided blood for the assessment of plasma IL-6 and TNFα. Cross-sectional associations of childhood trauma and cytokine measures were assessed in both depressed and healthy adolescents, along with exploratory analysis of childhood trauma subtypes. Longitudinal relationships between childhood trauma and cytokine measures were also studied in an exploratory fashion within a subset of depressed participants (n = 36). RESULTS: Higher childhood trauma (particularly emotional abuse) was positively associated with TNFα in depressed adolescents. Childhood trauma was not linked to longitudinal changes in cytokine levels. DISCUSSION: In depressed adolescents, childhood trauma may relate to higher levels of the proinflammatory cytokine TNFα and contribute to heterogeneity in cytokine elevation among depressed adolescents. Such findings may ultimately help guide more effective individualized treatments for adolescents with depression.
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Experiências Adversas da Infância , Citocinas/sangue , Depressão/sangue , Depressão/complicações , Trauma Psicológico/sangue , Trauma Psicológico/complicações , Adolescente , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Interleucina-6/sangue , Masculino , Fator de Necrose Tumoral alfa/sangueRESUMO
Dopaminergic function is a critical transdiagnostic neurophysiological dimension with broad relevance in psychiatry. Normalized T2*-weighted (nT2*w) imaging has been previously investigated as a method to quantify biological properties of tissue in the striatum (e.g., tissue iron), providing a widely available, in vivo marker with potential relevance to dopaminergic function; but no prior study to our knowledge has examined this neuroimaging marker in clinical depression. In a treatment-seeking, clinically depressed sample (n = 110), we quantified tissue iron (nT2*w) in striatal regions. We assessed test-retest reliability and correlated values with dimensional features across levels of analysis, including demographic/biological (sex, age, Body Mass Index), neuroanatomical (hippocampal atrophy, which was quantified using a recently validated machine-learning algorithm), and performance-based (Affective Go/NoGo task performance) indices with relevance to depressive neurocognition. Across patients, decreased tissue iron concentration (as indexed by higher nT2*w) in striatal regions correlated with indices of decreased cognitive-affective function on the Affective Go/NoGo task. Greater caudate nT2*w also correlated with greater hippocampal atrophy. Striatal tissue iron concentrations were robustly lower in female patients than males but gender differences did not explain relations with other neurocognitive variables. A widely available fMRI index of striatal tissue properties, which exhibited strong psychometric properties and can be readily quantified from most fMRI datasets irrespective of study-specific features such as task design, showed relevance to multiple biobehavioral markers of pathophysiology in the context of moderate-to-severe, treatment-resistant depression. Striatal tissue iron may play a role in dimensional and subgroup-specific features of depression, with implications for future research on depression heterogeneity.
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Transtorno Depressivo Maior , Imageamento por Ressonância Magnética , Corpo Estriado/diagnóstico por imagem , Feminino , Humanos , Ferro , Masculino , Reprodutibilidade dos TestesRESUMO
Resting state functional connectivity (RSFC) in ventral affective (VAN), default mode (DMN) and cognitive control (CCN) networks may partially underlie heterogeneity in depression. The current study used data-driven parsing of RSFC to identify subgroups of patients with treatment-resistant depression (TRD; n = 70) and determine if subgroups generalized to transdiagnostic measures of cognitive-affective functioning relevant to depression (indexed across self-report, behavioral, and molecular levels of analysis). RSFC paths within key networks were characterized using Subgroup-Group Iterative Multiple Model Estimation. Three connectivity-based subgroups emerged: Subgroup A, the largest subset and containing the fewest pathways; Subgroup B, containing unique bidirectional VAN/DMN negative feedback; and Subgroup C, containing the most pathways. Compared to other subgroups, subgroup B was characterized by lower self-reported positive affect and subgroup C by higher self-reported positive affect, greater variability in induced positive affect, worse response inhibition, and reduced striatal tissue iron concentration. RSFC-based categorization revealed three TRD subtypes associated with discrete aberrations in transdiagnostic cognitive-affective functioning that were largely unified across levels of analysis and were maintained after accounting for the variability captured by a disorder-specific measure of depressive symptoms. Findings advance understanding of transdiagnostic brain-behavior heterogeneity in TRD and may inform novel treatment targets for this population.