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.

Topological properties of psychopathological networks of healthy and disordered individuals across mental disorders.

The identification of psychopathological markers has been the focus of several scientific fields. The results were inconsistent due to lack of a clear nosology. Network analysis, focusing on the interactions between symptoms, provided important insights into the nosology of mental disorders. These interactions originate several topological properties that could constitute markers of psychopathology. One of these properties is network connectivity, which has been explored in recent years. However, the results have been inconsistent, and the topological properties of psychopathological networks remain largely unexplored and unknown. We compared several topological properties (i.e., connectivity, average path length, assortativity, average degree, modularity, global clustering) of psychopathological networks of healthy and disordered participants across depression (N = 2830), generalized anxiety (N = 13,463), social anxiety (N = 12,814), and obsessive-compulsive disorder (N = 16,426). Networks were estimated using Bayesian Gaussian Graphical Models. The Janson-Shannon measure of divergence was used to identify differences between the network properties. Network connectivity distinguished healthy and disordered participants' networks in all disorders. However, in depression and generalized anxiety, network connectivity was higher in healthy participants. The presence and number of motifs also distinguished the networks of healthy and disordered participants. Other topological properties (i.e., modularity, clustering, average path length and average degree) seem to be disorder-specific. The psychopathological significance of network connectivity must be clarified. Some topological properties of psychopathological networks are promising markers of psychopathology and may contribute to clarifying the nosology of mental disorders.

Inhibition of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in Rats with Anxiety Disorders.

ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.

Alterations in neural circuit dynamics between the limbic network and prefrontal/default mode network in patients with generalized anxiety disorder.

BACKGROUND: Widespread functional alterations have been implicated in patients with generalized anxiety disorder (GAD). However, most studies have primarily focused on static brain network features in patients with GAD. The current research focused on exploring the dynamics within functional brain networks among individuals diagnosed with GAD. METHODS: Seventy-five participants were divided into patients with GAD and healthy controls (HCs), and resting-state functional magnetic resonance imaging data were collected. The severity of symptoms was measured using the Hamilton Anxiety Scale and the Patient Health Questionnaire. Co-activation pattern (CAP) analysis, centered on the bed nucleus of the stria terminalis, was applied to explore network dynamics. The capability of these dynamic characteristics to distinguish between patients with GAD and HCs was evaluated using a support vector machine. RESULTS: Patients with GAD exhibited disruptions in the limbic-prefrontal and limbic-default-mode network circuits. Particularly noteworthy was the marked reduction in dynamic indicators such as occurrence, EntriesFromBaseline, ExitsToBaseline, in-degree, out-degree, and resilience. Moreover, these decreased dynamic features effectively distinguished the GAD group from the HC in this study. CONCLUSIONS: The current findings revealed the underlying brain networks associated with compromised emotion regulation in individuals with GAD. The dynamic reduction in connectivity between the limbic-default mode network and limbic-prefrontal networks could potentially act as a biomarker and therapeutic target for GAD in the future.

Error-related brain activity shapes the association between trait neuroticism and internalizing symptomatology in two tasks.

The current study examined how individual differences in error-related brain activity might moderate the association between high trait neuroticism and internalizing symptoms. Data were collected from a sample of high-achieving young adults (N = 188) as part of a larger study on risk versus resiliency for psychopathology. Participants completed two behavioral tasks to elicit the error-related negativity (ERN): an arrow Flanker task and a Go/No-Go task. Analyses were constrained to two internalizing symptom dimensions of checking behavior and irritability. Contrary to expectations, ERN amplitude was not related to symptom severity at the bivariate level. However, ERN amplitude moderated the association between trait neuroticism and symptoms of ill temper, such that the neuroticism-irritability association was strongest among individuals with a blunted ERN. In addition, this finding was relatively consistent across tasks and across two complementary methods of scoring the ERN, suggesting an effect of ERN variance that is shared between tasks and that is relatively robust regarding processing differences. In all, the current study represents the first attempt to investigate how the ERN interacts with trait neuroticism to predict transdiagnostic symptom dimensions in adulthood.

Altered serum interleukin-17A and interleukin-23A levels may be associated with the pathophysiology and development of generalized anxiety disorder.

In recent times, the pathogenesis of generalized anxiety disorder (GAD) and the influence of pro- and anti-inflammatory cytokines on it have garnered considerable interest. Cytokine research, especially Th-17 cytokine research on GAD patients, is limited. Here, we aim to assess the role of interleukin-17A (IL-17A) and interleukin-23A (IL-23A) in the pathophysiology and development of GAD. This investigation included 50 GAD patients and 38 age-sex-matched healthy controls (HCs). A psychiatrist diagnosed patients with GAD and assessed symptom severity using the DSM-5 and the GAD-7 scales. The serum concentrations of IL-17A and IL-23A were determined using commercially available ELISA kits. GAD patients exhibited elevated levels of IL-17A (77.14 ± 58.30 pg/ml) and IL-23A (644.90 ± 296.70 pg/ml) compared to HCs (43.50 ± 25.54 pg/ml and 334.40 ± 176.0 pg/ml). We observed a positive correlation between disease severity and cytokine changes (IL-23A: r = 0.359, p = 0.039; IL-17A: r = 0.397, p = 0.032). These findings indicate that IL-17A and IL-23A may be associated with the pathophysiology of GAD. ROC analysis revealed moderately higher AUC values (IL-23A: 0.824 and IL-17A: 0.710), demonstrating their potential to discriminate between patients and HCs. Also, the sensitivity values of both cytokines were relatively higher (IL-23A: 80.49% and IL-17A: 77.27%). According to the present findings, there may be an association between peripheral serum levels of IL-17A and IL-23A and the pathophysiology and development of GAD. These altered serum IL-17A and IL-23A levels may play a role in directing the early risk of developing GAD. We recommend further research to ascertain their exact role in the pathophysiology and their performance as risk assessment markers of GAD.

Evaluating the effects of tDCS on depressive and anxiety symptoms from a transdiagnostic perspective: a systematic review and meta-analysis of randomized controlled trials.

Depressive and anxiety symptoms are prevalent among patients with various clinical conditions, resulting in diminished emotional well-being and impaired daily functioning. The neural mechanisms underlying these symptoms, particularly across different disorders, remain unclear, limiting the effectiveness of conventional treatments. Therefore, it is crucial to elucidate the neural underpinnings of depressive and anxiety symptoms and investigate novel, effective treatments across clinical conditions. Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that can help understand the neural underpinnings of symptoms and facilitate the development of interventions, addressing the two research gaps at both neural and clinical levels. Thus, this systematic review and meta-analysis aims to evaluate the existing evidence regarding the therapeutic efficacy of tDCS in reducing depressive and anxiety symptoms among individuals with diverse clinical diagnoses. This review evaluated evidence from fifty-six randomized, sham-controlled trials that administered repeated tDCS sessions with a parallel design, applying a three-level meta-analytic model. tDCS targeting the left dorsolateral prefrontal cortex (DLPFC) at 2-mA intensity demonstrates moderate efficacy in alleviating depressive symptoms, identifying the left DLPFC as a transdiagnostic neural mechanism of depressive symptoms across clinical conditions. In comparison, the findings on anxiety symptoms demonstrate greater heterogeneity. tDCS over the left DLPFC is effective in reducing depressive symptoms and shows promising effects in alleviating anxiety symptoms among individuals with diverse diagnoses. These findings enhance our understanding of the neuropsychological basis of depressive and anxiety symptoms, laying the groundwork for the development of more effective tDCS interventions applicable across clinical conditions.

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.

Cognitive Functioning in Youth with Anxiety Disorders: A Systematic Review.

Anxiety disorders are disorders involving cognition. Research on cognition in youth with anxiety can focus on cognitive content (e.g., self-talk) as well cognitive functioning. The present review examines domains of cognitive functioning (i.e., episodic memory, language, attention, executive functioning, motor skills, and visual functioning) in youth diagnosed with an anxiety disorder. A database search of Embase, PsycINFO, and PubMed yielded 28 studies that met inclusion criteria of youth aged 17 years or younger, a sample diagnosed with a principal anxiety disorder and a comparison sample of controls, a comparison between those samples, and use of a behavioral measure of neuropsychological performance. Findings did not identify any cognitive functioning strengths for anxious youth. Deficits were found in two domains (i.e., receptive language and motor skills) whereas no deficits were found in attention, visuospatial skills and one domain of executive functioning (i.e., inhibition). Most domains had mixed findings. Additional analysis indicated that anxiety disorders in youth are not associated with diminished IQ. Directions for future research are identified including (a) the prioritization of studies with larger, representative samples (b) the role of cognitive functioning as a predictor of anxiety treatment outcome (c) the examination of the effect of treatment on cognitive performance, and (d) the course of anxiety and potential impairment in cognitive functioning.

EEG coherences of the default mode network among patients comorbid with major depressive disorder and anxiety symptoms.

BACKGROUND: Higher functional connectivity within the default mode network (DMN) has been found in functional magnetic resonance imaging (fMRI) studies of major depressive disorder (MDD). We used electroencephalogram (EEG) coherence as an index of functional connectivity to examine group differences in DMN between the MDD and healthy control (HC) groups during the resting state. METHODS: MDD patients with comorbid anxiety symptoms (n = 154) and healthy controls (n = 165) completed the questionnaires of depression, anxiety, and rumination. A 19-channel EEG recording was measured under resting state for all participants. EEG coherences of the delta, theta, alpha, beta, and high beta in the anterior DMN (aDMN), posterior DMN (pDMN), aDMN-pDMN, DMN-parahippocampal gyrus (PHG), and DMN-temporal gyrus were compared between the two groups. The correlations between rumination, anxiety, and DMN coherence were examined in the MDD group. RESULTS: (1) No difference was found in the delta, theta, alpha, and beta within the DMN brain regions between the two groups; the MDD group showed higher high beta coherence within DMN brain regions than the HC group. (2) Rumination was negatively correlated with theta coherence of aDMN, and positively correlated with beta coherence of aDMN and with alpha coherence of pDMN and DMN-PHG. (3) Anxiety was positively correlated with high beta coherence of aDMN, pDMN, and DMN-PHG. CONCLUSIONS: MDD patients with comorbid anxiety symptoms exhibited hypercoherence within the DMN brain regions. Hypercoherences were related to symptoms of rumination, and anxiety may be a biomarker for MDD patients with comorbid anxiety symptoms.

GABAergic implications in anxiety and related disorders.

Evidence indicates that anxiety disorders arise from an imbalance in the functioning of brain circuits that govern the modulation of emotional responses to possibly threatening stimuli. The circuits under consideration in this context include the amygdala's bottom-up activity, which signifies the existence of stimuli that may be seen as dangerous. Moreover, these circuits encompass top-down regulatory processes that originate in the prefrontal cortex, facilitating the communication of the emotional significance associated with the inputs. Diverse databases (e.g., Pubmed, ScienceDirect, Web of Science, Google Scholar) were searched for literature using a combination of different terms e.g., "anxiety", "stress", "neuroanatomy", and "neural circuits", etc. A decrease in GABAergic activity is present in both anxiety disorders and severe depression. Research on cerebral functional imaging in depressive individuals has shown reduced levels of GABA within the cortical regions. Additionally, animal studies demonstrated that a reduction in the expression of GABAA/B receptors results in a behavioral pattern resembling anxiety. The amygdala consists of inhibitory networks composed of GABAergic interneurons, responsible for modulating anxiety responses in both normal and pathological conditions. The GABAA receptor has allosteric sites (e.g., α/γ, γ/ß, and α/ß) which enable regulation of neuronal inhibition in the amygdala. These sites serve as molecular targets for anxiolytic medications such as benzodiazepine and barbiturates. Alterations in the levels of naturally occurring regulators of these allosteric sites, along with alterations to the composition of the GABAA receptor subunits, could potentially act as mechanisms via which the extent of neuronal inhibition is diminished in pathological anxiety disorders.

Association of interleukin-2 and interleukin-10 with the pathophysiology and development of generalized anxiety disorder: a case-control study.

BACKGROUND: Generalized anxiety disorder (GAD) is a devastating mental health condition characterized by constant, uncontrolled worrying. Recent hypotheses indicate that pro-inflammatory cytokines and chemokines are potential contributors to the pathogenesis of GAD. Here, we aimed to assess the role of interleukin-2 (IL-2) and interleukin-10 (IL-10) in the pathophysiology and development of GAD. METHODS: This study recruited 50 GAD patients diagnosed according to the DSM-5 criteria and 38 age-sex-matched healthy controls (HCs). A qualified psychiatrist evaluated all study subjects. The socio-demographic and clinical characteristics of the study population were determined using pre-structured questionnaires or interviews, and cytokine serum levels were estimated using commercially available ELISA kits. RESULTS: We observed reduced serum IL-10 levels in GAD patients compared to HCs (33.69 ± 1.37 pg/ml vs. 44.12 ± 3.16 pg/ml). Also, we observed a significant negative correlation between altered IL-10 levels and GAD-7 scores (r=-0.315, p = 0.039). Moreover, IL-10 serum measurement exhibited good predictive value in receiver operating characteristics (ROC) analysis with an area under the curve (AUC) value of 0.793 (p < 0.001) with 80.65% sensitivity and 62.79% specificity at a cutoff value of 33.93 pg/ml. Conversely, we noticed elevated serum IL-2 levels in GAD patients than in HCs (14.81 ± 2.88 pg/ml vs. 8.08 ± 1.1 pg/ml); however, it failed to maintain any significant association with GAD-7 scores, implying that IL-2 might not be involved in GAD pathogenesis. The lower AUC value (0.640; p > 0.05) exhibited by IL-2 serum measurement in ROC analysis further supported that IL-2 might not be associated with GAD. CONCLUSION: This study provides new insights into the complex interplay between anti-inflammatory cytokines and GAD pathogenesis. Based on the present findings, we can assume that IL-10 but not IL-2 may be associated with the pathophysiology and development of GAD. However, further research with a larger population size and longitudinal design is required to confirm the potential diagnostic efficacy of IL-10.

Neural consequences of 5-Hz transcranial alternating current stimulation over right hemisphere: An eLORETA EEG study.

INTRODUCTION: Transcranial alternating current stimulation (tACS) at 5-Hz to the right hemisphere can effectively alleviate anxiety symptoms. This study aimed to explore the neural mechanisms that drive the therapeutic benefits. METHODS: We collected electroencephalography (EEG) data from 24 participants with anxiety disorders before and after a tACS treatment session. tACS was applied over the right hemisphere, with 1.0 mA at F4, 1.0 mA at P4, and 2.0 mA at T8 (10-10 EEG convention). With eLORETA, we transformed the scalp signals into the current source density in the cortex. We then assessed the differences between post- and pre-treatment brain maps across multiple spectra (delta to low gamma) with non-parametric statistics. RESULTS: We observed a trend of heightened power in alpha and reduced power in mid-to-high beta and low gamma, in accord with the EEG markers of anxiolytic effects reported in previous studies. Additionally, we observed a consistent trend of de-synchronization at the stimulating sites across spectra. CONCLUSION: tACS 5-Hz over the right hemisphere demonstrated EEG markers of anxiety reduction. The after-effects of tACS on the brain are intricate and cannot be explained solely by the widely circulated entrainment theory. Rather, our results support the involvement of plasticity mechanisms in the offline effects of tACS.

Genetic and polygenic investigation of heart rate variability to identify biomarkers associated with Anxiety disorders.

Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.

Diurnal variation in anxiety and activity is influenced by chronotype and probable anxiety-related disorder status.

Anxiety symptoms vary moment-to-moment within a day. One factor that may influence these variations is chronotype. Evening chronotypes prefer to engage in activities (e.g., sleep, physical and social activity) later in the day, and evening chronotype is implicated in psychopathology, including anxiety-related disorders. However, it is unknown whether chronotype influences diurnal variation in anxiety symptoms and whether these effects are amplified in individuals with a probable anxiety-related disorder. We examined the diurnal variation in anxiety symptoms and daily activities in morning and evening chronotypes with and without probable generalized anxiety disorder (GAD) or obsessive-compulsive disorder (OCD) in a community sample of adults (N = 410). Evening chronotypes reported higher anxiety symptoms, particularly in the evening hours, and lower engagement in daily activities, predominantly in the morning hours. Evening chronotypes with probable GAD or OCD reported worse anxiety symptoms in the evening. Our findings indicate that anxiety symptoms and engagement in daily activities fluctuate considerably across the day, and these patterns differ depending on chronotype. Evening chronotypes have more anxiety symptoms in the evening, despite preferring this time of day. Personalized treatment approaches that consider chronotype and target certain times of day may be efficient in alleviating peaks in anxiety symptoms.

Expressive suppression mediates the relationship between sleep quality and generalized anxiety symptomology.

Anxiety disorders are the most prevalent worldwide mental health disorder, resulting in high societal costs. Emotion regulation and sleep quality are associated with the development of psychopathologies including anxiety. However, it is unknown whether habitual emotion regulation strategy use can mediate the influence of sleep quality on anxiety symptomology. An opportunity sample in a healthy population completed the Pittsburgh Sleep Quality Index to provide a measure of sleep quality, the Emotion Regulation Questionnaire to assess habitual use of emotion regulation strategies, and the Generalized Anxiety Disorder Scale to record anxiety symptomology. Data were analysed using correlation and regression-based mediation analyses. Improved sleep quality was predictive of reduced habitual use of expressive suppression and reduced anxiety symptomology. Additionally, increased use of expressive suppression was predictive of greater anxiety symptomology. Cognitive reappraisal was not associated with sleep quality or anxiety severity. Further, novel findings using mediation analyses show that expressive suppression partially mediated the relationship between sleep quality and anxiety. Whilst longitudinal and experimental research are needed to establish causality, these findings suggest that simultaneously targeting improvements in sleep quality and the use of specific emotion regulation strategies, including expressive suppression, may improve the efficacy of interventions focussed on reducing anxiety-related symptomology.

Amplification of positivity for depression and anxiety: Neural prediction of treatment response.

Psychosocial treatments targeting the positive valence system (PVS) in depression and anxiety demonstrate efficacy in enhancing positive affect (PA), but response to treatment varies. We examined whether individual differences in neural activation to positive and negative valence incentive cues underlies differences in benefitting from a PVS-targeted treatment. Individuals with clinically elevated depression and/or anxiety (N = 88, ages 18 to 55) participated in one of two randomized, waitlist-controlled trials of Amplification of Positivity (AMP; NCT02330627, NCT03196544), a cognitive and behavioral intervention targeting the PVS. Participants completed a monetary incentive delay (MID) task during fMRI acquisition at baseline measuring neural activation to the possibility of gaining or losing money. Change in PA from before to after treatment was assessed using the Positive and Negative Affect Schedule. No significant associations were observed between baseline neural activation during gain anticipation and AMP-related changes in PA in regions of interest (striatum and insula) or whole-brain analyses. However, higher baseline striatal and insula activation during loss anticipation was associated with greater increases in PA post-AMP. This study provides preliminary evidence suggesting neural reactivity to negative valence cues may inform who stands to benefit most from treatments targeting the PVS.

Mechanistic studies in pathological health anxiety: A systematic review and emerging conceptual framework.

BACKGROUND: Pathological health anxiety (PHA) (e.g., hypochondriasis and illness anxiety disorder) is common in medical settings and associated with increased healthcare costs. However, the psychological and neurobiological mechanisms contributing to the development and maintenance of PHA are incompletely understood. METHODS: We performed a systematic review to characterize the mechanistic understanding of PHA. PubMed, PsycINFO, and Embase databases were searched to find articles published between 1/1/1990 and 12/31/2022 employing a behavioral task and/or physiological measures in individuals with hypochondriasis, illness anxiety disorder, and PHA more broadly. RESULTS: Out of 9141 records identified, fifty-seven met inclusion criteria. Article quality varied substantially across studies, and was overall inadequate. Cognitive, behavioral, and affective findings implicated in PHA included health-related attentional and memory recall biases, a narrow health concept, threat confirming thought patterns, use of safety-seeking behaviors, and biased explicit and implicit affective processing of health-related information among other observations. There is initial evidence supporting a potential overestimation of interoceptive stimuli in those with PHA. Neuroendocrine, electrophysiology, and brain imaging research in PHA are particularly in their early stages. LIMITATIONS: Included articles evaluated PHA categorically, suggesting that sub-threshold and dimensional health anxiety considerations are not contextualized. CONCLUSIONS: Within an integrated cognitive-behavioral-affective and predictive processing formulation, we theorize that sub-optimal illness and health concepts, altered interoceptive modeling, biased illness-based predictions and attention, and aberrant prediction error learning are mechanisms relevant to PHA requiring more research. Comprehensively investigating the pathophysiology of PHA offers the potential to identify adjunctive diagnostic biomarkers and catalyze new biologically-informed treatments.

A Systematic Review and Meta-Analysis of Impairment and Quality of Life in Children and Adolescents with Anxiety Disorders.

Anxiety disorders are common, emerge during childhood, and pose a significant burden to society and individuals. Research evaluating the impact of anxiety on functional impairment and quality of life (QoL) is increasing; however, there is yet to be a systematic review and meta-analysis of these relationships in pediatric samples. This systematic review and meta-analysis were conducted to determine the extent of impairments in functioning and QoL that young people with anxiety disorders experience relative to their healthy peers, as well as sociodemographic and clinical moderators of these relationships. Studies were included when they compared young people (mean age range within studies 7-17 years) with a primary clinical anxiety disorder to a healthy comparison group and measured impairment and/or QoL via a validated instrument. A total of 12 studies met criteria for this review (N = 3,129 participants). A majority of studies (K = 9) assessed impairment as an outcome measure, and three assessed QoL outcomes. Meta-analysis of nine studies (N = 1,457 children) showed large relationships between clinical anxiety and life impairment (g = 3.23) with the strongest effects seen for clinician report (g = 5.00), followed by caregiver (g = 2.15) and child (g = 1.58) report. The small number of studies and diversity in methodology prevented quantitative investigation of moderating factors. In the systematic review of QoL outcomes, all three studies reported significantly poorer QoL for youth with anxiety disorders relative to unaffected peers. Findings support the importance of measuring functioning and QoL as outcomes in clinical research and practice among anxious young people.This study is registered with PROSPERO under the identification number CRD42023439040.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.