Brain activity during reappraisal and associations with psychotherapy response in social anxiety and major depression: a randomized trial.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for patients with social anxiety disorder (SAD) or major depressive disorder (MDD), yet there is variability in clinical improvement. Though prior research suggests pre-treatment engagement of brain regions supporting cognitive reappraisal (e.g. dorsolateral prefrontal cortex [dlPFC]) foretells CBT response in SAD, it remains unknown if this extends to MDD or is specific to CBT. The current study examined associations between pre-treatment neural activity during reappraisal and clinical improvement in patients with SAD or MDD following a trial of CBT or supportive therapy (ST), a common-factors comparator arm. METHODS: Participants were 75 treatment-seeking patients with SAD (n = 34) or MDD (n = 41) randomized to CBT (n = 40) or ST (n = 35). Before randomization, patients completed a cognitive reappraisal task during functional magnetic resonance imaging. Additionally, patients completed clinician-administered symptom measures and a self-report cognitive reappraisal measure before treatment and every 2 weeks throughout treatment. RESULTS: Results indicated that pre-treatment neural activity during reappraisal differentially predicted CBT and ST response. Specifically, greater trajectories of symptom improvement throughout treatment were associated with less ventrolateral prefrontal cortex (vlPFC) activity for CBT patients, but more vlPFC activity for ST patients. Also, less baseline dlPFC activity corresponded with greater trajectories of self-reported reappraisal improvement, regardless of treatment arm. CONCLUSIONS: If replicated, findings suggest individual differences in brain response during reappraisal may be transdiagnostically associated with treatment-dependent improvement in symptom severity, but improvement in subjective reappraisal following psychotherapy, more broadly.

Withdrawal catastrophizing scale: initial psychometric properties and implications for the study of opioid use disorder and hyperkatifeia.

Background: Discovery of modifiable factors influencing subjective withdrawal experience might advance opioid use disorder (OUD) research and precision treatment. This study explores one factor - withdrawal catastrophizing - a negative cognitive and emotional orientation toward withdrawal characterized by excessive fear, worry or inability to divert attention from withdrawal symptoms.Objectives: We define a novel concept - withdrawal catastrophizing - and present an initial evaluation of the Withdrawal Catastrophizing Scale (WCS).Methods: Prospective observational study (n = 122, 48.7% women). Factor structure (exploratory factor analysis) and internal consistency (Cronbach's α) were assessed. Predictive validity was tested via correlation between WCS and next-day subjective opiate withdrawal scale (SOWS) severity. The clinical salience of WCS was evaluated by correlation between WCS and withdrawal-motivated behaviors including risk taking, OUD maintenance, OUD treatment delay, history of leaving the hospital against medical advice and buprenorphine-precipitated withdrawal.Results: WCS was found to have a two-factor structure (distortion and despair), strong internal consistency (α = .901), and predictive validity - Greater withdrawal catastrophizing was associated with next-day SOWS (rs (99) = 0.237, p = .017). Withdrawal catastrophizing was also correlated with risk-taking behavior to relieve withdrawal (rs (119) = 0.357, p < .001); withdrawal-motivated OUD treatment avoidance (rs (119) = 0.421, p < .001), history of leaving the hospital against medical advice (rs (119) = 0.373, p < .001) and buprenorphine-precipitated withdrawal (rs (119) = 0.369, p < .001).Conclusion: This study provides first evidence of withdrawal catastrophizing as a clinically important phenomenon with implications for the future study and treatment of OUD.

Obsessive-Compulsive Symptoms: Baseline Prevalence, Comorbidity, and Implications in a Clinically Anxious Pediatric Sample.

Subclinical symptoms of obsessive-compulsive disorder (i.e., obsessive compulsive symptoms, or "OCS") cause functional impairment, including for youth without full-syndrome OCD. Further, despite high rates of OCS in youth with anxiety disorders, knowledge of OCS in the context of specific anxiety disorders is limited. The present study seeks to: (1) compare OCS in pediatric patients with anxiety disorders and healthy youth, (2) determine which categorical anxiety disorder(s) associate most with OCS, and (3) determine relationships between OCS with anxiety severity and impairment. Data on OCS, anxiety, and functional impairment were collected from 153 youth with anxiety disorders and 45 healthy controls, ages 7-17 years (M = 11.84, SD = 3.17). Findings indicated that patients had significantly more OCS than healthy controls. Among patients, GAD was a significant predictor of OCS as well as OCD risk. These results suggest that OCS should be a primary diagnostic and treatment consideration for youth who present in clinical settings with GAD.

Self-focused brain predictors of cognitive behavioral therapy response in a transdiagnostic sample.

BACKGROUND: Effective biomarkers of cognitive behavioral therapy (CBT) response provide information beyond available behavioral or self-report measures and may optimize treatment selection for patients based on likelihood of benefit. No single biomarker reliably predicts CBT response. In this study, we evaluated patterns of brain connectivity associated with self-focused attention (SFA) as biomarkers of CBT response for anxiety and obsessive-compulsive disorders. We hypothesized that pre-treatment as well as pre-to post-treatment changes in functional connectivity would be associated with improvement during CBT in a transdiagnostic sample. METHODS: Twenty-seven patients with primary social anxiety disorder (n = 14) and primary body dysmorphic disorder (n = 13) were scanned before and after 12 sessions of CBT targeting their primary disorder. Eligibility was based on elevated trait SFA scores on the Public Self-Consciousness Scale. Seed-based resting state functional connectivity associated with symptom improvement was computed using a seed in the posterior cingulate cortex of the default mode network. RESULTS: At pre-treatment, stronger positive connectivity of the seed with the cerebellum, and stronger negative connectivity with the putamen, were associated with greater clinical improvement. Between pre-to post-treatment, greater anticorrelation between the seed and postcentral gyrus, extending into the inferior parietal lobule and precuneus/superior parietal lobule was associated with clinical improvement, although this did not survive thresholding. CONCLUSIONS: Pre-treatment functional connectivity with the default mode network was associated with CBT response. Behavioral and self-report measures of SFA did not contribute to predictions, thus highlighting the value of neuroimaging-based measures of SFA. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT02808702 https://clinicaltrials.gov/ct2/show/NCT02808702.

Nociplastic Pain and Pain-Motivated Drinking in Alcohol Use Disorder.

Heavy chronic alcohol use may produce pain amplification through neurochemical and neuroplastic changes at multiple levels of the nervous system. Similar changes are thought to underlie nociplastic pain. The American College of Rheumatology Fibromyalgia Survey has been used as a surrogate for nociplastic pain, including among individuals with alcohol use disorder (AUD). However, studies linking nociplastic pain to pain-motivated drinking are lacking. The present study aimed to determine if nociplastic pain is associated with pain-motivated drinking in AUD. To achieve this aim, a new scale-the Pain-Motivated Drinking Scale (PMDS)-was developed to measure how often participants were motivated by pain to drink alcohol. Measurement properties of this new scale were determined, including its factor structure, internal consistency reliability, and construct validity. In this cross-sectional observational study, participants with AUD (n = 138) were consecutively recruited from the patient pool at an academic addiction treatment facility. Seventy-two percent (95, 72.0%) reported they drank alcohol "to get relief from physical pain" at least some of the time, and over forty-two percent (56, 42.4%) reported pain relief motivated their drinking at least half of the time. PMDS had a single-factor structure, strong internal consistency reliability, and construct validity. A multiple hierarchical linear regression was run to determine if nociplastic pain was associated with pain-motivated drinking. Nociplastic pain was associated with PMDS even after controlling for potential confounders and pain severity. These findings suggest nociplastic pain is uniquely associated with pain-motivated drinking in AUD. PERSPECTIVE: Nociplastic pain is independently associated with pain-motivated drinking in alcohol use disorder (AUD). The Pain-Motivated Drinking Scale (PMDS) is a new scale to measure how often people drink to cope with pain. PMDS has promising psychometric properties. Nociplastic pain may be uniquely associated with pain-motivated drinking in AUD.

Sleep quality impacts the link between reactivity to uncertain threat and anxiety and alcohol use in youth.

Individual differences in reactivity to unpredictable threat (U-threat) have repeatedly been linked to symptoms of anxiety and drinking behavior. An emerging theory is that individuals who are hyper-reactive to U-threat experience chronic anticipatory anxiety, hyperarousal, and are vulnerable to excessive alcohol use via negative reinforcement processes. Notably, anxiety and alcohol use commonly relate to disruptions in sleep behavior and recent findings suggest that sleep quality may impact the link between reactivity to U-threat and psychiatric symptoms and behaviors. The aim of the current study was to examine the unique and interactive effects of reactivity to U-threat and sleep quality on anxiety symptoms and drinking behavior in a cohort of youth, ages 16-19 years. Participants (N = 112) completed a well-validated threat-of-shock task designed to probe individual differences in reactivity to U-threat and predictable threat (P-threat). Startle eyeblink potentiation was recorded during the task as an index of aversive reactivity. Participants also completed well-validated self-report measures of anxiety and depression symptoms, lifetime alcohol use, and current sleep quality. Results revealed significant startle reactivity to U-threat by sleep quality interactions on anxiety symptoms and lifetime drinking behavior. At high levels of sleep disturbance (only), greater reactivity to U-threat was associated with greater anxiety symptoms and total number of lifetime alcoholic beverages. These results suggest that sensitivity to uncertainty and chronic hyperarousal increases anxiety symptoms and alcohol use behavior, particularly in the context of poor sleep quality.

Default Mode Network Hypoalignment of Function to Structure Correlates With Depression and Rumination.

BACKGROUND: Recent studies have begun to examine how signals in the brain correspond to the underlying white matter structure using tools from the field of graph signal processing to quantify brain function alignment to brain network topology. Here, we applied this framework for the first time toward a transdiagnostic cohort of individuals with internalizing psychopathologies, including mood and anxiety disorders, to uncover how such alignment within the default mode network (DMN) is related to depression and rumination symptoms. METHODS: Both diffusion-weighted and resting-state functional magnetic resonance imaging were obtained from participants at baseline (n = 60 patients, n = 19 healthy control participants). Patients were randomized to 12 weeks of treatment with either a selective serotonin reuptake inhibitor or cognitive behavioral therapy, and symptom scales were readministered posttreatment (n = 46 patients at follow-up). Using graph signal processing methodology, we quantified the alignment of functional signals to their underlying white matter structural networks. RESULTS: We found that signal alignment within the posterior DMN was decreased in patients with internalizing psychopathologies compared with healthy control participants and was inversely (negatively) correlated with baseline depression and rumination scales. Signal alignment within the posterior DMN was also correlated with the ratio of total within-DMN to extra-DMN functional connectivity for these regions. CONCLUSIONS: These findings are consistent with previous literature regarding pathological promiscuity of posterior DMN connectivity and provide the first graph signal processing-based analyses in a transdiagnostic cohort of patients with internalizing psychopathologies.

Self-Focused Brain Predictors of Cognitive Behavioral Therapy Response in a Transdiagnostic Sample.

Background: Effective biomarkers of cognitive behavioral therapy (CBT) response provide information beyond available behavioral or self-report measures and may optimize treatment selection for patients based on likelihood of benefit. No single biomarker reliably predicts CBT response. In this study, we evaluated patterns of brain connectivity associated with self-focused attention (SFA) as biomarkers of CBT response for anxiety and obsessive-compulsive disorders. We hypothesized that pre-treatment as well as pre- to post-treatment changes in functional connectivity would be associated with improvement during CBT in a transdiagnostic sample. Methods: Twenty-seven patients with primary social anxiety disorder (n=14) and primary body dysmorphic disorder (n=13) were scanned before and after 12 sessions of CBT targeting their primary disorder. Eligibility was based on elevated trait SFA scores on the Public Self-Consciousness Scale. Seed-based resting state functional connectivity associated with symptom improvement was computed using a seed in the posterior cingulate cortex/precuneus that delineated a self-other functional network. Results: At pre-treatment, stronger positive connectivity of the seed with the cerebellum, insula, middle occipital gyrus, postcentral gyrus, and precuneus/superior parietal lobule, and stronger negative connectivity with the putamen, were associated with greater clinical improvement. Between pre- to post-treatment, greater anticorrelation between the seed and precuneus/superior parietal lobule was associated with clinical improvement, although this did not survive thresholding. Conclusions: Pre-treatment functional connectivity between regions involved in attentional salience, self-generated thoughts, and external attention predicted greater CBT response. Behavioral and self-report measures of SFA did not contribute to predictions, thus highlighting the value of neuroimaging-based measures of SFA. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT02808702 https://clinicaltrials.gov/ct2/show/NCT02808702.

Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

BACKGROUND: Prior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal-striatal-thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset. METHODS: In this study, unmedicated female patients with OCD (ages 8-21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN. RESULTS: Functional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other. CONCLUSIONS: Our findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

Neural responses during down-regulation of negative emotion in patients with recently diagnosed bipolar disorder and their unaffected relatives.

BACKGROUND: Aberrant emotion regulation has been posited as a putative endophenotype of bipolar disorder (BD). We therefore aimed to compare the neural responses during voluntary down-regulation of negative emotions in a large functional magnetic resonance imaging study of BD, patients' unaffected first-degree relatives (URs), and healthy controls (HCs). METHODS: We compared neural activity and fronto-limbic functional connectivity during emotion regulation in response to aversive v. neutral pictures in patients recently diagnosed with BD (n = 78) in full/partial remission, their URs (n = 35), and HCs (n = 56). RESULTS: Patients showed hypo-activity in the left dorsomedial, dorsolateral, and ventrolateral prefrontal cortex (DMPFC and DLPFC) during emotion regulation while viewing aversive pictures compared to HCs, with URs displaying intermediate neural activity in these regions. There were no significant differences between patients with BD and HCs in functional connectivity from the amygdala during emotion regulation. However, exploratory analysis indicated that URs displayed more negative amygdala-DMPFC coupling compared with HCs and more negative amygdala-cingulate DLPFC coupling compared to patients with BD. At a behavioral level, patients and their URs were less able to dampen negative emotions in response aversive pictures. CONCLUSIONS: The findings point to deficient recruitment of prefrontal resources and more negative fronto-amygdala coupling as neural markers of impaired emotion regulation in recently diagnosed remitted patients with BD and their URs, respectively.

Altered bed nucleus of the stria terminalis and amygdala responses to threat in combat veterans with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) significantly impacts many veterans. Although PTSD has been linked to alterations in the fear brain network, the disorder likely involves alterations in both the fear and anxiety networks. Fear involves responses to imminent, predictable threat and is driven by the amygdala, whereas anxiety involves responses to potential, unpredictable threat and engages the bed nucleus of the stria terminalis (BNST). The BNST has been implicated in PTSD, but the role of the BNST in combat veterans with PTSD has yet to be examined. Identifying alterations in BNST responses to unpredictable threat could provide important new targets for treatment. The current study examined whether veterans with PTSD have altered BNST or amygdala responses (function and connectivity) to unpredictable and predictable threat. The fMRI task involved viewing predictable threat cues followed by threat images, predictable neutral cues followed by neutral images, and unpredictable threat cues followed by either a threat or neutral image. Participants included 32 combat-exposed veterans with PTSD and 13 combat-exposed controls without PTSD. Across all conditions, veterans with PTSD had heightened BNST activation and displayed stronger BNST and amygdala connectivity with multiple fear and anxiety regions (hypothalamus, hippocampus, insula, ventromedial prefrontal cortex) relative to controls. In contrast, combat controls showed a pattern of stronger connectivity during neutral conditions (e.g., BNST-vmPFC), which may suggest a neural signature of resilience to developing PTSD, ηp 2 = .087-.527, ps < .001. These findings have implications for understanding fear and anxiety networks that may contribute to the development and maintenance of PTSD.

Neural reactivity to neutral and aversive stimuli: Evidence for altered precuneus function in internalizing psychopathologies.

Individuals with internalizing psychopathologies (IPs) demonstrate a negativity bias in emotion and self-related processing that contributes to negative interpretation of neutral information. However, most neuroimaging studies of emotional experience in IPs do not specifically investigate reactivity to neutral stimuli. Thus, little is known about the neural processes underlying emotional experience for neutral stimuli and how those processes may differ between groups and during neutral versus negative stimuli. To address this gap, we asked: (1) does neural reactivity to neutral and negative stimuli differ between IPs and control groups in brain regions associated with emotional and self-referential processing, and (2) does neural activity during neutral condition relate to clinical symptoms? Adults with IPs (n = 103) and healthy volunteers (HVs; n = 40) completed a well-validated fMRI task probing neural responses to neutral and negative images. A flexible factorial model revealed a significant group-by-condition interaction, such that individuals with IPs had less precuneus activation during the neutral condition relative to HVs. In IPs, precuneus activation during the neutral condition was negatively correlated with depression symptom severity. Individuals with IPs demonstrate abnormal precuneus reactivity to neutral stimuli that is associated with depression symptoms. This may reflect altered default mode network activity and/or self-referential processing in IPs.

The interplay of childhood maltreatment and maternal depression in relation to the reward positivity in youth.

Guided by developmental psychopathology and dual-risk frameworks, the present study examined the interplay between childhood maltreatment and maternal major depression history in relation to neural reward responsiveness in youth. The sample consisted of 96 youth (ages 9-16; M = 12.29 years, SD = 2.20; 68.8% female) drawn from a large metropolitan city. Youth were recruited based on whether their mothers had a history of major depressive disorder (MDD) and were categorized into two groups: youth with mothers with a history of MDD (high risk; HR; n = 56) and youth with mothers with no history of psychiatric disorders (low risk; LR; n = 40). The reward positivity (RewP), an event-related potential component, was utilized to measure reward responsiveness and the Childhood Trauma Questionnaire measured childhood maltreatment. We found a significant two-way interaction between childhood maltreatment and risk group in relation to RewP. Simple slope analysis revealed that in the HR group, greater childhood maltreatment was significantly associated with reduced RewP. The relationship between childhood maltreatment and RewP was not significant among the LR youth. The present findings demonstrate that the association between childhood maltreatment and blunted reward responsiveness is dependent on whether offspring have mothers with histories of MDD.

Neural responsiveness to reward and suicidal ideation in social anxiety and major depression before and after psychotherapy.

Suicidality is prevalent in Social Anxiety Disorder (SAD) and Major Depressive Disorder (MDD). Limited data indicate the reward positivity (RewP), a neurophysiological index of reward responsivity, and subjective capacity for pleasure may serve as brain and behavioral assays for suicide risk though this has yet to be examined in SAD or MDD in the context of psychotherapy. Therefore, the current study tested whether suicidal ideation (SI) relates to RewP and subjective capacity for anticipatory and consummatory pleasure at baseline and whether Cognitive Behavioral Therapy (CBT) impacts these measures. Participants with SAD (n = 55) or MDD (n = 54) completed a monetary reward task (gains vs. losses) during electroencephalogram (EEG) before being randomized to CBT or supportive therapy (ST), a comparator common factors arm. EEG and SI data were collected at baseline, mid-treatment, and post-treatment; capacity for pleasure was collected at baseline and post-treatment. Baseline results showed participants with SAD or MDD were comparable in SI, RewP, and capacity for pleasure. When controlling for symptom severity, SI negatively corresponded with RewP following gains and SI positively corresponded with RewP following losses at baseline. Yet, SI did not relate to subjective capacity for pleasure. Evidence of a distinct SI-RewP association suggests RewP may serve as a transdiagnositic brain-based marker of SI. Treatment outcome revealed that among participants with SI at baseline, SI significantly decreased regardless of treatment arm; also, consummatory, but not anticipatory, pleasure increased across participants regardless of treatment arm. RewP was stable following treatment, which has been reported in other clinical trial studies.

Actigraphic Wake after Sleep Onset and Symptom Severity Correspond with Rumination in Trauma-Exposed Individuals.

Rumination and worry are forms of repetitive negative thinking (RNT) commonly associated with internalizing psychopathologies, although less is known about RNT in trauma-exposed individuals with internalizing psychopathologies. Separate lines of research show RNT also plays a role in problematic sleep, which is frequently experienced after trauma exposure. To address gaps in the literature, the current study examines the impact of sleep and symptoms on RNT in trauma-exposed participants. A transdiagnostic sample of 46 unmedicated treatment-seeking trauma-exposed participants completed standard measures of rumination and worry, as well as clinical measures that assessed posttraumatic stress, depression, and anxiety severity. Actigraphic sleep variables were sleep duration, wake after sleep onset (WASO), and sleep efficiency. Sleep and clinical measures were submitted to multiple regression analyses with rumination and worry as dependent variables. The regression results showed that rumination was significantly explained by WASO and posttraumatic stress symptom (PTSS) severity, and the omnibus test was significant. Depression, anxiety, and other estimates of sleep were not significant. No significant results emerged for worry. Preliminary findings suggest that PTSS and WASO, an index of fragmented sleep, may contribute to rumination, but not worry, in trauma-exposed individuals. Longitudinal studies are needed to determine potential causal relationships.

Impact of alcohol use, combat exposure, and posttraumatic stress on verbal and visual working memory performance in post-9/11 veterans.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and alcohol use (AU) are highly prevalent and comorbid among post-9/11 U.S. military veterans. Both issues are associated with working memory (WM) deficits, but have rarely been studied concurrently in cognitive studies of post-9/11 veterans. They also have been measured inconsistently, with variable outcomes, in prior veteran studies despite their relevance to new intervention paradigms involving WM. METHOD: The present study evaluated 52 post-9/11 veterans [predominantly male (94.2%); White (44.2%) or Black (36.5%); 50% being diagnosed with PTSD based on CAPS-5 results] with objectively verified valid neuropsychological test performance on measures of PTSD, AU, combat exposure, and verbal and visual WM. RESULTS: PTSD was not associated with verbal or visual WM performances, whereas AU and combat exposure were significantly associated with poorer visual WM performances. CONCLUSIONS: AU and prior combat exposure may influence visual WM performances in post-9/11 veterans, which is relevant to novel PTSD treatment paradigms. This sample was limited to mostly male and White or Black participants, and future studies should focus on sampling more heterogeneous groups of veterans with regard to sex and ethnicity. Improvements in specification/multimodal WM assessment are important for future research, as these may directly impact developing intervention efforts. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Neurobiological Profile Underlying Comorbidity Load and Prospective Increases in Dysphoria in a Focal Fear Sample.

BACKGROUND: Knowledge of the neural mechanisms underlying increased disease burden in anxiety disorders that is unaccounted for by individual categorical diagnoses could lead to improved clinical care. Here, we tested the utility of a joint functional magnetic resonance imaging-electroencephalography neurobiological profile characterized by overvaluation of negative stimuli (amygdala) in combination with blunted elaborated processing of these same stimuli (the late positive potential [LPP], an event-related potential) in predicting increased psychopathology across a 2-year period in people with anxiety disorders. METHODS: One hundred ten participants (64 female, 45 male, 1 other) including 78 participants with phobias who varied in the extent of their internalizing comorbidity and 32 participants who were free from psychopathology viewed negative and neutral pictures during separate functional magnetic resonance imaging blood oxygen level-dependent and electroencephalogram recordings. Dysphoria was assessed at baseline and 2 years later. RESULTS: Participants with both heightened amygdala activation and blunted LPPs to negative pictures showed the greatest increases in dysphoria 2 years later. Cross-sectionally, participants with higher comorbidity load (≥2 additional diagnoses, n = 34) showed increased amygdala activation to negative pictures compared with participants with lower comorbidity load (≤1 additional diagnosis, n = 44) and compared with participants free from psychopathology. In addition, high comorbid participants showed reduced LPPs to negative pictures compared with low comorbid participants. CONCLUSIONS: Heightened amygdala in response to negative stimuli in combination with blunted LPPs could indicate overvaluation of threatening stimuli in the absence of elaborated processing that might otherwise help regulate threat responding. This brain profile could underlie the worsening and maintenance of internalizing psychopathology over time.

Acute orexin antagonism selectively modulates anticipatory anxiety in humans: implications for addiction and anxiety.

Research indicates that heightened anticipatory anxiety underlies several forms of psychopathology. Anticipatory anxiety can be reliably and objectively measured in the laboratory using the No-Predictable-Unpredictable (NPU) threat paradigm. The NPU paradigm is an ideal research tool for the NIH 'Fast-Fail' approach of screening promising compounds and testing human target engagement. Evidence from preclinical studies suggests that the hypocretin/orexin (ORX) hypothalamic neuropeptide system is a potential means for modulating anticipatory anxiety and disrupting stress-related alcohol use. The current study tested this question using a psychophysiological probe of the ORX system in humans. We examined whether a single dose of suvorexant (SUV; 10 mg; dual ORX receptor antagonist) can effectively and selectively target a well-validated human laboratory index of exaggerated anticipatory anxiety using a within-subjects placebo-controlled design. A total of twenty-one volunteers completed two laboratory sessions during acute administration of 10 mg SUV or placebo. Across sessions, we administered the NPU paradigm probing sustained anticipatory anxiety and fear while startle eyeblink was recorded as an index of aversive reactivity. Questionnaires assessing mood states and subjective drug effects were also collected. Results indicated SUV was well-tolerated. Compared with placebo, SUV was associated with decreased startle reactivity during anticipatory anxiety but not fear or no-threat conditions. Therefore, SUV selectively and effectively reduced objective indicators of anticipatory anxiety in humans and engaged our laboratory target of psychopathology. ORX antagonism may be a promising strategy for modulating human anxiety and potentially, stress-related alcohol use.

Central sensitization in opioid use disorder: a novel application of the American College of Rheumatology Fibromyalgia Survey Criteria.

Introduction: Central sensitization (CS) involves dysfunctional central nervous system pain modulation resulting in heightened pain perception. Central sensitization is not commonly assessed among patients with opioid use disorder (OUD), despite the fact that pain has been implicated in the development, maintenance, and relapse of OUD and chronic opioid use may produce opioid-induced hyperalgesia. Central sensitization is a plausibly important mechanism underlying the complex relationship between OUD and chronic pain. However, this premise is largely untested. Methods: Participants with OUD (n = 141) were recruited from an academic addiction treatment center in Columbus, Ohio. An established surrogate measure of CS, the American College of Rheumatology 2011 Fibromyalgia Survey Criteria, was administered using electronic survey. Participants also responded to questions about pain interference (Brief Pain Inventory), quality of life (RAND-36), and items regarding pain beliefs and expectations of pain and addiction treatment. Descriptive analyses, Spearman rho correlations, and Mann-Whitney U tests were performed. Results: Hypothesized relationships were confirmed between degree of CS, pain interference, and health-related quality of life. Degree of CS was also positively correlated with greater endorsement of pain as a reason for the onset, maintenance, and escalation of OUD; treatment delay; and OUD relapse. Participants with the American College of Rheumatology 2011 Fibromyalgia Survey Criteria ≥13 had significantly greater endorsement of pain as a reason for delaying OUD treatment, continuing and increasing opioid use, and precipitating OUD relapse. Conclusions: This study provides early evidence CS may underlie previously observed connections between clinically salient features of chronic pain and OUD, potentially informing future mechanistic research and precision treatment.

Neural reactivity to affective stimuli and internalizing symptom dimensions in a transdiagnostic patient sample.

BACKGROUND: Internalizing psychopathologies (IPs) are highly comorbid and exhibit substantial overlap, such as aberrant affective reactivity. Neural reactivity to emotional images, measured via the late positive potential (LPP) event-related potential (ERP) component, has been utilized to index affective reactivity in IPs. The LPP is often examined in isolation with a specific disorder, ignoring overlap between IPs. The current study examined how transdiagnostic IP symptom dimensions relate to neural affective reactivity in a highly comorbid patient sample. METHODS: Participants (N = 99) completed a battery of IP symptom assessments as well as a target categorization task while viewing pleasant, unpleasant, and neutral images during electroencephalography recording. ERPs to each image valence were averaged from 400 to 1000 ms following picture onset at pooled centroparietal and occipital electrodes to calculate the LPP. A principal components analysis performed on the IP symptom measures resulted in two factors: affective distress/misery and fear-based anxiety. RESULTS: Fear-based anxiety was associated with enhanced LPP reactivity to unpleasant, but not pleasant, images. Distress/misery was related to attenuated average LPP reactivity across images. CONCLUSIONS: Results revealed a dissociable effect of IP symptom factors in a transdiagnostic sample such that enhanced reactivity to negative images was specific to enhanced fear-based anxiety symptoms while distress/misery symptoms predicted blunted affective reactivity. Neural affective reactivity may serve as an objective biological marker to elucidate the nature of psychological concerns in individuals with comorbid IPs.