Anhedonia in adolescents at transdiagnostic familial risk for severe mental illness: Clustering by symptoms and mechanisms of association with behavior.

BACKGROUND: Anhedonia is a transdiagnostic symptom of severe mental illness (SMI) and emerges during adolescence. Possible subphenotypes and neural mechanisms of anhedonia in adolescents at risk for SMI are understudied. METHODS: Adolescents at familial risk for SMI (N = 81) completed anhedonia (e.g., consummatory, anticipatory, social), demographic, and clinical measures and one year prior, a subsample (N = 46) completed fMRI scanning during a monetary reward task. Profiles were identified using k-means clustering of anhedonia type and differences in demographics, suicidal ideation, impulsivity, and emotional processes were examined. Moderation analyses were conducted to investigate whether levels of brain activation of reward regions moderated the relationships between anhedonia type and behaviors. RESULTS: Two-clusters emerged: a high anhedonia profile (high-anhedonia), characterized by high levels of all types of anhedonia, (N = 32) and a low anhedonia profile (low-anhedonia), characterized by low levels of anhedonia types (N = 49). Adolescents in the high-anhedonia profile reported more suicidal ideation and negative affect, and less positive affect and desire for emotional closeness than low-anhedonia profile. Furthermore, more suicidal ideation, less positive affect, and less desire for emotional closeness differentiated the familial high-risk, high-anhedonia profile adolescents from the familial high-risk, low-anhedonia profile adolescents. Across anhedonia profiles, moderation analyses revealed that adolescents with high dmPFC neural activation in response to reward had positive relationships between social, anticipatory, and consummatory anhedonia and suicidal ideation. LIMITATIONS: Small subsample with fMRI data. CONCLUSION: Profiles of anhedonia emerge transdiagnostically and vary on clinical features. Anhedonia severity and activation in frontostriatal reward areas have value for clinically important outcomes such as suicidal ideation.

Cervical pessary for preterm birth prevention after an episode of arrested preterm labor: a retrospective cohort study with targeted maximum likelihood estimation of the average treatment effect.

OBJECTIVE: To evaluate whether cervical pessary effectively reduces the preterm birth < 37 weeks rate in patients who have not delivered after an episode of arrested preterm labor. PATIENTS AND METHODS: Retrospective cohort study was conducted on singleton pregnant patients admitted to our institution between January 2016 and June 2021 for threatened preterm labor and who had a cervical length < 25 mm. Women in whom a cervical pessary was placed were considered as exposed, while women in whom expectant management was preferred were considered as unexposed. The primary outcome was the rate of preterm birth before 37 weeks. A targeted maximum likelihood estimation was used to estimate the average treatment effect of cervical pessary by adjusting for a-priori-defined confounders. RESULTS: A cervical pessary was placed in 152 (36.6%) patients (exposed), while the remaining 263 (63.4%) were managed expectantly (unexposed). The adjusted average treatment effect was -14% (-18 to -11%), -17% (-20 to -13%), and -16% (-20 to -12%) for preterm birth < 37 weeks, < 34 weeks, and < 32 weeks, respectively. The average treatment effect for adverse neonatal outcomes was -7% (-8 to -5%). No difference in gestational weeks at delivery between exposed and unexposed emerged when gestational age at first admission was > 30.1 gestational weeks. CONCLUSIONS: The positioning of a cervical pessary placement may be evaluated to reduce the risk of a subsequent preterm birth after an episode of arrested preterm labor in pregnant patients with onset of symptoms before 30 gestational weeks.

Childhood adversities and risk of posttraumatic stress disorder and major depression following a motor vehicle collision in adulthood.

AIMS: Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions. METHODS: Data came from n = 999 patients ages 18-75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect and bullying. Both dichotomous measures of ever experiencing each CA type and numeric measures of exposure frequency were included in the analysis. Risk ratios (RRs) of these CA measures as well as complex interactions among these measures were examined as predictors of APNS 3 months post-MVC. APNS was defined as meeting self-reported criteria for either PTSD based on the PTSD Checklist for DSM-5 and/or MDE based on the PROMIS Depression Short-Form 8b. We controlled for pre-MVC lifetime histories of PTSD and MDE. We also examined mediating effects through peritraumatic symptoms assessed in the emergency department and PTSD and MDE assessed in 2-week and 8-week follow-up surveys. Analyses were carried out with robust Poisson regression models. RESULTS: Most participants (90.9%) reported at least rarely having experienced some CA. Ever experiencing each CA other than emotional neglect was univariably associated with 3-month APNS (RRs = 1.31-1.60). Each CA frequency was also univariably associated with 3-month APNS (RRs = 1.65-2.45). In multivariable models, joint associations of CAs with 3-month APNS were additive, with frequency of emotional abuse (RR = 2.03; 95% CI = 1.43-2.87) and bullying (RR = 1.44; 95% CI = 0.99-2.10) being the strongest predictors. Control variable analyses found that these associations were largely explained by pre-MVC histories of PTSD and MDE. CONCLUSIONS: Although individuals who experience frequent emotional abuse and bullying in childhood have a heightened risk of experiencing APNS after an adult MVC, these associations are largely mediated by prior histories of PTSD and MDE.

Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma.

BACKGROUND: Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time. METHODS: As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors. RESULTS: Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants. CONCLUSIONS: The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories.

Using diffusion MRI data acquired with ultra-high gradient strength to improve tractography in routine-quality data.

The development of scanners with ultra-high gradient strength, spearheaded by the Human Connectome Project, has led to dramatic improvements in the spatial, angular, and diffusion resolution that is feasible for in vivo diffusion MRI acquisitions. The improved quality of the data can be exploited to achieve higher accuracy in the inference of both microstructural and macrostructural anatomy. However, such high-quality data can only be acquired on a handful of Connectom MRI scanners worldwide, while remaining prohibitive in clinical settings because of the constraints imposed by hardware and scanning time. In this study, we first update the classical protocols for tractography-based, manual annotation of major white-matter pathways, to adapt them to the much greater volume and variability of the streamlines that can be produced from today's state-of-the-art diffusion MRI data. We then use these protocols to annotate 42 major pathways manually in data from a Connectom scanner. Finally, we show that, when we use these manually annotated pathways as training data for global probabilistic tractography with anatomical neighborhood priors, we can perform highly accurate, automated reconstruction of the same pathways in much lower-quality, more widely available diffusion MRI data. The outcomes of this work include both a new, comprehensive atlas of WM pathways from Connectom data, and an updated version of our tractography toolbox, TRActs Constrained by UnderLying Anatomy (TRACULA), which is trained on data from this atlas. Both the atlas and TRACULA are distributed publicly as part of FreeSurfer. We present the first comprehensive comparison of TRACULA to the more conventional, multi-region-of-interest approach to automated tractography, and the first demonstration of training TRACULA on high-quality, Connectom data to benefit studies that use more modest acquisition protocols.

Interplay of Val66Met and BDNF methylation: effect on reward learning and cognitive performance in major depression.

BACKGROUND: There is a growing interest in the role of brain-derived neurotrophic factor (BDNF) in major depressive disorder (MDD). BDNF potentially exhibits opposite effects in the pathways linked to anhedonia and reward learning on the one hand and cognitive performance, on the other hand. However, the epigenetic mechanisms behind this remain unknown. In the present study, we aimed to investigate the interplay of DNA methylation of different BDNF exons and the common Val66Met polymorphism on anhedonia, reward learning and cognitive performance in MDD. METHODS: We recruited 80 depressed patients and 58 age- and gender-matched healthy controls. Participants underwent clinical assessment including neuropsychological testing and a probabilistic reward task to assess reward learning. Val66Met polymorphism and DNA methylation of BDNF promoters I, IV and exon IX were assessed from whole blood derived DNA, using pyrosequencing. RESULTS: BDNF promoter I methylation was lower in MDD patients (p = 0.042) and was negatively associated with self-reported anhedonia. In depressed patients, both Val66Met polymorphism and DNA methylation of promoter I were significantly associated with reward bias (p < 0.050 and p = 0.040, respectively), without an interaction effect. On the other hand, methylation of exon IX had a negative impact on executive functioning (p = 0.002) and mediated the effect of Val66Met on this outcome in patients with MDD. CONCLUSIONS: Our results provide the first evidence of Val66Met susceptibility to differential epigenetic regulation of BDNF exons in reward learning and executive functioning in MDD, which needs to be further explored.

Brain function and clinical characterization in the Boston adolescent neuroimaging of depression and anxiety study.

We present a Human Connectome Project study tailored toward adolescent anxiety and depression. This study is one of the first studies of the Connectomes Related to Human Diseases initiative and is collecting structural, functional, and diffusion-weighted brain imaging data from up to 225 adolescents (ages 14-17 years), 150 of whom are expected to have a current diagnosis of an anxiety and/or depressive disorder. Comprehensive clinical and neuropsychological evaluations and longitudinal clinical data are also being collected. This article provides an overview of task functional magnetic resonance imaging (fMRI) protocols and preliminary findings (N = 140), as well as clinical and neuropsychological characterization of adolescents. Data collection is ongoing for an additional 85 adolescents, most of whom are expected to have a diagnosis of an anxiety and/or depressive disorder. Data from the first 140 adolescents are projected for public release through the National Institutes of Health Data Archive (NDA) with the timing of this manuscript. All other data will be made publicly-available through the NDA at regularly scheduled intervals. This article is intended to serve as an introduction to this project as well as a reference for those seeking to clinical, neurocognitive, and task fMRI data from this public resource.

Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response.

BACKGROUND: Exposure to threat-related early life stress (ELS) has been related to vulnerability for stress-related disorders in adulthood, putatively via disrupted corticolimbic circuits involved in stress response and regulation. However, previous research on ELS has not examined both the intrinsic strength and flexibility of corticolimbic circuits, which may be particularly important for adaptive stress responding, or associations between these dimensions of corticolimbic dysfunction and acute stress response in adulthood. METHODS: Seventy unmedicated women varying in history of threat-related ELS completed a functional magnetic resonance imaging scan to evaluate voxelwise static (overall) and dynamic (variability over a series of sliding windows) resting-state functional connectivity (RSFC) of bilateral amygdala. In a separate session and subset of participants (n = 42), measures of salivary cortisol and affect were collected during a social-evaluative stress challenge. RESULTS: Higher severity of threat-related ELS was related to more strongly negative static RSFC between amygdala and left dorsolateral prefrontal cortex (DLPFC), and elevated dynamic RSFC between amygdala and rostral anterior cingulate cortex (rACC). Static amygdala-DLPFC antagonism mediated the relationship between higher severity of threat-related ELS and blunted cortisol response to stress, but increased dynamic amygdala-rACC connectivity weakened this mediated effect and was related to more positive post-stress mood. CONCLUSIONS: Threat-related ELS was associated with RSFC within lateral corticolimbic circuits, which in turn was related to blunted physiological response to acute stress. Notably, increased flexibility between the amygdala and rACC compensated for this static disruption, suggesting that more dynamic medial corticolimbic circuits might be key to restoring healthy stress response.

COMT Val(158) Met genotype is associated with reward learning: a replication study and meta-analysis.

Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158) Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants (ß = 0.20, t = 2.75, P < 0.01; ΔR(2) = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.

Abnormal error processing in depressive states: a translational examination in humans and rats.

Depression has been associated with poor performance following errors, but the clinical implications, response to treatment and neurobiological mechanisms of this post-error behavioral adjustment abnormality remain unclear. To fill this gap in knowledge, we tested depressed patients in a partial hospital setting before and after treatment (cognitive behavior therapy combined with medication) using a flanker task. To evaluate the translational relevance of this metric in rodents, we performed a secondary analysis on existing data from rats tested in the 5-choice serial reaction time task after treatment with corticotropin-releasing factor (CRF), a stress peptide that produces depressive-like signs in rodent models relevant to depression. In addition, to examine the effect of treatment on post-error behavior in rodents, we examined a second cohort of rodents treated with JDTic, a kappa-opioid receptor antagonist that produces antidepressant-like effects in laboratory animals. In depressed patients, baseline post-error accuracy was lower than post-correct accuracy, and, as expected, post-error accuracy improved with treatment. Moreover, baseline post-error accuracy predicted attentional control and rumination (but not depressive symptoms) after treatment. In rats, CRF significantly degraded post-error accuracy, but not post-correct accuracy, and this effect was attenuated by JDTic. Our findings demonstrate deficits in post-error accuracy in depressed patients, as well as a rodent model relevant to depression. These deficits respond to intervention in both species. Although post-error behavior predicted treatment-related changes in attentional control and rumination, a relationship to depressive symptoms remains to be demonstrated.

A computational analysis of flanker interference in depression.

BACKGROUND: Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study. METHOD: One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials). RESULTS: Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007). CONCLUSIONS: Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.

Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties.

BACKGROUND: Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored. METHOD: In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties). RESULTS: Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later. CONCLUSIONS: These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.

Stress and reward: long term cortisol exposure predicts the strength of sexual preference.

Healthy individuals tend to consume available rewards like food and sex. This tendency is attenuated or amplified in most stress-related psychiatric conditions, so we asked if it depends on endogenous levels of the 'canonical stress hormone' cortisol. We unobtrusively quantified how hard healthy heterosexual men would work to consume erotic images of women versus men and also measured their exposure to endogenous cortisol in the prior two months. We used linear models to predict the strength of sexual preference from cortisol level, after accounting for other potential explanations. Heterosexual preference declines with self-reported anhedonia but increases with long term exposure to endogenous cortisol. These results suggest that cortisol may affect reward-related behavior in healthy adults.

Differential effects of acute stress on anticipatory and consummatory phases of reward processing.

Anhedonia is one of the core symptoms of depression and has been linked to blunted responses to rewarding stimuli in striatal regions. Stress, a key vulnerability factor for depression, has been shown to induce anhedonic behavior, including reduced reward responsiveness in both animals and humans, but the brain processes associated with these effects remain largely unknown in humans. Emerging evidence suggests that stress has dissociable effects on distinct components of reward processing, as it has been found to potentiate motivation/'wanting' during the anticipatory phase but reduce reward responsiveness/'liking' during the consummatory phase. To examine the impact of stress on reward processing, we used a monetary incentive delay (MID) task and an acute stress manipulation (negative performance feedback) in conjunction with functional magnetic resonance imaging (fMRI). Fifteen healthy participants performed the MID task under no-stress and stress conditions. We hypothesized that stress would have dissociable effects on the anticipatory and consummatory phases in reward-related brain regions. Specifically, we expected reduced striatal responsiveness during reward consumption (mirroring patterns previously observed in clinical depression) and increased striatal activation during reward anticipation consistent with non-human findings. Supporting our hypotheses, significant Phase (Anticipation/Consumption)×Stress (Stress/No-stress) interactions emerged in the putamen, nucleus accumbens, caudate and amygdala. Post hoc tests revealed that stress increased striatal and amygdalar activation during anticipation but decreased striatal activation during consumption. Importantly, stress-induced striatal blunting was similar to the profile observed in clinical depression under baseline (no-stress) conditions in prior studies. Given that stress is a pivotal vulnerability factor for depression, these results offer insight to better understand the etiology of this prevalent disorder.

Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research.

Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long-Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D2/D3 receptor agonist pramipexole (0.1 mg kg(-1), subcutaneous) or the psychostimulant amphetamine (0.5 mg kg(-1), intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species.

The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning.

Research suggests that stress disrupts reinforcement learning and induces anhedonia. The mineralocorticoid receptor (MR) determines the sensitivity of the stress response, and the missense iso/val polymorphism (Ile180Val, rs5522) of the MR gene (NR3C2) has been associated with enhanced physiological stress responses, elevated depressive symptoms and reduced cortisol-induced MR gene expression. The goal of these studies was to evaluate whether rs5522 genotype and stress independently and interactively influence reward learning. In study 1, participants (n = 174) completed a probabilistic reward task under baseline (i.e. no-stress) conditions. In study 2, participants (n = 53) completed the task during a stress (threat-of-shock) and no-stress condition. Reward learning, i.e. the ability to modulate behavior as a function of reinforcement history, was the main variable of interest. In study 1, in which participants were evaluated under no-stress conditions, reward learning was enhanced in val carriers. In study 2, participants developed a weaker response bias toward a more frequently rewarded stimulus under the stress relative to no-stress condition. Critically, stress-induced reward learning deficits were largest in val carriers. Although preliminary and in need of replication due to small sample size, findings indicate that psychiatrically healthy individuals carrying the MR val allele, gene, which has been recently linked to depression, showed a reduced ability to modulate behavior as a function of reward when facing an acute, uncontrollable stressor. Future studies are warranted to evaluate whether rs5522 genotype interacts with naturalistic stressors to increase the risk of depression and whether stress-induced anhedonia might moderate such risk.

The heritability of hedonic capacity and perceived stress: a twin study evaluation of candidate depressive phenotypes.

BACKGROUND: Anhedonia and stress sensitivity have been identified as promising depressive phenotypes. Research suggests that stress-induced anhedonia is a possible mechanism underlying the association between stress and depression. The present proof-of-concept study assessed whether hedonic capacity and stress perception are heritable and whether their genetic and environmental contributions are shared. METHOD: Twenty monozygotic (MZ) and 15 dizygotic (DZ) twin pairs completed a probabilistic reward task that provides an objective behavioral measure of hedonic capacity (reward responsiveness) and completed several questionnaires including the Perceived Stress Scale (PSS). Bivariate Cholesky models were used to investigate whether covariation between (1) depressive symptoms and hedonic capacity, (2) depressive symptoms and perceived stress, and (3) perceived stress and hedonic capacity resulted from shared or residual genetic and environmental factors. RESULTS: Additive genetic (A) and individual-specific environment (E) factors contributed to 46% and 54% of the variance in hedonic capacity, respectively. For perceived stress, 44% and 56% of the variance was accounted for by A and E factors, respectively. The genetic correlation between depression and hedonic capacity was moderate (ra=0.29), whereas the correlation between depression and stress perception was large (ra=0.67). Genetic and environmental correlations between hedonic capacity and stress perception were large (ra=0.72 and re=-0.43). CONCLUSIONS: The present study provides initial feasibility for using a twin approach to investigate genetic contributions of a laboratory-based anhedonic phenotype. Although these preliminary findings indicate that hedonic capacity and perceived stress are heritable, with substantial shared additive genetic contributions, replications in larger samples will be needed.

Electrophysiological evidence of attentional biases in social anxiety disorder.

BACKGROUND: Previous studies investigating attentional biases in social anxiety disorder (SAD) have yielded mixed results. Recent event-related potential (ERP) studies using the dot-probe paradigm in non-anxious participants have shown that the P1 component is sensitive to visuospatial attention towards emotional faces. We used a dot-probe task in conjunction with high-density ERPs and source localization to investigate attentional biases in SAD. METHOD: Twelve SAD and 15 control participants performed a modified dot-probe task using angry-neutral and happy-neutral face pairs. The P1 component elicited by face pairs was analyzed to test the hypothesis that SAD participants would display early hypervigilance to threat-related cues. The P1 component to probes replacing angry, happy or neutral faces was used to evaluate whether SAD participants show either sustained hypervigilance or decreased visual processing of threat-related cues at later processing stages. RESULTS: Compared to controls, SAD participants showed relatively (a) potentiated P1 amplitudes and fusiform gyrus (FG) activation to angry-neutral versus happy-neutral face pairs; (b) decreased P1 amplitudes to probes replacing emotional (angry and happy) versus neutral faces; and (c) higher sensitivity (d') to probes following angry-neutral versus happy-neutral face pairs. SAD participants also showed significantly shorter reaction times (RTs) to probes replacing angry versus happy faces, but no group differences emerged for RT. CONCLUSIONS: The results provide electrophysiological support for early hypervigilance to angry faces in SAD with involvement of the FG, and reduced visual processing of emotionally salient locations at later stages of information processing, which might be a manifestation of attentional avoidance.

The cognitive consequences of emotion regulation: an ERP investigation.

Increasing evidence suggests that emotion regulation (ER) strategies modulate encoding of information presented during regulation; however, no studies have assessed the impact of cognitive reappraisal ER strategies on the processing of stimuli presented after the ER period. Participants in the present study regulated emotions to unpleasant pictures and then judged whether a word was negative or neutral. Electromyographic measures (corrugator supercilli) confirmed that individuals increased and decreased negative affect according to ER condition. Event-related potential analyses revealed smallest N400 amplitudes to negative and neutral words presented after decreasing unpleasant emotions and smallest P300 amplitudes to words presented after increasing unpleasant emotions whereas reaction time data failed to show ER modulations. Results are discussed in the context of the developing ER literature, as well as theories of emotional incongruity (N400) and resource allocation (P300).

Functional but not structural subgenual prefrontal cortex abnormalities in melancholia.

Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.