Impaired neural response to negative prediction errors in cocaine addiction.

Learning can be guided by unexpected success or failure, signaled via dopaminergic positive reward prediction error (+RPE) and negative reward-prediction error (-RPE) signals, respectively. Despite conflicting empirical evidence, RPE signaling is thought to be impaired in drug addiction. To resolve this outstanding question, we studied as a measure of RPE the feedback negativity (FN) that is sensitive to both reward and the violation of expectation. We examined FN in 25 healthy controls; 25 individuals with cocaine-use disorder (CUD) who tested positive for cocaine on the study day (CUD+), indicating cocaine use within the past 72 h; and in 25 individuals with CUD who tested negative for cocaine (CUD-). EEG was acquired while the participants performed a gambling task predicting whether they would win or lose money on each trial given three known win probabilities (25, 50, or 75%). FN was scored for the period in each trial when the actual outcome (win or loss) was revealed. A significant interaction between prediction, outcome, and group revealed that controls showed increased FN to unpredicted compared with predicted wins (i.e., intact +RPE) and decreased FN to unpredicted compared with predicted losses (i.e., intact -RPE). However, neither CUD subgroup showed FN modulation to loss (i.e., impaired -RPE), and unlike CUD+ individuals, CUD- individuals also did not show FN modulation to win (i.e., impaired +RPE). Thus, using FN, the current study directly documents -RPE deficits in CUD individuals. The mechanisms underlying -RPE signaling impairments in addiction may contribute to the disadvantageous nature of excessive drug use, which can persist despite repeated unfavorable life experiences (e.g., frequent incarcerations).

Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.

The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.

Reward dysfunction in major depression: multimodal neuroimaging evidence for refining the melancholic phenotype.

Reward dysfunction is thought to play a core role in the pathophysiology of major depressive disorder (MDD). Event-related potential (ERP) and functional magnetic resonance imaging (fMRI) studies have identified reward processing deficits in MDD, but these methods have yet to be applied together in a single MDD sample. We utilized multimodal neuroimaging evidence to examine reward dysfunction in MDD. Further, we explored how neurobiological reward dysfunction would map onto subtypes of MDD. The feedback negativity (FN), an ERP index of reward evaluation, was recorded in 34 unmedicated depressed individuals and 42 never-depressed controls during a laboratory gambling task. Ventral striatal (VS) activation to reward was recorded in a separate fMRI session, using an identical task, among a subgroup of 24 depressed individuals and a comparison group of 18 non-depressed controls. FN amplitude was blunted in MDD. This effect was driven by a MDD subgroup characterized by impaired mood reactivity to positive events, a core feature of melancholic MDD. A similar pattern was observed for VS activation, which was also blunted among the MDD subgroup with impaired mood reactivity. Neither FN amplitude nor VS activation was related to the full, DSM-defined melancholic or atypical MDD subtypes. Across the MDD sample, FN amplitude and VS activation were correlated, indicating convergence across methods. These results indicate that not all MDD is characterized by reward dysfunction, and that there is meaningful heterogeneity in reward processing within MDD. The current study offers neurobiological evidence that impaired mood reactivity is a key phenotypic distinction for subtyping MDD, and further suggests that the existing melancholic phenotype may require further refinement.

Neural indicators of error processing in generalized anxiety disorder, obsessive-compulsive disorder, and major depressive disorder.

The ability to detect and respond to errors is critical to successful adaptation to a changing environment, and variation in error-related brain activity has been linked to psychopathology. The error-related negativity (ERN), an event-related potential component, represents a unique neural response to errors and is generated in the anterior cingulate cortex (ACC). In the present study, we measured the ERN in a sample of individuals with Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), Major Depressive Disorder (MDD), or some combination of the 3. Also included were 56 healthy control participants. Consistent with previous research, a diagnosis of GAD, only in the absence of a comorbid diagnosis of depression, was characterized by a larger ERN than controls. No such enhancement was evident in the depressed group, or the comorbid group, suggesting comorbid depression may eliminate the relationship between the ERN and GAD. Across all groups, symptoms of checking were associated with a larger ERN, whereas symptoms of psychomotor retardation were associated with a smaller ERN. The results of the present study indicate that interactions among transdiagnostic dimensions will likely need to be considered in the creation of neurobiologically informed classification schemes.

Anterior cingulate activity to monetary loss and basal ganglia activity to monetary gain uniquely contribute to the feedback negativity.

OBJECTIVE: The feedback negativity (FN) is an event-related potential that differentiates unfavorable versus favorable outcomes. Although thought to reflect error-related activity within the anterior cingulate cortex, recent work indicates the FN may also reflect reward-related activity that has been linked to the basal ganglia. To date, it remains unclear how to reconcile these conflicting perspectives. METHODS: We decomposed the FN by applying time-frequency analysis to isolate activity unique to monetary losses and gains. The FN was recorded from 84 individuals during a laboratory gambling task. RESULTS: Two signals contributed to the FN elicited by unpredictable outcomes: theta activity (4-7Hz) was increased following monetary loss, and delta activity (<3Hz) was increased following monetary gain. Predictable outcomes elicited delta but not theta activity. Source analysis revealed distinct generators, with loss-related theta localized to the anterior cingulate cortex and gain-related delta to a possible source in the striatum. Symptoms of depression, anxiety, and stress reactivity were specifically associated with blunted gain-related delta. CONCLUSIONS: The FN may be a composite of loss- and gain-related neural activity, reflecting distinct facets of reward processing. SIGNIFICANCE: Gain-related delta activity may provide unique information about reward dysfunction in major depression and other internalizing psychopathology.

Midbrain volume predicts fMRI and ERP measures of reward reactivity.

Ventral striatal activation measured with functional magnetic resonance imaging (fMRI) and feedback negativity amplitude measured with event-related potentials (ERPs) are each enhanced during reward processing. Recent research has found that these two neural measures of reward processing are also related to one another, such that increases in ventral striatal activity are accompanied by increases in the amplitude of the feedback negativity. Although there is a long history of research implicating the midbrain dopamine system in reward processing, there has been little research into the possibility that structural variability in the midbrain may be linked to functional variability in reward reactivity. Here, we used structural MRI to measure midbrain volumes in addition to fMRI and ERP measures of functional neural reactivity to rewards in a simple gambling task. The results suggest that as midbrain volumes increase, fMRI reward reactivity in the ventral striatum and medial prefrontal cortex also increases. A similar relationship exists between midbrain structure and the amplitude of the feedback negativity; further, this relationship is mediated specifically by activity in the ventral striatum. These data demonstrate convergence between neuroanatomical, hemodynamic, and electrophysiological measures. Thus, structural variability in the midbrain relates to variability in fMRI and ERP measures of functional reward reactivity, which may play a critical role in reward-related psychopathologies and the treatment of these disorders.

Early Parenting Moderates the Association between Parental Depression and Neural Reactivity to Rewards and Losses in Offspring.

Children of parents with depression exhibit neural abnormalities in reward processing. Examining contributions of parenting could provide insight into the development of these abnormalities and to the etiology of depression. We evaluated whether early parenting moderates the effects of parental depression on a neural measure of reward and loss processing in mid-late childhood. Parenting was assessed when children were preschoolers. At age nine, children completed an event-related potential assessment and the feedback negativity (FN) was measured following rewards and losses (N=344). Maternal authoritative parenting moderated the effect of maternal depression; among offspring of mothers with histories of depression, low authoritative parenting predicted a blunted FN. Observed maternal positive parenting interacted with paternal depression in a comparable manner, indicating that maternal parenting may buffer the effects of paternal depression. Early parenting may be important in shaping the neural systems involved in reward processing among children at high risk for depression.

An Event-Related Potential Investigation of Fear Generalization and Intolerance of Uncertainty.

Fear generalization is a key process in the development and maintenance of anxiety disorders. Psychobiological investigations of fear generalization have predominantly focused on defensive system activation (e.g., startle reflex), and it is unclear whether aberrant attentional processing contributes to fear generalization. The late positive potential (LPP) is an event-related potential component that indexes sustained attention and elaborative processing of motivationally salient information, and is larger in response to arousing compared to nonarousing stimuli. In the present study 48 participants completed a fear generalization paradigm using electric shocks. The LPP and retrospective risk ratings of shock likelihood were measured in response to the conditioned stimulus (CS+) and multiple generalization stimuli (GS) that varied in perceptual similarity to the CS+. In addition, intolerance of uncertainty (IU) was examined in relation to fear generalization. The LPP was enhanced for the CS+relative to the GS, but the GS did not differ from one another. Thus, overall the LPP did not reflect fear generalization. However, the LPP to the GS differed as a function of IU, such that high Prospective IU was associated with an attenuated LPP to the GS, and this was independent of trait anxiety. Risk ratings tracked fear generalization irrespective of IU. We discuss the potential influence of IU and attentional processing on fear generalization. Overall, the present study supports the LPP as a useful tool for examining individual differences in fear generalization.

Electrocortical evidence of increased post-reappraisal neural reactivity and its link to depressive symptoms.

Few studies have examined whether effortful emotion regulation has a protracted impact on subsequent affective appraisal, and even fewer have investigated this effect on a trial-by-trial basis. In this study, we hypothesized that engaging cognitive resources via reappraisal during a trial would result in a subsequent period of increased reactivity on the next trial, as quantified using event-related potentials and oscillations. Forty-eight healthy individuals passively viewed unpleasant and neutral pictures followed by an auditory instruction to either continue viewing normally or reappraise emotional response to pictures. Viewing unpleasant pictures yielded increased late positive potential (LPP) and decreased posterior alpha (8-13 Hz) compared with neutral pictures. A similar pattern was observed on trials that immediately 'followed' emotion regulation instructions. Moreover, individuals with increased self-reported depressive symptoms showed greater LPP and alpha modulation following emotion regulation, suggesting that these responses may relate to compromised emotion regulation ability. This study demonstrates that cognitive reappraisal induces subsequent heightened reactivity that may reflect transient resource depletion, and these effects are more pronounced among those with increased depressive symptoms. Interventions that focus on emotion regulation might use these electrocortical markers to track changes in regulatory efficacy.

Perceived emotional intelligence is impaired and associated with poor community functioning in schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder have been associated with shared and distinct emotion processing abnormalities. Initial findings indicate that these disorders differ with respect to the domain of emotional intelligence (EI). Individuals with schizophrenia display deficits on performance measures of EI, whereas those with bipolar disorder do not. However, no research has examined patients' subjective beliefs about their own EI (referred to as "perceived EI"). This study examined perceived EI, assessed with the Trait Meta-Mood Scale (TMMS), and its clinical and functional correlates in outpatients with schizophrenia (n=35) or bipolar disorder I (n=38) and matched healthy controls (n=35). The TMMS includes three subscales that assess beliefs about one's ability to attend to (Attention to Feelings), understand (Clarity of Feelings), and repair emotions (Mood Repair). Participants in the clinical groups also completed community functioning and symptom assessments. Both clinical groups reported significantly lower perceived EI than controls, but did not differ from each other. Higher total TMMS correlated with higher levels of independent living in the schizophrenia group (r=.36) and better social functioning in the bipolar group (r=.61). In addition, although higher Attention to Feelings scores correlated with greater psychiatric symptoms in the schizophrenia group, higher scores across all subscales correlated with less manic symptoms in the bipolar group. The findings suggest that perceived EI is impaired and related to community functioning in both disorders.

Intolerance of uncertainty mediates reduced reward anticipation in major depressive disorder.

BACKGROUND: Reduced reward sensitivity has long been considered a fundamental deficit of major depressive disorder (MDD). One way this deficit has been measured is by an asymmetry in electroencephalogram (EEG) activity between left and right frontal brain regions. MDD has been associated with a reduced frontal EEG asymmetry (i.e., decreased left relative to right) while anticipating reward. However, the mechanism (or mediator) of this association is unclear. The present study examined whether intolerance of uncertainty (IU) mediated the association between depression and reduced reward anticipation. METHODS: Data were obtained from a prior study reporting reduced frontal EEG asymmetry while anticipating reward in early-onset MDD. Participants included 156 individuals with early-onset MDD-only, panic disorder-only, both (comorbids), or controls. Frontal EEG asymmetry was recorded during an uncertain reward anticipation task. Participants completed a self-report measure of IU. RESULTS: All three psychopathology groups reported greater IU relative to controls. Across all participants, greater IU was associated with a reduced frontal EEG asymmetry. Furthermore, IU mediated the relationship between MDD and frontal EEG asymmetry and results remained significant after controlling for neuroticism, suggesting effects were not due to broad negative affectivity. LIMITATIONS: MDD participants were limited to those with early-onset depression. Measures were collected cross-sectionally, precluding causal relationships. CONCLUSIONS: IU mediated the relationship between MDD and reduced reward anticipation, independent of neuroticism. Explanations are provided regarding how IU may contribute to reduced reward anticipation in depression. Overall, IU appears to be an important mechanism for the association between depression and reduced reward anticipation.