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).

Psychophysiological prediction of choice: relevance to insight and drug addiction.

An important goal of addiction research and treatment is to predict behavioural responses to drug-related stimuli. This goal is especially important for patients with impaired insight, which can interfere with therapeutic interventions and potentially invalidate self-report questionnaires. This research tested (i) whether event-related potentials, specifically the late positive potential, predict choice to view cocaine images in cocaine addiction; and (ii) whether such behaviour prediction differs by insight (operationalized in this study as self-awareness of image choice). Fifty-nine cocaine abusers and 32 healthy controls provided data for the following laboratory components that were completed in a fixed-sequence (to establish prediction): (i) event-related potential recordings while passively viewing pleasant, unpleasant, neutral and cocaine images, during which early (400-1000 ms) and late (1000-2000 ms) window late positive potentials were collected; (ii) self-reported arousal ratings for each picture; and (iii) two previously validated tasks: one to assess choice for viewing these same images, and the other to group cocaine abusers by insight. Results showed that pleasant-related late positive potentials and arousal ratings predicted pleasant choice (the choice to view pleasant pictures) in all subjects, validating the method. In the cocaine abusers, the predictive ability of the late positive potentials and arousal ratings depended on insight. Cocaine-related late positive potentials better predicted cocaine image choice in cocaine abusers with impaired insight. Another emotion-relevant event-related potential component (the early posterior negativity) did not show these results, indicating specificity of the late positive potential. In contrast, arousal ratings better predicted respective cocaine image choice (and actual cocaine use severity) in cocaine abusers with intact insight. Taken together, the late positive potential could serve as a biomarker to help predict drug-related choice--and possibly associated behaviours (e.g. drug seeking in natural settings, relapse after treatment)--when insight (and self-report) is compromised.

Motivated attention to cocaine and emotional cues in abstinent and current cocaine users--an ERP study.

Event-related potentials (ERPs) are a direct measure of neural activity and are ideally suited to study the time-course of attentional engagement with emotional and drug-related stimuli in addiction. In particular, the late positive potential (LPP) appears to be enhanced following cocaine-related compared with neutral stimuli in human participants with cocaine use disorders (CUD). However, previous studies have not directly compared cocaine-related with emotional stimuli while examining potential differences between abstinent and current cocaine users. The present study examined ERPs in 55 CUD (27 abstinent and 28 current users) and 29 matched healthy controls while they passively viewed pleasant, unpleasant, neutral and cocaine-related pictures. To examine the time-course of attention to these stimuli, we analysed both an early and later window in the LPP as well as the early posterior negativity (EPN), established in assessing motivated attention. Cocaine pictures elicited increased electrocortical measures of motivated attention in ways similar to affectively pleasant and unpleasant pictures in all CUD, an effect that was no longer discernible during the late LPP window for the current users. This group also exhibited deficient processing of the other emotional stimuli (early LPP window - pleasant pictures; late LPP window - pleasant and unpleasant pictures). Results were unique to the LPP and not EPN. Taken together, results support a relatively early attention bias to cocaine stimuli in cocaine-addicted individuals, further suggesting that recent cocaine use decreases such attention bias during later stages of processing but at the expense of deficient processing of other emotional stimuli.

Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior.

No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a(-/-) mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression.

Neural response to emotional pictures is unaffected by concurrent task difficulty: an event-related potential study.

The late positive potential (LPP) is an event-related potential that is enhanced when viewing arousing (pleasant and unpleasant) pictures compared to neutral pictures. The affective modulation of the LPP is believed to reflect the increased attention to, and perceptual processing of, emotional stimuli. The present study examined whether concurrent task difficulty (performing mathematics) would modulate the LPP while participants viewed emotionally arousing stimuli. Results indicated that the LPP was larger following pleasant and unpleasant stimuli than it was following neutral stimuli; moreover, the magnitude of this increase was not influenced by concurrent task difficulty. This finding suggests that the affective modulation of neural activity during picture viewing is relatively automatic and is insusceptible to competing task demands. Results are further discussed in terms of the LPP's role in motivated attention and implications for research on emotion regulation.

Error-related negativities elicited by monetary loss and cues that predict loss.

Event-related potential studies have reported error-related negativity following both error commission and feedback indicating errors or monetary loss. The present study examined whether error-related negativities could be elicited by a predictive cue presented prior to both the decision and subsequent feedback in a gambling task. Participants were presented with a cue that indicated the probability of reward on the upcoming trial (0, 50, and 100%). Results showed a negative deflection in the event-related potential in response to loss cues compared with win cues; this waveform shared a similar latency and morphology with the traditional feedback error-related negativity.

Gradients of Fear Potentiated Startle During Generalization, Extinction, and Extinction Recall--and Their Relations With Worry.

It is well established that fear conditioning plays a role in the development and maintenance of anxiety disorders. Moreover, abnormalities in fear generalization, extinction, and extinction recall have also been associated with anxiety. The present study used a generalization paradigm to examine fear processing during phases of generalization, extinction, and extinction recall. Specifically, participants were shocked following a CS+ and were also presented with stimuli that ranged in perceptual similarity to the CS+ (i.e., 20%, 40%, or 60% smaller or larger than the CS+) during a fear generalization phase. Participants were also presented with the same stimuli during an extinction phase and an extinction recall phase 1week later; no shocks were presented during extinction or recall. Lastly, participants completed self-report measures of worry and trait anxiety. Results indicated that fear potentiated startle (FPS) to the CS+ and GS±20% shapes was present in generalization and extinction, suggesting that fear generalization persisted into extinction. FPS to the CS+ was also evident 1 week later during extinction recall. Higher levels of worry were associated with greater FPS to the CS+ during generalization and extinction phases. Moreover, individuals high in worry had fear response gradients that were steeper during both generalization and extinction. This suggests that high levels of worry are associated with greater discriminative fear conditioning to threatening compared to safe stimuli and less fear generalization to perceptually similar stimuli.

The effects of contextual threat and anxiety on affective startle modulation.

The startle reflex is attenuated and potentiated when participants are viewing pleasant and unpleasant images, respectively. Research demonstrates that threatening contexts also potentiate startle, but it remains unclear how a threatening context might impact startle modulation to emotional images, especially as a function of trait anxiety. The present study measured startle reactivity while 43 participants viewed pleasant, unpleasant, and neutral images across conditions of threat-of-shock and safety (i.e., no shock). Compared to neutral images, startle was potentiated during unpleasant images and attenuated during pleasant images. Threat-of-shock potentiated startle during all picture types, suggesting that threat-of-shock broadly sensitized the defensive system but did not change affective modulation of startle. Lastly, higher levels of trait anxiety were associated with less startle potentiation during unpleasant images across both conditions-a finding in line with previous research demonstrating deficient threat mobilization in response to unpleasant stimuli among highly anxious individuals.

In the face of anger: startle modulation to graded facial expressions.

In the present study, the startle reflex was examined with respect to the degree of anger displayed in facial expressions. To this end, 52 participants viewed faces that were morphed to display 0, 20, 40, 60, 80, or 100% anger. As the percentage of anger in faces increased from 0 to 100%, faces were perceived as increasingly angry; however, relative to neutral facial expressions, startle amplitude was only potentiated to maximally angry faces. These data imply a non-linear relationship between the intensity of angry faces and defensive physiological activity. This pattern of startle modulation suggests a categorical distinction between threatening (100% anger) and other facial expressions presented. These results are further discussed in terms of existing data, and how this paradigm might be utilized in psychopathology research.

See no evil: directing visual attention within unpleasant images modulates the electrocortical response.

The late positive potential (LPP) is larger for emotional than neutral stimuli, and reflects increased attention to motivationally salient stimuli. Recent studies have shown that the LPP can also be modulated by stimulus meaning and task relevance. The present studies sought to determine whether the magnitude of the LPP can be manipulated by directing attention to more or less arousing aspects within an emotional stimulus. To this end, trials included a passive viewing and directed attention portion. In both Studies 1 and 2, unpleasant compared to neutral images were associated with an increased LPP during passive viewing; additionally, directing attention to non-arousing compared to highly arousing areas of unpleasant images resulted in a decreased LPP. Results are discussed in terms of the utility of using the LPP to understand emotion-cognition interactions, especially with regard to directed visual attention as an emotion regulation strategy.

Motivated and controlled attention to emotion: time-course of the late positive potential.

OBJECTIVE: The present study examined the time-course of automatic and controlled modulation of the late positive potential (LPP) during emotional picture viewing. METHODS: Participants (N=32) viewed neutral and unpleasant stimuli for 6000 ms; at 3000 ms, one of two tones signaled participants to attend either to a more or less arousing portion of the picture. The time-course of the LPP was examined both during the passive viewing and directed attention portions of the trial using the method proposed by Guthrie and Buchwald [Guthrie D, Buchwald JS. Significance testing of difference potentials. Psychophysiology 1991;28(2):240-4]. RESULTS: During passive viewing, the LPP became reliably larger following the presentation of unpleasant pictures from 160 ms onward; the magnitude of the LPP became reliably smaller beginning 620 ms after participants were instructed to attend to the less arousing aspects of unpleasant pictures - and this difference was maintained throughout the duration of the trial. CONCLUSIONS: The LPP reflects relatively automatic attention to emotional visual stimuli, but is also sensitive to manipulations of directed attention toward arousing versus neutral aspects of such stimuli. SIGNIFICANCE: These results shed further light on the time-course of emotional and cognitive modulation of the LPP, and suggest that the LPP reflects the relatively rapid and dynamic allocation of increased attention to emotional stimuli.

Enhanced choice for viewing cocaine pictures in cocaine addiction.

BACKGROUND: Individuals with cocaine use disorder (CUD) chose cocaine over nondrug rewards. In two newly designed laboratory tasks with pictures, we document this modified choice outside of a cocaine administration paradigm. METHODS: Choice for viewing cocaine, pleasant, unpleasant, or neutral pictures--under explicit contingencies (choice made between two fully visible side-by-side images) and under more implicit contingencies (selections made between pictures hidden under flipped-over cards)--was examined in 20 CUD and 20 matched healthy control subjects. Subjects also provided self-reported ratings of each picture's pleasantness and arousal. RESULTS: Under both contingencies, CUD subjects chose to view more cocaine pictures than control subjects, group differences that were not fully explained by the self-reported picture ratings. Furthermore, whereas CUD subjects' choice for viewing cocaine pictures exceeded choice for viewing unpleasant pictures (but did not exceed choice for viewing pleasant pictures, in contrast to their self-reported ratings), healthy control subjects avoided viewing cocaine pictures as frequently as, or even more than, unpleasant pictures. Finally, CUD subjects with the most cocaine viewing selections, even when directly compared with selections of the pleasant pictures, also reported the most frequent recent cocaine use. CONCLUSIONS: Enhanced drug-related choice in cocaine addiction can be demonstrated even for nonpharmacologic (pictorial) stimuli. This choice, which is modulated by alternative stimuli, partly transcends self-reports (possibly indicative of a disconnect in cocaine addiction between self-reports and objective behavior) to provide an objective marker of addiction severity. Neuroimaging studies are needed to establish the neural underpinnings of such enhanced cocaine-related choice.

Neurobehavioral mutants identified in an ENU-mutagenesis project.

We report on a battery of behavioral screening tests that successfully identified several neurobehavioral mutants among a large-scale ENU-mutagenized mouse population. Large numbers of ENU-mutagenized mice were screened for abnormalities in central nervous system function based on abnormal performance in a series of behavior tasks. We developed and used a high-throughput screen of behavioral tasks to detect behavioral outliers. Twelve mutant pedigrees, representing a broad range of behavioral phenotypes, have been identified. Specifically, we have identified two open-field mutants (one displaying hyperlocomotion, the other hypolocomotion), four tail-suspension mutants (all displaying increased immobility), one nociception mutant (displaying abnormal responsiveness to thermal pain), two prepulse inhibition mutants (displaying poor inhibition of the startle response), one anxiety-related mutant (displaying decreased anxiety in the light/dark test), and one learning-and-memory mutant (displaying reduced response to the conditioned stimulus). These findings highlight the utility of a set of behavioral tasks used in a high-throughput screen to identify neurobehavioral mutants. Further analysis (i.e., behavioral and genetic mapping studies) of mutants is in progress with the ultimate goal of identification of novel genes and mouse models relevant to human disorders as well as the identification of novel therapeutic targets.

Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches.

BACKGROUND: NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene. METHODOLOGY/PRINCIPAL FINDINGS: We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction. CONCLUSIONS: Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation.