The tipping point: Value differences and parallel dorsal-ventral frontal circuits gating human approach-avoidance behavior.

Excessive avoidance and diminished approach behavior are both prominent features of anxiety, trauma and stress related disorders. Despite this, little is known about the neuronal mechanisms supporting gating of human approach-avoidance behavior. Here, we used functional magnetic resonance imaging (fMRI) to track dorsal anterior cingulate and medial prefrontal (dACC/dmPFC) activation along an approach-avoidance continuum to assess sensitivity to competing appetitive and aversive contingencies and correspondence with behavior change. Behavioral and fMRI experiments were conducted using a novel approach-avoidance task where a monetary reward appeared in the presence of a conditioned stimulus (CS), or threat, that signaled increasing probability of unconditioned stimulus (US) delivery. Approach produced the reward or probabilistic US, while avoidance prevented US delivery, and across trials, reward remained fixed while the CS threat level varied unpredictably. Increasing the CS threat level (i.e., US probability) produced the desired approach-avoidance transition and inverted U-shaped changes in decision times, electrodermal activity and activation in pregenual ACC, dACC/dmPFC, striatum, anterior insula and inferior frontal regions. Conversely, U-shaped changes in activation were observed in dorsolateral and ventromedial prefrontal cortex and bimodal changes in the orbitofrontal and ventral hippocampus. These new results show parallel dorsal-ventral frontal circuits support gating of human approach-avoidance behavior where dACC/dmPFC signals inversely correlate with value differences between approach and avoidance contingencies while ventral frontal signals correlate with the value of predictable outcomes. Our findings provide an important bridge between basic research on brain mechanisms of value-guided decision-making and value-focused clinical theories of anxiety and related interventions.

Working hard to avoid: Fixed-ratio response effort and maladaptive avoidance in humans.

Maladaptive avoidance of safe stimuli is a defining feature of anxiety and related disorders. Avoidance may involve physical effort or the completion of a fixed series of responses to prevent occurrence of, or cues associated with, the aversive event. Understanding the role of response effort in the acquisition and extinction of avoidance may facilitate the development of new clinical treatments for maladaptive avoidance. Despite this, little is known about the impact of response effort on extinction-resistant avoidance in humans. Here, we describe findings from two laboratory-based treatment studies designed to investigate the impact of high and low response effort on the extinction (Experiment 1) and return (Experiment 2) of avoidance. Response effort was operationalised as completion of fixed-ratio (FR) reinforcement schedules for both danger and safety cues in a multi-cue avoidance paradigm with behavioural, self-report, and physiology measures. Completion of the FR response requirements cancelled upcoming shock presentations following danger cues and had no impact on the consequences that followed safety cues. Both experiments found persistence of high response-effort avoidance across danger and safety cues and sustained (Experiment 1) and reinstated (Experiment 2) levels of fear and threat expectancy. Skin conductance responses evoked by all cues were similar across experiments. The present findings and paradigm have implications for translational research on maladaptive anxious coping and treatment development.

Generalized anxiety modulates frontal and limbic activation in major depression.

BACKGROUND: Anxiety is relatively common in depression and capable of modifying the severity and course of depression. Yet our understanding of how anxiety modulates frontal and limbic activation in depression is limited. METHODS: We used functional magnetic resonance imaging and two emotional information processing tasks to examine frontal and limbic activation in ten patients with major depression and comorbid with preceding generalized anxiety (MDD/GAD) and ten non-depressed controls. RESULTS: Consistent with prior studies on depression, MDD/GAD patients showed hypoactivation in medial and middle frontal regions, as well as in the anterior cingulate, cingulate and insula. However, heightened anxiety in MDD/GAD patients was associated with increased activation in middle frontal regions and the insula and the effects varied with the type of emotional information presented. CONCLUSIONS: Our findings highlight frontal and limbic hypoactivation in patients with depression and comorbid anxiety and indicate that anxiety level may modulate frontal and limbic activation depending upon the emotional context. One implication of this finding is that divergent findings reported in the imaging literature on depression could reflect modulation of activation by anxiety level in response to different types of emotional information.

Pediatric functional magnetic resonance neuroimaging: tactics for encouraging task compliance.

BACKGROUND: Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population. METHOD: In this preliminary investigation, we describe the development and application of an approach for increasing the number of fMRI tasks children complete during neuroimaging. Twenty-eight healthy children ages 9-13 years participated. Generalization of the approach was examined in additional fMRI and event-related potential investigations with children at risk for depression, children with anxiety and children with depression (N=120). Essential features of the approach include a preference assessment for identifying multiple individualized rewards, increasing reinforcement rates during imaging by pairing tasks with chosen rewards and presenting a visual 'road map' listing tasks, rewards and current progress. RESULTS: Our results showing a higher percentage of fMRI task completion by healthy children provides proof of concept data for the recommended tactics. Additional support was provided by results showing our approach generalized to several additional fMRI and event-related potential investigations and clinical populations. DISCUSSION: We proposed that some forms of task noncompliance may emerge from less than optimal reward protocols. While our findings may not directly support the effectiveness of the multiple reward compliance protocol, increased attention to how rewards are selected and delivered may aid cooperation with completing fMRI tasks. CONCLUSION: The proposed approach contributes to the pediatric neuroimaging literature by providing a useful way to conceptualize and measure task noncompliance and by providing simple cost effective tactics for improving the effectiveness of common reward-based protocols.

Human social defeat and approach-avoidance: Escalating social-evaluative threat and threat of aggression increases social avoidance.

Basic research on avoidance by Murray Sidman laid the foundation for advances in the classification, conceptualization and treatment of avoidance in psychological disorders. Contemporary avoidance research is explicitly translational and increasingly focused on how competing appetitive and aversive contingencies influence avoidance. In this laboratory investigation, we examined the effects of escalating social-evaluative threat and threat of social aggression on avoidance of social interactions. During social-defeat learning, 38 adults learned to associate 9 virtual peers with an increasing probability of receiving negative evaluations. Additionally, 1 virtual peer was associated with positive evaluations. Next, in an approach-avoidance task with social-evaluative threat, 1 peer associated with negative evaluations was presented alongside the peer associated with positive evaluations. Approaching peers produced a positive or a probabilistic negative evaluation, while avoiding peers prevented a negative evaluation (and forfeited a positive evaluation). In an approach-avoidance task with social aggression, virtual peers gave and took money away from participants. Escalating social-evaluative threat and aggression increased avoidance, ratings of feeling threatened and threat expectancy and decreased ratings of peer favorableness. These findings underscore the potential of coupling social defeat and approach-avoidance paradigms for translational research on the neurobehavioral mechanisms of social approach-avoidance decision-making and anxiety.

Amygdala involvement in human avoidance, escape and approach behavior.

Many forms of psychopathology and substance abuse problems are characterized by chronic ritualized forms of avoidance and escape behavior that are designed to control or modify external or internal (i.e., thoughts, emotions, bodily sensations) threats. In this functional magnetic resonance imaging investigation, we examined amygdala reactivity to threatening cues when avoidance responding consistently prevented contact with an upcoming aversive event (money loss). In addition, we examined escape responding that terminated immediate escalating money loss and approach responding that produced a future money gain. Results showed cues prompting avoidance, escape and approach behavior recruited a similar fronto-striatal-parietal network. Within the amygdala, bilateral activation was observed to threatening avoidance and escape cues, even though money loss was consistently avoided, as well as to the reward cue. The magnitude of amygdala responses within subjects was relatively similar to avoidance, escape and approach cues, but considerable between-subject differences were found. The heightened amygdala response to avoidance and escape cues observed within a subset of subjects suggests threat-related responses can be maintained even when aversive events are consistently avoided, which may account for the persistence of avoidance-coping in various clinical disorders. Further assessment of the relation between amygdala reactivity and avoidance-escape behavior may prove useful in identifying individuals with or at risk for neuropsychiatric disorders.

Nothing to fear? Neural systems supporting avoidance behavior in healthy youths.

Active avoidance involving controlling and modifying threatening situations characterizes many forms of clinical pathology, particularly childhood anxiety. Presently our understanding of the neural systems supporting human avoidance is largely based on nonhuman research. Establishing the generality of nonhuman findings to healthy children is a needed first step towards advancing developmental affective neuroscience research on avoidance in childhood anxiety. Accordingly, this investigation examined brain activation patterns to threatening cues that prompted avoidance in healthy youths. During functional magnetic resonance imaging, fifteen youths (ages 9-13) completed a task that alternately required approach or avoidance behaviors. On each trial either a threatening 'Snake' cue or a 'Reward' cue advanced towards a bank containing earned points. Directional buttons enabled subjects to move cues away from (Avoidance) or towards the bank (Approach). Avoidance cues elicited activation in regions hypothesized to support avoidance in nonhumans (amygdala, insula, striatum and thalamus). Results also highlighted that avoidance response rates were positively correlated with amygdala activation and negatively correlated with insula and anterior cingulate activation. Moreover, increased amygdala activity was associated with decreased insula and anterior cingulate activity. Our results suggest that nonhuman neurophysiological research findings on avoidance may generalize to neural systems associated with avoidance in childhood. Perhaps most importantly, the amygdala/insula activation observed suggests that threat-related responses can be maintained even when aversive events are consistently avoided, which may account for the persistence of avoidance-coping in childhood anxiety. The present approach may offer developmental affective neuroscience a conceptual and methodological framework for investigating avoidance in childhood anxiety.

Testosterone reactivity is associated with reduced neural response to reward in early adolescence.

The marked increase in adolescent reward-seeking behavior has important implications for adaptive and maladaptive development. Reward-seeking is linked to increased testosterone and increased neural responses to reward cues. How acute testosterone changes modulate neural reward systems remains unclear. Based on previous work, adolescents, particularly males, showing an increase in endogenous testosterone reactivity were hypothesized to show increased neural response to reward in ventromedial prefrontal cortex, ventral striatum, and posterior cingulate cortex. Sixty-one healthy adolescents aged 10-13 (38 female, mean age = 12.01 [SD = 1.00]) completed a reward-cue processing task during fMRI. Saliva samples to be assayed for testosterone were collected immediately before and after scanning. Acute testosterone changes were not associated with variation in behavioral performance. Within ventromedial prefrontal and posterior cingulate cortices, increased acute testosterone change was associated with reduced discrimination between rewarded and un-rewarded trials. Results suggest that increasing levels of testosterone may result in reduced attention to/salience of task irrelevant information. In contrast to previous studies that found a positive association between testosterone and neural response to reward, the reward information in the current paradigm was irrelevant to success in task performance. These results are consistent with theoretical conceptualization of testosterone's role in reproduction, which involves a shift in salience to short-term relative to long-term goals. These data further emphasized the need to consider context in the study of hormones; specific behaviors will be up- or down-regulated by a hormone based on the fit of the behavior with the broader contextual goal being orchestrated by the hormone.

Renewal of fear and avoidance in humans to escalating threat: Implications for translational research on anxiety disorders.

Exposure-based treatment for threat avoidance in anxiety disorders often results in fear renewal. However, little is known about renewal of avoidance. This multimodal laboratory-based treatment study used an ABA renewal design and an approach-avoidance (AP-AV) task to examine renewal of fear/threat and avoidance in twenty adults. In Context A, 9 visual cues paired with increases in probabilistic money loss (escalating threats) produced increases in ratings of feeling threatened and loss expectancies and skin-conductance responses (SCR). During the AP-AV task, a monetary reinforcer was available concurrently with threats. Approach produced the reinforcer or probabilistic loss, while avoidance prevented loss and forfeited reinforcement. Escalating threat produced increasing avoidance and ratings. In Context B with Pavlovian extinction, threats signaled no money loss and SCR declined. During the AP-AV task, avoidance and ratings also declined. In a return to Context A with Pavlovian threat extinction in effect during the AP-AV task, renewal was observed. Escalating threat was associated with increasing ratings and avoidance in most participants. SCR did not show renewal. These are the first translational findings to highlight renewal of avoidance in humans. Further research should identify individual difference variables and altered neural mechanisms that may confer increased risk of avoidance renewal.

Neural systems underlying reward cue processing in early adolescence: The role of puberty and pubertal hormones.

Affective neuroscience research suggests that maturational changes in reward circuitry during adolescence present opportunities for new learning, but likely also contribute to increases in vulnerability for psychiatric disorders such as depression and substance abuse. Basic research in animal models and human neuroimaging has made progress in understanding the normal development of reward circuitry in adolescence, yet, few functional neuroimaging studies have examined puberty-related influences on the functioning of this circuitry. The goal of this study was to address this gap by examining the extent to which striatal activation and cortico-striatal functional connectivity to cues predicting upcoming rewards would be positively associated with pubertal status and levels of pubertal hormones (dehydroepiandrosterone, testosterone, estradiol). Participants included 79 adolescents (10-13 year olds; 47 girls) varying in pubertal status who performed a novel reward cue processing task during fMRI. Pubertal maturation was assessed using sex-specific standardized composite measures based on Tanner staging (self-report and clinical assessment) and scores from the Pubertal Development Scale. These composite measures were computed to index overall pubertal maturation as well as maturation of the adrenal and gonadal axes separately for boys and girls. Basal levels of circulating pubertal hormones were measured using immunoassays from three samples collected weekly upon awakening across a three-week period. Results indicated greater striatal activation and functional connectivity between nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) to reward cue (vs. no reward cue) on this task. Also, girls with higher levels of estradiol showed reduced activation in left and right caudate and greater NAcc-putamen connectivity. Girls with higher levels of testosterone showed greater NAcc connectivity with the anterior cingulate cortex and the insula. There were no significant associations in boys. Findings suggest that patterns of activation and connectivity in cortico-striatal regions are associated with reward cue processing, particularly in girls. Longitudinal follow-up neuroimaging studies are needed to fully characterize puberty-specific effects on the development of these neural regions and how such changes may contribute to pathways of risk or resilience in adolescence.

Neural correlates of derived relational responding on tests of stimulus equivalence.

BACKGROUND: An essential component of cognition and language involves the formation of new conditional relations between stimuli based upon prior experiences. Results of investigations on transitive inference (TI) highlight a prominent role for the medial temporal lobe in maintaining associative relations among sequentially arranged stimuli (A > B > C > D > E). In this investigation, medial temporal lobe activity was assessed while subjects completed "Stimulus Equivalence" (SE) tests that required deriving conditional relations among stimuli within a class (A identical with B identical with C). METHODS: Stimuli consisted of six consonant-vowel-consonant triads divided into two classes (A1, B1, C1; A2, B2, C2). A simultaneous matching-to-sample task and differential reinforcement were employed during pretraining to establish the conditional relations A1:B1 and B1:C1 in class 1 and A2:B2 and B2:C2 in class 2. During functional neuroimaging, recombined stimulus pairs were presented and subjects judged (yes/no) whether stimuli were related. SE tests involved presenting three different types of within-class pairs: Symmetrical (B1 A1; C1 B1; B2 A2; C2 B2), and Transitive (A1 C1; A2 C2) and Equivalence (C1 A1; C2 A2) relations separated by a nodal stimulus. Cross-class 'Foils' consisting of unrelated stimuli (e.g., A1 C2) were also presented. RESULTS: Relative to cross-class Foils, Transitive and Equivalence relations requiring inferential judgments elicited bilateral activation in the anterior hippocampus while Symmetrical relations elicited activation in the parahippocampus. Relative to each derived relation, Foils generally elicited bilateral activation in the parahippocampus, as well as in frontal and parietal lobe regions. CONCLUSION: Activation observed in the hippocampus to nodal-dependent derived conditional relations (Transitive and Equivalence relations) highlights its involvement in maintaining relational structure and flexible memory expression among stimuli within a class (A identical with B identical with C).

Positive reinforcement modulates fronto-limbic systems subserving emotional interference in adolescents.

Fronto-limbic systems play an important role in supporting resistance to emotional distraction to promote goal-directed behavior. Despite evidence that alterations in the functioning of these systems are implicated in developmental trajectories of psychopathology, most studies have been conducted in adults. This study examined the functioning of fronto-limbic systems subserving emotional interference in adolescents and whether differential reinforcement of correct responding can modulate these neural systems in ways that could promote resistance to emotional distraction. Fourteen healthy adolescents (ages 9-15) completed an emotional delayed working memory task during fMRI with emotional distracters (none, neutral, negative) while positive reinforcement (i.e., monetary reward) was provided for correct responses under some conditions. Adolescents showed slightly reduced behavioral performance and greater activation in amygdala and prefrontal cortical regions (ventrolateral, ventromedial, dorsolateral) on correct trials with negative distracters compared to those with no or neutral distracters. Positive reinforcement yielded an overall improvement in accuracy and reaction times and counteracted the effects of negative distracters as evidenced by significant reductions in activation in key fronto-limbic regions. The present findings extend results on emotional interference from adults to adolescents and suggest that positive reinforcement could be used to potentially promote insulation from emotional distraction. A challenge for the future will be to build upon these findings for constructing reinforcement-based attention training programs that could be used to reduce emotional attention biases in anxious youth.

Medial frontal theta dissociates unsuccessful from successful avoidance and is modulated by lack of perseverance.

Medial frontal activity in the EEG is enhanced following negative feedback and varies in relation to dimensions of impulsivity. In 22 undergraduate students (Mage = 18.92 years, range 18-22 years), we employed a probabilistic negative reinforcement learning paradigm in which choices to avoid were followed by cues indicating successful or unsuccessful avoidance of an impending aversive noise. Our results showed that medial frontal theta power was enhanced following a cue that signaled avoidance was unsuccessful. In addition, self-reported lack of perseverance, a dimension of impulsivity characterized by an inability to maintain focus and determination during a challenging task, was negatively correlated with medial frontal theta elicited to an unsuccessful avoidance cue. We also observed robust differences in alpha attenuation and beta modulation following unsuccessful avoidance cue presentation. To our knowledge, this is the first study in humans to show a functional relation between medial frontal theta modulation and avoidance success. We discuss our findings in the context of frontal theta and self-regulation, negative reinforcement, and anxiety.

Occipitoparietal contributions to recognition memory: stimulus encoding prompted by verbal instructions and operant contingencies.

BACKGROUND: Many human neuroimaging investigations on recognition memory employ verbal instructions to direct subject's attention to a stimulus attribute. But do the same or a similar neurophysiological process occur during nonverbal experiences, such as those involving contingency-shaped responses? Establishing the spatially distributed neural network underlying recognition memory for instructed stimuli and operant, contingency-shaped (i.e., discriminative) stimuli would extend the generality of contemporary domain-general views of recognition memory and clarify the involvement of declarative memory processes in human operant behavior. METHODS: Fifteen healthy adults received equivalent amounts of exposure to three different stimulus sets prior to neuroimaging. Encoding of one stimulus set was prompted using instructions that emphasized memorizing stimuli (Instructed). In contrast, encoding of two additional stimulus sets was prompted using a GO/NO-GO operant task, in which contingencies shaped appropriate GO and NO-GO responding. During BOLD functional MRI, subjects completed two recognition tasks. One required passive viewing of stimuli. The second task required recognizing whether a presented stimulus was a GO/NO-GO stimulus, an Instructed stimulus, or novel (NEW) stimulus. Retrieval success related to recognition memory was isolated by contrasting activation from each stimulus set to a novel stimulus (i.e., an OLD > NEW contrast). To explore differences potentially related to source memory, separate contrasts were performed between stimulus sets. RESULTS: No regions reached supralevel thresholds during the passive viewing task. However, a relatively similar set of regions was activated during active recognition regardless of the methods and included dorsolateral and ventrolateral prefrontal cortex, right inferior and posterior parietal regions and the occipitoparietal region, precuneus, lingual, fusiform gyri and cerebellum. Results also showed the magnitude of the functional response in the occipitoparietal region was inversely correlated with reaction times (RTs), such that the largest functional response and slowest RTs occurred to Instructed stimuli and the smallest functional response and fastest RTs occurred to GO stimuli, with effects to NO-GO stimuli intermediate. The inverse relation was also present bilaterally in the parahippocampus and hippocampus. Comparisons between stimulus sets also revealed regional differences potentially related to source memory. CONCLUSION: Recognition of stimuli previously associated with instructions and operant contingencies (i.e., discriminative stimuli) generally recruited similar inferior frontal and occipitoparietal regions and right posterior parietal cortex, with the right occipitoparietal region showing the largest effect. These findings suggest domain-general views of recognition memory may be applicable to understanding the neural correlates of control exerted by discriminative stimuli and suggest declarative memory processes are involved in human operant behavior.

Proton magnetic resonance spectroscopy in obsessive-compulsive disorder: a pilot investigation comparing treatment responders and non-responders.

Proton magnetic resonance spectroscopic imaging was performed to compare brain metabolism in patients with obsessive-compulsive OCD. Evaluation was done on responders and non-responders to pharmacotherapy and on healthy controls. The results showed significantly lower NAA/Cr ratios in the right basal ganglia in non-responders than in responders or in controls and higher Cho/Cr ratios in the right thalamus in non-responders than responders. Abnormal neuronal metabolism in the right basal ganglia and right thalamus may be indicating lack of response to treatment to selective serotonin reuptake inhibitor.

New knowledge derived from learned knowledge: functional-anatomic correlates of stimulus equivalence.

Forming new knowledge based on knowledge established through prior learning is a central feature of higher cognition that is captured in research on stimulus equivalence (SE). Numerous SE investigations show that reinforcing behavior under control of distinct sets of arbitrary conditional relations gives rise to stimulus control by new, derived relations. This investigation examined whether frontal-subcortical and frontal-parietal networks known to support reinforced conditional relations also support derived conditional relations. Twelve adult subjects completed matching-to-sample (MTS) training with correct/wrong feedback to establish four trained conditional relations within two distinct, three-member stimulus classes: (1) A1-->B1, B1-->C1 and (2) A2-->B2, B2-->C2. Afterwards, functional neuroimaging was performed when MTS trials were presented involving matching two identical circles (a sensorimotor control condition), trained relations (A-->B, B-->C), and derived relations: symmetry (B-->A, C-->B), transitivity (A-->C), and equivalence (C-->A). Conditional responding to trained and derived relations was similarly correlated with bilateral activation in the targeted networks. Comparing trained to derived relations, however, highlighted greater activation in several prefrontal regions, the caudate, thalamus, and putamen, which may represent the effects of extended training or feedback present during imaging. Each derived relation also evidenced a unique activation pattern. Collectively, the findings extend the role of frontal-subcortical and frontal-parietal networks to derived conditional relations and suggest that regional involvement varies with the type of derived conditional relation.

"Watch out!": Effects of instructed threat and avoidance on human free-operant approach-avoidance behavior.

Approach-avoidance paradigms create a competition between appetitive and aversive contingencies and are widely used in nonhuman research on anxiety. Here, we examined how instructions about threat and avoidance impact control by competing contingencies over human approach-avoidance behavior. Additionally, Experiment 1 examined the effects of threat magnitude (money loss amount) and avoidance cost (fixed ratio requirements), whereas Experiment 2 examined the effects of threat information (available, unavailable and inaccurate) on approach-avoidance. During the task, approach responding was modeled by reinforcing responding with money on a FR schedule. By performing an observing response, participants produced an escalating "threat meter". Instructions stated that the threat meter levels displayed the current probability of losing money, when in fact loss only occurred when the level reached the maximum. Instructions also stated pressing an avoidance button lowered the threat level. Overall, instructions produced cycles of approach and avoidance responding with transitions from approach to avoidance when threat was high and transitions back to approach after avoidance reduced threat. Experiment 1 revealed increasing avoidance cost, but not threat magnitude, shifted approach-avoidance transitions to higher threat levels and increased anxiety ratings, but did not influence the frequency of approach-avoidance cycles. Experiment 2 revealed when threat level information was available or absent earnings were high, but earnings decreased when inaccurate threat information was incompatible with contingencies. Our findings build on prior nonhuman and human approach-avoidance research by highlighting how instructed threat and avoidance can impact human AA behavior and self-reported anxiety.

Learned, instructed and observed pathways to fear and avoidance.

BACKGROUND AND OBJECTIVES: Conditioned fear may emerge in the absence of directly experienced conditioned stimulus (CS)--unconditioned stimulus (US) pairings. Here, we compared three pathways by which avoidance of the US may be acquired both directly (i.e., through trial-and-error instrumental learning) and indirectly (i.e., via verbal instructions and social observation). METHODS: Following fear conditioning in which CS+ was paired with shock and CS- was unpaired, three separate groups of participants learned by direct experience (Instrumental-learning), were instructed about (Instructed-learning), or observed (Observational-learning) a demonstrator performing an avoidance response that canceled upcoming US (shock) presentations. Groups were then tested in extinction with presentations of the directly experienced CS+ and CS-, and either a novel CS (Instrumental and observational groups) or an instructed CS (instructed-group). RESULTS: Similar to instrumental learning, results demonstrate that avoidance may be acquired via instructions and social observation in the absence of directly learning that an avoidance response prevents the US. Retrospective US expectancy ratings were modulated by the assumed presence or absence of avoidance. Overall, these findings suggest that instrumental-, instructed-, and observational-learning pathways to avoidance in humans are similar. LIMITATIONS: Alternative experimental designs would permit direct comparison between the pathways for stimuli with no prior experience of fear conditioning, and trial-by-trial US expectancy ratings would help track the modulation of fear by avoidance pathway. CONCLUSIONS: Instrumental-, instructed-, and observational-learning pathways of avoidance are similar. Findings may have implications for understanding the etiology of clinical avoidance in anxiety.

Integrating functional neuroimaging and human operant research: brain activation correlated with presentation of discriminative stimuli.

Results of numerous human imaging studies and nonhuman neurophysiological studies on "reward" highlight a role for frontal, striatal, and thalamic regions in operant learning. By integrating operant and functional neuroimaging methodologies, the present investigation examined brain activation to two types of discriminative stimuli correlated with different contingencies. Prior to neuroimaging, 10 adult human subjects completed operant discrimination training in which money was delivered following button pressing (press-money contingency) in the presence of one set of discriminative stimuli, and termination of trials followed not responding (no response-next trial contingency) in the presence of a second set of discriminative stimuli. After operant training, subjects were instructed to memorize a third set of control stimuli unassociated with contingencies. Several hours after training, functional magnetic resonance imaging was performed while subjects viewed discriminative and control stimuli that were presented individually for 1,500 ms per trial, with stimulus presentations occurring, on average, every 6 s. Activation was found in frontal and striatal brain regions to both sets of discriminative stimuli relative to control stimuli. In addition, exploratory analyses highlighted activation differences between discriminative stimuli. The results demonstrate the utility of coupling operant and imaging technologies for investigating the neural substrates of operant learning in humans.

Generalization of socially transmitted and instructed avoidance.

Excessive avoidance behavior, in which an instrumental action prevents an upcoming aversive event, is a defining feature of anxiety disorders. Left unchecked, both fear and avoidance of potentially threatening stimuli may generalize to perceptually related stimuli and situations. The behavioral consequences of generalization mean that aversive learning experiences with specific threats may lead to the inference that classes of related stimuli are threatening, potentially dangerous, and need to be avoided, despite differences in physical form. Little is known however about avoidance generalization in humans and the learning pathways by which it may be transmitted. In the present study, we compared two pathways to avoidance-instructions and social observation-on subsequent generalization of avoidance behavior, fear expectancy and physiological arousal. Participants first learned that one cue was a danger cue (conditioned stimulus, CS+) and another was a safety cue (CS-). Groups were then either instructed that a simple avoidance response in the presence of the CS+ cancelled upcoming shock (instructed-learning group) or observed a short movie showing a demonstrator performing the avoidance response to prevent shock (observational-learning group). During generalization testing, danger and safety cues were presented along with generalization stimuli that parametrically varied in perceptual similarity to the CS+. Reinstatement of fear and avoidance was also tested. Findings demonstrate, for the first time, generalization of socially transmitted and instructed avoidance: both groups showed comparable generalization gradients in fear expectancy, avoidance behavior and arousal. Return of fear was evident, suggesting that generalized avoidance remains persistent following extinction testing. The utility of the present paradigm for research on avoidance generalization is discussed.