Greater Early Posttrauma Activation in the Right Inferior Frontal Gyrus Predicts Recovery From Posttraumatic Stress Disorder Symptoms.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with altered emotion processing and modulation in specific brain regions, i.e., the amygdala, insula, and medial prefrontal and anterior cingulate cortices. Functional alterations in these regions, recorded shortly after trauma exposure, may predict changes in PTSD symptoms. METHODS: Survivors (N = 104) of a traumatic event, predominantly a motor vehicle accident, were included. Functional magnetic resonance imaging was used to assess brain activation 1, 6, and 14 months after trauma exposure (T1, T2, and T3, respectively). Participants performed the Shifted-attention Emotional Appraisal Task, which probes 3 affective processes: implicit emotional processing (of emotional faces), emotion modulation by attention shifting (away from these faces), and emotion modulation by appraisal (of the participants' own emotional response to these faces). We defined regions of interest based on task-related activations, extracted beta weights from these regions of interest, and submitted them to a series of analyses to examine relationships between neural activation and PTSD severity over the 3 time points. RESULTS: At T1, a regression model containing activations in the left dorsolateral prefrontal cortex, bilateral inferior frontal gyrus (IFG), and medial prefrontal cortex during emotion modulation by appraisal significantly predicted change in PTSD symptoms. More specifically, greater right IFG activation at T1 was associated with greater reduction in symptom severity (T1-T3). Exploratory analysis also found that activation of the right IFG increased from T1 to T3. CONCLUSIONS: The results suggest that greater early posttrauma activation during emotion appraisal in the right IFG, a region previously linked to cognitive control in PTSD, predicts recovery from PTSD symptoms.

Characterizing neurological status in individuals with tetraplegia using transcutaneous spinal stimulation.

Transcutaneous spinal stimulation (TSS) is emerging as a valuable tool for electrophysiological and clinical assessment. This study had the objective of examining the recruitment patterns of upper limb (UL) motor pools through the delivery of TSS above and below a spinal lesion. It also aimed to explore the connection between the recruitment pattern of UL motor pools and the neurological and functional status following spinal cord injury (SCI). In eight participants with tetraplegia due to cervical SCI, TSS was delivered to the cervical spinal cord between the spinous processes of C3-C4 and C7-T1 vertebrae, and spinally evoked motor potentials in UL muscles were characterized. We found that responses observed in UL muscles innervated by motor pools below the level of injury demonstrated relatively reduced sensitivity to TSS compared to those above the lesion, were asymmetrical in the majority of muscles, and were dependent on the level, extent, and side of SCI. Overall, our findings indicate that electrophysiological data acquired through TSS can offer insights into the extent of UL functional asymmetry, disruptions in neural pathways, and changes in motor control following SCI. This study suggests that such electrophysiological data can supplement clinical and functional assessment and provide further insight regarding residual motor function in individuals with SCI.

Transcutaneous spinal stimulation provides characterization of neurological status in individuals with tetraplegia.

Transcutaneous spinal stimulation (TSS) is emerging as a valuable tool for electrophysiological and clinical assessment. This study had the objective of examining the recruitment patterns of upper limb (UL) motor pools through the delivery of TSS above and below a spinal lesion. It also aimed to explore the connection between the recruitment pattern of UL motor pools and the neurological and functional status following spinal cord injury (SCI). In eight participants with tetraplegia due to cervical SCI, TSS was delivered to the cervical spinal cord between the spinous processes of C3-C4 and C7-T1 vertebrae, and spinally evoked motor potentials in UL muscles were characterized. We found that responses observed in UL muscles innervated by motor pools below the level of injury demonstrated relatively reduced sensitivity to TSS compared to those above the lesion, were asymmetrical in the majority of muscles, and were dependent on the level, extent, and side of SCI. Overall, our findings indicate that electrophysiological data acquired through TSS can offer insights into the extent of UL functional asymmetry, disruptions in neural pathways, and changes in motor control following SCI. This study suggests that such electrophysiological data can supplement clinical and functional assessment and provide further insight regarding residual motor function in individuals with SCI.

Fear Extinction Learning in Posttraumatic Stress Disorder.

Impairments in fear extinction processes have been implicated in the genesis and maintenance of debilitating psychopathologies, including Posttraumatic stress disorder (PTSD). PTSD, classified as a trauma- and stressor-related disorder, is characterized by four symptom clusters: intrusive recollections of trauma, avoidance of trauma-related stimuli, alterations in cognition and mood, and hyperarousal. One of the key pathological feature associated with the persistence of these symptoms is impaired fear extinction, as delineated in multiple studies employing Pavlovian fear-conditioning paradigms. These paradigms, comprising fear acquisition, extinction, extinction recall, and fear renewal phases, have illuminated the neurobiological substrates of PTSD. Dysfunctions in the neural circuits that mediate these fear learning and extinction processes can result in failure to extinguish fear responses and retain extinction memory, giving rise to enduring experience of fear and anxiety. The protective avoidance behaviors observed in individuals with PTSD further exacerbate intrusive symptoms and pose challenges to effective treatment strategies. A comprehensive analysis of fear conditioning and extinction processes, along with the underlying neurobiology, could significantly enhance our understanding of PTSD pathophysiology. This chapter delineates the role of fear extinction processes in PTSD, investigates the underlying neurobiological substrates, and underscores the therapeutic implications, while also identifying future research directions.

Transcutaneous spinal stimulation alters cortical and subcortical activation patterns during mimicked-standing: A proof-of-concept fMRI study.

Transcutaneous spinal stimulation (TSS) is a non-invasive neuromodulation technique that has been used to facilitate the performance of voluntary motor functions such as trunk control and self-assisted standing in individuals with spinal cord injury. Although it is hypothesized that TSS amplifies signals from supraspinal motor control networks, the effect of TSS on supraspinal activation patterns is presently unknown. The purpose of this study was to investigate TSS-induced activity in supraspinal sensorimotor regions during a lower-limb motor task. Functional magnetic resonance imaging (fMRI) was used to assess changes in neural activation patterns as eleven participants performed mimicked-standing movements in the scanner. Movements were performed without stimulation, as well as in the presence of (1) TSS, (2) stimulation applied to the back muscle, (3) paresthesia stimulation, and (4) neuromuscular electrical stimulation. TSS was associated with greater activation in subcortical and cortical sensorimotor regions involved in relay and processing of movement-related somatosensory information (e.g., thalamus, caudate, pallidum, putamen), as compared to the other stimulation paradigms. TSS also resulted in deactivation in both nucleus accumbens and posterior parietal cortex, suggesting a shift toward somatosensory feedback-based mechanisms and more reflexive motor control. Together, these findings demonstrate that spinal stimulation can alter the activity within supraspinal sensorimotor networks and promote the use of somatosensory feedback, thus providing a plausible neural mechanism for the stimulation-induced improvements of sensorimotor function observed in participants with neurological injuries and disorders.

Characterization of interlimb interaction via transcutaneous spinal stimulation of cervical and lumbar spinal enlargements.

The use of transcutaneous electrical spinal stimulation (TSS) to modulate sensorimotor networks after neurological insult has garnered much attention from both researchers and clinicians in recent years. Although many different stimulation paradigms have been reported, the interlimb effects of these neuromodulation techniques have been little studied. The effects of multisite TSS on interlimb sensorimotor function are of particular interest in the context of neurorehabilitation, as these networks have been shown to be important for functional recovery after neurological insult. The present study utilized a condition-test paradigm to investigate the effects of interenlargement TSS on spinal motor excitability in both cervical and lumbosacral motor pools. Additionally, comparison was made between the conditioning effects of lumbosacral and cervical TSS and peripheral stimulation of the fibular nerve and ulnar nerve, respectively. In 16/16 supine, relaxed participants, facilitation of spinally evoked motor responses (sEMRs) in arm muscles was seen in response to lumbosacral TSS or fibular nerve stimulation, whereas facilitation of sEMRs in leg muscles was seen in response to cervical TSS or ulnar nerve stimulation. The decreased latency between TSS- and peripheral nerve-evoked conditioning implicates interlimb networks in the observed facilitation of motor output. The results demonstrate the ability of multisite TSS to engage interlimb networks, resulting in the bidirectional influence of cervical and lumbosacral motor output. The engagement of interlimb networks via TSS of the cervical and lumbosacral enlargements represents a feasible method for engaging spinal sensorimotor networks in clinical populations with compromised motor function.NEW & NOTEWORTHY Bidirectional interlimb modulation of spinal motor excitability can be evoked by transcutaneous spinal stimulation over the cervical and lumbosacral enlargements. Multisite transcutaneous spinal stimulation engages spinal sensorimotor networks thought to be important in the recovery of function after spinal cord injury.

Deep learning model of fMRI connectivity predicts PTSD symptom trajectories in recent trauma survivors.

Early intervention following exposure to a traumatic life event could change the clinical path from the development of post traumatic stress disorder (PTSD) to recovery, hence the interest in early detection and underlying biological mechanisms involved in the development of post traumatic sequelae. We introduce a novel end-to-end neural network that employs resting-state and task-based functional MRI (fMRI) datasets, obtained one month after trauma exposure, to predict PTSD symptoms at one-, six- and fourteen-months after the exposure. FMRI data, as well as PTSD status and symptoms, were collected from adults at risk for PTSD development, after admission to emergency room following a traumatic event. Our computational method utilized a per-region encoder to extract brain regions embedding, which were subsequently updated by applying the algorithmic technique of pairwise attention. The affinities obtained between each pair of regions were combined to create a pairwise co-activation map used to perform multi-label classification. The results demonstrate that the novel method's performance in predicting PTSD symptoms, in a prospective manner, outperforms previous analytical techniques reported in the fMRI literature, all trained on the same dataset. We further show a high predictive ability for predicting PTSD symptom clusters and PTSD persistence. To the best of our knowledge, this is the first deep learning method applied on fMRI data with respect to prospective clinical outcomes, to predict PTSD status, severity and symptom clusters. Future work could further delineate the mechanisms that underlie such a prediction, and potentially improve single patient characterization.

Associations between resting-state functional connectivity and treatment response in a randomized clinical trial for posttraumatic stress disorder.

BACKGROUND: Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response. METHODS: Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN). RESULTS: At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042). CONCLUSIONS: Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.

Neural function during emotion processing and modulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with exaggerated threat processing and deficits in emotion modulation circuitry. It remains unknown how neural circuits are associated with response to evidence-based treatments for PTSD. METHOD: We examined associations between PTSD symptoms and indicators of neural response in key emotion processing and modulation regions. Fifty-six military Veterans with PTSD were randomly assigned to one of three evidence-based treatments (prolonged exposure, sertraline, and PE plus sertraline) in a randomized clinical trial ("PROGrESS"; 2018, Contemp Clin Trials, 64, 128-138). Twenty-seven combat-exposed controls (CCs) served as a comparison group at pretreatment. Before and after PTSD treatment, functional magnetic resonance imaging was used to assess brain activation and connectivity during the validated Shifted Attention Emotion Appraisal Task (2003, J Neurosci, 23, 5627-5633; 2013, Biol Psychiatry, 73, 1045-1053). RESULTS: Greater activation in emotion processing (anterior insula) and modulation (prefrontal cortex) regions and increased connectivity between attentional control (dorsolateral prefrontal cortex and superior parietal cortex) and emotion processing (amygdala) regions, at pretreatment, were associated with subsequent PTSD symptom improvement. CONCLUSIONS: This study is one of the first to examine task-based activation and functional connectivity in a PTSD treatment trial, and provides evidence to suggest that activation in and connectivity between emotion processing and modulation regions are important predictors of treatment response.

Altered resting-state functional connectivity in adolescents is associated with PTSD symptoms and trauma exposure.

Alterations in resting-state functional connectivity (rsFC) have been demonstrated in Posttraumatic Stress Disorder (PTSD). However, such reports have primarily focused on adult participants, whereas findings in adolescents with PTSD are mixed and not entirely consistent with the adult literature. Here, we examined rsFC in a non-treatment seeking adolescent sample with posttraumatic stress symptoms (PTSS; n = 59) relative to asymptomatic controls (n = 226). We also examined differences between trauma-exposed and non-exposed control subgroups (TEC n = 73 and Non-TEC n = 153) to examine alterations associated with more general trauma exposure. Finally, we compared the PTSS and TEC groups, to confirm that the reported alterations in PTSS were not driven by trauma exposure. Using a seed-based approach, we examined connectivity of default-mode (DMN) and salience (SN) networks, where alterations have been previously reported. Results suggest that PTSS are associated with less within-DMN connectivity and greater SN-DMN connectivity, as well as altered connectivity with attention regions. Trauma exposure is associated with greater within-SN connectivity. Additionally, we report findings from exploratory connectome-based analysis, which demonstrate a number of topological alterations within DMN in the PTSS group. Overall, our findings replicate prior reports of altered rsFC in PTSD and extend them to non-treatment seeking, trauma-exposed adolescents, who did or did not report PTSS. They specifically highlight SN-DMN desegregation, lower within-DMN and greater within-SN connectivity, as well as altered connectivity with attention regions, in trauma-exposed adolescents. Future research is required to confirm that adolescents with diagnosed PTSD have similar/exacerbated connectivity patterns.

Neural correlates of emotional reactivity and regulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder.

Posttraumatic Stress Disorder (PTSD) is a debilitating condition often associated with difficulty in emotion regulation, including reappraising negative emotions. This study assessed neural mechanisms associated with emotion regulation in veterans prior to and following treatment for PTSD. Participants with PTSD and combat exposed controls (CC) completed diagnostic evaluation and underwent fMRI scanning while completing Emotion Regulation Task (ERT) and Emotional Faces Assessment Task (EFAT). Participants with PTSD were randomly assigned to Prolonged Exposure plus placebo (PE+PLB), Sertraline plus enhanced medication management (SERT+EMM), or PE plus SERT (PE+SERT) and repeated diagnostic evaluation and MRI scanning following treatment. The amygdala, dmPFC, and dlPFC were examined as regions of interest. On ERT, veterans with PTSD showed significantly less dmPFC activation than CCs during reappraisal vs emotional maintenance. Within the PTSD group, results demonstrated a significant association between less activation in the dmPFC during emotion reappraisal vs maintenance trials before treatment and greater reductions in symptoms from pre- to post-treatment. During the EFAT, there were no group differences between participants with PTSD and CCs in brain activation, and no relationships between brain function and PTSD symptoms. These findings suggest that less emotional reactivity might potentially reflect less need for recruitment of prefrontal regions when reappraising negative emotion, and is an individual factor associated with better treatment outcome.

Maladaptive avoidance patterns in Parkinson's disease are exacerbated by symptoms of depression.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder, characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Given that dopamine is critically involved in learning and other cognitive processes, such as working memory, dopamine loss in PD has been linked both to learning abnormalities and to cognitive dysfunction more generally in the disease. It is unclear, however, whether avoidance behavior is impacted in PD. This is significant, as this type of instrumental behavior plays an important role in both decision-making and emotional (dys) function. Consequently, the aim of the present study was to examine avoidance learning and operant extinction in PD using a computer-based task. On this task, participants control a spaceship and attempt to shoot an enemy spaceship to gain points. They also learn to hide in safe areas to protect from (i.e., avoid) aversive events (on-screen explosions and point loss). The results showed that patients with PD (N = 25) acquired an avoidance response during aversive periods to the same extent as healthy age-matched controls (N = 19); however, patients demonstrated greater hiding during safe periods not associated with aversive events, which could represent maladaptive generalization of the avoidance response. Furthermore, this impairment was more pronounced during the extinction phase, and in patients who reported higher levels of depression. These results demonstrate for the first time that PD is associated with maladaptive avoidance patterns, which could possibly contribute to the emergence of depression in the disease.

Diminished Value Discrimination in Obsessive-Compulsive Disorder: A Prospect Theory Model of Decision-Making Under Risk.

Introduction: It has been hypothesized that people diagnosed with anxiety and obsessive-compulsive disorder (OCD) exhibit behavioral aberrations when faced with the potential for negative outcomes, but the specific cognitive aspects of decision-making that may be altered have not been systematically studied in clinical populations. Here, we studied decision-making in a clinical cohort using a task that allows for examination of the decision weights and values associated with different choice outcomes. Methods: Patients diagnosed with OCD (n = 10), generalized anxiety disorder (n = 15), social anxiety disorder (n = 14), and healthy controls (n = 20) were given a decision-making task and choices were modeled using a cumulative prospect theory framework. Results: We found OCD patients to have lower value discrimination than controls, as well as less optimal performance on the task, an effect that was mostly driven by trials with only positive outcomes. Discussion: Our results shed light on the cognitive processes that drive altered decision-making under risk in OCD. Specifically, they demonstrate that OCD patients have diminished sensitivity to positive outcomes, which might be associated with risk aversion and altered learning of gain. These findings also extend prior reports, suggesting that altered cognitive processing during decision-making is linked to altered perception of value, but not probability, in these patients.

A pilot study of escape, avoidance, and approach behaviors in treated alcohol-dependent males.

Alcohol-dependent individuals are often reported to use behavioral strategies both to escape from and avoid negative affective states, and also to approach positive affective states. However, there has been little examination of how these individuals acquire and express these types of behaviors. In this study, male adults meeting the International Classification of Diseases-10th Revision (ICD-10) criteria for alcohol dependence recruited from an outpatient treatment clinic and healthy male controls were given a computer-based task to assess learning and performance of escape, avoidance, and approach behaviors. In this task, participants control a spaceship and can either gain points by shooting an enemy spaceship or hide in safe areas to escape or avoid on-screen aversive events. We found that patients with alcohol dependence exhibited greater escape and approach behaviors, tended to show greater avoidance behavior, and achieved higher total score on the computer task than healthy controls. This is the first demonstration of such behavioral differences in this population, supporting the overactivation of both positive and negative reinforcement systems in alcohol dependence, and suggesting that such behavioral biases are not limited to alcohol-related cues. The contribution of this work to behavioral assessment and therapeutic approaches, as well as possible future directions, are discussed.

Greater avoidance behavior in individuals with posttraumatic stress disorder symptoms.

While avoidance is a core symptom of PTSD, little is known about whether individuals with PTSD show a general cognitive bias to acquire and express avoidance, in situations not related to trauma or fear. Here, we used a computer-based task to examine operant acquisition and extinction of avoidance in participants with and without severe self-reported PTSD symptoms. A total of 119 participants (77 male, 42 female; 74 veteran, 45 civilian) with symptoms (PTSS; n = 63) or with few/no symptoms (noPTSS; n = 56) performed a task, in which they controlled a spaceship and could shoot a target to gain points or hide in "safe areas" to escape or avoid on-screen aversive events. Results show that participants with PTSS exhibited more avoidance across trials than noPTSS participants, particularly due to more avoidance behavior in PTSS females compared to noPTSS females. Avoidance behavior decreased across extinction trials but interactions with PTSS and gender fell short of significance. Overall, PTSD symptoms were associated with propensity to acquire and express avoidance behavior, in both civilians and veterans, and even in a cognitive task that does not explicitly involve trauma or fear. This effect was more pronounced in females, highlighting the role of gender differences in PTSD symptomatology. Importantly, this study also demonstrates the potential of an objective assessment of avoidance behavior, which could be used to supplement the common but limited self-report tools.

Circuit dysregulation and circuit-based treatments in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that develops in some individuals in the aftermath of exposure to traumatic events, such as actual or threatened death, serious injury or sexual assault. It has been hypothesized that dysregulations in a number of specific neurocircuits, characterized by heightened responsivity of amygdala, dACC and insula, diminished responsivity of mPFC, impaired hippocampal function and deficits in cortical regions, underlie the development and expression of key PTSD symptoms. Here, we concisely describe three functional neural circuits implicated in PTSD pathophysiology and briefly review selected treatment strategies in the context of these neural circuits. We start with the commonly implicated neurocircuit model, namely, the fear learning and threat detection circuits, and then discuss the context processing circuitry, which plays an important role among others, in fear regulation. We then discuss the emotion regulation circuitry, which can further contribute to PTSD pathophysiology, and conclude with a discussion of the therapeutic approaches that might be targeting dysregulation in these circuits in PTSD patients. Specifically, we discuss how exposure-based treatments might be targeting fear learning circuits, and the pharmacological and brain-stimulation interventions aimed to augment these therapies. Finally, we discuss other pharmacological and cognitive therapeutic approaches that can augment or restore the function of the context processing and emotional regulation circuits.

Prognostic utility of admission cell-free DNA levels in patients with chronic obstructive pulmonary disease exacerbations.

BACKGROUND: Chronic obstructive pulmonary disease exacerbations (COPDEs) are associated with increased morbidity and mortality. Cell-free DNA (cfDNA) is a novel biomarker associated with clinical outcomes in several disease states but has not been studied in COPD. The objectives of this study were to assess cfDNA levels during a COPDE, to evaluate the association of cfDNA with clinical parameters and to explore the prognostic implications of cfDNA levels on long-term survival. METHODS: This was an observational study that assessed cfDNA levels in patients admitted to hospital for a COPDE. Plasma cfDNA levels of COPDE patients were compared to those of matched stable COPD patients and healthy controls. Multivariable and Cox regression analyses were used to assess the association of cfDNA levels with blood gas parameters and long-term survival. RESULTS: A total of 62 patients (46 males, forced expiratory volume in 1 second [FEV1] 38%±13%) were included. The median cfDNA levels on admission for COPDE patients was 1,634 ng/mL (interquartile range [IQR] 1,016-2,319) compared to 781 ng/mL (IQR 523-855) for stable COPD patients, matched for age and disease severity, and 352 ng/mL (IQR 209-636) for healthy controls (P<0.0001, for both comparisons). cfDNA was correlated with partial arterial pressure of carbon dioxide (PaCO2, r=0.35) and pH (r=-0.35), P=0.01 for both comparisons. In a multivariable analysis, PaCO2 was the only independent predictor of cfDNA. Using a cfDNA level of 1,924 ng/mL (threshold for abnormal PaCO2), those with high levels had a trend for increased 5-year mortality risk adjusted for age, sex and FEV1% (hazard ratio 1.92, 95% confidence interval 0.93-3.95, P=0.08). CONCLUSION: Plasma cfDNA might offer a novel technique to identify COPD patients at increased risk of poor outcomes, but the prognostic utility of this measurement requires further study.

Exaggerated acquisition and resistance to extinction of avoidance behavior in treated heroin-dependent men.

OBJECTIVE: Addiction is often conceptualized as a behavioral strategy for avoiding negative experiences. In rodents, opioid intake has been associated with abnormal acquisition and extinction of avoidance behavior. Here, we tested the hypothesis that these findings would generalize to human opioid-dependent subjects. METHOD: Adults meeting DSM-IV criteria for heroin dependence and treated with opioid medication (n = 27) and healthy controls (n = 26) were recruited between March 2013 and October 2013 and given a computer-based task to assess avoidance behavior. For this task, subjects controlled a spaceship and could either gain points by shooting an enemy spaceship or hide in safe areas to avoid on-screen aversive events. Hiding duration during different periods of the task was used to measure avoidance behavior. RESULTS: While groups did not differ on escape responding (hiding) during the aversive event, heroin-dependent men (but not women) made more avoidance responses during a warning signal that predicted the aversive event (analysis of variance, sex × group interaction, P = .007). Heroin-dependent men were also slower to extinguish the avoidance response when the aversive event no longer followed the warning signal (P = .011). This behavioral pattern resulted in reduced opportunity to obtain reward without reducing risk of punishment. Results suggest that, in male patients, differences in avoidance behavior cannot be easily explained by impaired task performance or by exaggerated motor activity. CONCLUSIONS: This study provides evidence for abnormal acquisition and extinction of avoidance behavior in opioid-dependent patients. Interestingly, data suggest that abnormal avoidance is demonstrated only by male patients. Findings shed light on cognitive and behavioral manifestations of opioid addiction and may facilitate development of therapeutic approaches to help affected individuals.

Probabilistic reward- and punishment-based learning in opioid addiction: Experimental and computational data.

Addiction is the continuation of a habit in spite of negative consequences. A vast literature gives evidence that this poor decision-making behavior in individuals addicted to drugs also generalizes to laboratory decision making tasks, suggesting that the impairment in decision-making is not limited to decisions about taking drugs. In the current experiment, opioid-addicted individuals and matched controls with no history of illicit drug use were administered a probabilistic classification task that embeds both reward-based and punishment-based learning trials, and a computational model of decision making was applied to understand the mechanisms describing individuals' performance on the task. Although behavioral results showed that opioid-addicted individuals performed as well as controls on both reward- and punishment-based learning, the modeling results suggested subtle differences in how decisions were made between the two groups. Specifically, the opioid-addicted group showed decreased tendency to repeat prior responses, meaning that they were more likely to "chase reward" when expectancies were violated, whereas controls were more likely to stick with a previously-successful response rule, despite occasional expectancy violations. This tendency to chase short-term reward, potentially at the expense of developing rules that maximize reward over the long term, may be a contributing factor to opioid addiction. Further work is indicated to better understand whether this tendency arises as a result of brain changes in the wake of continued opioid use/abuse, or might be a pre-existing factor that may contribute to risk for addiction.

The Role of Informative and Ambiguous Feedback in Avoidance Behavior: Empirical and Computational Findings.

Avoidance behavior is a critical component of many psychiatric disorders, and as such, it is important to understand how avoidance behavior arises, and whether it can be modified. In this study, we used empirical and computational methods to assess the role of informational feedback and ambiguous outcome in avoidance behavior. We adapted a computer-based probabilistic classification learning task, which includes positive, negative and no-feedback outcomes; the latter outcome is ambiguous as it might signal either a successful outcome (missed punishment) or a failure (missed reward). Prior work with this task suggested that most healthy subjects viewed the no-feedback outcome as strongly positive. Interestingly, in a later version of the classification task, when healthy subjects were allowed to opt out of (i.e. avoid) responding, some subjects ("avoiders") reliably avoided trials where there was a risk of punishment, but other subjects ("non-avoiders") never made any avoidance responses at all. One possible interpretation is that the "non-avoiders" valued the no-feedback outcome so positively on punishment-based trials that they had little incentive to avoid. Another possible interpretation is that the outcome of an avoided trial is unspecified and that lack of information is aversive, decreasing subjects' tendency to avoid. To examine these ideas, we here tested healthy young adults on versions of the task where avoidance responses either did or did not generate informational feedback about the optimal response. Results showed that provision of informational feedback decreased avoidance responses and also decreased categorization performance, without significantly affecting the percentage of subjects classified as "avoiders." To better understand these results, we used a modified Q-learning model to fit individual subject data. Simulation results suggest that subjects in the feedback condition adjusted their behavior faster following better-than-expected outcomes, compared to subjects in the no-feedback condition. Additionally, in both task conditions, "avoiders" adjusted their behavior faster following worse-than-expected outcomes, and treated the ambiguous no-feedback outcome as less rewarding, compared to non-avoiders. Together, results shed light on the important role of ambiguous and informative feedback in avoidance behavior.