JOINT MODELING FOR LEARNING DECISION-MAKING DYNAMICS IN BEHAVIORAL EXPERIMENTS.

Anxiety and anhedonia in depression: Associations with neuroticism and cognitive control

Irritability in pediatric samples is associated with higher rates of subsequent suicide-related outcomes. No study, to date, has evaluated the longitudinal association between irritability and suicidal ideation (SI) in adults with major depressive disorder (MDD). This report evaluated whether irritability is associated with SI at the same visit (i.e., concurrently) and whether early changes in irritability with antidepressant treatment predict subsequent levels of SI. Participants of Combining Medications to Enhance Depression Outcomes (CO-MED, n = 665), Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC, n = 296), and Suicide Assessment Methodology Study (SAMS, n = 266) were included. Repeated-measures mixed model analyses evaluated concurrent association throughout the trial between irritability (five-item irritability domain of Concise Associated Symptom Tracking scale) and SI (three-item suicidal thoughts factor of Concise Health Risk Tracking scale) after controlling for overall depression (excluding suicidality-related item), and predicted subsequent levels of SI (repeated observations from week-2-to-week-8) based on early (baseline-to-week-2) changes in irritability after controlling for early changes in overall depression. Higher irritability was associated with higher SI concurrently; estimates (standard error) were 0.18 (0.02, p < 0.0001), 0.64 (0.02, p < 0.0001), and 0.26 (0.04, p < 0.0001) in CO-MED, EMBARC, and SAMS respectively. Greater baseline-to-week-2 reductions in irritability predicted lower levels of subsequent SI; estimates (standard errors) were -0.08 (0.03, p = 0.023), -0.50 (0.05, p < 0.0001), and -0.12 (0.05, p = 0.024) in CO-MED, EMBARC, and SAMS, respectively. Controlling for anxiety or insomnia produced similar results. In conclusion, irritability and SI were consistently linked in adults with MDD. These findings support careful assessment of irritability in suicide risk assessment.

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the "trial and error" approach in choosing the most effective antidepressant treatment for each patient allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, cross the blood-brain-barrier, and be highly sensitive to changes in both synaptic activity and neuronal receptor signaling. Here we present evidence that expression of the brain-enriched circRNA, CDR1as, is associated with symptomatic response to SSRI treatment, and regulated by serotonin and Brain-Derived Neurotrophic Factor (BDNF) receptor activity. We present data using circRNA-specific PCR in baseline whole blood samples from two independent cohorts, drawn from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) and the Biomarkers of ANTidepressant RESponse (ANTARES) clinical studies, showing that before treatment CDR1as is differentially expressed between future symptomatic responders and non-responders to treatment with the SSRI sertraline. Additional data from naturalistic antidepressant response studies further highlight the association between CDR1as and antidepressant effects of SSRIs as a class. In addition, we show that CDR1as levels are altered following sertraline treatment in responders with the trajectory of change post-treatment associated with long-term remission. Furthermore, we report that levels of CDR1as in the blood can specifically predict remission with SSRI treatment, but not response/remission with Placebo or Bupropion treatments. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting mouse Cdr1as is strongly regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.

Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design

Patients with psychosis spectrum disorders exhibit deficits in social and neurocognition, as well as hallmark abnormalities in motivation and reward processing. Aspects of reward processing may overlap behaviorally and neurobiologically with some elements of cognitive functioning, and abnormalities in these processes may share partially overlapping etiologies in patients. However, whether reward processing and cognition are associated across the psychoses and linked to state and trait clinical symptomatology is unclear. The present study examined associations between cognitive functioning, reward learning, and clinical symptomatology in a cross-diagnostic sample. Patients with schizophrenia (SZ; n = 37), bipolar I disorder with psychosis (BD; n = 42), and healthy controls (n = 29) were assessed for clinical symptoms (patients only), neurocognitive functioning using the MATRICS Battery (MCCB) and reward learning using the probabilistic reward task (PRT). Groups were compared on neurocognition and PRT response bias, and associations between PRT response bias and neurocognition or clinical symptoms were examined controlling for demographic variables and PRT task difficulty (discriminability). Patients with SZ performed worse than controls on most measures of neurocognition; patients with BD exhibited deficits in some domains between the level of patients with SZ and controls. The SZ - but not BD - group exhibited deficits in social cognition compared to controls. Patients and controls did not differ on PRT response bias, but did differ on PRT discriminability. Better response bias across the sample was associated with poorer social cognition, but not neurocognition; conversely, discriminability was associated with neurocognition but not social cognition. Symptoms of psychosis, particularly negative symptoms, were associated with poorer response bias across patient groups. Reward learning was associated with symptoms of psychosis - in particular negative symptoms - across diagnoses, and was predictive of worse social cognition. Reward learning was not associated with neurocognitive performance, suggesting that, across patient groups, social cognition but not neurocognition may share common pathways with this aspect of reinforcement learning. Better understanding of how cognitive dysfunction and reward processing deficits relate to one another, to other key symptom dimensions (e.g., psychosis), and to diagnostic categories, may help clarify shared etiological pathways and guide efforts toward targeted treatment approaches.

Statistical Analysis Plan for Stage 1 EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) Study

Major depressive disorder (MDD), bipolar disorder, and schizophrenia involve disruptions in processing rewarding stimuli. In this review, we propose that distinct mechanistic pathways underlie these disruptions in mood disorders versus schizophrenia, and we highlight the importance of understanding these differences for developing personalized treatments. We summarize evidence suggesting that reward processing abnormalities in mood disorders are driven by dysregulated motivational systems; MDD is characterized by blunted responses to reward cues, and bipolar disorder is characterized by heightened responses. In contrast, we argue that reward processing disruptions in schizophrenia do not reflect abnormalities in motivation or hedonic experience; rather, they reflect impairments in the cognitive representation of past and future rewards as well as misdirected attention to irrelevant stimuli. To integrate these findings, we present a neurodevelopmental framework for the onset of mood and psychotic disorders and explore how disruptions in normative brain development contribute to their pathophysiology, timing, and onset. Additionally, we move beyond viewing these conditions as homogeneous disorders and discuss how reward processing profiles may align with specific symptom dimensions.

Lifetime history of major depressive disorder is associated with decreased reward learning: Evidence from a novel online version of the probabilistic reward task

Major depressive disorder (MDD) and nicotine dependence are highly comorbid, with studies showing that ~50% of individuals with MDD smoke. The link between these disorders persists even after the clinical symptoms of depression subside, as indicated by high levels of nicotine dependence among individuals with remitted depression (rMDD). Recent evidence indicates that individuals with rMDD show blunted responses to reward as measured by a probabilistic reward task (PRT), which assesses the ability to modify behavior as a function of reward history. Given nicotine's ability to enhance reward responsiveness, individuals with rMDD might smoke to address this persistent reward deficit. However, it is unclear whether smokers with rMDD show enhanced reward responsiveness relative to rMDD individuals who do not smoke. To test this hypothesis, we evaluated reward responsiveness on the PRT in four groups (N=198): individuals with and without rMDD who were or were not nicotine dependent. As hypothesized, rMDD nonsmokers had lower reward responsiveness relative to both control nonsmokers and rMDD smokers; conversely, smokers with rMDD showed behavioral patterns comparable to those without a history of depression. Given nicotine's ability to enhance reward sensitivity, it is possible that nicotine normalizes the otherwise blunted reward responsiveness in individuals with rMDD. Therapies aimed at enhancing this reward-based deficit may be beneficial in the treatment of both nicotine dependence and MDD.

Sex differences in the association of baseline c-reactive protein (CRP) and acute-phase treatment outcomes in major depressive disorder: Findings from the EMBARC study

This thesis is concerned with two studies which have the common pursuit to improve the investigation of pathomechanisms underlying schizophrenic and affective disorders. They were motivated by the fact, that the diagnosis of mental disorders is a complex process and despite advances still error prone. It is proposed that during the pathogenesis of mental disorders interaction of genes and environment lead to functional changes in brain regions and related brain networks. Indeed, abnormalities in reward, stress and emotion processing are described for mental disorders. It is expected that neuroimaging studies might identify brain activation or connectivity patterns that could aid their differential diagnosis disorders or guide treatment selection. The first study investigated if living in big cities could affect the mesolimbic reward system and densely connected cortical and subcortical structures. 147 healthy subjects provided information about current and residency during their first years of life and performed the Desire-Reason-Dilemma paradigm during functional magnetic resonance imaging. Compared with subjects from less urban areas, city dwellers showed an altered activation and modulation capability of the midbrain dopamine system. City dwellers also revealed exaggerated responses in other brain regions involved in reward processing, and in the regulation of stress and emotions such as amygdala, orbitofrontal and pregenual anterior cingulate cortex. This study provided evidence for an influence of an environmental risk factor on cortico-subcortical networks involved in reward and emotion processing. Dysfunctions of these brain networks are involved in the development of schizophrenic and affective disorders. The aim of the second study was to investigate dynamic functional interactions between amygdala, nucleus accumbens and prefrontal cortex that underlie the influences of emotions, desires and rationality on human decisions because quite little is known about dynamic functional interactions between these brain circuits that underlie reward processing, self-controlled pursuit of long-term goals and emotions. For this purpose, the Desire-Reason-Dilemma paradigm was extended by an affective component. One half of the stimuli showed a gray ellipse representing non-emotional stimuli and the other half showed an emotional face in its center. Seventeen healthy volunteers were included in the study and nine additional subjects were excluded due to excessive head movements. The behavioral data revealed that fearful faces generally increased avoidance tendency to non-reward stimuli leading to significantly slower acceptance and faster rejection of these stimuli. But reward counteracted the avoidance tendency of fearful faces. The functional MRI analysis showed that increased functional connectivity between amygdala and nucleus accumbens facilitated the approach of immediate reward in the presence of emotional information. This was not observed in the absence of reward. Further, increased functional interactions of the anteroventral prefrontal cortex with amygdala and nucleus accumbens were associated with rational decisions in dilemma situations. The second work provided an experimental paradigm that for the first time enabled the in vivo investigation of the interaction between amygdala, nucleus accumbens und antero-ventral prefrontal cortex when emotional-, reward related information and self-controlled pursuit of long-term goals guided human decisions and reward-directed actions. It was shown that the activity in the amygdala, which is hypothesized as an integration region of cognition and emotion, is influenced by a risk factor contributing to development of mental disorders and that the amygdala interacts with cortical regions and the mesolimbic dopamine system to coordinate goal directed behavior. Future application of the affective DRD paradigm and the inclusion of additional information, e.g. genetic variation might provide additional insight in the underlying neuro-mechanisms of schizophrenic and affective disorders.

Exposure to acute stress is associated with reduced reward processing in laboratory studies in animals and humans. However, less clear is the association between reward processing and exposure to naturalistic stressful life events. The goal of the current study was to provide a novel investigation of the relation between past 6-month stressful life events and reward processing, and the extent to which this relation was moderated by depression diagnostic status and state symptoms of anhedonia. The current study included a secondary analysis of data from 107 adults (37 current-depressed, 25 past-depressed, 45 never-depressed; 75% women) drawn from two previous community studies. Past 6-month stressful life events were assessed with a rigorous contextual interview with independent ratings. Response to monetary reward was assessed with a probabilistic reward task. Among current-depressed participants, and among both current- and past-depressed participants with high levels of anhedonia, greater exposure to independent life events outside of individuals' control was significantly associated with poorer reward learning. In direct contrast, among those with low levels of anhedonia, greater exposure to independent life events was significantly associated with a greater overall bias toward the more frequently rewarded stimulus. Results suggest that depression and anhedonia are uniquely associated with vulnerability to blunted reward learning in the face of uncontrollable stressors. In contrast, in the absence of anhedonia symptoms, heightened reward processing during or following independent stressful life event exposure may represent an adaptive response.

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target—the KCNQ-type potassium channel—for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of ten weeks. Resting state functional magnetic resonance imaging data were collected at baseline and post-treatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: −13.7±9.7, p<0.001, d=2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: −6.1±5.3, p<0.001, d=1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n=14, voxel-wise p<0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n=9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

There are few reliable predictors of response to antidepressant treatments. In the present investigation, we examined pretreatment functional brain connectivity during reward processing as a potential predictor of response to Behavioral Activation Treatment for Depression (BATD), a validated psychotherapy that promotes engagement with rewarding stimuli and reduces avoidance behaviors. Thirty-three outpatients with major depressive disorder (MDD) and 20 matched controls completed two runs of the monetary incentive delay task during functional magnetic resonance imaging after which participants with MDD received up to 15 sessions of BATD. Seed-based generalized psychophysiological interaction analyses focused on task-based connectivity across task runs, as well as the attenuation of connectivity from the first to the second run of the task. The average change in Beck Depression Inventory-II scores due to treatment was 10.54 points, a clinically meaningful response. Groups differed in seed-based functional connectivity among multiple frontostriatal regions. Hierarchical linear modeling revealed that improved treatment response to BATD was predicted by greater connectivity between the left putamen and paracingulate gyrus during reward anticipation. In addition, MDD participants with greater attenuation of connectivity between several frontostriatal seeds, and midline subcallosal cortex and left paracingulate gyrus demonstrated improved response to BATD. These findings indicate that pretreatment frontostriatal functional connectivity during reward processing is predictive of response to a psychotherapy modality that promotes improving approach-related behaviors in MDD. Furthermore, connectivity attenuation among reward-processing regions may be a particularly powerful endophenotypic predictor of response to BATD in MDD.

Antisocial behavior is a heterogeneous construct that includes a range of behavioral problems and psychopathologies. With regard to classification, children and adolescents may be identified as having conduct disorder or callous–unemotional traits; whereas adults may be identified as having antisocial personality disorder or psychopathy. The adverse consequences of the behaviors and diagnoses related to this construct produce great burdens for the perpetrators, victims, family members, and society at large. Research has focused on identifying various factors contributing to antisocial behavior, with reward processing among one of the most studied. This chapter synthesizes self-report, behavioral, electrophysiological, and neuroimaging literature on reward processing in antisocial behavior across development. Findings are organized regarding key reward constructs within the Positive Valence Systems domain of the Research Domain Criteria matrix. Overall, children with conduct disorder display deficits in action selection, responsivity to reward, and reward prediction that result in risky choices, impaired performance in the face of reward, and poor integration of reward information. By contrast, children with callous–unemotional traits demonstrate poor reward learning and use of reward cues. In adults, those with antisocial personality disorder display deficits in reward valuation; whereas those with psychopathy show context-dependent abnormalities in multiple components of reward processing. Ultimately, an integrative focus on abnormal reward processing across subtypes of individuals who engage in antisocial behavior might help refine the phenotype and improve the prediction of onset and recovery of these disorders.