Michael A. Rapp

Reward Feedback Alterations in Unmedicated Schizophrenia Patients: Relevance for Delusions

BACKGROUND Increased attribution of incentive salience to neutral or aversive stimuli might be associated with dysfunction of neuronal processing of positive and negative reinforcement and contribute to the formation of delusions in schizophrenia. METHODS Fifteen unmedicated patients with schizophrenia (8 drug-naive and 7 drug-free for at least 3 months) and 15 age- and gender-matched healthy control participants underwent functional magnetic resonance imaging to investigate neural responses to feedback of (successful vs. unsuccessful) monetary gain or avoidance of loss. Functional connectivity was assessed between the medial prefrontal cortex (MPFC) and ventral striatum (VS), brain areas known to be activated by feedback of reward and loss. RESULTS Responses to negative outcome in reward trials (omission of expected reward) were exaggerated in the MPFC of patients with schizophrenia. In contrast, schizophrenia patients showed reduced neural responses to successful versus unsuccessful avoidance of loss in the VS. Increased severity of delusions in schizophrenia patients was associated with a decrease in MPFC activation elicited by successful versus unsuccessful avoidance of loss. Functional connectivity between the MPFC and the VS was reduced in patients with schizophrenia compared with healthy control subjects. CONCLUSIONS These findings demonstrate a differential impairment of-and reduced connectivity between--VS and MPFC during processing of reward and loss-avoidance in drug-free patients with schizophrenia. Moreover, our results provide a link between the formation of delusions and the neural processing of aversive outcomes.

Striatal dysfunction during reversal learning in unmedicated schizophrenia patients

Subjects with schizophrenia are impaired at reinforcement-driven reversal learning from as early as their first episode. The neurobiological basis of this deficit is unknown. We obtained behavioral and fMRI data in 24 unmedicated, primarily first episode, schizophrenia patients and 24 age-, IQ- and gender-matched healthy controls during a reversal learning task. We supplemented our fMRI analysis, focusing on learning from prediction errors, with detailed computational modeling to probe task solving strategy including an ability to deploy an internal goal directed model of the task. Patients displayed reduced functional activation in the ventral striatum (VS) elicited by prediction errors. However, modeling task performance revealed that a subgroup did not adjust their behavior according to an accurate internal model of the task structure, and these were also the more severely psychotic patients. In patients who could adapt their behavior, as well as in controls, task solving was best described by cognitive strategies according to a Hidden Markov Model. When we compared patients and controls who acted according to this strategy, patients still displayed a significant reduction in VS activation elicited by informative errors that precede salient changes of behavior (reversals). Thus, our study shows that VS dysfunction in schizophrenia patients during reward-related reversal learning remains a core deficit even when controlling for task solving strategies. This result highlights VS dysfunction is tightly linked to a reward-related reversal learning deficit in early, unmedicated schizophrenia patients.

Definitions and distinctions among depressive syndromes and symptoms: implications for a better understanding of the depression-cardiovascular disease association.

Objective: A prognostic role for depressive disorder presence and/or elevated depressive symptoms in the onset and recurrence of cardiovascular disease has been largely supported. Depression is a multifaceted disorder, encompassing a wide range of somatic, cognitive, and mood symptoms; it varies in intensity, duration, frequency, course, and family history; it can be assessed continuously or categorically; it can be obtained by interview or by self-report; and importantly, the cardiac prognostic impact of these distinctions may vary. We provide an overview of definitions and possible assessment of depression, and we discuss key assessment distinctions. Conclusion: Examining the predictive ability of these key distinctions of depression for acute coronary syndrome recurrence would be of benefit to future research in this field. CVD = cardiovascular disease; ACS = acute coronary syndrome; MDD = major depressive disorder; SCID = Structured Clinical Interview for DSM-IV; DIS = Diagnostic Interview Schedule; DISH = Depression Interview and Structured Hamilton.

Ventral Striatal Prediction Error Signaling is Associated with Dopamine Synthesis Capacity and Fluid Intelligence

Fluid intelligence represents the capacity for flexible problem solving and rapid behavioral adaptation. Rewards drive flexible behavioral adaptation, in part via a teaching signal expressed as reward prediction errors in the ventral striatum, which has been associated with phasic dopamine release in animal studies. We examined a sample of 28 healthy male adults using multimodal imaging and biological parametric mapping with (1) functional magnetic resonance imaging during a reversal learning task and (2) in a subsample of 17 subjects also with positron emission tomography using 6‐[18F]fluoro‐L‐DOPA to assess dopamine synthesis capacity. Fluid intelligence was measured using a battery of nine standard neuropsychological tests. Ventral striatal BOLD correlates of reward prediction errors were positively correlated with fluid intelligence and, in the right ventral striatum, also inversely correlated with dopamine synthesis capacity (FDOPA K  inapp ). When exploring aspects of fluid intelligence, we observed that prediction error signaling correlates with complex attention and reasoning. These findings indicate that individual differences in the capacity for flexible problem solving relate to ventral striatal activation during reward‐related learning, which in turn proved to be inversely associated with ventral striatal dopamine synthesis capacity. Hum Brain Mapp, 2013.

Model-Based and Model-Free Decisions in Alcohol Dependence

Background: Human and animal work suggests a shift from goal-directed to habitual decision-making in addiction. However, the evidence for this in human alcohol dependence is as yet inconclusive. Methods: Twenty-six healthy controls and 26 recently detoxified alcohol-dependent patients underwent behavioral testing with a 2-step task designed to disentangle goal-directed and habitual response patterns. Results: Alcohol-dependent patients showed less evidence of goal-directed choices than healthy controls, particularly after losses. There was no difference in the strength of the habitual component. The group differences did not survive controlling for performance on the Digit Symbol Substitution Task. Conclusion: Chronic alcohol use appears to selectively impair goal-directed function, rather than promoting habitual responding. It appears to do so particularly after nonrewards, and this may be mediated by the effects of alcohol on more general cognitive functions subserved by the prefrontal cortex.

Dimensional psychiatry: reward dysfunction and depressive mood across psychiatric disorders

RationaleA dimensional approach in psychiatry aims to identify core mechanisms of mental disorders across nosological boundaries.ObjectivesWe compared anticipation of reward between major psychiatric disorders, and investigated whether reward anticipation is impaired in several mental disorders and whether there is a common psychopathological correlate (negative mood) of such an impairment.MethodsWe used functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task to study the functional correlates of reward anticipation across major psychiatric disorders in 184 subjects, with the diagnoses of alcohol dependence (n = 26), schizophrenia (n = 44), major depressive disorder (MDD, n = 24), bipolar disorder (acute manic episode, n = 13), attention deficit/hyperactivity disorder (ADHD, n = 23), and healthy controls (n = 54). Subjects’ individual Beck Depression Inventory-and State-Trait Anxiety Inventory-scores were correlated with clusters showing significant activation during reward anticipation.ResultsDuring reward anticipation, we observed significant group differences in ventral striatal (VS) activation: patients with schizophrenia, alcohol dependence, and major depression showed significantly less ventral striatal activation compared to healthy controls. Depressive symptoms correlated with dysfunction in reward anticipation regardless of diagnostic entity. There was no significant correlation between anxiety symptoms and VS functional activation.ConclusionOur findings demonstrate a neurobiological dysfunction related to reward prediction that transcended disorder categories and was related to measures of depressed mood. The findings underline the potential of a dimensional approach in psychiatry and strengthen the hypothesis that neurobiological research in psychiatric disorders can be targeted at core mechanisms that are likely to be implicated in a range of clinical entities.

Working memory training improvements and gains in non-trained cognitive tasks in young and older adults

ABSTRACT Previous studies on working memory training have indicated that transfer to non-trained tasks of other cognitive domains may be possible. The aim of this study is to compare working memory training and transfer effects between younger and older adults (n = 60). A novel approach to adaptive n-back training (12 sessions) was implemented by varying the working memory load and the presentation speed. All participants completed a neuropsychological battery of tests before and after the training. On average, younger training participants achieved difficulty level 12 after training, while older training participants only reached difficulty level 5. In younger participants, transfer to Verbal Fluency and Digit Symbol Substitution test was found. In older participants, we observed a transfer to Digit Span Forward, CERAD Delayed Recall, and Digit Symbol Substitution test. Results suggest that working memory training may be a beneficial intervention for maintaining and improving cognitive functioning in old age.

Depression predicts mortality in the young old, but not in the oldest old : Results from the Berlin Aging Study

OBJECTIVE There is evidence that depression in old age is associated with an increased mortality risk, but studies have also yielded inconclusive results. Possible moderators of the depression-mortality association in old age discussed in the literature are differences in cardiovascular morbidity, effects of multimorbidity, and increasing effects of subthreshold depression symptoms, such as minor depression and loneliness, on mortality. This study is concerned with the depression-mortality association in old and very old age. METHOD Information about mortality status and dates of death for 497 participants of the Berlin, Germany, Aging Study (mean age: 85.16 years; range: 70-103 years), a population based, age-stratified, longitudinal study, were obtained from the Berlin, Germany, City Registry for up to 15 years. The authors calculated proportional hazard regression models to examine associations between clinical diagnosis of depression at baseline assessment and subsequent mortality for young-old (70-84 years; N = 243; 68% deceased) and oldest-old participants (85+ years; N = 254; 98% deceased). In an additional step, the authors examined whether depression-mortality associations remained after statistically controlling for the effects of other mortality predictors including age, gender, education, dementia, cardiovascular risk factors, and other somatic diseases. RESULTS Our analyses revealed strong predictive effects of depression diagnoses for mortality among the young old (Relative Risk = 1.60, 95% Confidence Interval = 1.13-2.26) that were not due to the effects of other mortality predictors (Relative Risk = 1.56, 95% Confidence Interval = 1.09-2.22). Among the oldest old, no depression-mortality associations were found. CONCLUSION Depression is a significant risk factor for all-cause mortality in old age, yet the risk conveyed by depression does not hold in very old age. Possible underlying mechanisms in the very old are discussed.

Working Memory Load-Dependent Brain Response Predicts Behavioral Training Gains in Older Adults

In the domain of working memory (WM), a sigmoid-shaped relationship between WM load and brain activation patterns has been demonstrated in younger adults. It has been suggested that age-related alterations of this pattern are associated with changes in neural efficiency and capacity. At the same time, WM training studies have shown that some older adults are able to increase their WM performance through training. In this study, functional magnetic resonance imaging during an n-back WM task at different WM load levels was applied to compare blood oxygen level-dependent (BOLD) responses between younger and older participants and to predict gains in WM performance after a subsequent 12-session WM training procedure in older adults. We show that increased neural efficiency and capacity, as reflected by more “youth-like” brain response patterns in regions of interest of the frontoparietal WM network, were associated with better behavioral training outcome beyond the effects of age, sex, education, gray matter volume, and baseline WM performance. Furthermore, at low difficulty levels, decreases in BOLD response were found after WM training. Results indicate that both neural efficiency (i.e., decreased activation at comparable performance levels) and capacity (i.e., increasing activation with increasing WM load) of a WM-related network predict plasticity of the WM system, whereas WM training may specifically increase neural efficiency in older adults.

Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence

In detoxified alcohol‐dependent patients, alcohol‐related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian‐to‐Instrumental‐Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol‐dependent patients; (2) PIT was significantly associated with blood oxygen level‐dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT‐related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow‐up period) in alcohol‐dependent patients. These observations show for the first time that PIT‐related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.