Iris Lange

Measuring “waiting” impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task

Background Premature responding is a form of motor impulsivity that preclinical evidence has shown to predict compulsive drug seeking but has not yet been studied in humans. We developed a novel translation of the task, based on the rodent 5-choice serial reaction time task, testing premature responding in disorders of drug and natural food rewards. Methods Abstinent alcohol- (n = 30) and methamphetamine-dependent (n = 23) subjects, recreational cannabis users (n = 30), and obese subjects with (n = 30) and without (n = 30) binge eating disorder (BED) were compared with matched healthy volunteers and tested on the premature responding task. Results Compared with healthy volunteers, alcohol- and methamphetamine-dependent subjects and cannabis users showed greater premature responding with no differences observed in obese subjects with or without BED. Current smokers exhibited greater premature responding versus ex-smokers and nonsmokers. Alcohol-dependent subjects also had lower motivation for explicit monetary incentives. A Motivation Index correlated negatively with alcohol use and binge eating severity. Conclusions Premature responding on a novel translation of a serial reaction time task was more evident in substance use disorders but not in obese subjects with or without BED. Lower motivation for monetary incentives linked alcohol use and binge eating severity. Our findings add to understanding the relationship between drug and natural food rewards.

Increased ventral striatal volume in college-aged binge drinkers.

Background Binge drinking is a serious public health issue associated with cognitive, physiological, and anatomical differences from healthy individuals. No studies, however, have reported subcortical grey matter differences in this population. To address this, we compared the grey matter volumes of college-age binge drinkers and healthy controls, focusing on the ventral striatum, hippocampus and amygdala. Method T1-weighted images of 19 binge drinkers and 19 healthy volunteers were analyzed using voxel-based morphometry. Structural data were also covaried with Alcohol Use Disorders Identification Test (AUDIT) scores. Cluster-extent threshold and small volume corrections were both used to analyze imaging data. Results Binge drinkers had significantly larger ventral striatal grey matter volumes compared to controls. There were no between group differences in hippocampal or amygdalar volume. Ventral striatal, amygdalar, and hippocampal volumes were also negatively related to AUDIT scores across groups. Conclusions Our findings stand in contrast to the lower ventral striatal volume previously observed in more severe forms of alcohol use disorders, suggesting that college-age binge drinkers may represent a distinct population from those groups. These findings may instead represent early sequelae, compensatory effects of repeated binge and withdrawal, or an endophenotypic risk factor.

Reflection impulsivity in binge drinking: behavioural and volumetric correlates.

The degree to which an individual accumulates evidence prior to making a decision, also known as reflection impulsivity, can be affected in psychiatric disorders. Here, we study decisional impulsivity in binge drinkers, a group at elevated risk for developing alcohol use disorders, comparing two tasks assessing reflection impulsivity and a delay discounting task, hypothesizing impairments in both subtypes of impulsivity. We also assess volumetric correlates of reflection impulsivity focusing on regions previously implicated in functional magnetic resonance imaging studies. Sixty binge drinkers and healthy volunteers were tested using two different information‐gathering paradigms: the beads task and the Information Sampling Task (IST). The beads task was analysed using a behavioural approach and a Bayesian model of decision making. Delay discounting was assessed using the Monetary Choice Questionnaire. Regression analyses of primary outcomes were conducted with voxel‐based morphometry analyses. Binge drinkers sought less evidence prior to decision in the beads task compared with healthy volunteers in both the behavioural and computational modelling analysis. There were no group differences in the IST or delay discounting task. Greater impulsivity as indexed by lower evidence accumulation in the beads task was associated with smaller dorsolateral prefrontal cortex and inferior parietal volumes. In contrast, greater impulsivity as indexed by lower evidence accumulation in the IST was associated with greater dorsal cingulate and precuneus volumes. Binge drinking is characterized by impaired reflection impulsivity suggesting a deficit in deciding on the basis of future outcomes that are more difficult to represent. These findings emphasize the role of possible therapeutic interventions targeting decision‐making deficits.

Neuronal correlates of risk-seeking attitudes to anticipated losses in binge drinkers

Background Abnormal decision making under risk is associated with a number of psychiatric disorders. Here, we focus on binge drinkers (BD), characterized by repeated episodes of heavy alcohol intoxication. Previous studies suggest a decreased sensitivity to aversive conditioning in BD. Here, we asked whether BD might be characterized by enhanced risk seeking related to decreased sensitivity to the anticipation of negative outcomes. Methods Using an anticipatory risk-taking task (40 BD and 70 healthy volunteers) and an adapted version of this task for functional magnetic resonance imaging (21 BD and 21 healthy volunteers), we assessed sensitivity to reward and loss across risk probabilities. Results In the behavioral task, BD showed a higher number of risky choices in high-risk losses. In the neuroimaging task, the high-risk attitude in the loss condition was associated with greater activity in dorsolateral prefrontal, lateral orbitofrontal, and superior parietal cortices in BD. Explicit exposure of BD to the probability and magnitude of loss, via introduction of feedback, resulted in a subsequent decrease in risky choices. This change in risk attitude in BD was associated with greater activity in inferior frontal gyrus, which also correlated with the percentage of decrease in risky choices after feedback presentation, suggesting a possible role for cognitive control toward risk-seeking attitudes. Conclusions Our findings suggest that a decrease in sensitivity to the anticipation of high-risk negative outcomes might underlie BD behavior. Presentation of explicit feedback of probability and loss in BD can potentially modify risk-taking attitudes, which have important public health implications and suggest possible therapeutic targets.

CO2 exposure as translational cross-species experimental model for panic.

The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral–emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.

The anatomy of fear learning in the cerebellum: A systematic meta-analysis.

Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV-VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders.

Amiloride-sensitive cation channel 2 genotype affects the response to a carbon dioxide panic challenge

Until recently, genetic research into panic disorder (PD) has had only limited success. Inspired by rodent research, demonstrating that the acid-sensing ion channel 1a (ASIC1a) is critically involved in the behavioral fear response to carbon dioxide (CO2) exposure, variants in the human homologue gene amiloride-sensitive cation channel 2 (ACCN2) were shown to be associated with PD. However, the relationship between changes in brain pH and ACCN2, as done in rodents by CO2 exposure, has not been investigated yet in humans. Here, we examined this link between the ACCN2 gene and the response to CO2 exposure in two studies: in healthy volunteers as well as PD patients and using both behavioral and physiological outcome measures. More specifically, 107 healthy volunteers and 183 PD patients underwent a 35% CO2 inhalation. Negative affect was assessed using visual analogue scales and the panic symptom list (PSL), and, in healthy volunteers, cardiovascular measurements. The single nucleotide polymorphism rs10875995 was significantly associated with a higher emotional response in PD patients and with an increase in systolic as well as diastolic blood pressure in healthy subjects. In all measurements, subjects homozygous for the T-allele showed a heightened reactivity to CO2. Furthermore, a trend towards an rs685012 genotype effect on the emotional response was found in PD patients. We provide the first evidence that genetic variants in the ACCN2 are associated with differential sensitivity to CO2 in PD patients as well as healthy volunteers, further supporting ACCN2 as a promising candidate for future research to improve current treatment options.

Behavioral pattern separation and its link to the neural mechanisms of fear generalization

Abstract Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD.

Real-Life Validation of Reduced Reward Processing in Emerging Adults With Depressive Symptoms

Subclinical symptoms of depression are common in emerging adults. Anhedonia is one such symptom that specifically puts one at risk for developing clinical depression. Recently, important progress has been made in elucidating the underlying neurobiology of anhedonia. This progress rests on many experimental studies examining how subjects with depressive symptoms respond to anticipating and consuming rewarding stimuli. Translating these findings to real-life reward processing dynamics is an important next step in order to guide fine-tuning of preventive treatments. We propose that the Experience Sampling Methodology (ESM) represents a useful tool in addressing this issue. ESM requires individuals to carry a device that beeps at semirandom moments, inviting them to fill out a short questionnaire on mood, context, and behavior. Using this methodology, we aimed to decompose the construct of reward processing into its daily life dynamics, by investigating how positive affect (PA), reward anticipation and active behavior influence each other over time. A group of emerging adults (aged 16–25) was included, of which two-thirds presented with subclinical depressive symptoms. Associations between PA, reward anticipation and active behavior manifested in the flow of daily life. Depressive symptoms were significantly associated with reduced time-lagged associations between reward anticipation and active behavior (&bgr; = −.005, p = .006) and active behavior and reward anticipation (&bgr; = −.002, p = .027). The moderating effect of depressive symptoms on the time-lagged association between reward anticipation and PA approached significance (&bgr; = −.002, p = .051). These findings represent an important step in translating experimental knowledge on reward processing into daily life processes.

Brain and Behavior Changes following Exposure Therapy Predict Outcome at 8-Year Follow-Up.

local ethics committee approved the study, and written consent was obtained. Behavioral change was examined with repeated measures analyses of variance. Short-term behavioral changes (T1–T0) were correlated with long-term outcome (SPQ). For the fMRI analyses in SPM8, we first created individual contrast images for spider > neutral, followed by statistical images of therapy-related change (T1– T0). A second-level regression analysis was used to evaluate baseline and changes (T1–T0) in neural activation associated with follow-up SPQ scores. A familywise error rate small-volume correction was applied for a priori regions of interest: left amygdala, anterior cingulate cortex, and left insula, as these regions showed therapy-induced changes [2] . Additionally, an exploratory whole-brain second-level analysis was conducted. Figure 1 shows an overview of the behavioral and neural results. Although SPQ scores at follow-up were increased compared to SPQ scores at T1 (p < 0.01), they were still lower than T0 ratings [F(1.37, 19.19) = 57.342; p < 0.001; post hoc p < 0.001], indicating that the therapy effect was partially maintained over 8 years. Furthermore, SPQ and fear/arousal score reductions from preto posttherapy assessments (T1–T0; r = 0.78, p < 0.01; r = 0.57, p < 0.05; r = 0.70, p < 0.01) were associated with a lower SPQ score at follow-up. Similarly, a lower SPQ score at follow-up was associated with more attenuation in the BOLD response from preto posttherapy time points (T1–T0) in the left anterior insula (cluster extending into the lateral orbitofrontal cortex, peak voxel MNI coordinates –26/24/–12, cluster size = 29 voxels, t = 7.20, p < 0.01, r = 0.89). This effect was not driven by changes in processing of neutral images between T0 and T1. Change in activation (T1–T0) in other brain regions did not correlate with the follow-up SPQ scores, as tested by the small-volume correction analysis and whole-brain analysis. To check whether the observed associations were driven by T1–T0 variance, we further tested whether associations existed between the follow-up SPQ score and behavioral and neural data at T0 and T1. We only found a correlation with the T1 SPQ score and the follow-up SPQ score (r = 0.91, p < 0.001). In conclusion, the present findings show strong negative correlations between phobia severity at the 8-year follow-up and changes (T1–T0) in anterior insula activation and fear scores. Recently, it has been argued that symptom reduction directly following exposure therapy for phobia is only weakly predictive of treatment outcome [3] . The present findings, however, point to the usefulness of assessing fear levels in the evaluation of the therapy effect when not measured immediately after therapy, but after allowing time for consolidation of learning. The demonstrated association between the extent of insular activity reduction and better clinical outcome at 8 years of followEven the most effective psychological treatments, such as cognitive behavioral therapy, show high percentages of relapse in the long term [1] . Predicting the persistence of therapy effects remains a major unanswered question, which is complicated by psychiatric comorbidity and by limited insight into the effectiveness of different therapy components applied during cognitive behavioral therapy. Neuroimaging offers the possibility of objective measures for predicting long-term therapy success and to elucidate its mechanisms. A first step to disentangle the problem of predicting therapy persistence is to (1) investigate a phenotypically clear disorder like specific phobia and (2) choose one cognitive behavioral therapy component targeting a single therapeutic mechanism such as exposure therapy, the clinical application of extinction learning [1] . Here, we link behavioral and neural changes following exposure therapy for specific phobia with behavioral measures at 8-year follow-up, to investigate which outcome measures of short-term therapeutic assessment are associated with long-term persistence of therapeutic response. Sixteen right-handed, unmedicated female spider phobic subjects received one prolonged (3–5 h) session of group-based exposure therapy. The diagnosis of specific phobia was made by an experienced psychiatrist (K.S.) based on DSM-IV criteria. Any further psychopathology was excluded by means of a structured psychiatric interview. Subjects were scanned twice, 1 week before (T0) and 2 weeks after therapy (T1), while undergoing a symptom provocation functional magnetic resonance imaging (fMRI) paradigm. Behavioral ratings at T0 and T1 consisted of phobia severity (Spider Phobia Questionnaire, SPQ) and fear/arousal for spiders [2] . At 8 years of follow-up, 15 subjects agreed to participate in the follow-up study and rated phobia severity on the SPQ again. The Received: July 23, 2015 Accepted after revision: November 6, 2015 Published online: May 27, 2016