Annemieke M. Apergis-Schoute

Enhanced Avoidance Habits in Obsessive-Compulsive Disorder

Background Obsessive-compulsive disorder (OCD) is a psychiatric condition that typically manifests in compulsive urges to perform irrational or excessive avoidance behaviors. A recent account has suggested that compulsivity in OCD might arise from excessive stimulus-response habit formation, rendering behavior insensitive to goal value. We tested if OCD patients have a bias toward habits using a novel shock avoidance task. To explore how habits, as a putative model of compulsivity, might relate to obsessions and anxiety, we recorded measures of contingency knowledge, explicit fear, and physiological arousal. Methods Twenty-five OCD patients and 25 control subjects completed a shock avoidance task designed to induce habits through overtraining, which were identified using goal-devaluation. The relationship between habitual behavior, erroneous cognitions, and physiological arousal was assessed using behavior, questionnaires, subjective report, and skin conductance responses. Results A devaluation sensitivity test revealed that both groups could inhibit unnecessary behavioral responses before overtraining. Following overtraining, OCD patients showed greater avoidance habits than control subjects. Groups did not differ in conditioned arousal (skin conductance responses) at any stage. Additionally, groups did not differ in contingency knowledge or explicit ratings of shock expectancy following the habit test. Habit responses were associated with a subjective urge to respond. Conclusions These data indicate that OCD patients have a tendency to develop excessive avoidance habits, providing support for a habit account of OCD. Future research is needed to fully characterize the causal role of physiological arousal and explicit fear in habit formation in OCD.

Effects of acute tryptophan depletion on prefrontal-amygdala connectivity while viewing facial signals of aggression.

Background Reduced levels of serotonin (5-HT) within prefrontal cortex (PFC)–amygdala circuits have long been implicated in impulsive aggression. However, whether lowering 5-HT alters the dynamic interplay between the PFC and the amygdala has not been directly tested in humans. It is known that manipulating 5-HT via acute tryptophan depletion (ATD) causes variable effects on brain responses to a variety of emotional stimuli, but it remains unclear whether ATD affects functional connectivity in neural networks involved in processing social signals of aggression (e.g., angry faces). Methods Thirty healthy individuals were enrolled in a randomized, double-blind, placebo-controlled ATD study. On each treatment, brain responses to angry, sad, and neutral faces were measured with functional magnetic resonance imaging. Two methods (psycho-physiological-interaction in a general linear model and dynamic causal modeling) were used to assess the impact of ATD on the functional connectivity between PFC and amygdala. Results Data from 19 subjects were available for the final analyses. A whole-brain psycho-physiological-interaction in a general linear model showed that ATD significantly modulated the connectivity between the amygdala and two PFC regions (ventral anterior cingulate cortex and ventrolateral PFC) when processing angry vs. neutral and angry vs. sad but not sad vs. neutral faces. Dynamic causal modeling corroborated and extended these findings by showing that 5-HT depletion reduced the influence of processing angry vs. neutral faces on circuits within PFC and on PFC–amygdala pathways. Conclusions We provide strong support for neurobiological accounts positing that 5-HT significantly influences PFC–amygdala circuits implicated in aggression and other affective behaviors.

Auditory Fear Conditioning and Long-Term Potentiation in the Lateral Amygdala Require ERK/MAP Kinase Signaling in the Auditory Thalamus: A Role for Presynaptic Plasticity in the Fear System

In the present study, we examined the role of the auditory thalamus [medial division of the medial geniculate nucleus and the adjacent posterior intralaminar nucleus (MGm/PIN)] in auditory pavlovian fear conditioning using pharmacological manipulation of intracellular signaling pathways. In the first experiment, rats were given intrathalamic infusions of the MEK (mitogen-activated protein kinase-kinase) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene (U0126) before fear conditioning. Findings revealed that long-term memory (assessed at 24 h) was impaired, whereas short-term memory (assessed at 1-3 h) of fear conditioning was intact. In the second experiment, rats received immediate posttraining intrathalamic infusion of U0126, the mRNA synthesis inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB), or infusion of the protein synthesis inhibitor anisomycin. Posttraining infusion of either U0126 or DRB significantly impaired long-term retention of fear conditioning, whereas infusion of anisomycin had no effect. In the final experiment, rats received intrathalamic infusion of U0126 before long-term potentiation (LTP)-inducing stimulation of thalamic inputs to the lateral nucleus of the amygdala (LA). Findings revealed that thalamic infusion of U0126 impaired LTP in the LA. Together, these results suggest the possibility that MGm/PIN cells that project to the LA contribute to memory formation via ERK (extracellular signal-regulated kinase)-mediated transcription, but that they do so by promoting protein synthesis-dependent plasticity locally in the LA.

Serotonin modulates striatal responses to fairness and retaliation in humans

Humans are willing to incur personal costs to punish others who violate social norms. Such “costly punishment” is an important force for sustaining human cooperation, but the causal neurobiological determinants of punishment decisions remain unclear. Using a combination of behavioral, pharmacological, and neuroimaging techniques, we show that manipulating the serotonin system in humans alters costly punishment decisions by modulating responses to fairness and retaliation in the striatum. Following dietary depletion of the serotonin precursor tryptophan, participants were more likely to punish those who treated them unfairly, and were slower to accept fair exchanges. Neuroimaging data revealed activations in the ventral and dorsal striatum that were associated with fairness and punishment, respectively. Depletion simultaneously reduced ventral striatal responses to fairness and increased dorsal striatal responses during punishment, an effect that predicted its influence on punishment behavior. Finally, we provide behavioral evidence that serotonin modulates specific retaliation, rather than general norm enforcement: depleted participants were more likely to punish unfair behavior directed toward themselves, but not unfair behavior directed toward others. Our findings demonstrate that serotonin modulates social value processing in the striatum, producing context-dependent effects on social behavior.

Functional Neuroimaging of Avoidance Habits in Obsessive-Compulsive Disorder

OBJECTIVE The purpose of this study was to determine the neural correlates of excessive habit formation in obsessive-compulsive disorder (OCD). The authors aimed to test for neurobiological convergence with the known pathophysiology of OCD and to infer, based on abnormalities in brain activation, whether these habits arise from dysfunction in the goal-directed or habit system. METHOD Thirty-seven OCD patients and 33 healthy comparison subjects learned to avoid shocks while undergoing a functional MRI scan. Following four blocks of training, the authors tested whether the avoidance response had become a habit by removing the threat of shock and measuring continued avoidance. Task-related differences in brain activity in three regions of interest (the caudate, the putamen, and the medial orbitofrontal cortex) were tested at a statistical threshold set at <0.05 (family-wise-error corrected). RESULTS Excessive habit formation in OCD patients, which was associated with hyperactivation in the caudate, was observed. Activation in this region was also associated with subjective ratings of increased urge to perform habits. The OCD group, as a whole, showed hyperactivation in the medial orbitofrontal cortex during the acquisition of avoidance; however, this did not relate directly to habit formation. CONCLUSIONS OCD patients exhibited excessive habits that were associated with hyperactivation in a key region implicated in the pathophysiology of OCD, the caudate nucleus. Previous studies indicate that this region is important for goal-directed behavior, suggesting that habit-forming biases in OCD may be a result of impairments in this system, rather than differences in the buildup of stimulus-response habits themselves.

Serotonin Modulates the Effects of Pavlovian Aversive Predictions on Response Vigor

Updated theoretical accounts of the role of serotonin (5-HT) in motivation propose that 5-HT operates at the intersection of aversion and inhibition, promoting withdrawal in the face of aversive predictions. However, the specific cognitive mechanisms through which 5-HT modulates withdrawal behavior remain poorly understood. Behavioral inhibition in response to punishments reflects at least two concurrent processes: instrumental aversive predictions linking stimuli, responses, and punishments, and Pavlovian aversive predictions linking stimuli and punishments irrespective of response. In the current study, we examined to what extent 5-HT modulates the impact of instrumental vs Pavlovian aversive predictions on behavioral inhibition. We used acute tryptophan depletion to lower central 5-HT levels in healthy volunteers, and observed behavior in a novel task designed to measure the influence of Pavlovian and instrumental aversive predictions on choice (response bias) and response vigor (response latencies). After placebo treatment, participants were biased against responding on the button that led to punishment, and they were slower to respond in a punished context, relative to a non-punished context. Specifically, participants slowed their responses in the presence of stimuli predictive of punishments. Tryptophan depletion removed the bias against responding on the punished button, and abolished slowing in the presence of punished stimuli, irrespective of response. We suggest that this set of results can be explained by a role for 5-HT in Pavlovian aversive predictions. These findings suggest additional specificity for the influence of 5-HT on aversively motivated behavioral inhibition and extend recent models of the role of 5-HT in aversive predictions.

Converging evidence for central 5-HT effects in acute tryptophan depletion.

Acute tryptophan depletion (ATD), a dietary technique for manipulating brain serotonin (5-HT) function, has advanced our understanding of 5-HT mechanisms in the etiology and treatment of depression and other affective disorders.1 A recent review article in Molecular Psychiatry questioned the validity of ATD.2 Although we agree that ATDs effects on 5-HT activity at the molecular level need further clarification, van Donkelaar et al.2 goes too far in challenging whether ATD exerts its effects through serotonergic mechanisms. There is strong evidence that ATD reduces brain 5-HT and disrupts stimulated 5-HT release,3, 4 and converging translational findings support a central role for brain 5-HT in ATDs effects on cognition and behavior.

Specific Frontostriatal Circuits for Impaired Cognitive Flexibility and Goal-Directed Planning in Obsessive-Compulsive Disorder: Evidence From Resting-State Functional Connectivity

Background A recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity. Methods Multiecho resting-state acquisition, combined with micromovement correction by blood oxygen level–dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects. We measured cognitive flexibility (attentional set-shifting) and goal-directed performance (planning of sequential response sequences) by means of well-validated, standardized behavioral cognitive paradigms. Functional connectivity strength of striatal seed regions was related to cognitive flexibility and goal-directed performance. To gain insights into fundamental network alterations, graph theoretical models of brain networks were derived. Results Reduced functional connectivity between the caudate and the ventrolateral prefrontal cortex was selectively associated with reduced cognitive flexibility. In contrast, goal-directed performance was selectively related to reduced functional connectivity between the putamen and the dorsolateral prefrontal cortex in OCD patients, as well as to symptom severity. Whole-brain data-driven graph theoretical analysis disclosed that striatal regions constitute a cohesive module of the community structure of the functional connectome in OCD patients as nodes within the basal ganglia and cerebellum were more strongly connected to one another than in healthy control subjects. Conclusions These data extend major neuropsychological models of OCD by providing a direct link between intrinsically abnormal functional connectivity within dissociable frontostriatal circuits and those cognitive processes underlying OCD symptoms.

What are the Odds? The Neural Correlates of Active Choice during Gambling

Gambling is a widespread recreational activity and requires pitting the values of potential wins and losses against their probability of occurrence. Neuropsychological research showed that betting behavior on laboratory gambling tasks is highly sensitive to focal lesions to the ventromedial prefrontal cortex (vmPFC) and insula. In the current study, we assessed the neural basis of betting choices in healthy participants, using functional magnetic resonance imaging of the Roulette Betting Task. In half of the trials, participants actively chose their bets; in the other half, the computer dictated the bet size. Our results highlight the impact of volitional choice upon gambling-related brain activity: Neural activity in a distributed network – including key structures of the reward circuitry (midbrain, striatum) – was higher during active compared to computer-dictated bet selection. In line with neuropsychological data, the anterior insula and vmPFC were more activated during self-directed bet selection, and responses in these areas were differentially modulated by the odds of winning in the two choice conditions. In addition, responses in the vmPFC and ventral striatum were modulated by the bet size. Convergent with electrophysiological research in macaques, our results further implicate the inferior parietal cortex (IPC) in the processing of the likelihood of potential outcomes: Neural responses in the IPC bilaterally reflected the probability of winning during bet selection. Moreover, the IPC was particularly sensitive to the odds of winning in the active-choice condition, when the processing of this information was required to guide bet selection. Our results indicate an important role of the IPC in human decision-making under risk and help to integrate neuropsychological data of risk-taking following vmPFC and insula damage with models of choice derived from human neuroimaging and monkey electrophysiology.

Aberrant Disgust Responses and Immune Reactivity in Cocaine-Dependent Men

Background Infectious diseases are the most common and cost-intensive health complications associated with drug addiction. There is wide belief that drug-dependent individuals expose themselves more regularly to disease-related pathogens through risky behaviors such as sharing pipes and needles, thereby increasing their risk for contracting an infectious disease. However, evidence is emerging indicating that not only lifestyle but also the immunomodulatory effects of addictive drugs, such as cocaine, may account for their high infection risk. As feelings of disgust are thought to be an important psychological mechanism in avoiding the exposure to pathogens, we sought to investigate behavioral, physiological, and immune responses to disgust-evoking cues in both cocaine-dependent and healthy men. Methods All participants (N = 61) were exposed to neutral and disgust-evoking photographs depicting food and nonfood images while response accuracy, latency, and skin conductivity were recorded. Saliva samples were collected before and after exposure to neutral and disgusting images, respectively. Attitudes toward disgust and hygiene behaviors were assessed using questionnaire measures. Results Response times to disgust-evoking photographs were prolonged in all participants, and specifically in cocaine-dependent individuals. While viewing the disgusting images, cocaine-dependent individuals exhibited aberrant skin conductivity and increased the secretion of the salivary cytokine interleukin-6 relative to control participants. Conclusion Our data provide evidence of a hypersensitivity to disgusting stimuli in cocaine-dependent individuals, possibly reflecting conditioned responses to noningestive sources of infection. Coupled with a lack of interoception of bodily signals, aberrant disgust responses might lead to increased infection susceptibility in affected individuals.