Biology subjects

Denys, D.

Publications and source records attributed to Denys, D..

11 recordsLinked to original sources

bioRxiv2024

Rescuing behavioral flexibility in a mouse model for OCD by enhancing reward-cue salience

Deficits in cognitive flexibility are a frequent symptom of obsessive-compulsive disorder (OCD) and have been hypothesized to underlie compulsive behavior. Sign- and goal-tracking behaviors are thought to be related to cognitive flexibility, yet have not been studied in this context. To investigate the relationship between sign- and goal-tracking behavior and cognitive flexibility, we tested SAPAP3 knockout mice (SAPAP3-/-) and wild-type littermate controls in a Pavlovian reversal-learning task with two conditioned stimuli, one predicting reward delivery and the other reward omission. SAPAP3-/- displayed a heterogenous reversal-learning performance: Half of the population failed to acquire the reversed cue-reward contingencies, whereas the other half reversed their approach behavior similar to control mice. Surprisingly, such behavioral inflexibility and compulsive-like grooming were unrelated, suggesting a non-causal relationship between these traits. Importantly, compromised reversal learning in impaired mice was associated with diminished sign-tracking behavior (and therefore presumably with an overreliance on goal-tracking behavior). Administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the first-line pharmacological OCD treatment, ameliorated both anxiety-like behavior and compulsive-like grooming, but did not improve behavioral flexibility in SAPAP3-/-. In contrast, enhancing reward-cue salience by altering conditioned stimuli brightness improved behavioral flexibility through augmenting sign-tracking behavior. These findings suggest that deficits in behavioral flexibility are associated with imbalanced sign- and goal-tracking behaviors in SAPAP3-/-, and enhancing reward-cue salience can rescue behavioral flexibility by restoring the balance. Thus, sign- and goal-tracking behavior might be an underexplored cognitive mechanism that could potentially be exploited to improve cognitive flexibility in OCD patients.

neuroscience↗

bioRxiv2022

Unraveling the therapeutic mechanism of deep-brain stimulation

Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while compulsive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

neuroscience↗

bioRxiv2022

Conscious perception and the role of the basal ganglia: preliminary findings from a deep brain stimulation study

Conscious perception is thought to depend on global amplification of sensory input. In recent years, the basal ganglia have been implicated in gating conscious access due to their consistent involvement in thalamocortical loops. However, much of the evidence implicating the basal ganglia in these processes in humans is correlational. The current study is a preliminary investigation in four patients to explore whether deep brain stimulation (DBS) in the basal ganglia might improve conscious perception. In our study, treatment-resistant obsessive-compulsive disorder (OCD) patients with a striatal DBS implant completed two canonical conscious perception tasks: emotion-induced blindness and backward masking. We found preliminary evidence in support of a role played by the basal ganglia in conscious perception at the behavioral level: patients performed better when stimulation was active, but we could not establish neural effects corresponding to these behavioral findings, possibly due to our small sample size. We discuss the potential implications and limitations of our study and delineate avenues for future research.

neuroscience↗

bioRxiv2021

Metacognition and the effect of incentive motivation in two compulsive disorders: gambling disorder and obsessive-compulsive disorder

Compulsivity is a common phenotype amongst various psychiatric disorders, such as obsessive-compulsive disorder (OCD) and gambling disorder (GD). Deficiencies in metacognition, such as the inability to properly estimate ones own performance via well-calibrated confidence judgments could contribute to pathological decision-making in these psychiatric disorders. Earlier research has indeed suggested that OCD and GD patients reside at opposite ends of the confidence spectrum, with OCD patients exhibiting underconfidence, and GD patients exhibiting overconfidence. Recently, several studies established that motivational states (e.g. monetary incentives) influence metacognition, with gain (respectively loss) prospects increasing (respectively decreasing) confidence judgments. Here, we reasoned that the OCD and GD symptomatology might correspond to an exacerbation of this interaction between metacognition and motivational states. We hypothesized GDs overconfidence to be exaggerated during gain prospects, while OCDs underconfidence to be worsened in loss context, which we expected to see represented in ventromedial prefrontal cortex (VMPFC) blood-oxygen-level-dependent (BOLD) activity. We tested those hypotheses in a task-based functional magnetic resonance imaging (fMRI) design. Our initial analyses showed increased confidence levels for GD versus OCD patients, that could partly be explained by sex and IQ. Although our primary analyses did not support the hypothesized interaction between incentives and groups, exploratory analyses did show increased confidence in GD patients specifically in gain context. fMRI analyses confirmed a central role for VMPFC in the processing of confidence and incentives, but with no differences between the clinical samples. The trial is registered in the Dutch Trial Register (Trial NL6171, registration number: NTR6318) (https://www.trialregister.nl/trial/6171).

neuroscience↗

bioRxiv2020

How motivational signals disrupt metacognitive signals in the human VMPFC.

A growing body of evidence suggests that, during decision-making, BOLD signal in the VMPFC correlates both with motivational variables - such as incentives and expected values - and metacognitive variables - such as confidence judgments, which reflect the subjective probability of being correct. At the behavioral level, we recently demonstrated that the value of monetary stakes bias confidence judgments, with gain (respectively loss) prospects increasing (respectively decreasing) confidence judgments, even for similar levels of difficulty and performance. If and how this value-confidence interaction is also reflected in VMPFC signals remains unknown. Here, we used an incentivized perceptual decision-making task that dissociates key decision-making variables, thereby allowing to test several hypotheses about the role of the VMPFC in the incentive-confidence interaction. While initial analyses seemingly indicate that VMPFC combines incentives and confidence to form an expected value signal, we falsified this conclusion with a meticulous dissection of qualitative activation patterns. Rather, our results show that strong VMPFC confidence signals observed in trials with gain prospects are disrupted in trials with no - or negative (loss) monetary prospects. Deciphering how decision variables are represented and interact at finer scales (population codes, individual neurons) seems necessary to better understand biased (meta)cognition.

neuroscience↗

bioRxiv2019

Deep brain stimulation modulates directional frontolimbic connectivity in obsessive-compulsive disorder

Deep brain stimulation (DBS) is effective for patients with treatment-refractory obsessive-compulsive disorder. DBS of the ventral anterior limb of the internal capsule (vALIC) rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects of vALIC-DBS, we studied functional interactions within the affective amygdala circuit. We compared resting state functional magnetic resonance imaging data during chronic stimulation versus one week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test-retest effects. Imaging data were analyzed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following DBS was associated with reduced amygdala-insula functional connectivity. Directional connectivity analysis revealed that DBS increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of OCD, and suggest a neural systems model through which negative mood and anxiety are modulated by vALIC-DBS for OCD and possibly other psychiatric disorders.\n\nOne Sentence SummaryDeep brain stimulation improves mood and anxiety in obsessive-compulsive disorder by altering connectivity between the amygdala, insula and prefrontal cortex.

neuroscience↗

bioRxiv2019

Genetic meta-analysis of obsessive-compulsive disorder and self-report compulsive symptoms.

We investigated whether obsessive compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing OCD. We performed a GWAS on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N=8267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case-control GWAS (rG=0.61, p=0.017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (rG=-0.02 and rG=0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant SNPs (combined N=17992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, inclusion of dimensional symptom data in genome-wide association on clinical case-control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene-expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.

genetics↗

bioRxiv2019

The effect of acute stress on the balance between goal-directed and habit networks in obsessive-compulsive disorder.

The classical cognitive-behavioral theory of obsessive-compulsive disorder (OCD) holds that compulsions are performed to reduce distress that is evoked by obsessions, whereas a recent neuroscience-inspired theory suggests that compulsivity results from a disbalance between goal-directed and habit-related neural networks. To bridge these theories, we investigated whether the balance between goal-directed and habit networks in patients with OCD was affected in the late aftermath of stress. Twenty-three OCD patients and twenty-three healthy controls participated in a controlled stress induction paradigm using the socially evaluated cold-pressor test in a crossover design. Stress responses were evaluated through cortisol levels, blood pressure, and anxiety ratings. Functional connectivity of the caudate nucleus and posterior putamen was assessed using seed region analysis of resting-state functional magnetic resonance imaging data, which are hubs of the goal-directed and habit network, respectively. Stress induction increased blood pressure and psychological stress measures across groups and resulted in blunted cortisol responses in patients. Furthermore, patients showed a blunted reduction in connectivity between the caudate nucleus and precuneus in the aftermath of stress, which was positively correlated with compulsivity but not obsession severity. The posterior putamen showed no significant group differences in stress-induced connectivity. These results suggest that compulsivity in OCD in the aftermath of stress is associated with altered connectivity between the goal-directed and default mode networks.

neuroscience↗

bioRxiv2018

Behavioral flexibility in an OCD mouse model: Impaired Pavlovian reversal learning in SAPAP3 mutants

Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior, and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3-/-) exhibit compulsive behavior (grooming), anxiety, and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3-/- display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3-/- and wild-type littermates (WT) were trained in a Pavlovian conditioning task pairing the delivery of visual cues with that of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS-), contingencies were reversed (CS+ became CS- and vice versa). Additionally, we assessed grooming, anxiety, and general activity. SAPAP3-/- acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3-/- were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming, and anxiety were unrelated. This study demonstrates that SAPAP3-/- are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3-/- do not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3-/- as a suitable model for OCD. The observation that compulsive-like behavior, anxiety, and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for OCD patients.

animal behavior and cognition↗

bioRxiv2017

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity

Oscillations in neuronal activity are widely thought to play a crucial role in information processing and cortical communication 1-8. Brain oscillations have been widely investigated as biomarkers of psychiatric disorders and variation in normal human behavior 9, 10, including intelligence 11, 12, schizophrenia 13, 14, attentional deficits 15, 16, and substance use 17, 18. Beyond the biomarker, oscillatory activity may indeed cause variation in behavior, as it has been shown that disrupting oscillatory activity by blocking GABAergic fast-spiking interneurons in the frontal cortex of mice impairs behavioral flexibility8, consistent with ...

genetics↗

bioRxiv2017

Two sides of the same coin: monetary incentives concurrently improve and bias confidence judgments.

Decisions are accompanied by a feeling of confidence, i.e., a belief about the decision being correct. Confidence accuracy is critical, notably in high-stakes situations such as medical or financial decisionmaking. Here, we investigated how incentive motivation influences confidence accuracy by combining a perceptual task with a confidence incentivization mechanism. Importantly, by varying the magnitude and valence (gains or losses) of monetary incentives, we orthogonalized their motivational and affective components. Corroborating theories of rational decision-making and motivation, our results first reveal that the motivational value of incentives improves aspects of confidence accuracy. However, in line with a value-confidence interaction hypothesis we further show that the affective value of incentives concurrently biases confidence reports, thus degrading confidence accuracy. Finally, we demonstrate that the motivational and affective effects of incentives differentially impact how confidence builds on perceptual evidence. Altogether, these findings may provide new hints about confidence miscalibration in healthy or pathological contexts.

animal behavior and cognition↗