Translational approach to study flexibility as an endophenotype of obsessive compulsive disorders

2014 ◽  
Vol 29 (S3) ◽  
pp. 546-546
Author(s):  
N. Benzina ◽  
S.L. Mondragon ◽  
N. Ouarti ◽  
L. Mallet ◽  
E. Burguiere
Keyword(s):  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Repetitive Behaviors ◽  
Reward Contingency ◽  
Neural Basis ◽  
Obsessive Compulsive ◽  
Compulsive Behaviors ◽  
Translational Approach ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Behavioral flexibility is the ability of a subject to change its behavior according to contextual cues. In humans, Obsessive Compulsive Disorders (OCD) is characterized by repetitive behavior, performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients may have diminished behavioral flexibility. To address this question we developed innovative translational approaches across multiple species, including human patients suffering from obsessive-compulsive disorders, and rodent genetic models of OCD to provide original data in the perspective of enlightening the neurocognitive bases of compulsive behaviors. Behavioral flexibility may be challenged in experimental tasks such as reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. After this first association has been learned, reward contingency are inverted, so that the previously neutral stimulus is now rewarded, while the previously rewarded stimulus is not. Performance in reversal learning is indexed by the number of perseverative errors committed when participants maintain their response towards previously reinforced stimulus in spite of negative reward. Unsurprisingly, this behavioral task has been adapted to mice using various response modalities (T-maze, lever press, nose-poke). Using animal models of compulsive behaviors give much more possibilities to study the deficient functions and their underlying neural basis that could lead to pathological repetitive behaviors. Here we present new behavioral set-ups that we developed in parallel in human (i.e. healthy subjects and OCD patients) and mice (i.e. controls and SAPAP3-KO mice) to study the role of the behavioral flexibility as a possible endophenotype of OCD. We observed that the subjects suffering of compulsive behaviors showed perseverative maladaptive behaviors in these tasks. By comparing the results of a similar task-design in humans and mouse models we will discuss the pertinence of such translational approach to further study the neurocognitive basis of compulsive behaviors.

scholarly journals A cross-species assessment of behavioral flexibility in compulsive disorders

2019 ◽  
Author(s):  
Nabil Benzina ◽  
Karim N’Diaye ◽  
Antoine Pelissolo ◽  
Luc Mallet ◽  
Eric Burguière
Keyword(s):  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Common Symptom ◽  
Obsessive Compulsive ◽  
Homogeneous Groups ◽  
Impaired Performance ◽  
Compulsive Disorder ◽  
Compulsive Behaviors

ABSTRACTBackgroundCompulsive behaviors, one of the core symptoms of Obsessive-Compulsive Disorder (OCD), are defined as repetitive behaviors performed through rigid rituals. The lack of behavioral flexibility has been as being one of the primary causes of compulsions, but studies exploring this dimension have shown inconsistencies in different tasks performed in human and animal models of compulsive behavior. The aim of this study was so to assess the involvement of behavioral flexibility in compulsion, with a similar approach across different species sharing a common symptom of compulsivity.Methods40 OCD patients, 40 healthy individually matched control subjects, 26 C57BL/6J Sapap3 KO mice and 26 matched wildtype littermates were included in this study. A similar reversal learning task was designed to assess behavioral flexibility in parallel in these two species.ResultsWhen considered as homogeneous groups, OCD patients and KO mice expressing compulsive behaviors did not significantly differ from their controls regarding behavioral flexibility. When clinical subtypes were considered, only patients exhibiting checking compulsions were impaired with more trials needed to reach the reversal criterion. In KO mice, a similarly impaired subgroup was identified. For both species, this impairment did not result in a greater perseveration after reversal, but in a greater lability in their responses in the reversal condition. Moreover, this impairment did not correlate with the severity of compulsive behaviors.ConclusionsIn our cross-species study, we found no consistent link between compulsive behaviors and a lack of behavioral flexibility. However, we showed in both species that the compulsive group was heterogeneous in term of performance in our reversal learning task. Among the compulsive subjects, we identified a subgroup with impaired performance not due to perseverative and rigid behaviors as commonly hypothesized, but rather to an increase in response lability.

scholarly journals A cross-species assessment of behavioral flexibility in compulsive disorders

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nabil Benzina ◽  
Karim N’Diaye ◽  
Antoine Pelissolo ◽  
Luc Mallet ◽  
Eric Burguière
Keyword(s):  
Reversal Learning ◽  
Cognitive Deficits ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Common Symptom ◽  
Distinct Subgroup ◽  
Compulsive Behaviors ◽  
Compulsive Disorders

AbstractLack of behavioral flexibility has been proposed as one underlying cause of compulsions, defined as repetitive behaviors performed through rigid rituals. However, experimental evidence has proven inconsistent across human and animal models of compulsive-like behavior. In the present study, applying a similarly-designed reversal learning task in two different species, which share a common symptom of compulsivity (human OCD patients and Sapap3 KO mice), we found no consistent link between compulsive behaviors and lack of behavioral flexibility. However, we showed that a distinct subgroup of compulsive individuals of both species exhibit a behavioral flexibility deficit in reversal learning. This deficit was not due to perseverative, rigid behaviors as commonly hypothesized, but rather due to an increase in response lability. These cross-species results highlight the necessity to consider the heterogeneity of cognitive deficits in compulsive disorders and call for reconsidering the role of behavioral flexibility in the aetiology of compulsive behaviors.

Compulsivity and probabilistic reversal learning in OCD and cocaine addiction

2015 ◽  
Vol 30 (S2) ◽  
pp. S110-S111 ◽  
Author(s):  
P. Smith ◽  
N. Benzina ◽  
F. Vorspan ◽  
L. Mallet ◽  
K. N’Diaye
Keyword(s):  
Reversal Learning ◽  
A Priori ◽  
Behavioral Flexibility ◽  
Learning Task ◽  
Repetitive Behaviors ◽  
Cocaine Addiction ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Cocaine Users ◽  
Probabilistic Reversal Learning

Compulsive behavior is a core symptom of both obsessive compulsive disorder (OCD) and cocaine addiction (CA). Across both pathologies, one can identify a priori goal-directed actions (purportedly anxiolytic checking or washing in OCD and pleasure-seeking drug use in addiction) that turn into rigid, ritualized and repetitive behaviors over which the patient loose control. One possible psychopathological mechanism underlying compulsivity is behavioral inflexibility, namely a deficit in the aptitude to dynamically adapt to novel contexts and changing reward rules. The probabilistic reversal learning paradigm allows to objectively assess behavioral flexibility by challenging participants with a task where they have to learn through trials-and-errors which of two stimuli is the most-often rewarded one, while adjusting to sudden inconspicuous contingency reversals. We therefore hypothesized that both OCD and CA would be associated with impaired cognitive flexibility, as measured through perseverative response rate following contingency reversals in this task. Interestingly, impulsivity may also be assessed within this task via the tendency of participants to switch from one stimulus to the other following probabilistic errors. To investigate cognitive inflexibility in relation to CA and OCD respectively, we first compared the performance in a probabilistic reversal learning task of cocaine users, ex cocaine users (abstinent for 2 months or more), and controls, as well as that of participants from the general population whose obsessive-compulsive traits were assessed using the OCI-R, a well-validated self-questionnaire. Our task yielded results similar to those found in the literature: cocaine addicts changed their responses more often, and learned less effectively. Ex-cocaine addicts performed better than addicts but worse than controls, suggesting that addicts’ poor results may be in part explained by reversible cognitive consequences of addiction. Addicts with less cognitive impairments may also be less likely to relapse. Regarding the relationship of flexibility to subclinical OCD traits, we found no link between OCI-R score and perseveration, or between impulsiveness and excessive switching.

Is There a Distinct OCD Spectrum?

CNS Spectrums ◽  
1996 ◽  
Vol 1 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Eric Hollander ◽  
Stephanie D. Benzaquen
Keyword(s):  
Biological Markers ◽  
Repetitive Behaviors ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Dimensional Classification ◽  
Important Approach ◽  
Wide Group ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

The obsessive-compulsive disorders spectrum concept has grown in recent years because of the common clinical features, such as obsessive thinking and compulsive rituals, biological markers, presumed etiology, and treatment response, that these disorders may share with obsessive-compulsive disorder (OCD). This concept has important implications in regard to diagnosis, nosology, neurobiology, and treatment of a wide group of diverse disorders affecting up to 10% of the population. New insights in central nervous system (CNS) mechanisms that drive the repetitive behaviors of the obsessive-compulsive spectrum disorders have heightened interest in the spectrum in researchers, clinicians, and those involved in drug development.An important approach in neuropsychiatry centers on employing a dimensional classification of psychopathology. Psychiatric phenomena often fall on a continuum. A dimensional approach allows for the classification of patients who fall at the border of classical entities or who are otherwise atypical. Diagnostic categories are considered along a spectrum if there is considerable overlap in symptoms and in etiology, as demonstrated by familial linkage biological markers, and pharmacological dissection. Categorical and dimensional approaches to the OCD spectrum could have significant implications for diagnosis, nosology, neurobiology, and treatment of a wide group of disorders affecting a sizable percentage of the population.Recent interest has focused on spectrums in movement disorders, affective disorders, schizophrenia, epileptic and impulsive disorders, and obsessive-compulsive disorders (which we will examine here); in addition, there has been interest in the overlap between these spectrums. Viewing disorders in terms of overlapping spectrums provides researchers and clinicians a framework with which to better understand and treat these disorders.

scholarly journals Duplex optogenetic stimulation system modulates compulsive behaviors bidirectionally

2021 ◽  
Vol 2 (3) ◽  
Author(s):  
Edenia Menezes ◽  
◽  
David Ashurov ◽  
Catarina Sousa Cunha ◽  
◽  
...  
Keyword(s):  
Mental Illnesses ◽  
Projection Neurons ◽  
Spine Density ◽  
Indirect Pathway ◽  
Obsessive Compulsive ◽  
Optogenetic Stimulation ◽  
Compulsive Behaviors ◽  
Stimulation System ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Decisions enable us to consider our actions while adjusting behaviors to a relentlessly changing environment. Since conscious decision making requires our full attention and is therefore expensive, we use a cheaper system for everyday and repetitive tasks that run automatically without conscious evaluations, commonly described as habits. The combination of these two systems is highly adaptive. However, if there is a disruption in these systems’ balance, mental illnesses such as Obsessive-Compulsive Disorders (OCD) or addiction may arise. Now, how does a newly acquired memory or behavior transition to a habit? We know that the striatum’s dorsolateral region (DLS) plays a significant role in sustaining successful behaviors and habits manifestation. Furthermore, it has been shown that the micro-circuitry of the DLS is organized into two functional opposing pathways that consist of the direct pathway striatal spiny projection neurons (dSPNs), which facilitate movement, and the indirect pathway SPNs, which inhibit actions. Already Freud wrote in the letters to his friend Fliess that memory and motive are inseparable, and its recollection would have no force or meaning unless it would be coupled to a motive or emotion. Therefore, we hypothesize that emotional-associated cues would directly prime the DLS through the amygdala to turn newly acquired behaviors into habits. We are adding new supporting insight for this hypothesis by using a duplex optogenetic stimulation system of the amygdala input in the DLS, modulating specific compulsive behaviors bidirectionally. These behavior modulations were accompanied by spine density modulations and intrinsic excitability changes in the SPNs of the DLS. Keywords: Compulsions; Habits; Optogenetics; Neuromodulation; Dorsolateral striatum; Amygdala.

Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

2019 ◽  
Author(s):  
German I. Todorov ◽  
Karthikeyan Mayilvahanan ◽  
David Ashurov ◽  
Catarina Cunha
Keyword(s):  
Mouse Model ◽  
Autism Spectrum ◽  
Obsessive Compulsive ◽  
Cancer Treatments ◽  
Knock Out ◽  
Treatment Priority ◽  
Underlying Mechanisms ◽  
Knock Out Mice ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions.

The Use of Quetiapine for Comorbid Bipolar and Obsessive Compulsive Disorders

2016 ◽  
Vol 4 (2) ◽  
pp. 103-111
Author(s):  
María Yoldi-Negrete ◽  
Mónica Flores-Ramos ◽  
Alejandra Montserrat Rodríguez-Ramírez ◽  
Carvajal-Lohr Armando ◽  
Jorge Ávila-Solorio ◽  
...  
Keyword(s):  
Obsessive Compulsive ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders
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