Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

AbstractRationaleObsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated.ObjectiveTo determine the effects of genetic or pharmacological disruption of NE neurotransmission on marble burying (MB) and nestlet shredding (NS) in two animal models of OCD.MethodsWe assessed NE-deficient (Dbh -/-) mice and NE-competent (Dbh +/-) controls in MB and NS tasks. We also measured the effects of anti-adrenergic drugs on NS and MB in control mice and the effects of pharmacological restoration of central NE in Dbh -/- mice. Finally, we compared c-fos induction in the locus coeruleus (LC) and ACC of Dbh -/- and control mice following both tasks.ResultsDbh -/- mice virtually lacked MB and NS behaviors seen in control mice but did not differ in the elevated zero maze (EZM) model of general anxiety-like behavior. Pharmacological restoration of central NE synthesis in Dbh -/- mice completely rescued NS behavior, while NS and MB were suppressed in control mice by anti-adrenergic drugs. Expression of c-fos in the ACC was attenuated in Dbh -/- mice after MB and NS.ConclusionThese findings support a role for NE transmission to the ACC in the expression of stress-induced compulsive behaviors and suggest further evaluation of anti-adrenergic drugs for OCD is warranted.

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Spontaneously Occurring Animal Models of OCD

10.1093/med/9780190228163.003.0032 ◽

2017 ◽

Author(s):

Nicholas H. Dodman ◽

Louis Shuster

Keyword(s):

Animal Models ◽

Obsessive Compulsive Disorder ◽

Behavioral Disorders ◽

Human Disease ◽

Animal Species ◽

Repetitive Behavior ◽

Repetitive Behaviors ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Core Features

This chapter summarizes what we know about compulsive behavioral disorders in several animal species. Animals can develop repetitive behaviors in a range of circumstances, generally associated with anxiety or stress. It is increasingly apparent that these behaviors recapitulate core features of obsessive-compulsive disorder. They are clearly partially genetic; for example, specific breeds of dog are susceptible to specific compulsive behavioral disorders. Understanding such OCD-like behaviors provides a potentially fruitful avenue towards understanding OCD in humans. This chapter reviews this literature, emphasizing the points of parallelism between repetitive behavior syndromes in animals and human disease. Recent advances in our understanding of the biology of these spontaneously occurring animal models, especially in dogs, have great potential to elucidate the pathophysiology of OCD.

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Obsessive–Compulsive Disorder

Journal of Pharmacy Practice ◽

10.1177/0897190014521996 ◽

2014 ◽

Vol 27 (2) ◽

pp. 116-130 ◽

Cited By ~ 23

Author(s):

Gyula Bokor ◽

Peter D. Anderson

Keyword(s):

Obsessive Compulsive Disorder ◽

Selective Serotonin Reuptake Inhibitors ◽

Atypical Antipsychotics ◽

Package Insert ◽

Repetitive Behaviors ◽

Anterior Cingulate ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Mental Acts ◽

The Brain

Obsessive–compulsive disorder (OCD) is a common heterogeneous psychiatric disorder manifesting with obsessions and compulsions. Obsessions are intrusive, recurrent, and persistent unwanted thoughts. Compulsions are repetitive behaviors or mental acts that an individual feels driven to perform in response to the obsessions. The heterogeneity of OCD includes themes of obsessions, types of rituals, presence or absence of tics, etiology, genetics, and response to pharmacotherapy. Complications of OCD include interpersonal difficulties, unemployment, substance abuse, criminal justice issues, and physical injuries. Areas of the brain involved in the pathophysiology include the orbitofrontal cortex, anterior cingulate gyrus, and basal ganglia. Overall, OCD may be due to a malfunction in the cortico–striato–thalamo–cortical circuit in the brain. Neurotransmitters implicated in OCD include serotonin, dopamine, and glutamate. Numerous drugs such as atypical antipsychotics and dopaminergic agents can cause or exacerbate OCD symptoms. The etiology includes genetics and neurological insults. Treatment of OCD includes psychotherapy, pharmacotherapy, electroconvulsive therapy, transcranial magnetic simulation, and in extreme cases surgery. Exposure and response prevention is the most effective form of psychotherapy. Selective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacotherapy. Higher doses than listed in the package insert and a longer trial are often needed for SSRIs than compared to other psychiatric disorders. Alternatives to SSRIs include clomipramine and serotonin/norepinephrine reuptake inhibitors. Treatment of resistant cases includes augmentation with atypical antipsychotics, pindolol, buspirone, and glutamate-blocking agents.

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Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

Science ◽

10.1126/science.1234733 ◽

2013 ◽

Vol 340 (6137) ◽

pp. 1234-1239 ◽

Cited By ~ 271

Author(s):

Susanne E. Ahmari ◽

Timothy Spellman ◽

Neria L. Douglass ◽

Mazen A. Kheirbek ◽

H. Blair Simpson ◽

...

Keyword(s):

Obsessive Compulsive Disorder ◽

Orbitofrontal Cortex ◽

Progressive Increase ◽

Repetitive Behaviors ◽

Mouse Behavior ◽

First Line ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Chronic Fluoxetine

Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)–ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.

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Voxel-wise meta-analysis of grey matter changes in obsessive–compulsive disorder

The British Journal of Psychiatry ◽

10.1192/bjp.bp.108.055046 ◽

2009 ◽

Vol 195 (5) ◽

pp. 393-402 ◽

Cited By ~ 441

Author(s):

Joaquim Radua ◽

David Mataix-Cols

Keyword(s):

Obsessive Compulsive Disorder ◽

Grey Matter ◽

Antidepressant Treatment ◽

Meta Analysis ◽

Anterior Cingulate ◽

Control Group ◽

Grey Matter Volume ◽

Obsessive Compulsive ◽

Caudate Nuclei ◽

Compulsive Disorder

BackgroundSpecific cortico-striato-thalamic circuits are hypothesised to mediate the symptoms of obsessive–compulsive disorder (OCD), but structural neuroimaging studies have been inconsistent.AimsTo conduct a meta-analysis of published and unpublished voxel-based morphometry studies in OCD.MethodTwelve data-sets comprising 401 people with OCD and 376 healthy controls met inclusion criteria. A new improved voxel-based meta-analytic method, signed differential mapping (SDM), was developed to examine regions of increased and decreased grey matter volume in the OCD group v. control group.ResultsNo between-group differences were found in global grey matter volumes. People with OCD had increased regional grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, as well as decreased volumes in bilateral dorsal medial frontal/anterior cingulate gyri. A descriptive analysis of quartiles, a sensitivity analysis as well as analyses of subgroups further confirmed these findings. Meta-regression analyses showed that studies that included individuals with more severe OCD were significantly more likely to report increased grey matter volumes in the basal ganglia. No effect of current antidepressant treatment was observed.ConclusionsThe results support a dorsal prefrontal–striatal model of the disorder and raise the question of whether functional alterations in other brain regions commonly associated with OCD, such as the orbitofrontal cortex, may reflect secondary compensatory strategies. Whether the reported differences between participants with OCD and controls precede the onset of the symptoms and whether they are specific to OCD remains to be established.

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Improvements in error-monitoring and symptoms following low-frequency rTMS of dorsal anterior cingulate cortex in obsessive compulsive disorder; a randomized, sham-controlled study

Brain and Cognition ◽

10.1016/j.bandc.2021.105809 ◽

2021 ◽

Vol 154 ◽

pp. 105809

Author(s):

Benjamin P. Meek ◽

Aryandokht Fotros ◽

Mohamed Abo Aoun ◽

Mandana Modirrousta

Keyword(s):

Anterior Cingulate Cortex ◽

Obsessive Compulsive Disorder ◽

Low Frequency ◽

Anterior Cingulate ◽

Controlled Study ◽

Error Monitoring ◽

Obsessive Compulsive ◽

Dorsal Anterior Cingulate Cortex ◽

Compulsive Disorder ◽

Low Frequency Rtms

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Associations of Observed Performance Monitoring During Preschool With Obsessive-Compulsive Disorder and Anterior Cingulate Cortex Volume Over 12 Years

JAMA Psychiatry ◽

10.1001/jamapsychiatry.2018.1805 ◽

2018 ◽

Vol 75 (9) ◽

pp. 940 ◽

Cited By ~ 4

Author(s):

Kirsten E. Gilbert ◽

Margot E. Barclay ◽

Rebecca Tillman ◽

Deanna M. Barch ◽

Joan L. Luby

Keyword(s):

Anterior Cingulate Cortex ◽

Obsessive Compulsive Disorder ◽

Performance Monitoring ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Obsessive Compulsive ◽

Compulsive Disorder

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Toward a unified connectomic target for deep brain stimulation in obsessive-compulsive disorder

10.1101/608786 ◽

2019 ◽

Cited By ~ 2

Author(s):

Ningfei Li ◽

Juan Carlos Baldermann ◽

Astrid Kibleur ◽

Svenja Treu ◽

Harith Akram ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Clinical Improvement ◽

Obsessive Compulsive Disorder ◽

Brain Stimulation ◽

Internal Capsule ◽

Anterior Cingulate ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Fiber Tracts ◽

Deep Brain

AbstractMultiple surgical targets have been proposed for treating obsessive-compulsive disorder (OCD) with deep brain stimulation (DBS). However, different targets may modulate the same neural network responsible for clinical improvement. Here we analyzed data from four cohorts of OCD patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NAcc) or the subthalamic nucleus (STN). Fiber tracts that were predominantly connected to electrodes in good or poor DBS responders were isolated from a normative structural connectome and assigned a predictive value. Strikingly, the same fiber bundle was related to treatment response when independently analyzing two large training cohorts that targeted either ALIC or STN. This discriminative tract is a subsection of the ALIC and connects frontal regions (such as the dorsal anterior cingulate, dACC, and ventral prefrontal, vlPFC, cortices to the STN). When informing the tract solely based on one cohort (e.g. ALIC), clinical improvements in the other (e.g. STN) could be significantly predicted, and vice versa. Finally, clinical improvements of eight patients from a third center with electrodes in the NAcc and six patients from a fourth center in which electrodes had been implanted in both STN and ALIC were significantly predicted based on this novel tract-based DBS target. Results suggest a functional role of a limbic hyperdirect pathway that projects from dACC and vlPFC to anteriomedial STN. Obsessive-compulsive symptoms seem to be tractable by modulating the specific bundle isolated here. Our results show that connectivity-derived improvement models can inform clinical improvement across DBS targets, surgeons and centers. The identified tract is now three-dimensionally defined in stereotactic standard space and will be made openly available.

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Relapse of obsessive–compulsive disorder after cerebral venous sinus thrombosis: a case report

Neuropsychiatrie ◽

10.1007/s40211-019-00327-8 ◽

2019 ◽

Vol 34 (1) ◽

pp. 27-29

Author(s):

Vid Velikić ◽

Andreas Wippel ◽

Marion Freidl

Keyword(s):

Obsessive Compulsive Disorder ◽

Sinus Thrombosis ◽

Cerebral Venous Sinus Thrombosis ◽

Tricyclic Antidepressant ◽

Repetitive Behaviors ◽

Venous Sinus ◽

Obsessive Compulsive ◽

Venous Sinus Thrombosis ◽

Compulsive Disorder ◽

Sagittal Sinus

SummaryObsessive–compulsive disorder (OCD) is characterized by repetitive, persistent and unwanted thoughts and ritualistic, repetitive behaviors. The pathophysiology of OCD involves many distinct cortical and subcortical regions and it has been reported that OCD may occur as a consequence of traumatic brain injury, infections and tumors as well as cerebrovascular insult such as cerebral venous sinus thrombosis (CVST). We here describe the case of a 36-year-old woman who developed OCD at the age of 13 with almost complete remission of the symptoms after a 1 year-long treatment. Interestingly, after suffering CVST at the superior sagittal sinus at the age of 33, she experienced a relapse of OCD. The patient was successfully treated with Sertraline and Clomipramine. Previous studies revealed cases of OCD following different cerebrovascular accidents, i.e. predominantly arterial stroke. However, the present case is the first to describe OCD after venous thrombosis. Based on our clinical experience, the most effective treatment of OCD after CVST represents the combination of the selective serotonin reuptake inhibitor Sertraline and the tricyclic antidepressant Clomipramine.

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Admixture analysis of age at onset in obsessive–compulsive disorder

Psychological Medicine ◽

10.1017/s0033291704003253 ◽

2005 ◽

Vol 35 (2) ◽

pp. 237-243 ◽

Cited By ~ 81

Author(s):

RICHARD DELORME ◽

JEAN-LOUIS GOLMARD ◽

NADIA CHABANE ◽

BRUNO MILLET ◽

MARIE-ODILE KREBS ◽

...

Keyword(s):

Obsessive Compulsive Disorder ◽

Late Onset ◽

Age At Onset ◽

Admixture Analysis ◽

Obsessive Compulsive ◽

General Anxiety Disorder ◽

General Anxiety ◽

Compulsive Disorder ◽

History Of ◽

Best Fitting

Background. Age at onset (AAO) has been useful to explore the clinical, neurobiological and genetic heterogeneity of obsessive–compulsive disorder (OCD). However, none of the various thresholds of AAO used in previous studies have been validated, and it remains an unproven notion that AAO is a marker for different subtypes of OCD. If AAO is a clinical indicator of different biological subtypes, then subgroups based on distinct AAOs should have separate normal distributions as well as different clinical characteristics.Method. Admixture analysis was used to determine the best-fitting model for the observed AAO of 161 OCD patients.Results. The observed distribution of AAO in OCD is a mixture of two Gaussian distributions with mean ages of 11·1±4·1 and 23·5±11·1 years. The first distribution, defined by early-onset OCD, had increased frequency of Tourette's syndrome and increased family history of OCD. The second distribution, defined by late-onset OCD, showed elevated prevalence of general anxiety disorder and major depressive disorder.Conclusions. These results, based on a statistically validated AAO cut-off and those of previous studies on AAO in OCD, suggest that AAO is a crucial phenotypic characteristic in understanding the genetic basis of this disorder.

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