Potential biomarkers and therapeutic targets for obsessive compulsive disorder: Evidences from clinical studies

Highlights The study proposes a set of potential biomarkers for obsessive compulsive disorder Methods to assess their concentrations in biological samples are critically analyzed Links between the disorder, diabetes and circadian disruptions are assessed The implications of biomarkers as therapeutic biotargets are discussed Obsessive compulsive disorder (OCD) is a prevalent behavioral disorder with a complex etiology. However, the underlying pathogenic molecular pathways and the associated risk factors are largely obscure. This has hindered both the identification of relevant prognostic biomarkers and the development of effective treatment strategies. Because of the diverse range of clinical manifestations, not all patients benefit from therapies currently practiced in the clinical setting. Nevertheless, several lines of evidence indicate that neurotrophic, neurotransmitter, and oxidative signaling are involved in the pathophysiology of OCD. Based upon evidences from clinical (and pre-clinical studies), the present review paper sets out to decipher the utilities of three parameters (i.e. brain-derived neurotrophic factor; BDNF, noradrenalin-synthesizing enzyme dopamine beta-hydroxylase; DBH; and oxidative damage marker malondialdehyde; MDA) as diagnostic peripheral biomarkers as well as bio-targets for therapeutic strategies. While the data indicates promising results, there is necessitation for future studies to further confirm and establish these. Further, based again on the available clinical data, we investigated the possibilities of exploiting the etiological links between disruptions in the sleep-wake cycle and insulin signaling, and OCD for the identification of potential anti-OCD ameliorative agents with the ability to elicit multimodal effects, including attenuation of the alterations in BDNF, noradrenergic and redox pathways. In this respect, agomelatine and metformin may represent particularly interesting candidates; however, further clinical studies are warranted to establish these as singular or complementary medications in OCD subjects

Nest -Building Behavior In House Mice (Mus Musculus), A Potential Model Of Obsessive -Compulsive Disorder In Humans

Thesis (Ph.D.) University of Alaska Fairbanks, 2007OCD (obsessive-compulsive disorder) is a chronic and debilitating psychiatric condition characterized by intrusive and persistent thoughts (obsessions) and repetitive behaviors (compulsions) that become ritualistic in an attempt to escape the obsessions. Currently there is a paucity of animal models with robust and spontaneous (non-drug or non-behaviorally induced) compulsive-like behaviors. This study is aimed at validating a novel robust and spontaneous genetic mouse model of OCD. The compulsive-like nest-building behavior in mice selected for high levels of nest-building behavior (BIG) has good face validity, with a behavioral phenotype that resembles hoarding behavior characteristic of OCD. In addition, male and female BIG mice displayed compulsivelike digging behavior relative to mice selected for low levels of nest-building behavior (SMALL), as assessed by the marble-burying test. Both chronic oral fluoxetine and clomipramine treatment reduced compulsive-like nest-building behavior in male BIG mice. Furthermore, chronic oral fluoxetine administration decreased nest-building behavior of BIG mice in a dose-dependent manner, while desipramine, an antidepressant not effective for treating OCD, did not significantly alter this behavior. The administration of fluoxetine did not cause a decrease in general locomotor behavior. These findings suggest that the nest-building phenotype has predictive validity. In addition, chronic oral fluoxetine treatment reduced compulsive-like digging behavior in male and female BIG mice as compared to SMALL mice. Gender effects were also found in treatment response. Clomipramine did not reduce nest-building in female BIG mice in a dose-dependent manner, which is consistent with previous studies. These data are in contrast to previous studies using BIG male mice which had a significant decrease in nest-building behavior with oral clomipramine. These results are consistent with studies on humans, which have found gender differences in the treatment effects of antidepressants. Additional construct validity is implicated by the results of targeted serotonergic lesions of the raphe nuclei in male BIG mice, which reduced repetitive nest-building behavior. More research is necessary to confirm the appropriateness of this model for human OCD; however, this model is promising based on the data that support good face, predictive and construct validity

An investigation into the repetitive pathophysiology and the effect of a noninvasive targeted treatment strategy in an animal model overexpressing the dopamine transporter

Introduction: Treatment of neuropsychiatric disorders may be optimized through targeted strategies that interact with neurobiological processes responsible for symptom generation. The overexpression of the dopamine transporter (DAT) has been linked to a wide range of neuropsychiatric afflictions with a specific involvement in repetitive disorders. However, the direct consequences of DAT overexpression remain unexplored. Transcranial direct current stimulation (tDCS) is a non-invasive technique suggested as a treatment for repetitive disorders. In-depth investigation into the role of DAT overexpression in repetitive pathophysiology and how tDCS potentially regulates these processes are clinically challenging, yet possible by employment of adequate animal models. Objectives: The aim of the present thesis was to investigate the direct consequences of DAT overexpression in relation to the pathophysiology of repetitive behavior and to test the potency of tDCS as a therapeutic approach for repetitive disorders. Methods: Initially, a transgenic rat overexpressing DAT (DAT-tg) was generated and its neurobiological and behavioral properties were assessed (study 1+2). Extensive deep brain stimulation (DBS) was applied to identify, which brain areas were involved in modulating repetitive behavior in the DAT-tg rat. Subsequently, DAT-tg rats received tDCS above the frontal cortex followed by behavioral and neurobiological assessment (study 3). Results: The DAT-tg rat displayed several neurobiological deficits within the corticostriatal circuit related to repetitive pathophysiology, which translated into repetitive behavior and treatment sensitivity as observed Tourette syndrome. Further, DAT-tg rats presented with profound cognitive deficits. The application of frontal anodal tDCS led to a decrease in repetitive symptoms in the DAT-tg rats, which was assigned to a specific modulation within the corticostriatal sensorimotor circuit. Conclusion: This thesis shows that DAT overexpression is implicated in the generation of among others repetitive pathophysiology, thus supporting the need for further investigations into its role in repetitive disorders. It further shows that the DAT-tg rat constitutes an ideal model for this endeavor, as it allows for a direct assessment of the neurobiological implications and how new interventions interact with these processes. This thesis further found, that following application of the appropriate stimulation parameters, tDCS reduces repetitive behavior by modulating the neuronal circuit considered responsible for symptom manifestation in the DAT-tg rats. This sets the stage for investigations into tDCS as targeted treatment for repetitive disorders.Einleitung: Die Behandlung neuropsychiatrischer Erkrankungen kann durch gezielte Therapiestrategien, die in die neurobiologischen Prozesse der Symptomgenerierung eingreifen, optimiert werden. Die Überexpression des Dopamin-Transporters (DAT) wird mit einer Vielzahl neuropsychiatrischer Erkrankungen, die mit repetitiven Störungen einhergehen, in Verbindung gebracht. Dennoch sind die direkten Folgen der Überexpression des DAT bisher unerforscht. Die transkranielle Gleichstromstimulation (tDCS) ist eine nichtinvasive Technik, die zur Behandlung repetitiver Störungen vorgeschlagen wird. Die ausführliche Untersuchung der Rolle der DAT-Überexpression in der repetitiven Pathophysiologie sowie der potentiellen Regulation dieser Prozesse durch die tDCS ist klinisch herausfordernd, jedoch durch die Verwendung geeigneter Tiermodelle möglich. Ziele: Ziel der vorliegenden Studie war es, die direkten Konsequenzen einer DAT-Überexpression in Bezug auf die Pathophysiologie von repetitivem Verhalten zu untersuchen und die Wirksamkeit von tDCS als therapeutischen Ansatz für repetitive Störungen zu testen. Methoden: Zunächst wurde eine transgene Ratte mit überexprimiertem DAT (DAT-tg) generiert und ihre neurobiologischen und Verhaltensmerkmale untersucht (Studie 1+2). Um herauszufinden, welche Gehirnbereiche bei der Modulation des repetitiven Verhaltens in der DAT-tg-Ratte involviert sind, wurde eine umfassende Tiefenhirnstimulation (DBS) angewendet. Anschließend erhielten DAT-tg-Ratten tDCS über dem Frontalkortex und Auswirkungen auf Verhalten und Neurobiologie wurden geprüft (Studie 3). Ergebnisse: Die DAT-tg-Ratte wies in den kortikostriatalen Verbindungen mehrere neurobiologische Defizite auf, wie sie sich im repetitivem Verhalten und der Behandlungsempfindlichkeit bei Tourette- Syndrom beobachten lassen. Des weiteren zeigten DAT-tg-Ratten schwerwiegende kognitive Defizite. Die Anwendung von einer frontalen anodalen tDCS führte zu einer Abnahme der repetitiven Symptomatik bei den DAT-tg-Ratten, die einer spezifischen Modulation innerhalb des kortikostriatalen-sensomotorischen Schaltkreises zugeordnet werden konnte. Schlussfolgerung: Diese Studie zeigt, dass die Überexpression des DAT unter anderem bei der Entstehung von repetitiver Pathophysiologie eine Rolle spielt. Dies unterstreicht die Notwendigkeit weiterer Untersuchungen zur Rolle der DAT Überexpression bei repetitiven Störungen. Es zeigt außerdem, dass die DAT-tg-Ratte ein ideales Modell dafür darstellt, als dass es die direkte Untersuchung neurobiologischer Implikationen und die Wirkung neuartiger Interventionen auf diese Prozesse ermöglicht. Diese Arbeit zeigt, dass tDCS nach Anwendung geeigneter Stimulationsparameter repetitives Verhalten durch Modulation des neuronalen Schaltkreises, welcher für die Symptommanifestation bei den DAT-tg-Ratten verantwortlich gemacht wird, reduziert. Damit sind die Voraussetzungen für tDCS als gezielte Behandlung von repetitiven Erkrankungen geschaffen

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Abstract This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies

Obsessive-Compulsive Disorder

Although Obsessive-Compulsive Disorder (OCD) has been known since the ancient times, the exact etiology and pathogenesis of OCD unfortunately still remain unknown. In addition, the therapeutic approaches elaborated for the treatment of OCD as a whole are not perfect, and this disorder as a rule is characterized by unfavorable course and lack of full therapeutic response. In the current book some modern data on pathogenesis, phenomenology and treatment of OCD are presented. Besides, the data on co-morbidity of OCD with other neurological and psychiatric disorders are also included. This book is intended for broad circle of readers, but mostly for psychiatrists, psychologists and neurologists

Neurochemical modulation of affective and behavioural control: Models and applications for psychiatry

Impairments in emotional reactivity and behavioural flexibility are pervasive across disparate psychiatric conditions as traditionally defined. Here, I provide new evidence on how these processes are altered by neuromodulators in humans, with a primary focus on serotonin (5- HT; 5-hydroxytryptamine). Emotional reactions prepare the body for action. Some emotion is primitive, implicit, and critical for surviving threats, yet can inappropriately persist in times of safety. Other emotions are more complex, self-conscious and important in maintaining harmonious interpersonal relationships. At the same time, learned behaviours that are adaptive in the first instance, may become irrelevant or even disadvantageous as circumstances change. In Chapters 3 through 6, I report on experiments in healthy human volunteers that employed the dietary technique acute tryptophan depletion (ATD). ATD temporarily lowers serotonin synthesis and release by depleting its biosynthetic precursor tryptophan. Chapter 3 is a study of self-reported social emotion. ATD enhanced emotion in response to social injustice non-specifically; however, consideration of personality traits revealed that highly empathic participants reported more guilt under ATD, whereas individuals high in trait psychopathy demonstrated more annoyance. Chapter 4, in contrast, considers evolutionarily ancient automatic emotional reactions to threats. This was assayed instead by an objective measure, the skin conductance response (SCR). Here, ATD conversely attenuated the retention of Pavlovian conditioned emotional memory to threat. Traits again influenced this response: individuals more intolerant of uncertainty displayed the greatest attenuation of emotional reactions. Chapter 5 both extends the studies on emotion and bridges to the remaining empirical work by investigating reversal learning, an index of cognitive flexibility, in two experiments. Individuals again underwent Pavlovian (stimulus-outcome) threat conditioning, whereby one stimulus predicted threat, and another was safe. These contingencies then swapped (reversed). In a separate experiment, participants underwent instrumental (stimulus-response-outcome) conditioning on a deterministic schedule (the correct option was always correct), followed by reversal of the contingencies. ATD impaired both Pavlovian and instrumental reversal learning. Chapters 6 through 8 instead examine instrumental reversal learning that was probabilistic (the correct option was correct most but not all of the time), rather than deterministic. Chapter 6 expands on previous ATD studies of probabilistic reversal learning (PRL) in the literature, which had not found effects on choice behaviour. Despite nearly tripling the sample size, behaviour here assessed by conventional methods was unaffected, replicating previously published null results. Applying reinforcement learning (RL) models, however, revealed ATD elevated a basic perseverative tendency, referred to as “stimulus stickiness”; behaviour was more stimulus-bound and insensitive to the outcome of actions, consistent with the deterministic instrumental reversal impairment following ATD. Chapters 7 and 8 apply RL models as well, to existing datasets on PRL for comparison. Chapter 7 shows that healthy volunteers under lysergic acid diethylamide (LSD), which acts both at serotonin but also dopamine receptors, showed enhanced learning from positive feedback in particular, which was related to perseveration. Chapter 8 applies computational methods to PRL in clinical populations. RL modelling revealed a computational signature that dissociated PRL in stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD): Individuals with SUD showed heightened stimulus stickiness, as occurred following ATD in healthy volunteers, whereas the OCD group (under serotonergic medication) demonstrated lower stimulus stickiness than healthy controls. Dopaminergic agents remediated a reward learning deficit in SUD, among other measures. The general discussion considers these various findings in terms of theories of central serotonin function, in relation to the animal literature, and its relevance to mental disorder. These results, collectively, advance knowledge of neurochemical and computational mechanisms underlying psychiatric conditions trans-diagnostically, with implications for revised psychiatric classifications in line with the Research Domain Criteria (RDoC).Gates Cambridge Trust Wellcome Trus

Compulsive use of dopaminergic drugs in Parkinson's disease.

A small group of patients with Parkinson's disease (PD) compulsively use dopaminergic medications despite the frequent emergence of harmful physical, psychiatric and social effects. This behavioural syndrome has been termed the dopamine dysregulation syndrome (DDS) and although closely related, should be distinguished from impulse control disorders. The phenomenology, risk factors and neurobiology of DDS have been explored in a series of observational, neuropsychological and pharmacological clinical studies. Dopaminergic drug-responsive complex repetitive stereotypical behaviours (punding) were identified and characterised in PD outpatients selected on the basis of their dopaminergic drug intake. In animal models of Parkinson's disease, stereotypies are known to index the neuroadaptive changes of sensitisation. Punding was found to be associated with DDS, dyskinesia severity and harmful neuropsychiatric disturbances raising the possibility that the biological mechanisms underlying drug-reward and these behaviours may overlap. Psychostimulant drugs have powerful effects on dopamine release and re-uptake in the presynaptic dopamine system and are capable of inducing neuroplastic changes in the basal ganglia particularly after their intermittent administration. Psychostimulant drugs have dopaminergic effects but have only been demonstrated to have weak anti-Parkinsonian effects. The acute effects of L-dopa and methylphenidate were examined (which has effects similar to psychostimulant drugs) in 15 untreated PD patients, before and again after a mean 18 months of sustained dopaminergic drug therapy. After sustained dopaminergic therapy, the motor effects of L-dopa and the euphoriant effects of methylphenidate were augmented. This provided clinical support in humans for the first time that sustained dopaminergic drug therapy may result in psychomotor sensitisation. In an effort to facilitate early identification of DDS and for planning prompt therapeutic interventions personality traits were examined in PD patients with DDS and compared to those without DDS and healthy controls. DDS patients were found to differ from control PD patients and age-matched healthy controls in personality dimensions linked with substance dependence i.e. high impulsive sensation seeking traits, low harm avoidance, reward dependence, self-directedness and cooperativeness. Impulsive sensation seeking traits in particular, in addition to premorbid addictive behaviour were also found to predict the emergence of DDS suggesting a common neurobiological vulnerability. DDS patients complain of an aversive drug withdrawal state akin to the withdrawal state seen in other forms of addiction. Many patients attribute avoidance of aversive "ofTs" as the reason behind their compulsive drive to self-medicate. This aversive "off'-state was examined in 20 DDS patients and PD controls and found to be associated with behaviours that may lead to sensitisation of brain reward systems. Most authorities believe that compulsive drug-taking and associated behavioural disorders are mediated through the mesolimbic dopaminergic projections and the nucleus accumbens. DDS was investigated using a two-scan nC-Raclopride protocol. Drug-induced sensitisation of ventral striatal- circuitry appeared to mediate compulsive drug "wanting" - providing the first evidence of such in humans. Greater understanding of compulsive dopaminergic drug use in PD should not only inform the management of PD but may provide insight into the mechanisms underlying impulse control disorders

Narušená Funkce Hipokampu u Modelu Obsedantně-Kompulsivní Poruchy Vyvolané Quinpirolem

Obsedantně kompulzivní porucha (OCD) je závažné psychiatrické onemocnění, které se projevuje opakovanými nutkavými myšlenkami a následně stereotypním kompulzivním chováním. Do patofyziologie OCD jsou zapojeny změny kortiko-thalamo-striato-kortikálních obvodů. Mnoho studií však také zjistilo změněný objem, tvar a aktivitu hipokampu u pacientů s OCD. Tato práce byla zaměřena na aktivitu hipokampálních CA1 buněk během stereotypního kontrolního chování podobného kompulzivní kontrole a na kognitivní flexibilitu v potkaním modelu sensitizace dopaminovim D2 agonistem quinpirolem (QNP). U sensitizovaných potkanů a kontrol byla hodnocena aktivita hipokampálních buněk v oblasti CA1 během stereotypní kontroly v otevřeném poli s vloženými objekty. Stanovili jsme profily exprese ranneho genu Arc+ (aktivitou regulovaného cytoskeletálního proteinu neboli Arg 3.1) v koronálních hipokampálních řezech v oblasti CA1. Po ustavení stereotypního kontrolovani (10 sezení) byli potkani vystaveni aréně a přesně po 5 minutách humánně usmrceni. Sensitizovaná zvířata navštěvovala konkrétní objekty v jednotlivých sezeních s konsistentní preferencí, zatímco kontrolní tuto preferenci měnila od jednoho sezení k druhému. Lokomoční aktivita byla v testovacím sezení mezi oběma skupinami srovnatelná. Po usmrcení byly mozky potkanů bleskově...Obsessive-compulsive disorder (OCD) is a serious psychiatric condition manifested by repeated thoughts followed by stereotypic compulsive behavior. Alterations to cortico-thalamo-striato- cortical circuits are most often implicated in the pathophysiology of OCD. However, many studies have also found a changed volume, shape and activity of the hippocampus in OCD patients. This work focused on the activity of hippocampal CA1 cells during stereotypical checking behavior and on cognitive flexibility in a quinpirole (QNP) sensitization model of OCD. The activity of CA1 hippocampal cells during stereotypical checking was assessed in an enriched open-field test in QNP sensitized rats. Arc+ (activity-regulated cytoskeletal associated protein, or Arg 3.1) mRNA expression profiles were determined in CA1 coronal hippocampal sections following stereotypical checking. After the establishment of stereotypical checking (10 sessions), rats were exposed to the arena and sacrificed after 5 minutes. QNP sensitized animals visited the same objects with the same frequency as during previous sessions, while control rats did not. Locomotor activity was comparable between QNP treated rats and controls. Following sacrifice, rat brains were flash frozen and sliced to 20 µm thick sections. Sections, mounted on slides, were hybridized...1. lékařská fakultaFirst Faculty of Medicin

Effects of dance therapy on balance, gait and neuro-psychological performances in patients with Parkinson's disease and postural instability

Postural Instability (PI) is a core feature of Parkinson’s Disease (PD) and a major cause of falls and disabilities. Impairment of executive functions has been called as an aggravating factor on motor performances. Dance therapy has been shown effective for improving gait and has been suggested as an alternative rehabilitative method. To evaluate gait performance, spatial-temporal (S-T) gait parameters and cognitive performances in a cohort of patients with PD and PI modifications in balance after a cycle of dance therapy