Research on neural circuits and biological markers involved in obsessive-compulsive disorder using behavioral paradigms of fear and anxiety

Abstract

The obsessive-compulsive disorder (OCD) is the fourth most common psychiatric disorder and is related to significant disability, poor quality of life and disrupted family functioning. Despite the existence of effective therapeutic interventions for OCD (e.g. serotonin reuptake inhibitors and behavior psychotherapy), up to half of OCD patients do not respond satisfactorily with treatment. Therefore, new therapeutic alternatives are still needed. Moreover, the neurobiological mechanisms that underlie OCD etiology and the effect of treatments are only partially comprehended. To fill this gap in the literature, we concluded, after analyzing the results of our studies as well as others, that the conceptualization of OCD as a unitary disorder is outdated and that it is necessary to improve our investigative methods. We aim to comprehend OCD having the specific components of its behavioral chain as our starting point. We will investigate the behavioral components known as unconditioned fear response (inate response or reflex also known as "startle"), conditioned fear response after matching with aversive stimuli, the inhibition of the unconditioned fear response (prepulse inihibition), and several neuropsychological measures related to executive functions and attentional bias. In prallel, we will investigate both health subjects and OCD patients with functional neuroimaging, electroencephalography, peripheral biomarkers (such as oxytocin and BDNF) and peripheral markers of gene expression related to the immunological system. A portion of our patients we also be followed during treatment with a selective serotonin reuptake inhibitor and we will be able to investigate if any alterations in the response to the behavioral paradigms, neuropsycholagical tests or peripheral biomarkers will be associated with treatment response. As well, in another portion of patients, we will evaluate the effect of neurosurgical interventions (gamaknife neurosurgery and deep brain stimulation) as treatment strategies for refractory OCD. Inserted in a translational perspective, we will work with an animal model for OCD (injection of oxytocin in the central nucleus of the amygdala inducing grooming behaviors). The animals will be evaluated according equivalents of the behavioral paradigms and treatment interventions used in humans. The manipulation of variables and the access to brain material is much easier within animal models so we will be able to isolate the effect of specific variables over the pharmacological treatment response as well as to understand the molecular mechanisms underneath. We will also be able to study brain material of OCD patients post-mortem. These analyses will provide us with clues linking the peripheral alterations to the processes in the brain. With the results obtained in this study, we expect to improve the comprehension of which neurocircuits and neurophysiologic mechanisms are involved in OCD etiology and response to pharmacological as well as neurosurgical treatment. We aim to understand the OCD related manifestations in the light of the circuits responsible for the phenomena of fear response and aversive stimuli discrimination; and to make the link between observed behavioral phenomena and underlying molecular mechanisms. (AU)