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Willuhn Group

Seed grant for research into mechanisms of deep brain stimulation for OCD

The Foundation for OCD Research has awarded a Seed Grant to the research group of Ingo Willuhn. They will receive $800,000 over four years for exploring neural mechanisms of deep-brain stimulation in a mouse model for OCD.

Deep-brain stimulation (DBS) is an effective therapy for otherwise treatment-resistant OCD patients. However, optimizing DBS parameters requires months and its neural mechanism of action is largely unknown. “To improve DBS therapy, we will use SAPAP3 mutant mice, a model system that captures key elements of OCD. We aim to characterize the effects of DBS on compulsive behavior and neural activity in OCD-relevant brain circuits in these mice” explains Ingo Willuhn.

FFOR

FFOR’s strategy is designed with the intention to deliver a “functional” cure for OCD. To do that, FFOR is pursuing multiple projects across multiple disciplines simultaneously: Genetics, Neuroscience, and Therapeutics.

 

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Willuhn Group

Neuromodulation & Behavior

This pre-clinical research group headed by Ingo Willuhn is embedded in a larger clinical research team at the AMC department of Psychiatry. The group is driven by the question: “How do we control our behavior?”. Specifically, the Neuromodulation and Behavior group is interested in the neurobiology of compulsive behavior and in mechanisms through which actions become automatic with a focus on basal ganglia function and dopamine signaling. Furthermore, the group studies the effects of deep-brain stimulation (DBS) on brain and behavior.

What is compulsivity? Compulsivity is behavior that is out of control, behavior we perform despite not wanting to perform it or despite its negative outcome. Compulsive behavior is performed persistently, repetitively, and inflexibly. But how does compulsivity develop? What is its neurobiological basis? To answer these questions, we investigate different aspects of compulsivity (e.g., automation of behavior, cognitive (in-)flexibility) and measure/modulate neuronal activity in the brain simultaneously.

Compulsivity is a core feature in several neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD) and drug addiction. In otherwise therapy-resistant patients of such disorders, DBS has been effective. However, our understanding of the mechanisms of action of DBS is still limited. Therefore, we aim to investigate how DBS affects compulsivity and what the neurobiological basis of these effects is.

Our group has a strong collaborative relationship to the Department of Psychiatry at the Amsterdam Medical Center (AMC) lead by Damiaan Denys and therefore has close ties with clinicians and clinical researchers, providing optimal conditions for a translational and multidisciplinary approach. Specifically, we translate clinical findings from studies in humans into relevant animal models, and vice versa we aim to apply our conclusions in the clinical setting. At the very core of our research is the study of rodent behavior. On one hand, we test compulsive behavior itself by using behavioral, (e.g., signal attenuation, schedule-induced polydipsia), pharmacological (drug self-administration), and genetic (SAPAP3-KO mice) animal models. On the other hand, we study “normal’ behavioral faculties such as habit formation, response flexibility, emotion, and cognition (e.g., elevated plus maze, operant chambers) that may contribute to compulsivity when dysregulated. We combine behavioral testing with state-of-the-art research tools including diverse methods for brain stimulation (e.g., DBS, chemogenetics, optogenetics), neurochemical measurements (e.g., microdialysis, fast-scan cyclic voltammetry), calcium imaging (implantable miniaturized microscopes), and electrophysiological recordings (e.g., single-unit activity, local field potentials (LFPs)). Furthermore, we use functional magnetic resonance imaging (fMRI) in rodents to detect the effects of drugs and DBS throughout the brain.

 

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