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The neurobiological basis for novel experimental therapeutics in dystonia.

ABSTRACT: Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics.

SUBMITTER: Downs AM

PROVIDER: S-EPMC6885011 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The neurobiological basis for novel experimental therapeutics in dystonia.

Downs Anthony M AM Roman Kaitlyn M KM Campbell Simone A SA Pisani Antonio A Hess Ellen J EJ Bonsi Paola P

Neurobiology of disease 20190704

Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances i ...[more]

PMID: 31279827

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Project description:Background:The dystonias include a clinically and etiologically very diverse group of disorders. There are both degenerative and non-degenerative subtypes resulting from genetic or acquired causes. Traditionally, all dystonias have been viewed as disorders of the basal ganglia. However, there has been increasing appreciation for involvement of other brain regions including the cerebellum, thalamus, midbrain, and cortex. Much of the early evidence for these other brain regions has come from studies of animals, but multiple recent studies have been done with humans, in an effort to confirm or refute involvement of these other regions. The purpose of this article is to review the new evidence from animals and humans regarding the motor network model, and to address the issues important to translational neuroscience. Methods:The English literature was reviewed for articles relating to the neuroanatomical basis for various types of dystonia in both animals and humans. Results:There is evidence from both animals and humans that multiple brain regions play an important role in various types of dystonia. The most direct evidence for specific brain regions comes from animal studies using pharmacological, lesion, or genetic methods. In these studies, experimental manipulations of specific brain regions provide direct evidence for involvement of the basal ganglia, cerebellum, thalamus and other regions. Additional evidence also comes from human studies using neuropathological, neuroimaging, non-invasive brain stimulation, and surgical interventions. In these studies, the evidence is less conclusive, because discriminating the regions that cause dystonia from those that reflect secondary responses to abnormal movements is more challenging. Discussion:Overall, the evidence from both animals and humans suggests that different regions may play important roles in different subtypes of dystonia. The evidence so far provides strong support for the motor network model. There are obvious challenges, but also advantages, of attempting to translate knowledge gained from animals into a more complete understanding of human dystonia and novel therapeutic strategies.

Project description:Modeling Instruction (MI) for University Physics is a curricular and pedagogical approach to active learning in introductory physics. A basic tenet of science is that it is a model-driven endeavor that involves building models, then validating, deploying, and ultimately revising them in an iterative fashion. MI was developed to provide students a facsimile in the university classroom of this foundational scientific practice. As a curriculum, MI employs conceptual scientific models as the basis for the course content, and thus learning in a MI classroom involves students appropriating scientific models for their own use. Over the last 10 years, substantial evidence has accumulated supporting MI's efficacy, including gains in conceptual understanding, odds of success, attitudes toward learning, self-efficacy, and social networks centered around physics learning. However, we still do not fully understand the mechanisms of how students learn physics and develop mental models of physical phenomena. Herein, we explore the hypothesis that the MI curriculum and pedagogy promotes student engagement via conceptual model building. This emphasis on conceptual model building, in turn, leads to improved knowledge organization and problem solving abilities that manifest as quantifiable functional brain changes that can be assessed with functional magnetic resonance imaging (fMRI). We conducted a neuroeducation study wherein students completed a physics reasoning task while undergoing fMRI scanning before (pre) and after (post) completing a MI introductory physics course. Preliminary results indicated that performance of the physics reasoning task was linked with increased brain activity notably in lateral prefrontal and parietal cortices that previously have been associated with attention, working memory, and problem solving, and are collectively referred to as the central executive network. Critically, assessment of changes in brain activity during the physics reasoning task from pre- vs. post-instruction identified increased activity after the course notably in the posterior cingulate cortex (a brain region previously linked with episodic memory and self-referential thought) and in the frontal poles (regions linked with learning). These preliminary outcomes highlight brain regions linked with physics reasoning and, critically, suggest that brain activity during physics reasoning is modifiable by thoughtfully designed curriculum and pedagogy.

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The neurobiological basis for novel experimental therapeutics in dystonia.

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The neurobiological basis for novel experimental therapeutics in dystonia.

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