Current Projects

Funding Dystonia Investigators

The ultimate goal of the Science Program is to support the discovery of improved therapies and a cure.

The DMRF is dedicated to stimulating the field of dystonia research and supporting the collaborations and projects necessary to accelerate progress. Each funded project addresses one or more of the core directions necessary to advance the dystonia field. These core directions include furthering our fundamental understanding of what dystonia is, uncovering the mechanisms in the nervous system that lead to symptoms, creating models of dystonia to use in experiments, and discovering targets for new and improved therapeutics designed specifically to treat dystonia.

Congratulations to our current award recipients, and infinite thanks to our supporters for making this research funding possible.

Research Grants & Contracts

Research grants are available in support of hypothesis-driven research at the genetic, molecular, cellular, systems, or behavioral levels that may lead to a better understanding of the pathophysiology or to new therapies for any or all forms of dystonia. Contracts provide the opportunity to direct research through the identification of specific, milestone-driven projects to be conducted by identified investigators and closely monitored by the DMRF’s Chief Scientific Officer.

David Arkadir, MD, PhD
Hadassah Medical Center and Hebrew University of Jerusalem

Some types of dystonia are hereditary, for example, DYT1 dystonia caused by mutation in the TOR1A gene. It is not clear, however, why individuals with the same genetic mutation can develop different severities of symptoms. On the extremes, one individual may experience severe dystonia that starts in childhood and leads to significant motor disability while another individual may be totally asymptomatic and not even aware of having the genetic mutation. The researchers believe that other genes, yet to be discovered, determine wither an individual carrying a potentially dystonia-causing genetic mutation will develop this movement disorder or not. They propose to find this gene(s) by comparing the genomes of individuals who have mutation in the TOR1A gene, with or without apparent dystonia symptoms. The goal is to find genes that protect some individuals from developing dystonia, even in the presence of the mutated gene.

Jesse H. Goldberg, MD/PhD
Cornell University

The DMRF is partnering with Jesse H. Goldberg, MD, PhD of Cornell University on a project to engineer a revolutionary new generation of deep brain stimulation (DBS) devices to treat dystonia and other  neurological diseases.

Dystonia results from abnormal brain activity that can be corrected by direct electrical stimulation of dysfunctional brain pathways. In current DBS systems, an implanted medical device delivers continuous stimulation to the brain and adjustments to the stimulation must be made using a remote control device in the hands of a highly trained clinician. A major obstacle to providing patients with maximum benefit from this therapy is knowing where in the brain to stimulate and tailoring stimulation parameters to the unique needs of each patient.

Dr. Goldberg proposes a radically new approach to DBS. He is using artificial intelligence to develop a system in which a computer, interconnected with the brain, figures out exactly how and where to stimulate to restore normal movement.

In this three-year project, Dr. Goldberg will establish the feasibility of this concept in mice. He is collaborating with Mert Sabuncu, PhD in the School of Electrical and Computer Engineering and School of Biomedical Engineering at Cornell University.

Cecile Gallea, PhD
Salpêtrière Hospital, Paris

Myoclonus-dystonia (M-D) is a movement disorder caused by mutations in the SGCE/DYT11 gene. The neurological basis of this disorder remains elusive, but evidence points towards a network dysfunction  involving the cerebellum, the striatum, and the cortical motor areas. The myoclonus in M-D often improves after consuming ethylic alcohol (EthA). While other treatment options have frequently been ineffective or poorly-tolerated, the addictive and neurodegenerative consequences of chronic alcohol consumption prevent its use as a sustainable treatment option. Octanoic alcohol (OctA) may represent a beneficial alternative to EthA: it alleviates motor symptoms in patients with essential tremor in a way similar to EthA but without causing intoxication or other adverse effects. However, the mechanism of action of OctA and the neural circuits it affects are currently unknown. This collaborative project will use a translational and multimodal approach. In an M-D mouse model, the researchers will investigate the efficacy of OctA to reduce dystonia and repetitive, myoclonic-like, jerking movements in mice that have improved after administration of EthA. In M-D patients, the research team will test whether OctA reduces myoclonus severity as well as non-motor symptoms such as anxiety. Lastly, they will isolate the OctA-responsive network using functional MRI (magnetic resonance imaging) in M-D patients and electrophysiological recordings in the M-D mouse model. The project will provide preliminary data to explore new non-invasive therapeutic options. These preliminary data will be the starting point of a bigger collaborative work to unify efforts to deepen understanding of the mechanisms underlying M-D symptoms and pathophysiology

Karen Grütz, PhD
University of Lübeck (Germany)

Myoclonus-dystonia (M-D) is a movement disorder presenting with brief, lightning-like jerks (myoclonus) combined with sustained muscle contractions (dystonia). In about 25% of patients, the disorder is caused by mutations in the SGCE gene. M-D is inherited in an autosomal-dominant way, meaning that one mutated version of SGCE, inherited from a parent, is enough to cause the disorder. Typically, only individuals who inherit the mutation from their fathers are affected by the disorder. This is because a mechanism called maternal imprinting silences the information handed down from the mother, leading to incomplete penetrance of clinical symptoms. Of interest, the severity of symptoms and the age of onset varies widely between individuals (related and unrelated) even with the exact same mutation. It is possible that some of these variations can be explained by slight changes in the underlying mechanism of maternal imprinting. The protein product of the SGCE gene is called ε-sarcoglycan and is localized at membranes in various tissues within the body and, importantly, has been identified as component of a membrane-bound complex within the brain.

Dr. Grütz is using highly specialized techniques and cell models to help explain the variation of clinical symptoms and severity among M-D patients. This approach will help clarify the mechanism behind the development of M-D and also contribute to the generation of therapeutics and possibly even personalized treatments.

Xin Jin, PhD
The Salk Institute for Biological Studies (USA)

The intricate networks in the human brain responsible for controlling body movement are comprised of many millions of neurons across dozens of brain areas. Dr. Jin and his team are working to understand the network activity that underlies dystonia symptoms, and to possibly prevent symptoms from developing. This grant is focusing on blepharospasm, a focal dystonia of the eyelid and brow muscles, as a model to understand dystonia networks more broadly. Partial support provided by the Benign Essential Blepharospasm Research Foundation.

Andrea Kühn, MD
University Medicine Berlin (Germany)

Deep brain stimulation is a neurosurgical therapy that uses an implanted medical device to treat dystonia and other neurological disorders. The medical device delivers electrical stimulation to the areas of the brain responsible for dystonia symptoms. Many dystonia patients respond dramatically to deep brain stimulation therapy, but not all. Dr. Kühn and her team seek to clarify the underlying mechanisms of deep brain stimulation in order to better understand why some patients benefit from this therapy while others do not.

Mark LeDoux, MD, PhD
University of Memphis (USA)

The aim of this project is to establish a virtual biorepository, as well as a physical biorepository, for de-identified clinical records and associated biological samples (DNA, RNA, fibroblasts, lymphocytes, etc.)  Dr. LeDoux will also be conducting an analysis of myoclonus-dystonia associated genetic variants identified in population databases and assisting other clinicians with in silico analysis of variants identified in myoclonus-dystonia associated genes.  Finally, Dr. LeDoux will provide biological samples and associated de-identified clinical information to scientists with interest in myoclonus-dystonia and related disorders of the nervous system.


Scott Norris, MD
Washington University School of Medicine

Cervical dystonia produces excessive involuntary muscle contractions in the neck. These muscle contractions result in uncomfortable, awkward, and sometimes painful positions of the head, neck, and shoulders. This research project focuses on improving understanding of the brain’s role in cervical dystonia, specifically directed toward improved treatment. The investigators will use state-of-the-art brain imaging techniques, positron emission tomography (PET) and magnetic resonance imaging (MRI), to observe the working brain. PET allows researchers to observe chemical messengers (neurotransmitters) in the brain, in this case acetylcholine. MRI allows researchers us to observe how one region of the brain communicates with other brain regions. Combining PET and MRI techniques provides a powerful opportunity to determine how altered chemical messenger levels may influence the way brain regions communicate in cervical dystonia by comparing brain activity of patients with cervical dystonia and control volunteers without cervical dystonia. Acetylcholine is a neurotransmitter of interest because some dystonia patients improve when taking medications that alter levels of acetylcholine. The researchers suspect that brain regions that use acetylcholine are damaged in patients with cervical dystonia and therefore the communication between brain regions that rely on acetylcholine is disrupted. If they find that acetylcholine affects how brain regions communicate in cervical dystonia, future research can attempt to correct the communication problem with new medication or brain stimulation therapies.

Richard Reilly, PhD
Trinity College Dublin (Ireland)

Dr. Reilly and his team are in search of biomarkers in the brain for cervical dystonia, a focal dystonia that causes involuntary head movements and neck postures. To do so, they will use multimodal analysis on a dataset from structural, resting state, and functional MRI (magnetic resonance imaging) in a group of cervical dystonia patients. They will compare results against a group of patients with spasmodic dysphonia, a focal dystonia of the vocal cords muscles. The goal is to advance understanding of the structural and functional brain differences in cervical dystonia.

Aasef Shaikh, MD, PhD
Case Western Reserve University (USA)

Cervical dystonia, affecting the neck muscles, is the most common form of dystonia. It is believed that cervical dystonia is caused by abnormal activity in the basal ganglia, a part of the brain that coordinates movement. However, new studies are suggesting that impairments to the cerebellum, the part of the brain that control coordination, and sense of body position (proprioception) can cause dystonia as well. Dr. Shaikh hypothesizes that these three brain functions—cerebellum, basal ganglia, and proprioception—work together as a ‘unifying network’ to influence the control of head movements. This study will focus on proprioception and the effect that neck vibration will have on reducing proprioceptive impairment to help treat dystonia. The investigators will measure the effects of neck vibration on the head movements of patients with cervical dystonia using a high-resolution magnetic field position tracking system. they will also measure the effects of neck vibration on the activity of the basal ganglia by measuring the activity of single brain neuron. The goal of this project is to define non-invasive, painless, and cost-effective therapies based on a novel, unifying network model detailing the biological mechanisms of cervical dystonia. Dr. Shaikh is a past DMRF Clinical Fellow.

Mariangela Scarduzio, PhD
University of Alabama at Birmingham

Dystonia is challenging to adequately treat, particularly because the underlying brain circuitry problem is not well understood. Studies indicate that a specific population of brain cells, namely striatal cholinergic interneurons, is dysfunctional in both dystonia animal models and in dystonia patients. Accordingly, dystonia is most effectively treated with drugs that reduce striatal cholinergic interneuron function, suggesting that enhanced cholinergic function may play a key role in dystonia. Utilizing a genetic animal model of dystonia that exhibits dystonia triggered by caffeine (transgenic paroxysmal nonkinesigenic dyskinesia (PNKD) mutant mice), the researchers have obtained preliminary data showing striatal cholinergic interneuron dysfunction similar to that observed in non-manifesting dystonia models. In this proposal, they will attempt to correlate dysfunction of striatal cholinergic interneurons with dystonic symptoms in dystonia-manifesting PNKD mice. They expect the experiments to answer crucial questions necessary for linking disease causing mutations to abnormal movements.

Roy Sillitoe, PhD
Baylor College of Medicine (USA)

This project uses a unique genetic mouse model of dystonia and diffusor tensor imaging, a type of magnetic resonance imaging (MRI), to define how specific brain network changes lead to dystonia symptoms. This work also seeks to better understand developmental aspects of dystonia, namely why and how dystonia progresses over time. Dr. Sillitoe and team are ultimately seeking to define the functional brain network of dystonia as a way to better target therapies such as oral medications and deep brain stimulation.

An Vo, PhD
The Feinstein Institute for Medical Research (USA)

Brain imaging techniques have advanced the understanding of metabolic network abnormalities in inherited and sporadic dystonia. It remains elusive, however, whether dystonia-related brain networks can be identified with resting state functional MRI (magnetic resonance imaging) utilizing time-series information. It is also unclear whether such networks relate to underlying anatomical connections. Dr. Vo hypothesizes that dystonia is characterized by distinct functional and structural network topographies in the resting state. To test this hypothesis, she and her team will examine resting state functional MRI and diffusion MRI data in patients with inherited and sporadic dystonia. The proposed work will advance the understanding of brain network architecture in dystonia. The new information will help identify areas within the network space for optimal therapeutic targeting and individually customized treatment.

Yulia Worbe, MD, PhD
Salpêtrière Hospital (France)

Muscle jerks, or myoclonus, often affecting the upper body, represent the most disabling symptom in many patients with myoclonus-dystonia (M-D). Treatment of the jerking movements can be challenging. Understanding the mechanism by which the jerks are generated within the brain may clarify new strategies for treatment. In M-D, two brain circuits have been related to myoclonic jerks: one links the posterior part of the brain called the cerebellum to the upper part of the brain called the cortex. The other potentially involved network links the cortex to the basal ganglia. Recent studies have shown that the cerebellum and basal ganglia are interconnected, and through these connections they can influence how different movements are performed.

Despite some progress in understanding how the brain generates myoclonic jerks, there is so far no direct evidence of brain alteration accounting for myoclonus. This is mainly due to difficulties encountered when studying patients who have jerking movements that interfere with the techniques available to study of their brain activity. Magnetoencephalography (MEG) is a non-invasive technique for investigating human brain activity. Dr. Worbe is using a new and very innovative MEG system that is worn like a helmet, allowing free and natural movement during scanning. This system opens up new possibilities because the myoclonic jerks experienced by patients will no longer interfere with brain activity studies and investigators will be able to identify the sequence of brain events that leads to the generation of these jerks. This challenging and highly novel study will help identify the neuronal origins of jerking movements in M-D. Understanding the brain alterations leading to myoclonus could eventually guide the use of non-invasive brain stimulation as a possible treatment.

Research Fellowships

Over the years, DMRF has created funding awards to support young investigators at different stages in their scientific training. Postdoctoral fellowship awards recognize and support outstanding young scientists who have earned a doctoral degree and have embarked on a period of mentored research.

DMRF is supporting postdoctoral fellows who are working to fundamentally improve our understanding of brain dysfunction and molecular mechanisms underlying dystonia.

Lilian Cruz, PhD
Massachusetts General Hospital (USA)

Mentors: Xandra Breakefield, PhD & Cris Bragg, PhD

CRISPR/Cas9 is a unique technology that has attracted a great deal of attention in recent months. It enables researchers to edit DNA. Dr. Cruz is applying this technology in an attempt to repair neurons that are abnormal due to a dystonia-causing mutation in the DYT1 gene. Her work will also study how the mutated torsinA protein encoded by the gene interferes with the functions of neurons; this may lead to uncovering new strategies to treat the disorder.

Maria Daniela Cirnaru, PhD
Mount Sinai Beth Israel (USA)

Mentor: Michelle Ehrlich, MD

X-linked dystonia parkinsonism (XDP) is an inherited and degenerative form of dystonia that affects men from Panay Island in the Philippines. Unlike other dystonias, XDP is characterized by extensive neuron loss in a brain region involved in movement control and reward. Dr. Cirnaru hypothesizes that two genes, TAF1 and N-TAF1, control the expression of important factors that influence the health of these neurons. This project may enhance understanding of the role of TAF1 in the pathogenesis of XDP and accelerate the development of novel therapeutic strategies for XDP and other dystonias.

Anthony Rampello, PhD, Yale University

Mentor: Christian Schlieker, PhD

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) represents a profound advancement in genome editing technology. CRISPR is used to edit genetic material in living organisms easier, faster, and with greater precision than previous methods. While popular news reports tend to focus on the potential use of CRISPR for genome editing in humans, the primary application has been in basic research using cell and animal models. Dr. Rampello is using CRISPR to establish a TorsinA interaction map by systemically tracking down genes and proteins that have a functional relationship to TorsinA. Mapping the network of cellular processes in which TorsinA is involved is critical to understanding how TorsinA causes dystonia when made dysfunctional by errors in the DYT1 gene. This project is supported by the family of Ron and Barbara Oliver and the Barbara Oliver Memorial Research Fund.

Lisa Rauschenberger, MD, PhD, University Hospital of Würzburg (Germany)

Mentor: Chi Wang Ip, MD, PhD

Dystonia represents a group of movement disorders, with diverse symptoms and numerous causative genes identified. Environmental factors such as peripheral trauma have been suggested as a possible trigger for dystonia in genetically predisposed individuals. A mutation in the TOR1A gene is responsible for early-onset torsion dystonia, among the most well-studied dystonia types. The pathophysiology of dystonia is largely unclear, but maladaptive synaptic plasticity is suspected to be one of the driving factors. Movements that the brain has learned over time—blinking, writing, walking, etc.— become abnormal. Movements that were once mastered get “re-learned” incorrectly, resulting in in dystonia. And the brain cannot easily un-learn the abnormal movements or postures once they are imprinted. Dr. Rauschenberger hypothesizes that a disruption of sensorimotor integration causes maladaptive plasticity, which is in part supported by microglia, a group of highly-specialized cells involved in neuronal plasticity and remodeling of networks. The researchers aim to analyze the pathophysiological concepts behind early-onset torsion dystonia by creating and analyzing transgenic dystonia mouse models. The models will be highly valuable in future research, paving the way for treatment studies. Analyzing the role of microglia in dystonia is the first experiment of its kind and may lead to breakthrough insights into the pathogenesis of the disorder.

Barbara Oliver Memorial Dystonia Research Award

Gabriela Huelgas-Morales, PhD, University of Minnesota

Mentor: David Greenstein, PhD

In 1997 researchers discovered that a tiny error in the DYT1 gene was responsible for a severe type of childhood dystonia. The genetic error interferes with the ability of a protein in the brain called TorsinA to function correctly. Dystonia investigators around the world have been working to understand how TorsinA operates normally and what cellular functions go wrong when the protein is dysfunctional. Dr. Morales is using a worm model to identify TorsinA substrates, i.e. proteins that TorsinA acts upon. This is critical to understanding the basic cellular functions of TorsinA and origins of DYT1 childhood dystonia.

Ashley Helseth, MD, PhD, Duke University (USA)

Mentor: Nicole Calakos, MD, PhD

Existing dystonia treatment options suppress symptoms without correcting the disease process. This project proposes to advance understanding of dystonia mechanisms and explore specific cellular pathways to target for treatment. Observations in multiple types of dystonia have implicated a specific cellular pathway in the brain as a central source of dysfunction. This pathway is involved in responding to cellular stressors and mediating plasticity responses in the brain. Dr. Helseth proposes to identify the brain regions, cell types, and developmental periods in which the pathway’s activation is disrupted in dystonia mouse models and to test whether targeting the pathway through genetic manipulations will modulate the negative effects. This knowledge will advance understanding of the cellular mechanism of dystonia and provide key proof-of-principle experiments to determine whether targeting the pathway for treatment is beneficial.

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