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.
Nicole Calakos, MD, PhD
Duke University Medical Center (USA)
Although dystonia is among the top three most common conditions evaluated in neurological movement disorder clinics, the precise mechanisms for dystonia are poorly understood and there are no known disease-modifying treatments. This project proposes to advance our understanding of dystonia mechanisms and to explore specific cellular pathways to target in order to treat the disease. Observations in multiple forms 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. This study 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 a genetic manipulation that would boost the pathway’s activity will reduce negative effects of the DYT1 mutation. This knowledge will advance our understanding of the cellular mechanism of dystonia and provide key proof-of-principle experiments to determine whether targeting the pathway is beneficial.
Marina A.J. de Koning-Tijssen, MD, PhD
University of Groningen (The Netherlands)
This study will compare the present symptoms of M-D patients to the symptoms they had 10 years ago to assess how the symptoms evolve over time. Since M-D patients frequently experience non-motor symptoms including psychological difficulties, sleep disturbances, and fatigue, it is believed these symptoms are part of the disease, not secondary consequences. These non-motor symptoms may result from an altered metabolism of a brain neurotransmitter called serotonin. This study will analyze serotonin levels in the blood of M-D patients, healthy controls, and cervical dystonia patients. A genetic study of serotonin-related genes will be performed using DNA collected from all three groups.
Jesse H. Goldberg, MD/PhD
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.
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.
Ellen Hess, PhD
Emory University (USA)
The causes of dystonia are not clearly understood but abnormal signaling within the striatum, a region of the brain that controls movement, is thought to be involved. It is now possible to record the firing patterns of dozens of neurons simultaneously in the striatum of awake dystonic mice to reveal the abnormal neural code associated with dystonia. Technology known as in vivo microscopy will be used in mice with dystonia to visualize the firing patterns of neurons within the striatum. Mice will be recorded while they are dystonic and after they have been treated with drugs that alleviate the dystonia. By comparing the different firing patterns with and without dystonia, these experiments will reveal the neural code associated with dystonia for the first time. In the short term, these experiments will provide important information that could be useful to guide stimulation parameters for deep brain stimulation in dystonia patients. In the long-term, understanding the neural code of dystonia will provide important information for the development of novel therapeutics that target the abnormal neural code.
William Hutchison, PhD
Toronto Western Hospital (Canada)
Intervention by chronic deep brain stimulation (DBS) in the globus pallidus internus (GPi) has been found beneficial in treating severe cases of dystonia but the mechanisms underlying the pathophysiology and the DBS treatment are poorly understood. This study seeks to better understand how and why DBS works. The researchers propose using microelectrode recordings of dystonia patients to investigate cell activity in an area of the brain called the the globus pallidus. In addition, they will use microstimulation and focally evoked field potentials (fEPs) to determine whether there are functional abnormalities in inhibitory processes at neurosurgical target sites. They will obtain synaptic plasticity measures and correlate these to the type and severity of dystonia using clinical rating scores. The goal is to gain insight into the mechanisms of tremor and dystonia. The researchers hope to possibly translate this knowledge to develop new targets for pharmacological intervention. This project is funded by Dystonia Medical Research Foundation Canada.
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.
Patrick Lusk, PhD
Yale University (USA)
DYT1 dystonia is caused by an underlying genetic abnormality that leads to the expression of a defective form of a protein called TorsinA in cells throughout the body. Although TorsinA’s substrates or its function have not yet been identified, several lines of data support that it works to maintain the integrity of the nuclear membranes that enclose and protect the human genome. For example, the morphology of the nuclear membranes is disrupted in neurons expressing mutant TorsinA with distinct herniations. This research group has recently established that these herniations result from a disruption in the assembly of nuclear pores, the nuclear membrane’s essential transport channels. They uncovered a novel link between nuclear pores and TorsinA. Researchers hypothesize that a disruption of nuclear pore assembly by mutant TorsinA leads to the loss of the highly regulated and essential transport of specific cargo molecules in and out of the cell nucleus. They will use experimental strategies that draw on the collective expertise of a consortium, which includes experts in nuclear transport and the biochemistry and cell biology of Torsins, to test this hypothesis. Data from the proposed study are expected to substantially advance our understanding of Torsin (dys)function, and to facilitate the development of more effective treatment strategies.
Alexandra Nelson, MD, PhD
University of California San Francisco (USA)
The underlying causes of dystonia are not known, though the fact that the brain appears normal in many forms of dystonia suggests that the connections between brain regions, or the activity within these brain regions, are responsible. This study uses a new mouse model of dystonia, based on a genetic form of the human disease called paroxysmal kinesigenic dystonia (PKD), to dissect how the connection between cells is altered, putting patients at risk of developing dystonia. This project will first test the movement of PKD model mice versus their healthy siblings, looking for evidence of dystonia. The second phase of the project will involve making recordings of the connections between cells in two brain regions believed to contribute to dystonia: the striatum and the cerebellum. Researchers hope this study will form the foundation for a larger research program aimed at understanding the fundamental cellular and circuit changes that cause dystonia, so that new and more effective drugs or brain stimulation approaches can be developed.
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.
Giuseppe Sciamanna, PhD
University of Rome tor Vergata (Italy)
DYT1 dystonia pathophysiology is not well understood, but evidence points to alterations of the basal ganglia circuit. Moreover, it has been suggested that external globus pallidus (GPe) may be strongly involved in generation of dystonic symptoms. Alterations in the firing pattern of GPe neurons in both humans and rodent models have been found. GPe receives strong inhibitory input from the striatum and it projects to all other nuclei of basal ganglia. Thanks to this large interconnection, GPe has a crucial role in processing of sensorimotor information and its abnormal activity can have major consequences for basal ganglia function and activity. To date no exhaustive investigation has been conducted about the role of GPe in dystonia. By means of electrophysiological, optogenetic, and biochemical approaches, this project aims to investigate in a mouse model of DYT1 dystonia, potential abnormality in neural activity of GPe neurons together with alterations of mutual synaptic connection between striatum and GPe. The project will characterize for the first time the role of GPe in the pathogenesis of dystonia investigating how the interaction among distinct basal ganglia nuclei may be altered, and could represent a crucial step to understand the cellular basis of dystonic symptoms
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.
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.
Patrik Verstreken, PhD
VIB Leuven (Belgium)
TorsinA is the protein encoded by the DYT1 dystonia gene. This research group recently identified that mouse TorsinA, human TorsinA, and fly Torsin regulate cellular lipid metabolism. Lipids are small molecules that are the building blocks of cell membranes. There are a wide variety of different types of lipids, and their data indicates that Torsin activity is critical for the normal balance of lipid production. The hypothesis is that abnormal lipid biology is the origin of DYT1 dystonia. The fruit fly is an ideal system to study individual neurons, rapidly introduce gene mutations, and one that is accessible to microscopy to see cell structure and perform electrophysiology to record neuronal activity. The plan is to investigate how abnormal Torsin lipid biology affects neurons, and to relate this to the endoplasmic reticulum defects previously described in Torsin model systems. The researchers will also test whether manipulation of lipid enzymes overcomes neuronal defects of Torsin dysfunction. These experiments are important for the field to know whether lipid regulation by Torsins is relevant in neurons. It is also vital to build a cloud of mechanistic information around Torsin regulated lipid biology in order for the field and industry to be confident that lipid metabolism is indeed a key target for DYT1 dystonia, and determine whether lipid biology is important broadly.
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
Salpetriere Hospital (France)
The sense of agency, which refers to the experience of initiating and controlling one’s own actions, is an integral part of cognitive movement control. In this study, investigators aim to show that an altered sense of agency is common mechanism across the different types of dystonia by investigating myoclonus-dystonia (M-D) patients. Investigators will use a battery of computerized tests, the results from which will be integrated with brain imaging to identify brain pathways implicated in the sense of agency. The goal is to provide a new perspective on the fundamental mechanism of M-D and direct involvement of cognitive processes in dystonia.
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.
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.