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.
New in 2023
Daniel Corp, PhD
Deakin University, Victoria, Australia
The goal of this study is to reveal the anatomy of dystonia by analyzing causal links between symptoms and brain structures affected by lesions. This will ultimately identify targets for new brain stimulation methods.
Jean-Francois Nankoo, PhD
University Health Network, Toronto, Canada
This project aims to explore the effects of a novel non-invasive brain stimulation technique that has the potential to be a safer, less costly, and more accessible alternative to deep brain stimulation.
Christian Schlieker, PhD
Yale University, New Haven, CT
This project will use advanced molecular methods to develop new pharmacological approaches that disrupt the cellular cascade leading to neuronal dysfunction with the aim to select specific compounds with drug-like properties that may potentially be developed into dystonia drugs.
Brian Berman, MD, MS
Virginia Commonwealth University
This research proposal will lead to an increased understanding of the neurobiology of cervical dystonia and the role that altered inhibition plays in the disorder. This study will further help establish whether GABA (an amino acid that works as a neurotransmitter) levels in the sensorimotor network change when the dystonia is treated with botulinum neurotoxin injections and whether measurement of GABA levels is stable over time. If positive, the findings from this research could lead to a reliable imaging test to aid in the diagnosis of cervical dystonia or to an objective way to track responses to novel therapies and thereby accelerate much-needed treatment development. Findings from this research study could further provide the preliminary data needed to apply for a larger federal grant to investigate the role abnormal inhibition plays in other types of dystonia as well as in the progression and spread of dystonia in affected individuals.
Xandra Breakefield, PhD
Massachusetts General Hospital
Gene therapy is proving beneficial in an increasing number of neurological diseases. This proposal represents a step in evaluating whether gene therapy could be effective in DYT1 dystonia. Dr. Breakefield’s lab has shown that selective disruption of the mutant TOR1A/DYT1 gene can normalize biologic cell functions in patient skin cells. Since dystonia is a neurological disease, the next step is to evaluate whether this approach can normalize function in TOR1A/DYT1 neurons (brain cells). Through the work of Dr. D. Cristopher Bragg and Dr. Nutan Sharma the investigators have access to stem cells from DYT1 patients, which can be turned into neurons. If successful in rescuing neurons, the lab will work with Dr. David Standaert to translate the technology into a mouse model which would provide some of the data needed for the Food & Drug Administration to allow a clinical trial. Ultimately, Dr. Breakefield envisions a clinical trial in which children carrying the mutant TOR1A/DYT1 gene and manifesting symptoms at an early age are administered gene therapy in a single dose. This could be done at the same time as deep brain stimulation (DBS), with the intent to eventually turn off the DBS device to assess if it remains needed. The ultimate goal of this effort is the development of better therapies for DYT1 dystonia.
Cecile Gallea, PhD
Salpêtrière Hospital, Paris
Connie and Jim Brown Early Stage Investigator Award
Myoclonus-dystonia (M-D) is a movement disorder caused by mutations in the SGCE/DYT11 gene. The neurological basis of this disorder remain 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 DYT11 symptoms and pathophysiology.
Leighton Hinkley, PhD
University of California, San Francisco
Supported by the Cure Dystonia Now Fund of the DMRF
Non-invasive neuromodulation—where brain stimulation is delivered without surgery—is an exciting new method for treating movement disorders including focal dystonia. One particular technique, repetitive transcranial magnetic stimulation (rTMS), has provided clinical benefit for the treatment of many neurological and psychiatric conditions and has been approved by the US Food & Drug Administration (FDA) to treat conditions such as major depressive disorder. While great effort has been made over the past two decades trying to develop rTMS as a treatment option for focal dystonia, studies have failed to deliver a consistent, effective protocol to reduce the dystonia symptoms.
Although there are different ways to deliver rTMS dosage, most of the studies that have been done using rTMS for dystonia stimulate the exact same region of the brain across all patients, assuming that this one location is the focus of the disorder. Focal dystonia is a very heterogeneous condition, impacting different structures of the body, for example, the vocal cords in laryngeal dystonia or the hand in task-specific focal hand dystonia. One reason why previous rTMS trials for dystonia have not had great success may be because the optimal rTMS stimulation target for dystonia treatment may not be in the exact same location for each and every patient.
In this study, investigators adopt a personalized approach for identifying the correct place to stimulate using rTMS for focal dystonia. They hypothesize that the specific regions of the brain that act as dystonia “hotspots” for stimulation will vary across the frontal and parietal lobes of the brain in each patient, true to the nature of dystonia being different in every individual. To identify these specific hotspots, they take a next-generation approach using non-invasive neuroimaging including functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) to identify abnormally connected or abnormally active regions of the brain in patients. Resting-state fMRI maps are a powerful way to look at functional connections in the brain and differences in those connections. Guided by this brain imaging data, the investigators will generate personalized maps of optimal sites to stimulate with rTMS. Using these personalized maps as a guide, they will deliver a single session of rTMS to see if stimulating that patient-specific region changes some of the clinical characteristics of laryngeal dystonia and task-specific focal hand dystonia as well as some of the cognitive and behavioral features identifiable in those movement disorders.
The goal of the project is to provide a framework and option for delivering neuromodulation in a better way than what is currently available. The investigators need to understand the best way to deliver neuromodulation for each patient before the next steps to large scale treatment trials and ultimately the clinic. A more informed approach guided by neuroscience for the treatment of dystonia will ultimately help patients get the greatest benefit from neuromodulation.
Simon Little, PhD
University of California, San Francisco
Supported by Jennifer and Philip Maritz
In addition to being a treatment, deep brain stimulation (DBS) is helping researchers understand how dystonia affects the brain. Recent work has shown that brain signals in dystonia are different from those without dystonia or with other neurological disorders. This has revealed a pattern of activity in the deep parts of the brain that repeats around five times per second in people with dystonia and is linked to muscle activity. However, investigators don’t yet know the significance of this signal and whether it causes muscles to contract or is simply a marker that they have done so. Also, if it is a cause of dystonia, it isn’t yet known how this interferes with the healthy sensory messages that come into the brain or the movement signals that leave the brain. To answer these questions, Dr. Little and team are using new sensing-enabled DBS devices which can record brain signals as well as provide stimulation therapy. They have implanted this device in a small group of dystonia patients and found that the dystonia signals are present in all patients recorded so far. They are investigating how this signal relates to muscle activity and sensory processing. They are also testing this new type of adaptive stimulation to see if it may be more effective and cause fewer side effects than standard continuous DBS. This study will further understanding of how brain signaling goes wrong in dystonia, knowledge which could potentially lead to the design of new and improved therapies.
Stephanie Moon, PhD
University of Michigan, Ann Arbor
The goal of this research project is to understand how small changes in Protein Kinase R cause dystonia. Human genetics researchers found that mutations in the DNA that codes for Protein Kinase R causes an early-onset dystonia in children. Some children with this form of early-onset dystonia had worse symptoms after viral infection or surgery, conditions that can stress the body. These observations suggest that small changes in Protein Kinase R could interfere with the cell’s ability to react to stresses and perhaps contribute to dystonia. Dr. Moon’s lab is interested in how Protein Kinase R helps cells called neurons grow and respond to stresses to allow brain function and controlled body movement. Ideally, this research will help scientists understand why changes in Protein Kinase R affect neurons in normal and stressed conditions, which will in turn provide new drug targets to develop treatments for dystonia.
Antonio Pisani, MD
University of Pavia
Dr. Pisani and his team are studying brain circuits in two types of genetic dystonia: DYT1 dystonia, which is the most common inherited form, and DYT25 dystonia which is rarer. They are testing the idea that loss of these genes leads to changes in brain plasticity, which is how the brain learns motor tasks and adapts to new environments. They believe that abnormal plasticity is a shared factor responsible for abnormal movements observed in patients. They will study two animal models, one with the DYT1/TOR1A gene mutation and the other with loss of DYT25/GNAO1. By conducting studies on brain circuits in these models, they hope to learn about the effects of the loss of these genes on brain plasticity. One of the features of abnormal movements in dystonia is that once the symptoms develop, they can be difficult to treat and may become permanent. This is a kind of dysfunctional plasticity. Therefore, if investigators can understand the mechanisms and control the abnormal plasticity, they might be able to ‘undo’ the changes in the brain that cause these movements, leading to better treatments.
Richard Reilly, PhD
Trinity College Dublin
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.
Emmanuel Roze, MD
Paris Brain Institute
The striatum is a deep structure in the brain that plays a critical role in the control of movements. cAMP is a molecule that regulates many cell functions, including in neurons (brain cells). The cAMP signaling pathway controls processes important for the function of neurons in the striatum and the control of movements. (A signaling pathway is the string of communication among a group of molecules to complete a specific task in the cell.) Various genes that encode proteins involved in this cAMP pathway can cause dystonia when mutated, particularly GNAL/DYT25 and ADCY5. Mutations of GNAL/DYT25 lead to reduced cAMP production while mutations of ADCY5 lead to increased cAMP production. To better understand how disruptions in the cAMP pathway produce dystonia, the investgators will characterize movement dysfunction and striatal biochemical abnormalities of genetic mouse models. To investigate the cAMP pathway as a target to treat dystonia, they will correct the abnormal cAMP pathway in the mouse models using drugs and investigate whether treatment improves the biochemical abnormalities and movement dysfunction. Finally, they will evaluate the effect of caffeine in ADCY5-related dystonia patients which is suspected to reduce excess of cAMP production and has been found to be helpful in some patients. To this end, they will use questionnaires and a randomized, controlled clinical trial with a single dose of caffeine.
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.
Anne Weissbach, MD
University of Lübeck
Connie and Jim Brown Early Stage Investigator Award
Myoclonus-dystonia (M-D) is a neurological movement disorder often characterized by a combination of generalized myoclonic jerks, dystonia, and psychiatric disorders. Mutations in the SGCE and VPS16 genes have been identified as genetic causes of the disease. Both genes are important for the function of an area of the brain called the cerebellum. These investigators and others have demonstrated that individuals with M-D have deficits of cerebellar mediated learning. How cerebellar malfunction in these patients affects the cortex of the brain, particularly regions important for motor control is of particular interest. Dr. Weissbach is leading the first study to investigate potential symptom reduction and neurophysiological changes in M-D patients before and after repetitive non-invasive transcranial magnetic stimulation (rTMS). The study aims to identify the clinical cerebellar deficit, identify abnormalities of cerebellar function and its interaction with the cortex of the brain as well as examine the reversibility of these abnormalities through the application of cerebellar rTMS. These findings will foster development of new treatment strategies.
Dhananjay Yellajoshyula, PhD
Case Western Reserve University, Cleveland, Ohio
In this proposal, Dr. Yellajoshyula and his team will investigate the cellular mechanism by which the DYT-THAP1 disease mutation results in white matter brain abnormalities. They will test the hypothesis that DYT-THAP1 disease mutation disrupts cellular pathways commonly regulated by the two dystonia genes, THAP1 and YY1, in the glial cells necessary for generating the white matter. They will additionally use proteomic studies to identify the molecular binding partners of THAP1 and define how these interactions are disrupted from DYT-THAP1 disease mutation.
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.
New in 2023
Filipa França de Barros, PhD, Champalimaud Foundation, Lisbon, Portugal
The aim of the project is to quantify and manipulate the brain activity underlying a dystonic forelimb movement in mice. The results should facilitate targeting specific neuronal populations of the direct basal ganglia to produce more efficient therapies.
Linda Kim, PhD, Baylor College of Medicine, Houston, TX
Mahlon DeLong Young Investigator Award
Dr. Kim will test the hypothesis that the unique pathophysiological cerebellar neural signals in dystonia can serve as robust biomarkers for triggering an adaptable closed-loop deep brain stimulation response to restore movement with high precision.
Simon Lowe, MD
University College London
Amanda Pocratsky, PhD
University College London
While the characteristic features of dystonia are movement related, there is also a widely-recognized sensory component to this movement disorder. For example, patients often use “sensory tricks” where they perform simple voluntary maneuvers, such as lightly touching the affected body region, to temporarily alleviate their dystonia symptoms. These alleviating effects can be reproduced by applying sensory stimulation to the affected regions. These, and many other observations collectively implicate a role for the sensory system in dystonia, but the underlying biological mechanisms remain unknown. Dr. Pocratsky will investigate how sensory dysfunction occurs in a new DYT1 animal model. The experiments outlined in this project will provide scientists with a solid understanding of where and how sensory dysfunction occurs in dystonia from transduction (how the sensory stimulus gets turned into a nerve signal) to conduction (how the signal propagates to the nervous system) to transmission (how the signal communicates with other nerve cells). These data will provide key insight into the underlying biological mechanisms of sensory dysfunction in dystonia. Not only could these findings transform our understanding of dystonia, but they may also reveal key sensory-based targets for symptom alleviating therapies.