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.

New in 2022

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.

Leighton Hinkley, PhD
University of California, San Francisco

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.

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.

Dhananjay Yellajoshyula, PhD
University of Michigan, Ann Arbor

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.

 

Continuing Projects

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. Dr. Arkadir and his team believe that additional 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.

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.

Simon Little, MBBS, MRCP, PhD
University of California, San Francisco

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.

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 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.

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.

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.

New in 2022

Stephanie Cernera, PhD
The Regents of the University of California, San Francisco

In this study, Dr. Stephanie Cernera will be exploring individual dystonia patients' brain signals while they are performing various movements in the comfort of their homes. Gathering this information will provide insight into different brain patterns and relate them to corresponding behavioral/movement states. Changes in personal patterns will also be monitored when brain stimulation is or off. Understanding how such personal signatures are changing with stimulation, will allow for using such patterns to program the patient’s deep brain stimulation (DBS) device improving their treatment.

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.

Continuing Awards

Simon Lowe, PhD
University College London Institute of Neurology

While researchers have uncovered a number of genetic mutations that cause dystonia, and it is well-known that dystonia affects certain areas of the brain, not enough is known about the mechanisms that ultimately cause the movement dysfunction. Some disease-causing mutations act acutely, which means they cause a disorder by directly altering the function of the brain, affecting its ability to perform tasks. Other mutations act developmentally, which means they alter the way the brain develops, causing lasting alterations in the way the brain works. Knowing which is happening is key to understanding and treating a disorder. Dr. Lowe is investigating a form of dystonia caused by a single mutation in the gene KCNMA1, which has a number of important roles in neurons (brain cells). Dr. Lowe and his team developed the first animal model of this disorder in the fruit fly. Using advanced genetic techniques he is able to turn the mutation ‘on’ and ‘off’ at different stages of the flies’ lifecycle. Preliminary data show that turning the mutation on in the adult fly has no effect, but turning the mutation on and then back off again during its development causes severe, lasting movement defects in the adult fly. These defects very much resemble the movement dysfunction seen in humans. This is a clear demonstration that the mutation causes movement dysfunction in the fly by altering nervous system development. Dr. Lowe aims to confirm this and delineate the key developmental stage with additional experiments, and then ask the question how this mutation affects development. The investigation intends to provide mechanistic insights into a specific form of inherited dystonia and answer key questions about when and how dystonia occurs that may be the same in other forms of dystonia.

 

Lisa Rauschenberger, MD, PhD
University Hospital of Würzburg

David Rudolph Dystonia Research Fund Award

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 DYT1/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. This means movements that the brain has learned—blinking, writing, walking—get “re-learned” incorrectly, resulting in dystonia. The brain cannot easily un-learn the abnormal movements or postures once they are imprinted. Dr. Rauschenberger hypothesizes that a disruption in how the nervous system integrates motor and sensory information causes maladaptive plasticity, which is in part supported by microglia, a group of highly-specialized cells. 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 origins of the disorder.

Meike van der Heijden, PhD
Baylor College of Medicine

The wide range of underlying causes for dystonia has made it difficult to develop one-size-fits-all treatment. Development of a treatment that would be broadly effective across the dystonias would be highly beneficial. Recent studies have suggested that the cerebellum may be a central node in a brain network that triggers dystonia in humans and mouse models. One specific area of the cerebellum, the cerebellar nuclei, sends neural signals to other regions of the brain and spinal cord that are involved in motor control. Imaging studies in dystonia patients and electrical recordings in dystonia mouse models have shown that these neuronal signals are different from people without symptoms and control mice, respectively. Interestingly, therapeutic stimulation of the cerebellar nuclei using deep brain stimulation (DBS) alleviates symptoms in some people with acquired dystonia and in a mouse model with severe dystonia. Dr. van der Heijden hypothesizes that the cerebellar nuclei act as a fulcrum in the expression of dystonia symptoms. On the one hand, abnormal neuronal signals in the cerebellar nuclei can cause dystonia-associated symptoms. On the other hand, stimulating these nuclei with DBS can alleviate dystonia-associated symptoms. However, to fully understand how to best optimize DBS treatment, it is necessary know precisely what the balanced state neuronal signaling is in the cerebellar nuclei, and in what direction these communication signals are skewed in mouse models of dystonia. To answer this question, the investigators are recording brain activity profiles in multiple mouse models of dystonia with different severities of dystonia-associated symptoms. They will use mathematical computations to determine what aspect of the neural signals are abnormal and cause dystonia-associated movement impairments. They hope to find precisely how cerebellar signals contribute to dystonias with different causes. This knowledge will be an important step for optimizing cerebellar DBS to become a first-line treatment for patients with dystonia.

 

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