Current Projects

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.

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.

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.