Inhibitory and Network Dysfunction in Primary Focal Dystonia

Brian Berman, M.D., M.S.

University of Colorado Denver, Aurora, CO, Department of Neurology

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2014, for 3 years

Funding Amount:


Lay Summary

PET and fMRI imaging in dystonia patients may reveal how the disease occurs

Researchers will combine PET and fMRI imaging in patients with cervical dystonia to see if deficits in the neurotransmitter GABA alter the brain’s sensorimotor circuit to produce the disorder’s characteristic involuntary muscle contractions that affect the head, neck and shoulders.

People with cervical dystonia suffer from uncontrolled spasms of their neck muscles that cause their head to involuntarily turn to the side or be pulled frontward or backward. The neck muscle spasms can also lead to raised shoulders and head tremor. Patients often have pain associated with their symptoms. The disorder’s cause remains elusive and treatments are only partially effective.

No obvious pathology in the brains of patients with cervical dystonia has been found. Yet imaging studies have reported abnormal brain activity in a wide array of brain regions. Moreover, related studies in other forms of dystonia suggest that the disorder may involve problems with one of the brain’s inhibitory neurotransmitters, called GABA, or the brain circuits that utilize GABA to communicate between brain regions.

The Colorado investigators, based on their prior research, suspect that the disorder involves problems both with GABA and with abnormal connections within the brain’s motor circuitry. More specifically, they hypothesize that reduced inhibitory control over sensorimotor circuit functioning causes dystonia. They will test this hypothesis in 15 people with cervical dystonia and 15 healthy volunteers. Participants will undergo PET imaging to see whether patients, but not healthy controls, have reduced binding of the inhibitory neurotransmitter GABA to brain cell receptors. Thereafter, participants will undergo fMRI imaging to see whether patients, but not healthy controls, have altered function in sensorimotor networks involving the brain’s basal ganglia and cerebellum. Then the investigators will determine whether functional connectivity problems in these sensorimotor circuits correlate with decreased binding by GABA to the neurotransmitter’s receptors on brain cells.

Significance: The findings could lead to development of new therapeutic strategies for cervical dystonia aimed at increasing the effectiveness of GABA transmission, and at modifying motor network functioning using deep brain stimulation or transcranial magnetic stimulation.


Inhibitory and network dysfunction in primary focal dystonia

Dystonia is a chronic, disabling neurological disorder characterized by involuntary sustained muscle contractions that result in abnormal postures or movements. An estimated 300,000 people in the North America have been diagnosed with dystonia, though up to 1 million may not know they have it or have been misdiagnosed. Primary dystonia refers to dystonias that are not accompanied by other neurological abnormalities and have no known cause except for gene mutations identified in a small minority cases. Primary focal dystonia (PFD), the most common form of primary dystonia, is an affects one body region such as the face or limbs. In cervical dystonia (CD), the most prevalent form of PFD, dystonia affects the neck muscles and causes involuntary and often painful head turning, pulling or jerking. To date, no consistent abnormal brain pathology has been identified in PFD. Animal models and human physiological studies using advanced imaging and transcranial magnetic stimulation techniques suggest that defective inhibition, which is mediated largely by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), may play a key role in the pathogenesis of dystonia. A wide range of abnormal imaging findings in PFD have been reported, however, leading many to propose that PFD stems from network dysfunction. Despite advances made in our understanding of PFD, its pathophysiology remains poorly understood and current treatment options only minimally and transiently effective. A better understanding of the pathophysiology of PFD is greatly needed to help drive the development of mechanism-based treatment strategies and improve the lives of patients. Based on prior physiological studies in PFD and our recently acquired preliminary data, we hypothesize that a reduction in GABA function in patients with CD leads to disturbances within sensorimotor circuits that underlie the motor symptoms of this disorder. By combining PET and functional MRI (fMRI), we propose the following aims to test our hypothesis: Aim 1: Determine if GABAA receptor binding is reduced in CD. Using radiolabeled flumazenil—a GABAA subtype receptor antagonist—a recent PET study found reduced GABAA binding in the primary motor and sensory cortex, premotor cortex, secondary sensory cortex and cingulate motor area in a mixed population of 14 dystonia patients. Our preliminary flumazenil PET data suggest that patients with CD have similarly reduced GABAA binding within sensorimotor network. We aim to build on these data and test the hypothesis that GABAA binding is significantly reduced in CD. Aim 2: Determine if basal ganglia and cerebellar circuit function are altered in CD. Evidence from a variety of functional imaging studies suggests that disturbances within the basal ganglia-thalamo-cortical and cerebello-thalamo-cortical circuits underlie motor symptoms in PFD. Our preliminary resting state fMRI data suggest that patients with PFD have abnormal connectivity within their sensorimotor circuit. We aim to build on these preliminary data and test the hypothesis that both basal ganglia-thalamo-cortical and cerebello-thalamo-cortical motor circuits are altered in CD. Aim 3: Determine whether functional connectivity changes within basal ganglia and cerebellar circuits are correlated to changes in GABAA receptor binding. While the pathophysiology of CD remains poorly understood, converging lines of evidence suggest that the disorder arises from abnormal inhibitory control over sensorimotor circuit functioning. This relationship has not been directly investigated in patients with CD. We aim to combine data from Aims 1 and 2 to test the hypothesis that GABAergic function at the molecular level is linked to sensorimotor circuit function. The short-term impact of this novel multi-modal imaging research includes a greatly increased understanding of the relationship between the brain’s inhibitory mechanisms and resting state network function and how disturbances in inhibitory control alters brain circuit functioning in CD. This knowledge could help drive the development of new therapeutic interventions through the identification of a GABA-related therapeutic target. Additionally, knowledge gained on how brain circuits are disturbed in CD could facilitate ideal brain target selection for emerging network-modulating treatment approaches like transcranial magnetic stimulation and deep brain stimulation.

Investigator Biographies

Brian Berman, M.D., M.S.

Dr. Brian D. Berman, M.D., M.S., is an assistant professor of neurology at the University of Colorado Denver Anschutz Medical Campus. He received a Bachelors of Science in physics from the University of New Mexico followed by a Masters of Science in medical physics and a Medical Degree from the University of Colorado. Dr. Berman completed his neurology residency training at the University of California at San Francisco and then received fellowship training in Movement Disorders under Dr. Mark Hallett at the National Institutes of Health before returning to join the faculty at the University of Colorado Denver. His clinical duties include seeing patients with movement disorders in the Movement Disorders Center at the University of Colorado Hospital and at the Denver Veteran’s Affairs Medical Center. Dr. Berman’s primary research focus involves using advanced imaging techniques such as PET and fMRI to study the pathophysiology of dystonia and Parkinson’s disease with the goals of finding ways imaging can improve their diagnosis, inform treatment development, and ultimately contribute to finding a cure for these neurological disorders.