Impact of rTMS on Abnormal Cortical fMRI in Patients With Dystonia

Dystonia is a neurological movement disorder characterized by spontaneous involuntary muscle contractions that cause repetitive twisting motions. These involuntary movements affect various body regions, including the face (blepharospasm), jaw (bruxism, oromandibular dystonia), head and neck (torticollis), voice box (laryngeal spasm), hands (writer's cramp), or as multiple body segments simultaneously. Dystonia lacks defining neuropathological change, making diagnosis challenging, and rendering symptom management incomplete. Advanced imaging techniques, particularly spatial covariance analysis and graph theory computations have revealed insights into dystonia's underlying brain networks. This approach shows that the relative strength of the metabolic function at each brain region (called "hubs") regulates information flow within the network and between the network and the rest of the brain. The identification of accessible cortical hubs as integral parts of the dystonia network raises new therapeutic possibilities though non-invasive techniques. Continuous theta-burst stimulation (cTBS), a modified form of rTMS that mimics natural brain rhythms (theta 4-8Hz), can effectively inhibit the cortical hyperactivity in targeted hubs with shorter treatment times than traditional approaches. The rationale for this proposed pilot experiment is to combine advanced analysis of standard neuroimaging to refine target location for a test of whether the application of non-invasive rTMS (in the form of cTBS) modulates abnormal cortical regions or the entire brain network, or both, as these networks underlie dystonia.

Our PET investigations of patients with dystonia (DYT1 carriers both symptomatic and non-symptomatic) have identified hyperactive subcortical regions including the lentiform nuclei, cerebellum, and supplementary motor cortex. The dystonia-related brain metabolic networks that we generated with PET scanning, can now be generated with rs-fMRI, a less invasive technique that avoids radiation exposure and blood sampling. Graph Theory analysis indicates that the bilateral motor cortex (spanning the inter-hemispheric sulcus) and the left pre-motor region serve as critical hyperactive hubs. We hypothesize that modulating these hubs will disrupt the information flow in patients with dystonia. Using frameless stereotaxic optical system (Polaris Vicra, BrainSight 2.2), we can precisely target these cortical hubs with cTBS, the inhibitory form of rTMS.

We are encouraged by recent studies that showed that a single cTBS run (40sec) precisely targeted significantly modified brain networks in patients with dystonia.

Ameliorating dystonia has been one of the most controversial and challenging topics in treating hyperkinetic movement disorders, because it is difficult to estimate the overall whole brain responses after focal alterations caused by brain stimulation techniques. Our approach offers several innovations:

• Enhanced and personalized hypermetabolic cortical hub identification.
• Use of independent component analysis and graph theory to optimize location for cTBS delivery.
• Individual response to the single cTBS stimulation site will be used for customized modeling of the TMS effect.

Although previous attempts to use TMS to improve dystonia have been inconsistent, our precisely targeted approach may improve outcomes. Success with this method could expand TMS application beyond its established use in depression to other neurological disorders. The shift from PET to rs-fMRI for network mapping represents a significant advance, making the technique/treatment more accessible and easier on patients.

Inclusion criteria

• Male or female
• 18 and 80 years of age.
• Patients who manifest dystonia - sustained involuntary movement of the head, neck, trunk or limbs.
• The dystonia may be spontaneous or genetic, specifically DYT1 or DYT6 and then only those patients who are demonstrating dystonia. The patient/subject will have a normal neurological exam except for dystonia.

Exclusion criteria

• Heredodegenrative dystonia of the type DYT8,9 or 10.
• Past history of head trauma, stroke, epilepsy, demyelinating disease
• Hypertension in excess of 160mmHg systolic and 90mmHg diastolic
• Congestive heart failure
• Diabetes
• Past psychiatric conditions: e.g., depression
• Systemic metabolic disease: e.g., Wilson's disease, progressive neurodegenerative disease (like supranuclear palsy or corticobasal ganglionic degeneration)
• Magnetizable incorporated metal parts - like pacemakers
• History or diagnosis of Parkinson's disease
• Presence of myoclonus
• No previous surgery for dystonia
• Long term exposure to benzodiazepines, neuroleptics or anticonvulsants
• No botulinum toxin within 12 weeks of baseline assessment and fMRI.
• Moderate to severe cognitive impairment (judged by a minimental status of <24.)