Clinical/Scientific Notes E.W. Tsang, MSc C. Hamani, MD, PhD E. Moro, MD, PhD F. Mazzella, RN A.M. Lozano, MD, PhD I.J. Yeh, MD R. Chen, MBBChir, MSc, FRCPC Supplemental data at www.neurology.org Supplemental Data PROMINENT 5–18 HZ OSCILLATIONS IN THE PALLIDAL-THALAMIC CIRCUIT IN SECONDARY DYSTONIA Previous studies in primary dystonia suggested that abnormal oscillations of 5–18 Hz in the bilateral internal globus pallidus (GPi) may be a specific feature of dystonia.1–3 Moreover, voluntary movements were associated with bilateral desynchronization of ␤ (⬍30 Hz) and contralateral synchronization of ␥ (⬃70 Hz) frequencies in the GPi.2– 4 We recorded local field potentials (LFPs) from the GPi and motor thalamus in a patient with severe hemidystonia to test the following hypotheses. First, the 5–18 Hz synchronization is present in the basal ganglia (BG)– thalamic circuit in patients with secondary dystonia. Second, the bilaterally coherent 5–18 Hz activity may be transmitted between the hemispheres through the motor thalamus. Finally, if the 5–18 Hz rhythm is related to dystonia, attempted movements of dystonic muscles would result in less attenuation of this 5–18 Hz oscillation compared to normal movements. Methods. We studied a 43-year-old woman with severe left hemidystonia secondary to a cryptogenic stroke in the right putamen and the external globus pallidus 5 years earlier (figure e-1 on the Neurology® Web site at www.neurology.org). She received unilateral right GPi and ventral intermediate nucleus of the thalamus (Vim) deep brain stimulation (DBS) implants (table e-1). GPi/Vim LFPs were recorded from the quadripolar DBS electrodes using linked-ears reference 2 days after electrode implantations. EMG were recorded from the extensor and flexor carpi radialis muscles. The patient made brisk self-initiated right wrist extension and attempted left wrist extension approximately once every 10 seconds. Each side was studied for ⬃10 –15 minutes. See appendix e-1 for further details. Results. Attempted movements of the left wrist produced barely perceptible movements but was associated with discrete EMG bursts that were of much lower amplitude than the normal right wrist (figure 1, A and B). Left wrist movement led to a diffuse ⬃6 –25 Hz event-related desynchronization (ERD) and a high amplitude 64 – 68 Hz event-related synchronization (ERS) in the right GPi and Vim (figure 1, C and E). This ␥ activity showed coherence between the GPi and Vim (figure 1G). Right wrist movements were associated with 6 –25 Hz ERD but no ␥ ERS at the right GPi and Vim (figure 1, B, D, and F). A strong resting 5–18 Hz coherence with strength of ⬃0.8 was observed between the right GPi and Vim, which attenuated during movements of the unaffected ipsilateral right wrist (figure 1H), but not during attempted movements of the dystonic left wrist (figure 1G). Discussion. Coherence between GPi and motor thalamus in dystonia has not been reported. Several observations here are consistent with the hypothesis1–3,5 that 5–18 Hz rhythm is related to dystonia. First, the 5–18 Hz GPi-Vim coherence in our patient with severe hemidystonia (figure 1, G and H) is much stronger than the bilateral GPi coherence in patients with cervical dystonia (CD),2 suggesting its amplitude may be related to the severity of dystonia. Second, this 5–18 Hz oscillation is present in our patient with secondary dystonia in addition to primary dystonia demonstrated in previous studies,2,3 suggesting that the 5–18 Hz oscillation in the pallidal-thalamic circuit may be a general feature of dystonia. Third, we observed the attenuation of the 5–18 Hz GPi-Vim coherence only during ipsilateral normal arm movements (figure 1H) but not during attempted movement of the contralateral dystonic arm (figure 1G). Since previous studies found that unilateral wrist movements of unaffected hands in CD patients led to the attenuation of the resting 5–18 Hz coherence between the bilateral GPi,2 the present findings support the notion that excessive 5–18 Hz oscillation is related to dystonia. However, the failure to attenuate the 5–18 Hz coherence may also be related to the low movement amplitudes of the dystonic left hand. Our findings also suggest that the motor thalamus may be part of the circuit mediating the coherence between bilateral GPi in dystonia.2,5 Although the DBS was targeted to the Vim, the cerebellar receiving thalamus, some of the activities recorded likely originated from the adjacent pallidal receiving thalamus.6 Neurology 78 January 31, 2012 361 Figure 1 Movement-related event-related desynchronization (ERD) and event-related synchronization (ERS) and coherence in the right internal globus pallidus (GPi) and ventral intermediate nucleus of the thalamus (Vim) (A) Rectified averaged EMG recordings of the extensor carpi radialis (top) and flexor carpi radialis (bottom) muscles during attempted self-initiated extension movements of the dystonic left wrist and (B) extension movements of the unaffected right wrist. From C to F, movement-related ERD/ERS in the right GPi and Vim are shown. The baseline period comprised of recordings from ⫺4 to ⫺3 seconds. ERD/ERS power changes (left) are color coded in percentage relative to the mean of the baseline period. Blue represents ERD while red represents ERS. The abscissa denotes time in seconds, where the red marker at time 0 represents movement onset, and the ordinate denotes frequency from 4 to 100 Hz. In the corresponding permutation tests (right), blue areas indicate significant ERD while red areas indicate significant ERS. (C) ERD/ERS of the right GPi during attempted self-initiated extension movements of the dystonic left wrist and (D) self-initiated extension movements of the unaffected right wrist. (E) ERD/ERS of the right Vim during attempted self-initiated extension movements of the dystonic left wrist and (F) self-initiated extension movements of the unaffected right wrist. For G and H, coherences are shown on the left and the corresponding permutation tests on the right. The abscissa denotes time in seconds, where the red marker at time 0 represents movement onset, and the ordinate denotes frequency from 4 to 100 Hz. In the permutation tests, red areas indicate significant coherences. (G) Coherence between the right GPi and right Vim during attempted movements of the contralateral dystonic left wrist and (H) during movements of the unaffected ipsilateral right wrist. Anatomically, ⬃20% of pallidal-thalamic fibers cross over to the contralateral motor thalamus,6 which projects to the cortex and to the centromedian nucleus, which in turn projects to other BG nuclei such as the putamen, subthalamic nucleus, and GPi.6 362 Neurology 78 January 31, 2012 The finding for the ␥ band was opposite to that of the ␤ band with a 64 – 68 Hz GPi/Vim ERS and coherence contralateral to the movements of the dystonic arm (figure 1, C, E, and G) but no change with movements of the normal ipsilateral right wrist (figure 1, D, F, and H). The strictly contralateral modulation of the ␥ frequency is consistent with the previous finding in the cortex and GPi during normal wrist movements.2,4 Moreover, the moderately high amplitude ␥ coherence observed during attempted movements of severely dystonic left wrist (figure 1G) suggests that this ␥ oscillation in the pallidal-thalamic circuit may be related to the effort involved in movement execution and is not attenuated by the presence of dystonia. From the Division of Brain Imaging & Behaviour Systems–Neuroscience (E.W.T., F.M., A.M.L., I.J.Y., R.C.), Toronto Western Research Institute, University Health Network, Toronto; Institute of Medical Science (E.W.T., A.M.L., R.C.), University of Toronto, Toronto; Division of Neurosurgery (C.H., A.M.L.), Division of Neurology (E.M., I.J.Y., R.C.), University Health Network, University of Toronto, Toronto, Canada; and Department of Neurology (I.J.Y.), Songde Branch, Taipei City Hospital, Taipei, Taiwan. Author contributions: E.W. Tsang: data collection, analysis and interpretation, drafting and revising the manuscript. Dr. Hamani: data collection and analysis, manuscript revision. Dr. Moro: conceptualization of the study, data collection, manuscript revision. F. Mazzella: data collection, manuscript revision. Dr. Lozano: data collection, manuscript revision. Dr. Yeh: data analysis, manuscript revision. Dr. Chen: conceptualization of the study, data interpretation, manuscript revision. Study funding: Supported by the Canadian Institutes of Health Research (MOP15128). Eric W. Tsang was supported by a CIHR Canada Graduate Scholarship Doctoral Award. Robert Chen is supported by a CIHR–Industry Partnered Investigator Award and Andres Lozano is supported by Canada Research Chair in Neurosciences. Disclosure: E.W. Tsang received research support from a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship Doctoral Award. Dr. Hamani has received speaker honoraria from St. Jude Medical and Medtronic, Inc.; serves as a consultant for St. Jude Medical; serves as research support from the Canadian Institutes of Health Research, National Alliance for Research on Schizophrenia and Depression, and Ontario Mental Health Foundation. Dr. Moro has received speaker honoraria from Medtronic, Inc.; serves on the editorial board of Frontiers in Teleneurology; serves as a consultant for Medtronic, Inc.; receives research support from St. Jude Medical, CIHR-AF-BMBF, SickKids Foundation, IHDCYH, and CurePSP. F. Mazzella reports no disclosures. Dr. Lozano serves on scientific advisory boards for Johnson & Johnson, Codman & Shurtleff, Inc., Ceregene, Neurologix, Inc., and Functional Neuroscience, Inc.; serves as Deputy Editor of Brain Stimulation and on the editorial boards of the Journal of Neurosurgery, Neurosurgery, Movement Disorders, World Neurosurgery, Neurological Research Stereotactic and Functional Neurosurgery, Operative Neurosurgery, NeuroRx, Surgical Neurology, and Parkinsonism and Related Disorders; holds patents re: Methods of treating depres- sion, mood disorders and anxiety using neuromodulation; Method of treating mood disorders and/or anxiety disorders by brain stimulation; Brain stimulation lead used for lesioning; and Method of treating movement disorders by electrical stimulation and/or drug infusion of the pedunculopontine nucleus; receives royalties from the publication of Surgical Treatment of Parkinson’s Disease and Other Movement Disorders (Humana Press, 2002) and Textbook of Stereotactic and Functional Neurosurgery, 2nd ed. (Springer, 2009); has received honoraria and research support from Medtronic, Inc. and St. Jude Medical, Inc.; holds the Canada Research Chair in Neurosciences; and serves as a consultant for Medtronic, Inc., St. Jude Medical, Inc., Boston Scientific, Amgen, Ely Lilly and Company, Bristol-Myers Squibb, Elekta, Bayer Schering Pharma, and Schering-Plough Corp. Dr. Yeh reports no disclosures. Dr. Chen has served on scientific advisory boards for Medtronic, Inc., Teva Pharmaceutical Industries Ltd., Allergan, Inc., Novartis, and Biovail Corporation; has received funding for travel and speaker honoraria from Merz Pharmaceuticals, LLC and Allergan Inc.; serves/has served on the editorial boards of Clinical Neurophysiology, Muscle and Nerve, Journal of Motor Behavior, Canadian Journal of Neurological Sciences, Neural Plasticity, and Neurology; receives/has received research support from Medtronic Inc, CIHR, the Michael J. Fox Foundation for Parkinson’s Research, and the Dystonia Medical Research Foundation; and has provided expert testimony and affidavit in welding-related litigation. Received July 5, 2011. Accepted in final form September 29, 2011. Correspondence & reprint requests to Dr. Chen: robert.chen@uhn.ca Copyright © 2012 by AAN Enterprises, Inc. 1. 2. 3. 4. 5. 6. Sharott A, Grosse P, Kuhn AA, et al. Is the synchronization between pallidal and muscle activity in primary dystonia due to peripheral afferance or a motor drive? Brain 2008;131:473– 484. Tsang EW, Hamani C, Moro E, et al. Movement-related potentials and oscillatory activities in the human internal globus pallidus during voluntary movements. J Neurol Neurosurg Psychiatry 2012;83:91–97. Liu X, Wang S, Yianni J, et al. The sensory and motor representation of synchronized oscillations in the globus pallidus in patients with primary dystonia. Brain 2008; 131:1562–1573. Brucke C, Kempf F, Kupsch A, et al. 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