Evidence for Altered Basal Ganglia-Brainstem Connections in Cervical Dystonia Anne J. Blood 1,2,4,5,6,9 *, John K. Kuster 1,2,4,5,6,10 , Sandra C. Woodman 1,4,5 , Namik Kirlic 1,2,4,5 , Miriam L. Makhlouf 1,4,11 , Trisha J. Multhaupt-Buell 6 , Nikos Makris 3,4,5,9 , Martin Parent 12 , Lewis R. Sudarsky 8,9 , Greta Sjalander 1,4,6 , Henry Breiter 1,4,5 , Hans C. Breiter 1,2,4,5,7,9,13. , Nutan Sharma 6,8,9. 1 Mood and Motor Control Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 2 Laboratory of Neuroimaging and Genetics, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 3 Center for Morphometric Analysis, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 4 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 5 Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 6 Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 7 Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, 8 Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America, 9 Harvard Medical School, Boston, Massachusetts, United States of America, 10 Division of Graduate Medical Sciences, Boston University Medical School, Boston, Massachusetts, United States of America, 11 Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 12 Department of Psychiatry and Neuroscience, Faculty of medicine, Centre de recherche Universite ´ Laval Robert-Giffard, Universite ´ Laval, Quebec City, Quebec, Canada, 13 Department of Psychiatry and Behavioral Sciences, School of Medicine, Warren Wright Adolescent Center and Center for Self-Regulation, Northwestern University Feinberg, Chicago, Illinois, United States of America Abstract Background: There has been increasing interest in the interaction of the basal ganglia with the cerebellum and the brainstem in motor control and movement disorders. In addition, it has been suggested that these subcortical connections with the basal ganglia may help to coordinate a network of regions involved in mediating posture and stabilization. While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia. Methodology/Principal Findings: In the current study we investigated probabilistic diffusion tractography in DYT1- negative patients with cervical dystonia and matched healthy control subjects, with the goal of showing that patients exhibit altered microstructure in the connectivity between the pallidum and brainstem. The brainstem regions investigated included nuclei that are known to exhibit strong connections with the cerebellum. We observed large clusters of tractography differences in patients relative to healthy controls, between the pallidum and the brainstem. Tractography was decreased in the left hemisphere and increased in the right hemisphere in patients, suggesting a potential basis for the left/ right white matter asymmetry we previously observed in focal dystonia patients. Conclusions/Significance: These findings support the hypothesis that connections between the basal ganglia and brainstem play a role in the pathophysiology of dystonia. Citation: Blood AJ, Kuster JK, Woodman SC, Kirlic N, Makhlouf ML, et al. (2012) Evidence for Altered Basal Ganglia-Brainstem Connections in Cervical Dystonia. PLoS ONE 7(2): e31654. doi:10.1371/journal.pone.0031654 Editor: Paul L. Gribble, The University of Western Ontario, Canada Received June 23, 2011; Accepted January 16, 2012; Published February 22, 2012 Copyright: ß 2012 Blood et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Institute of Neurological Disorders and Stroke (grant number R01NS052368 to Dr. Blood, and grant number NINP50NS037409 to Dr. Breakefield with Dr. Sharma as PI of the clinical core), and a grant from the Dystonia Medical Research Foundation to Dr. Blood. The general infrastructure of the Martinos Center for Biomedical Imaging in which research on these grants was conducted, was supported by National Center for Research Resources (grant number P41 RR14075 to Dr. Rosen), and the Mental Illness and Neuroscience Discovery (MIND) Institute (Dr. Rosen). Prescreening and exams were conducted in the General Clinical Research Center, funded by National Center for Research Resources (grant number UL1 RR025758-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ablood@nmr.mgh.harvard.edu . These authors contributed equally to this work. Introduction In addition to the basal ganglia, the pontine brainstem [1,2,3,4], and cerebellum [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20] have been implicated in dystonia by numerous studies. As a synthesis of this literature and a number of other observations in dystonia, we recently hypothesized that the pallidal output neurons exhibiting extensive collateralization to the brainstem [21,22,23] are the neurons gating the functional system that is affected in dystonia. While many pallidothalamic fibers collateralize to the peduncu- lopontine nucleus (PPN), a subset of them collateralize more extensively and project to both the PPN and the red nucleus (RN) [21]. More broadly, we proposed that this latter set of projections helps to coordinate a network of regions involved in the neural control of posture and stabilization [24], including both static and dynamic programs, and that these programs may be affected in a PLoS ONE | www.plosone.org 1 February 2012 | Volume 7 | Issue 2 | e31654