Longitudinal changes in functional connectivity of cortico‐basal ganglia networks in manifests and premanifest huntington's disease

Huntington's disease (HD) is a genetic neurological disorder resulting in cognitive and motor impairments. We evaluated the longitudinal changes of functional connectivity in sensorimotor, associative and limbic cortico‐basal ganglia networks. We acquired structural MRI and resting‐state fMRI in three visits one year apart, in 18 adult HD patients, 24 asymptomatic mutation carriers (preHD) and 18 gender‐ and age‐matched healthy volunteers from the TRACK‐HD study. We inferred topological changes in functional connectivity between 182 regions within cortico‐basal ganglia networks using graph theory measures. We found significant differences for global graph theory measures in HD but not in preHD. The average shortest path length (L) decreased, which indicated a change toward the random network topology. HD patients also demonstrated increases in degree k, reduced betweeness centrality bc and reduced clustering C. Changes predominated in the sensorimotor network for bc and C and were observed in all circuits for k. Hubs were reduced in preHD and no longer detectable in HD in the sensorimotor and associative networks. Changes in graph theory metrics (L, k, C and bc) correlated with four clinical and cognitive measures (symbol digit modalities test, Stroop, Burden and UHDRS). There were no changes in graph theory metrics across sessions, which suggests that these measures are not reliable biomarkers of longitudinal changes in HD. preHD is characterized by progressive decreasing hub organization, and these changes aggravate in HD patients with changes in local metrics. HD is characterized by progressive changes in global network interconnectivity, whose network topology becomes more random over time. Hum Brain Mapp 37:4112–4128, 2016. © 2016 Wiley Periodicals, Inc.

[1]  J. Vonsattel,et al.  Huntington disease models and human neuropathology: similarities and differences , 2007, Acta Neuropathologica.

[2]  James J. Pekar,et al.  Impaired cortico-striatal functional connectivity in prodromal Huntington's Disease , 2012, Neuroscience Letters.

[3]  Joseph B. Martin.  Huntington's disease , 1984, Neurology.

[4]  Jian Lin,et al.  Functional Connectivity of Primary Motor Cortex Is Dependent on Genetic Burden in Prodromal Huntington Disease , 2014, Brain Connect..

[5]  James B. Brewer,et al.  Stability of resting fMRI interregional correlations analyzed in subject-native space: A one-year longitudinal study in healthy adults and premanifest Huntington's disease , 2012, NeuroImage.

[6]  S. Lehéricy,et al.  The structural correlates of functional deficits in early huntington's disease , 2013, Human brain mapping.

[7]  V Latora,et al.  Efficient behavior of small-world networks. , 2001, Physical review letters.

[8]  Jane S. Paulsen,et al.  Unified Huntington's disease rating scale: Reliability and consistency , 1996, Movement disorders : official journal of the Movement Disorder Society.

[9]  Edward T. Bullmore,et al.  Connectivity differences in brain networks , 2012, NeuroImage.

[10]  M. Greicius,et al.  Greater than the sum of its parts: a review of studies combining structural connectivity and resting-state functional connectivity , 2009, Brain Structure and Function.

[11]  Jonas Richiardi,et al.  Graph analysis of functional brain networks: practical issues in translational neuroscience , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[12]  Thomas T. Liu,et al.  A component based noise correction method (CompCor) for BOLD and perfusion based fMRI , 2007, NeuroImage.

[13]  M. Greicius,et al.  Resting-state functional connectivity reflects structural connectivity in the default mode network. , 2009, Cerebral cortex.

[14]  Thomas E. Nichols,et al.  Brain Network Analysis: Separating Cost from Topology Using Cost-Integration , 2011, PloS one.

[15]  Jane S. Paulsen,et al.  Network topology and functional connectivity disturbances precede the onset of Huntington's disease. , 2015, Brain : a journal of neurology.

[16]  O. Sporns,et al.  Rich-Club Organization of the Human Connectome , 2011, The Journal of Neuroscience.

[17]  C. Ross,et al.  Huntington's disease: from molecular pathogenesis to clinical treatment , 2011, The Lancet Neurology.

[18]  S. Rombouts,et al.  Reduced functional brain connectivity prior to and after disease onset in Huntington's disease☆☆☆ , 2013, NeuroImage: Clinical.

[19]  Diederick Stoffers,et al.  Basal ganglia atrophy in prodromal Huntington's disease is detectable over one year using automated segmentation , 2011, Movement disorders : official journal of the Movement Disorder Society.

[20]  M. MacDonald,et al.  CAG repeat number governs the development rate of pathology in Huntington's disease , 1997, Annals of neurology.

[21]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[22]  Nicholas Ayache,et al.  A three-dimensional histological atlas of the human basal ganglia. II. Atlas deformation strategy and evaluation in deep brain stimulation for Parkinson disease. , 2009, Journal of neurosurgery.

[23]  O. Sporns,et al.  The economy of brain network organization , 2012, Nature Reviews Neuroscience.

[24]  Mert R. Sabuncu,et al.  The influence of head motion on intrinsic functional connectivity MRI , 2012, NeuroImage.

[25]  A. Dale,et al.  Cortical Surface-Based Analysis II: Inflation, Flattening, and a Surface-Based Coordinate System , 1999, NeuroImage.

[26]  K. Gurney,et al.  Network ‘Small-World-Ness’: A Quantitative Method for Determining Canonical Network Equivalence , 2008, PloS one.

[27]  B. Schelter,et al.  Detection of preclinical neural dysfunction from functional connectivity graphs derived from task fMRI. An example from degeneration , 2013, Psychiatry Research: Neuroimaging.

[28]  Bruce Fischl,et al.  Within-subject template estimation for unbiased longitudinal image analysis , 2012, NeuroImage.

[29]  H. Benali,et al.  Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome. , 2012, Brain : a journal of neurology.

[30]  Nick C Fox,et al.  Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data , 2009, The Lancet Neurology.

[31]  Marcus Kaiser,et al.  Nonoptimal Component Placement, but Short Processing Paths, due to Long-Distance Projections in Neural Systems , 2006, PLoS Comput. Biol..

[32]  Dale E. Zand,et al.  Parallel Organization , 2014 .

[33]  B Fischl,et al.  Regional cortical thinning in preclinical Huntington disease and its relationship to cognition , 2005, Neurology.

[34]  J. Lupski,et al.  DUF1220-domain copy number implicated in human brain-size pathology and evolution. , 2012, American journal of human genetics.

[35]  Julie C Stout,et al.  Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study. , 2014, Journal of psychiatry & neuroscience : JPN.

[36]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[37]  J. Pillai.  Functional Connectivity. , 2017, Neuroimaging clinics of North America.

[38]  M. Breakspear,et al.  The connectomics of brain disorders , 2015, Nature Reviews Neuroscience.

[39]  Nikos Makris,et al.  Automatically parcellating the human cerebral cortex. , 2004, Cerebral cortex.

[40]  Habib Benali,et al.  Specific and Evolving Resting-State Network Alterations in Post-Concussion Syndrome Following Mild Traumatic Brain Injury , 2013, PloS one.

[41]  Anne-Catherine Bachoud-Lévi,et al.  The role of the striatum in rule application: the model of Huntington's disease at early stage. , 2005, Brain : a journal of neurology.

[42]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

[43]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[44]  G. E. Alexander,et al.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex. , 1986, Annual review of neuroscience.

[45]  J. Ridley.  Studies of Interference in Serial Verbal Reactions , 2001 .

[46]  Sébastien Ourselin,et al.  A three-dimensional, histological and deformable atlas of the human basal ganglia. I. Atlas construction based on immunohistochemical and MRI data , 2007, NeuroImage.

[47]  Jeroen van der Grond,et al.  Longitudinal resting state fMRI analysis in healthy controls and premanifest Huntington's disease gene carriers: A three‐year follow‐up study , 2015, Human brain mapping.

[48]  A. Brunetti,et al.  Default-Mode Network Changes in Huntington’s Disease: An Integrated MRI Study of Functional Connectivity and Morphometry , 2013, PloS one.

[49]  Olaf Sporns,et al.  Complex network measures of brain connectivity: Uses and interpretations , 2010, NeuroImage.

[50]  Timothy O. Laumann,et al.  Methods to detect, characterize, and remove motion artifact in resting state fMRI , 2014, NeuroImage.

[51]  N Jon Shah,et al.  Altered resting‐state connectivity in Huntington's Disease , 2014, Human brain mapping.