title: Functional connectivity modeling of consistent cortico-striatal degeneration in Huntington's disease.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG or IFJ in conjunction with the striatum were associated with cognitive functions, while the network formed by M1 and the striatum was driven by motor-related tasks. Thus, based on morphological changes in HD, we identified functionally distinct cortico-striatal networks resembling a cognitive and motor loop, which may be prone to early disruptions in different stages of the disease and underlie HD-related cognitive and motor symptom profiles. Our findings provide an important link between morphometrically defined seed-regions and corresponding functional circuits highlighting the functional and ensuing clinical relevance of structural damage in HD.
authors.affiliation: Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany ; Institute of Neuroscience and Medicine (INM-1, INM-4), Research Center Jülich GmbH, 52425 Jülich, Germany ; JARA - Translational Brain Medicine, Aachen, Jülich, Germany.
authors.forename: Imis
authors.initials: I
authors.lastname: Dogan
authors.affiliation: Institute of Neuroscience and Medicine (INM-1, INM-4), Research Center Jülich GmbH, 52425 Jülich, Germany ; Department of Psychiatry, Psychotherapy and Psychosomatic, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Eickhoff
authors.affiliation: Research Imaging Center, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7801, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Fox
authors.affiliation: Department of Physics, Florida International University, Modesto A. Maidique Campus, CP 204, 11200 SW 8th Street, Miami, FL 33199, USA.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Laird
authors.affiliation: Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany ; JARA - Translational Brain Medicine, Aachen, Jülich, Germany.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.affiliation: Institute of Neuroscience and Medicine (INM-1, INM-4), Research Center Jülich GmbH, 52425 Jülich, Germany ; Institute of Clinical Neuroscience and Medical Psychology, Heinrich-Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Simon B
authors.initials: SB
authors.lastname: Eickhoff
authors.affiliation: Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany ; Institute of Neuroscience and Medicine (INM-1, INM-4), Research Center Jülich GmbH, 52425 Jülich, Germany ; JARA - Translational Brain Medicine, Aachen, Jülich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reetz
mesh_terms: D001921:Brain / Q000503:physiopathology*; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology*; D008959:Models, Neurological; D009434:Neural Pathways / Q000502:physiology*
keywords: Atrophy; Functional MRI; Functional connectivity; Meta-analytic connectivity modeling; Neurodegeneration; Resting-state
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