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Abnormal resting-state connectivity of motor and cognitive networks in early manifest Huntington's disease

  • R. C. Wolf (a1), F. Sambataro (a2), N. Vasic (a3), M. S. Depping (a1), P. A. Thomann (a1), G. B. Landwehrmeyer (a4), S. D. Süssmuth (a4) and M. Orth (a4)...

Abstract

Background.

Functional magnetic resonance imaging (fMRI) of multiple neural networks during the brain's ‘resting state’ could facilitate biomarker development in patients with Huntington's disease (HD) and may provide new insights into the relationship between neural dysfunction and clinical symptoms. To date, however, very few studies have examined the functional integrity of multiple resting state networks (RSNs) in manifest HD, and even less is known about whether concomitant brain atrophy affects neural activity in patients.

Method.

Using MRI, we investigated brain structure and RSN function in patients with early HD (n = 20) and healthy controls (n = 20). For resting-state fMRI data a group-independent component analysis identified spatiotemporally distinct patterns of motor and prefrontal RSNs of interest. We used voxel-based morphometry to assess regional brain atrophy, and ‘biological parametric mapping’ analyses to investigate the impact of atrophy on neural activity.

Results.

Compared with controls, patients showed connectivity changes within distinct neural systems including lateral prefrontal, supplementary motor, thalamic, cingulate, temporal and parietal regions. In patients, supplementary motor area and cingulate cortex connectivity indices were associated with measures of motor function, whereas lateral prefrontal connectivity was associated with cognition.

Conclusions.

This study provides evidence for aberrant connectivity of RSNs associated with motor function and cognition in early manifest HD when controlling for brain atrophy. This suggests clinically relevant changes of RSN activity in the presence of HD-associated cortical and subcortical structural abnormalities.

Copyright

Corresponding author

* Address for correspondence: R. C. Wolf, M.D., University of Heidelberg, Center for Psychosocial Medicine, Department of General Psychiatry, Voßstraße 4, 69115 Heidelberg, Germany. (Email: christian.wolf@med.uni-heidelberg.de)

References

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Allen, EA, Erhardt, EB, Damaraju, E, Gruner, W, Segall, JM, Silva, RF, Havlicek, M, Rachakonda, S, Fries, J, Kalyanam, R, Michael, AM, Caprihan, A, Turner, JA, Eichele, T, Adelsheim, S, Bryan, AD, Bustillo, J, Clark, VP, Feldstein Ewing, SW, Filbey, F, Ford, CC, Hutchison, K, Jung, RE, Kiehl, KA, Kodituwakku, P, Komesu, YM, Mayer, AR, Pearlson, GD, Phillips, JP, Sadek, JR, Stevens, M, Teuscher, U, Thoma, RJ, Calhoun, VD (2011). A baseline for the multivariate comparison of resting-state networks. Frontiers in Systems Neuroscience. Published online 4 February 2011 . doi:10.3389/fnsys.2011.00002.
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. American Psychological Association: Washington, DC.
Ashburner, J (2007). A fast diffeomorphic image registration algorithm. NeuroImage 38, 95113.
Ashburner, J, Friston, KJ (2005). Unified segmentation. NeuroImage 26, 839851.
Aylward, EH, Nopoulos, PC, Ross, CA, Langbehn, DR, Pierson, RK, Mills, JA, Johnson, HJ, Magnotta, VA, Juhl, AR, Paulsen, JS (2011). Longitudinal change in regional brain volumes in prodromal Huntington disease. Journal of Neurology, Neurosurgery, and Psychiatry 82, 405410.
Bartenstein, P, Weindl, A, Spiegel, S, Boecker, H, Wenzel, R, Ceballos-Baumann, AO, Minoshima, S, Conrad, B (1997). Central motor processing in Huntington's disease. A PET study. Brain 120, 15531567.
Biswal, B, Yetkin, FZ, Haughton, VM, Hyde, JS (1995). Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magnetic Resonance in Medicine 34, 537541.
Brett, M, Anton, J-L, Valabregue, R, Poline, JB (2002). Region of interest analysis using an SPM toolbox [abstract, presented at 8th International Conference on Functional Mapping of the Human Brain, Sendai, Japan]. NeuroImage 16, 497.
Broyd, SJ, Demanuele, C, Debener, S, Helps, SK, James, CJ, Sonuga-Barke, EJ (2008). Default-mode brain dysfunction in mental disorders: a systematic review. Neuroscience and Biobehavioral Reviews 33, 279296.
Buckner, RL, Andrews-Hanna, JR, Schacter, DL (2008). The brain's default network: anatomy, function, and relevance to disease. Annals of the New York Academy of Sciences 1124, 138.
Calhoun, VD, Adali, T, Pekar, JJ (2004). A method for comparing group fMRI data using independent component analysis: application to visual, motor and visuomotor tasks. Magnetic Resonance Imaging 22, 11811191.
Calhoun, VD, Kiehl, KA, Pearlson, GD (2008). Modulation of temporally coherent brain networks estimated using ICA at rest and during cognitive tasks. Human Brain Mapping 29, 828838.
Casanova, R, Srikanth, R, Baer, A, Laurienti, PJ, Burdette, JH, Hayasaka, S, Flowers, L, Wood, F, Maldjian, JA (2007). Biological parametric mapping: a statistical toolbox for multimodality brain image analysis. NeuroImage 34, 137143.
Correa, N, Adali, T, Yi-Ou, L, Calhoun, VD (2005). Comparison of blind source separation algorithms for fMRI using a new Matlab toolbox: GIFT. Proceedings of the IEEE International Conference on Acoustics, Speech, Signal Processing 5, 401404.
Damoiseaux, JS, Rombouts, SA, Barkhof, F, Scheltens, P, Stam, CJ, Smith, SM, Beckmann, CF (2006). Consistent resting-state networks across healthy subjects. Proceedings of the National Academy of Sciences USA 103, 1384813853.
Dogan, I, Eickhoff, SB, Schulz, JB, Shah, NJ, Laird, AR, Fox, PT, Reetz, K (2013). Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis. Neurodegenerative Diseases 12, 2335.
Fox, MD, Corbetta, M, Snyder, AZ, Vincent, JL, Raichle, ME (2006). Spontaneous neuronal activity distinguishes human dorsal and ventral attention systems. Proceedings of the National Academy of Sciences USA 103, 1004610051.
Fox, MD, Greicius, M (2010). Clinical applications of resting state functional connectivity. Frontiers in Systems Neuroscience 4, 19.
Fox, MD, Snyder, AZ, Vincent, JL, Corbetta, M, Van Essen, DC, Raichle, ME (2005). The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proceedings of the National Academy of Sciences USA 102, 96739678.
Gavazzi, C, Nave, RD, Petralli, R, Rocca, MA, Guerrini, L, Tessa, C, Diciotti, S, Filippi, M, Piacentini, S, Mascalchi, M (2007). Combining functional and structural brain magnetic resonance imaging in Huntington disease. Journal of Computer Assisted Tomography 31, 574580.
Georgiou-Karistianis, N, Sritharan, A, Farrow, M, Cunnington, R, Stout, J, Bradshaw, J, Churchyard, A, Brawn, TL, Chua, P, Chiu, E, Thiruvady, D, Egan, G (2007). Increased cortical recruitment in Huntington's disease using a Simon task. Neuropsychologia 45, 17911800.
Gomez-Anson, B, Alegret, M, Munoz, E, Monte, GC, Alayrach, E, Sanchez, A, Boada, M, Tolosa, E (2009). Prefrontal cortex volume reduction on MRI in preclinical Huntington's disease relates to visuomotor performance and CAG number. Parkinsonism and Related Disorders 15, 213219.
Gray, MA, Egan, GF, Ando, A, Churchyard, A, Chua, P, Stout, JC, Georgiou-Karistianis, N (2013). Prefrontal activity in Huntington's disease reflects cognitive and neuropsychiatric disturbances: The IMAGE-HD study. Experimental Neurology 239, 218228.
Hasselbalch, SG, Oberg, G, Sorensen, SA, Andersen, AR, Waldemar, G, Schmidt, JF, Fenger, K, Paulson, OB (1992). Reduced regional cerebral blood flow in Huntington's disease studied by SPECT. Journal of Neurology, Neurosurgery, and Psychiatry 55, 10181023.
Hennenlotter, A, Schroeder, U, Erhard, P, Haslinger, B, Stahl, R, Weindl, A, von Einsiedel, HG, Lange, KW, Ceballos-Baumann, AO (2004). Neural correlates associated with impaired disgust processing in pre-symptomatic Huntington's disease. Brain 127, 14461453.
Himberg, J, Hyvarinen, A, Esposito, F (2004). Validating the independent components of neuroimaging time series via clustering and visualization. NeuroImage 22, 12141222.
Huntington Study Group (1996). The Unified Huntington's Disease Rating Scale: Reliability and Consistency. Movement Disorders 11, 136142.
Jafri, MJ, Pearlson, GD, Stevens, M, Calhoun, VD (2008). A method for functional network connectivity among spatially independent resting-state components in schizophrenia. NeuroImage 39, 16661681.
Kelly, C, Biswal, BB, Craddock, RC, Castellanos, FX, Milham, MP (2012). Characterizing variation in the functional connectome: promise and pitfalls. Trends in Cognitive Sciences 16, 181188.
Klöppel, S, Draganski, B, Siebner, HR, Tabrizi, SJ, Weiller, C, Frackowiak, RS (2009 a). Functional compensation of motor function in pre-symptomatic Huntington's disease. Brain 132, 16241632.
Klöppel, S, Henley, SM, Hobbs, NZ, Wolf, RC, Kassubek, J, Tabrizi, SJ, Frackowiak, RS (2009 b). Magnetic resonance imaging of Huntington's disease: preparing for clinical trials. Neuroscience 164, 205219.
Laird, AR, Fox, PM, Eickhoff, SB, Turner, JA, Ray, KL, McKay, DR, Glahn, DC, Beckmann, CF, Smith, SM, Fox, PT (2012). Behavioral interpretations of intrinsic connectivity networks. Journal of Cognitive Neuroscience 23, 40224037.
Lambrecq, V, Langbour, N, Guehl, D, Bioulac, B, Burbaud, P, Rotgea, J-Y (2013). Evolution of brain gray matter loss in Huntington's disease: a meta-analysis. European Journal of Neurology 20, 315321.
Lehrl, S, Triebig, G, Fischer, B (1995). Multiple choice vocabulary test MWT as a valid and short test to estimate premorbid intelligence. Acta Neurologica Scandinavica 91, 335345.
Li, YO, Adali, T, Calhoun, VD (2007). Estimating the number of independent components for functional magnetic resonance imaging data. Human Brain Mapping 28, 12511266.
Maitra, R (2009). Assessing certainty of activation or inactivation in test–retest fMRI studies. NeuroImage 47, 8897.
Manjon, JV, Coupe, P, Marti-Bonmati, L, Collins, DL, Robles, M (2010). Adaptive non-local means denoising of MR images with spatially varying noise levels. Journal of Magnetic Resonance Imaging 31, 192203.
McCabe, C, Mishor, Z (2011). Antidepressant medications reduce subcortical–cortical resting-state functional connectivity in healthy volunteers. NeuroImage 57, 13171323.
Olbrich, S, Mulert, C, Karch, S, Trenner, M, Leicht, G, Pogarell, O, Hegerl, U (2009). EEG-vigilance and BOLD effect during simultaneous EEG/fMRI measurement. NeuroImage 45, 319332.
Orth, M, Handley, OJ, Schwenke, C, Dunnett, SB, Craufurd, D, Ho, AK, Wild, E, Tabrizi, SJ, Landwehrmeyer, GB (2010). Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY. PLOS Currents 2, RRN1184.
Paulsen, JS, Zimbelman, JL, Hinton, SC, Langbehn, DR, Leveroni, CL, Benjamin, ML, Reynolds, NC, Rao, SM (2004). fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington's disease. American Journal of Neuroradiology 25, 17151721.
Penney, JB Jr, Vonsattel, JP, MacDonald, ME, Gusella, JF, Myers, RH (1997). CAG repeat number governs the development rate of pathology in Huntington's disease. Annals of Neurology 41, 689692.
Posner, J, Hellerstein, DJ, Gat, I, Mechling, A, Klahr, K, Wang, Z, McGrath, PJ, Stewart, JW, Peterson, B (2013). Antidepressants normalize the default mode network in patients with dysthymia. JAMA Psychiatry 70, 373382.
Priller, J, Ecker, D, Landwehrmeyer, GB, Craufurd, D (2008). A Europe-wide assessment of current medication choices in Huntington's disease. Movement Disorders 23, 1788.
Quarantelli, M, Salvatore, E, Giorgio, SM, Filla, A, Cervo, A, Russo, CV, Cocozza, S, Massarelli, M, Brunetti, A, De Michele, G (2013). Default-mode network changes in Huntington's disease: an integrated MRI study of functional connectivity and morphometry. PLOS ONE 8, e72159.
Raemaekers, M, Vink, M, Zandbelt, B, van Wezel, RJ, Kahn, RS, Ramsey, NF (2007). Test–retest reliability of fMRI activation during prosaccades and antisaccades. NeuroImage 36, 532542.
Rajapakse, JC, Giedd, JN, Rapoport, JL (1997). Statistical approach to segmentation of single-channel cerebral MR images. IEEE Transactions in Medical Imaging 16, 176186.
Reading, SA, Dziorny, AC, Peroutka, LA, Schreiber, M, Gourley, LM, Yallapragada, V, Rosenblatt, A, Margolis, RL, Pekar, JJ, Pearlson, GD, Aylward, E, Brandt, J, Bassett, SS, Ross, CA (2004). Functional brain changes in presymptomatic Huntington's disease. Annals of Neurology 55, 879883.
Ross, CA, Tabrizi, SJ (2011). Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurology 10, 8398.
Rub, U, Hoche, F, Brunt, ER, Heinsen, H, Seidel, K, Del Turco, D, Paulson, HL, Bohl, J, von Gall, C, Vonsattel, JP, Korf, HW, den Dunnen, WF (2012). Degeneration of the cerebellum in Huntington's disease (HD): possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process. Brain Pathology 23, 165177.
Sax, DS, Powsner, R, Kim, A, Tilak, S, Bhatia, R, Cupples, LA, Myers, RH (1996). Evidence of cortical metabolic dysfunction in early Huntington's disease by single-photon-emission computed tomography. Movement Disorders 11, 671677.
Seibert, TM, Majid, DS, Aron, AR, Corey-Bloom, J, Brewer, JB (2012). Stability of resting fMRI interregional correlations analyzed in subject-native space: a one-year longitudinal study in healthy adults and premanifest Huntington's disease. NeuroImage 59, 24522463.
Smith, SM, Fox, PT, Miller, KL, Glahn, DC, Fox, PM, Mackay, CE, Filippini, N, Watkins, KE, Toro, R, Laird, AR, Beckmann, CF (2009). Correspondence of the brain's functional architecture during activation and rest. Proceedings of the National Academy of Sciences USA 106, 1304013045.
Tabrizi, SJ, Langbehn, DR, Leavitt, BR, Roos, RA, Durr, A, Craufurd, D, Kennard, C, Hicks, SL, Fox, NC, Scahill, RI, Borowsky, B, Tobin, AJ, Rosas, HD, Johnson, H, Reilmann, R, Landwehrmeyer, B, Stout, JC (2009). Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurology 8, 791801.
Tabrizi, SJ, Reilmann, R, Roos, RA, Durr, A, Leavitt, B, Owen, G, Jones, R, Johnson, H, Craufurd, D, Hicks, SL, Kennard, C, Landwehrmeyer, B, Stout, JC, Borowsky, B, Scahill, RI, Frost, C, Langbehn, DR (2012). Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurology 11, 4253.
Tabrizi, SJ, Scahill, RI, Durr, A, Roos, RA, Leavitt, BR, Jones, R, Landwehrmeyer, GB, Fox, NC, Johnson, H, Hicks, SL, Kennard, C, Craufurd, D, Frost, C, Langbehn, DR, Reilmann, R, Stout, JC (2011). Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurology 10, 3142.
Takada, M, Tokuno, H, Hamada, I, Inase, M, Ito, Y, Imanishi, M, Hasegawa, N, Akazawa, T, Hatanaka, N, Nambu, A (2001). Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey. European Journal of Neuroscience 14, 16331650.
Tohka, J, Zijdenbos, A, Evans, A (2004). Fast and robust parameter estimation for statistical partial volume models in brain MRI. NeuroImage 23, 8497.
Tzourio-Mazoyer, N, Landeau, B, Papathanassiou, D, Crivello, F, Etard, O, Delcroix, N, Mazoyer, B, Joliot, M (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15, 273289.
Unschuld, PG, Joel, SE, Liu, X, Shanahan, M, Margolis, RL, Biglan, KM, Bassett, SS, Schretlen, DJ, Redgrave, GW, van Zijl, PC, Pekar, JJ, Ross, CA (2012). Impaired cortico-striatal functional connectivity in prodromal Huntington's disease. Neuroscience Letters 514, 204209.
van den Heuvel, MP, Hulshoff Pol, HE (2010). Exploring the brain network: a review on resting-state fMRI functional connectivity. European Neuropsychopharmacology 20, 519534.
Weeks, RA, Ceballos-Baumann, A, Piccini, P, Boecker, H, Harding, AE, Brooks, DJ (1997). Cortical control of movement in Huntington's disease. A PET activation study. Brain 120, 15691578.
Weir, DW, Sturrock, A, Leavitt, BR (2011). Development of biomarkers for Huntington's disease. Lancet Neurology 10, 573590.
Werner, CJ, Dogan, I, Saß, C, Mirzazade, S, Schiefer, J, Shah, NJ, Schulz, JB, Reetz, K (2013). Altered resting-state connectivity in Huntington's disease. Human Brain Mapping. Published online 24 August 2013 . doi:10.1002.hbm.22351.
Wolf, RC, Gron, G, Sambataro, F, Vasic, N, Wolf, ND, Thomann, PA, Saft, C, Landwehrmeyer, GB, Orth, M (2011). Magnetic resonance perfusion imaging of resting-state cerebral blood flow in preclinical Huntington's disease. Journal of Cerebral Blood Flow and Metabolism 31, 19081918.
Wolf, RC, Klöppel, S (2013). Clinical significance of frontal cortex abnormalities in Huntington's Disease. Experimental Neurology 247, 3944.
Wolf, RC, Sambataro, F, Vasic, N, Schonfeldt-Lecuona, C, Ecker, D, Landwehrmeyer, B (2008). Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease. Experimental Neurology 213, 137144.
Wolf, RC, Sambataro, F, Vasic, N, Wolf, ND, Thomann, PA, Saft, C, Landwehrmeyer, GB, Orth, M (2012). Default-mode network changes in preclinical Huntington's disease. Experimental Neurology 237, 191198.
Wolf, RC, Thomann, PA, Thomann, AK, Vasic, N, Wolf, ND, Landwehrmeyer, GB, Orth, M (2013). Brain structure in preclinical Huntington's disease: a multi-method approach. Neurodegenerative Diseases 12, 1322.
Wolf, RC, Vasic, N, Sambataro, F, Höse, A, Frasch, K, Schmidt, M, Walter, H (2009 a). Temporally anticorrelated brain networks during working memory performance reveal prefrontal and hippocampal dysconnectivity in patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 14641473.
Wolf, RC, Vasic, N, Schonfeldt-Lecuona, C, Ecker, D, Landwehrmeyer, GB (2009 b). Cortical dysfunction in patients with Huntington's disease during working memory performance. Human Brain Mapping 30, 327339.
Wolf, RC, Vasic, N, Schonfeldt-Lecuona, C, Landwehrmeyer, GB, Ecker, D (2007). Dorsolateral prefrontal cortex dysfunction in presymptomatic Huntington's disease: evidence from event-related fMRI. Brain 130, 28452857.
Worsley, KJ, Cao, J, Paus, T, Petrides, M, Evans, AC (1998). Applications of random field theory to functional connectivity. Human Brain Mapping 6, 364367.
Zandbelt, BB, Gladwin, TE, Raemaekers, M, van Buuren, M, Neggers, SF, Kahn, RS, Ramsey, NF, Vink, M (2008). Within-subject variation in BOLD-fMRI signal changes across repeated measurements: quantification and implications for sample size. NeuroImage 42, 196206.
Zigmond, AS, Snaith, RP (1983). The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica 67, 361370.
Zimbelman, JL, Paulsen, JS, Mikos, AE, Reynolds, NC, Hoffman, RG, Rao, SM (2007). fMRI detection of early neural dysfunction in preclinical Huntington's disease. Journal of the International Neuropsychological Society 13, 758769.

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Abnormal resting-state connectivity of motor and cognitive networks in early manifest Huntington's disease

  • R. C. Wolf (a1), F. Sambataro (a2), N. Vasic (a3), M. S. Depping (a1), P. A. Thomann (a1), G. B. Landwehrmeyer (a4), S. D. Süssmuth (a4) and M. Orth (a4)...

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