Journal of Neurology

, Volume 265, Issue 6, pp 1353–1364 | Cite as

Alterations in white matter network topology contribute to freezing of gait in Parkinson’s disease

  • Julie M. Hall
  • James M. Shine
  • Kaylena A. Ehgoetz Martens
  • Moran Gilat
  • Kathryn M. Broadhouse
  • Jennifer Y. Y. Szeto
  • Courtney C. Walton
  • Ahmed A. Moustafa
  • Simon J. G. Lewis
Original Communication


Freezing of gait (FOG) is a common symptom in advanced Parkinson’s disease (PD). Despite current advances, the neural mechanisms underpinning this disturbance remain poorly understood. To this end, we investigated the structural organisation of the white matter connectome in PD freezers and PD non-freezers. We hypothesized that freezers would show an altered network architecture, which could hinder the effective information processing that characterizes the disorder. Twenty-six freezers and twenty-four well-matched non-freezers were included in this study. Using diffusion tensor imaging, we investigated the modularity and integration of the regional connectome by calculating the module degree z score and the participation coefficient, respectively. Compared to non-freezers, freezers demonstrated lower participation coefficients in the right caudate, thalamus, and hippocampus, as well as within superior frontal and parietal cortical regions. Importantly, several of these nodes were found within the brain’s ‘rich club’. Furthermore, group differences in module degree z scores within cortical frontal and sensory processing areas were found. Together, our results suggest that changes in the structural network topology contribute to the manifestation of FOG in PD, specifically due to a lack of structural integration between key information processing hubs of the brain.


Parkinson’s disease Freezing of gait Connectome Diffusion imaging 



We thank the patients and their families who contribute to our research at the Parkinson’s Disease Research Clinic. This research was supported by Sydney Informatics Hub, funded by the University of Sydney. JMH is supported by a Western Sydney University Postgraduate Research Award; JMS is supported by a National Health and Medical Research Council CJ Martin Fellowship (1072403); KAEM is supported by a Parkinson Canada Fellowship; MG is supported by a University of Sydney International Scholarship; SJGL is supported by National Health and Medical Research Council-Australian Research Council Dementia Fellowship (#1110414) and this work was supported by funding to Forefront, a collaborative research group dedicated to the study of non-Alzheimer disease degenerative dementias, from the National Health and Medical Research Council of Australia program grant (#1037746 and #1095127). KMB, JYYS, CCW, and AAM have no funding source to disclose.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All persons gave their informed consent prior to their inclusion in registries. The registries were approved by the Human Research Ethics Committee of the University of Sydney. Patients were included after informed written consent had been obtained, as set forth by the Declaration of Helsinki (WMA, 1964–2014).

Supplementary material

415_2018_8846_MOESM1_ESM.docx (50 kb)
Supplementary material 1 (DOCX 49 kb)
415_2018_8846_MOESM2_ESM.png (78 kb)
Supplementary material 2 (PNG 78 kb)


  1. 1.
    Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A (2011) Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 10(8):734–744. CrossRefPubMedGoogle Scholar
  2. 2.
    Walton CC, Shine JM, Hall JM, O’Callaghan C, Mowszowski L, Gilat M, Szeto JY, Naismith SL, Lewis SJ (2015) The major impact of freezing of gait on quality of life in Parkinson’s disease. J Neurol 262(1):108–115. CrossRefPubMedGoogle Scholar
  3. 3.
    Plotnik M, Giladi N, Hausdorff JM (2012) Is freezing of gait in Parkinson’s disease a result of multiple gait impairments? Implications for treatment. Parkinson’s Dis 2012:8. CrossRefGoogle Scholar
  4. 4.
    Naismith SL, Shine JM, Lewis SJG (2010) The specific contributions of set-shifting to freezing of gait in Parkinson’s disease. Mov Disord 25(8):1000–1004. CrossRefPubMedGoogle Scholar
  5. 5.
    Ehgoetz Martens KA, Ellard CG, Almeida QJ (2014) A closer look at mechanisms underlying perceptual differences in Parkinson’s freezers and non-freezers. Neuroscience 274:162–169. CrossRefPubMedGoogle Scholar
  6. 6.
    Ehgoetz Martens KA, Ellard CG, Almeida QJ (2014) Does anxiety cause freezing of gait in Parkinson’s disease? PLoS One 9(9):e106561. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lewis SJ, Shine JM (2016) The next step: a common neural mechanism for freezing of gait. Neuroscientist 22(1):72–82. CrossRefPubMedGoogle Scholar
  8. 8.
    Schweder PM, Hansen PC, Green AL, Quaghebeur G, Stein J, Aziz TZ (2010) Connectivity of the pedunculopontine nucleus in parkinsonian freezing of gait. NeuroReport 21(14):914–916. CrossRefPubMedGoogle Scholar
  9. 9.
    Fling BW, Cohen RG, Mancini M, Nutt JG, Fair DA, Horak FB (2013) Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait. Brain 136(Pt 8):2405–2418. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Vercruysse S, Leunissen I, Vervoort G, Vandenberghe W, Swinnen S, Nieuwboer A (2015) Microstructural changes in white matter associated with freezing of gait in Parkinson’s disease. Mov Disord 30(4):567–576. CrossRefPubMedGoogle Scholar
  11. 11.
    Youn J, Lee JM, Kwon H, Kim JS, Son TO, Cho JW (2015) Alterations of mean diffusivity of pedunculopontine nucleus pathway in Parkinson’s disease patients with freezing of gait. Parkinsonism Rel Disord 21(1):12–17. CrossRefGoogle Scholar
  12. 12.
    Pietracupa S, Suppa A, Upadhyay N, Giannì C, Grillea G, Leodori G, Modugno N, Di Biasio F, Zampogna A, Colonnese C, Berardelli A, Pantano P (2018) Freezing of gait in Parkinson’s disease: gray and white matter abnormalities. J Neurol 265(1):52–62. CrossRefPubMedGoogle Scholar
  13. 13.
    Fling BW, Cohen RG, Mancini M, Carpenter SD, Fair DA, Nutt JG, Horak FB (2014) functional reorganization of the locomotor network in Parkinson patients with freezing of gait. PLoS One 9(6):e100291. (ARTN) CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Canu E, Agosta F, Sarasso E, Volonte MA, Basaia S, Stojkovic T, Stefanova E, Comi G, Falini A, Kostic VS, Gatti R, Filippi M (2015) Brain structural and functional connectivity in Parkinson’s disease with freezing of gait. Hum Brain Mapp 36(12):5064–5078. CrossRefPubMedGoogle Scholar
  15. 15.
    Shine JM, Poldrack RA (2017) Principles of dynamic network reconfiguration across diverse brain states. NeuroImage. CrossRefPubMedGoogle Scholar
  16. 16.
    Sporns O, Betzel RF (2016) Modular brain networks. Annu Rev Psychol 67:613–640. CrossRefPubMedGoogle Scholar
  17. 17.
    Bassett DS, Yang M, Wymbs NF, Grafton ST (2015) Learning-induced autonomy of sensorimotor systems. Nat Neurosci 18(5):744–751. CrossRefPubMedGoogle Scholar
  18. 18.
    Bertolero MA, Yeo BTT, D’Esposito M (2015) The modular and integrative functional architecture of the human brain. Proc Natl Acad Sci 112(49):E6798–E6807. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sporns O, Chialvo DR, Kaiser M, Hilgetag CC (2004) Organization, development and function of complex brain networks. Trends Cogn Sci 8(9):418–425. CrossRefPubMedGoogle Scholar
  20. 20.
    Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, Movement Disorder Society URTF (2008) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23(15):2129–2170. CrossRefPubMedGoogle Scholar
  21. 21.
    Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17(5):427–442CrossRefPubMedGoogle Scholar
  22. 22.
    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198CrossRefPubMedGoogle Scholar
  23. 23.
    Wechsler DS (1997) Wechsler memory scale. The Psychological Corporation, San AntonioGoogle Scholar
  24. 24.
    Army Battery IT (1944) Manual of directions and scoring. War Department, Adjutant General’s Office, Washington, DCGoogle Scholar
  25. 25.
    Giladi N, Shabtai H, Simon ES, Biran S, Tal J, Korczyn AD (2000) Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Rel Disord 6(3):165–170CrossRefGoogle Scholar
  26. 26.
    Shine JM, Moore ST, Bolitho SJ, Morris TR, Dilda V, Naismith SL, Lewis SJG (2012) Assessing the utility of freezing of Gait Questionnaires in Parkinson’s disease. Parkinsonism Rel Disord 18(1):25–29. CrossRefGoogle Scholar
  27. 27.
    Cammoun L, Gigandet X, Meskaldji D, Thiran JP, Sporns O, Do KQ, Maeder P, Meuli R, Hagmann P (2012) Mapping the human connectome at multiple scales with diffusion spectrum MRI. J Neurosci Methods 203(2):386–397. CrossRefPubMedGoogle Scholar
  28. 28.
    Daducci A, Gerhard S, Griffa A, Lemkaddem A, Cammoun L, Gigandet X, Meuli R, Hagmann P, Thiran J-P (2012) The connectome mapper: an open-source processing pipeline to map connectomes with MRI. PLoS One 7(12):e48121. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM (2002) Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33(3):341–355CrossRefPubMedGoogle Scholar
  30. 30.
    Zalesky A, Fornito A, Cocchi L, Gollo LL, van den Heuvel MP, Breakspear M (2016) Connectome sensitivity or specificity: which is more important? NeuroImage 142:407–420. CrossRefPubMedGoogle Scholar
  31. 31.
    de Reus MA, van den Heuvel MP (2013) Estimating false positives and negatives in brain networks. NeuroImage 70:402–409. CrossRefPubMedGoogle Scholar
  32. 32.
    Rubinov M, Sporns O (2010) Complex network measures of brain connectivity: uses and interpretations. NeuroImage 52(3):1059–1069. CrossRefPubMedGoogle Scholar
  33. 33.
    van den Heuvel MP, Sporns O (2011) Rich-club organization of the human connectome. J Neurosci 31(44):15775–15786. CrossRefPubMedGoogle Scholar
  34. 34.
    Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15(1):1–25. CrossRefPubMedGoogle Scholar
  35. 35.
    Bullmore E, Sporns O (2012) The economy of brain network organization. Nat Rev Neurosci 13(5):336–349. CrossRefPubMedGoogle Scholar
  36. 36.
    Robbins TW, Arnsten AFT (2009) The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Ann Rev Neurosci 32:267–287. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Crossley NA, Mechelli A, Scott J, Carletti F, Fox PT, McGuire P, Bullmore ET (2014) The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain 137(Pt 8):2382–2395. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Achard S, Salvador R, Whitcher B, Suckling J, Bullmore E (2006) A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs. J Neurosci 26(1):63–72. CrossRefPubMedGoogle Scholar
  39. 39.
    Guimera R, Amaral LA (2005) Cartography of complex networks: modules and universal roles. J Stat Mech 2005(P02001):nihpa35573. PubMedCrossRefGoogle Scholar
  40. 40.
    Bertolero MA, Yeo BTT, D’Esposito M (2017) The diverse club. Nat Commun 8(1):1277. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Herman T, Rosenberg-Katz K, Jacob Y, Giladi N, Hausdorff JM (2014) Gray matter atrophy and freezing of gait in Parkinson’s disease: is the evidence black-on-white? Mov Disord 29(1):134–139. CrossRefPubMedGoogle Scholar
  42. 42.
    Shine JM, Matar E, Ward PB, Bolitho SJ, Gilat M, Pearson M, Naismith SL, Lewis SJG (2013) Exploring the cortical and subcortical fMRI changes associated with freezing in Parkinson’s disease. Brain 136(4):1204–1215CrossRefPubMedGoogle Scholar
  43. 43.
    Sherman SM (2016) Thalamus plays a central role in ongoing cortical functioning. Nat Neurosci 16(4):533–541. CrossRefGoogle Scholar
  44. 44.
    Jarbo K, Verstynen TD (2015) Converging structural and functional connectivity of orbitofrontal, dorsolateral prefrontal, and posterior parietal cortex in the human striatum. J Neurosci 35(9):3865–3878. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hall JM, Shine JM, O’Callaghan C, Walton CC, Gilat M, Naismith SL, Lewis SJG (2015) Freezing of gait and its associations in the early and advanced clinical motor stages of Parkinson’s disease: a cross-sectional study. J Parkinson Dis 5(4):881–891. CrossRefGoogle Scholar
  46. 46.
    Vandenbossche J, Deroost N, Soetens E, Zeischka P, Spildooren J, Vercruysse S, Nieuwboer A, Kerckhofs E (2012) Conflict and freezing of gait in Parkinson’s disease: support for a response control deficit. Neuroscience 206:144–154. CrossRefPubMedGoogle Scholar
  47. 47.
    Walton CC, O’Callaghan C, Hall JM, Gilat M, Mowszowski L, Naismith SL, Burrell JR, Shine JM, Lewis SJG (2015) Antisaccade errors reveal cognitive control deficits in Parkinson’s disease with freezing of gait. J Neurol 262(12):2745–2754. CrossRefPubMedGoogle Scholar
  48. 48.
    Redgrave P, Rodriguez M, Smith Y, Rodriguez-Oroz MC, Lehericy S, Bergman H, Agid Y, DeLong MR, Obeso JA (2010) Goal-directed and habitual control in the basal ganglia: implications for Parkinson’s disease. Nat Rev Neurosci 11(11):760–772CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Wu T, Hallett M (2005) A functional MRI study of automatic movements in patients with Parkinson’s disease. Brain 128(Pt 10):2250–2259. CrossRefPubMedGoogle Scholar
  50. 50.
    Shine JM, Matar E, Ward PB, Frank MJ, Moustafa AA, Pearson M, Naismith SL, Lewis SJ (2013) Freezing of gait in Parkinson’s disease is associated with functional decoupling between the cognitive control network and the basal ganglia. Brain 136(Pt 12):3671–3681. CrossRefPubMedGoogle Scholar
  51. 51.
    Tessitore A, Amboni M, Esposito F, Russo A, Picillo M, Marcuccio L, Pellecchia MT, Vitale C, Cirillo M, Tedeschi G, Barone P (2012) Resting-state brain connectivity in patients with Parkinson’s disease and freezing of gait. Parkinsonism and Rel Disord 18(6):781–787. CrossRefGoogle Scholar
  52. 52.
    Park HJ, Friston K (2013) Structural and functional brain networks: from connections to cognition. Science 342(6158):1238411. CrossRefPubMedGoogle Scholar
  53. 53.
    Vandenbossche J, Deroost N, Soetens E, Coomans D, Spildooren J, Vercruysse S, Nieuwboer A, Kerckhofs E (2012) Freezing of gait in Parkinson’s disease: disturbances in automaticity and control. Front Hum Neurosci 6:356. PubMedCrossRefGoogle Scholar
  54. 54.
    Ehgoetz Martens KA, Pieruccini-Faria F, Almeida QJ (2013) Could sensory mechanisms be a core factor that underlies freezing of gait in Parkinson’s disease? PLoS One 8(5):e62602. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Davidsdottir S, Cronin-Golomb A, Lee A (2005) Visual and spatial symptoms in Parkinson’s disease. Vision Res 45(10):1285–1296. CrossRefPubMedGoogle Scholar
  56. 56.
    Nieuwboer A, De Weerdt W, Dom R, Lesaffre E (1998) A frequency and correlation analysis of motor deficits in Parkinson patients. Disabil Rehabil 20(4):142–150CrossRefPubMedGoogle Scholar
  57. 57.
    de Oliveira RV, Pereira JS (2017) The role of diffusion magnetic resonance imaging in Parkinson’s disease and in the differential diagnosis with atypical parkinsonism. Radiol Bras 50(4):250–257. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hall JM, Ehgoetz Martens KA, Walton CC, O’Callaghan C, Keller PE, Lewis SJ, Moustafa AA (2016) Diffusion alterations associated with Parkinson’s disease symptomatology: a review of the literature. Parkinsonism Rel Disord 33:12–26. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Julie M. Hall
    • 1
    • 2
  • James M. Shine
    • 2
  • Kaylena A. Ehgoetz Martens
    • 2
  • Moran Gilat
    • 2
  • Kathryn M. Broadhouse
    • 2
  • Jennifer Y. Y. Szeto
    • 2
  • Courtney C. Walton
    • 2
  • Ahmed A. Moustafa
    • 1
    • 3
  • Simon J. G. Lewis
    • 2
  1. 1.School of Social Sciences and PsychologyWestern Sydney UniversityMilperraAustralia
  2. 2.Brain and Mind CentreUniversity of SydneyCamperdownAustralia
  3. 3.MARCS InstituteWestern Sydney UniversityMilperraAustralia

Personalised recommendations