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Multimodal visual system analysis as a biomarker of visual hallucinations in Parkinson’s disease

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A Correction to this article was published on 06 December 2022

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Abstract

Visual hallucinations (VH) are present in up to 75% of Parkinson’s disease (PD) patients. However, their neural bases and participation of the visual system in VH are not well-understood in PD. Seventy-four participants, 12 PD with VH (PDVH), 35 PD without VH (PDnoVH) and 27 controls underwent a battery of primary visual function and visual cognition tests, retinal optical coherence tomography and structural and resting-state functional brain MRI. We quantified cortical thickness with Freesurfer and functional connectivity (FC) of Visual (VIS), Fronto-Parietal (FP), Ventral Attention (VAN) and Dorsal Attention (DAN) networks with CONN toolbox. Group comparisons were performed with MANCOVA. Area Under the Curve (AUC) was computed to assess the ability of visual variables to differentiate PDVH and PDnoVH. There were no significant PDVH vs PDnoVH differences in disease duration, motor manifestations, general cognition or dopamine agonist therapy (DA) use. Compared to PDnoVH and HC, and regardless of DA use, PDVH showed significantly reduced contrast sensitivity, visuoperceptive and visuospatial abilities, increased retina photoreceptor layer thickness, reduced cortical thickness mostly in right visual associative areas, decreased between-network VIS–VAN and VAN–DAN connectivity and increased within-network DAN connectivity. The combination of clinical and imaging variables that best discriminated PDVH and PDnoVH (highest AUC), where within-network DAN FC, photoreceptor layer thickness and cube analysis test from Visual Object and Space Perception Battery (accuracy of 81.8%). Compared to PDnoVH, PDVH have specific functional and structural abnormalities within the visual system, which can be quantified non-invasively and could potentially constitute biomarkers for VH in PD.

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References

  1. Diederich NJ, Fenelon G, Stebbins G, Goetz CG (2009) Hallucinations in Parkinson disease. Nat Rev Neurol 5:331–342

    CAS  Google Scholar 

  2. Ffytche DH, Creese B, Politis M, Chaudhuri KR, Weintraub D, Ballard C, Aarsland D (2017) The psychosis spectrum in Parkinson disease. Nat Rev Neurol 13:81–95

    Google Scholar 

  3. Anang JB, Gagnon JF, Bertrand JA, Romenets SR, Latreille V, Panisset M, Montplaisir J, Postuma RB (2014) Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83:1253–1260

    Google Scholar 

  4. Ramirez-Ruiz B, Junque C, Marti MJ, Valldeoriola F, Tolosa E (2006) Neuropsychological deficits in Parkinson’s disease patients with visual hallucinations. Mov Disord 21:1483–1487

    Google Scholar 

  5. Koerts J, Borg MA, Meppelink AM, Leenders KL, van Beilen M, van Laar T (2010) Attentional and perceptual impairments in Parkinson’s disease with visual hallucinations. Parkinsonism Relat Disord 16:270–274

    Google Scholar 

  6. Matsui H, Udaka F, Tamura A, Oda M, Kubori T, Nishinaka K, Kameyama M (2006) Impaired visual acuity as a risk factor for visual hallucinations in Parkinson’s disease. J Geriatr Psychiatry Neurol 19:36–40

    Google Scholar 

  7. Visser F, Apostolov VI, Vlaar AMM, Twisk JWR, Weinstein HC, Berendse HW (2020) Visual hallucinations in Parkinson’s disease are associated with thinning of the inner retina. Sci Rep 10:21110

    CAS  Google Scholar 

  8. Firbank MJ, Parikh J, Murphy N, Killen A, Allan CL, Collerton D, Blamire AM, Taylor JP (2018) Reduced occipital GABA in Parkinson disease with visual hallucinations. Neurology 91:e675–e685

    CAS  Google Scholar 

  9. Oishi N, Udaka F, Kameyama M, Sawamoto N, Hashikawa K, Fukuyama H (2005) Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations. Neurology 65:1708–1715

    CAS  Google Scholar 

  10. Shine JM, Muller AJ, O’Callaghan C, Hornberger M, Halliday GM, Lewis SJ (2015) Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson’s disease: a task-based fMRI study. NPJ Parkinsons Dis 1:15003

    Google Scholar 

  11. Mosimann UP, Collerton D, Dudley R, Meyer TD, Graham G, Dean JL, Bearn D, Killen A, Dickinson L, Clarke MP, McKeith IG (2008) A semi-structured interview to assess visual hallucinations in older people. Int J Geriatr Psychiatry 23:712–718

    Google Scholar 

  12. Holiday KA, Pirogovsky-Turk E, Malcarne VL, Filoteo JV, Litvan I, Lessig SL, Song D, Schiehser DM (2017) Psychometric Properties and Characteristics of the North-East Visual Hallucinations Interview in Parkinson’s Disease. Mov Disord Clin Pract 4:717–723

    Google Scholar 

  13. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184

    CAS  Google Scholar 

  14. Dalrymple-Alford JC, MacAskill MR, Nakas CT, Livingston L, Graham C, Crucian GP, Melzer TR, Kirwan J, Keenan R, Wells S, Porter RJ, Watts R, Anderson TJ (2010) The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology 75:1717–1725

    CAS  Google Scholar 

  15. Tewarie P, Balk L, Costello F, Green A, Martin R, Schippling S, Petzold A (2012) The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS ONE 7:e34823

    CAS  Google Scholar 

  16. Aytulun A, Cruz-Herranz A, Aktas O, Balcer LJ, Balk L, Barboni P, Blanco AA, Calabresi PA, Costello F, Sanchez-Dalmau B, DeBuc DC, Feltgen N, Finger RP, Frederiksen JL, Frohman E, Frohman T, Garway-Heath D, Gabilondo I, Graves JS, Green AJ, Hartung HP, Havla J, Holz FG, Imitola J, Kenney R, Klistorner A, Knier B, Korn T, Kolbe S, Kramer J, Lagreze WA, Leocani L, Maier O, Martinez-Lapiscina EH, Meuth S, Outteryck O, Paul F, Petzold A, Pihl-Jensen G, Preiningerova JL, Rebolleda G, Ringelstein M, Saidha S, Schippling S, Schuman JS, Sergott RC, Toosy A, Villoslada P, Wolf S, Yeh EA, Yu-Wai-Man P, Zimmermann HG, Brandt AU, Albrecht P (2021) APOSTEL 2.0 recommendations for reporting quantitative optical coherence tomography studies. Neurology 97:68–79

    Google Scholar 

  17. Fischl B (2012) FreeSurfer. Neuroimage 62:774–781

    Google Scholar 

  18. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31:968–980

    Google Scholar 

  19. Whitfield-Gabrieli S, Nieto-Castanon A (2012) Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2:125–141

    Google Scholar 

  20. Mattay VS, Tessitore A, Callicott JH, Bertolino A, Goldberg TE, Chase TN, Hyde TM, Weinberger DR (2002) Dopaminergic modulation of cortical function in patients with Parkinson’s disease. Ann Neurol 51:156–164

    CAS  Google Scholar 

  21. Archibald NK, Clarke MP, Mosimann UP, Burn DJ (2009) The retina in Parkinson’s disease. Brain 132:1128–1145

    Google Scholar 

  22. Moller JC, Eggert KM, Unger M, Odin P, Chaudhuri KR, Oertel WH (2008) Clinical risk-benefit assessment of dopamine agonists. Eur J Neurol 15(Suppl 2):15–23

    Google Scholar 

  23. Lee JY, Kim JM, Ahn J, Kim HJ, Jeon BS, Kim TW (2014) Retinal nerve fiber layer thickness and visual hallucinations in Parkinson’s disease. Mov Disord 29:61–67

    Google Scholar 

  24. Kopal A, Mejzlikova E, Preiningerova JL, Brebera D, Ulmanova O, Ehler E, Roth J (2015) Changes of retina are not involved in the genesis of visual hallucinations in Parkinson’s disease. Parkinsons Dis 2015:709191

    Google Scholar 

  25. Marques A, Beze S, Pereira B, Chassain C, Monneyron N, Delaby L, Lambert C, Fontaine M, Derost P, Debilly B, Rieu I, Lewis SJG, Chiambaretta F, Durif F (2020) Visual hallucinations and illusions in Parkinson’s disease: the role of ocular pathology. J Neurol 267:2829–2841

    Google Scholar 

  26. Diederich NJ, Goetz CG, Raman R, Pappert EJ, Leurgans S, Piery V (1998) Poor visual discrimination and visual hallucinations in Parkinson’s disease. Clin Neuropharmacol 21:289–295

    CAS  Google Scholar 

  27. Muller AJ, O’Callaghan C, Walton CC, Shine JM, Lewis SJ (2017) Retrospective neuropsychological profile of patients with Parkinson disease prior to developing visual hallucinations. J Geriatr Psychiatry Neurol 30:90–95

    Google Scholar 

  28. Pezzoli S, Cagnin A, Busse C, Zorzi G, Fragiacomo F, Bandmann O, Venneri A (2021) Cognitive correlates and baseline predictors of future development of visual hallucinations in dementia with Lewy bodies. Cortex 142:74–83

    Google Scholar 

  29. Delli Pizzi S, Franciotti R, Tartaro A, Caulo M, Thomas A, Onofrj M, Bonanni L (2014) Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: a cortical thickness MRI study. PLoS ONE 9:e86624

    Google Scholar 

  30. Bejr-Kasem H, Pagonabarraga J, Martinez-Horta S, Sampedro F, Marin-Lahoz J, Horta-Barba A, Aracil-Bolanos I, Perez-Perez J, Angeles Boti M, Campolongo A, Izquierdo C, Pascual-Sedano B, Gomez-Anson B, Kulisevsky J (2019) Disruption of the default mode network and its intrinsic functional connectivity underlies minor hallucinations in Parkinson’s disease. Mov Disord 34:78–86

    Google Scholar 

  31. Goldman JG, Stebbins GT, Dinh V, Bernard B, Merkitch D, deToledo-Morrell L, Goetz CG (2014) Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson’s disease with hallucinations. Brain 137:849–859

    Google Scholar 

  32. Gama RL, Bruin VM, Tavora DG, Duran FL, Bittencourt L, Tufik S (2014) Structural brain abnormalities in patients with Parkinson’s disease with visual hallucinations: a comparative voxel-based analysis. Brain Cogn 87:97–103

    Google Scholar 

  33. Shin S, Lee JE, Hong JY, Sunwoo MK, Sohn YH, Lee PH (2012) Neuroanatomical substrates of visual hallucinations in patients with non-demented Parkinson’s disease. J Neurol Neurosurg Psychiatry 83:1155–1161

    Google Scholar 

  34. Ibarretxe-Bilbao N, Ramirez-Ruiz B, Junque C, Marti MJ, Valldeoriola F, Bargallo N, Juanes S, Tolosa E (2010) Differential progression of brain atrophy in Parkinson’s disease with and without visual hallucinations. J Neurol Neurosurg Psychiatry 81:650–657

    Google Scholar 

  35. Vossel S, Geng JJ, Fink GR (2014) Dorsal and ventral attention systems: distinct neural circuits but collaborative roles. Neuroscientist 20:150–159

    Google Scholar 

  36. Yau Y, Zeighami Y, Baker TE, Larcher K, Vainik U, Dadar M, Fonov VS, Hagmann P, Griffa A, Misic B, Collins DL, Dagher A (2018) Network connectivity determines cortical thinning in early Parkinson’s disease progression. Nat Commun 9:12

    CAS  Google Scholar 

  37. Espeseth T, Westlye LT, Fjell AM, Walhovd KB, Rootwelt H, Reinvang I (2008) Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4. Neurobiol Aging 29:329–340

    CAS  Google Scholar 

  38. Fortea J, Sala-Llonch R, Bartres-Faz D, Bosch B, Llado A, Bargallo N, Molinuevo JL, Sanchez-Valle R (2010) Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. J Alzheimers Dis 22:909–922

    CAS  Google Scholar 

  39. Pagonabarraga J, Soriano-Mas C, Llebaria G, Lopez-Sola M, Pujol J, Kulisevsky J (2014) Neural correlates of minor hallucinations in non-demented patients with Parkinson’s disease. Parkinsonism Relat Disord 20:290–296

    Google Scholar 

  40. Sawczak CM, Barnett AJ, Cohn M (2019) Increased cortical thickness in attentional networks in Parkinson’s disease with minor hallucinations. Parkinsons Dis 2019:5351749

    Google Scholar 

  41. Gao Z, Zhu Q, Zhang Y, Zhao Y, Cai L, Shields CB, Cai J (2013) Reciprocal modulation between microglia and astrocyte in reactive gliosis following the CNS injury. Mol Neurobiol 48:690–701

    CAS  Google Scholar 

  42. Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist 11:400–407

    CAS  Google Scholar 

  43. Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A 97:11050–11055

    CAS  Google Scholar 

  44. Hepp DH, Foncke EMJ, Olde Dubbelink KTE, van de Berg WDJ, Berendse HW, Schoonheim MM (2017) Loss of functional connectivity in patients with Parkinson disease and visual hallucinations. Radiology 285:896–903

    Google Scholar 

  45. Shine JM, Halliday GM, Naismith SL, Lewis SJ (2011) Visual misperceptions and hallucinations in Parkinson’s disease: dysfunction of attentional control networks? Mov Disord 26:2154–2159

    Google Scholar 

  46. Stavitsky K, McNamara P, Durso R, Harris E, Auerbach S, Cronin-Golomb A (2008) Hallucinations, dreaming, and frequent dozing in Parkinson disease: impact of right-hemisphere neural networks. Cogn Behav Neurol 21:143–149

    Google Scholar 

  47. Jonas J, Frismand S, Vignal JP, Colnat-Coulbois S, Koessler L, Vespignani H, Rossion B, Maillard L (2014) Right hemispheric dominance of visual phenomena evoked by intracerebral stimulation of the human visual cortex. Hum Brain Mapp 35:3360–3371

    Google Scholar 

  48. Corbetta M, Patel G, Shulman GL (2008) The reorienting system of the human brain: from environment to theory of mind. Neuron 58:306–324

    CAS  Google Scholar 

  49. Huang L, Zhang D, Ji J, Wang Y, Zhang R (2021) Central retina changes in Parkinson’s disease: a systematic review and meta-analysis. J Neurol 268:4646–4654

    Google Scholar 

  50. Ortuno-Lizaran I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N (2018) Phosphorylated alpha-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord 33:1315–1324

    CAS  Google Scholar 

  51. Devos D, Tir M, Maurage CA, Waucquier N, Defebvre L, Defoort-Dhellemmes S, Destee A (2005) ERG and anatomical abnormalities suggesting retinopathy in dementia with Lewy bodies. Neurology 65:1107–1110

    CAS  Google Scholar 

  52. Langen CD, Cremers LGM, de Groot M, White T, Ikram MA, Niessen WJ, Vernooij MW (2018) Disconnection due to white matter hyperintensities is associated with lower cognitive scores. Neuroimage 183:745–756

    Google Scholar 

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Acknowledgements

The authors would like to thank all the participants involved in the study.

Funding

The Department of Health of the Basque Government through Project 2016111009 to J.C.G.E and I.G; M.D.C received a Post-doctoral research improvement fellowship from the Basque Government [POS_2018_1_0008].

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Author notes

  1. Maria Diez-Cirarda, Alberto Cabrera-Zubizarreta have contributed equally to the work.

Authors and Affiliations

  1. Neurodegenerative Diseases Group, Biocruces Bizkaia Health Research Institute, Cruces Plaza S/N, 48903, Barakaldo, Vizcaya, Spain

    Maria Diez-Cirarda, Ane Murueta-Goyena, Rocio Del Pino, Marian Acera, Beatriz Tijero, Juan Carlos Gómez-Esteban & Iñigo Gabilondo

  2. Magnetic Resonance Imaging Unit, Research and Innovation Department, Osatek SA, Bilbao, Spain

    Alberto Cabrera-Zubizarreta

  3. Department of Neurosciences, Faculty of Medicine and Nursery, University of the Basque Country (UPV/EHU), Leioa, Spain

    Ane Murueta-Goyena & Juan Carlos Gómez-Esteban

  4. Krembil Brain Institute, UHN & Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Canada

    Antonio P. Strafella

  5. Department of Psychology, Faculty of Health Sciences, Univesity of Deusto, Bilbao, Spain

    Olaia Lucas-Jiménez & Naroa Ibarretxe-Bilbao

  6. Department of Neurology, Cruces University Hospital, Barakaldo, Spain

    Beatriz Tijero, Juan Carlos Gómez-Esteban & Iñigo Gabilondo

  7. IKERBASQUE: The Basque Foundation for Science, Bilbao, Spain

    Iñigo Gabilondo

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  1. Maria Diez-Cirarda
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Corresponding authors

Correspondence to Maria Diez-Cirarda or Iñigo Gabilondo.

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Conflict of interest

A.P.S. has been a consultant for Hoffman La Roche; received honoraria from GE Health Care Canada LTD, Hoffman La Roche. The rest of the authors declare no conflict of interest.

Ethics and informed consent

The present study was approved by the Euskadi Drug Research Ethics Committee (CEIm-E) (Approval number: PI2012154) and participants provided written informed consent prior to research participation.

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The original online version of this article was revised: An error in figure 1 introduced during typesetting while in production.

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Diez-Cirarda, M., Cabrera-Zubizarreta, A., Murueta-Goyena, A. et al. Multimodal visual system analysis as a biomarker of visual hallucinations in Parkinson’s disease. J Neurol 270, 519–529 (2023). https://doi.org/10.1007/s00415-022-11427-x

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