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Anatomical Wiring and Functional Networking Changes in the Visual System Following Optic Neuritis

Educational Objective
To investigate how anatomic and functional connectivity is associated with recovery after optic neuritis.
1 Credit CME
Key Points

Question  How are anatomical connectivity and functional connectivity associated with recovery after optic neuritis?

Findings  In this study of 18 patients with optic neuritis as a clinically isolated syndrome and 21 patients with clinically isolated syndrome and damage elsewhere in the central nervous system, intact postgeniculate visual pathways were found but functional modification occurred as well, suggesting that functional network changes may be part of the recovery process.

Meaning  Potentially adaptive modifications in functional connectivity may be important in explaining recovery following demyelinating injury, with specific evidence provided from the visual pathway.

Abstract

Importance  Clinical outcome in multiple sclerosis was suggested to be driven by not only remyelination but also adaptive reorganization. This mechanism needs to be further understood.

Objective  To explore anatomical and functional visual networks in patients with optic neuritis (ON) to assess the relative weight of each connectivity modality to expedite visual recovery.

Design, Setting, and Participants  Between March 11, 2011, and May 26, 2014, 39 patients with either clinically isolated syndrome (CIS) ON (n = 18) or other CIS (non-ON) (n = 21) were recruited 1 to 28 months following an initial clinical event. These patients enrolled in an ongoing prospective cohort study (107 participants at the time of this present study) about the disease course of CIS and multiple sclerosis. Inclusion criteria were an age of 18 to 65 years, the suggestive clinical and paraclinical diagnosis of CIS or multiple sclerosis after relevant differential diagnoses have been ruled out, the existence of complete imaging data, and no ocular comorbidities. Anatomical connectivity was evaluated by diffusion tensor imaging, and functional connectivity was evaluated by resting-state functional magnetic resonance imaging. The visual pathways, including optic tracts, optic radiations, and splenial fibers, were delineated, and the resting-state visual networks were detected. Data analysis took place from September 1, 2015, to December 1, 2015.

Main Outcomes and Measures  Connectivity changes were quantified and compared to determine the association of ON with the visual network.

Results  This study included 18 patients with CIS ON, 11 (61%) of whom were women with a mean (SD) age of 32.83 (8.53) years, and 21 patients with CIS non-ON (11 [52%] of whom were women with a mean [SD] age of 30.86 [7.54] years). With the use of diffusion tensor imaging, reduced diffusivity (mean [SD] fractional anisotropy, 0.35 [0.03] vs 0.38 [0.03]; P < .01) was evident along the optic tracts of patients with ON, suggesting the extension of axonal injury from the damaged optic nerve. Neither the optic radiations nor the splenial fibers showed evidence of loss of integrity. Yet, in the presence of an intact postgeniculate anatomical network, the functional connectivity within the visual network was higher in the ON cohort. Functional connectivity observed in cortical motion–related areas was inversely correlated with the visual evoked potential–measured conduction velocity (r = −0.59; P < .05).

Conclusions and Relevance  In this cohort, local optic nerve demyelinating damage does not affect distant wiring, but even in the presence of an intact anatomical network, functional modification may occur. These functional network changes may be part of the recovery process, but further research is needed to elucidate this process.

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Article Information

Corresponding Author: Netta Levin, MD, PhD, Functional Imaging Unit, Department of Neurology, Hadassah-Hebrew University Medical Center, POB 12,000, Jerusalem 91120, Israel (netta@hadassah.org.il).

Accepted for Publication: October 8, 2017.

Published Online: January 2, 2018. doi:10.1001/jamaneurol.2017.3880

Author Contributions: Drs Paul and Levin contributed equally to the manuscript. Ms Backner and Dr Levin had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analyses.

Study concept and design: Backner, Raz, Paul, Levin.

Acquisition, analysis, or interpretation of data: Backner, Kuchling, Massarwa, Oberwahrenbrock, Finke, Bellmann-Strobl, Ruprecht, Brandt, Zimmermann, Paul.

Drafting of the manuscript: Backner, Massarwa, Raz, Levin.

Critical revision of the manuscript for important intellectual content: Backner, Kuchling, Oberwahrenbrock, Finke, Bellmann-Strobl, Ruprecht, Brandt, Zimmermann, Paul, Levin.

Statistical analysis: Backner, Massarwa, Oberwahrenbrock, Brandt.

Obtained funding: Backner, Ruprecht, Raz, Paul, Levin.

Administrative, technical, or material support: Kuchling, Finke, Bellmann-Strobl, Ruprecht, Brandt, Zimmermann, Paul.

Study supervision: Brandt, Paul, Levin.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded in part by research grant 5128-A-1 from the National Multiple Sclerosis Society and by the Teva Pharmaceutical Industries Ltd as part of the Israeli National Network of Excellence in Neuroscience. Dr Paul is supported by grant DFG Exc 257 from the Deutsche Forschungsgemeinschaft. Drs Brandt and Paul are supported by Bundesministerium für Bildung und Forschung (BMBF/Neu2, 16GW0079: N2-ADVISIMS Retinal imaging in neuroimmunological disorders).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Charcot  J-M.  Histologie de la sclerose en plaques.  Gazette des hopitaux. 1868;41:554-555.Google Scholar
2.
Filippi  M, Rocca  MA.  Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging.  Curr Opin Neurol. 2003;16(3):275-282.PubMedGoogle ScholarCrossref
3.
Shiee  N, Bazin  P-L, Zackowski  KM,  et al.  Revisiting brain atrophy and its relationship to disability in multiple sclerosis.  PLoS One. 2012;7(5):e37049.PubMedGoogle ScholarCrossref
4.
Kutzelnigg  A, Lucchinetti  CF, Stadelmann  C,  et al.  Cortical demyelination and diffuse white matter injury in multiple sclerosis.  Brain. 2005;128(pt 11):2705-2712.PubMedGoogle ScholarCrossref
5.
Azevedo  CJ, Overton  E, Khadka  S,  et al.  Early CNS neurodegeneration in radiologically isolated syndrome.  Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e102.PubMedGoogle ScholarCrossref
6.
Hackmak  K, Weygandt  M, Wuerfel  J,  et al.  Can we overcome the 'clinico-radiological paradox' in multiple sclerosis?  J Neurol. 2012;259(10):2151-2160. PubMedGoogle ScholarCrossref
7.
Schoonheim  MM, Filippi  M.  Functional plasticity in MS: friend or foe?  Neurology. 2012;79(14):1418-1419. PubMedGoogle ScholarCrossref
8.
Balcer  LJ, Miller  DH, Reingold  SC, Cohen  JA.  Vision and vision-related outcome measures in multiple sclerosis.  Brain. 2015;138(pt 1):11-27. PubMedGoogle ScholarCrossref
9.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194.PubMedGoogle ScholarCrossref
10.
Polman  CH, Reingold  SC, Banwell  B,  et al.  Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.  Ann Neurol. 2011;69(2):292-302. PubMedGoogle ScholarCrossref
11.
Sherbondy  AJ, Dougherty  RF, Ben-Shachar  M, Napel  S, Wandell  BA.  ConTrack: finding the most likely pathways between brain regions using diffusion tractography.  J Vis. 2008;8(9):1-16.PubMedGoogle ScholarCrossref
12.
Huang  H, Zhang  J, Jiang  H,  et al.  DTI tractography based parcellation of white matter: application to the mid-sagittal morphology of corpus callosum.  Neuroimage. 2005;26(1):195-205.PubMedGoogle ScholarCrossref
13.
Dougherty  RF, Ben-Shachar  M, Deutsch  GK, Hernandez  A, Fox  GR, Wandell  BA.  Temporal-callosal pathway diffusivity predicts phonological skills in children.  Proc Natl Acad Sci U S A. 2007;104(20):8556-8561.PubMedGoogle ScholarCrossref
14.
Hyvärinen  A, Oja  E.  Independent component analysis: algorithms and applications.  Neural Netw. 2000;13(4-5):411-430.PubMedGoogle ScholarCrossref
15.
Nichols  TE, Holmes  AP.  Nonparametric permutation tests for functional neuroimaging: a primer with examples.  Hum Brain Mapp. 2002;15(1):1-25. PubMedGoogle ScholarCrossref
16.
International Council of Ophthalmology Visual Functions Committee.  Visual acuity measurement standard.  Italian J Ophthalmol. 1988;2(1):1-15. http://www.icoph.org/dynamic/attachments/resources/icovisualacuity1984.pdf. Accessed November 15, 2017.Google Scholar
17.
Halliday  AM, McDonald  WI, Mushin  J.  Visual evoked response in diagnosis of multiple sclerosis.  Br Med J. 1973;4(5893):661-664.PubMedGoogle ScholarCrossref
18.
Raz  N, Bick  AS, Ben-Hur  T, Levin  N.  Focal demyelinative damage and neighboring white matter integrity: an optic neuritis study.  Mult Scler. 2015;21(5):562-571. PubMedGoogle ScholarCrossref
19.
Tootell  RB, Reppas  JB, Kwong  KK,  et al.  Functional analysis of human MT and related visual cortical areas using magnetic resonance imaging.  J Neurosci. 1995;15(4):3215-3230.PubMedGoogle Scholar
20.
Dasenbrock  HH, Smith  SA, Ozturk  A, Farrell  SK, Calabresi  PA, Reich  DS.  Diffusion tensor imaging of the optic tracts in multiple sclerosis: association with retinal thinning and visual disability.  J Neuroimaging. 2011;21(2):e41-e49.PubMedGoogle ScholarCrossref
21.
Kolbe  SC, Marriott  M, Walt  Av,  et al.  Diffusion tensor imaging correlates of visual impairment in multiple sclerosis and chronic optic neuritis.  Invest Ophthalmol Vis Sci. 2012;53(2):825-832.PubMedGoogle ScholarCrossref
22.
Gabilondo  I, Martínez-Lapiscina  EH, Martínez-Heras  E,  et al.  Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.  Ann Neurol. 2014;75(1):98-107.PubMedGoogle ScholarCrossref
23.
Pfueller  CF, Brandt  AU, Schubert  F,  et al.  Metabolic changes in the visual cortex are linked to retinal nerve fiber layer thinning in multiple sclerosis.  PLoS One. 2011;6(4):e18019.PubMedGoogle ScholarCrossref
24.
Tur  C, Goodkin  O, Altmann  DR,  et al.  Longitudinal evidence for anterograde trans-synaptic degeneration after optic neuritis.  Brain. 2016;139(pt 3):816-828.PubMedGoogle ScholarCrossref
25.
Levin  N, Dumoulin  SO, Winawer  J, Dougherty  RF, Wandell  BA.  Cortical maps and white matter tracts following long period of visual deprivation and retinal image restoration.  Neuron. 2010;65(1):21-31.PubMedGoogle ScholarCrossref
26.
Hoffmann  MB, Kaule  FR, Levin  N,  et al.  Plasticity and stability of the visual system in human achiasma.  Neuron. 2012;75(3):393-401.PubMedGoogle ScholarCrossref
27.
Gallo  A, Esposito  F, Sacco  R,  et al.  Visual resting-state network in relapsing-remitting MS with and without previous optic neuritis.  Neurology. 2012;79(14):1458-1465. PubMedGoogle ScholarCrossref
28.
Sperling  R.  Functional MRI studies of associative encoding in normal aging, mild cognitive impairment, and Alzheimer’s disease.  Ann N Y Acad Sci. 2007;1097:146-155. PubMedGoogle ScholarCrossref
29.
Wu  GF, Brier  MR, Parks  CA-L, Ances  BM, Van Stavern  GP.  An eye on brain integrity: acute optic neuritis affects resting state functional connectivity.  Invest Ophthalmol Vis Sci. 2015;56(4):2541-2546.PubMedGoogle ScholarCrossref
30.
Regan  D, Kothe  AC, Sharpe  JA.  Recognition of motion-defined shapes in patients with multiple sclerosis and optic neuritis.  Brain. 1991;114(pt 3):1129-1155.PubMedGoogle ScholarCrossref
31.
Barton  JJ, Rizzo  M.  Motion perception in optic neuropathy.  Neurology. 1994;44(2):273-278.PubMedGoogle ScholarCrossref
32.
Raz  N, Dotan  S, Benoliel  T, Chokron  S, Ben-Hur  T, Levin  N.  Sustained motion perception deficit following optic neuritis: behavioral and cortical evidence.  Neurology. 2011;76(24):2103-2111.PubMedGoogle ScholarCrossref
33.
Raz  N, Dotan  S, Chokron  S, Ben-Hur  T, Levin  N.  Demyelination affects temporal aspects of perception: an optic neuritis study.  Ann Neurol. 2012;71(4):531-538.PubMedGoogle ScholarCrossref
34.
Raz  N, Chokron  S, Ben-Hur  T, Levin  N.  Temporal reorganization to overcome monocular demyelination.  Neurology. 2013;81(8):702-709.PubMedGoogle ScholarCrossref
35.
Benoliel  T, Raz  N, Ben-Hur  T, Levin  N.  Cortical functional modifications following optic neuritis.  Mult Scler. 2017;23(2):220-227.PubMedGoogle ScholarCrossref
36.
Li  K, Lu  C, Huang  Y, Yuan  L, Zeng  D, Wu  K.  Alteration of fractional anisotropy and mean diffusivity in glaucoma: novel results of a meta-analysis of diffusion tensor imaging studies.  PLoS One. 2014;9(5):e97445.PubMedGoogle ScholarCrossref
37.
Boucard  CC, Hanekamp  S, Ćurčić-Blake  B, Ida  M, Yoshida  M, Cornelissen  FW.  Neurodegeneration beyond the primary visual pathways in a population with a high incidence of normal-pressure glaucoma.  Ophthalmic Physiol Opt. 2016;36(3):344-353.PubMedGoogle ScholarCrossref
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