Visuo-Cognitive Phenotypes in Early Multiple Sclerosis: A Multisystem Model of Visual Processing

Abstract

Background: Cognitive impairment can emerge in the earliest stages of multiple sclerosis (MS), with heterogeneity in cognitive deficits often hindering symptom identification and management. Sensory-motor dysfunction, such as visual processing impairment, is also common in early disease and can impact neuropsychological task performance in MS. However, cognitive phenotype research in MS does not currently consider the relationship between early cognitive changes and visual processing impairment.

Objectives: This study explored the relationship between cognition and visual processing in early MS by adopting a three-system model of afferent sensory, central cognitive and efferent ocular motor visual processing to identify distinct visuo-cognitive phenotypes.

Methods: Patients with clinically isolated syndrome and relapsing-remitting MS underwent neuro-ophthalmic, ocular motor and neuropsychological evaluation to assess each visual processing system. The factor structure of ocular motor variables was examined using exploratory factor analysis, and phenotypes were identified using latent profile analysis.

Results: Analyses revealed three ocular-motor constructs (cognitive control, cognitive processing speed and basic visual processing) and four visuo-cognitive phenotypes (early visual changes, efferent-cognitive, cognitive control and afferent-processing speed). While the efferent-cognitive phenotype was present in significantly older patients than was the early visual changes phenotype, there were no other demographic differences between phenotypes. The efferent-cognitive and cognitive control phenotypes had poorer performance on the Symbol Digit Modalities Test compared to that of other phenotypes; however, no other differences in performance were detected.

Conclusion: Our findings suggest that distinct visual processing deficits in early MS may differentially impact cognition, which is not captured using standard neuropsychological evaluation. Further research may facilitate improved symptom identification and intervention in early disease.

Keywords: cognition; multiple sclerosis; phenotypes; visual processing; visuo-cognitive.

Figure 1

Diagram of ocular motor tasks. (A). Visually guided task: 1. Participants initially fixated on a central green cross. 2. A saccade was then performed to a randomly appearing visual stimulus, which shifted from the centre to 5 or 10 degrees left and right of the centre over 24 trials. 3. Gaze was reoriented to the centre with the presentation of the central green cross. (B). Antisaccade task: 1. Participants initially fixated on a central green cross. 2. The central green cross disappeared concurrently with the appearance of a green cross either 5 or 10 degrees to the left or right of the centre over 48 trials. 3. Participants were instructed to inhibit a reflexive saccade to the suddenly appearing peripheral green cross and instead generate an equal-amplitude saccade in the mirror opposite direction (the correct response is depicted by a dotted-line cross). 4. Gaze was reoriented back to the centre when the central green cross re-appeared. (C). Memory-guided task: 1. Participants initially fixated on a central green cross. 2. A red cross appeared for 500 ms and participants were instructed to remember the spatial location of the red cross without looking at it. 3. Following 1500 or 2500 ms, the central cross disappeared and participants were required to generate a saccade to the approximate spatial location of the previously presented red cross (the correct response is depicted by a dotted-line cross). 4. A green cross was then presented in the same location as the red target cross to allow participants to adjust their final eye position. 5. Gaze was reoriented to the centre with the presentation of a central green cross. (D). Endogenously cued task: 1. Participants were required to fixate on a central green cross. 2. After 850 ms, this cross was replaced with an arrow pointing to a peripheral box on either the righthand or lefthand side for 500 ms. 3. Participants were instructed to shift their gaze towards a green cross when it appeared in one of the two boxes, with the arrow accurately predicting the location of the peripheral target in 75% of trials (48 trials in total). Valid trials are denoted by the arrow accurately predicting the location of the peripheral stimulus (3a), while invalid trials are denoted by the arrow pointing in the opposite direction (3b). 4. Gaze was reoriented to the centre with the presentation of a central black box. Adapted from Clough [28].

Figure 2

Exploratory factor analysis: 3-factor model of ocular motor variables. Abbreviations: VG, visually guided; EC, endogenously cued; AS, antisaccade; MG, memory guided; FEP, final eye position; VDI, versional dysconjugacy index, e^1–10; measurement error for each of the 10 indicators. * p < .05.

Figure 3

Inter-phenotype differences in clinical characteristics. (A) Difference in age between phenotypes. (B) Difference in performance on the Symbol Digit Modalities Test (SDMT) between phenotypes. * p < .05.