Multiple sclerosis (MS) is a demyelinating neurologic disease characterized by a range of cognitive and sensorimotor symptoms, including reduced information processing speed (IPS) (1), fatigue, and visual and oculomotor dysfunction (2). Visual symptoms include blurry vision, poor acuity, and accommodative dysfunction (3). Oculomotor symptoms include strabismus, internuclear ophthalmoplegia, nystagmus, saccadic hypermetria, saccadic oscillations, inhibition of the vestibulo-ocular reflex, and impaired vergence, stereopsis, and smooth pursuit (4). Furthermore, individuals with MS frequently report symptoms of visual discomfort and oculomotor fatigue (5).

Typically, individuals with MS experience intermittent attacks of acute neuroinflammation followed by full or partial recovery. Over time, many with MS experience a progressive neurodegenerative process secondary to the cumulative effects of these acute episodes (3). Visual and oculomotor symptoms are no exception: long-term deficits are common even when clinical recovery from an acute episode is achieved (2).

The King-Devick (K-D) test (6) is used for detecting oculomotor inefficiencies associated with sports-related concussion with high sensitivity and specificity via a rapid automatized naming task (7). The K-D has been used extensively in both clinical care and research for concussion and has recently been used in other neurological populations, including MS. Individuals with MS present with slower K-D performance than healthy controls, which is associated with visual dysfunction, neurologic disability, and reduced vision-specific quality of life (8–10).

Methylphenidate is a psychostimulant medication shown to be effective in reducing impulsivity, inattentiveness, and hyperactivity in individuals with attention deficit hyperactivity disorder (ADHD) (11). In addition to its general effects on arousal and attention, methylphenidate has been shown to improve visual and/or oculomotor function in those with ADHD as well as healthy participants (11). Methylphenidate has also been used to treat symptoms of multiple neurologic conditions including fatigue in MS (12).

The current study is a secondary analysis of data from a pilot randomized clinical trial that examined the efficacy of methylphenidate on self-reported fatigue in MS (12). The objectives of the current analyses were to (a) examine the specific impact of methylphenidate on oculomotor function via performance on the K-D and (b) determine if improvements on the K-D are associated with improvements in IPS via the Symbol Digit Modalities Test (SDMT) (13) and the Paced Auditory Serial Addition Test (PASAT) (14).

The mean time to complete the K-D differed significantly between conditions [F(2, 20) = 4.67, p = 0.022] with a large effect size (η² = 0.32). The pairwise comparison showed a significant reduction in mean K-D time in the methylphenidate condition as compared to the baseline condition (37.1 [SE = 3.6] vs. 41.2 [SE = 4.1] seconds, respectively, p = 0.035, Cohen’s d = 0.3; see Figure 1). No significant reduction was found for mean time to complete the K-D in the placebo condition (38.2 [SE = 3.2] seconds) as compared to baseline (p = 0.250) and no significant difference was found in the number of errors between the baseline and methylphenidate conditions (p = 0.625).

We did not find a significant difference in SDMT scores [F(2,20) = 0.94, p = 0.407]. However, a series of Pearson correlations showed a strong association between change on the K-D and change on the SDMT (r² = −0.80, p = 0.003). We found significant differences for the PASAT [F(2,18) = 5.77, p = 0.012] with a post hoc pairwise comparison using the Bonferroni correction showing a marginally significant improvement in PASAT scores in the methylphenidate condition as compared to the baseline condition (43.7 ± 4.0 vs. 38.7 ± 4.9, respectively, p = 0.053). No significant differences were found for the PASAT in the placebo condition (41.2 ± 4.4) as compared to baseline (p = 0.245). No association was found between change on the K-D and change on the PASAT (r² = 0.14, p = 0.695). One participant reported visual symptoms but continued in the study after medical consultation determined the symptoms were unrelated to the study.

In this pilot randomized controlled trial, we used a crossover design to examine the effects of methylphenidate on performance on the K-D in 11 participants with clinically definite MS. We found that participants had significantly improved K-D scores while taking methylphenidate with no significant change in K-D scores in the placebo condition. We found that change on the K-D strongly correlated with change on the SDMT, which assesses visuomotor IPS, but did not correlate with change on the PASAT, which assesses auditory IPS and working memory. These results are consistent with past research that found that the K-D explained 31% of the variance in the SDMT (20). In addition, our finding that performance on the K-D improved while taking methylphenidate is consistent with prior studies that have demonstrated improved visual processing speed and oculomotor function in both children with ADHD and healthy adults when taking methylphenidate (11).

Deficits of MS, such as cognitive dysfunction and reduced IPS, are traditionally captured by neuropsychological measures specific to these domains. However, it remains unclear if performance on these measures is predicted or confounded by deficits in other cognitive domains (3, 20, 21). The interdependence of cognitive deficits in various domains and their impact on one another is not well understood.

According to the tri-factor model of IPS in MS (1), the construct of IPS is reliant on cognitive speed, sensorial speed (e.g., visual processing speed), and motor speed (e.g., oculomotor function). The SDMT involves all three factors of the tri-factor model. Thus, it is sensitive to detect change in MS but is insufficient to determine the granular factors that underlie performance and performance deficits (1, 22). Prior research from our group found an association between MS-related oculomotor dysfunction and poorer performance on the SDMT, which suggests that the oculomotor demands of the task may influence the cognitive demands of the task. Our finding that improvements on the K-D between the baseline and experimental conditions correlated with improvements on the SDMT is consistent with this and other prior studies that explored visual and oculomotor correlates of SDMT performance (3, 20, 21).

In contrast to the SDMT, improvements on the K-D did not correlate with change on the PASAT, which, in addition to working memory and attention, emphasizes auditory rather than visual IPS (23). Although all of these domains are affected by MS, deficits in IPS have been shown to underlie poor performance on the PASAT (24). In the context of the tri-factor model of IPS in MS, our findings suggest that methylphenidate improved oculomotor speed rather than cognitive or sensorial speed in our sample.

There are important limitations to this study that should be considered. First, this was secondary analysis of a pilot randomized clinical trial, so the sample was small. Thus, more robust analyses of mediation and moderation were not possible. Second, we relied on the final score of the K-D to frame our analyses. Although the K-D is considered to be a measure of oculomotor function, many disparate neurocognitive functions other than oculomotility could be involved. Therefore, future studies examining the impact of impaired visual or oculomotor function to the overall functional picture of individuals with multiple sclerosis should include oculography and/or detailed ophthalmometric examination.

In conclusion, participants with MS showed improved oculomotor function while taking methylphenidate as compared to placebo. In addition, this improvement was associated with improved IPS as measured by the SDMT, which has visuomotor demands; but was not associated with improved IPS as measured by the PASAT, which has auditory-verbal demands. Thus, methylphenidate may be beneficial for individuals with MS who experience oculomotor deficits and may indirectly promote improved processing speed for visuomotor tasks.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Kessler Foundation Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

TR: Writing – review & editing, Writing – original draft, Formal analysis, Conceptualization. AA: Writing – review & editing, Writing – original draft. ED: Writing – review & editing, Investigation, Data curation. NC: Writing – review & editing, Supervision. JD: Writing – review & editing, Funding acquisition. SLC: Writing – review & editing, Writing – original draft, Supervision, Investigation, Formal analysis, Conceptualization.