3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2026, Ladek et al

[forestglip]

3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Spoiler: Authors

Ladek, Anja-Maria; Priebe, Leonie; Harrer, Thomas; Harrer, Ellen; Michelson, Georg; Knauer, Thomas S.; Dias-Nunes, Diogo X.; Mardin, Christian Y.; Bergua, Antonio; Hohberger, Bettina

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder, characterized by symptoms such as post-exertional malaise (PEM) and cognitive impairments. This study assessed reaction time (RT) metrics in three-dimensional (3D) visual tasks with the aim of objectively quantifying the cognitive impairments in ME/CFS patients compared to controls.

Methods
A total of 120 participants (60 ME/CFS patients and 60 controls) were recruited at the Department of Ophthalmology, Universität of Erlangen-Nürnberg. RT was assessed using a virtual reality–oculomotor test system, presenting 3D stimuli at three disparity levels (275″, 550″, and 1100″) within three gaming repetitions (R1, R2, and R3). Mixed-effects models were used to evaluate group differences, with age and gender as covariates.

Pairwise contrasts were calculated to assess changes across repetitions. Fatigue self-assessments were recorded by validated questionnaires, (FACIT Fatigue Scale, Chalder Fatigue Scale, Bell Score and Health Assessment Questionnaire), and their correlation with RT metrics was portrayed using a Spearman correlation matrix.

Results
Estimated means (EM-means) for RT were significantly prolonged in ME/CFS patients compared to controls at disparity 275″ (1969 ms vs. 1384 ms; p = 0.0001), 550″ (1409 vs. 1071 ms; p = 0.0012) and 1100″ (1126 ms vs. 891 ms; p = 0.00223). Age was a significant covariate (p < 0.001), while gender showed no effect.

Both groups demonstrated improvements in RT over repetitions; however, ME/CFS patients showed a significantly lower improvement compared to controls, reaching significance in R3 (p = 0.0042). RT metrics did not correlate with patients’ self-assessment scores.

Conclusions
ME/CFS patients showed consistently slower RTs compared to controls, particularly in later, easier gaming repetitions, potentially reflecting the impact of fatigue.

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[Utsikt]

They really go after the questionnaires when discussing the lack of correlation with the objective results:

We had hoped to be able to show correlation between the RT metrics in VR-OTS performance and the self-assessment questionnaires (patient-reported outcome measures, PROMs). Neither anamnestic reports nor PROMs correlated with any RT outcome metrics. The greatest correlation was achieved between the Chalder Fatigue Scale and the RT at 275″ disparity. Other RT metrics showed singular correlations with the Chalder Fatigue Scale without showing a clear pattern.

Rather than supposing that the predictive value of VR-OTS for ME/CFS severity is low, we assume that although these questionnaires are commonly used in diagnostics of ME/CFS and help in observing changes within a person, they are subjective.

Difficulties comparing greater populations have been documented in other studies as well [36,37], particularly when the patient’s own interpretation of each question is allowed in self-assessment. This is supported by the literature, as ceiling effects and bad internal consistency [36,37] as well as poor prediction across subscales has led to PROMs being criticized even beyond scales used in ME/CFS [38,39].

Comparison of questionnaire assessments and sensor measurements for time spent upright showed not only overestimation of actual time spent upright by the ME/CFS cohort but also demonstrated the lack of correlation between PROMs and time spent upright in ME/CFS cohorts [40].

In line with this, Stussman et al. [13] recently showed that qualitative interviews are more sensitive than questionnaires when quantifying PEM changes.