Salivary microRNA Biomarkers Reflect the Complex Interrelationship between Sleep and Psychological Symptoms During Concussion Recovery

Poor sleep and psychological symptoms (depressive or anxiety symptoms) are common following concussion. Saliva microRNAs (miRNAs) are promising concussion biomarkers based on associations with the presence of a concussion in prior work. The purpose of this study was to identify saliva miRNAs that differ between participants with and without concussion and show correlations with sleep and/or psychological symptoms. We analyzed salivary miRNAs and concussion symptom data from n = 272 concussion cases (median: 2.5 days postinjury, interquartile range: 2.41–10.65) and n = 153 uninjured controls. Concussion symptoms were quantified with the Post-Concussion Symptom Scale (PCSS). miRNAs were quantified with high-throughput small RNA sequencing. Spearman rank correlations were used to evaluate the association between miRNAs and PCSS sleep (“Drowsiness,” “Trouble falling asleep”) and PCSS psychological (“Feeling More Emotional,” “Irritability,” “Sadness,” and “Nervousness”) symptoms. Wilcoxon rank sum tests evaluated differences in miRNAs between the concussion versus the uninjured controls. All tests were evaluated at the Benjamini-Hochberg adjusted alpha level of 0.05. We identified 14 miRNAs that were correlated with sleep symptoms ( n = 5 positively and n = 9 negatively correlated), 28 with psychological symptoms ( n = 12 positively and n = 16 negatively correlated), and 4 miRNAs with both (miR-361-5p, miR-4510, miR-193a-3p, miR-3074-5p). Gene targets for miRNAs correlated with both sleep and psychological symptoms were significantly enriched within “spinocerebellar ataxia,” “dopaminergic synapse,” “axon guidance,” and “circadian entrainment” pathways. Of the four miRNAs correlated with both psychological and sleep symptoms, miR-4510 and miR-193a-3p were also differentially expressed between the concussion cases and the uninjured controls. miR-4510 and miR-193a-3p were differentially expressed in individuals with concussion and were correlated with both sleep and psychological symptoms. Additional research is needed to confirm the temporal relationship between alterations in these miRNAs, concussion occurrence, and onset of sleep and/or psychological symptoms.