Review of 'Altered auditory brainstem responses are post-acute sequela of SARS-CoV-2 (PASC)'

This study, published in Scientific Reports (Nature Portfolio, 18 March 2025), investigates the neurophysiological underpinnings of Post-Acute Sequelae of SARS-CoV-2 (PASC), commonly known as Long COVID, by analyzing auditory brainstem responses (ABRs) in 82 participants (37 PASC patients, 45 controls). The researchers hypothesized that ABR metrics specifically wave V latency differences between slow (21.1 clicks/sec), and fast (61.1 clicks/sec) stimulus rates and the V/I amplitude ratio (a measure of midbrain central gain) would correlate with PASC-related cognitive fatigue and auditory symptoms.

1. Level of Importance: Excellent

This study provides critical insights into the neurophysiological mechanisms of Long COVID (PASC), addressing a pressing gap in objective biomarker research. By linking auditory brainstem response (ABR) abnormalities specifically wave V latency delays and elevated V/I amplitude ratios to subjective cognitive fatigue and tinnitus, the authors establish a novel framework for understanding PASC-related central nervous system (CNS) dysfunction. The discovery of accelerated auditory aging in younger PASC patients is particularly groundbreaking, suggesting neuroinflammatory or neurodegenerative processes that warrant further exploration. These findings are highly relevant to clinicians, neuroscientists, and public health experts, offering actionable tools for diagnosis and monitoring.

2. Level of Validity: Good

• Strengths: Hypotheses are clearly formulated and supported by mechanistic links to neuroinflammation and central gain dysregulation. Methodologically rigorous, with matched peripheral hearing thresholds and mixed-effects models to handle repeated measures. Age subgroup analysis mitigates confounding effects, isolating PASC-specific auditory changes.
• Limitations: Age mismatch: The PASC group is significantly older (mean age 47.5 vs. 38.5 in controls), potentially conflating age-related and PASC-specific effects. Self-reported controls: Lack of serological confirmation for COVID-negative status risks misclassification. Uncorrected multiple comparisons: Increases Type I error risk (e.g., tinnitus-fatigue correlations).

3. Level of Completeness: Good

• Strengths: Contextualizes findings within literature on SARS-CoV-2 neurotropism, ABR in neurological disorders, and central gain mechanisms. Transparent discussion of limitations, including age effects and measurement gaps.
• Gaps: Tinnitus assessment: Relies on NHANES questions rather than validated tools (e.g., Tinnitus Handicap Inventory). Extended high-frequency thresholds: Not measured, despite their relevance to cochlear health and tinnitus etiology. Pre-COVID baselines: Absence of pre-infection auditory/tinnitus data limits causal inferences.

4. Level of Comprehensibility: Excellent

The study is well-organized and accessible, with logical progression from hypothesis to subgroup analyses. Figures 1–4 (ABR waveforms, V/I ratios by age) are clearly labeled and visually reinforce key findings. Technical terms (e.g., central gain, interpeak latencies) are succinctly defined, making the work accessible to a multidisciplinary audience. Tables 1–4 concisely summarize demographics and statistical outcomes, though simplified visual summaries (e.g., bar graphs for latency differences) could enhance readability for non-specialists.

5. Key Contributions:

• Objective biomarkers: ABR metrics (wave V latency differences, V/I ratios) correlate with cognitive fatigue, offering a tool to quantify subjective symptoms.
• Accelerated auditory aging: Younger PASC patients exhibit ABR profiles resembling older adults, implicating neuroinflammation a finding with broad implications for post-viral syndromes.
• Tinnitus-fatigue link: Frequent tinnitus predicts worse cognitive fatigue, aligning with theories of GABAergic disruption and central gain dysregulation.

6. Recommendations for Future Research:

• Replicate in age-matched cohorts with serologically confirmed controls to isolate PASC-specific effects.
• Incorporate extended high-frequency audiometry and validated tinnitus tools (e.g., Tinnitus Handicap Inventory).
• Longitudinal designs: Track ABR changes pre-/post-COVID to establish causality and progression.
• Explore neuroimaging correlates: Combine ABR with fMRI/PET to map auditory-cognitive networks in PASC.

7. Summary

This pioneering study makes a valuable contribution to Long COVID research by demonstrating measurable auditory brainstem abnormalities (delayed wave V latency and elevated V/I amplitude ratios) that correlate with cognitive fatigue and tinnitus in PASC patients. The innovative use of ABR testing provides clinicians with potential objective biomarkers for neurological dysfunction, while the finding of accelerated auditory aging patterns in younger patients offers important insights into PASC's neurophysiological mechanisms. Despite some limitations inherent to early pandemic research, the work stands out for its rigorous methodology, clear clinical relevance, and significant advancement of our understanding of Long COVID's neurological manifestations, paving the way for improved diagnostic approaches and future therapeutic investigations.