Brainstem neurochemical profiles after hospitalisation for COVID-19: a 7T MR spectroscopy study

Abstract

Background: Somatic, cognitive and mental health issues have been identified in three-quarters of people 5 months after hospitalisation for severe acute SARS-CoV-2 (COVID-19) infection. The underlying neuroanatomical basis of these symptoms remains unclear, but recent studies suggest a role for altered brainstem physiology. We aimed to test the hypothesis that brainstem neurochemical profiles differ in patients who had been hospitalised for COVID-19 compared to matched controls using 7T magnetic resonance spectroscopy (MRS).

Methods: This prospective case-control study recruited 34 individuals who were hospitalised for COVID-19 and 15 healthy controls with no history of COVID-19 infection from two major UK hospitals before vaccines became available. The participants underwent 7T semi-adiabatic localization by adiabatic selective refocusing (sLASER) ¹H-MRS at the ponto-medullary junction. Water-referenced metabolite concentrations were compared between the patients and controls and correlated with infection severity, as measured by maximum C-reactive protein (CRP_max) assay during inpatient admission. Linear mixed modelling was used with a 0.05 significance level.

Results: Spectral quality was high/acceptable in 44/49 participants according to the MRS Consensus criteria. The magnitude of inflammation during patient admission (i.e., CRP_max) correlated positively with myo-inositol concentration (β = 0.005, p = 0.035), as did patient-reported symptoms (β = -0.564, p = 0.023). However, metabolite concentrations were not significantly different between the patients and controls.

Conclusion: We show the feasibility of assessing brainstem neurochemical profiles using 7T ¹H-MRS in a multi-centre study. Technical limitations at one site's 7T MRI led to variable repetition times, which limited our statistical power and should be avoided in future studies. Our findings highlight the need for further investigation into the role of neuroinflammation in post-acute COVID-19.

Keywords: 7T; COVID-19; brainstem; magnetic resonance spectroscopy; neuroinflammation.

Figure 1

(A) Recruitment flow chart and (B) patient timeline. (A) Flow diagram of patient and control recruitment and magnetic resonance spectroscopy (MRS) exclusion criteria at both sites. A total of 34 COVID-19 patients and an additional 15 healthy controls were recruited. (B) Timeline of data collection for patients relative to the day of hospital admission. Participants displayed in faint colours later failed to meet minimal MRS quality standards and were excluded from further analysis. MRS, magnetic resonance spectroscopy; QA, quality assurance.

Figure 2

Visual quality assessment of sLASER data acquired in this study. (A,B) Precision of voxel placement at the ponto-medullary junction is assessed through heatmaps plotted in blue for Site A and orange for Site B. Voxel placement was consistent throughout the study, as evidenced by the CSF proportion between the sites (p(f_CSF) = 0.064) and consistently high Sørensen–Dice coefficients (DSCs) of 75–77 (p(DSC) = 0.10). (C) Plots of mean spectra in each group. The shaded areas represent ±1 standard deviation. This shows consistent, high data quality. Quantitative measures of mean spectral quality were high—the signal-to-noise ratio (SNR) of N-acetyl aspartate (NAA) (SNR_NAA) was 64.2 ± 17.7 (mean ± SD) and NAA’s linewidth measured by the full-width at half maximum (FWHM_NAA) was 13.7 ± 2.6 Hz. SNR_NAA was similar between the sites (p = 0.33). FWHM_NAA was lower at Site A (difference = 16.1%, p = 0.0033). For detailed results, see Table 2 and Supplementary Figure 3. *Single subject spectra are included in Supplementary Figure 2. DSC, Sørensen–Dice coefficient; FWHM, full-width at half maximum; SNR, signal-to-noise ratio; sLASER, semi-adiabatic localization by adiabatic selective refocusing.

Figure 3

Metabolite concentrations corrected for tissue water content, reported for each group at both sites. Highlighted in purple are notable discrepancies between the sites, including a significant change in tCr (difference = 6.7%, p = 0.0068) and a trend for Gln (difference = 166.7%, p = 0.062). An equivalent plot normalised relative to tCr is provided for comparison (Supplementary Figure 5). Statistical comparisons were performed using two-sided t-tests. Brackets without labels indicate that the t-tests had a p-value > 0.1 (not significant, not a trend). GABA, γ-aminobutyric acid; Gln, glutamine; Glu, glutamate; Ins, myo-inositol; NAA, N-acetyl aspartate; tCho, choline containing compounds; tCr, combined creatine and phosphocreatine.

Figure 4

Correlation of clinical markers with metabolite concentrations. (A–G) The correlation between the highest C-reactive protein (CRP) assay value during hospital admission (CRP_max) and metabolite concentration, as determined by the linear mixed model from Equation (3). Ins correlated positively with CRP_max (p = 0.035), which may reflect neuroinflammation; and tCho showed a positive trend (p = 0.055), which may reflect increased membrane turnover consistent with neuroinflammation. Modelling results are summarised in Table 4. (H) Correlation of the second principal component (PC₂), which is highly loaded with patients’ mental health and anxiety outcomes (Supplementary Figures 10B,C). The negative correlation (p = 0.023) with Ins suggests that patients with overall poorer emotional wellbeing (lower PC₂) have higher Ins levels. CRP, C-reactive protein; GABA, γ-aminobutyric acid; Gln, glutamine; Glu, glutamate; Ins, myo-inositol; NAA, N-acetyl aspartate; PC₂, 2nd principal component; tCho, choline containing compounds; tCr, combined creatine and phosphocreatine.