0131

Longitudinal ²³Na MRI in mild traumatic brain injury

Teresa Gerhalter¹, Anna M Chen¹, Seena Dehkharghani^1,2, Rosemary Peralta¹, James S. Babb¹, Tamara Bushnik³, Alejandro Zarate³, Jonathan M Silver⁴, Brian S Im³, Stephen P Wall⁵, Ryan Brown^1,6, Ivan I Kirov^1,2,6, and Guillaume Madelin¹
¹Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States, ²Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States, ³Department of Rehabilitation Medicine, New York University Grossman School of Medicine, New York, NY, United States, ⁴Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, United States, ⁵Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, NY, United States, ⁶Center for Advanced Imaging Innovation and Research, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States

Synopsis

In this longitudinal sodium MRI study, mild traumatic brain injury (mTBI) patients and controls were scanned at 3T. Linear regression analysis was used to calculate total sodium concentrations (TSC) in global grey and white matter (GM, WM). Patient GM TSC increased back to control levels at 3-month and 1-year follow-ups. Decreased GM and WM TSC measured at one month were associated with worse cognitive performance, but not worse symptomalogy, at the follow-up visits.

Introduction

Traumatic brain injury (TBI) is one of the main causes of neurological disability worldwide.¹ Despite its low severity, mild TBI (mTBI) can cause physical, psychiatric, emotional and cognitive problems, which persist in 15-30% of patients.² The biological correlates of these manifestations, however, are not detected on conventional CT and MRI.³ It is hypothesized that the pathological cascade of tissue damage in mTBI is set forth by a perturbation in ionic homeostasis.⁴ The Na⁺/K⁺-exchange pump can be affected by energy deficits due to mitochondrial dysfunction, and by diffuse axonal injury, the histopathological signature of TBI.^5,6 In a prior study, ²³Na MRI was proposed as a non-invasive method to assess ionic disturbances in mTBI⁷, where decreased total sodium concentration (TSC) in global grey matter (GM) and white matter (WM) differentiated functionally non-recovered patients from controls. Here, we quantify TSC longitudinally at two additional time points over one year. We use linear regression to calculate GM and WM TSC globally, to increase the signal-to-noise ratio and reduce partial volume effects.⁸ We tested the hypotheses that global TSC measured within one month after injury⁷: (i) can predict whether patients functionally recover from their injury; and (ii) correlate with clinical presentation and neuropsychological function at 3 months and 1 year after injury.

Materials & Methods

Twenty-seven patients (18-60 years old, 20 females) with confirmed mTBI and twenty-one age-matched healthy volunteers (23-62 years old, 14 females) were scanned on 3T (Magnetom Prisma, Siemens Healthcare, Erlangen, Germany). Patients were scanned at one month (visit 1, v1)⁷, three months (visit 2, v2), and one year (visit 3, v3) after injury (Fig.1). Controls were scanned once. A 20-channel head coil was used for qualitative ¹H imaging.⁷ A radiologist examined the FLAIR and SWI images for evidence of parenchymal or extracerebral hemorrhage or features of diffuse or traumatic axonal injury, which were excluded for TSC quantification. ²³Na imaging was performed using an in-house ¹H/²³Na developed double-tuned head coil. All ²³Na images were acquired using a 3D FLORET sequence⁹ (TE=0.2 ms, TR=100 ms, 3 hubs at 45°, interleaves/hub=26, resolution=6 mm isotropic, 46 averages, TA=5:59 min). ²³Na signals were calibrated using the signal from vitreous humor. Brain segmentation was performed using SPM12 (UCL, UK) from low-resolution MPRAGE data (TR/TE=2100/4.2 ms, voxel size=1.5x1.5x1.5 mm³, TA=3:49 min). Global TSC values in WM and GM were obtained with linear regression over all brain voxels (Fig.2) as previously reported.⁷

All patients underwent clinical and neurocognitive testing which consisted of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ)¹⁰, the Glasgow Outcome Scale-Extended (GOSE)¹¹, and the Brief-Test-of-Adult-Cognition-by-Telephone (BTACT)¹². Mann-Whitney (MW) test was used to compare TSC measurements between mTBI and controls, as well as to compare TSC at v1 in patients who showed recovery at follow-up visits (GOSE=8) with patients who did not (GOSE<8). Within-subject change among patients was examined with the matched-pair Wilcoxon signed-rank test. Spearman rank correlations assessed the associations between TSC at v1 and symptomatology (RPQ) and cognitive functioning (BTACT) during follow-up visits. Statistical significance was defined as p<0.05.

Results

Demographics, clinical presentation, and cognitive testing results at each visit are compiled in Table 1. At v3 one year after injury, nine patients had not recovered from their injury. As previously reported, both GM and WM TSC were lower in mTBI at v1 than in controls.⁷ However, GM TSC values increased with time to control-level at v2 and v3 (Fig.3B). No increase was detected for WM TSC, but its levels were no longer reduced in patients compared to controls at v2 and v3 (Fig.3A). No group differences were observed in GM or WM TSC at v1 between recovered and non-recovered patients (based on GOSE stratification) at follow-up visits. GM and WM TSC at v1 correlated positively with BTACT sub-tests at follow-up visits (Fig.4A). No correlations were found for TSC at v1 and RPQ at follow-up. Changes in BTACT between v2 and v1 correlated with change in TSC over time (Fig.4B).

Discussion & Conclusion

We conducted a longitudinal ²³Na MRI study using linear regression quantification in GM and WM to test whether diffuse TSC reductions one month after mTBI7 are predictive of patients’ long-term outcome. No differences in GM and WM TSC were observed at 3 months and 1 year after injury, when compared to controls. GM TSC, however, increased with time, suggesting recovery to ionic homeostasis. WM TSC did not increase with time, but it was no longer significantly reduced at the follow-ups, suggesting either insufficient statistical power to observe an increase, or increase in the coefficient of variation (wider boxplots in Fig.3A). Lower TSC in mTBI in both tissue types at v1 correlated with future worse neuropsychological function, confirming the cross-sectional findings⁷ for a potential biomarker role for TSC. The initially observed GM an WM TSC decrease could be explained by cell swelling and sodium influx; a small increase in the intracellular volume can result in decreased TSC, even if the intracellular sodium concentration increases.⁷ The increase in GM TSC reported here might reflect the normalization of ionic balance and cell volume. These findings lay the groundwork for further studies aimed at understanding the pathophysiology of TBI from the standpoint of ionic balance.

Acknowledgements

This work was supported by grants R01NS097494 and R01EB026456 from the National Institutes of Health (NIH).

References

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Figures

Fig.1: Flow diagram of study enrollment. Imaging and clinical and neurocognitive assessments were performed at one month after injury (visit 1), three months after injury (visit 2), and one year after injury (visit 3). mTBI = mild traumatic brain injury

Fig.2: Linear regression for TSC quantification. A) ¹H images were segmented into GM, WM, and CSF masks, which were regridded to the ²³Na resolution and convolved with the point spread function to correct for CSF spill-over effects. B) Measured TSC maps and tissue volume fractions were used to solve the equation using a linear regression approach. C) Modeled TSC distribution using the calculated WM, GM and CSF concentrations and residual error map (delta TSC = measured - modeled TSC). D) Normal probability plot of the error residuals indicating a normal distribution (red dashed line).

Fig 3: TSC in global GM and WM. A) Boxplots showing the 1st, 2nd (median), and 3rd quartiles (box), and ±95% (whiskers) of the TSC distributions in controls and mTBI patients at visit 1 (v1), visit 2 (v2), and visit 3 (v3). Note that GM and WM TSC were decreased in mTBI compared to controls at v1⁷, but not at v2 and v3 (Mann-Whitney, ♦ p<0.5). B) Descriptive statistics of the within-subject change in TSC among mTBI patients. GM values increased significantly with time (change = follow-up - visit 1: v2-v1 and v3-v1) according to the matched-pair Wilcoxon signed-rank test (WSRT).

Fig 4: Correlations between clinical and TSC measures. A) Spearman correlations (r) and p-values are presented for the association of TSC at visit 1 with BTACT scores at follow-up visits. No correlation was found between TSC and RPQ, a measure of the presence and severity of post-concussion symptoms. B) Spearman correlations and p-values are presented for the association of change of TSC between follow-up visits and visit 1 with change of BTACT scores between follow-up visits and visit 1. Changes in TSC correlated with BTACT changes between visit 2 and 1, but not between visit 3 and 1.

Table 1: Demographic parameters, clinical outcomes, and MRI findings from mTBI patients. In parentheses are population ranges or percentages. GOSE¹¹ measures functional outcome; RPQ¹⁰ measures symptomatology; and BTACT¹² measures cognitive functioning. Total/composite scores are presented in italic. Note the reduction of post-concussion symptoms severity (reduced RPQ scores) and the improvement of cognitive scores over time (increased BTACT z-scores). After one year, nine patients are still not fully recovered (GOSE<8).

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

0131

DOI: https://doi.org/10.58530/2022/0131