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Single-patient analysis of quantitative T₁ values at 7T reveals global abnormalities in epilepsy

Gian Franco Piredda^1,2, Tom Hilbert^1,3,4, Samuele Caneschi¹, Gabriele Bonanno^5,6,7, David Seiffge⁸, Martina Goeldlin⁸, Robert Hoepner⁸, Kaspar Schindler⁸, Serge Vulliemoz⁹, Margitta Seeck⁹, Veronica Ravano^1,3,4, Bénédicte Maréchal^1,3,4, Roland Wiest^6,10, Tobias Kober^1,3,4, and Piotr Radojewski^6,10
¹Advanced Clinical Imaging Technology, Siemens Healthineers International AG, Lausanne, Switzerland, ²CIBM Center for Biomedical Imaging, Geneva, Switzerland, ³Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, ⁴LTS5, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ⁵Advanced Clinical Imaging Technology, Siemens Healthineers International AG, Bern, Switzerland, ⁶Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland, ⁷Magnetic Resonance Methodology, Institute of Diagnostic and Interventional Neuroradiology, University of Bern, Bern, Switzerland, ⁸Department of Neurology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland, ⁹EEG and Epilepsy Unit, Department of Clinical Neurosciences, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland, ¹⁰Support Center for Advanced Neuroimaging, Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland

Synopsis

Keywords: Epilepsy, Quantitative Imaging, ultra-high field, 7T MRI

Motivation: While widespread structural changes in epilepsy have been previously reported, the global secondary effects on the brain are yet to be fully understood.

Goal(s): To investigate the presence of global abnormalities in quantitative T₁ values in drug-resistant epilepsy at a single-patient level.

Approach: Seventy-eight epilepsy patients were studied using 7T MRI, and a previously established quantitative T₁ brain atlas of healthy subjects was used to calculate T₁ deviations in patients.

Results: Frontal and temporal gray matter exhibited the largest T₁ alterations, with significant correlations observed between T₁ deviations and the patients’ disease duration. These findings suggest widespread microstructural disruptions in epilepsy patients.

Impact: The observed quantitative T₁ changes reveal widespread microstructural disturbances in epilepsy patients that extend beyond the seizure onset zone. The proposed method may allow early diagnosis of previously undetectable microstructural abnormalities along brain areas involved into seizure formation and propagation.

Introduction

There has long been interest in the global secondary effects of epilepsy on the brain. In an attempt to comprehend the outcomes of epilepsy, cohort-level research has demonstrated that epilepsy is characterized by brain alterations that extend beyond the epileptic focus^1,2. In large multi-centric studies coordinated by the ENIGMA-consortium³, for instance, MRI-based analyses of brain morphology^4,5 and diffusion tensor imaging⁶ have revealed widespread structural changes in epilepsy. Such disruptions have been postulated to be the result of degenerative processes occurring over the course of the disease, including demyelination and axonal loss, leading to progressive functional decline⁶. However, it remains unclear whether such changes are reflecting the primary process of epileptogenesis.
On this basis, our study explores whether quantitative T₁ maps provide insights into global brain microstructure abnormalities on a single-patient level in epilepsy. To that end, previously established atlases of reference T₁ values¹⁰ were used to compute T₁ deviations in patients’ brain tissues. Additionally, the correlation of T₁ changes with the patient’s disease duration was investigated in an exploratory analysis.

Methods

Study population and MR protocol
A cohort of 78 patients (47 females, median age = 28 y/o, range = [15-69] y/o, median disease duration = 9 y, range = [0-57] y) with drug-resistant epilepsy and ambiguous findings at 3T underwent 7T MRI (MAGNETOM Terra, Siemens Healthcare, Erlangen, Germany) using a 1-channel Tx/32-channel Rx head coil (Nova Medical, Wilmington, MA). For the computation of the reference atlas, 127 healthy subjects (68 females, median age = 28 y/o, range = [15-74] y/o) were previously acquired¹⁰. T₁-weighted images and T₁ maps were obtained using an MP2RAGE research application sequence^7,8. Sequence parameters, as well as detailed patients’ demographics, are reported in Figure 1.
Image processing
Total intracranial volume and masks of 48 brain structures were segmented in each dataset using the MorphoBox research application adapted for 7T MP2RAGE T₁-weighted uniform images (“UNI”)^9,10.
Following previously reported methodologies^10,11, whole brain atlases of reference T₁ values at 7T were established from the healthy cohort by modelling the T₁ inter-subject variability accounting for sex differences and a quadratic evolution with age¹²:
$$E\{T_1\}=\beta_0+\beta_{sex}*sex+\beta_{age}*age+\beta_{age^2}*age^2\,\,.$$T₁ deviations from the expected reference values were assessed voxel-wise in patients by means of z-scores. To assess the sensitivity of the method to detect tissue alterations, T₁ z-scores were additionally calculated in the healthy cohort within a 10-fold cross-validation, iteratively establishing a T₁ atlas with 90% of the healthy subjects and computing z-scores in the remaining 10% of the healthy T₁ maps¹³.
For each segmented brain region, average T₁ z-scores, standard deviation of T₁ z-scores, and the percentage of voxels within the region with |z-scores|>2 were extracted. Spearman's correlation coefficients were computed between extracted T₁ z-score metrics and patients’ disease duration.

Results

Representative anatomical images and corresponding whole brain T₁ z-score maps are shown in Figure 2 for four example patients.
Average T₁ z-score, standard deviation of T₁ z-scores and percentage of voxels with |z-scores|>2 in cortical gray matter (GM) and white matter (WM) regions are reported in waterfall plots including each individual epilepsy patient in Figure 3. From the waterfall plots, a general alteration of T₁ values in the GM can be observed on a patient-level. In particular, the percentage of voxels with |z-scores|>2 was greater than the healthy cohort median for 72/78 (92%) of the enrolled patients (Figure 3E). The same trend occurred, instead, only to 10/78 patients (13%) in the WM (Figure 3F).
Among the different lobes of the cortical GM, the frontal and temporal lobe exhibit the largest T₁ alterations (Figure 4). In these regions, significant correlations were observed between the extracted T₁ z-score metrics and patients’ disease duration (Figure 5). The strongest correlations were found for the standard deviation of T₁ z-scores in the frontal lobe (ρ = 0.44, p<0.001) and the average T₁ z-score in the temporal lobe (ρ = 0.41, p<0.001).

Discussion and Conclusion

Alterations of T₁ values were assessed in a cohort of epilepsy patients scanned at 7T, suggesting widespread microstructural disruptions of brain tissues beyond the seizure onset zone, particularly in GM tissues. Additionally, correlations between T₁ z-score metrics and patients' disease duration were observed. The proposed method may thus allow early diagnosis of previously undetectable microstructural abnormalities along brain areas involved into seizure formation and propagation. Future work should focus on validating these results in larger patient cohorts while looking into additional relevant features of epilepsy such as type of seizures, their frequency, or response to treatment.

Acknowledgements

No acknowledgement found.

References

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7. Marques JP, Kober T, Krueger G, van der Zwaag W, Van de Moortele PF, Gruetter R. MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage. 2010;49(2):1271-1281. doi:10.1016/j.neuroimage.2009.10.002

8. Mussard E, Hilbert T, Forman C, Meuli R, Thiran J, Kober T. Accelerated MP2RAGE imaging using Cartesian phyllotaxis readout and compressed sensing reconstruction. Magn Reson Med. 2020;84(4):1881-1894. doi:10.1002/mrm.28244

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Figures

Figure 1. (A) Parameters of the acquired MP2RAGE sequence at 7T. (B, C) Demographics of enrolled healthy cohort (B) and epilepsy patients (C). (D) Distribution of the disease duration in the epilepsy cohort.

Figure 2. Representative MP2RAGE T₁-weighted uniform (UNI) images, T₁ maps, and T₁ z-scores overlaid onto UNI images in four example epilepsy patients.

Figure 3. Average T₁ z-score (A, B), standard deviation of T₁ z-scores (C, D), and percentage of voxels with an absolute T₁ z-score > 2 (E, F) are reported for every epilepsy patient enrolled in this study in cortical gray matter (left column) and white matter (right column) tissues. Dotted blue lines indicate the median value of the considered variable in the healthy cohort (HC).

Figure 4. Average T₁ z-score (A, B), standard deviation of T₁ z-scores (C, D), and percentage of voxels with an absolute T₁ z-score > 2 (E, F) are reported for every epilepsy patient enrolled in this study in frontal (right column) and temporal gray matter (left column) regions. Dotted blue lines indicate the median value of the considered variable in the healthy cohort (HC).

Figure 5. Correlations between epilepsy patients’ disease duration and average T₁ z-score (A, D, G), standard deviation of T₁ z-scores (B, E, H), and percentage of voxels with an absolute T1 z-score > 2 (C, F, I) are reported for cortical gray matter (upper row), frontal gray matter (middle row), and temporal gray matter (lower row) regions.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)

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DOI: https://doi.org/10.58530/2024/3221