Quantitative susceptibility mapping in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Quantitative susceptibility mapping (QSM) is a quantitative measure based on magnetic resonance imaging sensitive to iron and myelin content. This makes QSM a promising non-invasive tool for multiple sclerosis (MS) in research and clinical practice. OBJECTIVE: We performed a systematic review and meta-analysis on the use of QSM in MS. METHODS: Our review was prospectively registered on PROSPERO (CRD42022309563). We searched five databases for studies published between inception and 30th April 2023. We identified 83 English peer-reviewed studies that applied QSM images on MS cohorts. Fifty-five included studies had at least one of the following outcome measures: deep grey matter QSM values in MS, either compared to healthy controls (HC) (k = 13) or correlated with the score on the Expanded Disability Status Scale (EDSS) (k = 7), QSM lesion characteristics (k = 22) and their clinical correlates (k = 17), longitudinal correlates (k = 11), histological correlates (k = 7), or correlates with other imaging techniques (k = 12). Two meta-analyses on deep grey matter (DGM) susceptibility data were performed, while the remaining findings could only be analyzed descriptively. RESULTS: After outlier removal, meta-analyses demonstrated a significant increase in the basal ganglia susceptibility (QSM values) in MS compared to HC, caudate (k = 9, standardized mean difference (SDM) = 0.54, 95 % CI = 0.39-0.70, I2 = 46 %), putamen (k = 9, SDM = 0.38, 95 % CI = 0.19-0.57, I2 = 59 %), and globus pallidus (k = 9, SDM = 0.48, 95 % CI = 0.28-0.67, I2 = 60 %), whereas thalamic QSM values exhibited a significant reduction (k = 12, SDM = -0.39, 95 % CI = -0.66--0.12, I2 = 84 %); these susceptibility differences in MS were independent of age. Further, putamen QSM values positively correlated with EDSS (k = 4, r = 0.36, 95 % CI = 0.16-0.53, I2 = 0 %). Regarding rim lesions, four out of seven studies, representing 73 % of all patients, reported rim lesions to be associated with more severe disability. Moreover, lesion development from initial detection to the inactive stage is paralleled by increasing, plateauing (after about two years), and gradually decreasing QSM values, respectively. Only one longitudinal study provided clinical outcome measures and found no association. Histological data suggest iron content to be the primary source of QSM values in DGM and at the edges of rim lesions; further, when also considering data from myelin water imaging, the decrease of myelin is likely to drive the increase of QSM values within WM lesions. CONCLUSIONS: We could provide meta-analytic evidence for DGM susceptibility changes in MS compared to HC; basal ganglia susceptibility is increased and, in the putamen, associated with disability, while thalamic susceptibility is decreased. Beyond these findings, further investigations are necessary to establish the role of QSM in MS for research or even clinical routine.

Benefits of a mosaic approach for assessing cortical atrophy in individual multiple sclerosis patients.

OBJECTIVE: Cortical gray matter (GM) atrophy plays a central role in multiple sclerosis (MS) pathology. However, it is not commonly assessed in clinical routine partly because a number of methodological problems hamper the development of a robust biomarker to quantify GM atrophy. In previous work, we have demonstrated the clinical utility of the "mosaic approach" (MAP) to assess individual GM atrophy in the motor neuron disease spectrum and frontotemporal dementia. In this study, we investigated the clinical utility of MAP in MS, comparing this novel biomarker to existing methods for computing GM atrophy in single patients. We contrasted the strategies based on correlations with established biomarkers reflecting MS disease burden. METHODS: We analyzed T1-weighted MPRAGE magnetic resonance imaging data from 465 relapsing-remitting MS patients and 89 healthy controls. We inspected how variations of existing strategies to estimate individual GM atrophy ("standard approaches") as well as variations of MAP (i.e., different parcellation schemes) impact downstream analysis results, both on a group and an individual level. We interpreted individual cortical disease burden as single metric reflecting the fraction of significantly atrophic data points with respect to the control group. In addition, we evaluated the correlations to lesion volume (LV) and Expanded Disability Status Scale (EDSS). RESULTS: We found that the MAP method yielded highest correlations with both LV and EDSS as compared to all other strategies. Although the parcellation resolution played a minor role in terms of absolute correlations with clinical variables, higher resolutions provided more clearly defined statistical brain maps which may facilitate clinical interpretability. CONCLUSION: This study provides evidence that MAP yields high potential for a clinically relevant biomarker in MS, outperforming existing methods to compute cortical disease burden in single patients. Of note, MAP outputs brain maps illustrating individual cortical disease burden which can be directly interpreted in daily clinical routine.

Cortical Thin Patch Fraction Reflects Disease Burden in MS: The Mosaic Approach.

BACKGROUND AND PURPOSE: GM pathology plays an essential role in MS disability progression, emphasizing the importance of neuroradiologic biomarkers to capture the heterogeneity of cortical disease burden. This study aimed to assess the validity of a patch-wise, individual interpretation of cortical thickness data to identify GM pathology, the "mosaic approach," which was previously suggested as a biomarker for assessing and localizing atrophy. MATERIALS AND METHODS: We investigated the mosaic approach in a cohort of 501 patients with MS with respect to 89 internal and 651 external controls. The resulting metric of the mosaic approach is the so-called thin patch fraction, which is an estimate of overall cortical disease burden per patient. We evaluated the mosaic approach with respect to the following: 1) discrimination between patients with MS and controls, 2) classification between different MS phenotypes, and 3) association with established biomarkers reflecting MS disease burden, using general linear modeling. RESULTS: The thin patch fraction varied significantly between patients with MS and healthy controls and discriminated among MS phenotypes. Furthermore, the thin patch fraction was associated with disease burden, including the Expanded Disability Status Scale, cognitive and fatigue scores, and lesion volume. CONCLUSIONS: This study demonstrates the validity of the mosaic approach as a neuroradiologic biomarker in MS. The output of the mosaic approach, namely the thin patch fraction, is a candidate biomarker for assessing and localizing cortical GM pathology. The mosaic approach can furthermore enhance the development of a personalized cortical MS biomarker, given that the thin patch fraction provides a feature on which artificial intelligence methods can be trained. Most important, we showed the validity of the mosaic approach when referencing data with respect to external control MR imaging repositories.

Concurrent TMS-fMRI: Technical Challenges, Developments, and Overview of Previous Studies.

Transcranial magnetic stimulation (TMS) is a promising treatment modality for psychiatric and neurological disorders. Repetitive TMS (rTMS) is widely used for the treatment of psychiatric and neurological diseases, such as depression, motor stroke, and neuropathic pain. However, the underlying mechanisms of rTMS-mediated neuronal modulation are not fully understood. In this respect, concurrent or simultaneous TMS-fMRI, in which TMS is applied during functional magnetic resonance imaging (fMRI), is a viable tool to gain insights, as it enables an investigation of the immediate effects of TMS. Concurrent application of TMS during neuroimaging usually causes severe artifacts due to magnetic field inhomogeneities induced by TMS. However, by carefully interleaving the TMS pulses with MR signal acquisition in the way that these are far enough apart, we can avoid any image distortions. While the very first feasibility studies date back to the 1990s, recent developments in coil hardware and acquisition techniques have boosted the number of TMS-fMRI applications. As such, a concurrent application requires expertise in both TMS and MRI mechanisms and sequencing, and the hurdle of initial technical set up and maintenance remains high. This review gives a comprehensive overview of concurrent TMS-fMRI techniques by collecting (1) basic information, (2) technical challenges and developments, (3) an overview of findings reported so far using concurrent TMS-fMRI, and (4) current limitations and our suggestions for improvement. By sharing this review, we hope to attract the interest of researchers from various backgrounds and create an educational knowledge base.