Here, we present a protocol to acquire magnetic resonance (MR) images of multiple sclerosis (MS) patient brains at 7.0 Tesla. The protocol includes preparation of the setup including the radio-frequency coils, standardized interview procedures with MS patients, subject positioning in the MR scanner and MR data acquisition.
The overall goal of this article is to demonstrate a state-of-the-art ultrahigh field (UHF) magnetic resonance (MR) protocol of the brain at 7.0 Tesla in multiple sclerosis (MS) patients. MS is a chronic inflammatory, demyelinating, neurodegenerative disease that is characterized by white and gray matter lesions. Detection of spatially and temporally disseminated T2-hyperintense lesions by the use of MRI at 1.5 T and 3 T represents a crucial diagnostic tool in clinical practice to establish accurate diagnosis of MS based on the current version of the 2017 McDonald criteria. However, the differentiation of MS lesions from brain white matter lesions of other origins can sometimes be challenging due to their resembling morphology at lower magnetic field strengths (typically 3 T). Ultrahigh field MR (UHF-MR) benefits from increased signal-to-noise ratio and enhanced spatial resolution, both key to superior imaging for more accurate and definitive diagnoses of subtle lesions. Hence, MRI at 7.0 T has shown encouraging results to overcome the challenges of MS differential diagnosis by providing MS-specific neuroimaging markers (e.g., central vein sign, hypointense rim structures and differentiation of MS grey matter lesions). These markers and others can be identified by other MR contrasts other than T1 and T2 (T2*, phase, diffusion) and substantially improve the differentiation of MS lesions from those occurring in other neuroinflammatory conditions such as neuromyelitis optica and Susac syndrome. In this article, we describe our current technical approach to study cerebral white and grey matter lesions in MS patients at 7.0 T using different MR acquisition methods. The up-to-date protocol includes the preparation of the MR setup including the radio-frequency coils customized for UHF-MR, standardized screening, safety and interview procedures with MS patients, patient positioning in the MR scanner and acquisition of dedicated brain scans tailored for examining MS.
Multiple sclerosis (MS) is the most common chronic inflammatory and demyelinating disease of the central nervous system (CNS) that causes pronounced neurological disability in younger adults and leads to long term disability1,2. The pathological hallmark of MS is the accumulation of demyelinating lesions that occur in the gray and white matter of the brain and also diffuse neurodegeneration in the entire brain, even in normal-appearing white matter (NAWM)3,4. MS pathology suggests that inflammation drives tissue injury at all stages of the disease, even during the progressive stages of disease5. The first clinical manifestations of MS are commonly accompanied by reversible episodes of neurological deficits and referred to as a clinically isolated syndrome (CIS), when only suggestive of MS6,7. In the absence of a clear-cut CIS, caution should be exercised in making an MS diagnosis: the diagnosis should be confirmed by follow-up and initiation of long-term disease-modifying therapies should be postponed, pending additional evidence8.
Magnetic resonance imaging (MRI) is an indispensable tool in diagnosing MS and monitoring disease progression9,10,11. MRI at magnetic field strengths of 1.5 T and 3 T currently represents a crucial diagnostic tool in clinical practice to detect spin-spin relaxation time weighted (T2) hyperintense lesions and establish accurate diagnosis of MS based on the current version of the 2017 McDonald criteria8. Diagnostic criteria for MS emphasize the need to demonstrate dissemination of lesions in space and time, and to exclude alternative diagnoses8,12. Contrast enhanced MRI is the only method to assess acute disease and acute inflammation8but increasing concerns regarding potential long-term gadolinium brain deposition could potentially restrict contrast application as an important diagnostic tool13,14,17. Additionally, the differentiation of MS lesions from brain white matter lesions of other origins can sometimes be challenging due to their resembling morphology at lower magnetic field strengths.
While MRI is certainly the best diagnostic tool for MS patients, MR examinations and protocols should follow guidelines of the Magnetic Resonance Imaging in MS group (MAGNIMS) in Europe18,19 or the Consortium of Multiple Sclerosis Centers (CMSC) in North America20 for the diagnosis, prognosis and monitoring of MS patients. Standardized quality control studies in accordance with the latest guidelines across different hospitals and countries are also crucial21.
MRI protocols tailored for MS diagnosis and disease progression monitoring comprise multiple MRI contrasts including contrast governed by the longitudinal relaxation time T1, the spin-spin relaxation time T2, the effective spin-spin relaxation time T2*, and diffusion weighted imaging (DWI)22. Harmonization initiatives provided consensus reports for MRI in MS to move towards standardized protocols that facilitate clinical translation and comparison of data across sites23,24,25. T2-weighted imaging is well established and frequently used in clinical practice for identification of white matter (WM) lesions, which are characterized by hyperintense appearance26,27. While being an important diagnostic criterion for MS28, the WM lesion load correlates only weakly with clinical disability, due to its lack of specificity for lesion severity and the underlying pathophysiology26,27,29. This observation has triggered explorations into parametric mapping of the transverse relaxation time T2 30. T2*-weighted imaging has become increasingly important in imaging MS. The central vein sign in T2* weighted MRI is considered to be a specific imaging marker for MS lesions27,31,32,33. T2* is sensitive to iron deposition34,35, which may relate to disease duration, activity and severity36,37,38. T2* was also reported to reflect brain tissue changes in patients with minor deficits and early MS, and thus may become a tool to assess the development of MS already at an early stage39,40.
Improvements in MRI technology promise to better identify changes in the CNS of MS patients and to provide clinicians with a better guide to enhance the accuracy and speed of an MS diagnosis11. Ultrahigh field (UHF, B0≥7.0 T) MRI benefits from an increase in signal-to-noise ratio (SNR) that can be invested in enhanced spatial or temporal resolutions, both key to superior imaging for more accurate and definitive diagnoses41,42. Transmission field (B1+) inhomogeneities that are an adverse attribute of the 1H radio-frequency used at ultrahigh magnetic fields43 would benefit from multichannel transmission using parallel transmit (pTx) RF coils and RF pulse design approaches that enhance B1+ homogeneity and thus facilitate uniform coverage of the brain44.
With the advent of 7.0 T MRI, we have achieved more insight into demyelinating diseases such as MS with respect to increased sensitivity and specificity of lesion detection, central vein sign identification, leptomeningeal enhancement, and even with respect to metabolic changes45. MS lesions have long been shown from histopathological studies to form around veins and venules46. The perivenous distribution of lesions (central vein sign) can be identified with T2* weighted MRI46,47,48 at 3.0 T or 1.5 T, but can be best identified with UHF-MRI at 7.0 T49,50,51,52. Other than the central vein sign, UHF-MRI at 7.0 T has improved or uncovered MS-specific markers such as hypointense rim structures and differentiation of MS grey matter lesions53,54,55,56. A better delineation of these markers with UHF-MRI promises to overcome some of the challenges of differentiating MS lesions from those occurring in other neuroinflammatory conditions such as Susac syndrome53 and neuromyelitis optica54, while also identifying common pathogenetic mechanisms in other conditions or variants of MS such as Baló's concentric sclerosis57,58.
Recognizing the challenges and opportunities of UHF-MRI for the detection and differentiation of MS lesions, this article describes our current technical approach to study cerebral white and grey matter lesions in MS patients at 7.0 T using different imaging techniques. The up-to-date protocol includes the preparation of the MR setup including the radiofrequency (RF) coils tailored to the UHF-MR, standardized screening, safety and interview procedures with MS patients, patient positioning in the MR scanner and acquisition of brain scans dedicated to MS. The article is meant to guide imaging experts, basic researchers, clinical scientists, translational researchers, and technologists with all levels of experience and expertise ranging from trainees to advanced users and applications experts into the field of UHF-MRI in MS patients, with the ultimate goal of synergistically connecting technology development and clinical application across disciplinary domains.
This protocol is for studies that are approved by the ethics committee of the Charité – Universitätsmedizin Berlin (approval number: EA1/222/17, 2018/01/08) and the Data Protection Division and Corporate Governance of the Charité – Universitätsmedizin Berlin. Informed consent has been obtained from all subjects prior of being included in the study.
1. Subjects
NOTE: Recruitment of MS patients usually takes place at few days up to some weeks prior to the MR investigations at 7.0 T.
2. MR setup preparation
NOTE: The following is performed before the subject arrives at the UHF-MR Building.
3. Subject preparation
4. Data acquisition
NOTE: In the following, some of the references to user interface actions or specific scan procedures may only be valid for one specific MR system (7.0T Magnetom, Siemens healthineers, Erlangen, Germany). The commands and procedures vary between vendors and software versions. The following protocol follows the guidelines of the Magnetic Resonance Imaging in MS group (MAGNIMS) in Europe18,19 and the Consortium of Multiple Sclerosis Centers (CMSC) in North America20 for the diagnosis, prognosis and monitoring of MS patients.
5. Concluding the MR examination
6. Data backup
NOTE: Each MR center follows its own guidelines to save and safely backup MR data. Digital MR data should be stored on a password-protected server. The procedure below is typical for a Siemens 7.0 T MR system.
7. System shutdown
A 26-year-old woman diagnosed with relapsing remitting MS (RRMS) was examined at 7.0 T using the above protocols (Figure 11). Some distortions in the B1+ profile can be observed in the MR images. This is anticipated when moving to higher resonance frequencies43; the shorter wavelengths increase destructive and constructive interferences105,106. To acquire the MR images (Figure 11, Figure 12, Figure 13, Figure 14), we used a single channel transmit volume coil on a Siemens 7.0 T MR system in which a manual adjustment of phase and amplitude was not possible to offset the B1+ inhomogeneities. Multi-transmit technologies offer the degrees of freedom of parallel transmission required to dynamically modulate the B1+ field distribution44. While the B1+ pattern cannot be modified for a single transmit element of a given coil, the electromagnetic properties of the surrounding environment may be altered, as has been shown with dielectric padding filled with water107 or calcium titanate suspensions108 used at 7.0 T. Geometrically tailored dielectric pads have been shown to be effective at imaging the brain 109,110 and particularly the inner ear111, a challenging place to image due to inhomogeneities from susceptibility differences between inner ear fluids and bone.
Shown in Figure 11 are sagittal and transversal views of the patient's brain using different protocols providing different contrasts. Four and a half years prior to the 7.0 T MR examination the patient presented with diplopia and blurry vision. Diagnosis was initially established, based on the 2017 McDonald criteria8 due to periventricular, juxtacortical and infratentorial MR lesion distribution and based on the occurrence of both gadolinium-enhancing and non-enhancing lesions at 3.0 T. CSF findings were within normal limits. Medication with natalizumab (NTZ) was subsequently initiated. The MS diagnosis was subsequently challenged due to an increase in T2 lesions and multiple clinical relapses with incomplete remission despite the highly efficacious NTZ treatment. However, 7.0 T MRI supported the MS diagnosis by revealing the central vein sign in the majority of periventricular and juxtacortical lesions (Figure 12). The MS diagnosis was further corroborated by cortical pathology (Figure 13) and hypointense rim structures surrounding a subset of T2 hyperintense lesions (Figure 14). The diagnostic re-evaluation also included a search for other autoimmune, infectious, and metabolic disorders but did not reveal further abnormal results. Eventually the patient was tested positive for antibodies against NTZ, indicating antibody-mediated neutralization and explaining the insufficient treatment response towards NTZ 112. Therefore, an MS diagnosis with an unresponsiveness towards NTZ therapy was concluded in this patient. Medication was switched from NTZ to Ocrelizumab and the patient has been relapse-free during the ensuing stages.
Figure 1. Switch box of Siemens MR scanner Please click here to view a larger version of this figure.
Figure 2. Connecting a dedicated RF coil to the MR system. (a) Transmit (Tx), 24- or 32 channel receive (Rx) radio frequency head coil tailored for brain MRI at 7.0 T (b) Instruct the subject to move closer to the RF head coil and position the head of the subject over the lower RX-coil and beneath the upper RX-coil (left panel). Next move the TX-part of the RF head coil over the RX-coil (bottom right). Please click here to view a larger version of this figure.
Figure 3. Running adjustments (Siemens system). (a) Basic frequency adjustment, (b) Transmitter voltage adjustment, (c) Generation of B0 Map and 3D shimming. Please click here to view a larger version of this figure.
Figure 4. MR sequence planning on 7.0 T MR systems from different vendors. (a) Siemens, (b) Philips and (c) General Electric. Please click here to view a larger version of this figure.
Figure 5. Planning 3D MP2RAGE imaging sequence Please click here to view a larger version of this figure.
Figure 6. Planning 3D SPACE-FLAIR imaging sequence Please click here to view a larger version of this figure.
Figure 7. Planning 2D FLASH-ME imaging sequence Please click here to view a larger version of this figure.
Figure 8. Planning 3D susceptibility weighted imaging sequence Please click here to view a larger version of this figure.
Figure 9. Planning QSM-FC Please click here to view a larger version of this figure.
Figure 10. Planning diffusion-weighted echo-planar imaging sequence Please click here to view a larger version of this figure.
Figure 11. Representative results of high-resolution brain MRI of an RRMS patient Upper panel from left to right: (a) sagittal view of a T1w 3D inversion recovery-prepared spoiled-GRE sequence (MPRAGE), (b) transversal view of T1w 3D MPRAGE, (c) transversal view of T2*w 2D FLASH sequence with multi-echo readout (FLASH-ME), (d) transversal view of a T2w fluid-attenuated inversion recovery using sampling perfection with application-optimized contrasts using different flip angle evolutions (SPACE-FLAIR), (e) transversal view of flow compensated quantitative susceptibility mapping (QSM-FC). Lower panel from left to right: (f) sagittal view of a T1w 3D magnetization-prepared rapid gradient echo sequence (MP2RAGE), (g) transversal view of T1w 3D MP2RAGE, (h) transversal view of 3D susceptibility weighted imaging (SWI) using magnitude and phase data of a fully flow-compensated GE sequence, (i) combined fractional anisotropy map and directional map of an echo-planar diffusion-weighted imaging sequence (2D EPI), (j) transversal view of T2*w 2D gradient echo imaging with flow compensation (GRE-FC). Please click here to view a larger version of this figure.
Figure 12. Representative white-matter MS lesions with central vein sign (a and b) Transversal view of T2*w 2D FLASH sequence with multi-echo readout (FLASH-ME) reveals highly MS-specific central vein sign (red arrow) within exemplary periventricular lesions, (c) a right-hemispheric thalamic lesion (d), and a parietal juxtacortical lesion, substantiating the patient's MS diagnosis. Please click here to view a larger version of this figure.
Figure 13. Representative cortical MS lesion. (a) Sagittal view of a T1w 3D magnetization-prepared rapid gradient echo sequence (MP2RAGE) delineates subpial cortical lesion (red arrow heads) within parietal cortex (b) with corresponding hyperintensity in transversal view of a T2w fluid-attenuated inversion recovery (SPACE-FLAIR), indicating the occurrence of cortical MS pathology in the relapsing-remitting MS patient. Please click here to view a larger version of this figure.
Figure 14. Representative hypointense rim structures. (a) Transversal view of T2*w 2D FLASH sequence with multi-echo readout (FLASH-ME) reveals an ovoid periventricular MS lesion, and (b) transversal view of 3D susceptibility weighted imaging (SWI) delineates a hypointense rim structure around the lesion, suggesting iron-laden macrophages to be present as a potential surrogate for MS lesion activity. Please click here to view a larger version of this figure.
Metallic implants (can malfunction due to magnetic fields or cause injury) |
Electronic devices e.g. pacemakers, defibrillators, insulin pump, nerve stimulators |
Aneurysm and haemostatic clips, prosthetic heart valves |
Cochlear, otologic implants |
Drug infusion devices |
Deep brain stimulation electrodes |
Lead electrocardiogram wires |
Other contraindications (risk of skin burns, swelling or damage via magnetic field effects) |
Some medication patches |
Metallic foreign bodies e.g. shrapnel or other minute metal fragments in the eye |
Some tattoo and cosmetics (permanent makeup) |
Body piercing jewellery |
Pregnancy (possible adverse biological effects by magnetic fields) |
Known claustrophobia |
Table 1. Principal contraindications of an MRI examination. The most common contraindications are metallic implants. Implants are becoming increasingly MR safe (MRI-conditional) but remain a major concern.
The protocol presented here describes a series of MRI sequences with different contrasts that are typically used when examining MS patients at 7.0 T. Together with emerging technological developments, they provide the basis for explorations into more advanced applications in metabolic or functional imaging.
Aside from brain lesions, lesions in the spinal cord frequently affect MS patients causing motor, sensory and autonomic dysfunction. However spinal cord imaging, particularly at 7.0 T, is technically challenging113. Further developments in parallel transmission and parallel imaging are warranted to overcome the hurdles of distorted B1 field profiles114.
The goal of this protocol is to disseminate and synergistically connect technology developments and clinical application across disciplinary domains. Aside from the expected enhancements in spatial and temporal resolution, opportunities from the changing physical characteristics of higher magnetic fields include better contrasts in susceptibility-weighted imaging (SWI) and phase-contrast techniques115, as well as imaging of X-nuclei such as sodium116,117 and fluorine118,119,120 for a more in depth assessment of the pathology as well as therapeutic monitoring.
The authors have nothing to disclose.
This project (T.N.) has received funding in part from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program under grant agreement No 743077 (ThermalMR). The authors wish to thank the teams at the Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; at the The Swedish National 7T Facility, Lund University Bioimaging Center, Lund University, Lund, Sweden and at the ECOTECH-COMPLEX, Maria Curie-Skłodowska University, Lublin, Poland for technical and other assistance.
7T TX/RX 24 Ch Head Coil | Nova Medical, Inc., Wilmington, USA | NM008-24-7S-013 | 1-channel circular polarized (CP) transmit (Tx), 24-channel receive (Rx) RF head coil |
Magnetom 7T System | Siemens Healthineers, Erlangen, Germany | MRB1076 | 7.0 T whole body research scanner |
syngoMR B17 Software | Siemens Healthineers, Erlangen, Germany | B17A | image processing software for the Magnetom 7T system |