Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Magn Reson Imaging. Author manuscript; available in PMC Feb 9, 2010.
Published in final edited form as:
PMCID: PMC2818352

Diminished visibility of cerebral venous vasculature in multiple sclerosis by susceptibility-weighted imaging at 3.0 T


Multiple sclerosis (MS) is a disease of the central nervous system characterized by widespread demyelination, axonal loss and gliosis, and neurodegeneration; susceptibility-weighted imaging (SWI), through the use of phase information to enhance local susceptibility or T2* contrast, is a relatively-new and simple MRI application that can directly image cerebral veins by exploiting venous blood oxygenation. Here, we use high-field SWI at 3.0 T to image fifteen patients with clinically definite relapsing-remitting (RR) MS and to assess cerebral venous oxygen level changes. We demonstrate significantly reduced visibility of periventricular white matter venous vasculature as compared to control subjects, supporting the concept of a widespread hypometabolic MS disease process. SWI may afford a noninvasive and relatively simple method to assess venous oxygen saturation in order to closely monitor disease severity, progression, and response to therapy.

Keywords: multiple sclerosis, magnetic resonance, susceptibility weighted imaging, oxygenation, venography


Although the classical teaching has been one of a chronic inflammatory demyelinating disease marked by multi-focal white matter lesions, multiple sclerosis (MS) is being increasingly recognized as a disease of the central nervous system (CNS) characterized by widespread demyelination, axonal loss and gliosis, and neurodegeneration (1). In line with these diffuse histopathological changes, prior study, such as through PET examination, has revealed decreased oxygen utilization and extraction, with extensive reduction in cerebral glucose metabolism in MS patients (2). As tissue damage in MS has been shown to invariably extend beyond the focal plaque, modern MRI techniques are being developed to allow for the qualitative and quantitative demonstration of the global, diffuse nature of neuropathological changes in order to closely monitor disease severity, progression, and response to therapy.

Susceptibility-weighted imaging (SWI) (3), through the unique use of phase information to enhance local susceptibility or T2* contrast, is a relatively-new and simple MRI application that can image cerebral veins by exploiting the magnetic susceptibility effects from paramagnetic deoxygenated hemoglobin. Using deoxyhemoglobin as an intrinsic contrast agent, SWI venography affords a direct and noninvasive assessment of venous blood oxygenation, which is related to the overall metabolic picture in MS. Here, we attempt to visualize oxygen level changes in the cerebral veins indicated by venous blood signal changes on SWI venography of patients with MS, and furthermore, evaluate the relationship between the vascular visibility and lesion load in these patients.

Materials and Methods


Fifteen patients with clinically definite relapsing-remitting MS (4) (11 women, 4 men; mean age: 38.5 years, range from 26 to 52 years), with a mean duration of disease of 5.6 years (range, 1.3-11.9 years), were examined. None of these patients had any evidence of or prior diagnoses of cardiovascular morbidity, cerebrovascular disease, or other neurological disease. All patients displayed a characteristic phenotype that included but was not limited to visual disturbances (i.e. diplopia), paresthesias, ataxia, dysphagia, fatigue, and non-specific disabling arthralgias. Expanded Disability Status Scale (EDSS) scores averaged 2.5 amongst the fifteen patients; none had used steroids within the previous 3 months; and five had received immunomodulating medication within 2 years of the current imaging study. The control population consisted of fourteen healthy individuals (9 women, 5 men; mean age: 39.2 years, range from 23 to 50 years). According to the institutional guidelines, all subjects gave informed written consent approved by our Institutional Review Board before undergoing the MRI scans.

MRI Acquisition

All imaging was conducted on a 3.0 T system (TIM Trio, Siemens, Erlangen, Germany) using an eight-channel array head coil. Standard protocol for MS study was performed, which included dual-echo fast spin-echo proton attenuation and T2-weighted imaging (TR/TE1/TE2, 5500 ms/19 ms/101 ms; matrix, 256×256; pixel size, 0.86×0.86 mm2) as well as contrast-enhanced T1-weighted imaging (TR/TE, 660 ms/14 ms). These routine sequences were acquired with 3-mm-thick contiguous axial sections for lesion identification. SWI was acquired with a 3D, radiofrequency spoiled, fast low-angle shot sequence and flow compensation in all three directions. This gradient moment nulling in all three orthogonal directions reduced signal loss in blood attributable to flow-dephasing (3). Thirty-two partitions (64 mm slab) were obtained with the following acquisition parameters: TR/TE/flip angle: 50ms/20ms/25°; matrix: 512×512; voxel size: 0.43×0.43×2mm3; and low bandwidth (80Hz per pixel). The total acquisition time of SWI was 5 minutes and 12 seconds with using the parallel imaging (GRAPPA, iPAT factor of 2) to reduce the acquisition time. SWI images were obtained in an axial orientation parallel to anterior commissure to posterior commissure (AC-PC) line. To keep consistence between subjects, the center of the 3D slab was placed in the inferior border of body of corpus callosum in order to cover the periventricular region, where most MS lesions occur.

Image Processing and Analysis

SWI is based on theoretical and experimental evidence, developed for enhanced susceptibility effects using phase information. The raw magnitude and phase from each SWI scan was obtained and used to generate SWI venography. All phase images were reconstructed and corrected for field inhomogeneities by use of a high-pass filter of 64 using in-house image-processing software (SPIN). A phase mask was used to manipulate magnitude images and to enhance venous visualization, and all positive phase values of 0 to +180° were set to unity and negative phase values of 0 to -π were normalized to a gray scale of values ranging linearly from 0 to 1, such that 0 corresponded to -180° and 1 corresponded to 0°. The original magnitude image was multiplied by this phase mask four times in order to enhance the visibility of venous structures. Finally, SWI venograms were created by performing minimum intensity projection technique (mIP) using contiguous sections (over 4 slices) of 8mm thickness for total 8 projections of constant locations between AC-PC line to the centrum semiovale in both MS patients and controls.

For comparison between detected venous vasculatures in patients and controls, quantification of SWI venous blood voxels was done through segmentation of the venous structures of the brain based on the SWI data. Venous segmentation was done using a statistical thresholding algorithm with several steps. First, 8mm-thick SWI mIP images with enhanced venous vasculature were generated after image processing using both magnitude and phase images. Second, a statistical local thresholding algorithm, which is similar to the algorithms that have been proposed for segmenting arteries (5) was applied to mark the veins based on the different contrast of veins versus other brain tissues. Third, a thresholding was applied to the complex data (magnitude and phase) to remove the background noise and skull as described elsewhere (6). Fourth, a novel shape filtering noise removal algorithm was used to remove false positives and the venous vasculature map was generated for the computation of venous blood voxels. This vessel segmentation was run using the same thresholding parameters in both patients and controls at the fixed level of brain. After all voxels were examined, clusters of connected voxels were discarded if they were below a certain size, to remove false positives. Clusters of connected voxels were further filtered through a shape analysis using the compactness (7) and relative anisotropy (RA) of each cluster to produce color-coded venous vasculature maps with each color representing a single cluster. Finally the number of voxels from each cluster was computed for quantification analysis. The threshold size, compactness, and RA for the segmentation and background removal are set manually after visual inspection of the results. The results were then reviewed to verify that the segmentation was accurate. Given the current image resolution, the very small veins visualized on SWI mIP images may not be detected on segmentation map due to the signal attenuation from partial volume effects when threshold was applied. The image processes of constructing SWI venography and segmentation results of venous vasculature from a normal volunteer are demonstrated in Figure 1.

Figure 1
Image post processing and segmentation of venous structures were based on SWI magnitude (A) and filtered phase (B) images. Four magnitude images (C) were manipulated with filtered phase mask by multiplication factor of 4 to create minimum intensity projection ...

In MS patients, we also computed the T2 lesion load based on dual-echo fast spin-echo (proton attenuation and T2-weighted) images based on 3D VIEWNIX software system with the concept of “fuzzy connectedness” (8, 9). The MS lesions, identified as “3D fuzzy objects”, and the voxels belonging to the lesions were created as 3D volume images, which provided the total number and volume of the lesions. The method of this segmentation of the T2 lesions has been described and validated previously (10), and the reproducibility was shown to be >99% for T2 lesion segmentation.

The differences of segmentation results of venous blood on SWI venography between patients with MS and normal controls were assessed using the upaired t test, where p < 0.05 was considered significant. The correlation between the number of voxels of venous blood and lesion load in patients was analyzed using linear regression.


A dramatic loss of contrast between the venous vessels and the parenchyma is observed on SWI venograms of MS patients (Fig. 2), reflecting decreased venous blood deoxyhemoglobin concentration. At the level of lateral ventricles, the longitudinal caudate vein of Schlesinger with its deep medullary tributaries is the primary collecting system for the cerebral deep white matter. As shown in Figure 2, at the level just below the centrum semiovale, collecting veins of both small and large diameter in the deep white matter are clearly delineated in healthy controls, as opposed to their decreased visibility on SWI venograms of MS patients. In addition, diminished visibility of veins is also found in the cortical and subcortical regions, suggesting that the process leading to the loss of contrast is widespread. The segmentation results with the mean number of venous blood voxels in patients (Mean/SD: 9724.2/1001.9) and in controls (mean/SD: 11024/708.7) show significant difference (p<0.001). Figure 3 demonstrates the distribution of segmented number of voxels of venous blood in each of the patients and controls.

Figure 2
Conventional T2-weighted and SWI mIP images in a normal control (A, B) and in a patient with MS (C, D) demonstrate significantly reduced susceptibility contrast of venous blood on SWI processed mIP image in patient as opposed to healthy control subject. ...
Figure 3
Segmented results of the number venous blood (number of voxels) in patients and control participants. A wider and downwards shifted distribution is found in patients with MS compared to controls and the dash (-) indicates the mean values.

Since most MS lesions occur in the periventricular white matter region, where the medullary venous system provides a rich drainage network for deep white matter, we also evaluated the relationship between venous visualization and MS lesion load. A moderate inverse correlation (r = -0.60, p = 0.02) is found between the number of venous blood voxels and lesion volume (cc) in patients with MS. As shown in Figure 4, the number of veins visualized on SWI venography is more apparently reduced in MS patients with a greater, as opposed to fewer, number of lesions seen on T2-weighted images.

Figure 4
Conventional T2-weighted (A1, B1, C1) and SWI mIP images (A2, B2, C2) at the periventricular level (8mm thick) in a normal control (A1, A2) and two MS patients (B1,B2,C1,C2) demonstrate a significantly reduced number of periventricular medullary veins ...


SWI employs a fully flow-compensated, 3D high resolution, gradient echo sequence, with the application of filtered phase images to enhance contrast via susceptibility differences between tissues (3). SWI venography, by use of a magnetic susceptibility difference between oxygenated and deoxygenated hemoglobin, allows for the detailed visualization of cerebral veins without the use of an exogenous contrast agent. During normal metabolic gas exchange at the capillary level, oxygen is extracted from hemoglobin molecule, inducing a conformational change and resulting in a deoxyhemoglobin molecule with four unpaired electrons. This paramagnetic deoxyhemoglobin molecule in the venous blood results in increased local magnetic field inhomogeneity against the external magnetic field, leading to spin dephasing and signal loss on SWI. Experiments of carbogen and caffeine ingestion (11, 12) have revealed that SWI venography is quite sensitive in detecting blood oxygen level changes. At higher field strengths of MR magnets, SWI has potential to provide even higher image resolution and contrast due to increased signal-to-noise ratio and increased susceptibility effects. Using SWI venography at high-field 3.0 T, we found significantly reduced visibility of periventricular white matter venous vasculature in patients with MS as compared to control subjects, and also noted that lesion load and venous visibility were negatively correlated.

Our finding of decreased visibility of veins in periventricular white matter in MS is thought to be a result of decreased oxygen utilization in the chronic and widespread diseased tissue state of MS that lends to decreased levels of oxygen extraction, or correspondingly, decreased levels of venous deoxyhemoglobin. In fact, prior PET investigation has shown that oxygen utilization, including regional cerebral oxygen utilization and oxygen extraction, is reduced significantly in both white matter and peripheral cortical gray matter in MS (2). Brain regional glucose metabolism in MS using FDG PET has revealed extensive hypometabolism throughout the cerebral cortex, subcortical nuclei, supratentorial white matter, and infratentorial structures (13), and it has even been demonstrated that decreases in the cortical cerebral metabolic rate of glucose correlate with total MS lesion area (14), corroborating our findings of a negative correlation between venous visualization and MS lesion load. This suggests that with more lesions, oxygen underutilization becomes more prominent. Qualitative estimation of venous oxygenation levels on SWI by venous visibility, or quantitative measure of segmented number of voxels of venous blood, may thus serve as a marker for determining the global hypometabolic status of the brain in MS.

There exists the possibility, however, that diminished venous vasculature on SWI in MS represents altered venous hemodynamics or venous vascular occlusion (15). A study of MS using perfusion MRI has found significantly reduced cerebral blood flow in normal appearing white matter (16). Such reduced blood perfusion and vascular occlusion or stasis, however, would be expected to contribute to the enhancement of susceptibility effects, resulting in greater visibility of venous structures by SWI, due to increased oxygen extraction from vessels experiencing reduced blood flow, as well as due to increased iron content within thrombosed cerebral veins. Compared to other sophisticated quantitative MR measures (17, 18) or invasive measurements of venous oxygenation, such as through the SjO2 catheter (19), SWI offers a simple, direct, and noninvasive method that can be used as a routine clinical tool without the need for much image post-processing. With markedly increased sensitivity in the detection of venous structures, SWI affords a way to qualitatively assess venous blood oxygenation, and subsequently, disease burden.

In summary, our finding of diminished venous visibility as a function of blood oxygen saturation and its relationship to lesion load on SWI in MS lends credence to the increasingly recognized concept of MS as diffuse and global brain pathology with a major vascular impact. The quantitative measures of detected number of venous structures on SWI may allow the clinician to closely monitor disease severity, progression, and response to therapies.


Grant Support: This work was supported by grant R01NS029029-16 from the National Institute of Health.


1. Filippi M. Multiple sclerosis: a white matter disease with associated gray matter damage. J Neurol Sci. 2001;185:3–4. [PubMed]
2. Brooks DJ, Leenders KL, Head G, Marshall J, Legg NJ, Jones T. Studies on regional cerebral oxygen utilisation and cognitive function in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1984;47:1182–1191. [PMC free article] [PubMed]
3. Haacke EM, Xu Y, Cheng YC, Reichenbach JR. Susceptibility weighted imaging (SWI) Magn Reson Med. 2004;52:612–618. [PubMed]
4. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13:227–231. [PubMed]
5. Wilson DL, Noble JA. An adaptive segmentation algorithm for time-of-flight MRA data. IEEE Trans Med Imaging. 1999;18:938–945. [PubMed]
6. Pandian DS, Ciulla C, Haacke EM, Jiang J, Ayaz M. Complex threshold method for identifying pixels that contain predominantly noise in magnetic resonance images. J Magn Reson Imaging. 2008;28:727–735. [PubMed]
7. Bribiesca E. A Measure of Compactness for 3D Shapes. Computers and Mathematics with Applications. 2000:1275–1284.
8. Udupa JK, Wei L, Samarasekera S, Miki Y, van Buchem MA, Grossman RI. Multiple sclerosis lesion quantification using fuzzy-connectedness principles. IEEE Trans Med Imaging. 1997;16:598–609. [PubMed]
9. Nyul LG, Udupa JK. MR image analysis in multiple sclerosis. Neuroimaging Clin N Am. 2000;10:799–816. x. [PubMed]
10. Udupa JK, Nyul LG, Ge Y, Grossman RI. Multiprotocol MR image segmentation in multiple sclerosis: experience with over 1,000 studies. Acad Radiol. 2001;8:1116–1126. [PubMed]
11. Rauscher A, Sedlacik J, Barth M, Haacke EM, Reichenbach JR. Nonnvasive assessment of vascular architecture and function during modulated blood oxygenation using susceptibility weighted magnetic resonance imaging. Magn Reson Med. 2005;54:87–95. [PubMed]
12. Ge Y, Haacke E, Grossman RI. Susceptibility weighted imaging (SWI) of cerebral blood oxygenation during voluntary hyperventilation and apnea. Intl Soc Magn Reson Med. 2007:2300.
13. Bakshi R, Miletich RS, Kinkel PR, Emmet ML, Kinkel WR. High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging. 1998;8:228–234. [PubMed]
14. Blinkenberg M, Rune K, Jensen CV, et al. Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology. 2000;54:558–564. [PubMed]
15. Wakefield AJ, More LJ, Difford J, McLaughlin JE. Immunohistochemical study of vascular injury in acute multiple sclerosis. J Clin Pathol. 1994;47:129–133. [PMC free article] [PubMed]
16. Law M, Saindane AM, Ge Y, et al. Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology. 2004;231:645–652. [PubMed]
17. Lu H, Ge Y. Quantitative evaluation of oxygenation in venous vessels using T2-Relaxation-Under-Spin-Tagging MRI. Magn Reson Med. 2008;60:357–363. [PMC free article] [PubMed]
18. Lu H, Zhao C, Ge Y, Lewis-Amezcua K. Baseline blood oxygenation modulates response amplitude: Physiologic basis for intersubject variations in functional MRI signals. Magn Reson Med. 2008;60:364–372. [PMC free article] [PubMed]
19. Clay HD. Validity and reliability of the SjO2 catheter in neurologically impaired patients: a critical review of the literature. J Neurosci Nurs. 2000;32:194–203. [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...