Clinical Anatomy 28:88–95 (2015)
Spinal Diffusion Tensor Imaging: A Comprehensive Review With Emphasis on Spinal Cord Anatomy and Clinical Applications PHILIPP HENDRIX,1 CHRISTOPH J. GRIESSENAUER,1 JULIEN COHEN-ADAD,2 SHANMUGANATHAN RAJASEKARAN,3 KEITH A. CAULEY,4 MOHAMMADALI M. SHOJA,5 PARHAM PEZESHK,6 AND R. SHANE TUBBS5* 1
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama 2 Department of Biomedical Engineering, Ecole Polytechnique de Montreal, Quebec, Canada 3 Department of Orthopaedic and Spine Surgery, Ganga Hospital, Coimbatore, India 4 Department of Radiology, Columbia-Presbyterian Medical Center, New York, New York 5 Department of Pediatric Neurosurgery, Children’s Hospital, Birmingham, Alabama 6 Department of Radiology, Veterans Affairs Long Beach Healthcare System, University of California, Irvine, California
Magnetic resonance imaging technology allows for in vivo visualization of ﬁber tracts of the central nervous system using diffusion-weighted imaging sequences and data processing referred to as “diffusion tensor imaging” and “diffusion tensor tractography.” While protocols for high-ﬁdelity diffusion tensor imaging of the brain are well established, the spinal cord has proven a more difﬁcult target for diffusion tensor methods. Here, we review the current literature on spinal diffusion tensor imaging and tractography with special emphasis on neuroanatomical correlations and clinical applications. Clin. Anat. 28:88–95, 2015. VC 2014 Wiley Periodicals, Inc. Key words: spinal cord; anatomy; diffusion tensor tractography
MECHANISM OF DIFFUSION TENSOR IMAGING Diffusion-Weighted Imaging Diffusion-weighted imaging is an MRI method sensitive to the movement of water molecules. Naturally, water molecules move freely in any direction, referred to as “unrestricted diffusion” or “isotropic diffusion.” In certain tissues, however, the structure of cells provides a biological barrier and restricts free diffusion (Le Bihan et al., 1986). In nerve ﬁbers, for example, the cell membrane and the myelin sheath pose such barriers and water molecules preferentially diffuse along the axon bundle’s longitudinal axis whereas perpendicular diffusion is relatively restricted. Mathematically, the probability density function of water diffusion can be represented by a tensor, which is deﬁned in space by three orthogonal vectors. If the norms of all vectors are equal, the tensor can be represented by a sphere and the diffusion is isotropic
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(water molecules diffuse equally in all directions). As water molecules move in a particular direction due to restricted diffusion, the shape of the tensor representation deviates from that of a sphere to that of a cigar-like structure (ellipsoid). The long vector is oriented along the axonal bundle in a longitudinal or parallel direction, which signiﬁes high diffusivity, whereas the other two vectors that are oriented radial or perpendicular to the axonal bundle are shorter, indicating decreased diffusivity. The extent by which the tensor changes its shape quantiﬁes anisotropy (Fig. 1; Jellison et al., 2004; Mukherjee et al., 2008; Yamada et al., 2009). Different metrics are available to display *Correspondence to: R. Shane Tubbs; Pediatric Neurosurgery, Children’s of Alabama, Birmingham, AL 35233. E-mail: [email protected]
Received 24 October 2013; Accepted 28 October 2013 Published online 4 February 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ca.22349
Spinal Cord Diffusion Tensor Tractography
diffusion anisotropy with fractional anisotropy (FA) being one of the most commonly used metric. While a FA value of 0 indicates isotropic diffusion, a FA that approximates 1 signiﬁes near perfect linear diffusion along the ﬁrst eigenvector (Jellison et al., 2004). The technique which consists in mapping the diffusion tensor is known as diffusion tensor imaging (DTI).
Tractography The information collected by DTI is used to create three-dimensional (3D) visualization of ﬁber tracts referred to as “ﬁber tracking” or “tractography” (Yamada et al., 2009). The longest vector of the tensor parallels the orientation of the axonal bundles (Mukherjee et al., 2008). Various algorithms have been proposed to assess ﬁber direction. These algorithms can be classiﬁed as probabilistic or deterministic (Yamada et al., 2009). The deterministic method of ﬁber tractography was developed ﬁrst, and requires starting and target white matter locations to be deﬁned. Tracts propagate from the starting location and continue along the white matter bundles as long as adjacent tensors are strongly aligned. Tractography terminates at points of low FA. Speciﬁc stop criteria may be deﬁned for a tensor that falls below a certain minimum FA value (Jellison et al., 2004). Probabilistic tractography on the other hand considers multiple, dispersing trajectories and creates a 3D volume of potential connectivities. Subsequently, accuracy is limited and visual interpretation can be challenging. Therefore, the probabilistic approach has not been established in spinal cord imaging yet (Mukherjee et al., 2008; Yamada et al., 2009). Examples of tractography applied to the brain and spinal cord are shown in Figure 2.
CORRELATION OF SPINAL CORD ANATOMY AND DTI AND TRACTOGRAPHY Spinal Cord Anatomy The spinal cord is composed of white and gray matter macroscopically organized in a “butterﬂy” or “Hshaped” pattern as the gray matter interiorly is surrounded by white matter on an axial section. The dorsal, lateral, and ventral gray matter sections contain the cell bodies for the neurons for the sensory, sympathetic and motor systems, respectively. The white matter consists of axonal bundles that ascend or descend the spinal cord. Anatomically, the white matter tracts
Fig. 1. The principle of spinal DTI and tractography. Panels A–C show the spinal cord, ﬁber bundles, and individual axons. As water molecules (blue spheres) come in closer proximity to the ﬁbers, diffusion is restricted as indicated by the shape of the tensor deviating from that of a sphere to that of a cigar-like structure (ellipsoid). The long vector is oriented along the axonal bundle in a longitudinal or parallel direction. [Color ﬁgure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Fig. 2. Example of tractography in the brain and spinal cord. Panel A shows a sagittal view of tractography, with an axial slice of anatomical data centered in the brain. The white box at the top and bottom of the image represent the seed points, that is, where the tractography starts and end (deterministic algorithm). Panel B shows the same subject with coronal orientation. Images were acquired with a 64-channel coil and a readout-segmented sequence (Keil et al., 2013). [Color ﬁgure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Schwartz et al. investigated tractography of rats that underwent lateral funiculotomy and showed a strong correlation between the appearance on tractography and histological examination in terms of ﬁber disruption. Fibers that had not been disrupted could be clearly identiﬁed on both modalities (Schwartz et al., 2005). Ciccarelli et al. investigated tractography as a tool to assess acute disability in multiple sclerosis patients. Anterior, lateral, and posterior columns were visualized using tractography and compared to healthy individuals. Abnormal tractography was found to correlate with neurological deﬁcits. Patients who had developed motor deﬁcits localizing to the upper cervical (C1 to C3) and displayed motor signs within the prior 4 weeks, and had at least one spinal cord lesion as documented on MRI, had signiﬁcantly lower connectivity rates and FA values in the corticospinal tract as well as the fasciculus gracilis and cuneatus of the posterior column (Ciccarelli et al., 2007). DeBoy et al. studied tractography and compared ﬁndings to immunohistochemistry in a rat model of demyelination and axonal loss. Selective injury to the dorsal column resulted in changes on tractography at the site of injury and distal to the lesion. Axonal degeneration and axonal loss correlated with FA and axial diffusivity (DeBoy et al., 2007). Cohen-Adad et al. performed tractography of dorsal, lateral, and ventral columns of healthy and injured cats and demonstrated the feasibility of assessing white matter integrity of single tracts
can be subdivided into dorsal, lateral, and ventral columns. Axons running in the dorsal columns predominantly carry ascending sensory information from somatic mechanoreceptors. Motor information from the corticospinal tract descends in the lateral columns. Anterior columns contain both ascending sensory and descending motor axons (Purves et al., 2001).
Spinal Cord Tractography Tractography of the spinal cord has been used to visualize white matter tracts ranging from the medulla oblongata to the cauda equina. Rajasekaran et al. demonstrated the axonal connections within the brain and brainstem with tractography delineating the decussation of the ascending medial lemniscus and descending corticospinal tracts (Rajasekaran et al., 2012). Xiangshui et al. used tractography of the cervical spinal cord to show how spinal nerve ﬁbers exit the spinal canal at their corresponding segmental level (Xiangshui et al., 2010). Others have shown for the exiting nerve roots at the thoracic and lumbar spine (Tsuchiya et al., 2008; Balbi et al., 2011). Filippi et al. were able to visualize distal spinal cord and the cauda equina with tractography (Fig. 3; Filippi et al., 2010).
Correlation of Spinal Cord Anatomy and Tractography Several studies have attempted to correlate tractography ﬁndings with the spinal cord anatomy.
Fig. 3. Tractography of the distal spinal distal spinal cord, conus medullaris (arrow), and nerve roots of cauda equina in 40-year-old healthy male subject. Panel A shows coronal T2-weighted image. Panel B shows a screen-capture tractography image of lower spinal cord through conus medullaris and cauda equina superimposed onto coronal T2-weighted image (Reproduced with permission from Filippi et al., Eur Radiol, 2010, 20, 2194– C Springer Science1Business Media). [Color ﬁgure 2199, V can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Spinal Cord Diffusion Tensor Tractography throughout several spinal segments. Within a single segment, nerve roots entering or exiting the spinal cord were visible as well (Cohen-Adad et al., 2008, 2011b). Rao et al. characterized posterolateral corticospinal tract and dorsal column ﬁbers in traumatic spinal cord injured patients by investigating the properties of residual ﬁbers within spinal cord lesions through selecting and subsequently identifying individual, residual ﬁbers (Rao et al., 2013).
Noninvasive imaging is essential in the management of spinal cord injury (SCI). While conventional MRI is considered the gold standard in the clinical setting, it is incapable of delineating axonal integrity. In preliminary studies, DTI and tractography have been used to shed light on axonal integrity in SCI (Fig. 4; Ellingson et al., 2008; Cohen-Adad et al., 2011a; Mohamed et al., 2011; Cohen-Adad et al., 2012; Petersen et al., 2012). Various datametrics involving axial diffusivity, radial diffusivity, FA, and apparent diffusion coefﬁcient (ADC) have been developed and extensively studied in patients with SCI. Datametrics as well as tractography appear to be sensitive markers for changes in axonal integrity in SCI. However, the interpretation of those values and their correlation to the management of SCI remain controversial. When compared to healthy individuals, reduction in FA at site of a SCI has been consistently reported. ADC values are more variable and differ from study to study. Chang et al. reported that ADC values did not vary between control individuals and patients, neither at site of the lesion nor in the adjacent cervical spinal cord (Chang et al., 2010). Shan-
muganathan et al., on the other hand, found that ADC was the parameter with the highest sensitivity for SCI (Shanmuganathan et al., 2008). The ability to compare datametrics across studies is considerably limited by spinal cord anatomy and choice of region of interest, degree and etiology of pathology, and data analysis and data processing. As both data acquisition and postprocessing methods advance, correlations between abnormal DTI datametrics and clinical ﬁndings are showing interesting and promising results. Song et al. and Kim et al. reported that axial and orthogonal diffusivity are sensitive and speciﬁc, noninvasive biomarkers of axonal and myelin damage (Song et al., 2003; Kim et al., 2006). Loy et al. demonstrated that DTI is capable of predicting severity of SCI in the hyperacute phase as early as 0–6 hr after SCI. Their DTI measurements of axial diffusivity signiﬁcantly correlated to the degree of axonal injury on histology (Loy et al., 2007). Kim et al. reported that DTI at 3 hr after traumatic SCI might be a valuable prognostic tool. In their study, they compared axial diffusivity and histology and assessed locomotor recovery in mice that underwent contusive SCI. Interestingly, the extent of spared white matter corresponded to axial diffusivity and correlated with locomotor recovery after 2 weeks (Kim et al., 2010). Rao et al. accurately displayed residual white matter tracts that were running across the spinal cord. These axonal tracts were selectively investigated and subsequently identiﬁed as either posterolateral corticospinal tract or dorsal column ﬁbers. Additionally, they found a striking reduction in FA in these residual ﬁbers compared to remote ﬁbers and ﬁbers from healthy individuals, raising the question whether residual ﬁbers progressively suffer additional damage from degeneration. Rajasekaran et al. and Vedantam et al. reported patients with Brown-Sequard Syndrome, classically
Fig. 4. Tractography in traumatic SCI. Panels A and B. Transection of the spinal cord with a thin blade in a fresh spinal cord specimen. The transection was hardly visible on conventional MRI. Tractography, however, showed the extent of the ﬁber disruption. Tractography in a patient with complete cervical dislocation and seed points placed above and below level of injury showing complete disrup-
tion of the ﬁbers. Panels C and D. Tractography in a patient with acute SCI at C5/6. Conventional MRI shows evidence of injury to the spinal cord, but the full extent of the injury becomes apparent on tractography. The patient did not recover any neurological function. [Color ﬁgure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
CLINICAL APPLICATIONS Spinal Cord Injury
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Fig. 5. Tractography for spinal dysraphism exempliﬁed in a 53-year-old women with diastematomyelia. Panel A shows two hemicords on an axial T2-weighted image at L3 level, with the larger cord on left (arrow). Panel B shows tractography of the two hemicords. The axial image represents color FA map. Larger tract (light blue) is composed of greater number of individual ﬁber tracts and corresponds to larger (left) hemicord (Reproduced with permission from Filippi et al., Eur Radiol, C Springer Science1Business 2010, 20, 2194–2199, V Media). [Color ﬁgure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
a hemicord injury characterized by ipsilateral motor weakness and hypoesthesia along with contralateral loss of pain and temperature sensation below the level of injury (Aminoff, 1996), and found tractography capable of delineating the unilateral ﬁber disruption that corresponded with the neurological deﬁcits (Rajasekaran et al., 2010; Vedantam et al., 2012).
Spinal Cord Demyelination, Inﬂammation, Multiple Sclerosis Multiple sclerosis is a complex inﬂammatory condition characterized by demyelination, gliosis, and axonal degeneration in the central nervous system. Autoimmune encephalomyelitis is an accepted animal model of this disease (Constantinescu et al., 2011). DeBoy et al. investigated the spinal cord of mice with autoimmune encephalomyelitis lesions induced in the dorsal column and found that DTI-derived parameters signiﬁcantly correlated with axon degeneration and loss showed demyelination and axonal loss not only within the site of lesion but also in adjacent area (DeBoy et al., 2007). Theaudin et al. suggested that MRI might underestimate the size of the lesions in multiple sclerosis. In their prospective study, lower FA and ADC values were generally found in the lesions than in normal appearing white matter. However, patients that beneﬁted from intravenous steroid therapy had a signiﬁcant reduction in radial diffusivity and increase of FA at site of the lesion. The results also indicated that patients with initially higher FA and reduced radial diffusivity may fare better and have a better outcome (Theaudin et al., 2012). Interestingly, Setzer et al. demonstrated that tractography ﬁbers can be traced through inactive, T2 hyperintense multiple sclerosis plaques, in contrast to other types of
lesions that displace, deform or interrupt ﬁbers (Setzer et al., 2010). Renoux et al. reported that decreased FA values matched T2 abnormalities in patients with myelitis. 60% of the patients, however, had decreased FA values at sites that did not show signal alterations in conventional MRI, suggesting the ability of DTI to identify white matter abnormalities which are not evident on routine MR imaging. In one third of the cases, these decreased FA values matched the neurologic deﬁcit the patients reported. Comparison studies with healthy individuals showed partial interruption of white matter tracts at the site of the lesion in myelitis (Renoux et al., 2006). Even though ADC values and some FA values varied among patients with myelitis, DTI appeared more sensitive than conventional MRI for identiﬁcation of white matter lesions of myelitis.
Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis is a fatal neurodegenerative disease characterized by combined effects on upper motor neurons and lower motor neurons. Although most DTI studies have focused on the brain, a few studies have applied DTI at the spinal level, notably to look at the degeneration of lower motor neurons (Valsasina et al., 2007; Agosta et al., 2009; Nair et al., 2010; Cohen-Adad et al., 2013). These studies notably reported that FA in the spinal corticospinal tract correlates with disease severity. Nair et al. and Cohen-Adad et al. found larger DTI abnormalities caudally to the spinal cord, suggesting that degeneration of the corticospinal tracts follows a retrograde pattern (“dying back”).
Spinal Cord Tumors The relationship between a spinal cord tumor and spinal cord tracts has serious implication for management and prognosis. Setzer et al. introduced a classiﬁcation of three types of spinal cord ﬁbers to predict resectability of spinal cord tumors. In Type 1, ﬁbers did not pass through the lesion; in Type 2, some ﬁbers traversed the lesion; and in Type 3, the ﬁbers were completely encased by the lesion. The classiﬁcation had substantial interrater agreement and reliably differentiated resectable from nonresectable lesions. Ependymomas, the most common intramedullary spinal cord tumor in adults, most frequently were classiﬁed as Type 1 lesions, thus resectable, and achieved good outcome (Setzer et al., 2010). Pilocytic or ﬁbrillary astrocytomas and especially malignant gliomas tend to have an inﬁltrative character and are, therefore, considered nonresectable. Other spinal cord neoplasms like metastasis were found to distort the axonal ﬁbers and complicate visualization with tractography (Setzer et al., 2010).
Vascular Disorders of the Spinal Cord In 2007, Ozanne et al. reported DTI surrounding a spinal cord arteriovenous malformation. Their work not only gave insight into the organization of ﬁber
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Fig. 6. Tractography in degenerative cervical myelopathy. Tractography is superior to conventional MR imaging in the ability to precisely localize the level of myelopathy and correlate severity of clinical symptoms with imaging ﬁndings. In a patient with multilevel degenerative cervical myelopathy, conventional MRI localizes the amount of maximum compression at C3/4 (Panel A). On tractography, however, there is a complete loss of
ﬁbers at C5/6 which was conﬁrmed by FA values most altered at that level (Panel B). In another patient with severe myelopathy on clinical examination, conventional MR imaging was suggestive of only mild myelopathy (Panel C). Tractography, however, shows almost complete loss of ﬁbers at C5/6 correlating with the patient’s clinical presentation (Panel D). [Color ﬁgure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
tracts in relation to Arteriovenous malformations (AVM) lesions but also provided additional understanding of pathophysiology of these complex vascular lesions. At the level of the AVM nidus, white matter tracts were normal, shifted, separated, or interrupted. FA values were signiﬁcantly decreased caudal to the lesion corresponding to loss of white matter tracts in that area and neurological deﬁcits. The observation that there is no focal interruption at the level of the nidus is in accordance with the current pathophysiological concept of AVMs. FA values were found to be decreased in the regions caudal of the nidus in patients with neurological deﬁcits, and did not show signiﬁcant FA alterations in patients with little or no deﬁcits (Ozanne et al., 2007). In one case of postoperative spinal cord ischemia tractography was indicative of interruption of ﬁbers, a ﬁnding that was later conﬁrmed by conventional MRI (Vargas et al., 2008).
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Spinal Dysraphism Hatem et al. used DTI to assess thermosensory impairment in patients with syringomyelia and compared them to healthy subjects and found signiﬁcantly lower FA in the patient group. Changes on tractography correlated with sensory deﬁcits, cold thresholds, and to changes in electrophysiological measurements. The correlation between the clinical ﬁndings and electrophysiologic measurements was the highest in the anterior aspect of the spinal cord where the spinothalamic tracts are located (Hatem et al., 2009). Others have correlated tractography in patients with tethered spinal cord and diastematomyelia with conventional MRI and proposed a potential beneﬁt in characterization of congenital spinal cord malformations for surgical planning (Fig. 5; Filippi et al., 2010).
Nakamura et al. used tractography to predict outcome in patients undergoing laminoplasty. Patients with cervical compressive myelopathy were examined before and after surgery with tractography and ﬁndings correlated signiﬁcantly with recovery rates. Preoperative injury to the cervical white matter correlated with DTI-derived measurements and postoperative results (Nakamura et al., 2012). Similarly, Jones et al. found a decreased FA in the cervical cord prior to the patient becoming symptomatic. In patients with ossiﬁcation of the posterior longitudinal ligament, tractography may be a useful tool to select surgical candidates and determine optimal timing of surgery (Jones et al., 2011). More recently these authors published a prospective study that underlined DTI as a valuable tool to assess the severity and predict outcome in patients with cervical spinal myelopathy (Jones et al., 2013). Figure 6 shows examples of tractography in degenerative cervical myelopathy.
CONCLUSIONS DTI of the spinal cord has allowed novel insight into spinal cord anatomy and pathology. DTI and diffusion tensor tractography offers information regarding the relationship between white matter tracts and spinal cord tumors that has been found to be particularly valuable for surgical planning. Diffusion tensor techniques have found numerous clinical applications in spinal cord with the ability to detect certain pathologic processes at an early stage, guide optimal therapy, and predict outcomes. DTI of spinal cord continues to be a very active area of investigation, with recent
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ﬁndings suggesting that it will soon ﬁnd its way into routine clinical practice.
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