Magnetic ResonanceNeurographyDiffusion Tensor Imaging and FutureDirections

Patrick Eppenberger, MDa, Gustav Andreisek, MDa,*,Avneesh Chhabra, MDb

KEYWORDS

� MR neurography (MRN) � Three-dimensional (3D) � Whole-body MR� Diffusion-weighted imaging (DWI) � Diffusion tensor imaging (DTI) � Magnetization transfer imaging� MR contrast

KEY POINTS

� Magnetic resonance (MR) neurography is an excellent technique for axial and multiplanar depictionof peripheral nerve anatomy and disorders.

� Three-dimensional isotropic spin-echo–type imaging is currently being used on high-field scannersfor longitudinal demonstration of nerve disorders for the benefit of referring physicians.

� Whole-bodyMR imaging is being widely used to image tumors. Whole-bodyMR neurography holdspromise in the depiction of diffuse peripheral nerve disorders and neurocutaneous syndromes.

� Diffusion-weighted imaging and diffusion tensor imaging permit functional imaging of nerves andrelated lesions, and allow tractography for presurgical planning and postsurgical follow-up.

� Magnetization transfer imaging and nerve-specific MR contrast agents are under development andin feasibility stages for the assessment of nerve degeneration and regeneration, which is beyondthe scope of anatomic pulse sequences.

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INTRODUCTION

Magnetic resonance (MR) neurography (MRN) isa noninvasive technique using high-resolutionmagnetic resonance (MR) imaging to diagnoseperipheral nerve disorders and their underlyingcauses, such as indirect or direct penetratinginjury, compression, stretch, friction, and iatro-genic insult, as well as to monitor processes ofperipheral nerve degeneration and regeneration.At present, anatomic MRN is being widely usedfor a variety of nerve disorders.1–9 Because ofthe continuous technological advancements,MRN diagnostic capabilities have improved in

a Department of Radiology, University Hospital Zurich, RUniversity of Texas Southwestern, 5323 Harry Hines Blvd* Corresponding author.E-mail address: gustav@andreisek.de

Neuroimag Clin N Am 24 (2014) 245–256http://dx.doi.org/10.1016/j.nic.2013.03.0311052-5149/14/$ – see front matter � 2014 Elsevier Inc. All

the last 2 decades, and MRN is therefore likelyto play an important role in the diagnostic algo-rithm of peripheral nerve disorders.1,10–16 Thisarticle reviews evolving novel MRN technologiescurrently used and under development with re-gard to their potential to meet the requirementsfor noninvasive imaging of peripheral nerves inboth clinical and research settings.

NERVE ANATOMY AND PERIPHERALNEUROPATHY

To understand the new MRN technologies, as wellas related normal and abnormal appearances of

amistrasse 100, Zurich CH – 8091, Switzerland; b The, Dallas, TX 75390-9178, USA

rights reserved. neuroimaging.theclinics

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the peripheral nervous system (PNS) using thesetechniques, an understanding of the peripheralnerve structure, composition of its different tis-sues, and knowledge of the widely used classifica-tion of peripheral neuropathy is important.The axon is the functional unit of the peripheral

nerve, supported by surrounding Schwann cellsand myelin layers. A layer of loose connective tissue,the endoneurium, surrounds each axon and itsSchwann cells, to form a nerve fiber. Multiple nervefibers are enclosed in robust connective tissue, theperineurium, to form a nerve fascicle. All nerve fasci-cles are surrounded by the epineurium, to form aperipheral nerve.2,7 Overall, peripheral nerve mor-phology shows a strong longitudinal order of itsdifferent compositional tissues. As a consequence,the axoplasmatic flow within peripheral nerves and,at a molecular level, the diffusion of water protonsis aligned along these longitudinal structures.Peripheral neuropathy is a general term. Three

subtypes might be distinguished, namely mono-neuropathy, mononeuropathy multiplex, or poly-neuropathy. In peripheral neuropathies, it isessential to also determine whether the primarypathophysiology is of demyelinating or axonaltype.17,18 Nerve injuries are traditionally classifiedaccording to the Seddon and Sunderland gradingsystems. The Seddon classification divides nerveinjuries based on their severity into neurapraxia,axonotmesis, and neurotmesis. Neurapraxia, themildest type of injury, involves only pathologicchanges in the myelin sheath around the axon re-sulting in a conduction block and transient func-tional loss. It is associated with a good prognosis.In axonotmesis, the axon suffers injury resulting inwallerian degeneration of its distal segment; how-ever, the supporting structures, including the peri-neurium and epineurium, remain intact. Theprognosis for recovery remains good, but time isrequired for axonal regeneration (w1 mm per day)from the point of injury to the target tissue. Neuro-tmesis is the most severe type of injury and refersto complete severance of the nerve. The functionalloss is complete, and unless early surgical interven-tion is performed clinical recovery is not expected.Sunderland proposed a 5-degree classification

system with first-degree and second-degree in-juries corresponding with neurapraxia and axo-notmesis and third, fourth, and fifth degreescorresponding with endoneural, perineural, andepineural injuries, respectively.1,19,20

LIMITATIONS OF CURRENT DIAGNOSTICTESTS AND IMAGING

In addition to the clinical examination, nerveconduction and electromyography (EMG) studies

and quantitative neurosensory testing are mostcommonly used to assess peripheral neuropathiesand nerve injuries. Although these techniquesremain the reference standard, there are limita-tions. First, the information about the exactlocation, extent, and cause of nerve disorders isoften limited.21 In addition, electrodiagnosticstudies depend on operative and interpretativeskills of the examiner and are not practical in pa-tients with, for example, skin disorders or bleedingdiathesis. In some studies, the positive predictivevalues are in the 30%–40% range and asymp-tomatic slowing of nerves is common. Nervebiopsy is often too invasive and may lead toconsiderable morbidity.2,8,22–25 Another funda-mental issue is the evaluation of stage-specific in-terventions, to improve nerve regeneration. Key tothis is the ability to follow the growth state of theneuron and associated axonal elongation/regener-ation in the nerve (pathway) before its reconnec-tion with target tissues.8,26–31 Current anatomicMRN techniques using fat-suppressed T2-weighted sequences are not able to sufficientlyshow nerve function and recovery.32,33 Therefore,further development of functional MRN technolo-gies are of foremost interest if they can provideuseful information not only on gross nervemorphology but also on microstructure, collagenintegrity, demyelination, and, if possible, nervefunction.

HIGH-RESOLUTION MRN AND NEWTHREE-DIMENSIONAL SEQUENCES

The increasing use of 3-T MR scanners, newphased-array surface coils, and parallel imagingtechniques allow the acquisition of high-resolutionand high-contrast images in short imaging times.Current state-of-the-art MRN provides detailedanatomic depiction of peripheral nerves andimproved characterization of pathologic states(Figs. 1 and 2).1,27,29,30

Axial T1-weighted and fluid-sensitive fat-sup-pressed T2-weighted images serve as themainstay in MRN interpretation for prudentassessment of peripheral nerve imaging charac-teristics, such as signal intensity evaluation,course, caliber, fascicular pattern, size, andperineural fibrosis, or mass lesions.1,10 Normalnerves show intermediate signal intensity (similarto muscle) on T1-weighted images and interme-diate to minimally increased signal intensity onT2-weighted images, depending on the amountof endoneural fluid and background fat suppres-sion (see Fig. 1).34 MRN is a highly sensitivetechnique and may show abnormalities notrevealed with electrophysiologic tests (Fig. 3).

Fig. 1. Axial T2 spectral adiabatic inversion recovery (SPAIR) (A) and T2-weighted (T2 W) (B) images show normalsciatic nerve fascicular appearance (arrows).

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However, the imaging abnormality may notrecede immediately and completely despite pa-tient improvement following treatment (Fig. 4).Serial evaluation is nonetheless helpful to assessincrease in size and signal abnormality in wors-ening cases. Focal alterations in nerve contour,course, and caliber are best depicted on longitu-dinal images reconstructed along the course ofthe nerve on dedicated imaging workstationsusing various techniques, such as multiplanarreconstruction, curved-planar reconstruction, andmaximum intensity projection (MIP).10,35 For suchreconstructions, imaging sequences should be

Fig. 2. Axial T2 SPAIR (A) and T2 W (B) images in a 51-yeavehicle accident. Notice abnormal vessel-like hyperintensimuscle denervation changes in the hamstrings in keeping

acquired as near isotropic as possible (eg,0.6–1 mm resolution). Only isotropic voxel sizesallow smooth reconstructions in any desired plane.Therefore, preferably three-dimensional (3D) se-quences such as 3D fast (turbo) spin-echo (TSE)or 3D gradient-echo sequences should be used.The advantages of 3D TSE sequences (acronymsinclude VISTA [Phillips, Best, the Netherlands],SPACE [Siemens, Erlangen, Germany], CUBE[GE, Waukeesha, WI]) are that they combine highspatial resolution and, in theory, pure T2 contrast,if needed. The latter is important for the superiorspatial depiction of the nerves coursing obliquely

r-old man presenting with foot drop following motorty of the nerve, mild nerve enlargement (arrows), andwith a stretch injury with axonotmesis.

Fig. 3. A 31-year-old woman with wrist pain and symptoms of carpal tunnel syndrome and normal nerve conduc-tion study. Axial proton density-weighted (A) and T2 SPAIR (B) images show effacement of deep carpal tunnel fatand moderate hyperintensity of the median nerve (white arrows) with normal appearance of the ulnar nerve(black arrows).

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and for the interpretation of mild T2 because thiscould be an isolated sign of neuropathy.34,36 Toenhance contrast/noise ratio between abnormalnerves with increased signal intensity and sur-rounding tissue, good fat-suppression techniquesusing spectral adiabatic inversion recovery(SPAIR) or short tau inversion recovery (STIR)techniques are frequently applied to those MRNsequences (Fig. 5). Some vendors even allowthe use of different strengths of fat saturation(eg, Phillips), which eases detection of abnormal-ities of thin nerves. In addition, 3D TSE sequencesprovide a familiar T2-weighted type of contrast.37

3D TSE is useful for longitudinal depiction of nervedisorders, for the benefit of referring physiciansand radiologists not reading MRN images on aroutine basis.Another new category of sequences to image

peripheral nerves in the extremities are 3Ddiffusion-weighted (DW) reversed fast imaging

Fig. 4. A 38-year-old woman who underwent neurolysis ofwall. The scans show the limitation of MRN. The nerve is aintense on the later scan (B) obtained many months after

with steady-state precession (3D DW-PSIF) se-quences. This imaging technique has previouslybeen used for the evaluation of cranial nervesand the lumbar plexus with good vascular sup-pression and has recently been applied to MRimaging of peripheral nerves.9,10,35,37–40 Besidesretaining all the advantages of a traditional 3Dsequence, 3D DW-PSIF provides a selective sup-pression of moving structures, including vascularflow, leading to an improved identification ofnerves compared with standard two-dimensionalT2-weighted images (Fig. 6). It should thereforebe incorporated in the MRN protocol wheneveraccurate nerve localization and/or presurgicalevaluation are required.38

In general, all new high-resolution and 3Dsequences benefit from high field strengthbecause of the significant increase in signal/noiseratio. If available, MRN studies should thereforebe performed on MR units with 3.0 T or higher.

the ilioinguinal nerve at the anterolateral abdominalbnormally bright on both scans (arrows), although lessthe first scan (A).

Fig. 5. A 44-year-old man with clinically suspected medial antebrachial cutaneous nerve mass. Axial T2 SPAIR (A)image shows the peripheral nerve sheath tumor with a classic target sign (arrow). Corresponding 3D STIR SPACEcoronal MIP (B) image shows the relationship of the mass with the antebrachial cutaneous nerve (arrows). Post-contrast T1 VIBE (volume-interpolated breath-hold examination) (C) and subtraction (D) images show peripheraland central enhancing components of the lesion (arrows).

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WHOLE-BODY MRN

Multimodality scanners which are able to acquirecoregistered structural and functional information,such as single-photon emission computed to-mography (SPECT)/computed tomography (CT)and positron emission tomography (PET)/CT,play an increasingly important role in the evalua-tion of human disease. However, disadvantagesof SPECT/CT and PET/CT are a long preparationtime for the examination, exposure to ionizing ra-diation, and possible mismatch between anatomicand functional data sets caused by the patient re-positioning.41 MR imaging is able to provide both

Fig. 6. A 3D DW-PSIF MIP image in a volunteer at thelevel of the elbow shows the normal median nerveand its muscular branch as well as the anterior interos-seus nerve (arrows).

anatomic and functional information within a sin-gle examination without these disadvantages.Whole-body MR imaging and whole-body DW im-aging (DWI) can be performed in the same scan-ner, without patient repositioning. Furthermore,whole-body DWI does not require any contrastagent administration. In 2004, Takahara and col-leagues3,32,42,43 showed the feasibility of whole-body DWI under free breathing. This concept isalso known as DW whole-body imaging withbackground body signal suppression (DWIBS).Whole-body DWI, using the concept of DWIBS,may be a powerful adjunct to anatomic whole-body MR imaging, by detecting subtle lesionsand pathologic changes in normal-sized struc-tures, thanks to its high contrast/noise ratio(CNR). Feasibility studies showed the potential ofDWI in visualizing the brachial plexus and thesacral plexus.3,32,42,43 Whole-body MR imagingalso has a significant potential in assessingdisease load and treatment response in casesof neurocutaneous syndromes (Fig. 7). However,for any disorders, whole-body DWI shouldalways be evaluated together with other (ana-tomic) whole-body MR imaging sequences, toavoid false-positive results.42,44–47 In addition,whole-body MRN is becoming feasible usingDWI (Fig. 8).3 These technical developmentswill likely play an important role in the assess-ment of disease burden in neurocutaneoussyndromes, such as neurofibromatosis andschwannomatosis, and in diffuse polyneurop-athy conditions such as Charcot-Marie-Toothdisease and chronic inflammatory demyelinatingpolyneuropathy (CIDP).

Fig. 7. A 47–year-old man with known schwannoma-tosis. Whole-body 3D STIR SPACE MIP MR imageshows multiple nerve sheath tumors (arrows).

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DIFFUSION TENSOR IMAGING/DWI

DWI and diffusion tensor imaging (DTI) in particularare MR imaging techniques based on the thermallydriven random motion (diffusion) of water mole-cules within biologic tissues. Tissues have distinctstructural properties which hinder diffusion insome directions and facilitate it in other directions.DTI shows great potential as a noninvasive

technology to detect axonal injury in the centralnervous system (CNS), which has been shown bya large number of studies; data in CNS studiesindicate that DTI parameters are sensitive andspecific imaging biomarkers for detection ofmyelinated axons and nerve fiber loss.35 Asmentioned earlier, there is also a substantial clin-ical need for reliable measures to assess thePNS, especially regarding regeneration after trau-matic injuries or nerve surgery. For these ap-plications, DTI is currently the most promisingtechnology with immediate availability.37,48–51

Neural tissues are densely packed with nerve fi-bers and tracts and water molecules thereforetend to diffuse in a preferential orientation alongthese nerve fibers and tracts; this is called aniso-tropic diffusion.52,53 To characterize the amountand principal direction of diffusion, image setsfrom 6 or more different DW acquisitions are usu-ally acquired. In DTI, the main diffusion direction isindicated by the tensor’s main eigenvector. Incolor-coded maps, the directional component isassigned to different colors (typically red, green,and blue). The resulting image is weighted withthe fractional anisotropy (FA) map to exclude tis-sues with isotropic diffusion. FA is an anisotropyindex describing the degree of anisotropy in a tis-sue. It is a scalar parameter, scaled between 0 and1; 0 representing random isotropic diffusion and1 representing complete anisotropy. Mean diffu-sivity, also called anisotropic diffusion coefficient(ADC), is a measure of diffusion magnitude alonga given direction, or averaged over several direc-tions. In addition, tractography can be used tovisualize the 3D course of nerve fibers and bundlesand the fiber density.54–56

DTI has recently been applied to the study ofperipheral nerves, to show the feasibility of themethod56–58 and to study nerve regeneration aftermedian-nerve injury and fascicular repair,56,59 aswell as nerve entrapment in carpal tunnel syn-drome.56,60–62 Various nerve abnormalities and in-juries, such as trauma, entrapment, tumor, andinflammation, may lead to decreased fractionalanisotropy and increased ADC values; therefore,these findings should be taken in the context ofmorphologic nerve findings on MRN studies alongwith the available clinical information.63 In general,

Fig. 8. A 28-year-old healthy volunteer. Whole-body high-resolution MRN with diffusion tensor imaging (DTI).Note the normal symmetric appearance of the brachial plexus (A), intercostal nerves (B), and sciatic plexus (C)on anatomic sequences as well as on DTI maps (D, E).

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increased mean diffusivity may reflect inflamma-tion or edema, whereas decreased FA may reflectdamaged tissue microstructure, demyelination,axonal loss, or increase in isotropic watervolume.56 Increasing FA values within peripheralnerves have also been observed in animal modelscorrelating with functional motor and sensory re-covery and may depict nerve regeneration aftersuccessful entrapment release.50,56–60,62 In pe-ripheral nerve sheath tumors, high diffusivityvalues are seen within benign lesions (1.1–2.0),whereas low diffusivity values (0.7–1.0) are seenin malignant lesions in early studies by the authors(Fig. 9). However, single measurements havelimited value in any lesion and interval measure-ments over time have significant potential useful-ness in follow-up of these lesions upon medicaltreatment. In addition, tractography providesanother insight into the pathophysiologic mecha-nisms of these lesions. With future research, DWIand DTI will likely play an important role in the eval-uation and further understanding of neuromus-cular diseases and are expected to be an

important adjunct to the currently established,mostly anatomy-based, MRN protocols.

Subtraction of unidirectionally encoded imagesfor suppression of heavily isotropic objects(SUSHI) is a recently proposed MR technique forselective peripheral nerve imaging that is relatedto DTI. Given that, in DWI, many structures sur-rounding a nerve, such as lymph nodes, bonemarrow, veins with slow blood flow, and articularfluids, in contrast with the nerve itself, show ahigh signal intensity regardless of the direction ofthe applied diffusion-sensitizing gradients, a DWIdata set acquired with a first pair of diffusion-sensitizing gradients with a direction parallel tothe course of the peripheral nerve to be imagedis subtracted from another DWI data set acquiredwith a second pair of diffusion-sensitizing gradi-ents in a perpendicular direction to the first dataset. This technique results in a selective represen-tation of the peripheral nerve of interest. Thismethod has been surveyed with 6 volunteers onthe brachial plexus, and with 7 volunteers on thesciatic, common peroneal, and tibial nerves at

Fig. 9. DTI of the same case as in Fig. 5. Trace image (A), ADC image (B), and FA image (C). The ADC value was 1.7,suggesting a benign peripheral nerve sheath tumor (arrows).

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the level of the knee, at 1.5 T. However, furtherexploration in patients with peripheral nerve disor-ders (eg, nerve degeneration, nerve trauma, andnerve tumors) is needed to assess the SUSHItechnique.42,64

MAGNETIZATION TRANSFER IMAGING

On conventional MR imaging, tissue contrast isgenerated from variations in proton density andrelaxation times of water protons. Longitudinaland transverse components of the magnetizationin homogeneous samples relax monoexponen-tially with characteristic decay times T1 and T2.In biologic tissues there are protons withfree mobility (water protons) and protons withrestricted mobility because of bonds to macromol-ecules or membranes. These restricted protonshave a T2 relaxation time too short to be detectedby conventional proton MR imaging techniques.Magnetization transfer (MT) imaging generatestissue contrast depending on the magnetizationexchange between free and restricted protons.MT effects in tissues are usually assessed bymeasuring the MT ratio (MTR), which yields acontrast sensitive to the protons associated withthe bound proton pool. The MTR is a semiquanti-tative parameter, and its value depends on thetype of MR sequence, as well as the sequenceparameters.7,65

MT imaging thus offers a characterization ofthe macromolecular protons invisible in standardMR imaging. Besides improving the contrast, MTprovides quantitative information about tissuestructure and pathologic changes beyond conven-tional T1, T2, and T2* contrast.65 Off-resonance

radiofrequency pulses are the most popular tech-nique to perform MT imaging. They are usuallyGaussian or sync pulses with a bandwidth of afew hundred Hertz at frequency offsets between50 Hz and 50 kHz from the free proton resonancefrequency. The pulses are applied before eachexcitation. High-energy deposition in tissue, asmeasured by the specific absorption rate, maybe a problem during application of this technique.In present clinical settings, MT imaging is pre-

dominantly used to suppress background signalsfrom tissues in MR angiography. Regarding thepotential application of MT imaging to peripheralnerve disorders, the tissue content and structureof the PNS must be considered in order to under-stand the origin of MT contrast in nerves. Thebound protons in peripheral nerves are repre-sented by collagen tissue, myelin, and the proteinscontained in the nerve fibers, all possibly contrib-uting to the observed MTR. Thus, MT imagingcould be advantageous in peripheral neuropathystudies because it may provide information onnerve damage, collagen integrity, and demyelin-ation. In studies of CNS disorders, such asmultiplesclerosis, MT contrast has shown its feasibility todetect plaques based on their altered macromo-lecular content.7,66 In the musculoskeletal system,MT imaging was used to assess muscle atrophyin patients with diabetic foot neuropathy andCIDP.7,67–69 To our knowledge, there is only 1report on MT imaging of peripheral nerves inwhich MTR was used for high-resolution trackingof thin forefoot nerves.7 Overall, MT imagingmight offer an alternative to the commonly usedT2-weighted sequences, in which higher signalintensity, originating from prolonged T2 relaxation,

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indicates nerve abnormality. Although MTR is asemiquantitative index, the MTR approach haspotential advantage compared with T2-weightednerve imaging because it permits longitudinalstudies when a change in MTRmay bemore usefulthan T2 signal intensity.7,65

CONTRAST AGENTS AND NON-MR IMAGINGTECHNIQUES

Because the current mainstay of MRN isT1-weighted and T2-weighted imaging, use ofextracellular contrast agents in peripheral neu-ropathy is clinically often limited to inflammatoryor infectious and tumorous conditions. It mayalso be used postoperatively to assess scar tis-sue and in diffuse peripheral neuropathies. As aconsequence, any new contrast agents to beintroduced for peripheral nerve imaging musthave a significant advantage compared with cur-rent extracellular contrast agents to overcometheir limitations. One possible new MR contrastagent is gadofluorine M, which accumulatesselectively in nerve fibers undergoing walleriandegeneration and disappears with remyelination.Thus, gadofluorine M has the potential to showdemyelination and remyelination processes inperipheral nerves. However, many clinical studieswith, for example, histopathologic correlation areneeded to prove this theory for a variety ofpathologic conditions before any US Food andDrug Administration (FDA) approval or wide-spread clinical use.

The most commonly applied contrast agentsfor cellular and molecular MR imaging purposesare superparamagnetic iron oxide particles,which come in a wide range of sizes and a varietyof coatings. The popularity of these agents ispredominantly based on their biocompatibilityand their capacity to efficiently disturb local mag-netic fields, thereby generating localized hypoin-tense areas on T2-weighted and T2*-weightedMR images.70–73 The second important class ofcontrast agents is formed by the FDA-approvedand European Medicines Evaluation Agency–approved low-molecular-weight paramagneticgadolinium (Gd) polyaminocarboxylate chelates(eg, Gd-diethylenetriamine pentaacetic acid andGd-tetraazacyclododecane tetraacetic acid),which are applied to induce hyperintense signalson T1-weighted MR images. Another establishedplatform for contrast enhancement is availablein the form of lipid-based nanoparticles. Lipid-based nanoparticles, such as micelles, emulsions,or liposomes, are composed of a biocompatiblelipid monolayer or bilayer coating that encapsu-lates either an aqueous or hydrophilic core,

offering a versatile and tunable compound for awide variety of applications.73–76 At present, mo-lecular labeling and fluorescent imaging is onlyapplicable to transgenic mice/animals labeledwith specific fluorescent proteins and not appli-cable for clinical use. Future studies in animalmodels and human subjects, including adequateassessment of safety issues associated with nano-particle injection, will provide further details on theusefulness of cellular and molecular MR imaging inpreclinical and clinical settings.73,77

SUMMARY

MRN has progressed greatly in the past 2decades. Excellent depiction of 3D nerve anatomyand disorders is currently possible using state-of-the-art MR imaging techniques. Further develop-ments in the years to come will include the useof high-resolution 3D and diffusion-based imagingand potentially nerve-specific MR contrast agentsas well as molecular imaging.

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