Special Issue Article

Global Spine Journal

2022, Vol. 12(1S) 130S–146S
Imaging and Electrophysiology for © The Author(s) 2021
Article reuse guidelines:
Degenerative Cervical Myelopathy [AO Spine sagepub.com/journals-permissions
DOI: 10.1177/21925682211057484
journals.sagepub.com/home/gsj
RECODE-DCM Research Priority Number 9]

Allan R. Martin, MD, PhD1, Lindsay Tetreault, MD, PhD2, Aria Nouri, MD, MSc3,
Armin Curt, MD, FRCPC4, Patrick Freund, MD PhD4, Vafa Rahimi-Movaghar, MD5,
Jefferson R. Wilson, MD PhD FRCSC6 , Michael G. Fehlings, MD, PhD, FRCSC, FACS6 ,
Brian K. Kwon, MD PhD FRCSC7, James S. Harrop, MD, MSHQS, FACS8,
Benjamin M. Davies, MRCS, BSc, MPhil9 , Mark R. N. Kotter, MD, MPhil, PhD9,
James D. Guest, MD, PhD, FACS10, Bizhan Aarabi, MD11, and Shekar N Kurpad, MD, PhD12

Abstract
Study Design: Narrative review.
Objective: The current review aimed to describe the role of existing techniques and emerging methods of imaging and
electrophysiology for the management of degenerative cervical myelopathy (DCM), a common and often progressive condition
that causes spinal cord dysfunction and significant morbidity globally.
Methods: A narrative review was conducted to summarize the existing literature and highlight future directions.
Results: Anatomical magnetic resonance imaging (MRI) is well established in the literature as the key imaging tool to identify
spinal cord compression, disc herniation/bulging, and inbuckling of the ligamentum flavum, thus facilitating surgical planning,
while radiographs and computed tomography (CT) provide complimentary information. Electrophysiology techniques are
primarily used to rule out competing diagnoses. However, signal change and measures of cord compression on con-
ventional MRI have limited utility to characterize the degree of tissue injury, which may be helpful for diagnosis,
prognostication, and repeated assessments to identify deterioration. Early translational studies of quantitative imaging and
electrophysiology techniques show potential of these methods to more accurately reflect changes in spinal cord mi-
crostructure and function.

1
Department of Neurological Surgery, University of California Davis, Davis, CA, USA
2
Department of Neurology, New York University, Langone Health, Graduate Medical Education, New York, NY, USA
3
Division of Neurosurgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland
4
University Spine Center, Balgrist University Hospital, Zurich, Switzerland
5
Department of Neurosurgery, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
6
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
7
Vancouver Spine Surgery Institute, Department of Orthopedics, The University of British Columbia, Vancouver, BC, Canada
8
Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA
9
Department of Neurosurgery, University of Cambridge, Cambridge, UK
10
Department of Neurosurgery and The Miami Project to Cure Paralysis, The Miller School of Medicine, University of Miami, Miami, FL, USA
11
Department of Neurosurgery, University of Maryland, Baltimore, MD, USA
12
Department of Neurosurgery, Medical College of Wisconsin, Wauwatosa, WI, USA

Corresponding Author:
Allan R. Martin, Department of Neurological Surgery, University of California Davis, Davis, CA, USA. Email: [email protected]
Creative Commons Non Commercial No Derivs CC BY-NC-ND: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs 4.0 License (https://creativecommons.org/licenses/by-nc-nd/4.0/) which permits non-commercial
use, reproduction and distribution of the work as published without adaptation or alteration, without further permission provided the
original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Martin et al. 131S

Conclusion: Currently, clinical management of DCM relies heavily on anatomical MRI, with additional contributions from
radiographs, CT, and electrophysiology. Novel quantitative assessments of microstructure, perfusion, and function have the
potential to transform clinical practice, but require robust validation, automation, and standardization prior to uptake.

Keywords
cervical myelopathy, imaging, diagnosis, electrophysiology, spinal cord compression, magnetic resonance, neural damage,
microstructure, assessment

Degenerative Cervical Myelopathy a view of bony structures and alignment under physiological
loads.15,16 Abnormalities in alignment such as kyphosis and
Degenerative cervical myelopathy (DCM) describes spinal cord spondylolisthesis are relatively common in DCM, whereas
dysfunction resulting from extrinsic compression due to degen- scoliosis is infrequently encountered, but these must be
erative changes of the joints, vertebrae, and ligaments.1 This considered during surgical planning.17 Lateral cervical spine
collective diagnosis is the most common cause of spinal cord radiographs allow measurement of sagittal balance and
dysfunction,2 representing an overlapping set of etiologies that alignment parameters, including T1 slope, cervical lordosis,
include degenerative disc disease, spondylosis, ossified posterior cervical sagittal vertebral axis (cSVA), chin brow angle, and
longitudinal ligament (OPLL), ligamentum flavum hypertrophy K-line.18 Anterior-posterior (AP) radiographs are helpful to
(and/or ossification), and spondylolisthesis. The natural history of identify scoliosis and measure Cobb angles. However,
DCM is poorly defined, and differences likely exist between the whole-spine standing radiographs are preferable to properly
various specific pathologies that are involved.3 The pathophysi- assess alignment, including measurement of global sagittal
ology of neurological injury in DCM is also not fully elucidated, vertebral axis (SVA), as abnormalities in the cervical spine
but appears to involve a combination of mechanisms including are interrelated with alignment of the lower segments. The
static compression causing ischemia and hypoxia, demyelination, visualization of bony anatomy with radiographs is limited,
axonal injury, gray matter injury, gliosis, and cavitation.1,3,4 Dy- but it is usually sufficient to diagnose OPLL and estimate
namic injury from repetitive microtrauma due to instability and canal size. Historical definitions of canal stenosis were based
movement of the compressed cord may also contribute, but to on radiographs, including AP diameter <13 mm19 or a Torg-
what degree is unknown.5 Spinal cord tension may also be an Pavlov ratio of <.82;20 however, these measures have largely
additional factor in the presence of cervical kyphosis.6 The clinical been supplanted by direct visualization of the spinal cord
presentation of DCM varies widely, owing to the complexity of with computed tomography (CT) myelography and magnetic
spinal cord function and the multitude of pathways; typical resonance imaging (MRI). Oblique views offer visualization
symptoms include neck pain, referred pain, upper limb incoor- of the neural foramina and uncovertebral joints. Flexion and
dination, gait imbalance, weakness, numbness, and sphincter extension views provide several pieces of useful information,
dysfunction.7 Accurate measurement of neurological and func- including identification of hypermobility, ankylosis, and the
tional deficits is challenging, with the modified Japanese Ortho- range of motion (ROM) that the patient will tolerate without
paedic Association (mJOA) score offering a convenient summary symptoms of cord impingement (e.g., L’Hermitte’s phe-
measure.8 However, an array of clinical assessments is needed to nomenon). Finally, radiographs also play an important role in
fully characterize functional impairment.9-11 Clinical practice following patients with DCM post-operatively, monitoring
guidelines (CPGs) recommend surgical treatment for moderate or alignment and integrity of surgical implants.
severe impairment, and for mild cases that show deterioration12;
however, there remains a lack of consensus on how to manage the
most common clinical scenarios, including the optimal treatment Computed Tomography
of patients that present with mild DCM (Figure 1). This offers a In 1974, CT became commercially available, offering the first
potential role for imaging and electrophysiology biomarkers that method of cross-sectional imaging of the spine; almost
(1) offer earlier diagnosis, (2) detect progressive spinal cord injury, 50 years later, CT continues to be useful for management of
or (3) predict deterioration.13,14 patients with DCM. CT provides high resolution 3D images
with excellent contrast between bone and soft tissue, allowing
Conventional Anatomical Imaging visualization of bony anatomy, spondylosis, osteophytes,
calcified discs, OPLL, and ossified ligamentum flavum. The
Radiography information gained from CT is often helpful in surgical
Also known as plain films or X-ray images, radiographs are planning for patients with DCM, including the decision be-
the oldest method of medical imaging dating back to 1895. tween anterior and posterior approaches, the extent of bony
Radiographs remain an important study in DCM as they offer decompression, bone quality, and planning screw trajectories.
132S Global Spine Journal 12(1S)

Figure 1. A 49-year-old female presents with symptoms of axial neck pain, mild intermittent numbness of the hands, and mild fine motor
dysfunction of the hands (clumsiness, dropping things). Her mJOA score is calculated as 16 (mild severity). Her neurological examination is
normal, including no weakness, no sensory deficits, slightly brisk reflexes (2+ to 3+) without Hoffman’s or Babinski signs, and normal tandem
gait. Radiographs (A, D) demonstrate normal alignment with loss of disc height at multiple levels. Anatomical T1-weighted (E) and T2-weighted
images (B, C, F) demonstrate mild spinal cord compression secondary to bulging discosteophyte complexes and ligamentum flavum
hypertrophy at C4-5 and C5-6 without intramedullary signal changes. Current CPGs do not offer a specific treatment recommendation for
this scenario. 12 Key knowledge gaps are if advanced imaging and/or electrophysiology methods can: (a) confirm a diagnosis of DCM? B)
localize which level(s) are symptomatic? (C) predict if she will deteriorate without surgery? (D) predict how much she will recovery with
surgery? (E) monitor for neurological deterioration with repeated measures? CPG = clinical practice guideline; DCM = degenerative cervical
myelopathy; mJOA = modified Japanese Orthopedic Association.

Furthermore, CT myelography (with intrathecal contrast) was compression is highly sensitive (>98%) for myelopathy,26 al-
used extensively prior to the availability of MRI for visual- though some have argued that flexion and extension views are
ization of cord compression, and remains useful when MRI is required to visualize dynamic compression in a fraction of
not possible (e.g., due to incompatible metal implants). patients.27-29 However, high-quality imaging with flexion/
extension MRI is difficult due to motion associated with hold-
Anatomical Magnetic Resonance Imaging ing uncomfortable postures for several minutes. Furthermore, it
appears that the spinal cord retains an abnormal shape in dynamic
MRI is a complex technique based on the manipulation of
hydrogen atoms within water molecules through pulses of compression due to its mechanical plasticity, suggesting a po-
radiofrequency (RF) electromagnetic radiation and reading the tential role for morphometric (shape) analysis.30 The specificity
net magnetization with induction coils. Since its clinical of cord compression for DCM is extremely low (<10%) because
emergence in the early 1980s, anatomical T1-weighted (T1w) 5–50% of healthy asymptomatic patients show some element of
and T2-weighted (T2w) magnetic resonance images have cord compression or deformation.30-32 In contrast to spinal cord
become the gold standard to visualize the spinal cord and to compression, intramedullary T2w hyperintensity has a high
confirm the clinical diagnosis of DCM.21-24 However, it must specificity of approximately 98% for DCM, but sensitivity is
be highlighted that neither compression of the spinal cord, limited as it is only present in 50–85% of patients.23,26,33–42 Thus,
defined as indentation, flattening, torsion, or circumferential the presence of spinal cord compression and signal change are
narrowing, nor intramedullary signal change are accurate useful to help confirm the presence of DCM, but MRI is not
diagnostic markers of myelopathy on their own.25 Spinal cord sufficient as a stand-alone diagnostic test.
Martin et al. 133S

As a tool for surgical planning, anatomical MRI allows T1w and T2w anatomical images offer only limited insight
visualization of the source (anterior vs posterior) and degree of into pathological tissue changes, prompting the development
spinal cord compression, and the number of levels at which of more advanced MRI sequences that assess specific features
spinal cord and/or exiting nerve roots require decompression. of microstructure and tissue injury.
The modified K-line, based on mid-sagittal MRI images,
predicts if a posterior approach will achieve sufficient de-
compression or if anterior decompression is necessary.43
Quantitative Imaging Techniques
Furthermore, when planning spinal fusion procedures, the The term “quantitative imaging” refers to the direct mea-
degree of degeneration of adjacent levels should be considered surement of a physical property of tissue, such as proton
as these will undergo additional stress and may cause recurrent density (PD) and the longitudinal, transverse, and effective
myelopathy/radiculopathy.44 However, supine MRI images transverse relaxation rates (R1, R2, and R2*, respectively) in
have limited utility to assess alignment and stability, and MRI. Many imaging methods that are labeled as quantitative
therefore should be routinely supplemented with upright and would be better described as semi-quantitative, as they pro-
flexion/extension radiographs for these purposes. vide only surrogate measures that rely on various assumptions,
Conventional MRI has also been studied as a tool to assess parameters, and calibration.59 In contrast, strict quantitative
the severity of spinal cord damage that has occurred, both in imaging is scanner-independent, accurate, and reproducible.
terms of correlation with current neurological status and Unfortunately, quantitative methods often require long ac-
prediction of post-surgical outcomes.23,26,33,45–49 Various quisition time, custom sequences, and specialized hardware,
measurements of spinal cord compression have been inves- rendering them impractical in clinical scenarios. Furthermore,
tigated, including AP diameter, AP to left-right compression quantitative measures often vary widely between healthy
ratio (CR),50 maximum canal compromise (MCC),23 maxi- subjects or with variables such as age, requiring substantial
mum spinal cord compromise (MSCC), and cross-sectional data to define normative ranges and for normalization. In this
area (CSA).51-53 Okada et al53 (1993) found that CSA posi- review, we utilize an inclusive definition of quantitative im-
tively correlated with current neurological status and post- aging to include surrogate measures and variables that are not
operative recovery (using Japanese Orthopaedic Association measured in physical units (such as computed ratios), as long
[JOA] scores and recovery ratio, respectively), whereas CR as they provide a meaningful measurement that can be
and signal intensity ratio were not correlated with outcomes.51 compared between regions and/or subjects (Table 1).60
Interestingly, Smith et al (2013) reported a similar positive
correlation between CSA and mJOA in lordotic patients, but
Measures of Microstructure
an opposite negative correlation was found in kyphotic pa-
tients.52 The remainder of cord compression measures (CR, A number of microstructural spinal cord MRI techniques have
MCC, and MSCC) have failed to show substantial correlation been identified for their clinical potential, namely diffusion
with the severity of neurological deficits.53,54 In contrast, tensor imaging (DTI), magnetization transfer (MT), myelin
MCC did show some promise in prediction of post-operative water-fraction (MWF), and magnetic resonance spectroscopy
recovery, being retained in a multivariate clinical-radiological (MRS).61,62 The microstructural components of interest in-
prediction model.23 clude myelin content (MT, MWF, DTI, MRS), axonal integrity
Similarly, numerous studies have investigated the utility (DTI, MRS), gliosis (MRS), hypoxia (MRS), and neuronal
of T2w hyperintensity and T1w hypointensity to mea- loss (MRS). However, acquisition of these sequences in the
sure spinal cord tissue injury, including the presence of spine faces several challenges, including magnetic field in-
these features, the signal change ratio (with normal cord homogeneity, respiratory- and cardiac-related motion, and the
or CSF as a reference), T2w/T1w ratio, the rostro-caudal small size of the cord.61 These challenges have partially been
length of signal change, and the area/volume of signal overcome with advances in acquisitions and analysis such as
change. 23,25,39,40,48,,55–57 Overall, T2w hyperintensity shows motion correction. A 2016 systematic review of the litera-
weak correlation with current neurological status, and weak or no ture62 identified a total of 25 studies utilizing these techniques
correlation with post-operative recovery, while T1w hypo- to study DCM, with 22 utilizing DTI, 3 using MRS, and 1
intensity shows moderate correlation with both current neuro- employing MT.13,63–87 However, this review found that the
logical status and post-operative recovery.23,25,39,40,48,55–57 This status of clinical translation of these techniques was early and
is likely because T1w hypointensity is more specifically re- much further work was needed, although several recent studies
lated to pathological changes of cavitation and cell loss, have further advanced the field. In addition, studies utilizing
whereas T2w hyperintensity may reflect transient or perma- T2*-weighted imaging have demonstrated its potential to
nent microstructural changes such as edema, gliosis, in- measure tract-specific atrophy and microstructural changes.88
flammation, demyelination, spongiform changes, necrosis, Diffusion MRI involves measurement of water diffusivity
and cavitation.3,4,40 T1w hypointensity is relatively rare, after applied diffusion gradients in multiple directions, with
occurring in only 19-30% of DCM patients, limiting its DTI representing the diffusivity as three orthogonal vectors,
utility.25,39,58 In summary, conventional MRI consisting of termed “eigenvectors.” Various metrics can be calculated such
 134S

Table 1. Summary of quantitative and semi-quantitative imaging techniques for measuring aspects of microstructure and tissue injury in the human spinal cord and their status toward
clinical translation.

Imaging Imaging contrast/ Current status of

Modality technique/sequence Tissue property measured Limitations translation

MRI Anatomical
T1-weighted Cavitation, cell loss, gliosis, and necrosis Semi-quantitative, moderate physiological Implemented
specificity
T2-weighted Edema, gliosis, inflammation, demyelination, spongiform changes, Semi-quantitative, poor physiological specificity Implemented
necrosis, and cavitation
T2*-weighted Iron, calcium, gliosis, myelin, and perfusion Semi-quantitative, moderate physiological Implemented
specificity
Diffusion
DTI Axon integrity, myelin Semi-quantitative, oversimplified model, not Early clinical use
specific to axonal injury
DKI Axon integrity Multiple b shells, acquisition time Human studies
ongoing
NODDI Axon integrity Multiple b shells, acquisition time, complex Human studies
analysis ongoing
DDE Axon integrity Semi-quantitative, only measures a single Pre-clinical studies
direction
Myelin imaging
MT Myelin Semi-quantitative, poor SNR, 2 acquisitions (for Early clinical use
MTR)
MWF Myelin Limited specificity for myelin, long acquisition Human studies
time, and poor SNR ongoing
Other
MRS NAA (neuronal density), choline (cell turnover), myo-inositol Semi-quantitative, poor SNR, long acquisition Human studies
(gliosis), and lactate (hypoxia) time ongoing
BOLD fMRI Deoxyhemoglobin (surrogate for brain activity via neurovascular Semi-quantitative, poor SNR, long acquisition Human studies
coupling) time ongoing
Perfusion MRI Tissue perfusion Semi-quantitative Human studies
ongoing
PET 18F-FDG Tissue metabolism Specialized equipment, radiotracers, long Human studies
acquisition time, poor SNR ongoing
DDE = double diffusion encoding; FDG = fluorodeoxyglucose; fMRI = functional MRI; MT = magnetization transfer; MTR = MT ratio; MWF = myelin water-fraction; MRS = magnetic resonance spectroscopy;
NODDI = Neurite orientation dispersion and density imaging; DKI = diffusion kurtosis imaging; SNR = signal-to-noise ratio.
Global Spine Journal 12(1S)
Martin et al. 135S

as axial diffusivity (AD), radial diffusivity (RD), mean dif- also appears to be useful in a multiparametric acquisition to
fusivity (MD), and fractional anisotropy (FA). In DCM, FA detect tissue injury and neurological deterioration.14,30 MT
(ranging from 0 for isotropic diffusion to 1 for anisotropic saturation is a similar metric derived from 3 acquisitions (T1-,
diffusion), appears to have the strongest results. Four studies MT-, and PD-weighted), which also correlates well with myelin,
investigated the diagnostic accuracy of FA to identify DCM, and when acquired with diffusion MRI, can estimate g-ratio
with sensitivity ranging from 72 to 95% and specificity from (axon diameter to myelin sheath diameter), although this ap-
50 to 100%.63,65,66,80 These values were consistently higher proach only showed weak differences in DCM subjects and no
than the sensitivity and specificity of T2WI hyperintensity. In correlation with mJOA.97
six studies, FA correlated well with clinical measures such as In contrast to MT, MWF employs a multi-echo sequence
JOA and mJOA.75,76,80,82,86,87 Among studies that investi- to estimate the T2 parameter in each compartment (myelin,
gated FA as a prognostic factor, only 1 of 3 found a correlation tissue, and CSF). Some evidence suggests that MTR is more
with post-operative JOA/mJOA,82 reporting that higher pre- specific and accurate for myelin density, while MWF is
operative FA corresponded with improved JOA recovery ratio sensitive to axon diameter, myelin thickness, and the re-
(P = .03). Other DTI metrics including MD, RD, and AD have sultant g-ratio.101 One study investigated MWF and found
demonstrated weaker and/or less consistent results.63,65,67 no group difference between patients with DCM and
More recently, several studies showed that FA correlated healthy subjects, but weak correlations were found between
well with focal and global deficits,52,88-91 identified pre- MWF and somatosensory evoked potential (SSEP)
clinical tissue injury in subjects with asymptomatic cord latencies.103
compression,30,88,92,93 and detected neurological progression MRS measures the concentration of key molecules, in-
in DCM patients managed non-operatively.14,91 More com- cluding N-acetylaspartate (NAA), choline (Cho), myo-inositol
plex diffusion imaging approaches have also been utilized, (MyoI), and lactate (Lac), which are known markers of neuron
such as those employing multiple b-value shells (strength of density, demyelination, gliosis, and hypoxia, respectively. The
diffusion gradients) to more accurately characterize axonal concentration of these molecules is often calculated as a ratio
features, at the expense of acquisition time and analysis with creatine (Cr), which is relatively invariant in pathological
complexity. One approach used two shells and calculated states. Holly et al68 (2009) used MRS to demonstrate in-
mean kurtosis and root mean square displacement, reflecting creased lactate in 1/3 of DCM patients and decreased NAA/Cr
the variation of diffusivity in different directions. Kurtosis ratio compared to healthy controls.67 The same group later
showed some promise as a more accurate biomarker than FA reported that baseline NAA/Cr and Cho/NAA ratios correlated
in one study involving DCM patients.94 Neurite orientation modestly with post-operative change in clinical scores, sug-
dispersion and density imaging (NODDI) is another complex gesting predictive value of these biomarkers.103 Two studies
approach that is more accurate than DTI for microstructural found NAA/Cr to be decreased in DCM compared to healthy
changes, evidenced by histopathological studies in MS.95,96 subjects, but no correlation was found with mJOA.67,78 In
NODDI has been elegantly applied to patients with DCM in 2 contrast, one study found superior results when combining
studies, showing decreased axonal volume fraction in the biomarkers as a ratio Cho/NAA, which showed a significant
WM,97 and good prediction of post-operative outcome,98 but correlation with mJOA (Pearson R= .45, P<.01)104; this
conflicting results regarding correlation with mJOA.97,98 approach is similar to multiparametric approaches that take
Another approach is to utilize double diffusion encoding advantage of multiple biomarkers to improve accuracy and
(DDE), involving a perpendicular diffusion gradient to sup- overcome noise.
press CSF and cord edema, and subsequent gradients that T2*-weighted (T2*w) imaging is based on the effective
measure diffusivity parallel to the cord, showing promise in a transverse relaxation (R2*), which is a physical parameter that
rat spinal cord injury (SCI) model, but yet to be studied in reflects both spin-spin interactions (R2) and local magnetic field
humans.99 inhomogeneity. In the spinal cord, T2*w imaging demonstrates
MT involves a pre-pulse that selectively excites water protons strong contrast between the gray and white matter, allowing
adjacent to macromolecules (primarily myelin), which causes segmentation between these anatomical compartments and
proportional signal dropout, providing a surrogate measure of calculation of CSA of specific sub-structures such as the dorsal
myelin density. MT ratio (MTR) is calculated as a signal intensity columns. Grabher et al (2016) demonstrated tract-selective
ratio between 2 scans with and without the pre-pulse, or the atrophy in the dorsal columns above the level of compres-
signal intensity can simply be compared in a ratio between the sion, which also correlated with light touch impairment.88
spinal cord and cerebrospinal fluid (MTCSF). MTR is more Martin et al (2017) described a novel biomarker by comput-
specific for myelin than MTCSF, due to contamination from T1- ing the ratio of T2*w signal intensity between WM and GM,52
weighting. However, MTR requires additional acquisition time which is believed to reflect iron content, demyelination, and
and accurate co-registration. In one study, MTR showed mod- tissue perfusion.105,106 This biomarker performed similarly well
erate correlation with global and focal deficits,52 but in another in comparison to FA and CSA, showing strong correlations
study only anterior cord MTR correlated with deficits.100 MTR with focal and global neurological deficits.52 Furthermore, it
136S Global Spine Journal 12(1S)

demonstrated clinical utility in detecting subclinical tissue Brain Imaging

injury and neurological deterioration over time.14,30
A lesion affecting one area of the CNS causes distant structural
and functional changes,114,115 a phenomenon described by the
Functional Spinal Cord Imaging term “diaschisis.”116,117 Numerous research groups have
An alternative approach involves functional MRI (fMRI) of the taken advantage of this, using brain imaging to investigate
spinal cord, which holds great potential to quantify neuronal spinal pathologies. One study found demonstrated cortical
activity within the spinal cord. Functional MRI relies upon the fMRI activation for tongue movements shifts significantly in
concept of neurovascular coupling, in which changes in neuro- patients following cervical SCI, revealing reorganization of
logical function produce corresponding changes in local blood the brain.118 Several groups have investigated brain rs-fMRI
flow and deoxyhemoglobin concentration. This contrast mecha- for changes in connectivity and found cortical regions with
nism is termed blood oxygen level–dependent (BOLD) fMRI, altered activity in DCM vs healthy subjects,119-122 but only
which typically utilizes rapid T2*-weighted acquisitions, two of four studies showed correlation with clinical
that are greatly affected by magnetic field inhomogeneity scores,120,121 and one showed prediction of post-operative
present in the spine. Study designs for fMRI may include recovery.121 However, the clinical relevance of rs-fMRI re-
motor tasks (e.g., finger tapping), sensory stimuli (e.g., cutaneous mains unclear, as the analysis and interpretation is extremely
heat), or resting state (rs-fMRI). However, only one spinal cord complex, and further prospective studies with a priori hy-
rs-fMRI study has investigated the population with DCM, potheses are needed. Similarly, microstructural imaging of
finding higher amplitude of low frequency fluctuations at all cortical and subcortical structures has demonstrated rostral
cervical cord segments in DCM vs healthy subjects, and in severe changes in SCI,123 but this approach has yet to be investigated
vs mild patients.107 in DCM.

Perfusion Imaging Electrophysiology of the Spinal Cord

Spinal cord perfusion is the volume of blood delivered to a mass of Electrophysiology (EP) studies of the nervous system have
spinal cord tissue over time. Similar to brain perfusion, spinal cord been employed in clinical practice for numerous decades. The
perfusion (1) exhibits a radical difference between GM (110 mL/ most common studies are electromyography (EMG), nerve
min/100g) and WM (25 mL/min/100g), (2) is increased by conduction studies (NCS), SSEPs, and motor evoked potentials
hypoxia or hypercapnia, (3) is controlled by autoregulation, and (4) (MEPs). Unfortunately, these have only modest sensitivity and
is increased by neuronal activity.108 Cerebral perfusion usually specificity for DCM and are time consuming, resource inten-
utilizes arterial spin labeling (ASL) methods, but these are more sive, and uncomfortable for patients, limiting their practicality.
difficult to implement in the spinal cord due to complex vascular However, EP studies fulfill niche roles in clinical management
anatomy. Instead, two studies have investigated spinal cord per- of DCM, including lesion localization, ruling out alternative
fusion in DCM using dynamic susceptibility contrast (DSC) diagnoses, and performing intraoperative monitoring. Similar
imaging with IV gadolinium, demonstrating that the degree of to neuroimaging, the field of EP is rapidly evolving and several
ischemia and hypoxia correlated with neurological status promising new techniques hold potential for clinical man-
(mJOA),109 and that post-operative improvement in perfusion agement of DCM, including contact heat evoked potentials
corresponds with neurological recovery.110 (CHEPs) and magnetospinography (MSG).

Electromyography
Metabolic Imaging With Positron
EMG studies the motor system by measuring muscular ac-
Emission Tomography
tivity with surface or inserted needle electrodes. Several re-
Direct measurement of cellular metabolism is possible using sults are typically obtained, including insertional activity,
positron emission tomography (PET), offering a unique and resting activity, and activity during voluntary contraction.
complimentary insight into the pathophysiology of DCM. Using Increased insertional activity is a sign of denervation (ap-
the radiotracer 18F-fluorodeoxyglucose (18F-FDG), metabolism pearing within days of lower motor neuron injury), whereas
can be measured on standardized uptake value (SUV) images. One decreased activity occurs with muscle atrophy. Abnormal
group has used this approach to demonstrate that individuals with resting activity may include fibrillations and sharp waves,
DCM show decreased 18F-FDG uptake below the site of com- which appear 1–4 weeks after lower motor neuron injury. The
pression.111 A follow-up study demonstrated that a subset of DCM amplitude and number of motor unit action potentials
patients had focally increased metabolism at the site of com- (MUAPs) during voluntary contraction is also informative.
pression prior to surgery, and this subgroup had superior recovery Complete denervation causes an absence of MUAPs, my-
after surgery than individuals that did not have this finding of opathy shows decreased MUAP amplitude, and chronic de-
hypermetabolism.112,113 nervation leads to increased MUAP amplitude due to
Martin et al. 137S

Figure 2. Intraoperative SSEP recording during surgical decompression for cervical compressive myelopathy. Typical tibial stimuli at 3HZ,
200 seconds square wave pulses with a 10–20 cranial montage. In the MRI image, cord compression is prominent at C3/4. At baseline, the
SSEPs are markedly prolonged bilaterally at 63.2 and 59.8 milliseconds for the right and left sides, respectively. Following spinal cord
decompression, there is an improvement within a few minutes of 12.4 and 7.8 milliseconds, respectively. Figure courtesy of Dr James Guest.

reinnervation and enlargement of motor units. In DCM, EMG recording, identifying lesions as sites of decreased velocity.
is often useful to diagnose and localize radiculopathy at The role of NCS in DCM is to diagnose peripheral nerve
specific spinal levels, but reduced amplitude corresponds with lesions such as entrapment, neuropathy, or brachial plexop-
the degree of paresis resulting from compression of anterior athy. Unfortunately, it is common for patients with DCM to get
horn cells or exiting nerve roots.124 Intraoperative monitoring mislabeled with unilateral or bilateral carpal tunnel and/or
during decompressive surgery for DCM also utilizes EMG to cubital tunnel syndrome, and NCS is the primary diagnostic
detect nerve root irritation or injury. One study found that study to rule these out. Given the depth and surrounding
DCM patients demonstrate a longer time to peak EMG during structures around the spinal cord and exiting nerve roots, it is
walking, indicating that muscles take longer to fully con- not possible to perform NCS at proximal sites, thus limiting its
tract.125 Furthermore, the same study found deltoids and utility to diagnose myelopathy and radiculopathy.
hamstrings remain abnormally active throughout gait, while
another study reported longer coactivation of the quadriceps
Somatosensory Evoked Potentials
and hamstrings,124 suggesting that DCM patients show
compensatory activity to maintain balance. Another study SSEPs are performed by applying electrical stimulation to a
found that abnormal EMG findings in non-myelopathic pa- peripheral nerve and measuring evoked potentials using
tients with asymptomatic spinal cord compression (ASCC) surface electrodes in positions over the spine, brainstem, and
predicted faster onset to myelopathy.126 somatosensory cortex. Abnormal SSEPs are found in lesions
of the dorsal column-medial lemniscus pathway and typically
show decreased amplitude, increased latency, or increased
Nerve Conduction Studies
dispersion of waveform. Numerous averages are required to
NCS measures the conduction velocity through a segment of a overcome noise, but myelin damage and axonal loss can cause
peripheral nerve, between the site of stimulation and the site of inconsistent conduction, potentially canceling out the signal
138S Global Spine Journal 12(1S)

using time-locked averaging and requiring advanced signal Contact Heat Evoked Potentials
processing.127,128 In DCM, SSEPs are commonly utilized for
intraoperative monitoring with good sensitivity and specificity CHEPs are a newer technique that utilize a thermal cutaneous
for iatrogenic injury.129 In some patients, one can observe stimulus to selectively excite heat receptors, which travels
improvements in SSEPs within minutes of decompression, through Aδ, and C nerve fibers and the spinothalamic tract,
indicating a component of reversible pathophysiology and can be measured as a cortical evoked potential.138 In
(Figure 2). As a diagnostic tool, upper limb SSEPs generally DCM, CHEPs have demonstrated high sensitivity (95%)
show poor sensitivity, ranging from 33 to 59%,72,83,102,130 compared with SSEPs (24%) at the maximally compressed
whereas lower limb SSEPs showed 100% sensitivity in 2 level, while also detecting abnormal sensation above and
small studies.131,132 The specificity of SSEPs for cervical below the compressed level.139 Furthermore, CHEPs showed
myelopathy is estimated at 70%.72 Various studies have also responsiveness to DCM patients that clinically deteriorated,
reported that abnormal SSEP latencies correspond with greater offering a possible role in clinical monitoring. Future studies
severity of DCM,72,82,83 and demyelination of the dorsal investigating this promising new tool are needed to determine
columns (measured using DTI or MWF imaging).83, However, its responsiveness after surgical intervention, and its utility in
inconsistent results have been reported regarding the prog- predicting outcomes.
nostic value of SSEP abnormalities, with one study finding
improved outcomes with the absence of SSEP abnormali- Magnetospinography
ties,133 while the remainder of studies showed no significant
associations.72,82,130 Another study found that abnormal MSG is a novel technology that is the spinal cord analog of
SSEPs in non-myelopathic patients with ASCC predicted magnetoencephalography (MEG) for the brain. MSG offers
faster onset to myelopathy.126 Further prospective studies non-invasive measurement and 3D visualization of the elec-
utilizing standardized SSEP techniques are needed to fully trical activity within the spinal cord or peripheral nerves
elucidate the clinical utility of this assessment. (termed “magnetoneurography”), blurring the lines between
the fields of electrophysiology and imaging. MSG uses an
array of 120 superconducting quantum interference device
Motor Evoked Potentials detectors and must be conducted in a controlled environment
MEPs are performed via electrical or transcranial magnetic with magnetic shielding.140 Pilot studies have demonstrated
stimulation of the motor cortex, while recording from distal that MSG can quantify and visualize electrical conduction
muscles. Similar to SSEPs, amplitude and latency are the through the cervical cord, cauda equina, and peripheral
primary measures used in MEPs. MEPs are widely utilized in nerves.141,142 It was also demonstrated that MSG identified the
intraoperative monitoring, providing a highly sensitive and site of dorsal column conduction block in one patient with
specific warning for cord compromise.129 Prolonged central DCM.141 However, the utility of this technology may be limited
motor conduction time (CMCT), calculated by subtracting the by issues of physiological noise and movement, which are
peripheral conduction time from the total MEP latency, has minimized in MEG by the closer proximity of the brain to the
been utilized to identify various pathological conditions such as skin surface and by placing the head in a tight-fitting helmet.
multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), High quality prospective research in patients with DCM is
and DCM. A complex technique called triple stimulation MEP needed to determine the utility of this exciting new device.
has been developed to help isolate anterior horn cell dys-
function and diagnose ALS. In DCM, MEPs have been showed
to be somewhat more sensitive and specific for cervical my-
Future Directions
elopathy than SSEPs, with sensitivity ranging from 50% to Looking ahead, clinical management of DCM will almost
92%72,133,134 and specificity of 74–100%.72,133 Prolonged certainly be driven by advances in imaging and electro-
CMCT also correlates well with clinical measures of DCM,135 physiology that can accurately quantify disease and direct
while improvement of CMCT after surgery corresponds with treatment decisions, often dubbed “personalized medicine.”
recovery in one of two studies,135,136 and pre-operative CMCT At present, major knowledge gaps exist in clinical manage-
appears to be predictive of post-operative recovery.135,137 One ment of patients with mild DCM and ASCC, including how to
study found superior performance using MEP recruitment monitor these individuals for deterioration and when to decide
parameters rather than MEP latencies, showing better re- on surgical treatment. However, this trend toward data-driven
sponsiveness to post-operative recovery.136 Another study treatment faces several hurdles, including (1) development of
found that abnormal MEPs in non-myelopathic patients with novel imaging/EP techniques to generate accurate data, (2)
ASCC predicted faster onset to myelopathy.126 Overall, histopathological or multimodal validation to ensure that
MEPs are a valued tool in measuring spinal cord function, biomarkers reflect true pathological changes, (3) the devel-
and further research efforts will help to establish their utility opment of robust automatic analysis, and (4) acceptance and
for prognostication. integration into clinical workflows.
Martin et al. 139S

Figure 3. Axial images through the cervical spinal cord in a healthy subject, including FA map from a DTI acquisition (A, D), MTR map from a
MT acquisition (B, E), and T2*-weighted images (C, F). Template-based analysis using the SCT (D–F) allows for probabilistic estimation of
tract-specific metrics from the lateral corticospinal tracts (blue) and dorsal columns (yellow–red). DTI = diffusion tensor imaging; FA =
fractional anisotropy; MT = magnetization transfer; MTR = MT ratio; SCT = spinal cord toolbox.

Novel Techniques injury and dysfunction may be useful for clinical applications,
but failure to identify their fundamental assumptions, con-
As scientific discovery charters new territories and expands founding factors, variations of normal, and limitations has the
our understanding of neurophysiology, we can expect new grave potential to cause medical errors. Ground truth data is
technologies that exceed our imagination. One needs only to often not available, and histopathological studies in ca-
consider the period before MRI to realize how difficult it is to davers or animals should be conducted to determine if
anticipate the future, and how one technological breakthrough microstructural measures reflect reality. Alternatively, cross-
can revolutionize medicine and clinical research. Among the validation of novel imaging or functional measures can be
vast array of promising technologies is functional near infrared performed by acquiring multiple confirmatory imaging,
spectroscopy, which can non-invasively measure neuronal electrophysiology, clinical, and/or molecular measures.
function in freely moving individuals.143 Another consideration
is the emergence of genomics, transcriptomics, and proteomics,
which have already found specific molecular blood markers of Quantitative Analysis
ischemia and neural injury in DCM,144 and how these might be
integrated with molecular imaging such as PET. Complex data requires complex analysis, and this must be-
come robust, automated, and easily interpretable to success-
fully enter into clinical use. Powerful tools for motion
Validation correction, outlier/artifact rejection, and template-based
With increasing acceptance and reliance on quantitative data analysis have emerged, and these suggest the possibility of
and surrogate measures, we must not forget that their vali- achieving full automation of quantitative image analysis
dation is of critical importance. Surrogate measures of neural (Figure 3).145 Multivariate models are often necessary to
140S Global Spine Journal 12(1S)

integrate data, and more complex analytic methods like deep for-profit organization. Study support was provided directly through
learning may produce superior performance for diagnosis, the AO Spine Research Department. MRNK is supported by the
clinical measurement, and outcome prediction.146-148 How- National Institute for Health Research (NIHR) Brain Injury MedTech
ever, the pros and cons of more complex analysis methods Co-operative based at Cambridge University Hospitals NHS Foun-
must be weighed, as these can make it more difficult to dation Trust and University of Cambridge, and BMD a NIHR Clinical
identify sources of error and bias. Doctoral Research Fellowship. The views expressed in this publi-
cation are those of the authors and not necessarily those of the NHS,
the National Institute for Health Research or the Department of
Clinical Uptake Health and Social Care. PF is funded by a SNF Eccellenza Pro-
Clinicians need to be engaged and buy in to the concept of fessorial Fellowship grant (PCEFP3_181362/1).
quantitative outputs, requiring a paradigm shift from current
practice (e.g., anatomical MRI) that will almost certainly ORCID iDs
occur incrementally rather than instantaneously. To ensure
Aria Nouri  https://orcid.org/0000-0002-4965-3059
safety and promote uptake, quantitative measures should first
Jefferson R. Wilson  https://orcid.org/0000-0001-5965-0305
be introduced as a decision-making adjunct that supports
Michael G. Fehlings  https://orcid.org/0000-0002-5722-6364
existing practices.14
Benjamin M. Davies  https://orcid.org/0000-0003-0591-5069
In addition, a massive effort of knowledge translation
will be needed to move these techniques from the hands
of researchers to clinicians and technicians, and post- References
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