Equate to Advancements in Our Knowledge of Recovery in Whiplash?

[ clinical commentary ]

JAMES M. ELLIOTT, PT, PhD1-3 • SUDARSHAN DAYANIDHI, PT, PhD4,5 • CHARLES HAZLE, PT, PhD6-8 • MARK A. HOGGARTH, MS1,9 JACOB MCPHERSON, PhD10 • CHERYL L. SPARKS, PT, PhD11 • KENNETH A. WEBER II, DC, PhD12 Advancements in Imaging Technology: Do They (or Will They) Equate to Advancements in Our Knowledge of Recovery in Whiplash?

TTSYNOPSIS: It is generally accepted that up resolution to reveal currently elusive anatomical to 50% of those with a whiplash injury following lesions (or, perhaps more importantly, temporal a motor vehicle collision will fail to fully recover. changes in physiological responses to assumed Twenty-five percent of these patients will dem- lesions) in those patients at risk of poor recovery. onstrate a markedly complex clinical picture that Preliminary findings from 2 prospective cohort includes severe pain-related disability, sensory and studies in 2 different countries suggest that this motor disturbances, and psychological distress. is so, as evidenced by changes to the structure of t is generally accepted that A number of psychosocial factors have shown skeletal muscles in those who do not fully recover. up to 50% of those with a prognostic value for recovery following whiplash In this clinical commentary, we will briefly intro- from a motor vehicle collision. To date, no manage- duce the available imaging decision rules and the whiplash injury should expect ment approach (eg, physical therapies, education, current knowledge underlying the pathomechanics to recover within the first 2 to 3 psychological interventions, or interdisciplinary and pathophysiology of whiplash. We will then I strategies) for acute whiplash has positively influ- acknowledge known prognostic factors underlying months following a motor vehicle enced recovery rates. For many of the probable functional recovery. Last, we will highlight emerg- collision (MVC). Accordingly, approxi- pathoanatomical lesions (eg, fracture, ligamentous ing evidence regarding the pathobiology of muscle 15 rupture, disc injury), there remains a lack of avail- degeneration/regeneration, as well as advance- mately 50% will not fully recover, of able clinical tests for identifying their presence. ments in neuroimaging and musculoskeletal imag- whom approximately 25% will demon- Fractures, particularly at the craniovertebral and ing techniques (eg, functional magnetic resonance strate a markedly complex set of signs/ imaging, magnetization transfer imaging, spec- cervicothoracic junctions, may be radiographically symptoms that include severe pain-relat- troscopy, diffusion-weighted imaging) that may be occult. While high-resolution computed tomogra- ed disability,113 changes in the structure phy scans can detect fractures, there remains a used as noninvasive and objective complements to of neck muscle,29,32,34,39 sensory and motor lack of prevalence data for fractures in this popula- known prognostic factors associated with whiplash 114 89,108,115 tion. Conventional magnetic resonance imaging recovery, in particular, poor functional recovery. disturbances, muscle weakness, has not consistently revealed lesions in patients J Orthop Sports Phys Ther 2016;46(10):861-872. and psychological distress.114,116 Though with acute or chronic whiplash, a “failure” that doi:10.2519/jospt.2016.6735 there is evidence to suggest damage to a may be due to limitations in the resolution of avail- TTKEY WORDS: cervical spine, functional number of tissues (facet joints and cap- able devices and the use of standard sequences. magnetic resonance imaging (fMRI), magnetic sules, the intervertebral disc, ligaments, Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. The technological evolution of imaging techniques resonance imaging (MRI) research, radiology/ 21 and sequences eventually might provide greater medical imaging, spinal pain vascular tissues, osseous structures), no definitive structural cause of the wide

1Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL. 2School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, Australia. 3Zürich University of Applied Sciences, Zürich, Switzerland. 4Rehabilitation Institute of Chicago, Chicago, IL. 5Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, IL. 6Division of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, KY. 7Walsh University, North Canton, OH. 8Griffith University, Gold Coast, Australia. 9Department of Biomedical Engineering, Northwestern University, Chicago, IL. 10Department of Biomedical Engineering, College of Engineering and Computing, Florida International University, Miami, FL. 11Rehabilitation Center of Expertise, OSF Healthcare, Peoria, IL. 12Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA. Dr Elliott is funded by the National Institutes of Health (NICHD/NCMRR grant 1 R01 HD079076-01A1). Dr Elliott’s relevant financial activities outside the body of work include a 35% ownership/investment in a medical consulting start-up, Pain ID, LLC. The authors certify that they have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the article. Address correspondence to Dr James M. Elliott, Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, 645 North Michigan Avenue, Suite 1100, Chicago, IL 60540. E-mail: [email protected] Copyright ©2016 Journal t of Orthopaedic & Sports Physical Therapy®

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46-10 Elliott.indd 862 9/14/2016 8:36:23 PM and varied symptomatology has been guidelines, as well as introduce techno- prior patient history, probable etiology, realized with available imaging appli- logical advances in our understanding of signs and symptoms, and results of prior cations.38,83-85,94,95,105 Recent prospective the underlying mechanisms of muscle de- imaging. These categories are referred studies from 2 different countries have, generation/regeneration. We will also in- to as “clinical conditions,” with subcat- however, identified changes in the neck troduce and propose the use of advanced, egories described as “variants.” Most ap- muscle structure (eg, muscle fatty infil- but available, functional magnetic reso- plicable within the ACR-AC for patients trates [MFIs]) of those with poor func- nance imaging (fMRI) sequences of the with apparent acute WAD is the clinical tional recovery,32,25 suggesting a core brain and spinal cord as having potential condition category of “suspected spine biological contribution to outcomes. scope in measuring the pain experience trauma.”22 The criteria for determina- While interesting, the precise mecha- for patients with whiplash injury. The tion of whether imaging is indicated and nisms underlying these muscular chang- intention is to facilitate development of the recommended modality are based es and their defined influence on recovery productive interdisciplinary collabora- upon the Canadian cervical spine rule remain largely unknown. tions that will propel research in the field (CCSR) and the National Emergency X- A number of psychosocial factors (eg, of whiplash and WAD into a new era of Radiography Utilization Study low-risk coping, expectations, anxiety, and de- understanding—and legitimacy on a pa- rule (NEXUS-LRR) (APPENDIX, available pression) have demonstrated prognostic tient-by-patient basis. Such efforts have at www.jospt.org), along with sugges- value in whiplash recovery.15 However, potential to generate more efficient man- tions of neurological or cervical vascular despite the presence and recognition of agement strategies for patients, perhaps injury. these factors, there remains a paucity of interrupting the progression and associat- The CCSR and NEXUS-LRR were best-evidence treatment options to sub- ed sequelae of chronic pain-related states. developed for the purposes of identify- stantially influence the rate of functional ing which patients needed imaging in recovery.61,67,79 IMAGING CLINICAL the emergency department for immedi- It is important to be aware of a num- DECISION RULES ate decision making and those for whom ber of emerging mechanistic models for diagnostic procedures were less war- whiplash recovery. These include, but linicians, including physical ranted. The investigations giving rise to are not limited to, (1) maladaptive be- therapists, are required in the these criteria were undertaken because liefs and cognition,120 (2) stress system Ccourse of routine care to make in- of acknowledgment of negative findings dysregulation,74,75,123 (3) genetic vulner- dividual judgments for initial and fur- in an overwhelming majority of imaging ability,12,13 and (4) mild injury involv- ther diagnostic tests (possibly including studies in acute cervical trauma and of ing the peripheral and central nervous imaging) for the patients they manage. the accompanying unwarranted expenses systems.32,34-36,40,42,128-130 This includes not only acutely injured and use of emergency department time This clinical commentary will not re- patients presenting to the emergency and resources.8,44,45,99,104 fute the multifactorial nature of whiplash- medicine department with concerns of In the presence of positive clinical associated disorders (WADs)26 or the large significant pathology, but also those pa- assessment findings derived from the prevalence and distribution of abnormal tients in whom the trajectory of recovery, CCSR18,117,118 or the NEXUS-LRR,55,91 findings on cervical spine magnetic reso- based on known prognostic factors, is not computed tomography (CT) is the initial nance imaging (MRI) in asymptomatic consistent with a satisfactory outcome.101 imaging modality determined to be “usu- populations.86 Nor will it attempt to sway The primary guideline in the Unit- ally appropriate” because of the primary the reader into believing that early and ed States for diagnostic imaging is the concern for fracture or other destabiliz- serial imaging should become a part of American College of Radiology Appro- ing injury (eg, zygapophyseal joint dislo- Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. standard of care for all patients exposed priateness Criteria (ACR-AC).2 The ACR- cation) in adults.22 to, and presumably injured in, a whiplash AC are a set of consensus-developed Magnetic resonance imaging is rec- event. Rather, the present commentary evidence-derived guidelines for health ommended as “usually appropriate” in will highlight previous and preliminary care providers to assist in decision mak- the ACR-AC suspected spine trauma findings to support the use of neuromus- ing for imaging based on apparent health variants in which neurological involve- culoskeletal imaging applications (eg, condition or potential condition requir- ment or overt ligamentous injury are fat-water MRI, diffusion-weighted MRI ing investigation. The stated goals of the suspected based on clinical examination, [DW-MRI], magnetization transfer im- ACR-AC are to enhance the quality of pa- emergent CT results, or if the patient is aging, and spectroscopy) as noninvasive tient care and to contribute to the most unevaluable for an extended period (eg, and objective complements to other prog- efficacious use of radiology. Within the unconscious or obtunded). Clinical sug- nostic measures. We will review the im- ACR-AC structure, patient presentations gestions of cervical vascular injury (ca- portant information related to imaging are categorized dependent on apparent rotid or vertebral arteries) can include

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nonspecific symptoms such as neck, oc- remains within physiologic limits,96 but ABC cipital, or suboccipital pain or more overt abnormal movements occur within indi- indications of neurological involvement vidual segments at upper and lower cervi- such as vertigo, ataxia, dysarthria, visual cal levels.49 This abnormal movement is field deficit, diplopia, altered cognitive referred to as the “S-shape” phase of neck status, and Horner’s syndrome.11,24,25 In motion (FIGURE 1), which consists of flex- Neutral 50-75 ms 150-175 ms cases of suspected cervical vascular in- posture ion at the upper spinal levels and exten- jury, either CT or magnetic resonance sion at the lower levels, and can exceed angiography may be used to evaluate the physiologic limits and potentially induce extent of vessel injury and perfusion by FIGURE 1. Schematic of the head-neck demonstrating subfailure injuries to a number of tissues contrast distribution.50,64 the period during which the cervical spine goes from (facet joints and capsules, the interverte- It is noteworthy that overt structural (A) the neutral posture prior to a rear-end impact bral disc, ligaments, vascular tissues, os- to the (B) “S-shaped” curve (50-75 milliseconds). or hard neurological clinical findings are seous structures).49,62,92,93 There remains During this time, the upper spinal levels flex and the rare in the vast majority of patients in the lower levels extend, exceeding physiologic limits and equivocal evidence that neck postures or emergent care setting,80,100 which seems potentially inducing subfailure injuries to a number axial rotation at the time of the collision to fit with the accepted position that most of vulnerable tissues. (C) Finally, all of the cervical can increase the risk of structural in- recovery should occur within the first 3 levels undergo extension, forming a “C-shaped” curve jury,58,112,124,129 but a definitive conclusion (150-175 milliseconds). Adapted with permission months following an MVC.15 However, likely requires more quantitative “real- from Grauer et al.49 Copyright ©1997 Wolters Kluwer for some patients, recovery is not spon- Health, Inc. world” metrics that currently do not, to taneous or unremarkable. Whether this our knowledge, exist. discrepancy in recovery rates relates to tic factors for poor recovery and for injury severity or the occurrence of le- individual patient circumstances in The Elusive Whiplash Lesion sions is unknown. What is known is that which the soft tissues require detailed and Clinical Practice there is no variant within the ACR-AC assessment. Tissue damage following a whiplash in- guidelines to specifically address the • To date, WAD is not recognized as a jury is evident from (1) laboratory-based clinical heterogeneity of WAD.1 Accord- specific patient presentation in the applications (simulated crash tests), (2) ingly, we contend that future updates to ACR-AC; thus, no specific guidelines experimental animal models, and (3) the ACR-AC should consider known risk are available for clinicians evaluat- postmortem studies. However, whether factors for the heterogeneous WAD con- ing patients having experienced such or not tissue damage is present in pa- dition. In purest terms, most individuals cervical spine trauma aside from tients with WAD is a clinical, not a labo- with WAD do not require imaging af- emergent concerns for fracture or ratory, issue. In purest terms, clinicians ter receiving a clear medical screen, but instability. evaluate patients to develop an informed some may. This clinical commentary will and effective treatment plan that ad- provide empirical and anecdotal evidence PATHOMECHANICS dresses potential tissue injuries and iden- to suggest this is the case and what types OF WHIPLASH tified impairments and dysfunctions on a of imaging may be most applicable in the case-by-case basis. acute and chronic stages on a patient-by- ere we provide a brief back- Unfortunately, to date, there are no patient basis. ground regarding the current un- radiological means for clinicians to ac- Hderstanding of the pathomechanics curately and consistently identify and di- Key Points of a typical whiplash injury from an agnose tissue injury in the vast majority Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. • Published imaging decision guide- MVC. Engineering-based investigations of patients with WAD. Plain radiography lines, primarily the ACR-AC, are of MVCs have focused on preventing or cannot detect soft tissue (eg, facet cap- valuable tools for clinicians assessing reducing the incidence of injury through sules and discs) damage/injury and even patients having experienced acute cer- the modification of the vehicle, including, some fractures, particularly at the cranio- vical trauma. but not limited to, energy-absorbing seat vertebral and cervicothoracic junctions, • For patients warranting imaging after designs and head-restraint geometry.59,60 which may be radiographically occult.70,97 cervical trauma, CT is the preferred Collectively, these studies involving bio- As stated, CT scanning best detects frac- initial modality. fidelic dummies, human cadavers, and tures, but to our knowledge, there have • Following cervical trauma, MRI may human volunteers have shown that the been no studies using high-resolution CT be warranted acutely with suggestions total movement of the head and neck, to determine the prevalence of fractures of neurological involvement or based spanning 200 milliseconds during a following whiplash. Conventional MRI on the presence of known prognos- typical rear-end vector impact, largely has not revealed structural lesions relat-

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46-10 Elliott.indd 864 9/14/2016 8:36:24 PM ed to symptoms in patients with WAD, dictive risk factors of poor recovery out the lifespan. Once activated, the SC but this may be due to limitations of the (higher pain-related disability, older proliferates (eg, increase in number) and image resolution of conventional devices age, and signs of hyperarousal). differentiates (combine with each other) and commonly used imaging sequences. • Routine imaging protocols (CT, radi- to create nascent myotubes that fuse Accordingly, the constant evolution of ography, MRI) may need to be recon- with and replace the damaged myofibers MRI magnets with improved signal-to- sidered in the vast majority of patients (FIGURE 2B). noise and contrast-to-noise ratios might following whiplash injury. Importantly, the classic process of re- provide greater image resolution, which pair also requires many other nonmyo- in the future may reveal currently elu- Etiology of MFI and Cellular Dynamics genic cellular players apart from the SC, sive lesions or physiological responses to It is plausible that functional outcomes in all of which act in a concerted temporal damaged tissues.28,29,31-35,39-42 whiplash are, at least somewhat, linked to fashion to ensure appropriate healing. healthy/unhealthy muscle architecture. During this process, the inflammatory MRI APPLICATIONS Our ability to effectively treat degenerat- cells, fibroblasts, endothelial cells, fibro- ed muscles relies, in part, on an improved adipogenic cells, and SCs interact with he expression of MFI in the cer- understanding of the distribution and each other in a time-sensitive fashion vical spine muscles in acute and etiology of fat deposition across the age (FIGURE 2C).9 Broadly speaking, after an Tpersistent whiplash has been spectrum. A major obstacle in the study injury, the immune response is initiated identified in cross-sectional and longi- of MFI is, however, our collective lack of by the regional presence of monocytes tudinal designs across 3 different cul- understanding on how, why, and when it and macrophages for clearing damaged tures.29,30,32,35,39,41,63 Such findings were occurs, particularly after an injury, mak- tissue components. Following this ini- not present to the same magnitude in ing informed disease characterization, tial response, there is a peak activation individuals with persistent idiopathic longitudinal evaluation, and therapeutic of the fibroblasts (1 week or less postin- neck pain,33 or those reporting milder modulation difficult. jury) and possibly the fibroadipogenic symptoms from WAD.35 Of note, the early What is known? Skeletal muscles have cells and the endothelial cells in order to and large expression of MFI has recently an incredible capacity for repair and re- create the ECM scaffold and vasculature. been shown to occur in those patients35 generation following injury.73 Here, we Finally, there is a marked increase in the at risk of poor recovery (higher pain- provide only a general background into numbers of SCs and myoblasts that re- related disability, older age, and signs of repair, as the processes governing this pair the injured myofibers. In particular, hyperarousal).101 While interesting, the process are complex and beyond the the ECM-associated fibroblasts and the precise mechanisms underlying muscular scope of this clinical commentary. For SCs have a complex relationship with degeneration (leading to MFI), and their a more detailed description, the reader each other. Once activated, the SCs fa- influence on recovery, remain largely un- is encouraged to read the work of ei- cilitate remodeling of the local ECM by known. There also remains equivocal evi- ther Bentzinger et al9 or Dayanidhi and increased expression of matrix metallo- dence to suggest that changes in muscle Lieber.23 proteinases.90,132 The biomechanical and cross-sectional area are not related to The primary myogenic stem cells in- biochemical factors of the ECM also af- symptoms in the long term.3,71,72,122 This dispensable for repair and regeneration68 fect the functionality of the SC. For ex- may have more to do with a wide variety are the satellite cells (SCs).23,125,136 Satel- ample, in vitro experiments have shown of measurement methods, requiring a lite cells are located in all muscles in their that the stiffness of the ECM affects not more concerted global effort to establish niche, that is, between the sarcolemma only the capacity of SCs to differentiate43 a preferred suite of imaging sequences37 of their associated myofiber and the sur- but also to self-renew.46 Apart from the Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. whereby pooled analyses can be realized rounding basal lamina of the extracellu- ECM, quiescent SCs are present in close and differences reconciled. lar matrix (ECM) (FIGURE 2A). They are in proximity to muscle microvasculature.17 a quiescent (latent) state until activated During repair, the SC interactions with Key Points by any number of stimuli, such as, but not endothelial cells, that is, those respon- • To date, no structural cause of WAD limited to, stretch121 (during growth), the sible for new capillaries, are facilitated has been found with available imaging presence of injury and inflammatory fac- for the coordination of angiogenesis and technology, supporting the position tors,136 or denervation27 (after experimen- myogenesis. It is important to under- that the clinical course is driven by tal injury). Satellite cells are considered stand that the total process of healing to both medical and noninjury-related bona fide adult stem cells in that they return to a preinjury state can take up to factors. self-renew106 to maintain the SC pool 4 weeks,9 and is dependent on the sever- • Increased levels of neck MFI on MRI and are able to create myogenic tissue, ity of the injury. In many musculoskel- occur in tandem with known pre- that is, muscle progenitors,20 through- etal conditions, like whiplash, where the

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adipocytes and connective tissue in the A Basal lamina lumbar multifidus (porcine and ovine, respectively) have been observed fol- Sarcolemma SC lowing experimental lesions to both the Muscle cell Myonuclei intervertebral disc and nerve root.53,54 A (Myoﬁber) follow-up study demonstrated that injury to the ovine intervertebral disc induces dramatic structural remodeling of B Quiescence Activation Proliferation Di erentiation the multifidus muscle, characterized by increased adipose and fibrotic tissue and muscle fiber changes, all of which provide for the exploration and development of Fusion novel interventions to impact muscle function and patient outcomes.54 Self-renewal While largely unknown, there is preliminary evidence that specific exercise can positively influence muscle structure C and function in chronic whiplash.89 Fur- SCs and muscle progenitors ther animal studies in which experimen-

Endothelial cells tal lesions typical of a whiplash injury can be controlled for are required to better Fibroadipogenic progenitor cells understand the repair process of skeletal muscle. Lastly, clinical trials investigating Fibroblast cells the parameters and effectiveness of various exercise programs targeting muscle Inﬂammatory cells structure and function are required be- 0 (Injury)7 14 fore definitive conclusions can be drawn. Repair Timeline, d Key Points FIGURE 2. (A) SC niche: SCs lie between the sarcolemma of their associated myofiber and the surrounding basal • Muscle stem cells, that is, SCs, play a lamina of the extracellular matrix. (B) SC activation: SCs remain in a quiescent state until activated by a number key role in repair and regeneration af- of stimuli, such as injury. The SCs are considered bona fide adult stem cells in that they self-renew to maintain ter injury to muscle. the SC pool and are able to create myogenic tissue, that is, muscle progenitors, throughout the lifespan. (C) Peak • A number of other cell types, such as activation of various cell types for repair: various nonmyogenic and myogenic cells act in a coordinated fashion to ensure appropriate repair. Abbreviation: SC, satellite cell. inflammatory cells, endothelial cells, fibroblasts, and fibroadipogenic cells, injury and healing are not so simplistic, These changes can be significant and may work in conjunction with SCs to en- there can be maladaptation of this repair influence the outcome of the repair pro- sure appropriate repair. process and possibly functional outcomes cess.47 While it is not known how the spe- • Maladaptation of this process could on a patient-by-patient basis. It remains cific changes occur at the cellular level, lead to pathological healing, such plausible that advanced imaging (eg, in humans the SC or skeletal muscle pro- as excess connective tissue and fatty Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. diffusion-weighted imaging and/or spec- genitors are higher in number in partial- infiltration. troscopy) could help identify acute-level thickness rotator cuff tears compared to • Future work is required to test the in- changes in the muscle cell (or ECM) that noninjured and full-thickness tears.78 Im- fluence that specific exercise may have could point to cause and effect and help to portantly, these cells were unable to pro- on the regeneration process. establish treatment planning/monitoring. liferate similarly, suggesting a decreased The expression of MFI has been well regenerative capacity and presumably a ADVANCEMENTS IN documented in injuries involving the ro- disruption of the dynamic balance be- NEUROIMAGING tator cuff complex. The injured rotator tween the cell types. cuff muscles (supraspinatus and infraspi- Interestingly, similar changes in Functional MRI natus in particular) show abnormal fibro- muscle structure have been observed in unctional MRI provides a means sis, fatty infiltration, and changes in fat animal injury models involving the lum- to indirectly measure neural activity deposits on CT, MRI, and ultrasound.66,77 bar spine. Specifically, rapid increases in Fby generating images that are sensi-

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46-10 Elliott.indd 866 9/14/2016 8:36:25 PM tive to blood oxygenation levels (ie, blood AB C Superior Superior oxygenation level-dependent [BOLD] 87,88 contrast images). As neural activity C2 increases in a brain region, blood flow to the activated region increases to deliver C3 Ant Le

oxygen to meet the increased metabolic C4 erior erior ft st demands of the active neurons. The he- Right Po C5 modynamic response during neural activity results in an uncoupling between C6 blood flow and oxygen metabolism, such C7 that blood flow increases more than the T1 metabolic consumption of oxygen. This creates a local increase in the concentra- y = 61 y = 61 Inferior Inferior tion of oxygenated hemoglobin and a lo- Anterior

cal increase in signal on BOLD contrast Le ft

images. In an fMRI study, the BOLD Right contrast images are collected over time z = 338 z = 338 Posterior to generate a series of images that can Z-score Z-score be statistically analyzed, and voxels that Left Left > Right significantly fit the model are considered 1.65 3.50 1.65 3.50 Right Right > Left 131 to be active. 1.65 3.50 1.65 3.50 Functional MRI has been used exten- FIGURE 3. (A) Functional images demonstrating group average cervical spinal cord activity during a left- (red- sively to map out the brain areas underly- yellow) and right-sided (blue-light blue) isometric upper extremity motor task. (B) Areas where the signal was ing the processing of nociceptive signals greater for the left-sided task compared to the right-sided task, and vice versa. The activity was lateralized to the and the perception of pain in the brain hemicord ipsilateral to the side of the task. (C) The legend shows the location of the coronal and axial slices on the (for review, see Apkarian et al5). Early MNI-Poly-AMU spinal cord template, with corresponding vertebrae labeled. Adapted with permission from Weber et fMRI pain studies primarily used experi- al.126 Copyright ©2016 Elsevier. mental acute pain paradigms, in which painful stimuli were delivered over the Baliki et al7 imaged patients over a course that chronic pain results from a maladap- course of the fMRI study (eg, with the of a year following an initial episode of tive learning process that converts the participant in the scanner). While pro- acute back pain. The strength of initial sensory-nociceptive-pain experiences viding much information on the neural functional connectivity between the nu- following an initial injury to a pathologi- circuitry involved in acute pain, experi- cleus accumbens and prefrontal cortex cal emotional state.4 This would certainly mental pain is fundamentally different was shown to be predictive of chronic help to explain the expectation of recov- from the clinical pain experience, which back pain, implying that corticostriatal ery, maladaptive beliefs/cognition, stress is unique and personal to the patient ex- circuitry is causally involved in the tran- system dysregulation, and perceived in- periencing the pain. A major advance- sition from acute to chronic pain.7 A justice following whiplash. ment in neuroimaging has been the shift follow-up study demonstrated signifi- It is thus plausible that the neural cir- from experimental pain paradigms to cant temporal reorganization of the con- cuitry involved in the chronicity of WAD the study of the brain regions underlying nectivity between the hippocampus and partially parallels, or is similar to, that Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. clinical pain.10,98,103 This work has demon- the cingulate gyrus and medial prefrontal documented in chronic low back pain. In strated distinct differences in the patterns cortex.82 Specifically, the connectivity be- WAD, the MVC could be regarded as the of brain activity for acute versus chronic tween the hippocampus and these brain initial painful event (time point zero), and, pain conditions, with a prominent fea- areas decreased in those who continued based on the state of the individual’s brain ture being that chronic pain appears to to have pain compared to those who re- at time point zero, a prognostic “picture” engage more of the brain’s emotional- ported recovery, and the decrease in con- could ensue. However, the application learning circuitry, suggesting a greater nectivity was correlated to the extent of of fMRI and other neuroimaging tech- emotional component to chronic pain.6 the pain experienced 1 year later.82 These niques to specifically study WAD, unlike The noninvasiveness of fMRI makes it findings suggest that reorganization in low back pain, has been limited to date. an ideal tool for longitudinal studies and the brain’s emotional learning circuitry Linnman and colleagues,69 using positron tracking the changes in the brain during may underlie the transition from acute to emission tomography, found bilateral in- the transition from acute to chronic pain. chronic pain, which has led to the theory creases in regional cerebral blood flow in

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the posterior cingulate cortex and para- AB hippocampal gyrus in individuals with WAD compared to pain-free controls.69 Such findings suggest that alterations in the brain’s resting state may be linked to an increased self-relevant evaluation of WAD-related pain and stress.69 An emerging and exciting area of research related to WAD has been the ap- C plication of fMRI to study spinal cord function.126 The same principles underlying the BOLD signal in the brain should also apply to the spinal cord; however, spinal cord fMRI has been slower to develop due to technical issues with the imaging of the spinal cord and the analysis 119 of spinal cord fMRI images. It is thus FIGURE 4. (A) A T2-weighted magnetic resonance image was used to plan the axial slices for MT- and non–MT- not surprising that the bulk of studies weighted acquisition, spanning the C2-7 area of the spinal cord. (B) Magnetization transfer image corresponding have been mainly proof-of-concept in na- to the region caudal to C4. (C) Non-MT image in the same region, with anatomically defined regions of interest ture, testing the feasibility of using spinal over the ventromedial and dorsal columns of the spinal cord. These images are used to measure the MT ratio, cord fMRI to detect signal changes dur- quantifying anomalies in white-matter pathways. Abbreviation: MT, magnetization transfer. ing motor and sensory tasks.127 Recent advancements are beginning to overcome • Neuroimaging has revealed differ- T2-weighted MRI in known spinal cord some of the mentioned technical barriers, ences in neural circuitry in individuals injury14) would suggest this is not the and the validity and reliability of spinal with acute and chronic low back pain; case. A recent, albeit preliminary, case se- cord fMRI are starting to be realized.126 however, this has yet to be sufficiently ries using MT imaging has quantified the With continued development, spinal cord studied in individuals with traumatic presence of losses in spinal cord motor fMRI may prove to be a valuable method neck pain. pathways, without the characteristic sig- to noninvasively study sensory and mo- nal from edema/hemorrhage, in a small tor (FIGURE 3) processing in the spinal cord MAGNETIZATION sample of patients with chronic WAD.36 and the changes in spinal cord function TRANSFER IMAGING Implementation of high-field MT mea- following injury to peripheral structures sures of the cervical spinal cord in the or the direct injury of the spinal cord.16,65 agnetization transfer (MT) is acute stage could potentially complement Overall, greater application of fMRI to an MRI method that creates con- the objective assessment and projection study the potential reorganization of the Mtrast based on the macromolecular of functional recovery.102 brain and spinal cord in individuals with content of tissues (FIGURE 4).52 In addition, WAD is warranted. Longitudinal studies by comparing images with and without SPECTROSCOPY are needed to expand on the work that MT contrast (known as MT ratio), the has been performed in low back pain. MT effect can be used to explore and or nearly 80 years, scientists Further use of fMRI in these individu- quantify anomalies in brain white matter have used magnetic resonance Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. als may lead to the discovery and devel- across multiple neurologic pathologies Fspectroscopy (MRS) to determine opment of patient-specific multimodal (eg, multiple sclerosis109 and traumatic chemical structure and function, and treatment pathways that incorporate brain injury110). Magnetization transfer understand the underlying mechanisms cognitive behavioral and neural feed- has also been shown to be sensitive to of various disease states. While the ma- back techniques in tandem with physical spinal cord demyelination.19 jority of radiographic investigations into therapy. In considering the pathomechanics of the pathophysiology of WAD (and other the typical whiplash injury event, a po- conditions such as myelopathy57) have Key Points tential underlying mechanism, at least in focused on damage/injury to anatomy • Functional MRI provides a means to a subset of patients, could involve a mild on a macroscopic scale, spectroscopy visualize indirect patterns of neural insult to the spinal cord. Conversely, the can be used to observe and quantify activity in the human brain and spinal lack of typical radiological signs of an in- biochemical function/dysfunction (eg, cord. jured cord (eg, edema or hemorrhage on altered metabolites) of the brain, spinal

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46-10 Elliott.indd 868 9/14/2016 8:36:27 PM acute phase may be an optimal time to remains unknown how the relative mag- % 30 consider MRS of muscle tissue, as the nitude and time course of ADC changes 25 expected lack of MFI would prevent any relate to other pathophysiological muscle 20 macroscopic lipid contamination. biomarkers (eg, MFI and potential MRS- om Baseline, Fr 15 related findings). Given the relatively re- 10 ease DIFFUSION-WEIGHTED cent application of DW-MRI to skeletal 5 muscle, systematic investigation of short- 0 IMAGING

ADC Incr Denervation Radiculopathy Exercise and long-term reliability is required prior iven that rapid compositional to any potential clinical consideration FIGURE 5. Changes in muscle physiology lead changes in muscles either directly of the evaluation of a patient following to increased ADC. Complete denervation of the or indirectly impacted by trauma whiplash in whom denervation or disuse hamstring (blue bar) leads to a rapid (1 day after G injury) increase (approximately 30%) in ADC. An may help predict of the rate and extent atrophy of the neck or extremity muscles approximate 25% increase in ADC has been observed of recovery following MVC, techniques may be suspected. Nevertheless, DW- within 1 month following onset of lumbosacral with the sensitivity to detect abnormali- MRI (potentially in conjunction with radiculopathy (orange bar), and brief submaximal ties during the first hours or days postin- MRS) may provide critical early insights contractions (50% maximum volitional contraction) jury hold considerable promise as clinical into the progression of WAD. can lead to approximately 15% to 20% increases in ADC after 10 minutes postexercise (green bar). tools. One such technique may be DW- Abbreviation: ADC, apparent diffusion coefficient. MRI, which is already used widely in the Key Points Denervation and radiculopathy data adapted clinical setting to identify regions of cere- • High-resolution MT sequences could from Holl et al,56 and exercise data adapted from bral ischemia associated with neurologi- be a means of further characterizing 135 Yanagisawa et al. cal insults (eg, stroke). Indeed, DW-MRI the whiplash condition by identifying can reveal regions of restricted blood early signs of changes in spinal cord or cord, and skeletal muscle on a micro- flow well in advance of conventional im- brain functioning. scopic scale. aging approaches (eg, T2-weighted MRI, • Magnetic resonance spectroscopy of In proton MRS, the common visible CT).111 In DW-MRI, signal intensity is the brain and spinal cord could pro- metabolites are creatine, choline, lactate, directly related to the rate of water diffu- vide a potentially clinically useful bio- lipid peaks, N-acetylacetate, and citrate. sion through a given tissue.76 Diffusion- marker for the characterization and Phosphorus spectroscopy is used to vi- weighted MRI scans are acquired at management of enigmatic musculo- sualize metabolites such as adenosine progressively increasing levels of diffusion skeletal conditions, and, if adapted to triphosphate, phosphocreatine, phospho- weighting, and from these images a com- skeletal muscle, may be particularly monoesters, phosphodiesters, and inor- posite image is generated that represents viable in the acute phase of WAD prior ganic phosphate. As the strength of the the apparent diffusion coefficient (ADC) to any changes in muscle structure. magnetic field increases, the separation at each voxel. This so-called ADC map • Early alterations in water diffusion between peaks and signal to noise with enables visualization of complex tissue within skeletal muscles, visualized MRS improves, providing a more robust properties, and can be used to highlight with diffusion-weighted imaging, may environment in which to noninvasively contrast between regions with relatively be associated with the clinical course. evaluate cellular biochemistry following free or restricted flow. Thus, DW-MRI may be a useful im- head/neck trauma—and possibly add to Diffusion-weighted MRI can be ap- aging application to assess physiologic the prediction of recovery. There is evi- plied to skeletal muscle,31,134 where it has variations in the acute stage. dence from MRS-based studies toward been used to detect both temporary ex- Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. the prediction of neurologic recovery ercise-induced changes in regional blood SUMMARY from pediatric trauma (“shaken-baby” flow81,135 and early signs of denervation56 syndrome)51 and the identification of (FIGURE 5). For example, significant in- he imaging measures and mecha- biomarkers in spondylosis.107 Preliminary creases in muscle ADC can be observed nistic models described in this pa- evidence from a small cohort of individu- during and following brief submaximal Tper represent a number of advances als with persistent whiplash-associated isometric contractions,133 following pe- toward explaining the genesis of chronic pain suggests that biochemical changes ripheral nerve injury and associated posttraumatic problems (with or without in the central nervous system could be denervation,48 and in individuals with concern for significant pathology), owing present.40 To our knowledge, the useful- subacute lumbosacral radiculopathy.56 to the pioneering work of many clinician/ ness of MRS has yet to be investigated in Although changes in ADC following research scientists before us. The inten- the acute phase of whiplash or in muscles denervation appear to precede findings tion of ongoing work in this field is to of individuals with WAD. However, the from electrophysiological testing,56 it grow from what we have learned, build-

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APPENDIX

IMAGING CONDITIONS CITED IN SUSPECTED SPINE TRAUMA (AMERICAN COLLEGE OF RADIOLOGY APPROPRIATENESS CRITERIA22)

Canadian Cervical Spine Rule18,117,118

Any high-risk factor? • Age ≥65 y, or • Dangerous mechanism (A), or • Upper extremity paresthesia

No Yes Any low-risk factor allowing range-of-motion assessment? • Simple rear-end motor vehicle collision (B), or No • Sitting position in external Imaging (D) rotation, or • Ambulatory at any time, or • Delayed-onset neck pain (C) , or • Absence of midline cervical spine tenderness No

Yes

Able to rotate neck 45° left and right?

Yes

No imaging (D) Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved. A. Dangerous mechanism: fall from 3 ft/5 stairs or higher, axial load, motor vehicle collision at greater than 60 mph or rollover or ejection, motorized recreational vehicle accident, bicycle collision B. Simple rear-end motor vehicle collision excludes: pushed into oncoming traffic, hit by bus or large truck, rollover, hit by high-speed vehicle C. Delayed-onset neck pain: no immediate onset after trauma D. At time of derivation, radiograph was chosen imaging. Now, American College of Radiology recommends computed tomography if positive on criteria

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[ clinical commentary ]

APPENDIX

National Emergency X-Radiography Utilization Study Low-Risk Rule55,91

Low probability of cervical spine injury if all 5 met: 1. No tenderness at posterior midline of the cervical spine 2. No focal neurological deficit 3. Normal level of alertness 4. No evidence of intoxication 5. No clinically apparent painful injury that might distract from pain of a cervical spine injury

E. At time of derivation, radiograph was chosen imaging. Now, American College of Radiology recommends computed tomography if positive on criteria Journal of Orthopaedic & Sports Physical Therapy® Downloaded from www.jospt.org at on January 12, 2017. For personal use only. No other uses without permission. Copyright © 2016 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

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