Diffusion MRI in acute nervous system injury
Graphical abstract
Introduction
Diffusion weighted MRI (DWI) has demonstrated a tremendous ability to probe the microstructure of the nervous system noninvasively that is not afforded through other methods. DWI is highly sensitive to certain neurological injuries where conventional MRI contrasts such as T1, T2, or T2∗ either fail to detect the injury or are otherwise non-specific. Most notably this occurs in acute ischemic stroke, but is similarly observed in other acute neurological injuries of the brain, spinal cord, and peripheral nervous system. In this capacity, DWI is a proven diagnostic tool that has gained widespread acceptance. However, while it is sensitive to microscopic changes, DWI is not inherently specific for any single pathological feature. Thus, the microstructural pathophysiology underlying DWI changes have been difficult to isolate even in a prominent change such as stroke. Quantitative metrics of the diffusion weighted signal, such as diffusion tensor imaging (DTI) have further enabled the ability to extract microstructural features from the diffusion weighted images and relate them to the underlying biological substrates. This is an active area of study that has seen strong growth in the last several decades. In this review, we focus on the role of DWI in the detection of acute nervous system injury with a major emphasis on the period of injury within the first 3 days following the onset of injury. Cerebral ischemia, spinal cord injury (SCI), traumatic brain injury (TBI), and acute peripheral nerve injury will be discussed in detail as these reflect rapid or sudden changes in which DWI is particularly sensitive. This review is principally targeted at relating the DWI changes in these injuries to the underlying pathophysiology, and advocates for the role of axonal and dendrite injury as a prominent factor in the sensitivity of DWI to acute neurological injury.
The majority of diffusion studies in acute injury use DWI or diffusion tensor imaging (DTI). This review presumes the reader is familiar with DWI and DTI principles, and several reviews are available [1]. We remind the reader of the parameters derived from DWI methods and briefly reiterate their interpretations. The apparent diffusion coefficient (ADC), or mean diffusivity (MD) describes the per-voxel averaged diffusivity and is invariant to direction of the diffusion weighting relative to the underlying tissues. Fractional anisotropy (FA) reflects the coherence of white matter fibers in the normal brain and is also orientationally invariant. On the other hand, DTI-derived parameters axial and radial diffusivity reflect directionally-dependent diffusion properties. Axial diffusivity (AD), also commonly called longitudinal diffusivity, represents the diffusivity along the fastest diffusion direction within each voxel. Radial diffusivity (RD), also commonly called transverse diffusivity, represents the diffusivity averaged perpendicular to axial diffusivity. It is important to note that in coherent white matter fibers, such as the corpus callosum or in the spinal cord, these parameters reliably reflect the fiber organization, with AD coinciding parallel to the axonal fiber tracts. However, it is also noted that in voxels with high degrees of dispersion or multiple intersecting fiber bundles, AD and RD no longer coincide with the underlying axons, and their interpretation in ambiguous. Moreover, while DTI is unable to resolve intra- and extra-cellular biological water “compartments”, its role in interpreting intra-axonal and extra-axonal diffusion properties are discussed throughout, since these have implications for understanding the relationship between DWI and DTI measurements and the pathophysiology in acute neurological injury.
In this review, the use of DWI to assess the effects of acute neurological injury will be summarized with an emphasis on the relationship between these changes and the underlying pathophysiology. We particularly focus on injuries with relatively sudden onsets, including acute cerebral ischemia, spinal cord injury, traumatic brain injury, and peripheral nerve injury. For each injury, the role of biophysical modelling, animal experiments, and human findings will be reviewed. The scope of the review is aimed at providing the reader with a critical view of the commonalities and differences in the pathophysiology of nervous system injury and how it relates to the detection and interpretation of DWI findings. A section on outlook and future directions will guide efforts to improve the sensitivity and specificity of DWI using advanced modelling and non-traditional diffusion encoding strategies.
Section snippets
DWI in acute cerebral ischemia
In 1990, Mosely et al. first demonstrated that MRI contrast sensitized to diffusion was uniquely reflective of acute stroke [2]. The ischemic lesion appeared hyperintense on diffusion weighted imaging within several minutes of the insult whereas the lesion was invisible with T2-weighted contrast, yielding a decrease in ADC by approximately one-half compared to the surrounding healthy brain tissue. It has become an integral part of the clinical management of stroke and its use in diagnosis of
Biophysical mechanisms
Spinal cord injury is caused by a physical insult most often the consequence of trauma from falls or motor vehicle accidents. Compared to ischemia, in which T2-weighted changes do not typically manifest early after injury, the acutely injured spinal cord exhibits prominent hyperintensity on T2-weighted imaging. Consequently, T2-weighting MRI is the modality of choice for clinical diagnosis. The T2 hyperintensity is due to both cytotoxic and vasogenic edema and may be accompanied by hemorrhage.
DWI in acute traumatic brain injury
TBI is caused by a physical insult to the brain through mechanical forces, causing a wide range of injury to the neuronal and vascular systems. TBI has a broad range of severity and manifestation of clinical symptoms that varies from severe, penetrating TBI to mild TBI or concussion. Despite numerous reports of the utility of DTI to identify individual (Fig. 3) and group differences across the severity spectrum of TBI, DTI has yet to be shown to be robust and useful as a clinical marker of
Biophysical mechanisms
DTI of the peripheral nerves has been explored to investigate the consequences of acute nerve injury or neuropathy (Fig. 4). Compared to central nervous system axons, axons of peripheral nerves exhibit somewhat different pathological time courses after injury. For instance, in an optic nerve injury, which is a part of the central nervous system, formation of axonal varicosities started within 30 min to an hour after the injury, and continued to evolve while the axon continued to disintegrate
Discussion
DWI is an accepted diagnostic tool for cerebral ischemia and it is available in most acute care settings. Its success is, in part, due to its unique sensitivity to detect injured brain tissue that remains invisible on other MRI contrasts. The biophysics underlying the abrupt ADC decreases are intimately related to cell swelling in which neurite beading is compatible with the observational and experimental findings. Further experiments to concretely implicate beading or other features would be
Acknowledgements
MDB acknowledges support from the Craig H. Neilsen Foundation and the U.S. Department of Veterans Affairs. NPS acknowledges support from the National Institutes of Health and the Medical Scientist Training Program. All animal procedures were approved by the Institutional Animal Care and Use Committees at the Medical College of Wisconsin and Clement J Zablocki VA Medical Center and were performed in accordance with the relevant guidelines and regulations.
References (126)
- et al.
Changes in diffusion parameters, energy-related metabolites and glutamate in the rat cortex after transient hypoxia/ischemia
Neurosci. Lett.
(2006) - et al.
Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation
Neurobiol. Dis.
(1996) - et al.
Cation-chloride cotransporters and neuronal function
Neuron
(2009) - et al.
Modeling axonal injury in vitro: injury and regeneration following acute neuritic trauma
J. Neurosci. Methods
(2000) - et al.
Comprehensive locomotor outcomes correlate to hyperacute diffusion tensor measures after spinal cord injury in the adult rat
Exp. Neurol.
(2012) - et al.
Longitudinal assessment of white matter pathology in the injured mouse spinal cord through ultra-high field (16.4 T) in vivo diffusion tensor imaging
NeuroImage
(2013) - et al.
Sensitivity and specificity of in vivo diffusion-weighted MRI in acute spinal cord injury
J. Clin. Neurosci.
(2010) - et al.
Diffusion tensor MR imaging in spinal cord injury
Injury
(2017) - et al.
Diffusion kurtosis as an in vivo imaging marker for reactive astrogliosis in traumatic brain injury
NeuroImage
(2012) - et al.
Quantitative MRI predicts long-term structural and functional outcome after experimental traumatic brain injury
NeuroImage
(2009)
Longitudinal changes in the DTI measures, anti-GFAP expression and levels of serum inflammatory cytokines following mild traumatic brain injury
Exp. Neurol.
Dendritic alterations after dynamic axonal stretch injury in vitro
Exp. Neurol.
Multi-modal MRI of mild traumatic brain injury
NeuroImage Clin.
The first week after concussion: blood flow, brain function and white matter microstructure
NeuroImage Clin.
Visualization of peripheral nerve degeneration and regeneration: monitoring with diffusion tensor tractography
NeuroImage
Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia
NeuroImage
Evolving Wallerian degeneration after transient retinal ischemia in mice characterized by diffusion tensor imaging
NeuroImage
Diffusion tensor imaging of symptomatic nerve roots in patients with cervical disc herniation
Acad. Radiol.
The basis of anisotropic water diffusion in the nervous system – a technical review
NMR Biomed.
Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats
AJNR Am. J. Neuroradiol.
Evidence-based guideline: the role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
Neurology
Fixed negative charge and the Donnan effect: a description of the driving forces associated with brain tissue swelling and oedema
Philos. Trans. Roy. Soc. A
Factors governing diffusing molecular signals in brain extracellular space
J. Neural Transm.
Time-dependent diffusion of water in a biological model system
PNAS
Evaluation of extra- and intracellular apparent diffusion in normal and globally ischemic rat brain via 19F NMR
Magn. Reson. Med.
Evaluation of intracellular diffusion in normal and globally-ischemic rat brain via 133Cs NMR
Magn. Reson. Med.
Separating changes in the intra- and extracellular water apparent diffusion coefficient following focal cerebral ischemia in the rat brain
Magn. Reson. Med.
Cs + ADC in rat brain decreases markedly at death
Magn. Reson. Med.
Changes in the diffusion of water and intracellular metabolites after excitotoxic injury and global ischemia in neonatal rat brain
J. Cereb. Blood Flow Metab.
Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic resonance microscopy
Stroke
Insignificance of active flow for neural diffusion weighted imaging: a negative result
Magn. Reson. Med.
Neurite beading is sufficient to decrease the apparent diffusion coefficient after ischemic stroke
PNAS
Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines
J. Neurosci.: J. Soc. Neurosci.
Chloride cotransporters as a molecular mechanism underlying spreading depolarization-induced dendritic beading
J. Neurosci.: J. Soc. Neurosci.
A biophysical model for cytotoxic cell swelling
J. Neurosci.: J. Soc. Neurosci.
Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke
Neuropharmacology
Histopathologic correlates of abnormal water diffusion in cerebral ischemia: diffusion-weighted MR imaging and light and electron microscopic study
Radiology
Comparison of diffusion- and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats
Magn. Reson. Med.
Oscillating gradient measurements of water diffusion in normal and globally ischemic rat brain
Magn. Reson. Med.
Non-Gaussian diffusion imaging for enhanced contrast of brain tissue affected by ischemic stroke
PloS One
Biexponential diffusion attenuation in various states of brain tissue: implications for diffusion-weighted imaging
Magn. Reson. Med.
Water diffusion compartmentation at high b values in ischemic human brain
AJNR Am. J. Neuroradiol.
How does water diffusion in human white matter change following ischemic stroke?
Magn. Reson. Med. Sci.
Stroke assessment with diffusional kurtosis imaging
Stroke
Reduction of diffusion-weighted imaging contrast of acute ischemic stroke at short diffusion times
Stroke
A recoverable state of axon injury persists for hours after spinal cord contusion in vivo
Nat. Commun.
Complex geometric models of diffusion and relaxation in healthy and damaged white matter
NMR Biomed.
Detection of acute nervous system injury with advanced diffusion-weighted MRI: a simulation and sensitivity analysis
NMR Biomed.
Simulation of changes in diffusion related to different pathologies at cellular level after traumatic brain injury
Magn. Reson. Med.
MRI characterization of diffusion coefficients in a rat spinal cord injury model
Magn. Reson. Med.
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