Advanced magnetic resonance (MR) neuroimaging modalities are becoming more available and useful as their value in the diagnosis and prognosis of central nervous system diseases is more fully understood and studied. Specifically, diffusion tensor imaging (DTI) has become increasingly studied and utilized in recent years and has become incorporated by many radiologists into routine clinical practice with most research performed on traumatic brain injury. DTI is a variant of diffusion-weighted imaging (DWI) which utilizes a tissue water diffusion rate for image production. The first application of DWI to the human brain was performed in 1986 and since has become the gold standard for detecting acute stroke.[1] DTI does not require contrast and is available on almost all modern MR scanners with relatively quick scan times for this sequence.[2]

Random thermal motion, also known as Brownian motion, is water molecular diffusion in three-dimensional space. Isotropy is defined as uniformity in all directions and when applied to water molecules, isotropy occurs when the diffusion of water is entirely uninhibited (such as water movement in a glass of water). Anisotropy is when there is a directionality in the diffusion of water present, and the movement of water is no longer random (such as water movement along straws placed in a glass). The greater the anisotropy; the more directional and linear the diffusion of water molecules. Water molecules will diffuse differently through space depending on the tissue type, components, structure, architecture, and integrity; these principles allow clinically significant imaging to occur, particularly the DTI. The latter measures movement of water along axons, analogous to the straws in a glass of water.

As early as May of 2002, medical literature reported that DTI showed abnormalities in patients who suffered from mild brain trauma as compared to normal control subjects. “This study included five patients with mild traumatic brain injury (three men and two women) and ten volunteers with no known neurological disorders (five men and five women).” This study reported abnormalities in the patients with a mild brain injury that were absent in the control subjects or the uninvolved sides of the injured patients' brains: “Patients displayed a significant reduction of diffusion anisotropy in several regions compared with the homologous ones in the contralateral hemisphere. Such differences were not observed in the control subjects. Significant reduction of diffusion anisotropy was also detected when diffusion tensor results from the patients were compared with those of the controls.”[3]

DWI uses volume elements (voxels) as a statistical method for data collection. When a voxel contains scalar values constituting a vector, it is known as a tensor, which is where DTI received its name and explains the additional information provided through DTI.[4] DTI MR settings can measure the diffusion of water along an axon in many directions, 6, 9, 33, and 90 directions are typical parameters used, with 33 directions and above increasing confidence in the accuracy. Ninety directions typically require upwards of 20 additional minutes in the MR scanner, therefore, it may not be suitable for routine clinical practice. In effect, DTI will provide an indirect method of assessing neuroanatomy structure on a microscopic level using water molecules’ degree of anisotropy and structural orientation within a voxel. Therefore, the principal application for DTI is in the imaging of white matter, where the orientation, location, and anisotropy of the tracts can be measured and evaluated. The architecture of the axons in parallel bundles and their myelin sheaths facilitate the diffusion of the water molecules preferentially along their main direction.

There are a number of measures calculated using DTI that can provide quantitative power. One of the most widely used DTI measures is fractional anisotropy (FA).[5] Others include mean diffusivity or apparent diffusion coefficient (ADC), radial (perpendicular) diffusivity, and axial (parallel) diffusivity. DTI uses mean diffusivity for the rate of molecular diffusion, FA for the summative direction of the diffusion which provides a prominent vector, axial diffusivity for the rate of diffusion parallel to the main vector, and radial diffusivity for the rate of diffusion perpendicular to the main vector.

FA quantifies the directionality of diffusivity in a summative manner and is highly sensitive to change in microstructure, however, it can unspecific to the cause of change. Mean diffusivity quantifies cellular and membrane density whereas an increase in mean diffusivity indicates disease processes such as edema or necrosis. Radial diffusivity quantifies myelin neuropathology and increases with demyelination. Axial diffusivity quantifies axonal degeneration and increases with brain maturation.[6][7]

FA values are a numerical value, based on the anisotropy of water along the axon, which reflects the health of the axon. Abnormal FA values indicate axonal damage. FA values can be calculated utilizing the region of interest (ROI) method, whole-brain analysis (Voxel-Based analysis), or tract-based spatial statistics. The whole-brain analysis is gaining popularity due to its automation and ability to analyze more tracts. ROI method, where the regions to be analyzed are traced by a technologist and then analyzed by a computer, remains reliable and replicable.[8][9][10][11] One of the more common and standardized ROI methods is the segmented corpus callosal values.[12][13][14] Being the largest axonal tract in the brain, damage to the corpus callosum is well described following head trauma and other pathologies.[15]

FA values can vary depending on which of the above three analyzing methods is used and other factors such as MR technique and type of post-processing performed.[5] Utilizing a standardized technique, FA values are highly reproducible and are not technologist dependent and can be subjectively interpreted by a radiologist as well as roughly compared to select values in the literature.

Pediatric normal values are slightly less than those of adults. However, most changes occur by age 5, and 90% of adult FA values are achieved by 11 years of age in the corpus callosum.[16] After adulthood, FA values tend to decrease with age linearly.

Additionally, FA values comparison across different scanners is now possible, even if those scanners are utilizing different techniques. This is achieved using ‘human phantom phenomena’ where a single subject is scanned on two different scanners, enabling a comparison between scanners by a scaling factor, or even to normative databases performed on a different scanner(s).[17][18]

3D reconstructions of the tensor tracts are accomplished with computer modeling and can beautifully illustrate the fiber tracts, identify pathology, and aid neurosurgeons. (Figure 1 illustrates a normal DTI 3D reconstruction on the right as compared to the image on the left showing diffuse frontal lobe injury and global brain injury in a patient with prominent bilateral frontal contusions)

DTI is generally sensitive but has a lower specificity. Specificity can be increased by combining the interpretation of DTI with the clinical history and the other findings on conventional imaging.

Artifacts and Noise

Artifacts are seen in all modalities of imaging including submodalities of magnetic resonance imaging (MRI) and have many causes. Artifacts can result in misinterpretation of imaging findings if the radiologist is unaware of these artifacts. With a thorough understanding of artifacts associated with DTI, measures should be taken to decrease the artifacts and to become more aware of unavoidable artifacts.

A limitation of DTI is that it currently has a low signal to noise ratio (SNR), which may increase scanning times. SNR compares the level of background noise to the level of the signal obtained. When the noise is too great in comparison to the signal (low SNR), image quality is poor. Two ways to improve on this signal to noise ratio is to either increase scan times or reduce image resolution.[19] Long scan times can result in patient motion artifact which also can cause artifact.

Voxels continue to decrease in size, but a current limitation in DTI is the size of voxels. Low anisotropy shown in a particular voxel may seem to represent unorganized tissue contained within. However, this may just be apparent and what actually lies within the particular voxel is multiple anisotropic structures orientated in multiple directions resulting in isotropy. This means that diffusion anisotropy will only show on DTI when all structures coursing a voxel align on a microscopic (microstructure, myelin sheath, protein filaments) and macroscopic (axons and dendrites) scale. In the cortex, low FA occurs because of macroscopic disorganization. As image resolution improves, the cortex will likely show higher patterns of anisotropy.

Other causes resulting in artifacts can include eddy currents and motion. Changing data acquisition methods can help decrease these artifacts.[20]

Acceptance

DTI has now moved beyond research investigation and is becoming incorporated into routine clinical practice. However, some have urged caution in the interpretation of DTI and other advanced imaging sequences at the individual level, including a 9/13/18 Radiological Society of North America (RSNA) guideline statement.[21][22] A minority of studies have not found a relationship between DTI and mild traumatic brain injury, although the majority of the literature is supportive.[23] Given the different techniques in performing DTI, and the wide variety of applications, this caution is well taken. However, if the interpreting radiologist has experience in DTI and has developed a standardized, replicable technique concordant with the literature, and particularly if a trauma database or normative database is available, these valid criticisms become moot, and DTI can be interpreted in individual patients. This approach has backing in the literature and studies performed on individual patients demonstrate reproducibility and accuracy in diagnosing individual patients with traumatic brain injury (TBI).[24][25][26] Specifically, DTI is most powerful when interpreted in concert with the clinical history and other findings on conventional imaging. The most comprehensive peer review article on TBI and DTI concluded:

"Despite significant variability in sample characteristics, technical aspects of imaging, and analysis approaches, the consensus is that DTI effectively differentiates patients with TBI and controls, regardless of the severity and timeframe following injury. Furthermore, many have established a relationship between DTI measures and TBI outcomes."[5]

DTI has proven to be highly sensitive to brain injury and a variety of pathological conditions and in many instances is becoming a routine part of clinical practice. Further research will continue to expand the application of DTI in evaluating neurological conditions.

Although much of the research on DTI has been in traumatic brain injury, other applications include aid in diagnosis, prognosis, and classifications of stroke, brain tumors, neurodegenerative diseases, developmental disorders, neuropsychiatric disorders, movement disorders, and neurogenetic developmental disorders.[27] The following topics are a few examples of described uses of DTI.

Traumatic Brain Injury/Diffuse Axonal Injury

Diffuse axonal injury (DAI) can be seen in traumatic brain injury. Diffuse axonal injury is diffuse brain injury damage to axonal microstructures and can potentially appear normal on traditional CT and MRI when there is an absence of macroscopic tissue disruption. Additionally, if there are macroscopic findings of DAI on computed tomography (CT) or MRI, it indicates poorer outcomes. A predominance of published literature on DTI is about diffuse axonal injury its close correlation with decreased FA values throughout specified regions of the brain. The clinical effectiveness of DTI has been compared to control subjects for validation in various scenarios involving the use of MRI to help diagnose a brain injury. There are numerous peer-reviewed and case-control studies in the medical literature allowing for individual evaluations of brain-injured patients using DTI. The comparison of cases (patients with a history of traumatic brain injury) and controls (no history of traumatic brain injury) utilizing DTI is an accepted methodology and standard technique utilized in order to demonstrate the clinical utility of DTI in adding incremental diagnostic information to structural MRI, multimodal MR studies, other imaging modalities, and the clinical condition.[28][29][30][31][23] Additionally, peer-reviewed articles on DTI and TBI have demonstrated regional associations between findings on conventional imaging and FA values and 3D DTI (as demonstrated at our centers in Figure 1).[32]

Carbon Monoxide (CO) Poisoning

DTI has utility for studying the brains of patients after CO poisoning.[33] The peer-reviewed literature supports the use of DTI for identifying and longitudinally monitoring the changes in the brain that can occur secondary to CO poisoning.[34] DTI has been shown to demonstrate the evolution of white matter injury in CO encephalopathy progression over months and to correlate with neuropsychological deficits.[35]

DTI has also demonstrated evidence of demyelination with abnormal FA values in the central nervous system of patients who develop chronic neurological symptoms in the subacute phase after CO intoxication.[36] A decrease in FA values correlates with clinically observed neurological symptoms and, conversely, improvement in FA values may parallel improvement in the neurological condition.[37]

Hypoxic Brain Injury

A recent 2018 multicenter review article demonstrated DTI might be more predictive of neurologic outcome than conventional MRI in patients with cardiac arrest and hypoxic brain injury.[38]

Demyelination/Dysmyelination

As the brain develops, diffusivity is found to decline particularly in the direction that myelination would be oriented. Damage to the myelin sheath affects diffusivity.[39] DTI has been used in multiple sclerosis to monitor disease progression and correlate with clinical status.[40] Suggestions are that radial diffusivity is a promising biomarker.[41]

Neoplasia

The application of DTI in instances of neoplasia is used mostly for surgical planning. With DTI and tractography, a more in-depth layout of neuroanatomy and specific eloquent white matter tracts can be seen allowing a neurosurgeon to plan precise surgical approaches to minimize damage to the critical tracts and preserving vital functions such as motor capabilities, language, and vision. DTI has even been used intraoperatively to compensate for shifting tissue to minimize complications.

Another application of DTI in neoplasia is using FA values. Correlations have been found between FA values and cell density. In neoplasia with high cell proliferation and density such as glioblastomas, higher FA values have been reported.

Some neoplastic disease requires radiation and DTI has found that FA decreases in areas targeted by radiation. By observing the changes of FA in the anatomy, it can potentially be used to monitor the dose distribution.

Epilepsy

The addition of the DTI sequence to the routine MRI protocol has been found to be of advantage in specific pediatric patient groups with temporal lobe epilepsy or for the planning of epilepsy surgery.[42]

Fetus/Neonate Imaging

A relatively new limb of DTI research has been showing correlations between DTI findings and developmental neuropathology in a fetus or neonate. Discovering the utility of DTI in fetuses and neonates has been hopeful for a field that has limited diagnostic imaging options.[43]

Extracranial DTI Applications

Additional DTI applications include imaging of peripheral nerves, including the brachial plexus.[44] Spinal cord DTI imaging has also demonstrated promising results.[45]

White Matter Tractography and Future Research

Using the assumption that diffusion anisotropy represents white matter bundles, these bundles of aligned voxels can be parcellated, providing a 3D map of white matter bundle tracts. Fiber tracking or reconstruction by starting with a voxel and propagating forward following the anisotropic path until encountering isotropy is also known as tractography and can give insight into brain connectivity. Further study and mapping of these tracts, in conjunction with fMRI, resting state, and other MRI submodalities remain exciting cutting edge research.[46] DTI remains in the research stage regarding neuropsychological conditions such as autism and ADHD.[47][48]