Matthew M. Cheung

Does diffusion kurtosis imaging lead to better neural tissue characterization? A rodent brain maturation study

Diffusion kurtosis imaging (DKI) can be used to estimate excess kurtosis, which is a dimensionless measure for the deviation of water diffusion profile from Gaussian distribution. Several recent studies have applied DKI to probe the restricted water diffusion in biological tissues. The directional analysis has also been developed to obtain the directionally specific kurtosis. However, these studies could not directly evaluate the sensitivity of DKI in detecting subtle neural tissue alterations. Brain maturation is known to involve various biological events that can affect water diffusion properties, thus providing a sensitive platform to evaluate the efficacy of DKI. In this study, in vivo DKI experiments were performed in normal Sprague-Dawley rats of 3 different ages: postnatal days 13, 31 and 120 (N=6 for each group). Regional analysis was then performed for 4 white matter (WM) and 3 gray matter (GM) structures. Diffusivity and kurtosis estimates derived from DKI were shown to be highly sensitive to the developmental changes in these chosen structures. Conventional diffusion tensor imaging (DTI) parameters were also computed using monoexponential model, yielding reduced sensitivity and directional specificity in monitoring the brain maturation changes. These results demonstrated that, by measuring directionally specific diffusivity and kurtosis, DKI offers a more comprehensive and sensitive detection of tissue microstructural changes. Such imaging advance can provide a better MR diffusion characterization of neural tissues, both WM and GM, in normal, developmental and pathological states.

Towards better MR characterization of neural tissues using directional diffusion kurtosis analysis

MR diffusion kurtosis imaging (DKI) was proposed recently to study the deviation of water diffusion from Gaussian distribution. Mean kurtosis, the directionally averaged kurtosis, has been shown to be useful in assessing pathophysiological changes, thus yielding another dimension of information to characterize water diffusion in biological tissues. In this study, orthogonal transformation of the 4th order diffusion kurtosis tensor was introduced to compute the diffusion kurtoses along the three eigenvector directions of the 2nd order diffusion tensor. Such axial (K(//)) and radial (K( upper left and right quadrants)) kurtoses measured the kurtoses along the directions parallel and perpendicular, respectively, to the principal diffusion direction. DKI experiments were performed in normal adult (N=7) and formalin-fixed rat brains (N=5). DKI estimates were documented for various white matter (WM) and gray matter (GM) tissues, and compared with the conventional diffusion tensor estimates. The results showed that kurtosis estimates revealed different information for tissue characterization. For example, K(//) and K( upper left and right quadrants) under formalin fixation condition exhibited large and moderate increases in WM while they showed little change in GM despite the overall dramatic decrease of axial and radial diffusivities in both WM and GM. These findings indicate that directional kurtosis analysis can provide additional microstructural information in characterizing neural tissues.

MR diffusion kurtosis imaging for neural tissue characterization.

In conventional diffusion tensor imaging (DTI), water diffusion distribution is described as a 2nd‐order three‐dimensional (3D) diffusivity tensor. It assumes that diffusion occurs in a free and unrestricted environment with a Gaussian distribution of diffusion displacement, and consequently that diffusion weighted (DW) signal decays with diffusion factor (b‐value) monoexponentially. In biological tissue, complex cellular microstructures make water diffusion a highly hindered or restricted process. Non‐monoexponential decays are experimentally observed in both white matter and gray matter. As a result, DTI quantitation is b‐value dependent and DTI fails to fully utilize the diffusion measurements that are inherent to tissue microstructure. Diffusion kurtosis imaging (DKI) characterizes restricted diffusion and can be readily implemented on most clinical scanners. It provides a higher‐order description of water diffusion process by a 2nd‐order 3D diffusivity tensor as in conventional DTI together with a 4th‐order 3D kurtosis tensor. Because kurtosis is a measure of the deviation of the diffusion displacement profile from a Gaussian distribution, DKI analyses quantify the degree of diffusion restriction or tissue complexity without any biophysical assumption. In this work, the theory of diffusion kurtosis and DKI including the directional kurtosis analysis is revisited. Several recent rodent DKI studies from our group are summarized, and DKI and DTI compared for their efficacy in detecting neural tissue alterations. They demonstrate that DKI offers a more comprehensive approach than DTI in describing the complex water diffusion process in vivo. By estimating both diffusivity and kurtosis, it may provide improved sensitivity and specificity in MR diffusion characterization of neural tissues. Copyright

B-value dependence of DTI quantitation and sensitivity in detecting neural tissue changes

Recently, remarkable success has been demonstrated in using MR diffusion tensor imaging (DTI) to characterize white matter. Water diffusion in complex biological tissue microstructure is not a free or Gaussian process but is hindered and restricted, thus contradicting the basic assumption in conventional DTI that diffusion weighted signal decays with b-value in a monoexponential manner. Nevertheless, DTI by far is still the fastest and most robust protocol in routine research and clinical settings. To assess the b-value dependence of DTI indices and evaluate their sensitivities in detecting neural tissues changes, in vivo DTI data acquired from rat brains at postnatal day 13, 21 and 120 with different b-values (0.5-2.5 ms/microm(2)) and 30 gradient directions were analyzed. Results showed that the mean and directional diffusivities consistently decreased with b-value in both white and gray matters. The sensitivity of axial diffusivity (lambda(//)) in monitoring brain maturation generally decreased with b-value whereas that of radial diffusivity (lambda( perpendicular)) increased. FA generally varied less with b-value but in a manner dependent of the age and tissue type. Analysis also revealed that the FA sensitivity in detecting specific tissue changes was affected by b-value. These experimental findings confirmed the crucial effect of b-value on quantitative DTI in monitoring neural tissue alterations. They suggested that the choice of b-value in conventional DTI acquisition can be optimized for detecting neural tissue changes but shall depend on the specific tissue type and its changes or pathologies targeted, and caution must be taken in interpreting DTI indices.

MRI of late microstructural and metabolic alterations in radiation‐induced brain injuries

To evaluate the late effects of radiation‐induced damages in the rat brain by means of in vivo multiparametric MRI.

In vivo retinotopic mapping of superior colliculus using manganese-enhanced magnetic resonance imaging.

The superior colliculus (SC) is a dome-shaped subcortical laminar structure in the mammalian midbrain, whose superficial layers receive visual information from the retina in a topological order. Despite the increasing number of studies investigating retinotopic projection in visual brain development and disorders, in vivo, high-resolution 3D mapping of topographic organization in the subcortical visual nuclei has not yet been available. This study explores the capability of 3D manganese-enhanced MRI (MEMRI) at 200 μm isotropic resolution for in vivo retinotopic mapping of the rat SC upon partial transection of the intraorbital optic nerve. One day after intravitreal Mn(2+) injection into both eyes, animals with partial transection at the right superior intraorbital optic nerve in Group 1 (n=8) exhibited a significantly lower T1-weighted signal intensity in the lateral region of the left SC compared to the left medial SC and right control SC. Partial transection toward the temporal or nasal region of the right intraorbital optic nerve in Group 2 (n=7) led to T1-weighted hypointensity in the rostral or caudal region of the left SC, whereas a clear border was observed separating 2 halves of the left SC in all groups. Previous histological and electrophysiological studies showed that the retinal ganglion cell axons emanating from superior, inferior, nasal and temporal retina projected respectively to the contralateral lateral, medial, caudal and rostral SC in rodents. While this topological pattern is preserved in the intraorbital optic nerve, it was shown that partial transection of the superior intraorbital optic nerve led to primary injury predominantly in the superior but not inferior retina and optic nerve. The results of this study demonstrated the sensitivity of submillimeter-resolution MEMRI for in vivo, 3D mapping of the precise retinotopic projections in SC upon reduced anterograde axonal transport of Mn(2+) ions from localized regions of the anterior visual pathways to the subcortical midbrain nuclei. Future MEMRI studies are envisioned that measure the topographic changes in brain development, diseases, plasticity and regeneration therapies in a global and longitudinal setting.

Functional MRI of postnatal visual development in normal and hypoxic-ischemic-injured superior colliculi.

The superior colliculus (SC) is a laminated subcortical structure in the mammalian midbrain, whose superficial layers receive visual information from the retina and the visual cortex. To date, its functional organization and development in the visual system remain largely unknown. This study employed blood oxygenation level-dependent (BOLD) functional MRI to evaluate the visual responses of the SC in normally developing and severe neonatal hypoxic-ischemic (HI)-injured rat brains from the time of eyelid opening to adulthood. MRI was performed to the normal animals (n=7) at postnatal days (P) 14, 21, 28 and 60. In the HI-injured group (n=7), the ipsilesional primary and secondary visual cortices were completely damaged after unilateral ligation of the left common carotid artery at P7 followed by hypoxia for 2 h, and MRI was performed at P60. Upon unilateral flash illumination, the normal contralateral SC underwent a systematic increase in BOLD signal amplitude with age especially after the third postnatal week. However, no significant difference in BOLD signal increase was found between P14 and P21. These findings implied the presence of neurovascular coupling at the time of eyelid opening, and the progressive development of hemodynamic regulation in the subcortical visual system. In the HI-injured group at P60, the BOLD signal increases in both SC remained at the same level as the normal group at P28 though they were significantly lower than the normal group at P60. These observations suggested the residual visual functions on both sides of the subcortical brain, despite the damages to the entire ipsilesional visual cortex. The results of this study constitute important evidence on the progressive maturation of visual functions and hemodynamic responses in the normal subcortical brain, and its functional plasticity upon neonatal HI injury.

BOLD fMRI investigation of the rat auditory pathway and tonotopic organization

Rodents share general anatomical, physiological and behavioral features in the central auditory system with humans. In this study, monaural broadband noise and pure tone sounds are presented to normal rats and the resulting hemodynamic responses are measured with blood oxygenation level-dependent (BOLD) fMRI using a standard spin-echo echo planar imaging sequence (without sparse temporal sampling). The cochlear nucleus (CN), superior olivary complex, lateral lemniscus, inferior colliculus (IC), medial geniculate body and primary auditory cortex, all major auditory structures, are activated by broadband stimulation. The CN and IC BOLD signal changes increase monotonically with sound pressure level. Pure tone stimulation with three distinct frequencies (7, 20 and 40 kHz) reveals the tonotopic organization of the IC. The activated regions shift from dorsolateral to ventromedial IC with increasing frequency. These results agree with electrophysiology and immunohistochemistry findings, indicating the feasibility of auditory fMRI in rats. This is the first fMRI study of the rodent ascending auditory pathway.

Somatosensory-evoked potentials as an indicator for the extent of ultrastructural damage of the spinal cord after chronic compressive injuries in a rat model

OBJECTIVE Somatosensory-evoked potentials (SEPs) were found to correlate well with the disability and postoperative recovery in patients with cervical spondylotic myelopathy. Yet the exact pathophysiology behind it remains to be elucidated. This study aims to characterise the ultrastructural changes of a chronically compressive spinal cord with various SEP responses in a rat model. METHODS A total of 15 rats were used with surgical implantation of a water-absorbing polymer sheet into the cervical spinal canal on the postero-lateral side, which expanded over time to induce chronic compression in the cord. At postoperative 6 months, the functional integrity of the cords was recorded by SEP responses by comparing injured and non-injured sides, and the ultrastructural integrity was assessed by 7-T magnetic resonance (MR) diffusion imaging, contrast-enhanced micro-computed tomography (μCT) and histological evaluations. RESULTS Six rats showed unchanged SEP, and the other nine showed decreased amplitude only (n=5) or delayed latency (n=4). The circulation insults of the cords were found among all the rats, showing central canal enlargement, intra-tissue bleeding or increased blood vessels in the central grey matter. Ultrastructural damage was noted in the rats with changed SEP responses, which was suggested by lower fractional anisotropy and higher contrast intensity radiologically and echoed by less myelin stain and cavitation changes histologically. In the animals with delayed latency, the cord showed significant loss of motoneurons as well as gross appearance distortion. CONCLUSIONS The categorised SEP responses by amplitude and latency could be an indicator for the extent of ultrastructural damage of the spinal cord after chronic compressive injuries. SIGNIFICANCE The findings built a solid foundation for SEP application in clinical diagnosis and prognostication of spinal cord injuries.

Advanced MR diffusion characterization of neural tissue using directional diffusion kurtosis analysis

MR Diffusion kurtosis imaging (DKI) was proposed recently to study the deviation of water diffusion from Gaussian distribution. Mean kurtosis (MK), directionally averaged kurtosis, has been shown to be useful in assessing pathophysilogical changes. However, MK is not sensitive to kurtosis change occurring along a specific direction. Therefore, orthogonal transformation of the 4th order kurtosis tensor was introduced in the current study to compute kurtoses along the 3 eigenvector directions of the 2nd order diffusion tensor. Such axial (K∥) and radial (K⊥) kurtoses measured the kurtoses along the directions parallel and perpendicular, respectively, to the principal diffusion direction. DKI experiments were performed in normal adult and formalin-fixed rat brain, and developmental brains. The results showed that directional kurtosis analysis revealed different information for tissue characterization.