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Quantitative UTE MRI of Demyelination in mTBI Mice Subject to Open-field Low-intensity Blast Injury

Yajun Ma¹, Qingbo Tang^1,2, Jiyo S Athertya¹, Xin Cheng^1,2, Roland Lee^1,2, Mingxiong Huang^1,2, Eric Y Chang^1,2, Catherine E Johnson³, Jiankun Cui⁴, Zezong Gu⁴, and Jiang Du^1,2,5
¹Radiology, UC San Diego, La Jolla, CA, United States, ²VA San Diego Healthcare System, La Jolla, CA, United States, ³Department of Explosive Engineering, Missouri University of Science and Technology, Rolla, MO, United States, ⁴Pathology and Anatomical Sciences, University of Missouri, Columbia, MO, United States, ⁵Bioengineering, UC San Diego, La Jolla, CA, United States

Synopsis

Keywords: Traumatic Brain Injury, Traumatic brain injury

Motivation: mTBI can lead to myelin damage, culminating in substantial cognitive function impairment. Yet, conventional neuroimaging methodologies often fall short in identifying abnormalities in a significant proportion of mTBI instances.

Goal(s): To assess the potential of UTE sequence in detecting demyelination in mTBI mice subject to an open-field LIB injury.

Approach: A new STAIR-UTE sequence was employed to study demyelination in mTBI mice subject to an open-field LIB injury at 3T.

Results: The STAIR-UTE measured MPFs in the corpus callosum region for the mTBI mice are significantly lower (8.5±0.4% vs. 8.8±0.4%; p-value = 0.0055) than those for the control mice.

Impact: STAIR-UTE sequence enables quantitative myelin imaging at 3T MRI, facilitating the detection of demyelination within the mouse brain's white matter following open-field LIB exposure. This innovative STAIR-UTE technique holds significant promise for in vivo mTBI diagnosis and treatment monitoring.

Introduction

Mild traumatic brain injury (mTBI) is a leading cause of long-term disability. The mechanical forces induced by both linear and rotational brain acceleration can result in severe damage in both axon and myelin sheath (1-3). Impairment of myelin can disrupt axonal transport, integrity, and plasticity, leading to a substantial speed reduction in signal transmission (4-6). Given its pivotal role in the development and maintenance of complex cognitive functions, demyelination may play a crucial role in mTBI pathogenesis. However, conventional neuroimaging techniques cannot accurately assess myelin and may not detect abnormalities in most mTBI cases (7-9). Ultrashort echo time (UTE) sequences enable the direct detection of myelin signals (10-15). Recent investigations have revealed myelin sheath abnormalities within corpus callosum (CC) of mice exposed to a low-intensity blast (LIB) in a well-established murine model of mTBI (16). These myelin irregularities were characterized by widespread instances of split layers, pronounced degeneration, myelin ballooning, myelin disruption, or myelin detachment at 7 days post-blast injury (DPI). In addition, these myelin disruptions demonstrated a return to their normal appearance by 30 days DPI, aligning with findings from related studies (16). In this study, we aim to assess the potential of a new 3D short TR adiabatic inversion recovery UTE (STAIR-UTE) sequence in detecting demyelination in mTBI mice subject to an open-field LIB injury (14-16).

Methods and Materials

Figure 1 shows the major features of the 3D STAIR-UTE sequence (14,15). In this study, the STAIR-UTE sequence was implemented on a 3T Bruker MRI system equipped with a gradient strength of 450 mT/m strength and a slew rate of 4200 T/m/s. Ensuring robust suppression of long T2 signals necessitates the utilization of a short TR in the STAIR-UTE sequence. Employing a short TR (e.g.,150 ms) guarantees effective suppression of the extensive spectrum of long T2 components with varying T1 values. The optimal TI is determined by numerical simulation (14).

The sequence parameters for 3D STAIR-UTE were set as follows: TR/TI=150/64.8ms, TE=0.015/1.6ms, field of view (FOV)=12×12×36mm³, resolution = 167×167×500µm³, flip angle (FA)=40º, number-of-spokes per TR=7, interspoke TR=4.4ms, bandwidth=50kHz, NEX=59, resulting in a total scan time of 5h42min. Additionally, a proton-density weighted UTE (PD-UTE) sequence was acquired in conjunction with STAIR-UTE to facilitate myelin proton fraction (MPF) quantification. The parameters for the proton-density weighted UTE sequence were TR=12ms, TE=0.015/1.6ms, FOV=12×12×36mm³, resolution=167×167×500µm³, FA=2º, bandwidth=50kHz, NEX=6, with a total scan time of 19min.

A total of 30 male C57BL/6 mice obtained from Jackson Laboratories, Bar Harbor, ME, and approximately 8 weeks of age, were included in this study in compliance with institutional guidelines. The mice were categorized into two groups, namely, the mTBI group (n=15) and the sham group (n=15). Two mice from each group were excluded from data analysis due to scanner malfunction. The mTBI group was subjected to a highly reproducible open-field LIB murine model as previously described (16). In this model, anesthetized mice were positioned prone, located at a distance of three meters from a 350g high-energy explosive C4 detonation (both 1 meter above ground) (Figure 2). One week following the blast procedures, the animals underwent MRI scanning.

Results and Discussion

Figure 3 shows the representative STAIR-UTE brain images at TE=0.015ms and TE=1.6ms from an adult control C57BL/6 mouse. The myelin signals in white matter regions are selectively imaged at the first echo but decay to near zero at the second echo, consistent with their short T2* relaxation times.

Figure 4 shows the representative STAIR-UTE and PD-UTE images as well as corresponding quantitative MPF maps from an adult control C57BL/6 mouse. The MPF values are much higher in white matter regions (e.g., CC) than those in grey matter regions.

Figure 5 shows representative brain MPF maps from a control mouse and an mTBI mouse as well as the summarized MPF measurements for CC in 13 controls and 13 mTBI. The measured MPF values in the body CC region for the mTBI mice are significantly lower (8.5±0.4% vs. 8.8±0.4%; p-value=0.0055) than those for the control mice.

Our results demonstrated the capability of the 3D STAIR-UTE technique for quantifying demyelination in mice subjected to open-field LIB injury-induced mTBI. Myelin staining for histological validation and behavioral assessments remain to be conducted or summarized to systematically compare the two groups of mice (normal vs. mTBI).

Conclusion

The 3D STAIR-UTE sequence enables quantitative myelin imaging in the murine brain using 3T MRI, facilitating the detection of demyelination within the mouse brain's white matter following open-field LIB exposure. This innovative STAIR-UTE technique holds significant promise for in vivo mTBI diagnosis and treatment monitoring.

Acknowledgements

The authors acknowledge grant support from National Institutes of Health (RF1AG075717), VA Research and Development Services (Merit Awards I01CX001388).

References

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Figures

Figure 1 3D STAIR-UTE sequence diagram. This sequence incorporates an adiabatic full passage (AFP) pulse to achieve the inversion of longitudinal magnetization primarily associated with long T2 water components, concurrently saturating signals from the shorter T2 myelin components. The TI is defined as the temporal interval between the center of the AFP pulse and the center of acquisition spokes. Data acquisition is carried out using a 3D radial UTE sequence with a TE of 20 µs. To enhance scanning efficiency, data acquisition is achieved through a series of UTE spokes within each TR.

Figure 2 Experimental setup for the murine model of mTBI induced by the open-field low-intensity blast (LIB) exposure. Anesthetized mice were positioned prone at a distance of three meters from a controlled detonation involving 350 grams of high-energy explosive C4, suspended at a height of 1 meter above ground level.

Figure 3 Representative STAIR-UTE brain images at TE = 0.015 ms (first two rows), and TE = 1.6 ms (last two rows, windowed 5X) from an adult control C57BL/6 mouse. The myelin signals in white matter regions are selectively imaged at the first echo but decay to near zero at the second echo, consistent with their short T2* relaxation times.

Figure 4 Representative STAIR-UTE (first row) and PD-UTE (second row) images as well as corresponding quantitative MPF maps (third row) from an adult control C57BL/6 mouse. The MPF values are much higher in white matter regions (e.g., corpus callosum (CC)) than those in grey matter regions.

Figure 5 Representative brain MPF maps from a control mouse (A) and an mTBI mouse (B) as well as bar plots of the summarized MPF measurements for 13 controls and 13 mTBI in the body part of the CC region (e.g., white matter region inside of the dashed rectangle in panel A) (C). The measured MPF values in the body CC region for the mTBI mice (MPF=8.5±0.4%) are significantly lower than those for the control mice (MPF=8.8±0.4%) (p-value = 0.0055). “**” in panel C indicates a p-value lower than 0.01.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)

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DOI: https://doi.org/10.58530/2024/1617