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Low-intensity focused ultrasound Reverses Cisplatin-Induced Cognitive Impairment in Rats: Behavioral and DTI Evidence
Xiaowei Han1, Jiahuan Liu1, Xisong Zhu1, and Jiangong Zhang2
1Department of Radiology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China, 2Department of Nuclear Medicine, The First people’s Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, China

Synopsis

Keywords: DWI/DTI/DKI, Diffusion Tensor Imaging

Motivation: Cisplatin-Induced cognitive impairment, resulting from chemotherapeutic agents, is typically addressed through pharmacological treatments absent of effective rehabilitation therapy.

Goal(s): Aim to investigate the therapeutic efficacy of Low-Intensity Focused Ultrasound (LIFUS), with a specific emphasis on the hippocampus, using an established animal model.

Approach: We scrutinized the behavioral and cerebral alterations in rats with cisplatin chemotherapy, utilizing pre- and post-treatment behavioral phenotypes and diffusion weighted imaging (DTI) with a 9.4T MRI scanner.

Results: Our findings revealed significant differences in indicators of biological behavior and DTI across specific brain regions in the LIFUS-treated group, suggesting that LIFUS holds potential in reversing brain damage.

Impact: Our research helps to understand brain plasticity changes after LIFUS treatment with cisplatin chemotherapy, providing the theoretical support for future clinical intervention in chemotherapy related cognitive impairment.

Introduction

The global population of cancer patients and survivors who have successfully undergone chemotherapy is witnessing a steady annual increase. A prevalent issue among these survivors is Chemotherapy-Related Cognitive Impairment (CRCI), which is frequently linked to the use of platinum-based chemotherapeutic drugs. Low-intensity Focused Ultrasound (LIFUS) has recently been recognized as a powerful tool for non-invasively modulating brain structure and functional activity, aligning with the modern direction in non-invasive neuromodulation strategies. However, there remains a research void regarding the mechanism through which LIFUS impacts the plasticity in key brain regions affected by cognitive deficits related to platinum-based chemotherapy. Further exploration using animal models is warranted. Consequently, we propose to utilize LIFUS to target neuromodulatory interventions to hippocampal brain regions in a rat model of cognitive impairment related to platinum-based drug chemotherapy. The effectiveness of this method will be validated through behavioral assays and magnetic resonance imaging studies.

Materials and Methods

Sixty-four Sprague Dawley rats were randomly segregated into four groups: the model group (E group), the sham treatment group (FE group), the healthy control group (H group), and the LIFUS treatment group (T group). Rats in the E, FE, and T groups received cisplatin injections, while the H group received normal saline injections. Treatment was initiated in the ninth week post drug administration, with Morris water maze, novel position and object recognition tests, and 9.4T brain DTI conducted on each group two weeks before and after the treatment. The software packages Graphpad Prism 9 (Version 9.4.0) and Adobe Illustrator 2022 (Version 2022) were utilized for data analysis, graphing, and ensemble organization respectively. Further, the fractional anisotropy (FA), mean diffusion (MD), axial diffusion (AD), and radial diffusion (RD) were extracted from each subregion of the hippocampus-inner olfactory cortex based on the SIGMA template, to be used as Regions of Interest (ROIs) for subsequent analysis. Differences between groups in behavioral tests and DTI results were examined, and neuroimaging markers were extracted based on magnetic resonance imaging.

Results

Our study demonstrated that rats undergoing cisplatin chemotherapy displayed significant cognitive impairments. These were primarily identified through behavioral changes such as a decrease in the time spent in the target quadrant, a reduction in the number of platform crossings, and an increase in escape latency. However, these indicators exhibited varying degrees of improvement following the administration of LIFUS treatment, suggesting its therapeutic impact (Figure 1). Furthermore, these rats demonstrated a diminished ability to recognize novel substances. Treatment with LIFUS partially reversed these cognitive deficits. The extraction of rat brain regions was conducted using a 3D pulse-coupled neural network (PCNN), which generated brain masks for further image alignment processing (Figure 2). In the H group, only FA values in certain brain regions dentate gyrus (DG) and internal olfactory cortex exhibited an increase. The E group showed an increase in MD, AD, or RD values in several brain regions (inner olfactory cortex, CA1, CA2, CA3, and Sub regions). Comparisons of FA, MD, AD and RD values in the FE group before and after treatment did not reveal statistically significant differences (Figure 3). However, certain brain regions (inner olfactory cortex, CA2, DG and PAS regions) in the T group showed decreases in MD, AD or RD values, indicating potential therapeutic effects of LIFUS (Figure 4).

Discussion And Conclusion

In the H group, an increase in FA values was observed in certain brain regions, such as the DG and internal olfactory cortex in this study. This could potentially indicate a more mature development of the rat brain, leading to increased myelin integrity in these regions. In contrast, the E group showed an increase in MD, AD, or RD values in several brain regions, including the inner olfactory cortex, CA1, CA2, CA3, and subregions. This suggests a progression of damage in these brain regions due to the effects of cisplatin. Interestingly, certain brain regions in the treatment group - namely the inner olfactory cortex, CA2, DG, and PAS regions - showed decreases in MD, AD, or RD values. This suggests an improvement in these regions, indicating the potential therapeutic effects of LIFUS. Overall, these findings provide valuable insights for future research on the treatment of cognitive impairments associated with chemotherapy. Furthermore, they lay a feasible neurobiology foundation for the development of subsequent noninvasive targeted therapies.

Acknowledgements

We sincerely thank Renyuan Liu (Department of Radiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School) for his help in the subregion’s extraction of hippocampus and calculation. Supported by funding from the 2021 National Natural Science Foundation of China（No.82171908）.

References

1. Wang B, Chen MX, Chen SC, et al. Low-Intensity Focused Ultrasound Alleviates Chronic Neuropathic Pain-Induced Allodynia by Inhibiting Neuroplasticity in the Anterior Cingulate Cortex. Neural Plast. 2022, 2022:6472475.

2. Wang X, Huang W, Su L, et al. Neuroimaging advances regarding subjective cognitive decline in preclinical Alzheimer's disease. Mol Neurodegener. 2020, 15(1):1-27.

Figures

Figure 1. Between-group comparisons of behavioral indicators before and after LIFUS treatment.

Figure 2. SIGMA template-based subregions of the hippocampus-inner olfactory cortex as ROIs for further extraction of FA, MD, AD & RD values (CA1，Cornu Ammonis 1；CA2，Cornu Ammonis 2；CA3，Cornu Ammonis 3；DG，Dentate Gyrus；PAS，Parasubiculum；Pre，Presubiculum；Sub，Subiculum；EC，Entorhinal Cortex；LEC，Lateral Entorhinal Cortex；LEC-I，Lateral Entorhinal Cortex Internal part；LEC-E，Lateral Entorhinal Cortex external part；MEC，Medial Entorhinal Cortex).

Figure 3. Between-group comparison of FA, MD, AD, and RD values before and after treatment in the sham treatment group.

Figure 4. Between-group comparison of FA, MD, AD, and RD values before and after treatment in the LIFUS treatment group.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
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DOI: https://doi.org/10.58530/2024/0111