Non-invasive and sensitive MRI assessment of radiation-induced cognitive dysfunction via voxel-based morphological and functional connectivity.

Background: Radiotherapy inevitably cause cognitive dysfunction. We aim to explore a non-invasive, sensitive strategy for assessing radiation-induced cognitive dysfunction, using voxel-based morphometry (VBM) and functional connectivity (FC), and to clarify the potential mechanisms from behavioral, histological, and molecular perspectives.

Methods: We employed a multimodal cross-validation strategy to evaluate cognitive dysfunction of C57BL/6j mice exposed to a single dose of 5 Gy or 15 Gy using a Co γ radiation source. The open field, novel object recognition, and Morris water maze tests were conducted on days 18, 19, and 21 after radiation, respectively, followed by fMRI scanning on day 27. VBM and FC analysis are used to assess cognitive function impairment after radiation. Histopathological analyses (HE and Nissl staining) and immunohistochemical assessments of neural damage markers (Iba-1 and GFAP) were conducted.

Results: The radiation group (5 Gy, 15 Gy) showed an increased escape latency, decreased number of platform crossings, and no difference in exploration preference for old versus new objects. In the radiation group, the arrangement of neurons in the hippocampal DG region was disordered, and a significant reduction of Nissl bodies was observed. The expression of Iba1 (in CA1, CA2, and CA3 regions) and GFAP (in CA1 and CA3 regions) was increased after radiation. The levels of pro-inflammatory factors such as IFN-gamma and IL-1beta were increased in the hippocampal tissue, while the expression of anti-inflammatory factors (IL-4 and IL-10) were decreased. The brain region with increased gray matter volume in the 5 Gy group was the right hippocampal DG region. Functional connectivity values were increased between 24 pairs of hippocampal subregions, such as CA1.R and DG-mo.L, while decreased between 29 pairs, such as CA3.R and ENTl1.R in the 5 Gy group. In the 15 Gy group, functional connectivity values increased between 31 pairs, such as DG-mo.L and HATA.R, and decreased between 20 pairs, such as CA2.R and DG-po.L. Compared to the 5 Gy group, the 15 Gy group had 33 pairs with increased functional connectivity values and 23 pairs with decreased values.

Conclusion: Functional magnetic resonance imaging can non-invasively and more efficiently assess cognitive function impairment in the brain after radiation doses using VBM and FC comparative methods. This provides new insights into the evaluation of cognitive function with non-invasive and sensitive methods.