Alterations in the Temporal Variation and Spatial Distribution of Blood-Brain Barrier Permeability Following Electromagnetic Pulse Radiation: A Study Based on Dynamic Contrast-Enhanced MRI

Abstract

Background: Previous studies have suggested that electromagnetic pulse (EMP) can induce openings in the blood-brain barrier (BBB). However, the temporal variation and spatial distribution of BBB permeability after EMP radiation are difficult to assess using conventional histopathological approaches. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a valuable tool for the in vivo evaluation of BBB permeability. The main purpose of this study was to investigate the temporal variation and spatial distribution of BBB permeability after EMP radiation in rats using DCE-MRI.

Methods: The dose of EMP was estimated through simulations utilizing a digital rat model comprising 16 distinct brain regions. Then, the changes in BBB permeability of the different rat brain regions at different time points (3 h and 24 h) after EMP radiation were evaluated using quantitative DCE-MRI. Furthermore, the spatial difference in BBB permeability was assessed 3 h after exposure. Finally, the dose-effect relationship between the electric field strength and the BBB permeability was also investigated.

Results: The results demonstrated that the changes in the values of volume transfer constant (ΔK^trans) significantly increased in several rat brain regions at 3 h after 400 kV/m EMP radiation. These changes vanished 24 h after exposure. Meanwhile, no significant spatial differences in BBB permeability were observed after EMP radiation. Moreover, Pearson's correlation analysis showed that there was a significant positive linear relationship between BBB permeability and the electric field strength within an external electric field strength range of 0 to 400 kV/m at 3 h after EMP radiation.

Conclusions: EMP radiation can induce a reversible increase in BBB permeability in rats. Moreover, no significant differences in BBB permeability were found across different brain regions. Additionally, the degree of BBB permeability was positively correlated with the regional electric field strength of EMP radiation within an external electric field strength range of 0 to 400 kV/m at 3 h after EMP radiation. These results indicate the promising potential of employing EMP for transient openings in the BBB, which could facilitate clinical pharmacological interventions via drug delivery into the brain.

Keywords: blood–brain barrier; dynamic contrast-enhanced magnetic resonance imaging; electromagnetic pulse; permeability; rat.

Figure 1

(A) The EMP radiation settings; (B) the experimental timeline.

Figure 2

Digital model construction and electric field strength simulation. (A) Schematic diagram of the digital model of EMP radiation. The top view (upper left), front view (upper right), side view (lower left), and perspective view (lower right) of the physical model of the EMP radiation source are shown. The rat was positioned in a prone position within the EMP radiation source. (B) The digital model of the rat brain with 16 independent brain regions, illustrating the relative positions of the cingulate cortex, motor cortex, somatosensory cortex, parietal cortex, retrosplenial cortex, visual cortex, cerebellum, orbital cortex, insular cortex, auditory cortex, temporal cortex, perirhinal cortex, striatum, hippocampus, amygdala, and entorhinal cortex. (C) The simulation results of the electric field distributions in different axial slices of the rats under EMP radiation, with peak external electric field strengths of 100 kV/m and 400 kV/m. The different electric field strengths in rats are indicated by pseudo-colors, and each electric field distribution map ranges from 0 to 15 kV/m. (D) The simulation results of the average electric field intensities in various brain regions under EMP radiation with different peak electric field strengths.

Figure 3

Comparison of the ΔK^trans values in each brain region of the rats among the Sham, EMP100, and EMP400 groups at 3 h after EMP radiation. (A–P) Comparisons of the ΔK^trans values in the 16 brain regions of the rats 3 h after EMP radiation, respectively. One-way ANOVA, followed by Tukey’s HSD post hoc tests, was used to compare the ΔK^trans in each brain region of the rats among the Sham, EMP100, and EMP400 groups. The p-values of one-way ANOVA were adjusted using the Benjamini–Hochberg FDR. For the post hoc test, compared with the Sham group, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001; compared with the EMP100 group, ^# indicates p < 0.05, and ^## indicates p < 0.01.

Figure 4

Comparison of the Δv_e values in each brain region of the rats among the Sham, EMP100, and EMP400 groups 3 h after EMP radiation. (A–P) Comparisons of the Δv_e values in the 16 brain regions of the rats 3 h after EMP radiation, respectively. One-way ANOVA, followed by Tukey’s HSD post hoc tests, was used to compare the Δv_e in each brain region of the rats among the Sham, EMP100, and EMP400 groups. The p-values of one-way ANOVA were adjusted using the Benjamini–Hochberg FDR. For the post hoc test, compared with the Sham group, * indicates p < 0.05.

Figure 5

Comparison of the ΔK^trans values in each brain region of the rats among the Sham, EMP100, and EMP400 groups 24 h after EMP radiation. (A–P) Comparisons of the ΔK^trans values in the 16 brain regions of the rats 24 h after EMP radiation, respectively. One-way ANOVA, followed by Tukey’s HSD post hoc tests, was used to compare the ΔK^trans in each brain region of the rats among the Sham, EMP100, and EMP400 groups. The p-values of one-way ANOVA were adjusted using the Benjamini–Hochberg FDR.

Figure 6

Comparison of the Δv_e values in each brain region of the rats among the Sham, EMP100, and EMP400 group 24 h after EMP radiation. (A–P) Comparisons of the Δv_e values in the 16 brain regions of the rats 24 h after EMP radiation, respectively. One-way ANOVA, followed by Tukey’s HSD post hoc tests, was used to compare the Δv_e in each brain region of the rats among the Sham, EMP100, and EMP400 groups. The p-values of one-way ANOVA were adjusted using the Benjamini–Hochberg FDR.

Figure 7

Comparison of the ΔK^trans and Δv_e values in the different brain regions of the rats 3 h after EMP irradiation. (A,C,E) show comparisons of the ΔK^trans values 3 h after EMP radiation in the different brain regions of the rats among the Sham group, EMP100 group, and EMP400 group, respectively. (B,D,F) show comparisons of the Δv_e values 3 h after EMP radiation in the different brain regions of the rats among the Sham group, EMP100 group, and EMP400 group, respectively. Paired t-tests were used to compare the ΔKtrans and Δve among the different brain regions in each group. The p-values of the paired t-tests were adjusted using the Benjamini–Hochberg FDR.

Figure 8

Results of the linear regression analysis between the regional electric field strength in the rat brain E in the rat brain and the ΔK^trans value and Δv_e value 3 h after EMP radiation. (A) The linear relationship between the E value and the corresponding ΔK^trans value within an external electric field strength range of 0 to 400 kV/m at 3 h after EMP radiation (r = 0.8859, p < 0.0001). (B) The linear relationship between the E and the corresponding Δv_e value within an external electric field strength range of 0 to 400 kV/m at 3 h after EMP radiation (r = 0.8811, p < 0.0001). Pearson’s correlation analysis was carried out to investigate the relationship between the E values and the corresponding ΔK^trans and Δv_e values of all brain regions in the rats. The linear regression equations were obtained by linear regression analysis. E represents the regional electric field strength in the rat brain.