title: Detection of electroporation-induced membrane permeabilization states in the brain using diffusion-weighted MRI.
abstract: BACKGROUND
  Tissue permeabilization by electroporation (EP) is a promising technique to treat certain cancers. Non-invasive methods for verification of induced permeabilization are important, especially in deep-seated cancers. In this study we evaluated diffusion-weighted magnetic resonance imaging (DW-MRI) as a quantitative method for detecting EP-induced membrane permeabilization of brain tissue using a rat brain model.
  
  
  METHODS
  Fifty-four anesthetized Sprague-Dawley male rats were electroporated in the right hemisphere, using different voltage levels to induce no permeabilization (NP), transient membrane permeabilization (TMP), and permanent membrane permeabilization (PMP), respectively. DW-MRI was acquired 5 minutes, 2 hours, 24 hours and 48 hours after EP. Histology was performed for validation of the permeabilization states. Tissue content of water, Na+, K+, Ca2+, and extracellular volume were determined. The Kruskal-Wallis test was used to compare the DW-MRI parameters, apparent diffusion coefficient (ADC) and kurtosis, at different voltage levels. The two-sample Mann- Whitney test with Holm's Bonferroni correction was used to identify pairs of significantly different groups. The study was approved by the Danish Animal Experiments Inspectorate.
  
  
  CONCLUSIONS
  Results showed significant difference in the ADC between TMP and PMP at 2 hours (p<0.001) and 24 hours (p<0.05) after EP. Kurtosis was significantly increased both at TMP (p<0.05) and PMP (p<0.001) 5 minutes after EP, compared to NP. Kurtosis was also significantly higher at 24 hours (p<0.05) and 48 hours (p<0.05) at PMP compared to NP. Physiological parameters indicated correlation with the permeabilization states, supporting the DW-MRI findings. We conclude that DW-MRI is capable of detecting EP-induced permeabilization of brain tissue and to some extent of differentiating NP, TMP and PMP using appropriate scan timing.
authors.affiliation: Center for Experimental Drug and Gene Electrotransfer (CEDGE), Department of Oncology, University of Copenhagen, Herlev Hospital , Herlev , Denmark.
authors.forename: Faisal
authors.initials: F
authors.lastname: Mahmood
authors.forename: Rasmus H
authors.initials: RH
authors.lastname: Hansen
authors.forename: Birgit
authors.initials: B
authors.lastname: Agerholm-Larsen
authors.forename: Hanne
authors.initials: H
authors.lastname: Gissel
authors.forename: Per
authors.initials: P
authors.lastname: Ibsen
authors.forename: Julie
authors.initials: J
authors.lastname: Gehl
mesh_terms: D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology*; D004058:Diffusion; D038524:Diffusion Magnetic Resonance Imaging; D018274:Electroporation / Q000379:methods*; D045604:Extracellular Fluid; D008297:Male; D016011:Normal Distribution; D011188:Potassium / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D012964:Sodium; D011188:Potassium; D002118:Calcium