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. 2019 Aug 14;5(8):eaau9309.
doi: 10.1126/sciadv.aau9309. eCollection 2019 Aug.

Reduction of Intratumoral Brain Perfusion by Noninvasive Transcranial Electrical Stimulation

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Free PMC article

Reduction of Intratumoral Brain Perfusion by Noninvasive Transcranial Electrical Stimulation

G Sprugnoli et al. Sci Adv. .
Free PMC article

Abstract

Malignant brain neoplasms have a poor prognosis despite aggressive treatments. Animal models and evidence from human bodily tumors reveal that sustained reduction in tumor perfusion via electrical stimulation promotes tumor necrosis, therefore possibly representing a therapeutic option for patients with brain tumors. Here, we demonstrate that transcranial electrical stimulation (tES) allows to safely and noninvasively reduce intratumoral perfusion in humans. Selected patients with glioblastoma or metastasis underwent tES, while perfusion was assessed using magnetic resonance imaging. Multichannel tES was applied according to personalized biophysical modeling, to maximize the induced electrical field over the solid tumor mass. All patients completed the study and tolerated the procedure without adverse effects, with tES selectively reducing the perfusion of the solid tumor. Results potentially open the door to noninvasive therapeutic interventions in brain tumors based on stand-alone tES or its combination with other available therapies.

Figures

Fig. 1
Fig. 1. Experimental design.
(A) Patients underwent a clinical MRI to define and characterize the brain tumor, including standard and gadolinium-enhanced T1w [CET1w (contrast-enhanced T1w)], T2w, fluid-attenuated inversion recovery (FLAIR), ASL, and resting-state T2-BOLD (blood oxygenation level–dependent) MRI [rs-fMRI (resting-state functional MRI)] images. Regions of interest (ROIs) were defined by parcellating the solid component and the necrotic core of the tumor (MTX in this example) using CE T1w sequences and the edema surrounding the tumor by using FLAIR images. (B) Conductivity values were assigned to each ROI as well as to healthy brain tissue according to existing literature (bottom), and then the E-field distribution of current was calculated (top). (C) The personalized multielectrode solution maximizing the E-field on the solid-edema interface was selected. The experimental session was planned 3 to 5 days preceding the surgical intervention, and multichannel tES was performed inside the MRI scanner by means of an MRI-compatible brain stimulation device. The stimulation session included the acquisition of (i) T1w, FLAIR, ASL, and rs-fMRI sequences before tES; (ii) rs-fMRI and ASL during tES; and (iii) FLAIR images after tES. (D) Roughly 1 week after the presurgery MRI, patients underwent neurosurgery with subsequent histological classification and immediate postsurgery computerized tomography (CT) acquisition. (E) Last, approximately 1 month after neurosurgery, selected patients underwent a new MRI acquisition and ROI segmentation to perform a second MRI-tES session (F), aimed at evaluating the safety and feasibility of applying tES after neurosurgery. Additional modeling based on CT scan was performed to account for the effects of skull defects created by craniotomy (see also Fig. 3). This was crucial to ensure safety and to study/quantify changes in electric field distribution in the presence of skull defects. Note: All images are presented in neurological convention (right = right).
Fig. 2
Fig. 2. Tumor tracing, modeling, and optimization.
(A) MRI images were manually segmented by two independent investigators. Following the Response Assessment in Neuro-Oncology recommendations, the solid part (red) of the tumor (GBM in this example) as well as the necrotic core (blue) were identified on CET1w images. The edema (green) of the tissue surrounding the tumor was segmented using FLAIR images. In the postsurgery phase, T2 Turbo Spin Echo (TSE) scans were used to correctly identify the vacuum created by the surgical intervention. ROIs were manually segmented on the corresponding anatomical scan using MRIcro software and 3D Slicer. ROIs were concentric, with the edema ROI usually including both solid and necrotic parts, while the solid tumor ROI included the necrotic one, such as currently done for planning of radiation therapy. (B) Top: Conductivity values were assigned to each ROIs as well as to healthy brain tissue according to existing literature: gray matter (GM) and white matter (WM), cerebrospinal fluid (CSF), skin, and skull. Bottom: A multielectrode solution maximizing stimulation over the edema-solid tumor interface was identified for each patient, with the corresponding E-field distribution calculated on patients’ head models. Resulting E-field was overlaid onto individual anatomical T1w scans, showing specificity of the tES solution targeting the solid tumor (C). (D) In detail, the T1w MRI of the participant was segmented into multiple tissue classes using MARS, SPM-8 segmentation toolbox, and FreeSurfer (left). Models of PITRODE electrodes (cylinders, 1-cm radius) were placed on scalp positions corresponding to the international 10/10 electroencephalography (EEG) system (green circles, center). A genetic algorithm [Stimweaver (12)] was then used to estimate the best multielectrode solution among those possible using 32 positions on the scalp (center), with the final personalized tES montage including up to eight electrodes placed over the hemisphere ipsilateral to the tumor (right). Note: All images are presented in neurological convention (right = right).
Fig. 3
Fig. 3. Postsurgical modeling.
(A) Structural MRI and CT images were used to model the impact of tES after surgery (shown: complete resection of a GBM). Ad hoc ROIs and three-dimensional (3D) renderings were created for both skull breaches and metallic clips that could respectively influence current shunting and affect electrode positioning. (B) New tissue conductivity values were derived by assigning skull defects a conductivity equal to that of the CSF (left), and the amount of current (i.e., E-field) shunting through them was estimated (right). (C) A new multielectrode stimulation solution was implemented to maximize stimulation over the resection borders, showing high spatial specificity and control of induced E-field. (D) In detail, new geometries of the different head tissues (healthy ones and ROIs) were computed after surgery, leading to a new optimized montage maximizing the current on the surgical borders. Note: All images are presented in neurological convention (right = right).
Fig. 4
Fig. 4. Safety.
FLAIR images acquired before and immediately after tES did not show significant changes in the edema, as shown for two representative patients with GBM at the presurgery (A) as well as postsurgery stimulation sessions (B). Note: Image constrast was manually adjusted to highlight edema borders. All images are presented in neurological convention (right = right).
Fig. 5
Fig. 5. Perfusion changes.
(A) Significant reduction in WM-corrected CBF (wmCBF = normalized CBF) was observed in the solid tumor during stimulation for both patients with GBM and MTX (−26 and − 45%, respectively; mean decrease = −36%, *P < 0.001), as compared with no changes in the edema (P < 0.328) and necrotic core (P < 0.294). absCBF, absolute CBF. (B) Control ROIs in the contra- and ipsilateral hemispheres to each tumor did not show significant changes in CBF. Note: y axis = normalized CBF calculated as: absolute CBF (ml/100 g per minute)/contralateral WM’s CBF (ml/100 g per minute).

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