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Cited by 131Glioma Diagnosis and TreatmentElectromagnetic Fields and Biological EffectsUltrasound and Hyperthermia Applications

Predicting the electric field distribution in the brain for the treatment of glioblastoma

Open access
Miranda, Pedro C, Mekonnen, Abeye, Salvador, Ricardo, Basser, Peter J·2014·Physics in Medicine and Biology
DOI 10.1088/0031-9155/59/15/4137PMC PMC4137229
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Abstract

The use of alternating electric fields has been recently proposed for the treatment of recurrent glioblastoma. In order to predict the electric field distribution in the brain during the application of such tumor treating fields (TTF), we constructed a realistic head model from MRI data and placed transducer arrays on the scalp to mimic an FDA-approved medical device. Values for the tissue dielectric properties were taken from the literature; values for the device parameters were obtained from the manufacturer. The finite element method was used to calculate the electric field distribution in the brain. We also included a 'virtual lesion' in the model to simulate the presence of an idealized tumor. The calculated electric field in the brain varied mostly between 0.5 and 2.0 V cm( - 1) and exceeded 1.0 V cm( - 1) in 60% of the total brain volume. Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces. These increases were strongest near the ventricles but were also present outside the tumor's necrotic core and in some parts of the gray matter-white matter interface. The electric field values predicted in this model brain are in reasonably good agreement with those that have been shown to reduce cancer cell proliferation in vitro. The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties. This could explain some of the variability in treatment outcomes. The proposed modeling framework could be used to better understand the physical basis of TTF efficacy through retrospective analysis and to improve TTF treatment planning.

AI snapshot

Written from the paper’s full text.

TL;DR

Using an MRI-derived finite element head model with scalp transducer arrays mimicking the NovoTTF device, this study predicts the electric field distribution in the brain during tumor treating fields for glioblastoma. The field is highly non-uniform, mostly 0.5–2.0 V/cm, exceeds 1.0 V/cm in 60% of brain volume, and depends strongly on tissue geometry and conductivity.

Key findings

  • At 200 kHz and 100 mA per active transducer, the calculated electric field in the brain varied mostly between 0.5 and 2.0 V/cm and exceeded 1.0 V/cm in 60% of total brain volume; 40% of the brain exceeded 1 V/cm in both left-right and anterior-posterior array configurations.
  • Local field enhancement (“hotspots”) occurred near interfaces between tissues with different conductivities where the field was perpendicular to the interface; increases were strongest near the ventricles, and also appeared outside the tumor’s necrotic core and at some gray matter–white matter interfaces.
  • In a virtual lesion model, the field was very low in the necrotic core, lower on average in the tumor shell than in contralateral white matter, but increased near the two “poles” and reduced around the “equator”; this directional effect was more pronounced in the left-right configuration.
  • Average electric field under all transducer arrays was 5.1 V/cm in scalp and 31 V/cm in skull; corresponding SAR values were 81 W/kg and 77 W/kg, and average SAR in the brain cuboid regions defined by the array pairs was 1.6 W/kg.

Methods

  • A realistic head model was created from MRI data and segmented into scalp, skull, cerebrospinal fluid, gray matter, and white matter. Two pairs of 3×3 transducer arrays were placed on the scalp: left-right temporal/parietal and anterior-posterior supraorbital/back-of-head. Transducers were ceramic disks 1 mm high and 9 mm radius, with center separations of 22 mm and 33 mm, and conductive gel 0.5–2 mm thick.
  • A “virtual lesion” of two concentric spheres was placed in white matter near a lateral ventricle, representing a necrotic core surrounded by a 3 mm-thick active tumor shell; inner and outer diameters were 1.4 cm and 2.0 cm.
  • The finite element method was used under the electro-quasistatic approximation to solve Laplace’s equation at 200 kHz, with 100 mA impressed current per active transducer (200 mA peak-to-peak). Tissues were assumed isotropic, with conductivity and relative permittivity values taken from the literature; calculations were performed for left-right active and anterior-posterior active configurations.

Limitations

  • The paper states uncertainty in the electric properties used, which could affect calculated field values, and notes that white matter anisotropy was not included; future work is planned to incorporate DTI-derived anisotropic conductivity and to perform sensitivity analyses for conductivity and tissue thickness.
  • The model uses an idealized virtual tumor and does not represent peritumoral edema, deformed ventricles, or real patient tumors; the paper states that patient-specific models could provide more accurate maps.
  • The paper notes little information is available on tumor conductivity at around 200 kHz. Evident from the text: results come from a single realistic head model with literature-derived “typical” tissue values, so inter-subject anatomical and dielectric variability is not captured.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1088/0031-9155/59/15/4137

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 17 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the brain, the calculated electric field varied mostly between 0.5 and 2.0 V/cm.

    “The calculated electric field in the brain varied mostly between 0.5 and 2.0 V/cm and exceeded 1.0 V/cm in 60% of the total brain volume.”
    Quote in the paperSubstantial claim
  • Findingown data

    The electric field distribution is highly non-uniform.

    “The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties.”
    • Also stated in: § CONCLUSION · plain
      “The distribution is highly nonuniform and depends on tissue geometry and dielectric properties, which could explain some of the variability in treatment outcomes.”
    Quote in the paperSubstantial claim
  • Findingown data

    Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces.

    “Regions of local field enhancement occurred near interfaces between tissues with different conductivities wherever the electric field was perpendicular to those interfaces.”
    Quote in the paperSubstantial claim
  • Findingown data

    The calculated electric field exceeded 1.0 V/cm in 60% of the total brain volume.

    “The calculated electric field in the brain varied mostly between 0.5 and 2.0 V/cm and exceeded 1.0 V/cm in 60% of the total brain volume.”
    Quote in the paperSubstantial claim
  • Findingown data

    The electric field distribution depends on tissue geometry and dielectric properties.

    “The electric field distribution is highly non-uniform and depends on tissue geometry and dielectric properties.”
    • Also stated in: § CONCLUSION · plain
      “The distribution is highly nonuniform and depends on tissue geometry and dielectric properties, which could explain some of the variability in treatment outcomes.”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingown data

    The local field increases were also present outside the tumor's necrotic core and in some parts of the gray matter-white matter interface.

    “These increases were strongest near the ventricles but were also present outside the tumor’s necrotic core and in some parts of the gray matter-white matter interface.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Near interfaces that are perpendicular to the applied electric field, the field is increased in the low conductivity tissue and decreased in the high conductivity region.

    “Also, near interfaces that are perpendicular to the applied electric field, the field is increased in the low conductivity tissue and decreased in the high conductivity region.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The average electric field values under all transducer arrays were 5.1 V/cm in the scalp and 31 V/cm in the skull.

    “The average electric field values under all transducer arrays were 5.1 V/cm in the scalp and 31 V/cm in the skull, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Electric field hotspots can occur far from the arrays, giving rise to a complex spatial distribution.

    “Also, electric field hotspots can occur far from the arrays, giving rise to a complex spatial distribution (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the tumor shell, the field is far from uniform: it is increased in the vicinity of the two poles where the applied electric field is perpendicular to the spherical surface, and it is reduced around the equator.

    “However, directional effects come into play here, too, and the field in the shell is far from uniform: in both configurations, it is increased in the vicinity of the two “poles” where the applied electric field is perpendicular to the spherical surface, and it is reduced around the “equator”.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The corresponding SAR values were 81 W/kg in the scalp and 77 W/kg in the skull.

    “The corresponding SAR values were 81 W/kg and 77 W/kg.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The magnitude of the electric field is lower in GM than in WM because GM conductivity is higher than that of WM.

    “For example, the magnitude of the electric field is lower in GM than in WM because its conductivity is higher than that of WM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The directional field effect is also present at WM-GM interfaces with the appropriate orientation relative to the applied electric field, but is smaller because the ratio of the conductivities of the two tissues is closer to 1.

    “It is also present at WM-GM interfaces with the appropriate orientation relative to the applied electric field. In this case, the effect is smaller because the ratio of the conductivities of the two tissues is closer to 1.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    WM is anisotropic as its conductivity depends on fiber orientation.

    “However, WM is anisotropic as its conductivity depends on fiber orientation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    There is some uncertainty in the electric properties used in this study, which could affect the calculated electric field values.

    “It should be noted that there is some uncertainty in the electric properties used in this study, which could affect the calculated electric field values.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The electromagnetic wavelength in the different tissue types is much larger than the size of the head, so the electro-quasistatic approximation of Maxwell's equations applies.

    “The electromagnetic wavelength in the different tissue types is much larger than the size of the head (15–150 m vs 0.2 m) and so the electro-quasistatic approximation of Maxwell’s equations applies (Haus and Melcher, 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Haus and Melcher, 1989

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The mean conductivity of WM is lower than that of GM by a factor of about 2.

    “It is also generally accepted that the mean conductivity of WM is lower than that of GM, by a factor of about 2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For purely resistive tissues, the secondary field depends only on the ratio of the conductivities of the two adjacent tissues, and is proportional to the strength of the normal component of the applied electric field.

    “For purely resistive tissues, the secondary field depends only on the ratio of the conductivities of the two adjacent tissues, and is proportional to the strength of the normal component of the applied electric field (Miranda et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miranda et al., 2007 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    No significant temperature increase is expected in the brain due to heat dissipation in the tissue.

    “No significant temperature increase is expected in the brain due to heat dissipation in the tissue.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Tumors close to the ventricles may be exposed to higher electric fields, as will superficial tumors close to a transducer.

    “For example, tumors close to the ventricles may be exposed to higher electric fields, as will superficial tumors close to a transducer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The non-uniformity of the electric field could lead to different treatment outcomes depending on the position of the tumor relative to different tissue interfaces, and to the transducers.

    “This non-uniformity of the electric field could lead to different treatment outcomes depending on the position of the tumor relative to different tissue interfaces, and to the transducers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    TTF could potentially target GBM cells selectively while leaving normal brain cells relatively unaffected because GBM cells divide rapidly while other brain cells divide infrequently.

    “Because GBM cells divide rapidly while other brain cells divide infrequently, the rationale of using TTFs is that they could potentially target GBM cells selectively while leaving normal brain cells relatively unaffected.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The presence of a tumor, peritumoral edema, and, in some cases, deformed ventricles, is expected to alter the electric field distribution substantially.

    “However, the presence of a tumor, peritumoral edema, and, in some cases, deformed ventricles, is expected to alter this distribution substantially.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    The figures presented in this study and the considerations outlined in this section give a reasonable characterization of the electric field distribution in the brain during a TTF treatment.

    “The figures presented in this study and the considerations outlined in this section give a reasonable characterization of the electric field distribution in the brain during a TTF treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because the electric field in the brain is not uniform, tumor size will influence the effective electric field over the whole tumor and therefore represents another potential source of variability of the treatment outcome.

    “Because the electric field in the brain is not uniform, tumor size will influence the effective electric field over the whole tumor and therefore represents another potential source of variability of the treatment outcome, in addition to tumor location and to heterogeneity effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The effect of an alternating electric field on membrane polarization is expected to diminish for frequencies greater than 10 kHz, given that the neural membrane time constant is about 100 μs or greater.

    “Since the neural membrane time constant is about 100 μs (Barker et al., 1991) or greater, the effect of an alternating electric field on membrane polarization is expected to diminish for frequencies greater than 10 kHz.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Barker et al., 1991

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Haematological adverse effects greater than grade 2 only affected 3% of TTF patients in the clinical trial, probably because the marrow in other bones was unaffected.

    “Nonetheless, haematological adverse effects greater than grade 2 only affected 3% of TTF patients in the clinical trial (Stupp et al., 2012), probably because the marrow in other bones was unaffected.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Stupp et al., 2012

      Not checked in the free run.

22 of 22

  • The authors state this as an assumption.

    The tissues in the head model are isotropic.

    “The tissues were assumed to be isotropic and the values for the electrical conductivity (σ) and relative permittivity (εr) at 200 kHz were estimated from the literature:”

  • The paper relies on this without support.

    No physics-based models exist to predict the electric field and current distributions in the scalp, skull, cerebrospinal fluid, and brain parenchyma produced by a TTF-generating medical device.

    “To date, however, there have been no physics-based models to predict the electric field and current distributions in the scalp, skull, cerebrospinal fluid, and brain parenchyma produced by a TTF-generating medical device.”

  • The paper relies on this without support.

    The core and edematous regions of glioblastoma have higher conductivities than normal tissue, whereas the high cellularity region has a lower conductivity.

    “The core and the edematous regions are likely to have higher conductivities than normal tissue whereas the high cellularity region may have a lower conductivity.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Either-configuration label uses an undefined LP configuration

    Minor

    The paper defines the two array configurations as LR and AP, but labels the volume exposed in either configuration as "LR+LP." The label is inconsistent with the stated configurations.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Barker A T, 1991, Electroencephalogr. Clin. Neurophysiol. Suppl., 43, 227
  2. Miranda P C, 2013, ISMRM

Cited by

Sorted by citations

Related

Authors
Miranda, P. C., Mekonnen, A., Salvador, R., & Basser, P. J.
Affiliations
  • University of Lisbon (PT)
  • National Institutes of Health (US)
Corresponding author
Miranda, Pedro C
ORCID
Venue
Physics in Medicine and Biology
Publisher
IOP Publishing
Published
2014-07-08
Volume
59
Issue
15
Pages
4137-4147
ISSN
  • 0031-9155 (ISSN-L)
  • 1361-6560
DOI
10.1088/0031-9155/59/15/4137
PMC
PMC4137229
OpenAlex
W2136891515
Semantic Scholar
d97c816ffda973fc60548ce0f614f31d48a45fd8
Cited by
131
References
45
Citations by year
2026: 4 · 2025: 9 · 2024: 12 · 2023: 9 · 2022: 12 · 2021: 15 · 2020: 10 · 2019: 12 · 2018: 10 · 2017: 10 · 2016: 16 · 2015: 11
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Physics in Medicine and Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • European Commission (222079)
  • Ministry of Science and Technology, Croatia
  • National Institutes of Health
  • Fundação para a Ciência e a Tecnologia
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD000268)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
Keywords
tumor treating fields, glioblastoma, electric field distribution, finite element analysis, realistic head model, tissue dielectric properties, transducer array, virtual lesion, treatment planning, recurrent glioblastoma
MeSH terms
Brain, Electricity, Glioblastoma, Humans, Models, Neurological, Brain Waves, Transcranial Direct Current Stimulation

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