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Cited by 121Electromagnetic Fields and Biological EffectsGlioma Diagnosis and TreatmentUltrasound and Hyperthermia Applications

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study

Open access
Wenger, Cornelia, Salvador, Ricardo, Basser, Peter J, Miranda, Pedro C·2015·Physics in Medicine and Biology
DOI 10.1088/0031-9155/60/18/7339PMC PMC4628548
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Abstract

Tumor treating fields (TTFields) are a non-invasive, anti-mitotic and approved treatment for recurrent glioblastoma multiforme (GBM) patients. In vitro studies have shown that inhibition of cell division in glioma is achieved when the applied alternating electric field has a frequency in the range of 200 kHz and an amplitude of 1-3 V cm(-1). Our aim is to calculate the electric field distribution in the brain during TTFields therapy and to investigate the dependence of these predictions on the heterogeneous, anisotropic dielectric properties used in the computational model. A realistic head model was developed by segmenting MR images and by incorporating anisotropic conductivity values for the brain tissues. The finite element method (FEM) was used to solve for the electric potential within a volume mesh that consisted of the head tissues, a virtual lesion with an active tumour shell surrounding a necrotic core, and the transducer arrays. The induced electric field distribution is highly non-uniform. Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less. A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature. Comparing results to a previously developed head model suggests significant inter-subject variability. This modelling study predicts that during treatment with TTFields the electric field in the tumour exceeds 1 V cm(-1), independent of modelling assumptions. In the future, computational models may be useful to optimize delivery of TTFields.

AI snapshot

Written from the paper’s full text.

TL;DR

This computational FEM study predicts the electric field distribution in the brain during TTFields therapy using realistic head models with anisotropic brain-tissue conductivity. It finds that the average field in the tumour shell exceeds the therapeutic threshold of 1 V/cm in most circumstances, with anisotropy increasing tumour field strength by about 10% or less and inter-subject differences reaching about 50%.

Key findings

  • Incorporating anisotropic GM/WM conductivity increased the average electric field in the tumour shell to approximately 111% and 106% of the isotropic value for LR and AP arrays in the dM model, and to 106% and 102% for LR and AP in the vN model; average brain field was higher in the vN model and equal or lower in the dM model.
  • Sensitivity to tissue conductivity produced percentage differences between highest and lowest average field strengths of 37%–42% in brain tissues for vN and dM LR stimulation, and 59%–68% in the tumour shell across the four models; when only healthy-tissue variations were considered, the tumour-shell difference was 30%–34%. Permittivity changes altered average field strength by less than 2%, maximum field strength by less than 5%, and ATV1 by less than 4%.
  • Inter-subject comparison showed s2 average field values about 20% higher than s1 for LR stimulation, and in AP stimulation a 25% increase in parenchyma and 50% increase in tumour tissues; LR produced about 40% higher average tumour field than AP in s2 and about 80% higher in s1. The tumour shell of s2 exceeded 1 V/cm for both array setups, whereas s1 did not.
  • The average field in the tumour shell exceeded 1 V/cm for almost all considered dielectric-property variations; the lowest tumour-shell fields were 0.79 V/cm (dM) and 0.74 V/cm (vN) when high shell conductivity was used, and 0.97 V/cm (dM) and 0.93 V/cm (vN) without tumour-conductivity variation due to low skull conductivity.

Methods

  • Two realistic head models were used: s1 from prior T1/PD MRI of a healthy young male, and s2 from T1-, T2-, and DTI data of a 20-year-old healthy female (1-mm³ T1/T2; DTI 1.25 × 1.25 × 3.5 mm, b = 1000 s/mm², 20 directions). A virtual cystic tumour in the right hemisphere near a lateral ventricle and contained in WM was modelled as a 1.4 cm necrotic core within a 2.0 cm active shell; Optune-like transducer arrays were modelled as 3 × 3 ceramic discs of 9 mm diameter with conductive gel, producing a volume mesh of approximately 6.1 million degrees of freedom.
  • Dielectric properties at 200 kHz were taken from literature with standard, minimum, and maximum values. Anisotropic GM/WM conductivity tensors were estimated from DTI using SimNibs with direct mapping (dM) and volume-normalized (vN) methods. The electroquasistatic approximation was solved with Comsol Multiphysics FEM at 200 kHz, with active transducers modelled as 100 mA current sources.
  • Analyses compared isotropic versus anisotropic conductivity, performed sensitivity analyses for tissue conductivity and permittivity, and compared s1 and s2 using average and maximum electric field strength and above-threshold volumes (ATV1, ATV2, ATV3 for >1, >2, and >3 V/cm).

Limitations

  • Stated: the virtual lesion was placed in a healthy brain and tumour tissues were always modelled as isotropic; the model did not include an edema region around the tumour, and more complex head models with additional segmented structures already exist.
  • Stated: the study did not compare cystic and solid tumours, and more simulations with different virtual tumour and transducer array positions should be carried out; patient-specific modelling is currently time-consuming.
  • Evident from the text: the findings are based on only two computational head models and literature-derived dielectric values, with no direct in vivo validation beyond the single existing intracranial measurement cited; inter-subject variability conclusions are therefore limited by the small number of subjects.

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

Integrity signals

Registry

Crossref · 10.1088/0031-9155/60/18/7339

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less.

    “Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less.”
    Quote in the paperSubstantial claim
  • Findingown data

    The induced electric field distribution within the brain during TTFields is highly non-uniform.

    “The induced electric field distribution is highly non-uniform.”
    • Also stated in: § 1. Introduction · boosted
      “We have already shown that the electric field distribution within the brain induced by TTFields is highly non-uniform.”
    Quote in the paperSubstantial claim
  • Findingown data

    A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature.

    “A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature.”
    Quote in the paperSubstantial claim
  • Findingown data

    The field distributions are similar for the isotropic, vN anisotropic, and dM anisotropic models.

    “The results in figure 3 show that field distributions are similar for all three models.”
    Quote in the paperSubstantial claim
  • Findingown data

    The average and maximum electric field values as well as the three ATVs were similar or higher in the vN model compared to the dM model for almost all tissues.

    “One general finding was that the average and maximum electric field values as well as the three ATVs were similar or higher in the vN model compared to the dM model for almost all tissues.”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • Classified as probably not a substantial claim. 25

  • May combine two claims.

    Findingown data

    The reduction in ATV1 with increased scalp conductivity is more pronounced for the AP setup compared to the LR setup for the tumour shell, but not in the brain where the reductions for LR and AP are approximately the same.

    “Also note that the reduction is more pronounced for the AP setup compared to the LR setup (blue curves) for the tumour shell, but not in the brain where the reductions for LR and AP are approximately the same (figure 4, right).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The average value of the electric field in the brain is higher for the vN model and equal or lower for the dM model, in comparison to the isotropic model.

    “As expected from figure 3, the average value of the electric field in the brain is higher for the vN model and equal or lower for the dM model, in comparison to the isotropic model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The LR configuration induces higher ATV1 in the tumour shell than in the brain, whereas following AP stimulation a bigger volume of the GM, WM, and the cerebellum are exposed to a field strength higher than 1 V/cm.

    “The LR configuration induces higher ATV1 in the tumour shell than in the brain, whereas following AP stimulation a bigger volume of the GM, WM, and the cerebellum are exposed to a field strength higher than 1 V/cm.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the tumour shell the vN model curves are lower than the dM curves, whereas in the brain parenchyma the opposite is true.

    “In the tumour shell (left) the solid curves that correspond to the vN model are lower than the dotted dM curves, whereas in the brain parenchyma (right) the opposite is true.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The maximum values in the brain were even more affected than the average values and showed large differences for the dM, vN and isotropic conductivity values.

    “The maximum values in the brain were even more affected than the average values and showed large differences for the dM, vN and isotropic conductivity values.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the tumour shell, the average electric field is increased to approximately 111% of the isotropic value for the LR configuration and to 106% for the AP configuration in the dM model, and to 106% for LR and 102% for AP in vN model.

    “In the tumour shell, the average electric field is increased to approximately 111% of the isotropic value for the LR configuration and to 106% for the AP configuration in the dM model, and to 106% for LR and 102% for AP in vN model respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For dM, the mean conductivity is 0.175 S/m within the WM and 0.215 S/m within the GM, whereas the corresponding values in the vN model are 0.127 S/m and 0.252 S/m.

    “For dM, the mean conductivity is 0.175 S/m within the WM and 0.215 S/m within the GM, whereas the corresponding values in the vN model are 0.127 S/m and 0.252 S/m and thus are similar to the isotropic values.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The whole-brain average value of the trace of the conductivity tensor divided by 3 is 0.195 S/m in the dM model and 0.182 S/m in the vN model.

    “The average of all mean conductivity values within the whole brain is similar for the two methods, i.e., the whole-brain average value of the trace of the conductivity tensor divided by 3 is 0.195 S/m in the dM model and 0.182 S/m in the vN model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The vN mapping method produces lower variations within the average field strength values in the brain for varying GM conductivity and higher variations when the WM conductivity is changed.

    “The vN mapping method produces lower variations within the average field strength values in the brain for varying GM conductivity and higher variations when the WM conductivity is changed.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    vN values are slightly higher in the tumour.

    “with slightly higher vN values in the tumour”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    In the brain tissue, the effect of both GM and WM conductivity changes on the electric field is large, with always rapidly decreasing field for increasing conductivities.

    “In the brain tissue, the effect of both changes on the electric field is large, with always rapidly decreasing field for increasing conductivities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The percentage difference between mean conductivity values in GM and WM is only 21% in the dM method, but 66% in the vN model.

    “The percentage difference between mean conductivity values in GM and WM is only 21% in the dM method, but 66% in the vN model.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    dM values are slightly higher in the brain.

    “and slightly higher dM values in the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Changing the WM conductivity has a larger effect on the values obtained by the vN method, whereas alterations of GM conductivity have a greater effect on the dM model results.

    “Thus, changing the WM conductivity has a larger effect on the values obtained by the vN method, whereas alterations of GM conductivity have a greater effect on the dM model results.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The average electric field in the brain parenchyma (GM, cerebellum and WM) of s2 is 1.41 V/cm, and only 1.18 V/cm in s1.

    “the average electric field in the brain parenchyma (GM, cerebellum and WM) of s2 is 1.41 V/cm, and only 1.18 V/cm in s1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the tumour shell, the introduction of anisotropy leads to an increase in the average electric field strength by about 110% and 106% for the LR configuration and 106% and 102% for the AP configuration for dM and vN models respectively.

    “In the tumour shell, the introduction of anisotropy leads to an increase in the average electric field strength by about 110% and 106% for the LR configuration and 106% and 102% for the AP configuration for dM and vN models respectively.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The total brain volume of s1 is 1623 cm3 compared to 1474 cm3 in s2, which corresponds to 91% of s1's total brain volume.

    “the total brain volume of s1 is 1623 cm3 compared to 1474 cm3 in s2, which corresponds to 91% of s1's total brain volume.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The tumour itself has the same size, with a shell volume of 2.7 cm3 and a core volume of 1.4 cm3.

    “The tumour itself has the same size, with a shell volume of 2.7 cm3 and a core volume of 1.4 cm3.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The shapes of the two heads are somewhat different.

    “The shapes of the two heads are also somewhat different.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither the brain nor the tumour shell shows significant regions affected by more than 3 V/cm.

    “Neither the brain nor the tumour shell shows significant regions affected by more than 3 V/cm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the AP configuration, a 25% increase is observed in the parenchyma and a 50% increase in the tumour tissues.

    “This difference is even more pronounced in the AP configuration, where a 25% increase is observed in the parenchyma and a 50% increase in the tumour tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the tumour tissues the dM method leads to higher average electric field values and bigger ATVs.

    “On the contrary, in the tumour tissues the dM method leads to higher average electric field values and bigger ATVs (tables 2, 3).”
    Quote in the paperSubstantial claim

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

    Findingnone given

    The ATVs for s1 follow a similar trend.

    “The ATVs for s1 follow a similar trend.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LR stimulation produces higher average field values in the tumour tissues than the AP stimulation, being about 40% higher in s2 and about 80% higher in s1.

    “the LR stimulation produces higher average field values in the tumour tissues than the AP stimulation, being about 40% higher in s2 and about 80% higher in s1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The average and maximum field strength as well as the ATVs differ for the two models.

    “However, the average and maximum field strength as well as the ATVs differ for the two models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The volume-weighted average for AP and LR is 1.4 W/kg in s1 and 2.3 W/kg in s2.

    “The volume-weighted average for AP and LR is 1.4 W/kg in s1 and 2.3 W/kg in s2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The tumour shell of s2 under LR stimulation shows the highest ATV1 of 91%, which is considerably higher than the 73% of s1.

    “the tumour shell of s2 under LR stimulation shows the highest ATV1 of 91%, which is considerably higher than the 73% of s1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These values are 79 W/kg in the scalp and 88 W/kg in the skull of s2.

    “These values are 79 W/kg in the scalp and 88 W/kg in the skull of s2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In one model with a tumour of the same size and in the same hemisphere but with a more frontal and more inferior location, the average field strength when incorporating dM tensors for the cortical tissues leads to an increase to 102% of the isotropic value for the LR setup and to 110% for the AP setup when the transducers remain at the same locations, instead of 110% and 106%, respectively for the

    “in one of our models with a tumour of the same size and in the same hemisphere but with a more frontal and more inferior location (not shown here), the average field strength when incorporating dM tensors for the cortical tissues leads to an increase to 102% of the isotropic value for the LR setup and to 110% for the AP setup when the transducers remain at the same locations, instead of 110% and”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The field increase is very pronounced in the WM near the ventricles, particularly for the LR array configuration, but can also be observed within the tumour and in the WM near some parts of the GM-WM interface.

    “this field increase is very pronounced in the WM near the ventricles, particularly for the LR array configuration, but can also be observed within the tumour and in the WM near some parts of the GM-WM interface (figure 6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The two mapping methods used in this study (dM and vN) predict different average field strengths in the brain tissues, with the vN method producing systematically higher values.

    “The two mapping methods used in this study (dM and vN) predict different average field strengths in the brain tissues, with the vN method producing systematically higher values (table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    This results in higher SAR values in the tumour, with the volume-weighted average SAR values for LR and AP setups increasing to 121% and 110% in the dM and vN models.

    “This in turn, also results in higher SAR values in the tumour, with the volume-weighted average SAR values for LR and AP setups increasing to 121% and 110% in the dM and vN models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In s2, the median thicknesses of the scalp and the skull are 94% and 75% of those of s1.

    “In s2, the median thicknesses of the scalp and the skull are 94% and 75% of those of s1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The lowest field in the tumour shell (all variations) was 0.79 V/cm and 0.74 V/cm for the dM and vN mapping methods, respectively, due to the high conductivity attributed to the shell.

    “The lowest field in the tumour shell (all variations) was 0.79 V/cm and 0.74 V/cm for the dM and vN mapping methods, respectively, due to the high conductivity attributed to the shell.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    An exploratory analysis of the two models showed that the scalp as well as the skull appears to be thicker in s1.

    “An exploratory analysis of the two models showed that the scalp as well as the skull appears to be thicker in s1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the tumour shell, the average electric field is 20% and 50% higher in s1 than in s2 for the LR and AP configurations, respectively.

    “In the tumour shell, the average electric field is 20% and 50% higher in s1 than in s2 for the LR and AP configurations, respectively (figure 6).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Complete proliferation arrest for rat glioma cells was seen after a 24h exposure to TTFields of 2.25V/cm.

    “Complete proliferation arrest for rat glioma cells was seen after a 24h exposure to TTFields of 2.25V/cm (Kirson et al 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirson et al 2004

      Not checked in the free run.

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

    Premisecitation

    Two perpendicular field directions were found to be about 20% more effective than a single direction.

    “Since these axes are randomly orientated in the tumour, multiple field directions are alternately applied to improve efficacy: two perpendicular field directions were found to be about 20% more effective than a single direction (Kirson et al 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirson et al 2007

      Not checked in the free run.

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

    Premisecitation

    For glioma cells, a frequency of 200 kHz leads to the greatest reduction in cell proliferation.

    “For each cell line there appears to be an optimal frequency for which the inhibitory effect on cell division is greatest, e.g., for glioma cells a frequency of 200 kHz leads to the greatest reduction in cell proliferation (Kirson et al 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirson et al 2007

      Not checked in the free run.

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

    Premisecitation

    The inhibitory effect of TTFields starts at 1 V/cm and increases with increasing field intensity.

    “Furthermore, the inhibitory effect of TTFields starts at 1 V/cm and increases with increasing field intensity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirson et al 2004

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Different field strengths in a virtual lesion that represents a tumour were predicted for the LR and AP array pairs.

    “Furthermore, different field strengths in a virtual lesion that represents a tumour were predicted for the LR and AP array pairs (Miranda et al 2014, Wenger et al 2013, 2014a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Miranda et al 2014 source

      Not checked in the free run.

    • cites Wenger et al 2013, 2014a

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Isotropic conductivity values are not known accurately since a wide range of values are reported in the literature.

    “Also, isotropic conductivity values are not known accurately since a wide range of values are reported in the literature (see Methods).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    TTFields are most effective when the applied electric field and the axis of cell division are parallel.

    “Concerning the orientation dependence, TTFields are most effective when the applied electric field and the axis of cell division are parallel (Kirson et al 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirson et al 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased scalp conductivity leads to more current between the two arrays being shunted through this tissue, and therefore less flowing across the skull into the cranial cavity.

    “This is due to more current between the two arrays being shunted through this tissue, and therefore less flowing across the skull into the cranial cavity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The limited impact of CSF conductivity is because of the narrow range of values used, which reflects the high precision with which this value is known.

    “This is because of the narrow range of values used, which reflects the high precision with which this value is known.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The negative slope of the CSF conductivity curve indicates that current is shunted through the CSF, as it is through the scalp.

    “The negative slope of the curve indicates that current is shunted through the CSF, as it is through the scalp.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In a heterogeneous conductor the electric field is higher in a tissue with lower conductivity, and vice versa.

    “This is due to the fact that in a heterogeneous conductor the electric field is higher in a tissue with lower conductivity, and vice versa.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    In practice, the OptuneTM system operates in a slightly different mode since the total current is controlled at the array level (900 mA) and not at the transducer level.

    “In practice, the Optune™ system operates in a slightly different mode since the total current is controlled at the array level (900 mA) and not at the transducer level.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    In the WM curve of the vN AP configuration, the exception to the negative slope may be due to more current through AP white matter pathways at the level of the tumour as WM conductivity increases, which then flows through the tumour.

    “One noticeable exception occurs in the WM curve in the vN AP configuration (not shown), possibly due to more current through AP white matter pathways at the level of the tumour as WM conductivity increases, and which then flows through the tumour.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    This is in agreement with a study on TMS where taking anisotropy into account consistently increases the average field strength in the brain for all conductivity mappings.

    “This is in agreement with a study on the electric field distribution in transcranial magnetic stimulation (TMS), where the authors reported that taking anisotropy into account consistently increases the average field strength in the brain for all conductivity mappings (Opitz et al 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Opitz et al 2011

      Not checked in the free run.

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

    Premisecitation

    Similar differences have been reported in a study of the effect of WM anisotropy on the electric field distribution in tDCS.

    “Similar differences have been reported in a study of the effect of WM anisotropy on the electric field distribution in tDCS (Shahid et al 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shahid et al 2013

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    One limitation of our anisotropic model is that a virtual lesion was placed in a healthy brain and that the tumour tissues were always modelled as isotropic tissues.

    “One limitation of our anisotropic model is that a virtual lesion was placed in a healthy brain and that the tumour tissues were always modelled as isotropic tissues.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The MIDA model offers a very detailed representation of 153 structures, including several distinct muscles, bones and skull layers, arteries and veins.

    “the freely available MIDA model (Iacono et al 2015), which offers a very detailed representation of 153 structures, including several distinct muscles, bones and skull layers, arteries and veins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Iacono et al 2015

      Not checked in the free run.

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

    Interpretationnone given

    In clinical practice, the transducers arrays are placed as close as possible to the tumour, which will increase the field in this region.

    “In clinical practice, the transducers arrays are placed as close as possible to the tumour, which will increase the field in this region.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Only limited adverse effects were reported in TTFields patients.

    “only limited adverse effects were reported in TTFields patients as discussed in more detail in a previous paper (Miranda et al 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miranda et al 2014 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Vessels passing through the skull and the presence or absence of cancellous bone significantly impacted current density, especially when these features occur near the electrodes.

    “They further showed that vessels passing through the skull and the presence or absence of cancellous bone significantly impacted current density, especially when these features occur near the electrodes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Russell et al 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this study the variability was largely dependent on the local architecture of the cranium but also on skull thickness.

    “In this study the variability was largely dependent on the local architecture of the cranium but also on skull thickness.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Russell et al 2013

      Not checked in the free run.

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

    Premisecitation

    Another tDCS study based on 18 subjects showed significant current density variation between subjects with the same applied electrode configuration.

    “Another tDCS study based on 18 subjects showed significant current density variation between subjects with the same applied electrode configuration (Russell et al 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Russell et al 2013

      Not checked in the free run.

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

    Premisecitation

    Results presented elsewhere suggest unaltered average field strength in the active part of the tumour, but changed ATVs due to a uniform field distribution in the solid tumour and additional hotspots in the cystic type.

    “The results were presented elsewhere (Wenger et al 2014a) and suggest unaltered average field strength in the active part of the tumour, but changed ATVs due to a uniform field distribution in the solid tumour and additional hotspots in the cystic type.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wenger et al 2014a

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Both of these factors could contribute to an increase of the electric field in the brain and tumour of s2 and also to the difference in SAR values in the scalp and skull.

    “Both of these factors could contribute to an increase of the electric field in the brain and tumour of s2 and also to the difference in SAR values in the scalp and skull.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Within this study we did not include the comparison between cystic and solid tumours.

    “Within this study we did not include the comparison between cystic and solid tumours”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Only in s2 is the therapeutic value of 1 V/cm reached for both stimulation directions, which would suggest a more effective treatment within s2 although the virtual lesion and the transducer layout are the same in both models.

    “only in s2 is the therapeutic value of 1 V/cm reached for both stimulation directions, which would suggest a more effective treatment within s2 although the virtual lesion and the transducer layout are the same in both models.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: An electric field strength of 1 V/cm and higher inhibits glioma cell division, making it a therapeutic threshold for TTFields treatment.

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

    Premisecitation

    One tDCS study showed that in 3 different subjects the percentage difference between highest and lowest values the electric field in the motor cortex was 29%.

    “One tDCS study showed that in 3 different subjects the percentage difference between highest and lowest values the electric field in the motor cortex was 29% (Edwards et al 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Edwards et al 2013

      Not checked in the free run.

63 of 63

  • The authors state this as an assumption.

    The ventricles are filled with CSF.

    “The ventricles were assumed to be filled with CSF.”

  • The authors state this as an assumption.

    The eigenvalues of the diffusion and conductivity tensors have a linear relationship in the direct mapping method.

    “The direct mapping (dM) method (Tuch et al 2001) assumes a linear relationship between the eigenvalues of the diffusion and conductivity tensors, i.e., σv=s∙dv, where s is a constant, and σv and dv are the vth eigenvalues of the conductivity and the diffusion tensors respectively.”

  • The paper relies on this without support.

    An electric field strength of 1 V/cm and higher inhibits glioma cell division, making it a therapeutic threshold for TTFields treatment.

    “since the inhibitory effect on glioma cell division was observed for field strengths of 1 V/cm and higher.”
    “the therapeutic value of 1 V/cm”

  • The paper relies on this without support.

    The conductivity of the tumour is known with limited accuracy.

    “The limited accuracy with which this conductivity value is known”
4 of 4

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.

  • Tumour field is not above 1 V/cm under every modelling assumption

    Major

    The abstract says the tumour field exceeds 1 V/cm independently of modelling assumptions, but the sensitivity analysis reports average tumour-shell fields as low as 0.74 V/cm.

  • Anisotropy increase is described as 110% rather than an increase to 110%

    Minor

    The results describe tumour-shell fields as approximately 111% and 106% of the isotropic value for dM, and 106% and 102% for vN. The discussion calls these increases *by* about 110%, 106%, 106% and 102%, which would mean roughly twice the isotropic field rather than the small increases reported earlier.

  • Discussion reverses which subject has the higher tumour-shell field

    Minor

    The results state that s2 has the higher field, including a 50% increase in tumour tissues for the AP configuration. The discussion instead says the tumour-shell field is 20% and 50% higher in s1 than in s2.

3 of 3

The citation lists haven’t been fetched yet

References 52 · Cited by 121

Research works printed but not linked: 3

  1. Haus H A, 1989, Electromagnetic Fields and Energy (Massachusetts Institute of Technology: MIT OpenCourseWare)
  2. Lee W H, 2011, Annual Int. Conf. of the IEEE Engineering in MEdicine and Biology Society, EMBC, 5473
  3. Wenger C, 2013, Neuro-Oncolgy, 15, TM–028

Authors
Wenger, C., Salvador, R., Basser, P. J., & Miranda, P. C.
Affiliations
  • University of Lisbon (PT)
  • National Institutes of Health (US)
Corresponding author
  • Wenger, Cornelia
  • Salvador, Ricardo
  • Basser, Peter J
  • Miranda, Pedro C
ORCID
Venue
Physics in Medicine and Biology
Publisher
IOP Publishing
Published
2015-09-09
Volume
60
Issue
18
Pages
7339-7357
ISSN
  • 0031-9155 (ISSN-L)
  • 1361-6560
DOI
10.1088/0031-9155/60/18/7339
PMC
PMC4628548
OpenAlex
W2312300111
Semantic Scholar
68e5255c542fbcdd05bc9d31455fab14540d66a4
Cited by
121
References
52
Citations by year
2026: 8 · 2025: 15 · 2024: 10 · 2023: 4 · 2022: 11 · 2021: 10 · 2020: 15 · 2019: 13 · 2018: 8 · 2017: 10 · 2016: 13 · 2015: 3
FWCI
6.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Physics in Medicine and Biology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Foundation for Science and Technology, Portugal
  • Novocure
  • National Institute of Child Health and Human Development (Intramural Research Program (IRP))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
Keywords
tumor treating fields, electric field distribution, glioblastoma, tissue dielectric properties, anisotropic conductivity, human head model, finite element analysis, transducer array, tumor necrosis, interindividual variability, sensitivity analysis, antimitotic therapy
MeSH terms
Adult, Brain, Brain Neoplasms, Electric Conductivity, Electric Stimulation Therapy, Female, Glioblastoma, Head, Humans, Image Processing, Computer-Assisted, Male, Models, Anatomic, Models, Neurological, Neoplasm Recurrence, Local, Anisotropy, Finite Element Analysis, Young Adult, Brain Waves

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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