[Show abstract][Hide abstract] ABSTRACT: Mouse models are widely used in studies of various forms of transcranial electric stimulation (TES). However, there is limited knowledge of the electric field distribution induced by TES in mice, and computational models to estimate this distribution are lacking. This study examines the electric field and current density distribution in the mouse brain induced by TES. We created a high-resolution finite element mouse model incorporating ear clip electrodes commonly used in mouse TES to study, for example, electroconvulsive therapy (ECT). The electric field strength and current density induced by an ear clip electrode configuration were computed in the anatomically realistic, inhomogenous mouse model. The results show that the median electric field strength induced in the brain at 1 mA of stimulus current is 5.57 V/m, and the strongest field of 20.19 V/m was observed in the cerebellum. Therefore, to match the median electric field in human ECT at 800 mA current, the electrode current in mouse should be set to approximately 15 mA. However, the location of the strongest electric field in posterior brain regions in the mouse does not model well human ECT which targets more frontal regions. Therefore, the ear clip electrode configuration may not be a good model of human ECT. Using high-resolution realistic models for simulating TES in mice may guide the establishment of appropriate stimulation parameters for future in vivo studies.
[Show abstract][Hide abstract] ABSTRACT: Rodent models are valuable for preclinical examination of novel therapeutic techniques, including transcranial magnetic stimulation (TMS). However, comparison of TMS effects in rodents and humans is confounded by inaccurate scaling of the spatial extent of the induced electric field in rodents. The electric field is substantially less focal in rodent models of TMS due to the technical restrictions of making very small coils that can handle the currents required for TMS. We examine the electric field distributions generated by various electrode configurations of electric stimulation in an inhomogeneous high-resolution finite element mouse model, and show that the electric field distributions produced by human TMS can be approximated by electric stimulation in mouse. Based on these results and the limits of magnetic stimulation in mice, we argue that the most practical and accurate way to model focal TMS in mice is electric stimulation through either cortical surface electrodes or electrodes implanted halfway through the mouse cranium. This approach could allow much more accurate approximation of the human TMS electric field focality and strength than that offered by TMS in mouse, enabling, for example, focal targeting of specific cortical regions, which is common in human TMS paradigms.
[Show abstract][Hide abstract] ABSTRACT: This study examines the characteristics of the electric field (E-field) induced in the brain by electroconvulsive therapy (ECT) and magnetic seizure therapy (MST). The electric field induced by five ECT electrode configurations (bilateral, bifrontal, right unilateral, focal electrically administered seizure therapy, and frontomedial) as well as an MST coil configuration (circular) was computed in an anatomically realistic finite element model of the human head. We computed the maps of the electric field strength relative to an estimated neural activation threshold, and used them to evaluate the stimulation strength and focality of the various ECT and MST paradigms. The results show that the median ECT stimulation strength in the brain is 3-11 times higher than that for MST, and that the stimulated brain volume is substantially higher with ECT (47-100%) than with MST (21%). Our study provides insight into the observed reduction of cognitive side effects in MST compared to ECT, and supports arguments for lowering ECT current amplitude as a means of curbing its side effects.
[Show abstract][Hide abstract] ABSTRACT: Myoclonus-dystonia is a movement disorder characterized by childhood onset of myoclonus and dystonia. We report a case of the epsilon-sarcoglycan mutation-negative myoclonus-dystonia patient who underwent bilateral globus pallidus interna deep-brain stimulation with subsequent improvement of both myoclonus and dystonia.
A 37-year-old woman with myoclonic jerks and dystonia affecting predominantly the lower limbs was treated with chronic bilateral globus pallidus interna deep-brain stimulation.
The movement subscore of the Burke-Fahns-Marsden Dystonia Rating Scale was 38 before surgery and improved to 7 after 3 years. The disability subscore of the Burke-Fahns-Marsden Dystonia Rating Scale improved from 7 to 2. The Unified Myoclonus Rating Scale also decreased significantly from 93 to 39. No hardware- or stimulation-related complications occurred during follow-up.
This report suggests that patients with myoclonus-dystonia may significantly benefit from bilateral globus pallidus interna deep-brain stimulation. Larger studies of this patient population are needed to confirm the optimal target.
[Show abstract][Hide abstract] ABSTRACT: Poor health-related quality of life (HRQOL) in patients with chronic heart failure (CHF) may be one of the most common predictors of mortality and rehospitalization. This study was conducted to identify factors affecting HRQOL in Korean patients with CHF using two HRQOL measurements.
The study included a sample of 114 patients. HRQOL was measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the World Health Organization's Quality of Life Instrument - Short Version (WHOQOL-BREF). Multiple regression analyses were performed to analyze the relationship between the factors and HRQOL.
Significant correlations were found between MLHFQ and WHOQOL-BREF in total and component scores, with the two exceptions of WHOQOL-BREF psychological and MLHFQ physical or total. The perceived economic status, functional status, and sex were factors identified as having an effect on HRQOL.
The MLHFQ was better able to differentiate sex, comorbidity, and functional status. Further studies are needed to implement cost-effective nursing interventions for patients with CHF to improve their HRQOL.
Japan Journal of Nursing Science 01/2014; 11(1):54-64. · 0.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although metastasis of hepatocellular carcinoma to the brain is uncommon, it is associated with a very high mortality rate and most patients usually expire within 1 year after brain metastasis. The aim of this study is to identify the effectiveness of the active interventions such as gamma knife radiosurgery or surgical intervention for these patients.
Brain tumor research and treatment. 10/2013; 1(2):78-84.
[Show abstract][Hide abstract] ABSTRACT: We have proposed that the current amplitude in electroconvulsive therapy (ECT) be lowered to produce stimulation closer to the neural activation threshold and individualized to account for anatomical variability across patients. A novel approach to individualize the ECT current amplitude could be via motor threshold (MT) determination with transcranial electric stimulation (TES) applied through the ECT electrodes instead of the fixed high current approach. This study derives an estimate of the electric field (E-field) neural activation threshold and tests whether individual differences in TES MT are explained by anatomical variability measurements and simulations in individual head models. The E-field distribution induced by a right unilateral (RUL) ECT electrode configuration was computed in subject-specific finite element head models of four nonhuman primates (NHPs) for whom MT was measured. By combining the measured MTs and the computed E-field maps, the neural activation threshold is estimated to be 0.45 ± 0.07 V/cm for 0.2 ms stimulus pulse width. The individual MT was correlated with the electrode-to-cortex distance under the superior electrode (R(2)=.96, p=.022) as well as with the simulated electrode-current/induced-E-field ratio (R(2)=.95, p=.026), indicating that both anatomical measurements and computational models could predict the individual current requirements for transcranial stimulation. These findings could be used with realistic human head models and in clinical studies to explore novel ECT dosing paradigms, and as a new noninvasive means to determine individual dosage requirement with ECT.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 07/2013; 2013:815-818.
[Show abstract][Hide abstract] ABSTRACT: This study examines the characteristics of the electric field induced in the brain by electroconvulsive therapy (ECT) with individualized current amplitude. The electric field induced by bilateral (BL), bifrontal (BF), right unilateral (RUL), and frontomedial (FM) ECT electrode configurations was computed in anatomically realistic finite element models of four nonhuman primates (NHPs). We generated maps of the electric field strength relative to an empirical neural activation threshold, and determined the stimulation strength and focality at fixed current amplitude and at individualized current amplitudes corresponding to seizure threshold (ST) measured in the anesthetized NHPs. The results show less variation in brain volume stimulated above threshold with individualized current amplitudes (16-36%) compared to fixed current amplitude (30-62%). Further, the stimulated brain volume at amplitude-titrated ST is substantially lower than that for ECT with conventional fixed current amplitudes. Thus individualizing the ECT stimulus current could compensate for individual anatomical variability and result in more focal and uniform electric field exposure across different subjects compared to the standard clinical practice of using high, fixed current for all patients.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 07/2013; 2013:3082-3085.
[Show abstract][Hide abstract] ABSTRACT: To establish safe and efficient transcranial direct current stimulation (tDCS), it is of particular importance to understand the electrical effects of tDCS in the brain. Since the current density (CD) and electric field (EF) in the brain generated by tDCS depend on various factors including complex head geometries and electrical tissue properties, in this work, we investigated the influence of anisotropic conductivity in the skull and white matter (WM) on tDCS via a 3D anatomically realistic finite element head model. We systematically incorporated various anisotropic conductivity ratios into the skull and WM. The effects of anisotropic tissue conductivity on the CD and EF were subsequently assessed through comparisons to the conventional isotropic solutions. Our results show that the anisotropic skull conductivity significantly affects the CD and EF distribution: there is a significant reduction in the ratio of the target versus non-target total CD and EF on the order of 12-14%. In contrast, the WM anisotropy does not significantly influence the CD and EF on the targeted cortical surface, only on the order of 1-3%. However, the WM anisotropy highly alters the spatial distribution of both the CD and EF inside the brain. This study shows that it is critical to incorporate anisotropic conductivities in planning of tDCS for improved efficacy and safety.
Physics in Medicine and Biology 10/2012; 57(21):6961-80. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigates the stimulation strength and focality of electroconvulsive therapy (ECT) with individualized current amplitude in a nonhuman primate (NHP) model. We generated an anatomically realistic finite element model of a NHP head incorporating tissue heterogeneity and white matter conductivity anisotropy based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. The electric field spatial distributions of three conventional ECT electrode placements (bilateral, bifrontal, and right unilateral) and an experimental frontomedial electrode configuration were simulated. We calibrated the electric field maps relative to an empirical neural activation threshold and evaluated the stimulation strength and focality of the various ECT electrode configurations with individualized current amplitudes corresponding to the motor threshold and seizure threshold assessed in the anesthetized NHP. Understanding the stimulation strength and focality of various forms of ECT could provide insight into the mechanisms of therapeutic seizure induction, and could provide support for the clinical investigation of ECT with individualized current amplitude as an intervention with potentially improved risk/benefit ratio.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2012; 2012:6430-3.
[Show abstract][Hide abstract] ABSTRACT: Radiation therapy, the most commonly used for the treatment of brain tumors, has been shown to be of major significance in tu-mor control and survival rate of brain tumor patients. About 200,000 patients with brain tumor are treated with either partial large field or whole brain radiation every year in the United States. The use of radiation therapy for treatment of brain tumors, however, may lead to devastating functional deficits in brain several months to years after treatment. In particular, whole brain radiation therapy results in a significant reduction in learning and memory in brain tumor patients as long-term consequences of treatment. Although a number of in vitro and in vivo studies have demonstrated the pathogenesis of radiation-mediated brain injury, the cel-lular and molecular mechanisms by which radiation induces damage to normal tissue in brain remain largely unknown. Therefore, this review focuses on the pathophysiological mechanisms of whole brain radiation-induced cognitive impairment and the iden-tification of novel therapeutic targets. Specifically, we review the current knowledge about the effects of whole brain radiation on pro-oxidative and pro-inflammatory pathways, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) system and extracellular matrix (ECM), and physiological angiogenesis in brain. These studies may provide a foundation for defin-ing a new cellular and molecular basis related to the etiology of cognitive impairment that occurs among patients in response to whole brain radiation therapy. It may also lead to new opportunities for therapeutic interventions for brain tumor patients who are undergoing whole brain radiation therapy.
Biomolecules and Therapeutics 07/2012; 20(4):357-370. · 0.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blood-brain barrier (BBB) disruption is one of the major consequences of radiation-induced normal tissue injury in the central nervous system. We examined the effects of whole-brain irradiation on matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and extracellular matrix (ECM) degradation in the brain.
Animals received either whole-brain irradiation (a single dose of 10 Gy γ-rays or a fractionated dose of 40 Gy γ-rays, total) or sham-irradiation and were maintained for 4, 8, and 24 h following irradiation. mRNA expression levels of MMPs and TIMPs in the brain were analyzed by real-time reverse transcriptase-polymerase chain reaction (PCR). The functional activity of MMPs was measured by in situ zymography, and degradation of ECM was visualized by collagen type IV immunofluorescent staining.
A significant increase in mRNA expression levels of MMP-2, MMP-9, and TIMP-1 was observed in irradiated brains compared to that in sham-irradiated controls. In situ zymography revealed a strong gelatinolytic activity in the brain 24 h postirradiation, and the enhanced gelatinolytic activity mediated by irradiation was significantly attenuated in the presence of anti-MMP-2 antibody. A significant reduction in collagen type IV immunoreactivity was also detected in the brain at 24 h after irradiation. In contrast, the levels of collagen type IV were not significantly changed at 4 and 8 h after irradiation compared with the sham-irradiated controls.
The present study demonstrates for the first time that radiation induces an imbalance between MMP-2 and TIMP-2 levels and suggests that degradation of collagen type IV, a major ECM component of BBB basement membrane, may have a role in the pathogenesis of brain injury.
International journal of radiation oncology, biology, physics 04/2012; 82(5):1559-66. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present the first computational study investigating the electric field (E-field) strength generated by various electroconvulsive therapy (ECT) electrode configurations in specific brain regions of interest (ROIs) that have putative roles in the therapeutic action and/or adverse side effects of ECT. This study also characterizes the impact of the white matter (WM) conductivity anisotropy on the E-field distribution. A finite element head model incorporating tissue heterogeneity and WM anisotropic conductivity was constructed based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. We computed the spatial E-field distributions generated by three standard ECT electrode placements including bilateral (BL), bifrontal (BF), and right unilateral (RUL) and an investigational electrode configuration for focal electrically administered seizure therapy (FEAST). The key results are that (1) the median E-field strength over the whole brain is 3.9, 1.5, 2.3, and 2.6 V/cm for the BL, BF, RUL, and FEAST electrode configurations, respectively, which coupled with the broad spread of the BL E-field suggests a biophysical basis for observations of superior efficacy of BL ECT compared to BF and RUL ECT; (2) in the hippocampi, BL ECT produces a median E-field of 4.8 V/cm that is 1.5-2.8 times stronger than that for the other electrode configurations, consistent with the more pronounced amnestic effects of BL ECT; and (3) neglecting the WM conductivity anisotropy results in E-field strength error up to 18% overall and up to 39% in specific ROIs, motivating the inclusion of the WM conductivity anisotropy in accurate head models. This computational study demonstrates how the realistic finite element head model incorporating tissue conductivity anisotropy provides quantitative insight into the biophysics of ECT, which may shed light on the differential clinical outcomes seen with various forms of ECT, and may guide the development of novel stimulation paradigms with improved risk/benefit ratio.
[Show abstract][Hide abstract] ABSTRACT: This paper investigates the effect industry life cycle phase shifts have on the effectiveness of firms’ knowledge creation strategies. Building on literature streams on strategic knowledge management and industry life cycles, we develop theoretical arguments for why the best knowledge search strategy should be different before the emergence of an industry compared to afterwards. Testing our hypotheses empirically in the emerging U.S. automotive airbag industry confirms the powerful forces of industry emergence: the best knowledge search strategy is initially one that looks inward into the organization but outside of the technology area, and later shifts to one that is looking outward from the organization and the technology. As practical implication we derive that R&D managers should (i) adjust their teams’ knowledge search strategies depending on the industry life cycle phase in which they find themselves, and (ii) especially look for new applications of their firm’s existing knowledge in related fields.
Acknowledgements: The authors would like to thank Carliss Baldwin, Michael Heeley, J. Peter Murmann, Karl Ulrich, seminar participants at Wharton and MIT, and three anonymous Academy of Management Annual Meeting Reviewers for their helpful comments on earlier versions of this paper. All errors remain our responsibility. The authors acknowledge financial support for this research from the National Science Foundation (SES-0620487).
Technology Analysis and Strategic Management 01/2012; · 0.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The etiology of radiation-induced cerebrovascular rarefaction remains unknown. In the present study, we examined the effect of whole-brain irradiation on endothelial cell (EC) proliferation/apoptosis and expression of various angiogenic factors in rat brain. F344 × BN rats received either whole-brain irradiation (a single dose of 10 Gy γ rays) or sham irradiation and were maintained for 4, 8 and 24 h after irradiation. Double immunofluorescence staining was employed to visualize EC proliferation/apoptosis in brain. The mRNA and protein expression levels of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), endothelial-specific receptor tyrosine kinase (Tie-2), and Ang-2 in brain were determined by real-time RT-PCR and immunofluorescence staining. A significant reduction in CD31-immunoreactive cells was detected in irradiated rat brains compared with sham-irradiated controls. Whole-brain irradiation significantly suppressed EC proliferation and increased EC apoptosis. In addition, a significant decrease in mRNA and protein expression of VEGF, Ang-1 and Tie-2 was observed in irradiated rat brains. In contrast, whole-brain irradiation significantly upregulated Ang-2 expression in rat brains. The present study provides novel evidence that whole-brain irradiation differentially affects mRNA and protein expression of VEGF, Ang-1, Tie-2 and Ang-2. These changes are closely associated with decreased EC proliferation and increased EC apoptosis in brain.
Radiation Research 09/2011; 176(6):753-60. · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study proposes an advanced finite element (FE) head modeling technique through which high-resolution FE meshes adaptive to the degree of tissue anisotropy can be generated. Our adaptive meshing scheme (called wMesh) uses MRI structural information and fractional anisotropy maps derived from diffusion tensors in the FE mesh generation process, optimally reflecting electrical properties of the human brain. We examined the characteristics of the wMeshes through various qualitative and quantitative comparisons to the conventional FE regular-sized meshes that are non-adaptive to the degree of white matter anisotropy. We investigated numerical differences in the FE forward solutions that include the electrical potential and current density generated by current sources in the brain. The quantitative difference was calculated by two statistical measures of relative difference measure (RDM) and magnification factor (MAG). The results show that the wMeshes are adaptive to the anisotropic density of the WM anisotropy, and they better reflect the density and directionality of tissue conductivity anisotropy. Our comparison results between various anisotropic regular mesh and wMesh models show that there are substantial differences in the EEG forward solutions in the brain (up to RDM=0.48 and MAG=0.63 in the electrical potential, and RDM=0.65 and MAG=0.52 in the current density). Our analysis results indicate that the wMeshes produce different forward solutions that are different from the conventional regular meshes. We present some results that the wMesh head modeling approach enhances the sensitivity and accuracy of the FE solutions at the interfaces or in the regions where the anisotropic conductivities change sharply or their directional changes are complex. The fully automatic wMesh generation technique should be useful for modeling an individual-specific and high-resolution anisotropic FE head model incorporating realistic anisotropic conductivity distributions towards more accurate analysis of bioelectromagnetic problems.
Medical Engineering & Physics 08/2011; 34(1):85-98. · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of this study is to investigate the influence of white matter conductivity anisotropy on the electric field strength induced by electroconvulsive therapy (ECT). We created an anatomically-realistic finite element human head model incorporating tissue heterogeneity and white matter conductivity anisotropy using structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. The electric field spatial distributions of three conventional ECT electrode placements (bilateral, bifrontal, and right unilateral) and an experimental electrode configuration, focal electrically administered seizure therapy (FEAST), were computed. A quantitative comparison of the electric field strength was subsequently performed in specific brain regions of interest thought to be associated with side effects of ECT (e.g., hippocampus and in-sula). The results show that neglecting white matter conductivity anisotropy yields a difference up to 19%, 25% and 34% in electric field strength in the whole brain, hippocampus, and insula, respectively. This study suggests that white matter conductivity anisotropy should be taken into account in ECT electric field models.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2011; 2011:5473-6.