DBS-relevant electric fields increase hydraulic conductivity of in vitro endothelial monolayers (original) (raw)
Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation
Cancers, 2019
Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood–brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the temporal, high-frequency electroporation (HFE)-mediated BBBD in an in vivo healthy rat brain model. 40 male Fisher rats underwent HFE treatment; two blunt tipped monopolar electrodes were advanced into the brain and 200 bursts of HFE were delivered at a voltage-to-distance ratio of 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye) at time points of 1, 24, 48, 72, and 96 h after HFE. Contrast enhanced T1W scans demonstrated BBBD for 1 to 72 h after HFE but intact BBB at 96 h. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced w...
Frontiers in Cell and Developmental Biology, 2021
Transcranial direct current stimulation (tDCS) is a non-invasive physical therapy to treat many psychiatric disorders and to enhance memory and cognition in healthy individuals. Our recent studies showed that tDCS with the proper dosage and duration can transiently enhance the permeability (P) of the blood-brain barrier (BBB) in rat brain to various sized solutes. Based on the in vivo permeability data, a transport model for the paracellular pathway of the BBB also predicted that tDCS can transiently disrupt the endothelial glycocalyx (EG) and the tight junction between endothelial cells. To confirm these predictions and to investigate the structural mechanisms by which tDCS modulates P of the BBB, we directly quantified the EG and tight junctions of in vitro BBB models after DCS treatment. Human cerebral microvascular endothelial cells (hCMECs) and mouse brain microvascular endothelial cells (bEnd3) were cultured on the Transwell filter with 3 μm pores to generate in vitro BBBs. Af...
Pharmaceuticals
The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell ablation. Eighteen male Fisher rats underwent craniectomy procedures and two blunt-tipped electrodes were advanced into the brain for pulsing. BBB disruption was verified with contrast T1W MRI and pathologically with Evans blue dye. High-frequency irreversible electroporation cell death of healthy rodent astrocytes was investigated in vitro using a collagen hydrogel tissue mimic. Numerical analysis was conducted to determine the electric fields in which BBB disruption and cell ablation occur. Differences between the BBB disruption and ablation thresholds for each waveform are as follows: 2-2-2 μs (1028 V/cm), 5-2-5 μs (721 V/cm), 10-1-10 μs...
Brain Research, 2004
The blood -brain barrier (BBB) maintains the homeostasis of the brain microenvironment, which is crucial for neuronal activity and function. Under pathological conditions, the BBB may fail due to yet unknown mechanisms. BBB failure is accompanied by an increase in the transendothelial permeability to substances such as sucrose that are normally extruded. Furthermore, altered BBB function may also lead to development of abnormal drug extrusion mechanisms including expression of multiple drug resistance proteins. Therefore, it is not surprising that strategies have been developed to ''repair'' the BBB in order to restore normal brain homeostasis and penetration/extrusion of pharmacologically active (noxious) substances. To this end, steroidal hormones and synthetic analogues such as dexamethasone (DEX) have been used to counteract BBB failure. However, several side effects limit the usefulness of steroid treatment in humans leading to the quest for developing novel strategies for BBB repair. We here show that, in an in vitro model of the BBB based on a co-culture of endothelial cells (EC) and glia, the natural compound glycerophosphoinositol (GPI) may replicate the effects of DEX. Thus, GPI in concentrations ranging from 3 to 100 AM promoted both BBB formation and repair in a dose dependent fashion. Similar effects were obtained with an elevated dose of DEX (10 AM); at higher concentrations (100 AM), DEX was cytotoxic. We conclude that the endogenous anti-inflammatory agent GPI may ameliorate BBB function with efficacy comparable to that of steroids, but with significantly fewer side effects. Further experiments will confirm the efficacy of this treatment in vivo and elucidate the pathways that lead to BBB repair after exposure to GPI. D
MRI Study on Reversible and Irreversible Electroporation Induced Blood Brain Barrier Disruption
PLoS ONE, 2012
Electroporation, is known to induce cell membrane permeabilization in the reversible (RE) mode and cell death in the irreversible (IRE) mode. Using an experimental system designed to produce a continuum of IRE followed by RE around a single electrode we used MRI to study the effects of electroporation on the brain. Fifty-four rats were injected with Gd-DOTA and treated with a G25 electrode implanted 5.5 mm deep into the striata. MRI was acquired immediately after treatment, 10 min, 20 min, 30 min, and up to three weeks following the treatment using: T1W, T2W, Gradient echo (GE), serial SPGR (DCE-MRI) with flip angles ranging over 5-25u, and diffusion-weighted MRI (DWMRI). Blood brain barrier (BBB) disruption was depicted as clear enhancement on T1W images. The average signal intensity in the regions of T1-enhancement, representing BBB disruption, increased from 1887683 (arbitrary units) immediately post treatment to 2246694 20 min post treatment, then reached a plateau towards the 30 min scan where it reached 2289687. DWMRI at 30 min showed no significant effects. Early treatment effects and late irreversible damage were clearly depicted on T2W. The enhancing volume on T2W has increased by an average of 2.2760.27 in the first 24-48 hours post treatment, suggesting an inflammatory tissue response. The permanent tissue damage, depicted as an enhancing region on T2W, 3 weeks post treatment, decreased to an average of 50610% of the T2W enhancing volumes on the day of the treatment which was 3365% of the BBB disruption volume. Permanent tissue damage was significantly smaller than the volume of BBB disruption, suggesting, that BBB disruption is associated with RE while tissue damage with IRE. These results demonstrate the feasibility of applying reversible and irreversible electroporation for transient BBB disruption or permanent damage, respectively, and applying MRI for planning/monitoring disruption volume/shape by optimizing electrode positions and treatment parameters.
Focal blood-brain-barrier disruption with high-frequency pulsed electric fields
TECHNOLOGY, 2014
The blood-brain-barrier (BBB), a network of tight junctions that impedes large molecule transport, limits the usefulness of systemic chemotherapeutic delivery for the treatment of malignant gliomas and other neurological diseases. Here, we present a tool for BBB disruption that uses bursts of sub-microsecond bipolar pulses to enhance the transfer of large molecules to the brain. Blunt needle electrodes were advanced into the motor cortex of anesthetized adult rats, and a series of 90–900 bursts were delivered with voltage-to-distance ratios of 250 or 2000 V/cm, a total programmed energized time of 100 μs, and a repetition rate of 1 Hz. BBB disruption was assessed via a gadolinium-Evans blue albumin tracer, and all experimental conditions were found to cause BBB disruption immediately following treatment without inducing local or distal muscle contractions. The lowest energy condition, 300 bursts consisting of 850 ns bipolar pulses, resulted in significant BBB disruption (0.51 cm3), ...
Nonthermal GSM RF and ELF EMF effects upon rat BBB permeability
The Environmentalist, 2011
: Subacute spongiform encephalopathy. Spongiform cerebral atrophy. Neurology, 13, 6, 455 -463. Brun A, Gottfries C G, and Roos B E (1971): Studies of the monoamine metabolism in the central nervous system in Jacob-Creutzfeldt disease. Acta Neurol. Scandinav. 47, 642 -645. Sulg I A and Brun A (1972): Spongiform encephalopathi återspeglad i EEG och patohistologi. Föredrag Medicinska Riksstämman, Hygiea. Stockholm 231. Mark J and Brun A (1973): Chromosomal deviations in Alzheimer's disease compared to those in senescence and senile dementia. Ger Clin 15, 253-258. Brun A (1973). Downs' syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Brun A (1974): Den presenila demensens patologi relaterad till cerebralt blodflöde. Svenska läkartidningen 71, 13, 1974: Svenska läkarsällskapets endagssymposium 73-11-07 över temat demens. Patofysiologi och klinik. 71, 1290 -1291. Brun A. and L.Gustafson (1974): Extent and severity of cerebral lesions related to clinical and regional cerebral blood flow in presenile dementia. In: PPProc of the V11th Intnl Congr of Neuropathology, Akademiai Kiado, Budapest 1974, p44. Gustafson L, D.H.Ingvar and A. Brun (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. In proc. of 2nd Intnl congr of CIANS Prague 1975. p. 371 Brun A, L Gustafson, DHI Ingvar (1974/5): Neuropathological findings related to Neuropsychiatric symptoms and regional cerebral blood flow in presenile dementia. Excerpta medica, Amsterdam, Akademiai Kiado, Budapest. Pp 101-5. Brun, A. and Gustafson, L. (1976). Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Arch Psychiatr Nervenkr, 223, 15-33. Gustafson L, Brun A and Ingvar D H (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. Activ nerv Sub (Praha) 19, 2, 351 -354. Gustafson L, A Brun, DHI Ingvar (1977): Presenile dementia: Clinical symptoms, pathoanatomical findings and cerebral blood flow. Cerebral vascular disease. A Brun, E Englund (1980): degeneration av hjärnans vita substans vid demens. Riksstämman, Hygiea. P 213 Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. + abstr Brun A and Dictor M (1981): Senile plaques and tangles in dialysis dementia. Acta Path. Microbiol Scand Sect A, 89, 193-198. Brun, A. and Englund, E. (1981). Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology, 5, 549-564. Englund E and Brun A (1981): Senile dementia -a structural basis for etiological and therapeutic considerations. Biological Psychiatry. Eds: C Perris and B Jonsson. Elsevier/North Holland Biomed Press 951 -956. Westermark P, Shirahama T, Skinner M, Brun A, Cameron R and Cohen A (1982): Immunohistochemical evidence for the lack of amyloid component in some intracrebral amyloids. Laboratory Investigation 5, 457 -460. Shirhama T, Skinner M, Westermark P, Rubinow A, Cohen A S, Brun A and Kemper T H (1982): Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaques, in the neurofibrillary tangle and in the microangiopathic lesion. Am J Pathol 107, 41-50. Brun A (1982): Strukturellt underlag vid organisk senil demens. Symposium Sandoz: Demenstillstånd -synpunkter på etiologi och behandling, 23 -34. Brun A (1982): Alzheimer's disease and its clinical implications. In: Geriatrics. Ed: D Platt. Springer Verlag Heidelberg, NY, 343 -390. Brun A and Englund E (1982): White matter incomplete infarction in dementia. Abstract 9th Internat. Congr. Neuropath. 201. Brun A, L Gusrafson (1983). Down's syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. pp. Brun A (1983): Hjärnskada bakom vanliga former av demens. Forskning och Praktik, 15, 7, 103-106. Brun A (1983): An overview of light and electron microscopical changes. In: Alzheimer's disease. Ed: B Reisberg. The Free Press. New York, a division of Mac Millan Inc, 3 -47. Gustafson L, Brun A, Risberg J and Johansson M (1984): Evaluation of organic dementia by regional cerebral blood flow measurements and clinical psychometric methods. Monogr Neural Sci, 11, 111 -117. Karger, Basel. . Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. p 23. Brun A (1984): The neuropathological background of clinical signs and symptoms in organic dementia. 2 nd Nordic meeting in Neuropsychology. Lund Sweden. Pp 18-19. Brun A (1985): The structural development of Alzheimer's disease. Danish Medical Bulletin, 32, 1, 25 -27. Friedland R P, A Brun, T F Budinger (1985): Pathological and positron emission tomographic correlations in Alzheimer's disease. The Lancet 8422, vol. I/85, p 228. Brun A and Englund E (1985): Regional variations of cortical degeneration in Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 7, 2, 167 Brun A and Englund E (1985): White matter changes in Alzheimer's presenile and senile dementia. In: Normal aging, Alzheimer's disease and senile dementia. Aspects on etiology, pathogenesis, diagnosis and treatment, Ed: C G Gottfries. Editions de lUniversité de Bruxelle's, 47 -50. Gustafson L, Brun A, Holmkvist-Franck A, Risberg J 1985: Regional Cerebral blood flow in degenerative frontal lobe dementia of non-Alzheimer type. Cerebr. Blood Flow Metabol. 5: 141-142. Gustafson L, A Brun, J Risberg (1985): Organic dementia: Clinical picture related to regional cerebral blood flow and neuropathologic al findings. Psychiatry vol. 2. Pp 605-611. Brun A, E Englund (1985): Alzheimer type dementia and white matter changes. Ata neurol. Scand. Vil 71. Pp 87-88. Gustafson L, A Brun, J Risberg (1985): Rating scales for diagnosis of Alzheimer´s disease and frontal lobe dementia of non-Alzheimer type. 26 Englund E, A Brun (1985): A White matter disorder common in Dementia of Alzheimer´s type. Pp 168-169. Englund E, A Brun (1985): demyelination contributes to Alzheimer´s disease. 18. Brun A, L Gustafson, E Englund (1985): Morphology of white matter, subcortical dementia in Alzheimer´s disease. Pp 79 -83. Brun A, Englund E (1986): A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986;19:253-262. -Brun A and Gustafson L (1990): Clinico-pathological correlates of dementia: The pathoanatomical substrate of Alzheimer's disease. Excerpta Medica. -Gustafson L, Brun A, Cronqvist S, Dalfelt G, Risberg J, Riesenfeldt W and Rosén I (1990): Regional cerebral blod flow, MRI and BEAM in Alzheimer's disease. J Cer Blood Flow Metab, 9, 1, 543. Brun A, Gustafson L, and Risberg J (1990): A review of 20 years dementia research. Psychiatric Medicine, vol 32k 7, 781 -788. Igakushoin Tokyo Japan. Brun A (1991): Trends in neuropathological enquiry into the dementias: The late life pattern. Workshop on therapeutic and epidemiological aspects. Proc. IPA workshop, Cambridge. Brun A (1991): Dementia of frontal lobe type. Elsevier Science Publishers B V. Biological Psychiatry. Volume 2. G Racagni et al, eds. Pp 126 -127. Pinheiro T, Tapper U A S, Sturesson K, Brun A (1991): Experimental investigation into sample preparation of Alzheimer tissue specimens for nuclear microprobe analysis. Nuclear Instruments and Methods in Physics Research B 54, 186 -190. Brun A (1991): Structural and topographic aspects of degenerative dementia: aspects of degenerative dmentia. Diagnostic considerations. Internat Psychogeriatrics, vol 3, supp. Pp. 75 -83. Englund E, Brun A (1991): Neuropathology of vascular dementia. 5th Congr. Int. Psychogeriatr. Ass. (IP), Rome, Italy, August 18 -23. Brun A (1992): Alzheimer -en demenssjukdom. Vandringar med Böcker. Bibliotekstjänst, Lund. Basun H, O Almquist, K Axelman , A Brun, T A Campbell, J Collinge, C Forsell . S Froelich , L-O Wahlund, L Wetterberg, L Lannfeldt (1997). Clinical characteristics of a family with chromosome 17 -linked rapidly progressive frontotemporal dementia . Arch Neurol, 54 : 539 -544 . Liu X and A Brun (1996): Regional and laminar synaptic pathology in frontal lobe degeneration of non-Alzheimer type. Int. J. Ger. Psych.11, 47-55. Liu X, C Erikson, A Brun (1996). Cortical synaptic changes and gliosis in normal aging, Alzheimer´s disease and frontal lobe degeneration. Dementia 7, 128-134. A 136 Brun A and Passant U (1996): Frontal lobe degeneration of non-Alzheimer type. Structural changes, diagnostic criteria and relation to other fronto-temporal dementias. Acta Neurol.Scand. Suppl 168 28 -30 . A Swedish state of the art document on dementia diseases .Eds L -O Wahlund , B Winblad . Ohlsson Y. A Brun, E Englund (1996): Fundamental pathological lesions in vascular dementia . Acta Neurol Scand Suppl 168, 31-38.A Swedish state of the art document on dementia diseases. ( 1997 ): Misclassification of dementia subtype using the Hachinski ischemic score : results of a meta-analysis of patients with pathologically verified dementias . Annals New York Academy of Sciences. 490 -492....