Virginia Tech Carilion (VTC)
Permanent URI for this community
Browse
Browsing Virginia Tech Carilion (VTC) by Department "Electrical and Computer Engineering"
Now showing 1 - 6 of 6
Results Per Page
Sort Options
- Aging into Perceptual Control: A Dynamic Causal Modeling for fMRI Study of Bistable PerceptionDowlati, Ehsan; Adams, Sarah E.; Stiles, Alexandra; Moran, Rosalyn J. (Frontiers, 2016-03-31)Aging is accompanied by stereotyped changes in functional brain activations, for example a cortical shift in activity patterns from posterior to anterior regions is one hallmark revealed by functional magnetic resonance imaging (fMRI) of aging cognition. Whether these neuronal effects of aging could potentially contribute to an amelioration of or resistance to the cognitive symptoms associated with psychopathology remains to be explored. We used a visual illusion paradigm to address whether aging affects the cortical control of perceptual beliefs and biases. Our aim was to understand the effective connectivity associated with volitional control of ambiguous visual stimuli and to test whether greater top-down control of early visual networks emerged with advancing age. Using a bias training paradigm for ambiguous images we found that older participants (n = 16) resisted experimenter-induced visual bias compared to a younger cohort (n = 14) and that this resistance was associated with greater activity in prefrontal and temporal cortices. By applying Dynamic Causal Models for fMRI we uncovered a selective recruitment of top-down connections from the middle temporal to Lingual gyrus (LIN) by the older cohort during the perceptual switch decision following bias training. In contrast, our younger cohort did not exhibit any consistent connectivity effects but instead showed a loss of driving inputs to orbitofrontal sources following training. These findings suggest that perceptual beliefs are more readily controlled by top-down strategies in older adults and introduce age-dependent neural mechanisms that may be important for understanding aberrant belief states associated with psychopathology.
- Circadian dynamics in measures of cortical excitation and inhibition balanceChellappa, Sarah L.; Gaggioni, Giulia; Ly, Julien Q. M.; Papachilleos, Soterios; Borsu, Chloe; Brzozowski, Alexandre; Rosanova, Mario; Sarasso, Simone; Luxen, Andre; Middleton, Benita; Archer, Simon N.; Dijk, Derk-Jan; Massimini, Marcello; Maquet, Pierre; Phillips, Christophe; Moran, Rosalyn J.; Vandewalle, Gilles (Springer Nature, 2016-09-21)Several neuropsychiatric and neurological disorders have recently been characterized as dysfunctions arising from a 'final common pathway' of imbalanced excitation to inhibition within cortical networks. How the regulation of a cortical E/I ratio is affected by sleep and the circadian rhythm however, remains to be established. Here we addressed this issue through the analyses of TMS-evoked responses recorded over a 29 h sleep deprivation protocol conducted in young and healthy volunteers. Spectral analyses of TMS-evoked responses in frontal cortex revealed non-linear changes in gamma band evoked oscillations, compatible with an influence of circadian timing on inhibitory interneuron activity. In silico inferences of cell-to-cell excitatory and inhibitory connectivity and GABA/Glutamate receptor time constant based on neural mass modeling within the Dynamic causal modeling framework, further suggested excitation/inhibition balance was under a strong circadian influence. These results indicate that circadian changes in EEG spectral properties, in measure of excitatory/inhibitory connectivity and in GABA/glutamate receptor function could support the maintenance of cognitive performance during a normal waking day, but also during overnight wakefulness. More generally, these findings demonstrate a slow daily regulation of cortical excitation/inhibition balance, which depends on circadian-timing and prior sleep-wake history.
- Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporationHendricks-Wenger, Alissa; Aycock, Kenneth N.; Nagai-Singer, Margaret A.; Coutermarsh-Ott, Sheryl; Lorenzo, Melvin F.; Gannon, Jessica; Uh, Kyungjun; Farrell, Kayla; Beitel-White, Natalie; Brock, Rebecca M.; Simon, Alexander; Morrison, Holly A.; Tuohy, Joanne L.; Clark-Deener, Sherrie; Vlaisavljevich, Eli; Davalos, Rafael V.; Lee, Kiho; Allen, Irving C. (Nature Research, 2021-04-07)New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.
- High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunityRingel-Scaia, Veronica M.; Beitel-White, Natalie; Lorenzo, Melvin F.; Brock, Rebecca M.; Huie, Kathleen E.; Coutermarsh-Ott, Sheryl; Eden, Kristin; McDaniel, Dylan K.; Verbridge, Scott S.; Rossmeisl, John H. Jr.; Oestreich, Kenneth J.; Davalos, Rafael V.; Allen, Irving C. (2019-06)Background: Despite promising treatments for breast cancer, mortality rates remain high and treatments for metastatic disease are limited. High-frequency irreversible electroporation (H-FIRE) is a novel tumor ablation technique that utilizes high-frequency bipolar electric pulses to destabilize cancer cell membranes and induce cell death. However, there is currently a paucity of data pertaining to immune system activation following H-FIRE and other electroporation based tumor ablation techniques. Methods: Here, we utilized the mouse 4T1 mammary tumor model to evaluate H-FIRE treatment parameters on cancer progression and immune system activation in vitro and in vivo. Findings: H-FIRE effectively ablates the primary tumor and induces a pro-inflammatory shift in the tumor microenvironment. We further show that local treatment with H-FIRE significantly reduces 4T1 metastases. H-FIRE kills 4T1 cells through non-thermal mechanisms associated with necrosis and pyroptosis resulting in damage associated molecular pattern signaling in vitro and in vivo. Our data indicate that the level of tumor ablation correlates with increased activation of cellular immunity. Likewise, we show that the decrease in metastatic lesions is dependent on the intact immune system and H-FIRE generates 4T1 neoantigens that engage the adaptive immune system to significantly attenuate tumor progression. Interpretation: Cell death and tumor ablation following H-FIRE treatment activates the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a pro-inflammatory state. The non-thermal damage to the cancer cells and increased innate immune system stimulation improves antigen presentation, resulting in the engagement of the adaptive immune system and improved systemic anti-tumor immunity. (C) 2019 The Authors. Published by Elsevier B.V.
- Patient Derived Xenografts Expand Human Primary Pancreatic Tumor Tissue Availability for ex vivo Irreversible Electroporation TestingBrock, Rebecca M.; Beitel-White, Natalie; Coutermarsh-Ott, Sheryl; Grider, Douglas J.; Lorenzo, Melvin F.; Ringel-Scaia, Veronica M.; Manuchehrabadi, Navid; Martin, Robert C. G.; Davalos, Rafael V.; Allen, Irving C. (2020-05-22)New methods of tumor ablation have shown exciting efficacy in pre-clinical models but often demonstrate limited success in the clinic. Due to a lack of quality or quantity in primary malignant tissue specimens, therapeutic development and optimization studies are typically conducted on healthy tissue or cell-line derived rodent tumors that don't allow for high resolution modeling of mechanical, chemical, and biological properties. These surrogates do not accurately recapitulate many critical components of the tumor microenvironment that can impact in situ treatment success. Here, we propose utilizing patient-derived xenograft (PDX) models to propagate clinically relevant tumor specimens for the optimization and development of novel tumor ablation modalities. Specimens from three individual pancreatic ductal adenocarcinoma (PDAC) patients were utilized to generate PDX models. This process generated 15-18 tumors that were allowed to expand to 1.5 cm in diameter over the course of 50-70 days. The PDX tumors were morphologically and pathologically identical to primary tumor tissue. Likewise, the PDX tumors were also found to be physiologically superior to other in vitro and ex vivo models based on immortalized cell lines. We utilized the PDX tumors to refine and optimize irreversible electroporation (IRE) treatment parameters. IRE, a novel, non-thermal tumor ablation modality, is being evaluated in a diverse range of cancer clinical trials including pancreatic cancer. The PDX tumors were compared against either Pan02 mouse derived tumors or resected tissue from human PDAC patients. The PDX tumors demonstrated similar changes in electrical conductivity and Joule heating following IRE treatment. Computational modeling revealed a high similarity in the predicted ablation size of the PDX tumors that closely correlate with the data generated with the primary human pancreatic tumor tissue. Gene expression analysis revealed that IRE treatment resulted in an increase in biological pathway signaling associated with interferon gamma signaling, necrosis and mitochondria dysfunction, suggesting potential co-therapy targets. Together, these findings highlight the utility of the PDX system in tumor ablation modeling for IRE and increasing clinical application efficacy. It is also feasible that the use of PDX models will significantly benefit other ablation modality testing beyond IRE.
- Retinal-input-induced epigenetic dynamics in the developing mouse dorsal lateral geniculate nucleusHe, Jianlin; Xu, Xiguang; Monavarfeshani, Aboozar; Banerjee, Sharmi; Fox, Michael A.; Xie, Hehuang David (2019-02-14)DNA methylation plays important roles in the regulation of nervous system development and in cellular responses to environmental stimuli such as light-derived signals. Despite great efforts in understanding the maturation and refinement of visual circuits, we lack a clear understanding of how changes in DNA methylation correlate with visual activity in the developing subcortical visual system, such as in the dorsal lateral geniculate nucleus (dLGN), the main retino-recipient region in the dorsal thalamus. Here, we explored epigenetic dynamics underlying dLGN development at ages before and after eye opening in wild-type mice and mutant mice in which retinal ganglion cells fail to form. We observed that development-related epigenetic changes tend to co-localize together on functional genomic regions critical for regulating gene expression, while retinal-input-induced epigenetic changes are enriched on repetitive elements. Enhancers identified in neurons are prone to methylation dynamics during development, and activity-induced enhancers are associated with retinal-input-induced epigenetic changes. Intriguingly, the binding motifs of activity-dependent transcription factors, including EGR1 and members of MEF2 family, are enriched in the genomic regions with epigenetic aberrations in dLGN tissues of mutant mice lacking retinal inputs. Overall, our study sheds new light on the epigenetic regulatory mechanisms underlying the role of retinal inputs on the development of mouse dLGN.