Rostral Agranular Insular Cortex Lesion with Motor Cortex Stimulation Enhances Pain Modulation Effect on Neuropathic Pain Model

It is well known that the insular cortex is involved in the processing of painful input. The aim of this study was to evaluate the pain modulation role of the insular cortex during motor cortex stimulation (MCS). After inducing neuropathic pain (NP) rat models by the spared nerve injury method, we made a lesion on the rostral agranular insular cortex (RAIC) unilaterally and compared behaviorally determined pain threshold and latency in 2 groups: Group A (NP + MCS; n = 7) and Group B (NP + RAIC lesion + MCS; n = 7). Also, we simultaneously recorded neuronal activity (NP; n = 9) in the thalamus of the ventral posterolateral nucleus and RAIC to evaluate electrophysiological changes from MCS. The pain threshold and tolerance latency increased in Group A with "MCS on" and in Group B with or without "MCS on." Moreover, its increase in Group B with "MCS on" was more than that of Group B without MCS or of Group A, suggesting that MCS and RAIC lesioning are involved in pain modulation. Compared with the "MCS off" condition, the "MCS on" induced significant threshold changes in an electrophysiological study. Our data suggest that the RAIC has its own pain modulation effect, which is influenced by MCS.ope

Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model

BACKGROUND: The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer's disease (AD). The neuropathologies of AD include the presence of amyloid-β deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-β proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia. METHODS: Adult male Sprague-Dawley rats (n = 48; 200-250 g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2'-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey's multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P < 0.05 was considered significant. RESULTS: Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P < 0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P < 0.05), early growth response protein 1 (EGR1) (P < 0.01), AHN (P < 0.01), and acetylcholinesterase activity in the frontal cortex (P < 0.05) and hippocampus (P < 0.01) and crossing over (P < 0.01) the platform in the Morris water maze relative to the SAP group after sonication. CONCLUSIONS: FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD.ope

The synergistic effect of focused ultrasound and biophotonics to overcome the barrier of light transmittance in biological tissue

Optical technology is a tool to diagnose and treat human diseases. Shallow penetration depth caused by the high optical scattering nature of biological tissues is a significant obstacle to utilizing light in the biomedical field. In this paper, light transmission enhancement in the rat brain induced by focused ultrasound (FUS) was observed and the cause of observed enhancement was analyzed. Both air bubbles and mechanical deformation generated by FUS were cited as the cause. The Monte Carlo simulation was performed to investigate effects on transmission by air bubbles and finite element method was also used to describe mechanical deformation induced by motions of acoustic particles. As a result, it was found that the mechanical deformation was more suitable to describe the transmission change according to the FUS pulse observed in the experiment.ope

Combined Effects of Focused Ultrasound and Photodynamic Treatment for Malignant Brain Tumors Using C6 Glioma Rat Model

Purpose: Glioblastoma (GBM) is an intractable disease for which various treatments have been attempted, but with little effect. This study aimed to measure the effect of photodynamic therapy (PDT) and sonodynamic therapy (SDT), which are currently be ing used to treat brain tumors, as well as sono-photodynamic therapy (SPDT), which is the combination of these two. Materials and Methods: Four groups of Sprague-Dawley rats were injected with C6 glioma cells in a cortical region and treated with PDT, SDT, and SPDT. Gd-MRI was monitored weekly and 18F-FDG-PET the day before and 1 week after the treatment. The acoustic power used during sonication was 5.5 W/cm2 using a 0.5-MHz single-element transducer. The 633-nm laser was illumi nated at 100 J/cm2. Oxidative stress and apoptosis markers were evaluated 3 days after treatment using immunohistochemistry (IHC): 4-HNE, 8-OhdG, and Caspase-3. Results: A decrease in tumor volume was observed in MRI imaging 12 days after the treatment in the PDT group (p<0.05), but the SDT group showed a slight increase compared to the 5-Ala group. The high expression rates of reactive oxygen species-related factors, such as 8-OhdG (p<0.001) and Caspase-3 (p<0.001), were observed in the SPDT group compared to other groups in IHC. Conclusion: Our findings show that light with sensitizers can inhibit GBM growth, but not ultrasound. Although SPDT did not show the combined effect in MRI, high oxidative stress was observed in IHC. Further studies are needed to investigate the safety parameters to apply ultrasound in GBM.ope

Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model

Background: Aducanumab (Adu), which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid, has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose (10 mg/kg) of the drug in Alzheimer's disease (AD) clinical trials. The purpose of this study was to investigate the effects of a lower dose of Adu (3 mg/kg) with enhanced delivery via focused ultrasound (FUS) in an AD mouse model. Methods: The FUS with microbubbles opened the blood-brain barrier (BBB) of the hippocampus for the delivery of Adu. The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly. Y-maze test, Brdu labeling, and immunohistochemical experimental methods were employed in this study. In addition, RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals. Results: The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains. The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone. Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice. Furthermore, RNA sequencing identified that 4 enriched canonical pathways including phagosome formation, neuroinflammation signaling, CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment. Conclusion: In conclusion, the enhanced delivery of a low dose of Adu (3 mg/kg) via FUS decreases amyloid deposits and attenuates cognitive function deficits. FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery. We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.ope

The neuromodulation of neuropathic pain by measuring pain response rate and pain response duration in animal

OBJECTIVE: Neuropathic pain causes patients feel indescribable pain. Deep Brain Stimulation (DBS) is one of the treatment methods in neuropathic pain but the action mechanism is still unclear. To study the effect and mechanism of analgesic effects from DBS in neuropathic pain and to enhance the analgesic effect of DBS, we stimulated the ventral posterolateral nucleus (VPL) in rats. METHODS: To observe the effect from VPL stimulation, we established 3 groups : normal group (Normal group), neuropathic pain group (Pain group) and neuropathic pain+DBS group (DBS group). Rats in DBS group subjected to electrical stimulation and the target is VPL. RESULTS: We observed the behavioral changes by DBS in VPL (VPL-DBS) on neuropathic pain rats. In our study, the pain score which is by conventional test method was effectively decreased. In specific, the time of showing withdrawal response from painful stimulation which is not used measuring method in our animal model was also decreased by DBS. CONCLUSION: The VPL is an effective target on pain modulation. Specifically we could demonstrate changes of pain response duration which is not used, and it was also significantly meaningful. We thought that this study would be helpful in understanding the relation between VPL-DBS and neuropathic pain.ope

Factors Associated with Energy Efficiency of Focused Ultrasound Through the Skull: A Study of 3D-Printed Skull Phantoms and Its Comparison with Clinical Experiences

While focused ultrasound (FUS) is non-invasive, the ultrasound energy is attenuated by the skull which results in differences in energy efficiency among patients. In this study, we investigated the effect of skull variables on the energy efficiency of FUS. The thickness and density of the skull and proportion of the trabecular bone were selected as factors that could affect ultrasound energy transmittance. Sixteen 3D-printed skull models were designed and fabricated to reflect the three factors. The energy of each phantom was measured using an ultrasonic sound field energy measurement system. The thickness and proportion of trabecular bone affected the attenuation of transmitted energy. There was no difference in the density of the trabecular bone. In clinical data, the trabecular bone ratio showed a significantly greater correlation with dose/delivered energy than that of thickness and the skull density ratio. Currently, for clinical non-thermal FUS, the data are not sufficient, but we believe that the results of this study will be helpful in selecting patients and appropriate parameters for FUS treatment.ope

Predicting successful defibrillation in ventricular fibrillation using WAFO and DENFIS

의공학과/박사[한글] 본 논문은 심실세동시 심전도 신호를 wave analysis for fatigue and oceanography(WAFO) 분석 방법을 이용하여 파라미터를 추출하고 dynamic evolving neural-fuzzy inference system(DENFIS)을 이용하여 소생성공 여부를 예측하는 연구이다.심실세동을 치료하는 방법에는 제세동, 심폐소생술, 약물투여 등이 있으며 이러한 치료에 의해 혈액흐름이 증가되면서 심장이 정상상태로 돌아오게 된다. 제세동은 심폐소생술 중에 자연 순환을 회복시킬 수 있는 결정적인 방법이지만 반복적인 제세동은 심근세포를 손상시켜 소생 이후에 심각한 후유증을 가져올 수 있다. 따라서 제세동의 성공여부를 예측하는 것은 반복적인 제세동을 방지하고 심폐소생술 등의 처치효과에 대한 분석을 가능하게 한다.본 연구에서는 제세동 성공을 예측하기 위해 총 15마리의 개에 대해 표준 심폐소생술 프로토콜을 실시하였고, 획득한 데이터를 30초씩 총5개의 A~E 구간으로 나누었다. 심폐소생술로 인한 동잡음을 제거하였 으며 WAFO 분석방법을 이용하여 불규칙도, 왜도, 첨도, 스펙트럼 모멘트, 위험도, 평균 레벨교차 스펙트럼 파워, 평균 알파-유효 지수를 특징 파라미터로 추출하였다. ROSC와 non-ROSC에 대한 각 파라미터들의 판별도를 평가하기 위해 t-test 를 적용했으며, 구간별로 가장 판별도가 높은 두 개의 파라미터를 선택하여 제세동 성공예측을 위한 추론 시스템의 입력 변수로 사용하였다. 추론 시스템은 기존의 뉴로-퍼지 기법의 단점인 연산속도를 향상시키고 입력의 특성에 따라 시스템 사용 중에도 새로운 퍼지 규칙들을 생성하고 갱신할 수 있도록 온라인 성능을 강화시킨 DENFIS에 의해 최종적인 제세동 예측지수를 구하였으며 다음과 같은 결론을 얻었다.(1) 스펙트럼 모멘트 , 스펙트럼 모멘트 , 평균 파워 스펙트럼, 평균 알파-유효 지수, 스펙트럼 모멘트 , 평균 주파수, 불규칙도, 위험도, 왜도, 첨도의 순서로 판별도가 높게 나타났다.(2) A구간에서는 평균 주파수, B 구간에서는 불규칙도, C 구간에서는 스펙트럼 모멘트 , D 구간에서는 스펙트럼 모멘트 , E 구간에서는 평균 레벨교차 스펙트럼 파워가 각각 가장 판별도가 높은 파라미터로 나타났다.(3) 구간별로 판별도가 높은 기준으로 보면, E > D > A > C > B 의 순서로 나타났다.(4) 구간별 소생 예측 성능은 A구간의 민감도와 특이도가 각각 83.3%와 77.8%로 가장 높았고, 정예측도와 부예측도도 각각 71.4%와 87.5%로 A구간이 가장 높았다.(5) 평균적으로는 민감도와 특이도가 각각 62.5%와 75.0%로 특이도가 더 높게 나타났고, 정예측도와 부예측도의 경우 각각 61.2%와 75.8%로 부예측도가 더 높게 나타났으며, 전체적으로 볼 때 소생 실패에 대한 예측성능이 소생 성공에 대한 예측성능보다 높게 나타났다. [영문]This paper described predicting successful defibrillation in ventricular fibrillation using parameters extracted by WAFO analyzing method and DENFIS method which is one of neuro-fuzzy algorithms. Treating methods for removing ventricular fibrillation were introduced to defibrillation, cardiopulmonary resuscitation(CPR), and drug administration. These treating methods result to increase blood-flow in the body and to help a heart to be recovered from abnormal status. Even though the defibrillation is ultimate treating method to recover a heart into the natural circulating status, this method can be caused to damage heart muscles by repeating defibrillations. Therefore, the predicting that defibrillation can result to be success or not helps to prevent repeated and unnecessary defibrillation and to analyze the effectiveness of a treatment by cardiopulmonary resuscitation.In this paper, total 15 dogs were tested for predicting successful defibrillation. The FIS band-pass filter of 5~30Hz was used for removing CPR and noise from ECG signals. Then feature parameters were extracted for discriminating return of spontaneous circulation(ROSC) and non-ROSC by WAFO method, and these parameters are an irregularity factor, skew, kurtosis, spectral moment, damage factor, mean of level-crossing spectrum power, and mean of -significant value. Additionally, two parameters by analyzing method of frequency were extracted into a mean of power spectrum and a mean frequency. Then extracted parameters were analyzed in which parameters result to have high performance of discriminating ROSC and non-ROSC by a statistical method of t-test, and final results show as follows:(1) The performance of discriminating parameter resulted in the order of a low value: spectral moment , spectral moment , mean of spectrum power, mean of -significant value, spectral moment , mean frequency, irregulariy factor, damage factor, skew and kurtosis(2) The parameters with the lowest value during the period A, B, C, D, and E were mean frequency, irregularity factor, spectral moment , spectral moment , and mean of level-crossing spectrum power, respectively.(3) The period resulted in the order of a good performance of discriminating ROSC and non-ROSC: E > D > A > C > B(4) The period ‘A’ resulted in the most good predicting performance which sensitivity, specificity, positive predictive factor, and negative predictive factor were 83.3%, 77.8%, 71.4%, and 87.5%, respectively.(5) The average of sensitivity, specificity, positive predictive factor, and negative predictive factor resulted in 62.5%, 75.0%, 61.2%, and 75.8%, respectively. From this result, as a whole, the predicting non-ROSC had more good performance than the predicting ROSC.ope

Detecting bladder fullness through the ensemble activity patterns of the spinal cord unit population in a somatovisceral convergence environment

OBJECTIVE: Chronic monitoring of the state of the bladder can be used to notify patients with urinary dysfunction when the bladder should be voided. Given that many spinal neurons respond both to somatic and visceral inputs, it is necessary to extract bladder information selectively from the spinal cord. Here, we hypothesize that sensory information with distinct modalities should be represented by the distinct ensemble activity patterns within the neuronal population and, therefore, analyzing the activity patterns of the neuronal population could distinguish bladder fullness from somatic stimuli. APPROACH: We simultaneously recorded 26-27 single unit activities in response to bladder distension or tactile stimuli in the dorsal spinal cord of each Sprague-Dawley rat. In order to discriminate between bladder fullness and tactile stimulus inputs, we analyzed the ensemble activity patterns of the entire neuronal population. A support vector machine (SVM) was employed as a classifier, and discrimination performance was measured by k-fold cross-validation tests. MAIN RESULTS: Most of the units responding to bladder fullness also responded to the tactile stimuli (88.9-100%). The SVM classifier precisely distinguished the bladder fullness from the somatic input (100%), indicating that the ensemble activity patterns of the unit population in the spinal cord are distinct enough to identify the current input modality. Moreover, our ensemble activity pattern-based classifier showed high robustness against random losses of signals. SIGNIFICANCE: This study is the first to demonstrate that the two main issues of electroneurographic monitoring of bladder fullness, low signals and selectiveness, can be solved by an ensemble activity pattern-based approach, improving the feasibility of chronic monitoring of bladder fullness by neural recording.ope

Machine learning-based feature combination analysis for odor-dependent hemodynamic responses of rat olfactory bulb

Rodents have a well-developed sense of smell and are used to detect explosives, mines, illegal substances, hidden currency, and contraband, but it is impossible to keep their concentration constantly. Therefore, there is an ongoing effort to infer odors detected by animals without behavioral readings with brain-computer interface (BCI) technology. However, the invasive BCI technique has the disadvantage that long-term studies are limited by the immune response and electrode movement. On the other hand, near-infrared spectroscopy (NIRS)-based BCI technology is a non-invasive method that can measure neuronal activity without worrying about the immune response or electrode movement. This study confirmed that the NIRS-based BCI technology can be used as an odor detection and identification from the rat olfactory system. In addition, we tried to present features optimized for machine learning models by extracting six features, such as slopes, peak, variance, mean, kurtosis, and skewness, from the hemodynamic response, and analyzing the importance of individuals or combinations. As a result, the feature with the highest F1-Score was indicated as slopes, and it was investigated that the combination of the features including slopes and mean was the most important for odor inference. On the other hand, the inclusion of other features with a low correlation with slopes had a positive effect on the odor inference, but most of them resulted in insignificant or rather poor performance. The results presented in this paper are expected to serve as a basis for suggesting the development direction of the hemodynamic response-based bionic nose in the future.restrictio