Focused Ultrasound as a Novel Non-Invasive Method for the Delivery of Gold Nanoparticles to Retinal Ganglion Cells.

Purpose: The blood-retinal barrier (BRB) restricts the delivery of intravenous therapeutics to the retina, necessitating innovative approaches for treating retinal disorders. This study sought to explore the potential of focused ultrasound (FUS) to non-invasively deliver intravenously administered gold nanoparticles (AuNPs) across the BRB. FUS-BRB modulation can offer a novel method for targeted retinal therapy. Methods: AuNPs of different sizes and shapes were characterized, and FUS parameters were optimized to permeate the BRB without causing retinal damage in a rodent model. The delivery of 70-kDa dextran and AuNPs to the retinal ganglion cell (RGC) layer was visualized using confocal and two-photon microscopy, respectively. Histological and statistical analyses were conducted to assess the effectiveness and safety of the procedure. Results: FUS-BRB modulation resulted in the delivery of dextran and AuNPs to the RGC and inner nuclear layer. Smaller AuNPs reached the retinal layers to a greater extent than larger ones. The delivery of dextran and AuNPs across the BRB with FUS was achieved without significant retinal damage. Conclusions: This investigation provides the first evidence, to our knowledge, of FUS-mediated AuNP delivery across the BRB, establishing a foundation for a targeted and non-invasive approach to retinal treatment. The results contribute to developing promising non-invasive therapeutic strategies in ophthalmology to treat retinal diseases. Translational Relevance: Modifying the BRB with ultrasound offers a targeted and non-invasive delivery strategy of intravenous therapeutics to the retina.

Optimal timing for drug delivery into the hippocampus by focused ultrasound: A comparison of hydrophilic and lipophilic compounds.

Aims: Previous studies have reported that focused ultrasound (FUS) helps modulate the blood-brain barrier (BBB). These studies have generally used the paracellular pathway owing to tight junction proteins (TJPs) regulation. However, BBB transport pathways also include diffusion and transcytosis. Few studies have examined transcellular transport across endothelial cells. We supposed that increased BBB permeability caused by FUS may affect transcytosis. We investigated drug delivery through transcytosis and paracellular transport to the brain after BBB modulation using FUS. Main methods: FUS and microbubbles were applied to the hippocampus of rats, and were euthanized at 1, 4, 24, and 48 h after sonication. To investigate paracellular transport, we analyzed TJPs, including zona occludens-1 (ZO-1) and occludin. We also investigated caveola-mediated transcytosis by analyzing caveola formation and major facilitator superfamily domain-containing 2a (Mfsd2a) levels, which inhibit caveola vesicle formation. Key findings: One hour after FUS, ZO-1 and occludin expression was the lowest and gradually increased over time, returning to baseline 24 h after FUS treatment. Compared with that of TJPs, caveola formation started to increase 1 h after FUS treatment and peaked at 4 h after FUS treatment before returning to baseline by 48 h after FUS treatment. Decreased Mfsd2a levels were observed at 1 h and 4 h after FUS treatment, indicating increased caveola formation. Significance: FUS induces BBB permeability changes and regulates both paracellular transport and caveola-mediated transcytosis. However, a time difference was observed between these two mechanisms. Hence, when delivering drugs into the brain after FUS, the optimal drug administration timing should be determined by the mechanism by which each drug passes through the BBB.

Radio frequency hyperthermia system for skin tightening effect by filled waveguide aperture antenna with compact metamaterials.

Radio frequency (RF) hyperthermia focuses on raising the target area temperature to a value exceeding 45°C. Collagen is stimulated when the temperature rises to 45°C at the dermal layer, resulting in skin tightening. However, most studies on RF hyperthermia have focused on tumor ablation or using electrodes to radiate an electromagnetic field, which is highly inefficient. This study proposed a non-invasive RF hyperthermia skin-tightening system with a compact metamaterial-filled waveguide aperture antenna. The proposed RF system increased the temperature by 11.6°C and 35.3°C with 20 and 80 W of 2.45 GHz RF power, respectively, within 60 s and exhibited a very focused effective area. Furthermore, a metamaterial was proposed to reduce the size of the waveguide aperture antenna and focus the electromagnetic field in the near-field region. The proposed metamaterial-filled waveguide aperture antenna was compact, measuring 10 mm × 17.4 mm, with a peak gain of 2.2 dB at 2.45 GHz. The measured hyperthermia performance indicated that the proposed RF system exhibited better power- and time-efficient hyperthermia performance than other RF hyperthermia systems in the cosmetic skin lifting commercial market. The proposed RF hyperthermia systems will be applied into a new generation of beauty cosmetic devices.

Arc-poration improves transdermal delivery of biomolecules.

BACKGROUND: To increase skin permeability, various transdermal delivery techniques have been developed. However, due to the stratum corneum as a skin barrier, transdermal delivery remains limited. AIMS: In this study, we evaluated efficacy and safety of arc-poration as a novel technique disrupting the stratum corneum. RESULTS: Optical images and histological analysis using reconstituted human skin and porcine skin showed that the treatment of arc-poration created micropores with an average diameter of approximately 100 µm only to the depth of the stratum corneum, but not viable epidermis. In addition, the Franz diffusion cell experiment using reconstituted human skin showed a remarkable increase in permeability following pretreatment with arc-poration. Clinical results clearly demonstrated the enhancement of the skin-improving effect of cosmetics by pretreatment of arc-poration in terms of gloss, hydration, flakiness, texture, tone, tone evenness, and pigmentation of skin, without causing abnormal skin responses. The concentration of ozone and nitrogen oxides generated by arc-poration was below the permissible value for the human body. CONCLUSIONS: Arc-poration can increase skin permeability by creating stratum corneum-specific micropores, which can enhance the skin-improving effect of cosmetics without adverse responses.

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 being 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 illuminated 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.

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.

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.

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.

Effect of Unmeasured Time Hours on Occupational Noise Exposure Assessment in the Shipbuilding Process in Korea.

Occupational noise is known to be one of the most hazardous risk factors, frequently exceeding the exposure limit thus causing hearing loss and other health outcomes among many field workers in various industries and workplaces. This study aims to characterize the levels of occupational noise exposure during the daily working hours and break periods (sampling preparation and lunch break), identify work-related characteristics affecting the noise exposure levels when including or excluding the break periods and finally determine the most effective approach for occupational noise exposure assessment by using the Korean and U.S. OSHA's guidelines. A total of 1575 workers employed by a large shipbuilding company participated in this study, and the historical exposure datasets of noise dosimeters, collected from 2016 to 2018, were classified by characteristics. A threshold level (TL) for the noise dosimeter was set as a value of 80 dBA during the break periods, including the preparation time for sampling instruments and one hour for the lunch break. The shipbuilding workers were exposed to high levels of occupational noise during the break periods, especially for those working in heating, grinding, and power processes in the painting-related departments. Out of 1575 samples, most cases were related to the preparation time (N = 1432, 90.9%) and lunch break (N = 1359, 86.9%). During the break time, the levels of noise exposure were measured depending on task-specific characteristics. When including the break time, the noise levels increased by approximately 1 dBA during the break, combining 0.8 dBA in the lunch hours and 0.2 dBA for the preparation of the sampling instrument. When excluding the break time, the levels of noise exposure collected using a Korean Occupational Safety and Health Administration (KOSHA) guide tended to be underestimated compared to those using the U.S. OSHA method. When including the break times, the proportion of noise exposure levels exceeding the compliance exposure limit declined from 37.9% to 34.5%, indicating that the break times might affect the decrease in the noise exposure levels. Taken together, shipbuilding workers could possibly be exposed to much greater amounts of noise exposure during break times in the shipbuilding processes, and the noise exposure levels in the department of painting were high. Therefore, it is recommended that industrial hygienists collect exposure monitoring data of occupational noise one hour after their job tasks begin and then consecutively monitor the noise exposure levels for at least 6 h including the break periods for each day.

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.

A novel rat robot controlled by electrical stimulation of the nigrostriatal pathway.

OBJECTIVE: Artificial manipulation of animal movement could offer interesting advantages and potential applications using the animal's inherited superior sensation and mobility. Although several behavior control models have been introduced, they generally epitomize virtual reward-based training models. In this model, rats are trained multiple times so they can recall the relationship between cues and rewards. It is well known that activation of one side of the nigrostriatal pathway (NSP) in the rat induces immediate turning toward the contralateral side. However, this NSP stimulation-induced directional movement has not been used for the purpose of animal-robot navigation. In this study, the authors aimed to electrically stimulate the NSP of conscious rats to build a command-prompt rat robot. METHODS: Repetitive NSP stimulation at 1-second intervals was applied via implanted electrodes to induce immediate contraversive turning movements in 7 rats in open field tests in the absence of any sensory cues or rewards. The rats were manipulated to navigate from the start arm to a target zone in either the left or right arm of a T-maze. A leftward trial was followed by a rightward trial, and each rat completed a total of 10 trials. In the control group, 7 rats were tested in the same way without NSP stimulation. The time taken to navigate the maze was compared between experimental and control groups. RESULTS: All rats in the experimental group successfully reached the target area for all 70 trials in a short period of time with a short interstimulus interval (< 0.7 seconds), but only 41% of rats in the control group reached the target area and required a longer period of time to do so. The experimental group made correct directional turning movements at the intersection zone of the T-maze, taking significantly less time than the control group. No significant difference in navigation duration for the forward movements on the start and goal arms was observed between the two groups. However, the experimental group showed quick and accurate movement at the intersection zone, which made the difference in the success rate and elapsed time of tasks. CONCLUSIONS: The results of this study clearly indicate that a rat-robot model based on NSP stimulation can be a practical alternative to previously reported models controlled by virtual sensory cues and rewards.

Non-invasively enhanced intracranial transplantation of mesenchymal stem cells using focused ultrasound mediated by overexpression of cell-adhesion molecules.

Although there have been reports of promising results regarding the transplantation of mesenchymal stem cells (MSCs) for neurodegenerative diseases through the use of neuronal differentiation or control of the microenvironment, traditional surgical transplantation methods like parenchymal or intravenous injection have limitations such as secondary injuries in the brain, infection, and low survival rate of stem cells in the target site. Focused ultrasound (FUS) treatment is an emerging modality for the treatment of brain diseases, including neurodegenerative disorders. The various biological effects of FUS treatment have been investigated; therefore, the goal is now to improve the delivery efficiency and function of MSCs by capitalizing on the advantages of FUS. In this study, we demonstrated that FUS increases MSC transplantation into brain tissue by >2-fold, and that this finding might be related to the activation of intercellular adhesion molecule-1 in endothelial and subendothelial cells and vascular adhesion molecule-1 in endothelial cells.

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-ß 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-ß 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.

Optimization of Medial Forebrain Bundle Stimulation Parameters for Operant Conditioning of Rats.

BACKGROUND: The medial forebrain bundle (MFB) is involved in the integration of pleasure and reward. Previous studies have used various stimulation parameters for operant conditioning, though the effectiveness of these parameters has not been systematically studied. OBJECTIVES: The purpose of the present study was to investigate the optimal MFB stimulation parameters for controlling the conditioned behavior of rats. METHODS: We evaluated four factors, including intensity, frequency, pulse duration, and train duration, to determine the effect of each on lever pressure applied by animals. We further compared burst and tonic stimulation in terms of learning and performance abilities. RESULTS: The number of lever presses increased with each factor. Animals in the burst stimulation group exhibited more lever presses. Furthermore, the average speed in the maze among burst stimulation group subjects was higher. CONCLUSION: We determined the optimal parameters for movement control of animals in operant conditioning and locomotor tasks by adjusting various electrical stimulation parameters. Our results reveal that a burst stimulation is more effective than a tonic stimulation for increasing the moving speed and number of lever presses. The use of this stimulation technique also allowed us to minimize the training required to control animal behavior.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

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.

Motor cortex stimulation and neuropathic pain: how does motor cortex stimulation affect pain-signaling pathways?

OBJECTIVE: Neuropathic pain is often severe. Motor cortex stimulation (MCS) is used for alleviating neuropathic pain, but the mechanism of action is still unclear. This study aimed to understand the mechanism of action of MCS by investigating pain-signaling pathways, with the expectation that MCS would regulate both descending and ascending pathways. METHODS: Neuropathic pain was induced in Sprague-Dawley rats. Surface electrodes for MCS were implanted in the rats. Tactile allodynia was measured by behavioral testing to determine the effect of MCS. For the pathway study, immunohistochemistry was performed to investigate changes in c-fos and serotonin expression; micro-positron emission tomography (mPET) scanning was performed to investigate changes of glucose uptake; and extracellular electrophysiological recordings were performed to demonstrate brain activity. RESULTS: MCS was found to modulate c-fos and serotonin expression. In the mPET study, altered brain activity was observed in the striatum, thalamic area, and cerebellum. In the electrophysiological study, neuronal activity was increased by mechanical stimulation and suppressed by MCS. After elimination of artifacts, neuronal activity was demonstrated in the ventral posterolateral nucleus (VPL) during electrical stimulation. This neuronal activity was effectively suppressed by MCS. CONCLUSIONS: This study demonstrated that MCS effectively attenuated neuropathic pain. MCS modulated ascending and descending pain pathways. It regulated neuropathic pain by affecting the striatum, periaqueductal gray, cerebellum, and thalamic area, which are thought to regulate the descending pathway. MCS also appeared to suppress activation of the VPL, which is part of the ascending pathway.

Longitudinal FDG microPET imaging of neuropathic pain: does cerebellar activity correlate with neuropathic pain development in a rat model?

BACKGROUND: We used [F-18] FDG microPET imaging as part of a longitudinal study to investigate changes in the brain. METHODS: Glucose metabolism during the development of neuropathic pain after tibial and sural nerve transection (TST) model rats. MicroPET images were obtained 1 week before operation and then weekly for 8 weeks post-operation. RESULTS: The behavioral test was performed immediately after the every FDG administration. After TST modeling, neuropathic pain rats showed increased mechanical sensitivity of the injured hind paw. The withdrawal response to mechanical pain stimulation by von Frey filaments was observed within the first week (3.8 ± 0.73), and it rapidly increased in the third week (7.13 ± 0.82). This response reached a peak in the fourth week after surgery (9.0 ± 0.53), which persisted until the eighth week. In microPET scan imaging, cerebellum, which initially started from the ansiform lobule, was activated gradually to all part from the third week in all image acquisitions through the eighth week. CONCLUSIONS: The longitudinal microPET scan study of brains from neuropathic pain rat models showed sequential cerebellar activity that was in accordance with results from behavioral test responses, thus supporting a role for the cerebellum in the development of neuropathic pain.

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.