A randomized clinical study on postoperative pain comparing between the supraglottic airway device and endotracheal tubing in transabdominal preperitoneal repair (TAPP).

BACKGROUND: Transabdominal preperitoneal (TAPP) repair is the most widely used laparoscopic technique for the treatment of inguinal hernia in Japan. Many studies have shown that in comparison with open hernia repair, laparoscopic repair results in less pain and a shorter convalescence. However, postoperative pain remains a concern. One possible cause of postoperative pain in the early postoperative phase is strain or cough on removal of the endotracheal tube. Use of a supraglottic airway (SGA) device helps to avoid such complaints. We evaluated postoperative pain after TAPP repair using the SGA for general anesthesia. METHODS: We evaluated the postoperative pain in 146 patients with inguinal hernia repaired by TAPP in our hospital between May 2013 and May 2016. A total of 144 adult patients of American Society of Anesthesiologists physical status I and II who underwent needlescopic TAPP surgery were randomly allocated to one of two groups of 72 patients: group A (SGA), in which the patient's airway was secured with an appropriately sized I-gel, and group B (endotracheal tube), in which the airway was secured under laryngoscopy. RESULTS: There was no significant difference between the groups regarding patient background, postoperative hospital stay, and operation time, and TAPP was performed safely in all cases. In the analysis of postoperative pain, the mean Numerical Rating Scale score of peak pain in group A was significantly less than that of group B (2.10 ± 2.05 vs 2.90 ± 2.65; p = 0.043). In group A, the percentage of patients who had an NRS score of 0 was 51.4% 30 min after surgery, 62.5% after 6 h and 68.1% at POD1, and compared to group B, the NRS scores were significantly higher at POD1 (p = 0.003), and the level of postoperative pain in group A tended to decrease earlier than that in group B. CONCLUSIONS: The results of this study are the first to show that an SGA device can reduce postoperative pain after laparoscopic surgery.

Impact of videogame play on the brain's microstructural properties: cross-sectional and longitudinal analyses.

Videogame play (VGP) has been associated with numerous preferred and non-preferred effects. However, the effects of VGP on the development of microstructural properties in children, particularly those associated with negative psychological consequences of VGP, have not been identified to date. The purpose of this study was to investigate this issue through cross-sectional and longitudinal prospective analyses. In the present study of humans, we used the diffusion tensor imaging mean diffusivity (MD) measurement to measure microstructural properties and examined cross-sectional correlations with the amount of VGP in 114 boys and 126 girls. We also assessed correlations between the amount of VGP and longitudinal changes in MD that developed after 3.0±0.3 (s.d.) years in 95 boys and 94 girls. After correcting for confounding factors, we found that the amount of VGP was associated with increased MD in the left middle, inferior and orbital frontal cortex; left pallidum; left putamen; left hippocampus; left caudate; right putamen; right insula; and thalamus in both cross-sectional and longitudinal analyses. Regardless of intelligence quotient type, higher MD in the areas of the left thalamus, left hippocampus, left putamen, left insula and left Heschl gyrus was associated with lower intelligence. We also confirmed an association between the amount of VGP and decreased verbal intelligence in both cross-sectional and longitudinal analyses. In conclusion, increased VGP is directly or indirectly associated with delayed development of the microstructure in extensive brain regions and verbal intelligence.

Development of an eyewear to measure eye and body movements.

To enable precise detection of mental and physical states of users in a daily life, we have been developing an eyewear to measure eye and body movement in a unrestricted way. The horizontal and vertical EOG (electrooculogram) signals are measured and amplified with three metal dry electrodes placed near nasion and both sides of rhinion, of which positions correspond to the bridge and nose pads of eyewear, respectively. The user's mental states like drowsiness, sleepiness, fatigue, or interest to objects can be identified by the movements and blinking of the eyes extracted from the measured EOG. And the six-axis motion sensor (three-axis accelerometer and three-axis gyroscope) mounted in the eyewear measures the body motion. As the sensor located near the head is on the body axis, this eyewear is suitable to measure user's movement or shift of center of gravity during physical exercise with a high precision. The measured signals are used to extract various events of eye and body movement by the mounted microcontroller chip, or can be transmitted to the external devices via Bluetooth communication. This device can enable you to look into "yourself", as well as outer scenes. In this presentation, the outline of the eyewear is introduced and some possible applications are shown.

Angular sway propagation in One Leg Stance and quiet stance with Inertial Measurement Units for older adults.

Postural stability degrades with age, threating the health and life quality of the older adults. One Leg Stance (OLS) is one of the standard and commonly adopted assessments for postural stability, and the postural sway in OLS has been demonstrated to be related with age. The propagation of postural sway between body segments could be a hint to the underlying mechanism of balance control. However, it is not yet fully understood. Therefore, the aim of this paper was to study the angular sways and their propagation of the head, trunk, and lower limb in healthy older adults. A cross-correlation of the normalized angular speeds was performed and the experiment with 68 older adults was conducted. The results showed that the head, hip and ankle joints affected the transfer of angular sway with a relatively lower correlation and longer latency.

Therapeutic adenoviral gene transfer of a glycosyltransferase for prevention of peritoneal dissemination and metastasis of gastric cancer.

Increased expression of sialyl Lewis(x/a) carbohydrates, ligands for E-selectin, correlates with clinically advanced stages and metastasis of gastric and colon cancers. In contrast, Sd(a) carbohydrate is abundantly detected in the normal gastrointestinal mucosa but dramatically reduced or lost in cancer tissues. A glycosyltransferase, ß1,4N-acetylgalactosaminyltransferase 2 (B4GALNT2) that catalyzes Sd(a) carbohydrate synthesis, is silenced in cancer. In the present study, we aimed at reducing the expression of sialyl Lewis(x/a) of cancer cells in vivo by forced expression of B4GALNT2 and Sd(a), thereby preventing dissemination/metastasis, especially metastasis triggered by surgical maneuvers. We used a fiber-modified adenovirus (Ad) vector that contained a chimeric construct with a serotype 5 shaft and a serotype 3 knob. Using this Ad5/3 vector, we successfully introduced the B4GALNT2 gene into a human gastric cancer cell line KATO III in vitro and confirmed replacement of sialyl Lewis(x) to Sd(a) with a decrease in E-selectin-dependent adhesion. Administration of Ad5/3-B4GALNT2 vectors into the peritoneal cavity of mice after inoculation of KATO III cells with laparotomy significantly reduced the incidence of metastasis. Our results indicate that the transfer of a single gene encoding B4GALNT2 modified carbohydrate chains of cancer cells in vivo and decreased tumor dissemination and metastasis.

Brain structural changes as vulnerability factors and acquired signs of post-earthquake stress.

Many survivors of severe disasters, even those without posttraumatic stress disorder (PTSD), need psychological support. To understand the pathogenesis of PTSD symptoms and prevent the development of PTSD, the critical issue is to distinguish neurological abnormalities as vulnerability factors from acquired signs of PTSD symptoms in the early stage of adaptation to the trauma in the normal population. The neurological underpinnings of PTSD have been well characterized, but the causal relationships with the traumatic event are still unclear. We examined 42 non-PTSD subjects to find brain morphometric changes related to the severity of PTSD symptoms in a longitudinal magnetic resonance imaging study extending through the Great East Japan Earthquake. We found that regional grey matter volume (rGMV) in the right ventral anterior cingulate cortex (ACC) before the earthquake, and decreased rGMV in the left orbitofrontal cortex (OFC) through the earthquake were negatively associated with PTSD symptoms. Our results indicate that subjects with smaller GMV in the ACC before the earthquake, and subjects with decreased GMV in the OFC through the earthquake were likely to have PTSD symptoms. As the ACC is involved in processing of fear and anxiety, our results indicate that these processing are related to vulnerability for PTSD symptoms. In addition, decreased OFC volume was induced by failing to extinct conditioned fear soon after the traumatic event. These findings provide a better understanding of posttraumatic responses in early stage of adaptation to the trauma and may contribute to the development of effective methods to prevent PTSD.

Quantifying the uncertainty of spontaneous Ca2+ oscillations in astrocytes: particulars of Alzheimer's disease.

The quantification of spontaneous calcium (Ca(2+)) oscillations (SCOs) in astrocytes presents a challenge because of the large irregularities in the amplitudes, durations, and initiation times of the underlying events. In this article, we use a stochastic context to account for such SCO variability, which is based on previous models for cellular Ca(2+) signaling. First, we found that passive Ca(2+) influx from the extracellular space determine the basal concentration of this ion in the cytosol. Second, we demonstrated the feasibility of estimating both the inositol 1,4,5-trisphosphate (IP(3)) production levels and the average number of IP(3) receptor channels in the somatic clusters from epifluorescent Ca(2+) imaging through the combination of a filtering strategy and a maximum-likelihood criterion. We estimated these two biophysical parameters using data from wild-type adult mice and age-matched transgenic mice overexpressing the 695-amino-acid isoform of human Alzheimer ß-amyloid precursor protein. We found that, together with an increase in the passive Ca(2+) influx, a significant reduction in the sensitivity of G protein-coupled receptors might lie beneath the abnormalities in the astrocytic Ca(2+) signaling, as was observed in rodent models of Alzheimer's disease. This study provides new, to our knowledge, indices for a quantitative analysis of SCOs in normal and pathological astrocytes.

Multiphoton fluorescent images with a spatially varying background signal: a ML deconvolution method.

By means of multiphoton laser scanning microscopy, neuroscientists can look inside the brain deeper than has ever been possible before. Multiphoton fluorescent images, as all optical images, suffer from degradation caused by a variety of sources (e.g. light dispersion and absorption in the tissue, laser fluctuations, spurious photodetection and staining deficiency). From a modelling perspective, such degradations can be considered the sum of stochastic noise and a background signal. Among the methods proposed in the literature to perform image deconvolution in either confocal or multiphoton fluorescent microscopy, Vicidomini et al. (2009) were the first to incorporate models for noise (a Poisson process) and background signal (spatially constant) in the context of regularized inverse problems. Unfortunately, the so-called split-gradient deconvolution method (SGM) they used did not consider possible spatial variations in the background signal. In this paper, we extend the SGM by adding a maximum-likelihood estimation step for the determination of a spatially varying background signal. We demonstrate that the assumption of a constant background is not always valid in multiphoton laser microscopy and by using synthetic and actual multiphoton fluorescent images, we evaluate the face of validity of the proposed method, and compare its accuracy with the previously introduced SGM algorithm.

Modeling the spontaneous Ca2+ oscillations in astrocytes: Inconsistencies and usefulness.

Spontaneous calcium (Ca2+) oscillations (SCOs) in astrocytes might be a crucial signaling for the multipurpose role of this type of cell in several brain functions. To interpret experimental data of astrocytic SCOs, which has been largely observed in the last decade, several groups have attempted to accommodate biophysical models that were developed in the past for Ca2+ signaling in other cell types. In most of the cases, only predictive strategies were used to estimate specific parameters of these modified models from actual experiments. In this study, we discuss the most remarkable models used to describe Ca2+ signaling in astrocytes. At the same time, we aim to revise the particulars of applying these models to interpret epifluorescent time series obtained from large regions of interest. Specially, we developed a detailed model for global Ca2+ signaling in the somata of astrocytes. In order to estimate some of the parameters in our model, we propose a deductive reasoning strategy, i.e., a statistical inference method that results from combining a filtering technique and a maximum likelihood principle. By means of computer simulations, we evaluate the accuracy of this estimation's strategy. Finally, we use the new model, in combination with a recent experimental findings by our group, to estimate the degree of cluster coupling inside the soma during the genesis of global Ca2+ events.

Spatio-temporal correlations from fMRI time series based on the NN-ARx model.

For the purpose of statistical characterization of the spatio-temporal correlation structure of brain functioning from high-dimensional fMRI time series, we introduce an innovation approach. This is based on whitening the data by the Nearest-Neighbors AutoRegressive model with external inputs (NN-ARx). Correlations between the resulting innovations are an extension of the usual correlations, in which mean-correction is carried out by the dynamic NN-ARx model instead of the static, standard linear model for fMRI time series. Measures of dependencies between regions are defined by summarizing correlations among innovations at several time lags over pairs of voxels. Such summarization does not involve averaging the data over each region, which prevents loss of information in case of non-homogeneous regions. Statistical tests based on these measures are elaborated, which allow for assessing the correlation structure in search of connectivity. Results of application of the NN-ARx approach to fMRI data recorded in visual stimuli experiments are shown. Finally, a number of issues related with its potential and limitations are commented.

E1A, E1B double-restricted replicative adenovirus at low dose greatly augments tumor-specific suicide gene therapy for gallbladder cancer.

Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 x 10(7) PFU, plaque-forming unit) plus AxCEAprTK (2 x 10(8) PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 x 10(7) PFU)/GCV or AxCEAprTK (2 x 10(9) PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.

A nursing tool validated as an effective measure over MMSE and FAB in dementia.

AIM: To evaluate the clinical use of the Abilities Assessment Instrument (AAI) when used together with Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB), thus examining the concurrent validity of the instrument. Also, to evaluate the effect of a learning program administered for elders with dementia. METHODS: Fourteen older people, who were afflicted with Alzheimer's disease or related dementias, were invited into a learning program. Measures were taken at baseline, at 3 months and 6 months to see the effects of the program. Instruments used in the study were the AAI, the MMSE and the FAB. FINDINGS: There were statistically significant differences measured by the Japanese version of the AAI in the subjects' abilities to perform the learning tasks between 3 and 6 months after intervention. No statistical significant differences were noted at any points in time measured by the MMSE or the FAB. CONCLUSION: The translated AAI promises to be a valid instrument for nurses' use in their day-to-day assessment of Japanese elders. The AAI appears also to be useful in learning programs with this population, and may have value as a screening tool.

Nonlinear local electrovascular coupling. II: From data to neuronal masses.

In the companion article a local electrovascular coupling (LEVC) model was proposed to explain the continuous dynamics of electrical and vascular states within a cortical unit. These states produce certain mesoscopic reflections whose discrete time series can be reconstructed from electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). In this article we develop a recursive optimization algorithm based on the local linearization (LL) filter and an innovation method to make statistical inferences about the LEVC model from both EEG and fMRI data, i.e., to estimate the unobserved states and the unknown parameters of the model. For a better understanding, the LL filter is described from a Bayesian point of view, providing the particulars for the case of hybrid data (e.g., EEG and fMRI), which could be sampled at different rates. The dynamics of the exogenous synaptic inputs going into the cortical unit are also estimated by introducing a set of Gaussian radial basis functions. In order to study the dynamics of the electrical and vascular states in the striate cortex of humans as well as their local interrelationships, we applied this algorithm to EEG and fMRI recordings obtained concurrently from two subjects while passively observing a radial checkerboard with a white/black pattern reversal. The EEG and fMRI data from the first subject was used to estimate the electrical/vascular states and parameters of the LEVC model in V1 for a 4.0 Hz reversion frequency. We used the EEG data from the second subject to investigate the changes in the dynamics of the electrical states when the frequency of reversion is varied from 0.5-4.0 Hz. Then we made use of the estimated electrical states to predict the effects on the vasculature that such variations produce.

Fusing EEG and fMRI based on a bottom-up model: inferring activation and effective connectivity in neural masses.

The elucidation of the complex machinery used by the human brain to segregate and integrate information while performing high cognitive functions is a subject of imminent future consequences. The most significant contributions to date in this field, known as cognitive neuroscience, have been achieved by using innovative neuroimaging techniques, such as electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI), which measure variations in both the time and the space of some interpretable physical magnitudes. Extraordinary maps of cerebral activation involving function-restricted brain areas, as well as graphs of the functional connectivity between them, have been obtained from EEG and fMRI data by solving some spatio-temporal inverse problems, which constitutes a top-down approach. However, in many cases, a natural bridge between these maps/graphs and the causal physiological processes is lacking, leading to some misunderstandings in their interpretation. Recent advances in the comprehension of the underlying physiological mechanisms associated with different cerebral scales have provided researchers with an excellent scenario to develop sophisticated biophysical models that permit an integration of these neuroimage modalities, which must share a common aetiology. This paper proposes a bottom-up approach, involving physiological parameters in a specific mesoscopic dynamic equations system. Further observation equations encapsulating the relationship between the mesostates and the EEG/fMRI data are obtained on the basis of the physical foundations of these techniques. A methodology for the estimation of parameters from fused EEG/fMRI data is also presented. In this context, the concepts of activation and effective connectivity are carefully revised. This new approach permits us to examine and discuss some future prospects for the integration of multimodal neuroimages.

fMRI activation maps based on the NN-ARx model.

The most significant progresses in the understanding of human brain functions have been possible due to the use of functional magnetic resonance imaging (fMRI), which when used in combination with other standard neuroimaging techniques (i.e., EEG) provides researchers with a potential tool to elucidate many biophysical principles, established previously by animal comparative studies. However, to date, most of the methods proposed in the literature seeking fMRI signs have been limited to the use of a top-down data analysis approach, thus ignoring a pool of physiological facts. In spite of the important contributions achieved by applying these methods to actual data, there is a disproportionate gap between theoretical models and data-analysis strategies while trying to focus on several new prospects, like for example fMRI/EEG data fusion, causality/connectivity patterns, and nonlinear BOLD signal dynamics. In this paper, we propose a new approach which will allow many of the abovementioned hot topics to be addressed in the near future with an underlying interpretability based on bottom-up modeling. In particular, the theta-MAP presented in the paper to test brain activation corresponds very well with the standardized t test of the SPM99 toolbox. Additionally, a new Impulse Response Function (IRF) has been formulated, directly related to the well-established concept of the hemodynamics response function (HRF). The model uses not only the information contained in the signal but also that in the structure of the background noise to simultaneously estimate the IRF and the autocorrelation function (ACF) by using an autoregressive (AR) model with a filtered Poisson process driving the dynamics. The short-range contributions of voxels within the near-neighborhood are also included, and the potential drift was characterized by a polynomial series. Since our model originated from an immediate extension of the hemodynamics approach [Friston, K.J., Mechelli, A., Turner, R., Price C.J. (2000a). Nonlinear responses in fMRI: the balloon model, volterra kernels, and other hemodynamics. NeuroImage 12, 466-477.], a natural interpretability of the results is feasible.

TNF combined with IFN-alpha accelerates NF-kappaB-mediated apoptosis through enhancement of Fas expression in colon cancer cells.

Immunostaining and EMSA revealed that NF-kappaB was activated strongly by TNF/IFN-alpha compared to TNF alone in a human colon adenocarcinoma cell line, RPMI4788. Although inhibition of activated NF-kappaB, by using an NF-kappaB decoy, reduced cell viability after treatment with TNF only, NF-kappaB decoy resulted in recovery of cell viability after TNF/IFN-alpha treatment. Caspase-3 activity was increased in cells induced by TNF/IFN-alpha, while suppression of caspase-3 activity was observed in cells transfected with NF-kappaB decoy and then treated by TNF/IFN-alpha. On the other hand, Fas expression was strongly enhanced by TNF/IFN-alpha, and inhibition of TNF/IFN-alpha-induced NF-kappaB activation, by using NF-kappaB decoy, decreased Fas expression. Cell viability and caspase-3 activity decreased in cells treated with TNF/IFN-alpha and anti-FasL antibody. Taken together, our findings suggest that activated NF-kappaB induced by the crosstalk between TNF and IFN-alpha is a novel pro-apoptotic signal acting via enhancement of Fas expression.

Apoptosis in normal tissues induced by anti-cancer drugs.

To investigate the damage mediated by anti-cancer drugs in normal cells, we examined the effect of such drugs on apoptosis of normal cells of the small intestinal epithelium and the bone marrow by in situ DNA end-labelling and transmission electron microscopy. Mice received a single dose of 5-fluorouracil (5-FU) or cisplatin, or repeated daily doses of 5-FU for 7 days. In mice treated with a single dose of 5-FU 50 mg/kg or cisplatin 5 mg/kg, the number of apoptotic cells appearing in the small intestine 12 h after injection was relatively small, but increased steadily reaching a peak after 36 h and then decreasing to close to that in the control group by 48 h. In bone marrow cells, results were similar in mice treated with single doses of 5-FU 50 mg/kg but apoptosis increased much less in those treated with cisplatin 5 mg/kg. The proportion of apoptotic cells reached peak values earlier at higher concentrations of 5-FU or cisplatin both in small intestine and in bone marrow. In the mice treated repeatedly with 5-FU 50 mg/kg, the proportion of apoptotic small intestinal epithelial cells reached a succession of peaks at 48-h intervals. Mice treated repeatedly with 5-FU 50 mg/kg also showed a rapid increase in diarrhoea symptoms and a steady decrease in the height of villi. Our results suggest it may be possible to prevent the side-effects of anti-cancer drugs by inhibiting apoptosis in the gastrointestinal tract.

Brain activation during the fist-edge-palm test: a functional MRI study.

The purpose of our study is to clarify, using functional MRI, brain regions activated during the fist-edge-palm task (FEP) compared to relatively simple hand motor tasks using either the right or the left hand in right-handed normal volunteers. The FEP was introduced to detect a disorder of voluntary movement, and it is believed to be closely related to contralateral frontal lobe damage. However, this assumption still remains controversial. Ten subjects participated in this study. Hand motor tasks were as follows: (1) the FEP, in which the subjects were requested to place their hand in three different positions sequentially: a fist resting horizontally, a palm resting vertically, and a palm resting horizontally; (2) a fist-palm task (FP), in which the subjects were asked to clench and unclench their fist alternately; and (3) a control task requiring the subjects to knock lightly with their clenched fist. The contralateral sensomotor and premotor areas were activated in the FP with the right hand and the contralateral sensorimotor, premotor, and supplementary motor areas (SMA) were activated in the FP with the left hand. In the FEP with either hand, bilateral premotor and left parietal areas and ipsilateral cerebellum were also activated as well as contralateral sensorimotor area and SMA. Our results suggest that successful performance of the FEP requires the participation of more brain areas than FP, which may explain why some patients without frontal lobe damage failed to perform the FEP.

Hypoperfusion in the supplementary motor area, dorsolateral prefrontal cortex and insular cortex in Parkinson's disease.

The changes of regional cerebral blood flow (rCBF) in Parkinson's disease (PD) were investigated. Because of individual differences in brain volume and the extent of brain atrophy, previous functional imaging studies involved potential methodological difficulties. In this study, using the statistical parametric mapping technique, 99mTechnetium-labeled hexamethylpropyleneamineoxime brain single-photon emission computed tomography images from 18 patients with PD were transformed into standard brain-based stereotaxic coordinate spaces and then compared with such images for 11 control subjects matched for age and extent of brain atrophy. A rCBF decrement in the supplementary motor area (SMA) and such decrement in the dorsolateral prefrontal cortex (DLPFC) were observed in the summarized PD images as compared with controls (p<0.005). In a subgroup in the Hoehn-Yahr III/IV stage (11 cases), the rCBF decrement was demonstrated not only in the SMA, but also in the DLPFC and insular cortex (p<0.001). There was a correlation between the degree of the rCBF decrement in the DLPFC or the insular cortex and the score of the unified Parkinson's disease rating scale (p<0.05), while the rCBF decrement in the SMA showed no relationship with the severity of disease. The function of the SMA is closely associated with the nigro-striatal pathway and its impairment can explain the basic akinetic symptoms in PD, which are responsive to L-DOPA treatment. On the other hand, the DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. We hypothesize that the impairment of the DLPFC and insular function is correlated with the progression of the disease and is related to DOPA-refractory symptoms, which are major problems in the care of patients with advanced PD.