Dextran sulfate sodium inhibits amyloid-ß oligomer binding to cellular prion protein.

Amyloid-ß peptide (Aß), especially its oligomeric form, is believed to play an important role in the pathogenesis of Alzheimer's disease (AD). To this end, the binding of Aß oligomer to cellular prion protein (PrP(C)) plays an important role in synaptic dysfunction in a mouse model of AD. Here, we have screened for compounds that inhibit Aß oligomer binding to PrP(C) from medicines already used clinically (Mizushima Approved Medicine Library 1), and identified dextran sulfate sodium (DSS) as a candidate. In a cell-free assay, DSS inhibited Aß oligomer binding to PrP(C) but not to ephrin receptor B2, another endogenous receptor for Aß oligomers, suggesting that the drug's action is specific to the binding of Aß oligomer to PrP(C) . Dextran on the other hand did not affect this binding. DSS also suppressed Aß oligomer binding to cells expressing PrP(C) but not to control cells. Furthermore, while incubation of mouse hippocampal slices with Aß oligomers inhibited the induction of long-term potentiation, simultaneous treatment with DSS restored the long-term potentiation. As DSS has already been approved for use in patients with hypertriglyceridemia, and its safety in humans has been confirmed, we propose further analysis of this drug as a candidate for AD treatment. Amyloid-ß peptide (Aß) oligomer-binding to cellular prion protein (PrP(C) ) is important in synaptic dysfunction in Alzheimer's disease (AD). We found here that dextran sulfate sodium (DSS) inhibits Aß oligomer binding to PrP(C) . Simultaneous treatment of hippocampal slices with DSS restored long-term potentiation (LTP) in the presence of Aß oligomers. Since DSS has already been approved for clinical use, we propose this drug is a candidate drug for AD treatment.

Comparison of structural effects of cholesterol, lanosterol, and oxysterol on phospholipid (POPC) bilayers.

Membrane sterols contribute to the function of biomembranes by regulating the physical properties of the lipid bilayers. Cholesterol, a typical mammalian sterol, is biosynthesized by oxidation of lanosterol. From a molecular evolutionary perspective, lanosterol is considered the ancestral molecule of cholesterol. Here, we studied whether cholesterol is superior to lanosterol in regulating the physical properties of the lipid bilayer in terms of the structural effect on model biomembranes composed of a phospholipid. For comparison, oxysterol, which is formed by oxidation of cholesterol, was also studied. The phospholipid used was 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), which is abundantly found in mammalian biomembranes, and 7ß-hydroxycholesterol, which is highly cytotoxic, was used as the oxysterol. The apparent molecular volume was calculated from the mass density determined by the flotation method using H2O and D2O, and the bilayer thickness was determined by reconstructing the electron density distribution from X-ray diffraction data of the POPC/sterol mixtures at a sterol concentration of 30 mol%. The apparent occupied area at the bilayer surface was calculated from the above two structural data. The cholesterol system had the thickest bilayer thickness and the smallest occupied area of the three sterols studied here. This indicates that the POPC/cholesterol bilayer has a better barrier property than the other two systems. Compared to cholesterol, the effects of lanosterol and 7ß-hydroxycholesterol on lipid bilayer properties can be interpreted as suboptimal for the function of mammalian biomembranes.

A web-based survey on the occurrence of emotional blunting in patients with major depressive disorder in Japan: Patient perceptions and attitudes.

AIMS: To determine the prevalence and impact of emotional blunting (EB) in patients with major depressive disorder (MDD) in Japan, and identify treatment needs for EB using patients' perceptions and attitudes. METHODS: Eligible patients in Japan (aged 18-59 years) who reported a diagnosis of MDD and antidepressant medication use for >3 months were eligible to complete an online survey. The primary outcome was the prevalence of EB, self-reported using a validated screening question. Secondary outcomes included the correlation between EB symptoms (measured by the Oxford Depression Questionnaire [ODQ]) and scores on the Patient Health Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7), Work and Social Adjustment Scale (WSAS), and the EuroQol 5-Dimension 5-Levels questionnaire (EQ-5D-5L). Descriptive questions were used to explore patients' perceptions and attitudes toward EB. RESULTS: In total, 3376 patients were included in the analysis (56% male; 48% aged 50-59 years). Overall, 67.1% of patients self-reported symptoms of EB, with 10% rating these as severe. The mean (SD) ODQ total score was 78.2 (21.5), which increased with worsening EB symptoms. There were correlations between ODQ total scores and the PHQ-9, GAD-7, WSAS, and EQ-5D-5L scores (correlation coefficients: 0.67, 0.55, 0.56, -0.51, respectively; all p < 0.0001). Descriptive analyses showed that one-third of patients reporting EB symptoms did not tell their physician, with two-thirds finding these symptoms distressing and likely to affect recovery. CONCLUSION: EB is an important clinical issue in Japan that needs to be considered alongside functional recovery when managing treatment of patients with MDD.

Clozapine treatment of a Japanese patient during pregnancy: Effect on fetal heart rate.

The current literature on the effects of clozapine on pregnancy is limited, and no cases of pregnant Japanese women have been reported. Decreased variability in the fetal heart rate due to clozapine exposure has been reported in countries other than Japan, but its association with serum concentrations of clozapine has not been documented. In this case, a 29-year-old Japanese primipara with treatment-resistant schizophrenia taking clozapine 250 mg/day experienced pregnancy. The pregnancy progressed without complications. At 40 weeks and 2 days of gestation, the patient developed premature rupture of membranes, and decreased variability in the fetal heart rate and variable deceleration were observed, leading to an emergency cesarean section. The neonate had no congenital malformations, metabolic disorders, seizures, floppy infant syndrome, leukopenia, or neutropenia. Serum concentrations of clozapine and norclozapine (N-desmethylclozapine), measured in the mother and in the neonate immediately after birth, suggested that clozapine and norclozapine were transported to the fetus during pregnancy. Based on these observations, the present case suggests that high fetal serum concentrations of clozapine and norclozapine may affect fetal heart rate. This case report concludes that, with careful monitoring, Japanese women taking clozapine can deliver successfully and emphasizes the importance of monitoring serum clozapine concentrations and fetal cardiac function throughout pregnancy, with particular attention to the later stages.

Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice.

Amyloid-ß peptide (Aß) plays an important role in the pathogenesis of Alzheimer's disease (AD). Aß is generated by proteolysis of ß-amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-ß1, stimulate this phagocytosis. In contrast, cellular upregulation of HSP70 expression provides cytoprotection against Aß. HSP70 activity in relation to inhibition of Aß oligomerization and stimulation of Aß phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression of HSP70 could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of Aß, Aß plaque deposition, and neuronal and synaptic loss than control mice. Immunoblotting experiments and direct measurement of ß- and γ-secretase activity suggested that overexpression of HSP70 does not affect the production Aß. In contrast, HSP70 overexpression did lead to upregulation of the expression of Aß-degrading enzyme and TGF-ß1 both in vivo and in vitro. These results suggest that overexpression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.

Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP(4) receptor.

Amyloid-ß peptide (Aß), which is generated by the ß- and γ-secretase-mediated proteolysis of ß-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E(2) (PGE(2) ) stimulates the production of Aß through both EP(2) and EP(4) receptors and that activation of the EP(4) receptor stimulates Aß production through endocytosis and activation of γ-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP(2) or EP(4) receptors, respectively. Mice lacking the EP(4) receptor also displayed lower levels of Aß plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP(4) receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Aß and suppressing endocytosis and activation of γ-secretase. Taken together, these results suggest that inhibition of the EP(4) receptor improves the cognitive function of APP23 mice by suppressing Aß production and reducing neuronal and synaptic loss. We therefore propose that EP(4) receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.

[Case of a giant cervical carotid artery aneurysm with contralateral severe stenosis treated using a covered stent].

We report a case of a cervical carotid artery pseudoaneurysm with contralateral severe stenosis, treated using a covered stent. A 79-year-old man admitted for a splenic artery aneurysm presented a pulsatile mass on the right side of his neck and lower cranial nerve palsy after misinsertion of a central venous line into the right carotid artery. MRI revealed a huge thrombosed aneurysm (30 mm×25 mm) in the right common carotid artery (CCA). We planned an aneurysmectomy and CCA interposition with a vascular graft. However the aneurysm continued to expand. We considered that it was difficult to expose the internal carotid artery (ICA) by a direct surgical technique, and therefore carried out placement of a covered stent over the orifice of the aneurysm using an endovascular surgical technique. Following placement of the covered stent, subsequent contrast-enhanced CT revealed leakage of contrast material into the aneurysm. An additional bare stent was placed into the proximal end of the covered stent at 15 days after the initial treatment. Angiography demonstrated no leakage of the contrast material. Following the second treatment, the pulsatile mass was reduced in size. Lower cranial nerve palsy remained but had slightly improved. We described the case of a huge cervical carotid pseudoaneurysm that was successfully treated using a covered stent.

Prediction of residual cognitive disturbances by early response of depressive symptoms to antidepressant treatments in patients with major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) frequently retain cognitive disturbances after recovery from mood symptoms. We investigated the relationship between early response of mood symptoms and/or remission, and residual cognitive disturbances after 6 months of antidepressant treatment. METHODS: 518 patients with MDD were followed up for 6 months after antidepressant treatment initiation (first-line or switch from a previous drug). Subjective and objective cognitive disturbances were assessed by the Perceived Deficits Questionnaire - Depression (PDQ-D) and digit symbol substitution test (DSST), respectively. Depressive symptoms, as well as remission and early response to treatment, were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Multivariable linear and logistic regression models were used to adjust for confounders. RESULTS: Early response of depressive mood (≥50% reduction in MADRS score at month 1) was related with fewer residual subjective cognitive symptoms, as evaluated by the PDQ-D at month 6 (p<0.001). Likewise, early remission status at month 2 was inversely associated with PDQ-D scores at month 6 (p<0.001). Among patients with baseline DSST scores of ≥1 standard deviation below the norm, early response/remission was associated with better performance on the DSST at month 6 (p<0.05). LIMITATIONS: The cohort may not be representative of the general MDD patient population, and the possible influence of concomitant medications was not evaluated. CONCLUSIONS: These findings suggest that early improvements in depressive symptoms predict better cognitive outcomes in patients with MDD. Grouping of patients by mood and cognition status in early stages of antidepressant treatments may facilitate efforts to improve long-term functional outcomes.

Suppression of expression of endoplasmic reticulum chaperones by Helicobacter pylori and its role in exacerbation of non-steroidal anti-inflammatory drug-induced gastric lesions.

Both the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, and infection with Helicobacter pylori are major causes of gastric ulcers. Although some clinical studies suggest that infection with H. pylori increases the risk of developing NSAID-induced gastric lesions, the molecular mechanism governing this effect is unknown. We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes. In vivo, inoculation of mice with H. pylori suppressed the expression of ER chaperones at gastric mucosa both with and without administration of indomethacin. Inoculation with H. pylori also stimulated formation of indomethacin-induced gastric lesions and mucosal cell death. In addition, we found that heterozygous ORP150-deficient mice are sensitive to the development of indomethacin-induced gastric lesions and mucosal cell death. The results of this study suggest that H. pylori exacerbates NSAID-induced gastric lesions through suppression of expression of ER chaperones, which stimulates NSAID-induced mucosal cell death.

Prevention of UVB radiation-induced epidermal damage by expression of heat shock protein 70.

Irradiation with UV light, especially UVB, causes epidermal damage via the induction of apoptosis, inflammatory responses, and DNA damage. Various stressors, including UV light, induce heat shock proteins (HSPs) and the induction, particularly that of HSP70, provides cellular resistance to such stressors. The anti-inflammatory activity of HSP70, such as its inhibition of nuclear factor kappa B (NF-kappaB), was recently revealed. These in vitro results suggest that HSP70 protects against UVB-induced epidermal damage. Here we tested this idea by using transgenic mice expressing HSP70 and cultured keratinocytes. Irradiation of wild-type mice with UVB caused epidermal damage such as induction of apoptosis, which was suppressed in transgenic mice expressing HSP70. UVB-induced apoptosis in cultured keratinocytes was suppressed by overexpression of HSP70. Irradiation of wild-type mice with UVB decreased the cutaneous level of IkappaB-alpha (an inhibitor of NF-kappaB) and increased the infiltration of leukocytes and levels of pro-inflammatory cytokines and chemokines in the epidermis. These inflammatory responses were suppressed in transgenic mice expressing HSP70. In vitro, the overexpression of HSP70 suppressed the expression of pro-inflammatory cytokines and chemokines and increased the level of IkappaB-alpha in keratinocytes irradiated with UVB. UVB induced an increase in cutaneous levels of cyclobutane pyrimidine dimers and 8-hydroxy-2'-deoxyguanosine, both of which were suppressed in transgenic mice expressing HSP70. This study provides genetic evidence that HSP70 protects the epidermis from UVB-induced radiation damage. The findings here also suggest that the protective action of HSP70 is mediated by anti-apoptotic, anti-inflammatory, and anti-DNA damage effects.

Suppression of melanin production by expression of HSP70.

Skin hyperpigmentation disorders due to abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and cosmetic problem. UV irradiation stimulates melanin production in melanocytes by increasing intracellular cAMP. Expression of heat shock proteins (HSPs), especially HSP70, is induced by various stressors, including UV irradiation, to provide cellular resistance to such stressors. In this study we examined the effect of expression of HSP70 on melanin production both in vitro and in vivo. 3-Isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, stimulated melanin production in cultured mouse melanoma cells, and this stimulation was suppressed in cells overexpressing HSP70. IBMX-dependent transcriptional activation of the tyrosinase gene was also suppressed in HSP70-overexpressing cells. Expression of microphthalmia-associated transcription factor (MITF), which positively regulates transcription of the tyrosinase gene, was up-regulated by IBMX; however, this up-regulation was not suppressed in HSP70-overexpressing cells. On the other hand, immunoprecipitation and immunostaining analyses revealed a physical interaction between and co-localization of MITF and HSP70, respectively. Furthermore, the transcription of tyrosinase gene in nuclear extract was inhibited by HSP70. In vivo, UV irradiation of wild-type mice increased the amount of melanin in the basal layer of the epidermis, and this increase was suppressed in transgenic mice expressing HSP70. This study provides the first evidence of an inhibitory effect of HSP70 on melanin production both in vitro and in vivo. This effect seems to be mediated by modulation of MITF activity through a direct interaction between HSP70 and MITF.

Patient and Physician Perspectives of Depressive Symptoms and Expectations for Treatment Outcome: Results from a Web-Based Survey.

PURPOSE: A previous international study suggested that perceptions of depression symptoms, social function, and treatment expectations are different between patients/physicians. We aimed to examine whether such differences exist in Japan. METHODS: A web-based survey was conducted with patients who reported that they had been diagnosed with depression, and physicians who reported that they had treated patients with depression, in Japan. Questionnaires were designed to quantify patients' perceptions of symptoms, social function, and treatment expectations. Patients were categorized into three stages of disorder based on their reported current symptoms: severe symptomatic, mild symptomatic, and remission. Physicians were assigned up to three patients, were provided with patient information from the questionnaire completed by those patients, and finally the completed questionnaire forms for each patient. Agreement between the perceptions of the patients and physicians was examined for each stage. RESULTS: Of the 2618 eligible patients, 828 were assigned to 326 eligible physicians. Overall, we found small differences in the perceptions of depression treatment between patients/physicians. Slightly fewer physicians than patients reported physical symptoms (85% vs 91%; p=0.018) in the mild symptomatic stage. Fewer physicians than patients reported cognitive symptoms in the severe (82% vs 87%; p=0.029) and mild (54% vs 66%; p=0.003) symptomatic stages. Social function was deemed to be lower by physicians than by patients, across all stages of disorder (p<0.001). Regarding treatment expectations, more physicians than patients reported "return to a normal life" in the mild symptomatic (51% vs 35%, p<0.001) and remission stages (57% vs 36%, p<0.001), and more patients than physicians reported "reduction of side effects" in the severe (10% vs 4%, p=0.004) and mild (12% vs 5%, p<0.001) symptomatic disorder stages. CONCLUSION: These results suggest small differences in patient/physician perceptions of depression treatment in Japan. Discrepancies between patients'/physicians' perceptions may vary depending on the medical environment.

Prostaglandin E2 stimulates the production of amyloid-beta peptides through internalization of the EP4 receptor.

Amyloid-beta (Abeta) peptides, generated by the proteolysis of beta-amyloid precursor protein by beta- and gamma-secretases, play an important role in the pathogenesis of Alzheimer disease. Inflammation is also important. We recently reported that prostaglandin E(2) (PGE(2)), a strong inducer of inflammation, stimulates the production of Abeta through EP(2) and EP(4) receptors, and here we have examined the molecular mechanism. Activation of EP(2) and EP(4) receptors is coupled to an increase in cellular cAMP levels and activation of protein kinase A (PKA). We found that inhibitors of adenylate cyclase and PKA suppress EP(2), but not EP(4), receptor-mediated stimulation of the Abeta production. In contrast, inhibitors of endocytosis suppressed EP(4), but not EP(2), receptor-mediated stimulation. Activation of gamma-secretase was observed with the activation of EP(4) receptors but not EP(2) receptors. PGE(2)-dependent internalization of the EP(4) receptor was observed, and cells expressing a mutant EP(4) receptor lacking the internalization activity did not exhibit PGE(2)-stimulated production of Abeta. A physical interaction between the EP(4) receptor and PS-1, a catalytic subunit of gamma-secretases, was revealed by immunoprecipitation assays. PGE(2)-induced internalization of PS-1 and co-localization of EP(4), PS-1, and Rab7 (a marker of late endosomes and lysosomes) was observed. Co-localization of PS-1 and Rab7 was also observed in the brain of wild-type mice but not of EP(4) receptor null mice. These results suggest that PGE(2)-stimulated production of Abeta involves EP(4) receptor-mediated endocytosis of PS-1 followed by activation of the gamma-secretase, as well as EP(2) receptor-dependent activation of adenylate cyclase and PKA, both of which are important in the inflammation-mediated progression of Alzheimer disease.

Positive role of CCAAT/enhancer-binding protein homologous protein, a transcription factor involved in the endoplasmic reticulum stress response in the development of colitis.

Although recent reports suggest that the endoplasmic reticulum (ER) stress response is induced in association with the development of inflammatory bowel disease, its role in the pathogenesis of inflammatory bowel disease remains unclear. The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a transcription factor that is involved in the ER stress response, especially ER stress-induced apoptosis. In this study, we found that experimental colitis was ameliorated in CHOP-null mice, suggesting that CHOP exacerbates the development of colitis. The mRNA expression of Mac-1 (CD11b, a positive regulator of macrophage infiltration), Ero-1alpha, and Caspase-11 (a positive regulator of interleukin-1beta production) in the intestine was induced with the development of colitis, and this induction was suppressed in CHOP-null mice. ERO-1alpha is involved in the production of reactive oxygen species (ROS); an increase in ROS production, which is associated with the development of colitis in the intestine, was suppressed in CHOP-null mice. A greater number of apoptotic cells in the intestinal mucosa of wild-type mice were observed to accompany the development of colitis compared with CHOP-null mice, suggesting that up-regulation of CHOP expression exacerbates the development of colitis. Furthermore, this CHOP activity appears to involve various stimulatory mechanisms, such as macrophage infiltration via the induction of Mac-1, ROS production via the induction of ERO-1alpha, interleukin-1beta production via the induction of Caspase-11, and intestinal mucosal cell apoptosis.

HSP70 inducers from Chinese herbs and their effect on melanin production.

Skin hyperpigmentation disorders as a result of abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and a cosmetic problem. This melanin production is mediated by tyrosinase whose expression is positively regulated by microphthalmia-associated transcription factor (MITF). We recently found that expression of heat shock protein 70 (HSP70) inhibits melanin production. In this study, we searched for HSP70 inducers from Chinese herbs and selected an ethanol extract of Eupatorium lindleyanum (E. lindleyanum). Not only melanin production but also the activity and expression of tyrosinase were significantly suppressed in cells treated with E. lindleyanum extract as well as in HSP70-overexpressing cells. The expression of MITF was clearly suppressed in cells treated with E. lindleyanum extract but not in HSP70-overexpressing cells. These results suggest that E. lindleyanum extract suppresses the expression of tyrosinase and melanin production through both HSP70-dependent and HSP70-independent mechanisms.

Effect of transient forebrain ischemia on flavoprotein autofluorescence and the somatosensory evoked potential in the rat.

In order to evaluate the effect of cerebral ischemia on the flavoprotein fluorescence (FPF), we compared the changes in the FPF and somatosensory evoked potential (SEP) during transient cerebral ischemia in the rat. We measured the FPF and SEP simultaneously via a cranial window made over the right sensorimotor cortex during the left median nerve stimulation in F344 rats. We compared change in FPF and SEP during cerebral ischemia for 60 min. The rCBF were rapidly recovered after reperfusion. However, the recovery rates of the FPF were significantly faster than those of the SEP after reperfusion. These findings indicate that activity-dependent changes of the FPF do not necessarily correlate with the electrical activity after transient cerebral ischemia.

Changes of evoked cerebral blood oxygenation and optical pathlength in the frontal lobe during language tasks: a study by multi-channel, time-resolved near-infrared spectroscopy and functional MRI.

To determine the alterations in optical characteristics and cerebral blood oxygenation (CBO) in the frontal lobe during language tasks, we evaluated the changes in mean optical pathlength (MOP) and CBO induced by a verbal fluency task (VFT) in the right and left frontal lobes in normal adults (n = 9, mean age = 29.6 +/- 4.8 years). We employed a newly developed 8-channel time-resolved near-infrared spectroscopy (TRS) instrument. The results demonstrated differences in MOP in the fronto-temporal areas with subject and wavelength; however, there was no significant difference between the right and left sides (p > 0.05). Also, the VFT did not affect the MOP significantly as compared to that before the tasks (p > 0.05). In all of the recording regions, the VFT caused increases in concentration of oxyhemoglobin and total hemoglobin associated with a decrease in deoxyhemoglobin concentration, indicating that these cortical areas were activated by the VFT. However, the mean concentration changes of oxyhemoglobin and total hemoglobin on the left side were larger than those on the right side. In addition, functional MRI demonstrated that the inferior frontal gyrus on the left side was activated in the subjects who exhibited increases in oxyhemoglobin concentration in these areas. These results suggest that TRS may be useful to study language function and to assess hemispheric dominance for language.

Comparison of somatosensory evoked potentials and cerebral blood oxygenation changes in the sensorimotor cortex during activation in the rat.

The relationship between changes in cerebral blood oxygenation and neuronal activity remains to be fully established. We compared somatosensory evoked potentials (SEP) and evoked cerebral blood oxygenation (CBO) changes in the sensorimotor cortex of the rat. In rats anesthetized with urethane and alpha-chloralose, we measured SEP and CBO using visible light spectroscopy (VLS) during neuronal activity. Increase of stimulus frequency caused a decrease of SEP amplitude, but an increase in concentration changes of deoxy-Hb and oxygen saturation. The difference in frequency responses between SEP and CBO might be caused by activation of inhibitory neurons, which could suppress excitatory neurons at high stimulus frequencies; activation of inhibitory neurons could reduce SEP amplitude, and increase oxygen saturation due to an increase of evoked cerebral blood flow.

Changes in cerebral blood oxygenation and hemodynamics after endovascular treatment of vascular malformation measured by time-resolved spectroscopy.

Although endovascular treatment has a high success rate, it is not clear how endovascular treatment affects cerebral perfusion and hemodynamics during the perioperative period. We evaluated changes in cerebral blood oxygenation (CBO) repeatedly after endovascular treatment employing time-resolved spectroscopy (TRS). We investigated a patient (10 months old, female) who suffered cerebral arteriovenous fistula. Cerebral angiography demonstrated a pial arteriovenous fistula with three feeders (left PICA, SCA, and AICA). TRS demonstrated a decrease of oxyhemoglobin, total hemoglobin, and oxygen saturation associated with an increase of deoxyhemoglobin in all of the regions measured just after embolization, indicating that embolization improved hyperemia caused by the AV shunt. Interestingly, progressive improvement of hyperemia was observed 3 and 8 days after embolization of the feeders. The present study demonstrated that embolization of the feeders caused progressive changes in CBO and hemodynamics during the perioperative period. TRS may be a useful tool for monitoring cerebral blood perfusion changes after endovascular surgery.

Development of a new rehabilitation system based on a brain-computer interface using near-infrared spectroscopy.

We describe the set-up for an electrical muscle stimulation device based on near-infrared spectroscopy (NIRS), designed for use as a brain-computer interface (BCI). Employing multi-channel NIRS, we measured evoked cerebral blood oxygenation (CBO) responses during real motor tasks and motor-imagery tasks. When a supra-threshold increase in oxyhemoglobin concentration was detected, electrical stimulation (50 Hz) of the biceps brachii muscle was applied to the side contralateral to the hand grasping task or ipsilateral to the motor-imagery task. We observed relatively stable and reproducible CBO responses during real motor tasks with an average accuracy of 100%, and during motor imagery tasks with an average accuracy of 61.5%. Flexion movement of the arm was evoked in all volunteers in association with electrical muscle stimulation and no adverse effects were noted. These findings suggest that application of the electrical muscle stimulation system based on a NIRS-BCI is non-invasive and safe, and may be useful for the physical training of disabled patients.