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Various animals, including humans, have been suggested to perform Bayesian inferences to handle noisy, time-varying external information. In performing Bayesian inference by the brain, the prior distribution must be acquired and represented by sampling noisy external inputs. However, the mechanism by which neural activities represent such distributions has not yet been elucidated. Our findings reveal that networks with modular structures, composed of fast and slow modules, are adept at representing this prior distribution, enabling more accurate Bayesian inferences. Specifically, the modular network that consists of a main module connected with input and output layers and a sub-module with slower neural activity connected only with the main module outperformed networks with uniform time scales. Prior information was represented specifically by the slow sub-module, which could integrate observed signals over an appropriate period and represent input means and variances. Accordingly, the neural network could effectively predict the time-varying inputs. Furthermore, by training the time scales of neurons starting from networks with uniform time scales and without modular structure, the above slow-fast modular network structure and the division of roles in which prior knowledge is selectively represented in the slow sub-modules spontaneously emerged. These results explain how the prior distribution for Bayesian inference is represented in the brain, provide insight into the relevance of modular structure with time scale hierarchy to information processing, and elucidate the significance of brain areas with slower time scales., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ichikawa, Kaneko. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. Cases comprised six females and two males, with a median age of 56.5 years (range, 46-71 years) and a median disease duration of 62.5 months (range, 0.6-252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for GFAP: (i) astrocyte lysis: extensive loss of astrocytes with fragmented and/or dust-like particles; (ii) progenitor recruitment: loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (iii) protoplasmic gliosis: presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (iv) fibrous gliosis: lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have recently been associated with epilepsy with FLAIR hyperintense cortical lesions on MRI. Association between anti-MOG antibodies and epilepsy without detectable structural brain lesion on MRI is unknown., Case Report: A 48-year-old right-handed man with a four-and-a-half year history of anti-MOG antibody associated demyelinating disease presented with persistent global aphasia. Brain MRI showed no new lesion or cortical lesion in the left hemisphere. Electroencephalogram, magnetoencephalography, and brain perfusion single-photon emission computed tomography suggested epileptic foci in the left temporal and parietal lobes, and the patient's aphasia transiently responded to intravenous diazepam, compatible with aphasic status epilepticus. Cerebrospinal fluid showed mildly elevated cell count and positive oligoclonal bands. The patient only partially responded to antiepileptic drugs but responded to steroid pulse therapy. Six months later, the patient again exhibited global aphasia. Brain MRI showed tumefactive white matter lesion in the left temporo-parietal lobes., Conclusion: Autoimmune epilepsy without obvious causative lesion on MRI can be seen in the course of anti-MOG antibody associated demyelinating disease. The subsequent emergence of tumefactive lesion closely located to the epileptic foci may suggest some association between autoimmune epilepsy and demyelinating lesions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in developmental regression after normal development during infancy. Transient presentation of many autistic features is also commonly seen in RTT. Anti-myelin oligodendrocyte glycoprotein (MOG)-antibody encephalitis is an acquired relapsing demyelinating syndrome characterized by a variety of neuroinflammatory symptoms. Here, we report a case of anti-MOG antibody encephalitis in a patient with genetically confirmed RTT, which mimicked many of the features of RTT., Case Report: A three-year-old girl presented with subacute verbal and motor dysfunction, along with involuntary movements and marked irritability. Magnetic resonance imaging (MRI) revealed extensive white matter lesions, with anti-MOG antibodies detected in the serum and cerebrospinal fluid, resulting in an initial diagnosis of anti-MOG antibody encephalitis. However, additional testing of the MECP2 gene was performed in response to persistent involuntary hand movements in combination with progressive verbal and motor deterioration. Sequencing analysis revealed a known pathogenic mutation in MEPC2, indicating a concurrent diagnosis of RTT., Conclusion: Both RTT and anti-MOG antibody encephalitis are rare conditions. Similarities in disease presentation suggest that anti-MOG antibody encephalitis may mimic many of the symptoms of RTT., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

In insect brains, the mushroom bodies (MBs, a higher center) comprise intrinsic neurons, termed Kenyon cells (KCs). We previously showed that the honeybee (Apis mellifera L.) MBs comprise four types of KCs, in addition to the previously known three types of KCs: class I large-type KCs (lKCs), class I small-type KCs (sKCs) and class II KCs, novel class I 'middle-type' KCs (mKCs), which are characterized by the preferential expression of a gene, termed mKast. Although mKast was originally discovered during the search for genes whose expression is enriched in the optic lobes (OLs) in the worker brain, subsequent analysis revealed that the gene is expressed in an mKC-preferential manner in the MBs. To gain more insights into the function of mKast in the honeybee brain, we here performed expression analysis of mKast and immunohistochemistry of the mKast protein. Prominent mKast expression was first detected in the brain after the P7 pupal stage. In addition, mKast was expressed almost selectively in the brain, suggesting its late pupal and adult specific functions in the brain. Immunohistochemistry revealed that mKast-like immunoreactivity is detected in several regions in the worker brain: inside and around the MB calyces, at the outer edges of the OL lobula, at the outer surface of and posterior to the antennal lobes (ALs), along the dorsal midline of the anterior brain and at the outer surface of the subesophageal ganglions (SOG). mKast-like immunoreactivities in the MBs, OLs, ALs and SOG were due to the corresponding neurons, while mKast-like immunoreactivities beneath/between the MB calyces were assumed to most likely correspond to the lateral/medial neurosecretory cells.

In the brain, external objects are categorized in a hierarchical way. Although it is widely accepted that objects are represented as static attractors in neural state space, this view does not take account interaction between intrinsic neural dynamics and external input, which is essential to understand how neural system responds to inputs. Indeed, structured spontaneous neural activity without external inputs is known to exist, and its relationship with evoked activities is discussed. Then, how categorical representation is embedded into the spontaneous and evoked activities has to be uncovered. To address this question, we studied bifurcation process with increasing input after hierarchically clustered associative memories are learned. We found a "dynamic categorization"; neural activity without input wanders globally over the state space including all memories. Then with the increase of input strength, diffuse representation of higher category exhibits transitions to focused ones specific to each object. The hierarchy of memories is embedded in the transition probability from one memory to another during the spontaneous dynamics. With increased input strength, neural activity wanders over a narrower state space including a smaller set of memories, showing more specific category or memory corresponding to the applied input. Moreover, such coarse-to-fine transitions are also observed temporally during transient process under constant input, which agrees with experimental findings in the temporal cortex. These results suggest the hierarchy emerging through interaction with an external input underlies hierarchy during transient process, as well as in the spontaneous activity., Competing Interests: The authors have declared that no competing interests exist.

Trichloroethylene (TCE) has been implicated as a causative agent for Parkinson's disease (PD). The administration of TCE to rodents induces neurotoxicity associated with dopaminergic neuron death, and evidence suggests that oxidative stress as a major player in the progression of PD. Here we report on TCE-induced behavioral abnormality in mice that are deficient in superoxide dismutase 1 (SOD1). Wild-type (WT) and SOD1-deficient (Sod1(-/-)) mice were intraperitoneally administered TCE (500 mg/kg) over a period of 4 weeks. Although the TCE-administrated Sod1(-/-) mice showed marked abnormal motor behavior, no significant differences were observed among the experimental groups by biochemical and histopathological analyses. However, treating mouse neuroblastoma-derived NB2a cells with TCE resulted in the down regulation of the SOD1 protein and elevated oxidative stress under conditions where SOD1 production was suppressed. Taken together, these data indicate that SOD1 plays a pivotal role in protecting motor neuron function against TCE toxicity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aim: This study investigated whether or not and how much milnacipran influences the indexes of I-metaiodobenzylguanidine (I-MIBG) scintigraphy, early heart-to-mediastinum (H/M) ratio, delayed H/M ratio, and wash-out rate., Methods: Six elderly depressed patients participated in the study. All six patients met the diagnostic criteria for a major depressive disorder. They were taking milnacipran for their depression. They needed differential diagnosis for Lewy body diseases due to their symptomatology. I-MIBG scintigraphy was performed twice for each subject, once under prescription of milnacipran and the other without prescription of milnacipran., Results: Both early and delayed phase H/M ratio were significantly lower when taking milnacipran (early phase H/M ratio, P < 0.01, Cohen's d 1.62; delayed phase H/M ratio, P < 0.005, Cohen's d 1.98) than when not taking the drug. Wash-out rate (%) was significantly higher when taking milnacipran (P < 0.05, Cohen's d 2.31) than when off the drug., Conclusion: Taking milnacipran substantially influences the indexes of I-MIBG scintigraphy, indicating that taking the drug possibly causes a false-positive result for Lewy body diseases diagnosis.

The mushroom bodies (a higher center) of the honeybee (Apis mellifera L) brain were considered to comprise three types of intrinsic neurons, including large- and small-type Kenyon cells that have distinct gene expression profiles. Although previous neural activity mapping using the immediate early gene kakusei suggested that small-type Kenyon cells are mainly active in forager brains, the precise Kenyon cell types that are active in the forager brain remain to be elucidated. We searched for novel gene(s) that are expressed in an area-preferential manner in the honeybee brain. By identifying and analyzing expression of a gene that we termed mKast (middle-type Kenyon cell-preferential arrestin-related protein), we discovered novel 'middle-type Kenyon cells' that are sandwiched between large- and small-type Kenyon cells and have a gene expression profile almost complementary to those of large- and small-type Kenyon cells. Expression analysis of kakusei revealed that both small-type Kenyon cells and some middle-type Kenyon cells are active in the forager brains, suggesting their possible involvement in information processing during the foraging flight. mKast expression began after the differentiation of small- and large-type Kenyon cells during metamorphosis, suggesting that middle-type Kenyon cells differentiate by modifying some characteristics of large- and/or small-type Kenyon cells. Interestingly, CaMKII and mKast, marker genes for large- and middle-type Kenyon cells, respectively, were preferentially expressed in a distinct set of optic lobe (a visual center) neurons. Our findings suggested that it is not simply the Kenyon cell-preferential gene expression profiles, rather, a 'clustering' of neurons with similar gene expression profiles as particular Kenyon cell types that characterize the honeybee mushroom body structure.

Background: Although protein kinase C-γ (PKC-γ) is a target for the effects of volatile anesthetics, the molecular mechanisms of the kinase function remain unclear. We examined the effects of different types of anesthetics on PKC-γ knockout mice, and investigated the dynamics of the kinase in mouse brain., Methods: We measured the required number of times for loss of righting reflex (rtfLORR) after administration of isoflurane, sevoflurane, and propofol on PKC-γ knockout mice and compared with those of wild-type mice. We also used immunoblotting to investigate the intracellular distribution of PKC-γ and phosphorylated PKC-γ (p-PKC-γ) in brain of wild-type mice anesthetized by these anesthetics., Results: Isoflurane and sevoflurane significantly prolonged the rtfLORRs in PKC-γ knockout mice compared with those in wild-type mice, while no significant difference was observed between knockout and wild-type mice treated with propofol. Examination of the cellular fractions showed that PKC-γ was significantly decreased, whereas p-PKC-γ was significantly increased in the synaptic membrane fraction (P2). There was no significant change in the supernatant fraction (S). In propofol-treated mice, PKC-γ and p-PKC-γ showed no significant changes in P2 or S., Conclusion: Our results provide new evidence to support the possibility of the involvement of PKC-γ in the actions of volatile anesthetics.

(Pro)renin receptor [(P)RR], a specific receptor for renin and prorenin, is a 350 amino acid protein with a single transmembrane domain. In the present study, the expression of (P)RR in the human brain and pituitary, and its co-localisation with arginine vasopressin and oxytocin in the human hypothalamus were studied by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry. Human brain and pituitary tissues were obtained at autopsy from the subjects without neurological or endocrinological disorders. The antiserum against (P)RR was raised in a rabbit by injecting the peptide fragment of human (P)RR corresponding to 224-237 amino acids conjugated with bovine serum albumin. Quantitative RT-PCR showed that (P)RR mRNA was widely expressed in every region of brain examined and pituitary, with the highest expression levels found in the pituitary and frontal lobe. Immunocytochemistry showed that (P)RR was expressed in the paraventricular and supraoptic nuclei of human hypothalami, and in anterior pituitary cells. Immunostaining of serial sections showed that (P)RR was co-localised with arginine vasopressin and oxytocin in the magnocellular neurones of the paraventricular and supraoptic nuclei. The preabsorption of the antibody by the antigen peptide abolished the immunostaining of (P)RR in the human hypothalamus. The present study has shown that (P)RR mRNA is widely expressed in the human brain and pituitary, consistent with the hypothesis that (P)RR is related to the various brain functions, such as cognitive function and brain development. Co-localisation of (P)RR with vasopressin in the hypothalamus raised the possibility that (P)RR may be related to the central control of water-electrolyte metabolism and blood pressure.

Background: The importance of visual sense in Hymenopteran social behavior is suggested by the existence of a Hymenopteran insect-specific neural circuit related to visual processing and the fact that worker honeybee brain changes morphologically according to its foraging experience. To analyze molecular and neural bases that underlie the visual abilities of the honeybees, we used a cDNA microarray to search for gene(s) expressed in a neural cell-type preferential manner in a visual center of the honeybee brain, the optic lobes (OLs)., Methodology/principal Findings: Expression analysis of candidate genes using in situ hybridization revealed two genes expressed in a neural cell-type preferential manner in the OLs. One is a homologue of Drosophila futsch, which encodes a microtubule-associated protein and is preferentially expressed in the monopolar cells in the lamina of the OLs. The gene for another microtubule-associated protein, tau, which functionally overlaps with futsch, was also preferentially expressed in the monopolar cells, strongly suggesting the functional importance of these two microtubule-associated proteins in monopolar cells. The other gene encoded a homologue of Misexpression Suppressor of Dominant-negative Kinase Suppressor of Ras 2 (MESK2), which might activate Ras/MAPK-signaling in Drosophila. MESK2 was expressed preferentially in a subclass of neurons located in the ventral region between the lamina and medulla neuropil in the OLs, suggesting that this subclass is a novel OL neuron type characterized by MESK2-expression. These three genes exhibited similar expression patterns in the worker, drone, and queen brains, suggesting that they function similarly irrespective of the honeybee sex or caste., Conclusions: Here we identified genes that are expressed in a monopolar cell (Amfutsch and Amtau) or ventral medulla-preferential manner (AmMESK2) in insect OLs. These genes may aid in visualizing neurites of monopolar cells and ventral medulla cells, as well as in analyzing the function of these neurons.

Ceruloplasmin (Cp) is the strongest ferroxidase in human plasma. Hereditary deficiency of this protein, named aceruloplasminemia, is an interesting model to elucidate the pathogenesis and pathophysiology of neurodegeneration induced by oxidative stress. Enhanced oxidative stress due to excessive iron accumulation is observed in the brains of aceruloplasminemia patients. Rotenone, a selective mitochondrial complex I inhibitor, induces neurodegeneration mimicking Parkinson's disease. We investigated the influence of Cp deficiency upon neurodegeneration using rotenone-treated, Cp-deficient mouse brains. Immunohistochemical examination showed that acrolein, one of the products of lipid peroxides, and ubiquitin were more markedly immunoreacted in the brains of rotenone-treated, Cp-deficient mice than in rotenone-untreated, Cp-deficient or rotenone-treated, wild-type mice. These molecules were localized in neuronal cells. These results suggested that rotenone-induced lipid peroxidation and accumulation of ubiquitin immunoreactivity were enhanced in the absence of Cp. Therefore, Cp may protect neuronal cells from oxidative stress-induced neurodegeneration.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by polyglutamine (polyQ) expansions in the huntingtin (Htt) protein. A hallmark of HD is the presence of aggregates-predominantly composed of NH(2)-terminal fragments of polyQ-expanded Htt-in the nucleus and cytoplasm of affected neurons. We previously proposed that 14-3-3zeta might act as a sweeper of misfolded proteins by facilitating the formation of aggregates possibly for neuroprotection; these aggregates are referred to as inclusion bodies. However, evidence available in this regard is indirect and circumstantial. In this study, analysis of the aggregation-prone protein Htt encoded by HD gene exon 1 containing polyglutamine expansions (Htt86Q) revealed that 17 residues in the NH(2)-terminal of this protein are indispensable for its aggregate formation. Immunoprecipitation assays revealed that 14-3-3beta, gamma, eta, and zeta interact with Htt86Q transfected in N2a cells. Interestingly, the small interfering ribonucleic acid (siRNA) suppression of 14-3-3zeta exclusively abolished Htt86Q aggregate formation, whereas 14-3-3beta or eta siRNA suppression did not. This indicates that 14-3-3zeta participates in aggregate formation under nonnative conditions. Our data support a novel role for 14-3-3zeta in the aggregate formation of nonnative, aggregation-prone proteins.

Objectives: To explore the cerebral hemodynamics in subclavian steal syndrome, we examined the cerebral perfusion of seven patients with subclavian steal (one symptomatic and six asymptomatic) using single-photon emission computed tomography (SPECT) during resting, arm exercise, and acetazolamide-activated conditions., Methods: The regional CBF (rCBF) was measured with SPECT under all conditions, and region of interest (ROI) analysis was performed using a three-dimensional stereotaxic ROI template (3DSRT). We evaluated the relationship between arm exercise-induced rCBF change and (1) presence of subclavian artery stenosis, (2) vertebral reverse flow severity, (3) presence of vertebro-basilar insufficiency (VBI) symptoms, and (4) cerebrovascular reactivity (CVR) to acetazolamide., Results: Overall, no arm exercise-induced rCBF reduction was observed on either the affected or the unaffected side, even in patients with severe vertebral reverse flow. One patient with VBI symptoms showed an arm exercise-induced global rCBF reduction in the cerebrum and cerebellum, whereas the other asymptomatic patients did not. The %rCBF changes in segments with severely impaired CVR (-8.6%+/-10.7%, mean+/-SD) were significantly lower than those in other segments with less impaired CVR (P<0.01)., Conclusions: Our results suggest that subclavian steal is a benign condition in asymptomatic patients. On the other hand, arm exercise-induced rCBF reduction can occur in the cerebrum and cerebellum in patients with VBI symptoms possibly related to low CVR.

Aceruloplasminemia (ACP) is an inherited disorder of iron metabolism caused by the lack of ceruloplasmin activity; the neuropathological hallmarks are excessive iron deposition, neuronal loss, bizarrely deformed astrocytes, and numerous 'grumose or foamy spheroid bodies (GFSBs)'. We histopathologically examined two autopsied ACP brains, and observed for the first time that GFSBs form in clusters at the ends of perivascular astrocytic foot processes. Both the deformed astrocytes and the GFSBs contained ferric iron and were intensely immunolabelled with antibodies against the antioxidant proteins ferritin and manganese superoxide dismutase (Mn SOD). Ceruloplasmin is largely produced by perivascular astrocytes in the central nervous system and exhibits a ferroxidase activity that inhibits iron-associated lipid peroxidation and hydroxyl radical formation; therefore, the lack of ceruloplasmin causes direct oxidative stress on astrocytes. The intense immunolabelling of ferritin and Mn SOD most likely reflects a defensive response to iron-mediated oxidative stress. This study suggests that astrocytes play key roles in iron trafficking and the detoxification of iron-mediated free radicals at the blood-brain barrier and in the parenchyma in ACP brain. The antioxidative ability of astrocytes is one of their essential neuroprotective effects, and the decompensation of this ability may lead to secondary neuronal cell death in ACP.

Objective: To clarify the relationship between D2 receptor binding and the cerebral metabolic rate for glucose (CMRGlu) in patients with parkinsonism, we simultaneously measured both of these factors, and then compared the results., Methods: The subjects consisted of 24 patients: 9 with Parkinson's disease (PD), 3 with Juvenile Parkinson's disease (JPD), 9 with multiple system atrophy (MSA), and 3 with progressive supranuclear palsy (PSP). The striatal D2 receptor binding was measured by the C-11 raclopride transient equilibrium method. CMRGlu was investigated by the F-18 fluorodeoxyglucose autoradiographic method., Results: The D2 receptor binding in both the caudate nucleus and putamen showed a positive correlation with the CMRGlu in the PD-JPD group, but the two parameters demonstrated no correlation in the MSA-PSP group. The left/right (L/R) ratio of D2 receptor binding in the putamen showed a positive correlation with that of CMRGlu in the MSA-PSP group, while the two demonsrated no correlation in the PD-JPD group., Conclusion: Our PET study showed striatal D2 receptor binding and the CMRGlu to be closely related in patients with parkinsonism, even though the results obtained using the L/R ratios tended to differ substantially from those obtained using absolute values. The reason for this difference is not clear, but this finding may reflect the pathophysiology of these disease entities.

Background: We evaluated the quantitative accuracy of the post-injection transmission-based segmented attenuation correction (SAC) technique and transmissionless calculated attenuation correction (CAC) technique in both 2D and 3D scanning for the brain, and compared the results with those obtained using the pre-injection transmission-based measured attenuation correction (MAC) technique, which is generally accepted as the 'gold standard'., Methods: We examined [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) on both a cylindrical phantom and in 10 patients with epilepsy. The statistical analyses were performed using both the region of interest (ROI) method and statistical parametric mapping (SPM)., Results: In the ROI analysis, [18F] activity concentration values obtained by the SAC technique were well correlated with those obtained by the MAC technique (2D, R2=0.94; 3D, R2=0.98; P<0.001), although these values were underestimated over the entire brain. The CAC technique was also found to have significant correlation with the MAC technique (2D, R2=0.84; 3D, R2=0.86; P<0.001), but this technique showed apparent overestimation or underestimation in several parts of the brain. In the SPM analysis, there were no significant differences between the SAC and MAC technique, while those values obtained by the CAC technique were significantly lower in the parieto-occipital region and higher in the lower frontal region (P<0.001, uncorrected)., Conclusion: The SAC technique was superior to the CAC technique in both 2D and 3D scanning, although we found that both the SAC and CAC techniques had some problems in quantitative evaluation. We considered that the SAC technique may yield adequate qualitative measurements of the [18F] activity concentration value after global normalization.

To clarify the utility of semi-quantitative cerebral blood flow (CBF) measurements using perfusion-weighted MR imaging (PWI), a comparison of this method with quantitative CBF obtained using PET was conducted in 10 patients with chronic occlusive cerebrovascular disease and unilateral occlusion of the cerebral artery. Semi-quantitative CBF obtained using PWI and quantitative CBF obtained using PET showed no statistically significant correlation. The CBF ratios of the affected side relative to the contralateral unaffected side obtained using PWI and PET were 0.94 +/- 0.22 and 0.88 +/- 0.19, respectively. A statistically significant positive correlation was obtained between these ratios (p < 0.01). The CBF ratio, but not the semi-quantitative CBF, obtained using PWI has a potential to detect changes in the CBF.

Rationale and Objectives: To evaluate the value of magnetic resonance (MR) perfusion imaging for diagnosis of Alzheimer disease (AD), the authors compared relative cerebral blood flow (CBF) maps obtained with MR perfusion imaging and technetium-99m hexamethyl-propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) in patients with AD., Materials and Methods: Eight patients with AD were studied with MR perfusion imaging and HMPAO SPECT. The relative CBF maps from the two techniques were spatially coregistered, and relative CBF values in 13 cerebral gray matter regions (total, 26 regions of interest) were compared with regression analysis. To evaluate the degree of deviation of each brain region from the regression line, a P value for the residual was calculated for each region., Results: A significant overall correlation was seen between the relative CBF values produced by the two techniques (r = .68, P < .0001). Smaller P values for the residuals were obtained in the anterior cingulate cortex (P = .05) and posterior cingulate cortex (P < .001), indicating larger deviations in these regions. When data from these two regions were eliminated, the correlation coefficient rose to 0.80 (P < .0001)., Conclusion: Despite fairly large discrepancies in the anterior and posterior cingulate cortices, the relative CBF map obtained with MR imaging is generally in close agreement with the HMPAO SPECT map, suggesting that MR perfusion imaging can provide clinically useful information regarding CBF abnormalities in patients with AD.

The role of nitric oxide (NO) in epileptogenesis was studied in pentylenetetrazole (PTZ)-treated animals using in vivo and ex vivo EPR spectroscopy. NO generation was measured directly in the brain of a PTZ-induced mouse in vivo by an L-band EPR spectrometer. An elevation in NO production in the brain was observed during convulsions, and more NO was generated in the tonic seizure vs. the clonic seizure. NO content in several brain tissues (including the cerebral cortex (CR), cerebellum (CL), olfactory bulb (OB), hippocampus (HI), and hypothalamus (HT)) of PTZ-doped rats was analyzed quantitatively ex vivo by X-band EPR. To test the involvement of NO in seizure development, pharmacological analyses were performed using the NO synthase (NOS) inhibitors N(G)-nitro-L-arginine (L-NNA), N(G)-monomethyl-L-arginine (L-NMMA), and 3-bromo-7-nitroindazole (3Br-7NI). All of these inhibitors suppressed the convulsions, holding them at the clonic level, and prevented development of a tonic convulsion in rats doped with up to 80 mg/kg PTZ. 3Br-7NI completely inhibited NO production, but L-NNA and L-NMMA showed only 70% inhibition of NO production in PTZ-doped rats. In order to examine the contributions of NO in convulsions, rats were treated with anticonvulsants (phenytoin and diazepam) before PTZ treatment. Both drugs completely suppressed tonic convulsion in PTZ-doped rats at doses up to 80 mg/kg, but NO levels were similar to those detected in a clonic convulsion. These results support the notion that NO does not directly induce a clonic convulsion, but may be generated as a consequence of onset of seizure., (Copyright 2002 Wiley-Liss, Inc.)

Aceruloplasminemia is an interesting disease, the study of which helps elucidate how iron-induced oxidative stress is involved in neuronal cell death. In order to study the neuropathological characteristics associated with oxidative stress, we scrutinized the brains of 5 patients with aceruloplasminemia histopathologically and immunohistochemically. The pathological findings were essentially similar in all patients. In the frontal cortices, iron deposition and neuronal cell loss were trivial, but in the basal ganglia (especially in the caudate nucleus and putamen), severe iron overload and extensive neuronal loss were noted. Iron deposition was more prominent in the astrocytes than in the neurons in both regions. 4-hydroxynonenal (HNE), one of the most physiologically active lipid peroxides, was strongly detected on neurons and astrocytes by immunostaining. Markedly deformed astrocytes were observed in the striatum. These astrocytes were similar to Alzheimer type 1 astrocytes. Globular structures were seen in proportion to the degree of iron deposition. They clearly reacted with anti-glial fibrillary acidic protein (GFAP) and anti-S-100 antibodies and contained glial fibril-like filaments, but showed no or only faint immunoreactivity to antibodies for neuronal marker proteins, such as neurofilament and synaptophysin. Therefore, the globular structures presumably originated from astrocytes. The structures also reacted positively to anti-HNE and anti-ubiquitin antibodies. We conclude that astrocytic deformities and globular structures are characteristic neuropathological features of aceruloplasminemia and are closely linked to iron overload and subsequent oxidative stress.

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) is believed to play an essential role for GABA synthesis in the central nervous system. Using mice with targeted disruption of the GAD65 gene (GAD65(-/-) mice) we investigated the contribution of GAD65 to GABA synthesis in different brain areas during postnatal development and in adulthood. In the amygdala, hypothalamus and parietal cortex of GAD65(+/+) mice an increase of GABA levels was observed during postnatal development, most prominently between the first and second month after birth. This increase appeared to be dependent on GAD65, as it was delayed by 2 months in GAD65(+/-) mice and was not observed in GAD65(-/-) mice. Likely as a consequence of their GABA deficit, adult GAD65(-/-) mice showed a largely abnormal neural activity with frequent paroxysmal discharges and spontaneous seizures. They furthermore displayed increased anxiety-like behaviour in a light/dark avoidance test and reduced intermale aggression, as well as a reduced forced-swimming-induced immobility indicative of an antidepressant-like behavioural change. Adult GAD65(+/-) mice did not show behavioural disturbances except for a reduced aggressive behaviour that was comparable to that in GAD65(-/-) mice. We conclude that GAD65-mediated GABA synthesis may be crucially involved in control of emotional behaviour and indispensable for a tonic inhibition that prevents the development of hyperexcitability in the maturating central nervous system. Aggressive, and possibly other social behaviour may be especially prone to regulation through GAD65-mediated GABA synthesis.

Aceruloplasminemia is characterized by excessive neurovisceral accumulation of iron due to mutations in the ceruloplasmin gene. We report that the levels of malonaldehyde (MDA) and 4-hydroxynonenals (4-HNE) were elevated both in the frontal cortex and putamen in two patients with aceruloplasminemia compared with those in controls. Immunohistochemical analysis with an antibody raised against HNE-modified protein showed a large number of immunoreactive neurons and glias in the brain of a patient. MDA and 4-HNE are good indicators of lipid peroxidation because they are generated in the process of oxidation of polyunsaturated fatty acids. The data strongly suggest that the increase of oxygen free radicals associated with excessive iron accumulation plays an important pathogenic role in the process of neuronal cell death in the brains of patients with aceruloplasminemia.

The molecular basis of the infectious, inherited and sporadic forms of prion diseases is best explained by a conformationally dimorphic protein that can exist in distinct normal and disease-causing isoforms. We identified a 55-residue peptide of a mutant prion protein that can be refolded into at least two distinct conformations. When inoculated intracerebrally into the appropriate transgenic mouse host, 20 of 20 mice receiving the beta-form of this peptide developed signs of central nervous system dysfunction at approximately 360 days, with neurohistologic changes that are pathognomonic of Gerstmann-Sträussler-Scheinker disease. By contrast, eight of eight mice receiving a non-beta-form of the peptide failed to develop any neuropathologic changes more than 600 days after the peptide injections. We conclude that a chemically synthesized peptide refolded into the appropriate conformation can accelerate or possibly initiate prion disease., (Copyright 2000 Academic Press.)

Living cells spontaneously emit ultraweak light during the process of metabolic reactions associated with the physiological state. The first demonstration of two-dimensional in vivo imaging of ultraweak photon emission from a rat's brain, using a highly sensitive photon counting apparatus, is reported in this paper. It was found that the emission intensity correlates with the electroencephalographic activity that was measured on the cortical surface and this intensity is associated with the cerebral blood flow and hyperoxia. To clarify the mechanism of photon emission, intensity changes from whole brain slices were examined under various conditions. The removal of glucose from the incubation medium suppressed the photon emission, and adding 50 mM potassium ions led to temporal enhancement of emission and subsequent depression. Rotenone (20 microM), an inhibitor of the mitochondrial electron transport chain, increased photon emission, indicating electron leakage from the respiratory chain. These results suggest that the photon emission from the brain slices originates from the energy metabolism of the inner mitochondrial respiratory chain through the production of reactive oxygen. Imaging of ultraweak photon emission from a brain constitutes a novel method, with the potential to extract pathophysiological information associated with neural metabolism and oxidative dysfunction of the neural cells.

Evoked spinal cord potentials (ESCPs) from the cervical and high thoracic epidural space following transcranial magnetic stimulation were recorded from eight subjects in awake and anesthetized condition. Motor evoked potentials (MEPs) from the right abductor digiti minimi (ADM) and rectus femoris (RF) muscles were simultaneously recorded during voluntary contraction. The stimulus intensity was at 30% above the MEPs threshold of the ADM when the coil center was fixed on 10-20 international Cz position. In awake condition, multiple ESCP components (greater than 3) were recorded from the cervical epidural space but no or minimal components were recorded from the upper thoracic epidural space. When the coil was moved anteriorly so that the posterior edge of the coil was positioned on Cz, the amplitude of the first ESCP component was significantly increased (P < 0.02) and shortened (not significant) at cervical levels. In addition, several ESCP components were more evident at high thoracic levels. Although the amplitude of the ADM was not enhanced, that of the RF was enhanced. During general anesthesia with volatile anesthetics (sevoflurane), only the first component of the ESCPs (D-wave) was elicited. Its amplitude was enhanced (P < 0.02) when the coil edge was fixed on Cz, similar to results in awake condition. This enhancement of the first ESCP component was accompanied by enhancement of those recorded from the high thoracic epidural space. However the amplitude of D-wave was the same in the two different coil positions when the stimulus intensity was set a 100% of the output. These results suggest that at low stimulus intensity, positioning the coil edge on Cz is optimal in inducing D-wave effectively but at high stimulus intensity, D-wave generation can be achieved in either if the two different coil position.

Evoked spinal cord potentials (ESCPs) from the cervical epidural space and motor evoked potentials (MEPs) from the hand muscles were recorded simultaneously in 6 subjects following transcranial magnetic stimulation in two different coil orientations on motor cortex. The onset latency of the MEPs was approximately 1 ms shorter when the induced current flowed in a latero-medial direction (L-M stimulation) on the motor cortex as compared to a postero-anterior direction (P-A stimulation). Hence, L-M stimulation elicited an earlier component of the ESCPs than that induced by P-A stimulation. During general anesthesia with Sevoflurane, only the first component of the ESCPs could be elicited routinely following L-M stimulation. In contrast, all components of the ESCPs were dramatically attenuated following P-A stimulation. Moreover, first component latency of the ESCPs induced by L-M stimulation was almost the same as that induced by transcranial anodal electrical stimulation. These results suggest that if the induced current following transcranial magnetic stimulation flows in a latero-medial direction on motor cortex, it preferentially stimulates the corticospinal tract non-synaptically (producing a D-wave). However, if the induced current flows in a postero-anterior direction, it preferentially stimulates the corticospinal tract trans-synaptically (producing I-waves). Therefore, the direction of magnetically induced current is crucial in determining corticospinal excitability in the human brain.

We measured [125I] iomazenil binding, labeling the central-type benzodiazepine receptor in 37 discrete rat brain areas following single (7.5 mg/kg, i.p.) and repeated (7.5 mg/kg/day x 14 days, i.p.) treatment with phencyclidine (PCP), a non-competitive antagonist of the N-methyl-D-aspartate(NMDA)-type glutamate receptor, using in vitro quantitative autoradiographic receptor binding assay. Both single and repeated PCP treatment produced heterogeneous changes in the rat brain in a similar manner, the magnitude of change in [125I] iomazenil binding being generally greater in the repeated treatment group than in the single treatment group. A significant increase in [125I] iomazenil binding was observed in the superficial layer (layer I-IV) of the parietal cortex in both of the PCP treatment groups and the CA1 of the hippocampus of the repeated PCP-treated group. There was a significant decrease in [125I] iomazenil binding in the piriform cortex of the repeated PCP-treated group. These results suggest that the blockade of NMDA receptor-mediated glutamatergic neurotransmission by PCP produces the compensational alterations in the central-type benzodiazepine receptor antagonist binding, and that the observed diversity may be due to dissimilar modes of organizations between glutamatergic and the GABA(gamma-aminobutyric acid)-benzodiazepine receptor complex.

The effects of chronic treatment with haloperidol on [3H]PK 11195 binding and labelling of the peripheral-type benzodiazepine receptor (PBR) in the rat brain and peripheral tissues were investigated using an in vitro receptor binding technique. The intraperitoneal injection with haloperidol (0.3 or 1.0 mg/kg) for 21 days produced a significant increase in the specific [3H]PK 11195 binding only in the olfactory bulb, but not in the other brain areas or peripheral tissues, while single or subchronic (4 days or 7 days) administration with the drug (0.3 mg/kg, i.p.) failed to increase the binding in the olfactory bulb. Scatchard analysis revealed a significant increase in the maximum number of [3H]PK 11195 binding sites in the olfactory bulb after chronic treatment with haloperidol, showing no change in the affinity of the binding. These results suggest that there is an interaction between PBR and the pharmacological actions of haloperidol in the brain area, and that some compensatory mechanism may be involved in the PBR changes.

Circulating autoantibody to a 48-kD nuclear protein in neurons and astrocytes of the human and bovine cerebrum were present in the serum of a demented patient with an autoimmune disorder. Other human visceral organs, dorsal root ganglion cells, neuroblastoma and glioblastoma cell lines, and rat cerebrum did not react with the patient's serum. No sera from age-matched controls, including those with Alzheimer's disease, reacted with the 48-kD protein. Only the mature neurons and astrocytes of humans and some mammals express the 48-kD protein. This antibody may be responsible for the patient's demented condition.