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Funder: European Research Council; FundRef: http://dx.doi.org/10.13039/501100000781; Grant(s): GAP: 502670428 - BRAIN2MIND_NEUROCOMP, How does the human brain encode semantic information about objects? This paper reconciles two seemingly contradictory views. The first proposes that local neural populations independently encode semantic features; the second, that semantic representations arise as a dynamic distributed code that changes radically with stimulus processing. Combining simulations with a well-known neural network model of semantic memory, multivariate pattern classification, and human electrocorticography, we find that both views are partially correct: information about the animacy of a depicted stimulus is distributed across ventral temporal cortex in a dynamic code possessing feature-like elements posteriorly but with elements that change rapidly and nonlinearly in anterior regions. This pattern is consistent with the view that anterior temporal lobes serve as a deep cross-modal 'hub' in an interactive semantic network, and more generally suggests that tertiary association cortices may adopt dynamic distributed codes difficult to detect with common brain imaging methods.

The spatiotemporal dynamics of interaction between slow (delta or infraslow) waves and fast (gamma) activities during wakefulness and sleep are yet to be elucidated in human electrocorticography (ECoG). We evaluated phase-amplitude coupling (PAC), which reflects neuronal coding in information processing, using ECoG in 11 patients with intractable focal epilepsy. PAC was observed between slow waves of 0.5–0.6 Hz and gamma activities, not only during light sleep and slow-wave sleep (SWS) but even during wakefulness and rapid eye movement (REM) sleep. While PAC was high over a large region during SWS, it was stronger in the posterior cortical region around the temporoparietal junction than in the frontal cortical region during REM sleep. PAC tended to be higher in the posterior cortical region than in the frontal cortical region even during wakefulness. Our findings suggest that the posterior cortical region has a functional role in REM sleep and may contribute to the maintenance of the dreaming experience.

Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and 11C-methionine (Met)-PET and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness–type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered.

Synaptic strength reduces during sleep, but the underlying mechanisms of this process are unclear. This study showed reduction of synaptic proteins in rat prefrontal cortex (PFC) at AM7 or Zeitgeber Time (ZT0), when the light phase or sleeping period for rats started. At this time point, microglia were weakly activated, displaying larger and more granular somata with increased CD11b expression compared with those at ZT12, as revealed by flow cytometry. Expression of opsonins, such as complements or MFG-E8, matrix metalloproteinases, and microglial markers at ZT0 were increased compared with that at ZT12. Microglia at ZT0 phagocytosed synapses, as revealed by immunohistochemical staining. Immunoblotting detected more synapsin I in the isolated microglia at ZT0 than at ZT12. Complement C3- or MFG-E8-bound synapses were the most abundant at ZT0, some of which were phagocytosed by microglia. Systemic administration of synthetic glucocorticoid dexamethasone reduced microglial size, granularity and CD11b expression at ZT0, resembling microglia at ZT12, and increased synaptic proteins and decreased the sleeping period. Noradrenaline (NA) suppressed glutamate-induced phagocytosis in primary cultured microglia. Systemic administration of the brain monoamine-depleting agent reserpine decreased NA content and synapsin I expression in PFC, and increased expression of microglia markers, C3 and MFG-E8, while increasing the sleeping period. A NA precursor l-threo-dihydroxyphenylserine abolished the reserpine-induced changes. These results suggest that microglia may eliminate presumably weak synapses during every sleep phase. The circadian changes in concentrations of circulating glucocorticoids and brain NA might be correlated with the circadian changes of microglial phenotypes and synaptic strength.

CLICs are the dimorphic protein present in both soluble and membrane fractions. As an integral membrane protein, CLICs potentially possess ion channel activity. However, it is not fully clarified what kinds of roles CLICs play in physiological and pathological conditions. In vertebrates, CLICs are classified into six classes: CLIC1, 2, 3, 4, 5, and 6. Recently, in silico analyses have revealed that the expression level of CLICs may have prognostic significance in cancer. In this review, we focus on CLIC2, which has received less attention than other CLICs, and discuss its role in the metastasis and invasion of malignant tumor cells. CLIC2 is expressed at higher levels in benign tumors than in malignant ones, most likely preventing tumor cell invasion into surrounding tissues. CLIC2 is also expressed in the vascular endothelial cells of normal tissues and maintains their intercellular adhesive junctions, presumably suppressing the hematogenous metastasis of malignant tumor cells. Surprisingly, CLIC2 is localized in secretory granules and secreted into the extracellular milieu. Secreted CLIC2 binds to MMP14 and inhibits its activity, leading to suppressed MMP2 activity. CLIC4, on the other hand, promotes MMP14 activity. These findings challenge the assumption that CLICs are ion channels, implying that they could be potential new targets for the treatment of malignant tumors.

[Objectives] This study investigated neuronal sources of slow cortical potentials (SCPs) evoked during vagus nerve stimulation (VNS) in patients with epilepsy who underwent routine electroencephalography (EEG) after implantation of the device. [Materials and Methods] We analyzed routine clinical EEG from 24 patients. There were 5 to 26 trains of VNS during EEG. To extract SCPs from the EEG, a high-frequency filter of 0.2 Hz was applied. These EEG epochs were averaged and used for source analyses. The averaged waveforms for each patient and their grand average were subjected to multidipole analysis. Patients with at least 50% seizure frequency reduction were considered responders. Findings from EEG analysis dipole were compared with VNS responses. [Results] VNS-induced focal SCPs whose dipoles were estimated to be located in several cortical areas including the medial prefrontal cortex, postcentral gyrus, and insula, with a significantly higher frequency in patients with a good VNS response than in those with a poor response. [Conclusions] This study suggested that some VNS-induced SCPs originating from the so-called vagus afferent network are related to the suppression of epileptic seizures.

Convergent evidence has demonstrated that semantics are represented by the interaction between a multimodal semantic hub at the anterior temporal lobe (ATL) and other modality-specific association cortical areas. Electrocorticogram (ECoG) recording with high spatiotemporal resolutions is efficient in evaluating such cortical interactions; however, this has not been a focus of preceding studies. The present study evaluated cortical interactions during picture naming using a novel ECoG cross-spectrum analysis, which was formulated from a computational simulation of neuronal networks and combined with a vector space model of semantics. The results clarified three types of frequency-dependent cortical networks: 1) an earlier-period (0.2–0.8 s from stimulus onset) high-gamma-band (90–150 Hz) network with a hub at the posterior fusiform gyrus, 2) a later-period (0.4–1.0 s) beta-band (15–40 Hz) network with multiple hubs at the ventral ATL and posterior middle temporal gyrus, and 3) a pre-articulation theta-band (4–7 Hz) network distributed over widely located cortical regions. These results suggest that frequency-dependent cortical interactions can characterize the underlying processes of semantic cognition, and the beta-band network with a hub at the ventral ATL is especially associated with the formation of semantic representation.

Purpose The purpose of this study was to evaluate the clinical usefulness of zero-echo-time (ZTE)–based magnetic resonance imaging (MRI) in planning the optimum surgical approach and applying ZTE for anatomical guidance during transcranial surgery. Methods Eleven of 26 patients who underwent transcranial surgery and carotid endarterectomy and in whom ZTE-based MRI and magnetic resonance angiography (MRA) data were obtained were analyzed by creating ZTE/MRA fusion images and 3D ZTE-based MRI models. We examined whether these images and models can be substituted for computed tomography imaging for neurosurgical procedures. Furthermore, the clinical usability of the 3D ZTE-based MRI models was evaluated by comparing them with actual surgical views. Results Zero-echo-time/MRA fusion images and 3D ZTE-based MRI models clearly illustrated the cranial and intracranial morphology without radiation exposure or the use of iodinated contrast medium. The models allowed determination of the optimum surgical approach to cerebral aneurysms, brain tumors near the brain surface, and cervical internal carotid artery stenosis by visualizing the relationship of lesions with adjacent bone structures. However, ZTE-based MRI did not provide useful information for surgery for skull base lesions such as vestibular schwannoma because bone structures of the skull base often include air components, which cause signal disturbance in MRI. Conclusions Zero-echo-time sequences on MRI allowed distinct visualization of not only bone but also vital structures around the lesion. This technology has low invasiveness for patients and was useful for preoperative planning and guidance of the optimum approach during surgery in a subset of neurosurgical diseases.

To preserve postoperative brain function, it is important for neurosurgeons to fully understand the brain's structure, vasculature, and function. Intraoperative high-frequency electrical stimulation during awake craniotomy is the gold standard for mapping the function of the cortices and white matter; however, this method can only map the “focal” functions and cannot monitor large-scale cortical networks in real-time. Recently, an in vivo electrophysiological method using cortico-cortical evoked potentials (CCEPs) induced by single-pulse electrical cortical stimulation has been developed in an extraoperative setting. By using the CCEP connectivity pattern intraoperatively, mapping and real-time monitoring of the dorsal language pathway is available. This intraoperative CCEP method also allows for mapping of the frontal aslant tract, another language pathway, and detection of connectivity between the primary and supplementary motor areas in the frontal lobe network. Intraoperative CCEP mapping has also demonstrated connectivity between the frontal and temporal lobes, likely via the ventral language pathway. Establishing intraoperative electrophysiological monitoring is clinically useful for preserving brain function, even under general anesthesia. This CCEP technique demonstrates potential clinical applications for mapping and monitoring large-scale cortical networks.

Even after total resection of glioblastoma core lesions by surgery and aggressive post-surgical treatments, life-threatening tumors inevitably recur. A characteristic obstacle in effective treatment is high intratumoral heterogeneity, both longitudinally and spatially. Recurrence occurs predominantly at the brain parenchyma-tumor core interface, a region termed tumor edge. Given the difficulty of accessing it surgically, the composition of the tumor edge, harboring both cancerous and non-cancerous cells, remains largely unknown. Here, to identify phenotypic diversity among heterogeneous glioblastoma core and edge lesions, we uncovered the existence of three phenotypically-distinct clonal subpopulations within individual tumors from glioblastoma patients. Clones from the tumor core shared the same phenotype, exclusively generating tumor-core cells. In contrast, two distinct clonal subtypes were identified at the tumor edge: one generated only edge-lesion cells and the other expanded more broadly to establish both edge- and core-lesions. Using multiple xenograft experimental models in mouse brains, tumor edge development was found to require that both somatic and tumor cells express the NADase CD38, combinedly elevating glioblastoma malignancy. In vitro data suggested that intracellular NADase activity at the edge was provoked through intercellular communication between edge clones and normal astrocytes. Systemic treatment of tumor-bearing mice with 78c, a small-molecule CD38 inhibitor, attenuated the formation of glioblastoma edge lesions, suggesting its clinical potential to pharmacologically eliminate tumor-edge lesions. Collectively, these findings provide novel phenotypic and mechanistic insights into clonal heterogeneity within glioblastoma, particularly in the surgically unresectable, currently understudied tumor edge.

SummaryThe rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD+) with aging, as old mice exposed to young blood via parabiosis or supplemented with the NAD+ precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF+/- young mice and in BDNF+/- mice undergoing tumor challenge, supporting the notion that the lower NAD+-BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD+ worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.

Background The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive and highly migratory glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence or progression, the highly invasive phenotype of GSCs changes to a less-motile, proliferative phenotype, thus generating tumor mass. Elucidating the molecular mechanism underlying this phenotypic transition could lead to the identification of effective molecular targets for treating GBM. Methods We examined mRNA expression of hypoxia-inducible factor (HIF)-1α, HIF-2α, CD44, and osteopontin in GBM tissues and investigated the effect of hypoxia (1% O2: severe or 5% O2: moderate) on expression of these molecules using two lines of cultured GSCs. We also analyzed the effect of osteopontin on the invasiveness, migration, and proliferation of GSCs under hypoxic conditions. In addition, the effect of CD44 knockdown on tumor growth and survival were investigated in vitro and in vivo using a mouse xenograft model. Results Severe hypoxia upregulates CD44 expression via activation of HIF-1α, inducing GSCs to assume a highly invasive phenotype. In contrast, moderate hypoxia upregulates osteopontin expression via activation of HIF-2α. Osteopontin in turn binds to CD44, simultaneously inhibiting CD44-promoted GSC migration and invasion and stimulating GSC proliferation, resulting in GSCs assuming a less-invasive, highly proliferative phenotype. CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo. However, although CD44 knockdown did not affect tumor growth in vitro, mouse brain tumors generated from GSCs with CD44 knockdown exhibited diminished invasiveness, and the mice survived significantly longer than control mice. In contrast, siRNA-mediated silencing of the osteopontin gene led to decreased GSC proliferation, but the osteopontin-mediated inhibition of high GSC migratory behavior and invasiveness was diminished. Conclusion The highly invasive phenotype of GSCs can be reversed by switching from severe to moderate hypoxia, leading to less-invasive and proliferative tumors. CD44 and osteopontin, which are expressed in a mutually exclusive manner under severe or moderate hypoxia, play a central role in regulating GSC invasion and proliferation by inducing a phenotypic transition, suggesting that these molecules could be effective targets for treating both primary and recurrent GBM.

In the dual-stream model of language processing, the exact connectivity of the ventral stream to the anterior temporal lobe remains elusive. To investigate the connectivity between the inferior frontal gyrus (IFG) and the lateral part of the temporal and parietal lobes, we integrated spatiotemporal profiles of cortico-cortical evoked potentials (CCEPs) recorded intraoperatively in 14 patients who had undergone surgical resection for a brain tumor or epileptic focus. Four-dimensional visualization of the combined CCEP data showed that the pars opercularis (Broca’s area) is connected to the posterior temporal cortices and the supramarginal gyrus, whereas the pars orbitalis is connected to the anterior lateral temporal cortices and angular gyrus. Quantitative topographical analysis of CCEP connectivity confirmed an anterior–posterior gradient of connectivity from IFG stimulus sites to the temporal response sites. Reciprocality analysis indicated that the anterior part of the IFG is bidirectionally connected to the temporal or parietal area. This study shows that each IFG subdivision has different connectivity to the temporal lobe with an anterior–posterior gradient and supports the classical connectivity concept of Dejerine; that is, the frontal lobe is connected to the temporal lobe through the arcuate fasciculus and also a double fan-shaped structure anchored at the limen insulae.

OBJECTIVE For future artificial intelligence-based brain mapping, development of a rational and safe scoring system for a brain motor mapping algorithm using electrocorticography (ECoG score), which contains various spectral, purely intrinsic brain activities, is necessary for either before or in the absence of electrical cortical stimulation (ECS). METHODS We evaluated 1114 electrodes of 10 consecutive focal epilepsy patients who underwent subdural electrode implantation before epilepsy surgery at Kyoto University Hospital during 2011-2017. Data from ECoG-based mapping (bandpass filter of 0.016-300/600 Hz) to define the primary motor area (M1) localization were used to create an ECoG score (range = 0-4) by assigning 1 point each for the occurrence of ECoG components: very slow movement-related cortical potentials (

Differentiating tumor from normal pituitary gland is very important for achieving complete resection without complications in endoscopic endonasal transsphenoidal surgery (ETSS) for pituitary adenoma. To facilitate such surgery, we investigated the utility of indocyanine green (ICG) fluorescence endoscopy as a tool in ETSS. Twenty-four patients with pituitary adenoma were enrolled in the study and underwent ETSS using ICG endoscopy. After administering 12.5 mg of ICG twice an operation with an interval > 30 min, times from ICG administration to appearance of fluorescence on vital structures besides the tumor were measured. ICG endoscopy identified vital structures by the phasic appearance of fluorescent signals emitted at specific consecutive elapsed times. Elapsed times for internal carotid arteries did not differ according to tumor size. Conversely, as tumor size increased, elapsed times for normal pituitary gland were prolonged but those for the tumor were reduced. ICG endoscopy revealed a clear boundary between tumors and normal pituitary gland and enabled confirmation of no more tumor. ICG endoscopy could provide a useful tool for differentiating tumor from normal pituitary gland by evaluating elapsed times to fluorescence in each structure. This method enabled identification of the boundary between tumor and normal pituitary gland under conditions of a low-fluorescence background, resulting in complete tumor resection with ETSS. ICG endoscopy will contribute to improve the resection rate while preserving endocrinological functions in ETSS for pituitary adenoma.

Background and Purpose: Recent studies have demonstrated that endovascular reperfusion therapy improves clinical outcomes at 90 days after ischemic stroke. However, the effects on long-term outcomes are not well known. We hypothesized that successful reperfusion might be associated with long-term improvement beyond 90 days after endovascular therapy. To assess the long-term effects beyond 90 days, we analyzed the association of successful reperfusion with a temporal change in modified Rankin Scale (mRS) score from 90 days to 1 year after endovascular therapy. Methods: We retrospectively analyzed a database of consecutive patients with acute ischemic stroke who received endovascular therapy between April 2006 and March 2016 at 4 centers. We compared the incidences of improvement and deterioration in patients with successful reperfusion (i.e., modified thrombolysis in cerebral infarction score of 2b or 3) with those in patients with unsuccessful reperfusion. We defined improvement and deterioration as decrease and increase on the mRS score by 1 point or more from 90 days to 1 year after endovascular therapy respectively. Results: A total of 268 patients were included in the current study. The rate of patients with improvement tended to be higher in patients with successful reperfusion than in patients with unsuccessful reperfusion (20% [34/167 patients] vs. 12% [12/101], p = 0.07). The rate of patients with deterioration was lower in patients with successful reperfusion than in patients with unsuccessful reperfusion (25% [42/167] vs. 42% [42/101], p < 0.01). After adjustment for confounders, successful reperfusion was associated with improvement (adjusted OR 2.65; 95% CI 1.23–5.73; p < 0.05) and deterioration (adjusted OR 0.33; 95% CI 0.18–0.62; p < 0.01), independent of the 90-day mRS score. Conclusions: Successful reperfusion has further beneficial legacy effects on long-term outcomes beyond 90 days after stroke.

Background The connection between the ventrolateral frontal and temporoparietal cortices has an important role in language function on the language-dominant side and spatial awareness on the nondominant side. However, the laterality of these pathways remains controversial. We investigated the laterality of this connection using corticocortical-evoked potentials (CCEPs). Methods From April 2014 to March 2016, 27 patients who had undergone frontotemporal craniotomy were enrolled. With the patients under general anesthesia, subdural electrodes were placed on both frontal and temporoparietal areas intraoperatively. Alternating 1-Hz electrical stimuli were delivered to the pars opercularis and pars triangularis with a stimulus intensity of 10 mA. CCEPs were obtained from temporoparietal areas by averaging the electrocorticogram time-locked to the stimulus onset. The amplitudes and latencies of the CCEP N1 components were compared between the dominant and nondominant sides. Results The median amplitudes of the CCEPs were 335.1 μV (range, 60.2–750) and 125.65 μV (range, 55.1–634) on the dominant and nondominant sides, respectively. The CCEP amplitudes were significantly larger on the dominant side than on the nondominant side (P = 0.013). In contrast, the median latency was 27.8 ms (range, 19.3–36.6) on the language-dominant side and 28.9 ms (range, 8.9–38.5) on the nondominant side. The latencies were not significantly different between the 2 sides (P = 0.604). Conclusions The CCEP amplitudes were significantly larger in the dominant hemisphere. These findings can lead to better hypotheses regarding the relationship between language functions and the development of the network connecting the frontal and temporoparietal cortices.

OBJECTIVEHigh invasiveness of malignant gliomas frequently causes early local recurrence of the tumor, resulting in extremely poor outcome. To control such recurrence, novel therapies targeted toward infiltrating glioma cells around the tumor border are required. Here, the authors investigated the antitumor activity of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas to explore the possibility for clinical use of 5-ALA–mediated SDT (5-ALA-SDT).METHODSIn vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry and TUNEL staining. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined by analysis of the effect of pretreatment with the radical scavenger edaravone. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated.RESULTSThe 5-ALA-SDT inhibited cell growth and changed cell morphology, inducing cell shrinkage, vacuolization, and swelling. Flow cytometric analysis and TUNEL staining indicated that 5-ALA-SDT induced apoptotic cell death in all gliomas. The 5-ALA-SDT generated significantly higher ROS than in the control group, and inhibition of ROS generation by edaravone completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. The proliferative activity of the entire tumor was markedly decreased. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact.CONCLUSIONSThe 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field, whereas the surrounding brain tissue remained normal, resulting in longer survival of the HIFU-treated mice compared with that of untreated mice. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

BACKGROUND The development of noninvasive approaches for identifying hypoperfused brain tissue at risk is of major interest. Recently, the temporal-shift (TS) maps estimated from resting-state blood oxygenation level-dependent (BOLD) signals have been proposed for determining hemodynamic state. OBJECTIVE To examine the equivalency of the TS map and the cerebrovascular reactivity (CVR) map derived from acetazolamide-challenged single-photon emission computed tomography (SPECT) in identifying hemodynamic impairment in patients with arterial occlusive diseases. METHODS Twenty-three patients with arterial occlusive diseases who underwent SPECT were studied. With a recursive TS analysis of low-frequency fluctuation of the BOLD signal, a TS map relative to the global signal was created for each patient. The voxel-by-voxel correlation coefficient was calculated to examine the image similarity between TS and SPECT-based cerebral blood flow (CBF) or CVR maps in each patient. Furthermore, simple linear regression analyses were performed to examine the quantitative relationship between the TS of BOLD signals and CVR in each cerebrovascular territory. RESULTS The within-patient, voxel-by-voxel comparison revealed that the TS map was more closely correlated with SPECT-CVR map ([Z(r)] = 0.42 ± 0.18) than SPECT-CBF map ([Z(r)] = 0.058 ± 0.11; P

Neuro-feedback (NFB) training by the self-regulation of slow potentials (SPs)0.5 Hz recorded from the vertex scalp has been applied for seizure suppression in patients with epilepsy. However, SP is highly susceptible to artifact contamination, such as the galvanic skin response (GSR). This study aimed to evaluate the correlation between SPs recorded from the scalp and intracranial electroencephalography (EEG) by event-related coherence analysis.The scalp and subdural SPs were simultaneously recorded during NFB training by the DC-EEG machine while undergoing invasive recordings before epilepsy surgery in 10 patients with refractory partial epilepsy. The SPs at the vertex electrode were used as a reference for coherence analysis.The coherence of SPs negatively correlated with the distance between the subdural and scalp electrodes. A significant negative correlation was noted between the linear subdural-scalp electrode distance and the coherence value (r = - 0.916, p 0.001).Scalp-recorded SPs from the vertex area primarily reflect the cortical activity of high lateral convexity.Our results strongly suggest that SPs in NFB recorded from the vertex scalp electrode is derived from the cortices of high lateral convexity but not from the artifacts, such as GSR.

Ischemic brain injuries caused release of damage-associated molecular patterns (DAMPs) that activate microglia/macrophages (MG/MPs) by binding to Toll-like receptors. Using middle cerebral artery transiently occluded rats, we confirmed that MG/MPs expressed inducible nitric oxide synthase (iNOS) on 3days after reperfusion (dpr) in ischemic rat brain. iNOS expression almost disappeared on 7dpr when transforming growth factor-β1 (TGF-β1) expression was robustly increased. After transient incubation with TGF-β1 for 24h, rat primary microglial cells were incubated with lipopolysaccharide (LPS) and released NO level was measured. The NO release was persistently suppressed even 72h after removal of TGF-β1. The sustained TGF-β1 effects were not attributable to microglia-derived endogenous TGF-β1, as revealed by TGF-β1 knockdown and in vitro quantification studies. Then, boiled supernatants prepared from ischemic brain tissues showed the similar sustained inhibitory effects on LPS-treated microglial cells that were prevented by the TGF-β1 receptor-selective blocker SB525334. After incubation with TGF-β1 for 24h and its subsequent removal, LPS-induced phosphorylation of IκB kinases (IKKs), IκB degradation, and NFκB nuclear translocation were inhibited in a sustained manner. SB525334 abolished all these effects of TGF-β1. In consistent with the in vitro results, phosphorylated IKK-immunoreactivity was abundant in MG/MPs in ischemic brain lesion on 3dpr, whereas it was almost disappeared on 7dpr. The findings suggest that abundantly produced TGF-β1 in ischemic brain displays sustained anti-inflammatory effects on microglial cells by persistently inhibiting endogenous Toll-like receptor ligand-induced IκB degradation.

CD200 mediates immunosuppression in immune cells that express its receptor, CD200R. There are two CD200 variants; truncated CD200 that lacks the part of N-terminal sequence necessary for CD200R binding (CD200S) and full-length CD200 (CD200L). We established a novel lung metastasis model by subcutaneously transplanting C6 glioma cells into the backs of neonatal Wistar rats. All transplanted rats developed large back tumors, nearly 90% of which bore lung metastases. To compare the effects of CD200S and CD200L on tumor immunity, CD200L (C6-L)- or CD200S (C6-S)-expressing C6 cells were similarly transplanted. The results showed that 100% of rats with C6-L tumors developed lung metastases, while metastases were found in only 44% of rats with C6-S tumors (n = 25). Tumors disappeared in approximately 20% of the C6-S-bearing rats, and these animals evaded death 180 d after transplantation, while all C6-L tumor-bearing rats died after 45 d. Next generation sequencing revealed that C6-S tumors expressed chemokines and granzyme B at much higher levels than C6-L tumors. Flow cytometry revealed that C6-S tumors contained more dead cells and more CD45+ cells, including natural killer cells and CD8+ lymphocytes. In particular, multiple subsets of dendritic cells expressing CD11c, MHC class II, CD8, and/or CD103 were more abundant in C6-S than in C6-L tumors. These results suggested that CD200S induced the accumulation of multiple dendritic cell subsets that activated cytotoxic T lymphocytes, leading to the elimination of metastasizing tumor cells.

Highlights • We report an elder case of cerebral amyloid angiopathy-related inflammation (CAA-ri) in the right occipital lobe. • It appears like an intraparenchymal tumor at first, and can be finally diagnosed only through biopsy. • CAA-ri should be considered among the differential diagnoses for unprovoked seizure onset, when associated with petechial hemorrhages on MRI. • Recently DFS staining has been considered more desirable to ascertain the deposition of amyloid protein., Introduction Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare and treatable variant of cerebral amyloid angiopathy, lacks specific imaging and clinical features, and requires invasive brain biopsy to confirm the diagnosis. We report the case of a patient with nonconvulsive status epilepticus (NCSE) caused by CAA-ri in the right occipital lobe. Presentation of case A 78-year-old man with a history of hypertension and rheumatoid arthritis was admitted to our hospital following an episode of seizures. CT scan showed a low-attenuating subcortical lesion in the right occipital lobe. MRI revealed the lesion as hypointense on T1-weighted imaging (WI) and hyperintense on T2-WI, showing no enhancement on T1-WI contrast-enhanced with gadolinium. In addition, T2*-weighted gradient-recalled echo (T2*-GRE) and susceptibility-weighted imaging (SWI) revealed extensive cortical microbleeds. Biopsy to determine the exact diagnosis revealed histological findings of reactive changes and perivascular inflammatory infiltration associated with amyloid deposition in vessel walls. These findings were consistent with CAA-ri. Corticosteroid therapy with dexamethasone was initiated for a short period as a diagnostic and therapeutic maneuver, resulting in marked reductions in the lesion. Discussion CAA is generally associated with intracerebral hemorrhage, dementia, and small cerebral infarctions in the elderly population, but in a small proportion of cases is related to inflammatory responses to vascular deposits of Aβ, as so-called CAA-ri. Conclusion CAA-ri should be considered among the differential diagnoses for causes of unprovoked seizure onset in elderly individuals, when associated with petechial hemorrhages on T2*-GRE and SWI sequences on MRI.

Small and broad-necked aneurysms are generally very difficult to treat using endovascular therapy. The arrival of the low-profile stent (e.g., Low-profile Visualized Intraluminal Support; LVIS) has enabled reconstructive treatment for these aneurysms. In addition, the bulging technique using LVIS is an effective and attractive technique for performing stent-assisted coiling to preserve parent arteries and achieve neck coverage. We report here a patient with a small and wide-necked ruptured basilar artery (BA) top aneurysm, in whom successful treatment was achieved by stent-assisted coiling with LVIS Jr. using the bulging technique. A 74-year-old woman with moderate hypertension consulted for treatment of subarachnoid hemorrhage with a ruptured BA top aneurysm measuring 2.7 mm in height with a 4.3 mm neck. We initially tried emergency balloon-assisted coiling, but coiling proved difficult. We therefore performed stent-assisted coiling with LVIS Jr. using the bulging technique. The postoperative course was uneventful, with no aggravation of neurological symptoms, and the patient was discharged 14 days postoperatively. This treatment strategy with LVIS Jr. using the bulging technique may be very useful for patients with a ruptured aneurysm with a small and broad neck that would otherwise require treatment with intravascular devices or open surgery.

Background The frontal aslant tract is a deep frontal pathway connecting the superior frontal gyrus (SFG) to Broca area. This fiber is assumed to be associated with language functions, especially speech initiation and spontaneity. The aim of this study was to electrophysiologically investigate this network using corticocortical evoked potentials (CCEPs). Methods This study enrolled 8 patients with brain tumors or medically intractable focal epilepsies who underwent frontal craniotomy over the language-dominant side. All patients underwent CCEP recordings during tumor resection or during invasive evaluation for epilepsy surgery. Alternating 1-Hz electrical stimuli were delivered to pars opercularis (pO) and pars triangularis (pT), corresponding to Broca area, and SFG via the subdural grid electrodes with intensity of 10 mA. Electrocorticograms from SFG and pO/pT time-locked to 50 stimuli were averaged in each trial to obtain CCEP responses. Results In all patients, stimulation of pO/pT induced CCEP responses in SFG. CCEP responses were recorded in lateral SFG in 5 patients and in supplementary motor areas in 4 patients. Reciprocality was observed in 7 patients in the stimulation of SFG. CCEP responses were significantly faster at SFG from pO/pT than at pO/pT from SFG (Wilcoxon signed rank test, P = 0.028). Conclusions The present study demonstrated a corticocortical network connecting Broca areas and SFG in a reciprocal manner. Our findings might provide new insight into language and motor integration.

Medulloepithelioma is a rare and highly malignant primitive neuroectodermal tumor that usually occurs in childhood. The diagnosis of this entity required only morphological analysis until the World Health Organization classification of central nervous system (CNS) tumors was revised, and now genetic analysis is necessary. We report a case of medulloepithelioma in the posterior cranial fossa that was diagnosed by both morphological and genetic analyses based on this classification. A 10-month-old girl was admitted to our hospital with consciousness disturbance and vomiting. Neuroimaging revealed a partially calcified mass and cyst formation in the posterior cranial fossa. Partial resection of the tumor was performed and histological findings revealed multilayered rosettes with LIN28A staining, but genetic analysis showed no amplification of the C19MC microRNA cluster at 19q14.32. Therefore, we diagnosed the tumor as medulloepithelioma belonging to other CNS embryonal tumors. The patient was immediately treated with systemic high-dose chemotherapy. Follow-up neuroimaging 10 months later showed no signs of recurrence. Medulloepitheliomas are difficult to diagnose by routine HE staining and require combined morphological, immunohistochemical and genetic analyses to provide an accurate diagnosis.

We investigated whether vagus nerve stimulation (VNS) induces a positive shift of slow cortical potentials (SCPs) in patients with50% seizure reduction (responders) but not in non-responders.We analyzed routine clinical electroencephalograms (EEGs) from 24 patients who were undergoing seizure treatment by VNS. The patients were divided into 2 groups by hardware time constant (TC) of EEG: the TC 10-s group (10 patients) and TC 2-s group (14 patients). We compared SCPs at 5 electrodes (Cz and adjacent ones) between the 2 states of VNS: during stimulation and between stimulations. Seizure reduction was independently judged. Correlation between SCP (positivity or not) and seizure reduction (50% or not) was estimated.In the TC 10-s group, the correlation between SCP and seizure reduction was significant (p0.05) (i.e., both good results in 4 and both negative results in 5). In TC 2-s group, the correlation between SCP and seizure reduction was not significant (p=0.209).A positive shift of SCP recorded by using a TC of 10s could be a surrogate marker for VNS response.SCP could be a biomarker of good responders to VNS.

Intracranial pure germinomas in children generally respond well to standard chemo-radiotherapy. However, some patients are refractory to standard therapy and require additional treatment. To investigate the characteristics of this subgroup, we retrospectively analyzed the clinical features and treatment outcomes of a cohort of 21 patients with intracranial pure germinomas who were diagnosed between April 2002 and December 2016 at Ehime University Hospital in Japan. Pure germinoma diagnosis was verified by histological examination of the tumor after surgery, and all patients received standard chemo-radiotherapy. A suite of clinical features, including neuroimaging, human chorionic gonadotropin-β subunit (HCG-β), and α-fetoprotein (AFP) in the cerebrospinal fluid (CSF), as well as immunohistochemical expression of HCG-β, AFP, and Ki-67 in the tumor tissue were analyzed. Nineteen of the 21 patients had a complete response to standard chemo-radiotherapy without early recurrence of the tumors. Of these 19 patients, 17 did not have elevated CSF HCG-β levels or express HCG-β in the tumor tissue. However, the two patients who were refractory to standard therapy had elevated CSF HCG-β levels and expressed HCG-β in the tumor cells. These data suggest that patients with pure germinoma presenting with both an elevation of HCG-β in the CSF and HCG-β expression in the tumor tissue may be refractory to frontline treatment. These markers may predict aggressive germinoma and may ultimately facilitate the development of more effective treatment options.

BackgroundGlioblastoma remains highly lethal due to its inevitable recurrence. This recurrence is found locally in most cases, indicating that post-surgical tumor-initiating cells (TICs) accumulate at tumor edge. These edge TICs then generate recurrent tumors harboring new core lesions. Here, we investigated the clinical significance of the edge-to-core transition (ECT) signature causing glioblastoma recurrence and sought to identify central mediators for ECT.MethodsFirst, we examined the association of the ETC-related expression changes and patient outcome in matched primary and recurrent samples (n=37). Specifically, we tested whether the combined decrease of the edge TIC marker PROM1 (CD133) with the increase of the core TIC marker CD109 representing ECT during the primary-to-recurrence progression indicates poorer patient outcome. We then investigated the specific molecular mediators that trigger tumor recurrence driven by the ECT signature. Subsequently, the functional and translational significance of the identified molecule was validated within our patient-derived tumor edge-TIC modelsin vitroandin vivo.ResultsPatients exhibiting a CD133down/CD109upsignature during recurrence representing ECT displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that PLAGL1 was tightly correlated with the core TIC marker CD109 and was linked to a shorter survival of glioblastoma patients. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, the glioblastoma edge-derived tumor growthin vivoand subsequent mouse survival, suggesting its essential role in the ECT-mediated glioblastoma development.ConclusionsECT is likely an ongoing lethal process in primary glioblastoma contributing to its recurrence partly in a PLAGL1/CD109-mediated mechanism.Key PointsECT is a pathobiological process contributing to glioblastoma lethalityThe CD133down/CD109upsignature is a novel prognostic molecular biomarker in ECTPLAGL1 regulates growth of edge-located tumor-initiating cellsImportance of the StudyVery few studies have sought to longitudinally characterize the transition of molecular landscapes from primary to recurrent glioblastoma. Post-surgical edge-located TICs are presumably the predominant source of tumor recurrence, yet this cellular subpopulation in glioblastoma remains largely uncharacterized. This study evaluates the significance of glioblastoma edge-derived core transition (ECT) for tumor recurrence in the primary-recurrent paired sample set. We elucidate a prognostically-significant shift in molecular and cellular phenotypes associated with ECT in the CD133down/CD109upgroup. Moreover, our results provide clinical and experimental evidence that PLAGL1 is a mediator of glioblastoma ECT and its subsequent tumor development by the direct transcriptional regulation of the core TIC marker CD109.

Background: Epithelioid glioblastoma is a rare aggressive variant of glioblastoma multiforme (GBM), which was formally recognized by the World Health Organization classification of the central nervous system in 2016. Clinically, epithelioid GBMs are characterized by aggressive features, such as metastases and cerebrospinal fluid dissemination, and an extremely poor prognosis. A rare case of epithelioid GBM that was discovered as a multicentric glioma with different histopathology is reported. Case Description: A 78-year-old man was admitted to our hospital with mild motor weakness of the right leg. Neuroimaging showed small masses in the left frontal and parietal lobes on magnetic resonance imaging. The abnormal lesion had been increasing rapidly for 3 weeks, and a new lesion appeared in the frontal lobe. 11C-methionine positron emission tomography (PET) showed abnormal uptake corresponding to the lesion. To reach a definitive diagnosis, surgical excision of the right frontal mass lesion was performed. Histological findings showed diffuse astrocytoma. Only radiotherapy was planned, but the left frontal and parietal tumors progressed further within a short period. Therefore, it was thought that these tumors were GBM, and a biopsy of the left parietal tumor was performed. The histological diagnosis was epithelioid GBM. Immunohistochemistry showed that most tumor cells were negatively stained for p53 and isocitrate dehydrogenase 1. BRAF V600E mutations were not identified, but TERT promoter mutations were identified. Immediately after surgery, the patient was given chemotherapy using temozolomide, extended local radiotherapy and then bevacizumab. After 6 months, he showed no signs of recurrence. Conclusion: Epithelioid GBM is one of the rarest morphologic subtypes of GBM and has a strongly infiltrative and aggressive nature. Therefore, careful identification of preoperative imaging studies and detailed evaluation of genetic studies are necessary to select the appropriate treatment for epithelioid GBM.

Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and

In the present study, we attempted to characterize two characteristic features within the dynamic behavior of wideband electrocorticography data, which were recorded as the brain waves of epilepsy, comprising high-frequency oscillations (HFOs) and interictal epileptic slow (red slow). The results of power spectrum and nonlinear time series analysis indicate that, on one hand, HFOs at epileptic focus are characterized by one-dimensional dynamical systems in ictal onset time segments at an epileptic focus for two patients’ datasets; on the other hand, an interictal epileptic slow is characterized by the residue of power spectrum. The results suggest that the degree of freedom of the brain dynamics during epileptic seizure with HFO degenerates to low-dimensional dynamics; hence, the interictal epileptic slow as the precursors of the seizure onset can be detected simply from interictal brain wave data for the dataset of one patient. Therefore, our results are essential to understand the brain dynamics in epilepsy.

How does the human brain encode semantic information about objects? This paper reconciles two seemingly contradictory views. The first proposes that local neural populations independently encode semantic features; the second, that semantic representations arise as a dynamic distributed code that changes radically with stimulus processing. Combining simulations with a well-known neural network model of semantic memory, multivariate pattern classification, and human electrocorticography, we find that both views are partially correct: semantic information is distributed across ventral temporal cortex in a dynamic code that possesses stable feature-like elements in posterior regions but with elements that change rapidly and nonlinearly in anterior regions. This pattern is consistent with the view that anterior temporal lobes serve as a deep cross-modal “hub” in an interactive semantic network, and more generally suggests that tertiary association cortices may adopt dynamic distributed codes difficult to detect with common brain imaging methods.

OBJECTIVE Multispectrum electrocorticographic components are critical for mapping the nonprimary motor area (NPMA). The objective of this study was to derive and validate a reliable scoring system for electrocorticography-based NPMA mapping (NPMA score) to replace electrical cortical stimulation (ECS) during brain surgery. METHODS We analyzed 14 consecutive epilepsy patients with subdural electrodes implanted in the frontal lobe at Kyoto University Hospital. The NPMA score was retrospectively derived from multivariate analysis in the derivation group (patients = 7, electrodes = 713, during 2010-2013) and validated in the validation group (patients = 7, electrodes = 772, during 2014-2017). We assessed the accuracy and reliability of the score relative to ECS in determining the NPMA and predicting postoperative functional outcomes. RESULTS Multivariate analysis in the derivation group led to an 8-point score for predicting ECS-based NPMA (1 point for anatomical localization of the electrode and 1 or 2 points for movement-related electrocorticographic components regardless of somatotopy in very slow cortical potential shifts [

Chloride intracellular channel protein 2 (CLIC2) belongs to the CLIC family of conserved metazoan proteins. Although CLICs have been identified as chloride channels, they are currently considered multifunctional proteins. CLIC2 is the least studied family member. We investigated CLIC2 expression and localization in human hepatocellular carcinoma, metastatic colorectal cancer in the liver, and colorectal cancer. Significant expression of mRNAs encoding CLIC1, 2, 4, and 5 were found in the human tissues, but only CLIC2 was predominantly expressed in non-cancer tissues surrounding cancer masses. Fibrotic or dysfunctional (aspartate aminotransferase ≥40) non-cancer liver tissues and advanced stage HCC tissues expressed low levels of CLIC2. Endothelial cells lining blood vessels but not lymphatic vessels in non-cancer tissues expressed CLIC2 as well as high levels of the tight junction proteins claudins 1 and 5, occludin, and ZO-1. Most endothelial cells in blood vessels in cancer tissues had very low expressions of CLIC2 and tight junction proteins. CD31+/CD45− endothelial cells isolated from non-cancer tissues expressed mRNAs encoding CLIC2, claudin 1, occludin and ZO-1, while similar cell fractions from cancer tissues had very low expressions of these molecules. Knockdown of CLIC2 expression in human umbilical vein endothelial cells (HUVECs) allowed human cancer cells to transmigrate through a HUVEC monolayer. These results suggest that CLIC2 may be involved in the formation and/or maintenance of tight junctions and that cancer tissue vasculature lacks CLIC2 and tight junctions, which allows the intravasation of cancer cells necessary for hematogenous metastasis.

Primary central nervous system lymphoma (PCNSL) has been immunohistochemically classified into two subtypes, germinal center (GC) B-cell and non-GC B-cell, but the prognostic impact of these subtypes remains debated. We investigated clinical features and prognostic significance of immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. We also analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy. Tumors from 32 PCNSL patients were immunohistochemically evaluated for expression of cluster of differentiation (CD) 10, B-cell lymphoma-6 (BCL-6), and multiple myeloma oncogene-1 (MUM-1) and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated. Twenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months) (P

Background: Onyx has already been reported as an effective and safe agent in transarterial embolization of cranial dural arteriovenous fistula (d-AVF). However, successful treatment is related to not only complete shunt obliteration but also preservation of a normal route of venous drainage. Here, we present a case of transverse sigmoid d-AVF in which successful treatment was achieved by transarterial Onyx embolization with targeted balloon protection of the venous drainage. Case Description: A 70-year-old man presented with a 3-month history of tinnitus in the left ear and mild headache. Magnetic resonance imaging (MRI) showed a cluster of abnormal blood vessels in the area of the left transverse sinus (TS)-sigmoid sinus (SS) junction. Cerebral angiography demonstrated a Cognard type IIa d-AVF at the left TS-SS junction, supplied mainly by vessels such as the left middle meningeal artery, left occipital artery, and left meningohypophyseal trunk. In the venous phase, the ipsilateral TS-SS was recognized as a functional sinus and the left vein of Labbe drained into the TS near the drainage channel. Based on these findings, we decided to perform endovascular treatment under a transarterial approach with Onyx using targeted balloon protection of the venous sinus to protect against Onyx migration and preserve antegrade sinus flow. The patient recovered well without sequelae, and follow-up MRI 12 months later showed complete disappearance of the d-AVF. Conclusion: This treatment strategy using targeted balloon protection may be very useful to preserve antegrade sinus flow in patients with Cognard type IIa d-AVF.

Background: Sarcoidosis is a multisystem disorder characterized by noncaseating epithelioid granulomas. However, neurosarcoidosis occurring only in the medulla oblongata is very rare and lacks specific imaging and clinical features. We report a rare case of neurosarcoidosis arising from the medulla oblongata alone, suggesting the significance of pathological findings for accurate diagnosis. Case Description: A 78-year-old woman with a history of rheumatoid arthritis was admitted to our hospital with a 3-month history of progressive numbness in bilateral lower extremities and gait disturbance. Neurological examination on admission showed mild bilateral paired paralysis of the lower limbs (manual muscle test: right 2/V; left 4/V) and marked numbness in the right lower limb. Neuroimaging revealed a solid mass with clear boundaries in the dorsal medulla oblongata appearing hypointense on T1-weighted imaging (WI), hyperintense on T2-WI, and hypointense on diffusion WI (DWI), with strong enhancement on gadolinium-enhanced T1-WI. Cerebrospinal fluid analysis showed moderately elevated levels of protein and lymphocytic cells. Biopsy to determine the exact diagnosis revealed histological findings of noncaseating epithelioid granulomas and inflammatory infiltration, consistent with sarcoidosis. Postoperatively, corticosteroid therapy with prednisolone was initiated as soon as possible, resulting in marked reductions in lesion size. Follow-up neuroimaging after 12 months showed no signs of recurrence. Conclusion: Neurosarcoidosis is difficult to diagnose from routine neuroimaging and laboratory findings. Accurate diagnosis requires careful identification of clinical signs, hypointensity on DWI, and morphological findings from surgical biopsy.

The aim of the study is to identify characteristic features of pineal germinoma that enhance preoperative accuracy in differentiating germinoma from other pineal region tumors. Twenty-one consecutive patients with pineal region tumors were enrolled. In all patients, tumor resection was performed to verify the histology. Clinical records including upward gaze palsy of Parinaud's syndrome and neuroimaging were analyzed. In addition, we evaluated the relationship between magnetic resonance imaging (MRI) findings and tumor progression patterns in pineal germinoma. Among 21 patients, 15 patients were diagnosed with germ cell tumor, 4 with pineal parenchymal cell tumor, and 2 with meningioma. Upward gaze palsy was seen in 11 patients; nine had pure germinomas and two had mixed germ cell tumors. These tumors occupied the pineal region with extension to the area of the mesodiencephalic junction (MDJ) and the bi-epithalamic area between the bilateral pulvinar and the third ventricle. Tumor involvement of the former area could cause upward gaze palsy by insulting the rostral interstitial nucleus of the medial longitudinal fasciculus located in the MDJ area. Tumor invasion into the latter area is commonly seen as a cardioid-shaped tumor as the tumor image on the axial MRI view. Upward gaze palsy and a cardioid-shaped tumor image on the axial MRI views were demonstrated to be specific features of pineal pure germinoma. It is suggested that combination of both features may become useful tools to preoperatively differentiate germinoma from other pineal tumors, resulting in achievement of the optimum treatment of pineal region tumors.

In order to preserve postoperative language function, we recently proposed a new intraoperative method to monitor the integrity of the dorsal language pathway (arcuate fasciculus; AF) using cortico-cortical evoked potentials (CCEPs). Based on further investigations (20 patients, 21 CCEP investigations), including patients who were not suitable for awake surgery (five CCEP investigations) or those without preoperative neuroimaging data (eight CCEP investigations including four with untraceable tractography due to brain edema), we attempted to clarify the clinical impact of this new intraoperative method. We monitored the integrity of AF by stimulating the anterior perisylvian language area (AL) by recording CCEPs from the posterior perisylvian language area (PL) consecutively during both general anesthesia and awake condition. After tumor resection, single-pulse electrical stimuli were also applied to the floor of the removal cavity to record subcortico-cortical evoked potentials (SCEPs) at AL and PL in 12 patients (12 SCEP investigations). We demonstrated that (1) intraoperative dorsal language network monitoring was feasible even when patients were not suitable for awake surgery or without preoperative neuroimaging studies, (2) CCEP is a dynamic marker of functional connectivity or integrity of AF, and CCEP N1 amplitude could even become larger after reduction of brain edema, (3) a 50% CCEP N1 amplitude decline might be a cut-off value to prevent permanent language dysfunction due to impairment of AF, (4) a correspondence (

In the last decade, single pulse electrical stimulation (SPES) has been used as an investigational tool in the field of epilepsy surgery. Direct cortical stimulation applied at a frequency of ∼1 Hz can probe cortico-cortical connections by averaging electrocorticogram time-lock to the stimuli (2 x 20–30 trials). These evoked potentials that emanate from adjacent and remote cortices have been termed cortico-cortical evoked potentials (CCEPs). Although limited to patients undergoing invasive presurgical evaluations with intracranial electrodes, CCEP provides a novel way to explore inter-areal connectivity in vivo in the living human brain to probe functional brain networks such as language and cognitive motor networks. In addition to its impact on systems neuroscience, this method, in combination with 50 Hz electrical cortical stimulation, could contribute clinically to map the functional brain systems by tracking the cortico-cortical connections among the functional cortical regions in each individual patient. This approach may help identify the normal cortico-cortical network within pathology as well as reveal connections that might arise from neural plasticity. Because of its high practicality, it has been recently applied for intraoperative monitoring of the functional brain networks for patients with brain tumor. With regard to epilepsy, SPES has been used for the two major purposes, one to probe cortical excitability of the focus, namely, epileptogenicity, and the other to probe seizure networks. Both early (i.e., CCEP) and delayed responses, and probably their high frequency oscillation counterparts, are regarded as a surrogate marker of epileptogenicity. With regards to its impact on the human brain connectivity map, worldwide collaboration is warranted to establish the standardized CCEP connectivity map as a solid reference for non-invasive connectome researches.