Accuracy of estimating strengths of dipole moments from a small number of magnetoencephalographic trial data.

The conventional analysis estimates both the locations and strengths of neural source activations from event-related magnetoencephalography data that are averaged across about a hundred trials. In the present report, we propose a new method based on a minimum modified-l 1-norm to obtain the dependence of strengths on the presented stimuli from a limited number of trial data. It estimates the strengths from 10-trial average data and the locations from 100-trial average data. The method can be applied to neural activations whose strengths, but not locations, depend on the presented stimuli. For instance, it can be used in experiments in which the activation in the anterior temporal area (aT) is measured by varying semantic relatedness between stimuli in linguistic experiments. We conducted a realistic simulation, following previous experiments on lexico-semantic processing, in which five neural sources were simultaneously activated. The results showed that when the signal-to-noise ratio was one for non-averaged data, the proposed method had standard deviations of 13 % for the normalized strengths in the aT. It is inferred on the basis of the general linear model in which the strength has a linear dependence on the stimulus parameters that the proposed method can detect the dependence at a significance level of 1 % if the peak-to-peak change in normalized strength is more than 49 %. It is smaller than 66 % for the conventional method, which estimated locations and strengths from 10-trial data for each point. Thus, the proposed method can plot an activation-strength versus stimulus-parameter curve with better sensitivity.

Diazepam treatment blocks the elevation of hippocampal activity and the accelerated proliferation of hippocampal neural stem cells after focal cerebral ischemia in mice.

Hippocampal neurogenesis is accelerated during the elevation of hippocampal neural activities under both physiological and pathophysiological conditions. One of these conditions, middle cerebral artery occlusion (MCAO), induces both the hyperactivities of hippocampal network and the elevation of neural stem cell (NSC) proliferation. However, the causal relationship between the elevated activity and the elevation of NSC proliferation is still unclear. In this study, to block the elevation of hippocampal activity after MCAO in mice, we utilized a typical γ-aminobutyric acid type A (GABAA ) receptor active modulator, diazepam. With MCAO mice treated with diazepam, we observed complete disappearance of the elevation of hippocampal activity. Additionally, the diazepam treatment blocked the elevation of NSC proliferation after MCAO. From this result, it is speculated that the increased NSC proliferation is blocked by the suppression of elevated neural activity. However, diazepam might have effects other than the suppression of hippocampal activity, so we performed additional experiment and found that diazepam did not affect the number of bromodeoxyuridine-positive cells under the normal condition, whereas the GABA agonist pentobarbital stimulated NSC/neural progenitor cell proliferation and differentiation. Next, we evaluated the expression of the diazepam-binding inhibitor (DBI) protein and found that the cells expressed DBI in soma and on the surface of cell membrane. From these observations, we can propose that diazepam blocks the elevation of hippocampal activity and also NSC proliferation after MCAO.

Involvement of glial P2Y1 receptors in cognitive deficit after focal cerebral stroke in a rodent model.

BACKGROUND: Neuroinflammation is associated with many conditions that lead to dementia, such as cerebrovascular disorders or Alzheimer's disease. However, the specific role of neuroinflammation in the progression of cognitive deficits remains unclear. To understand the molecular mechanisms underlying these events we used a rodent model of focal cerebral stroke, which causes deficits in hippocampus-dependent cognitive function. METHODS: Cerebral stroke was induced by middle cerebral artery occlusion (MCAO). Hippocampus-dependent cognitive function was evaluated by a contextual fear conditioning test. The glial neuroinflammatory responses were investigated by immunohistochemical evaluation and diffusion tensor MRI (DTI). We used knockout mice for P2Y1 (P2Y1KO), a glial ADP/ATP receptor that induces the release of proinflammatory cytokines, to examine the links among P2Y1-mediated signaling, the neuroinflammatory response, and cognitive function. RESULTS: Declines in cognitive function and glial neuroinflammatory response were observed after MCAO in both rats and mice. Changes in the hippocampal tissue were detected by DTI as the mean diffusivity (MD) value, which corresponded with the cognitive decline at 4 days, 1 week, 3 weeks, and 2 months after MCAO. Interestingly, the P2Y1KO mice with MCAO showed a decline in sensory-motor function, but not in cognition. Furthermore, the P2Y1KO mice showed neither a hippocampal glial neuroinflammatory response (as assessed by immunohistochemistry) nor a change in hippocampal MD value after MCAO. In addition, wild-type mice treated with a P2Y1-specific antagonist immediately after reperfusion did not show cognitive decline. CONCLUSION: Our findings indicate that glial P2Y1 receptors are involved in the hippocampal inflammatory response. The findings from this study may contribute to the development of a therapeutic strategy for brain infarction, targeting the P2Y1 receptor.

Opto-fMRI analysis for exploring the neuronal connectivity of the hippocampal formation in rats.

In recent years, optical stimulation of neurons that bear a light-gated cation channel, "Optogenetics", has opened a new avenue for exploring neuronal connectivity of the nervous system. In this study, we applied a technique, "Opto-fMRI", which combined optogenetics with blood oxygenation level-dependent (BOLD) functional MRI (fMRI), for examining the neuronal connectivity of the hippocampal formation in rats. Although the hippocampal formation is very important for memory formation and retrieval, there is little information on its neuronal connectivity, especially on its longitudinal axis of connection. For this purpose, we utilized a transgenic rat strain, expressing the light-gated cation channel channelrhodopsin-2 (ChR2) under the regulation of the Thy1.2 promoter which permits the expression of the integrated gene in neurons. After optical stimulation targeting the dentate gyrus of the transgenic rat, we detected BOLD response of not only the dentate gyrus (DG) but also at the CA3 area. In addition, we detected the longitudinal-axis activation of the hippocampus after optical stimulation. Our study suggests that Opto-fMRI could be a tool for exploring the neuronal connectivity of the hippocampal formation, to understand the neural basis of memory formation and retrieval.

Involvement of metabotropic glutamate receptor 5 signaling in activity-related proliferation of adult hippocampal neural stem cells.

Adult hippocampal neural stem cells can be activated by hippocampal neural activities. When focal cerebral ischemia, known as middle cerebral artery occlusion (MCAO), occurs, neural stem cells are activated to promote their proliferation. However, the mechanism by which these cells are activated is still unclear. Here, we indicate the involvement of metabotropic glutamate receptor 5 (mGluR5) signaling in neural stem cells in their activity-related proliferation after MCAO. We found mGluR5 molecules on neural stem cells by using calcium imaging. We detected the activation of neural stem cells by adding the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine. On a hippocampal slice, the activation of neural stem cells to promote their proliferation was initiated by theta-burst electrical stimulation at the perforant pathway, and this activation was significantly blocked by an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP). In addition to this, the injection of the blood-brain barrier-permeable mGluR5 agonist 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide into live mice promoted the proliferation of neural stem cells. Moreover, in vivo theta-burst electrical stimulation induced proliferation of neural stem cells. A chronic field recording study showed that the activity of the hippocampal formation was elevated after MCAO. Finally, we observed that the mGluR5 antagonist MPEP significantly blocked the stimulated proliferation of neural stem cells induced by MCAO, by blocking mGluR5 signaling. Our results suggest that glutamates released by the elevated neural activities after MCAO may trigger mGluR5 signaling in neural stem cells to promote their proliferation.

Phase-interpolated averaging for analyzing electroencephalography and magnetoencephalography epochs.

Stimulus-locked averages of electroencephalography (EEG) and magnetoencephalography (MEG) epochs reveal characteristic waveforms. EEG/MEG generation models to have reconstruct such waveforms have been recently proposed. These models assume that evoked, phase-modulated, and amplitude-modulated activities occur solely or simultaneously. We propose a two-stage stimulus-locked averaging method, called phase-interpolated averaging, to investigate the EEG/MEG generation process. First, virtual EEG/MEG epochs, which would be obtained as if instantaneous phases for each time sampling point were on a phase-grid, are interpolated from actually measured EEG/MEG epochs. Then, the virtual EEG/MEG epochs are discrete Fourier transformed. A simulation revealed that the zeroth Fourier term revealed the evoked activity, the first Fourier term revealed the amplitude-modulated activity, and the condition number of the interpolation reflected the phase-modulated activity. On the basis of these facts, a preliminary EEG analysis implied that the evoked activity is much smaller than what would be expected by using conventional averaging, the evoked and phase-modulated activities simultaneously occur, and the amplitude-modulated activity occasionally associates with the evoked and phase-modulated activities. To the best of our knowledge, this is the first time that these three activities have been shown to coexist by actually separating them.

Masked immediate-repetition-priming effect on the early lexical process in the bilateral anterior temporal areas assessed by neuromagnetic responses.

A masked priming paradigm has been used to measure unconscious and automatic context effects on the processing of words. However, its spatiotemporal neural basis has not yet been clarified. To test the hypothesis that masked repetition priming causes enhancement of neural activation, we conducted a magnetoencephalography experiment in which a prime was visually presented for a short duration (50 ms), preceded by a mask pattern, and followed by a target word that was represented by a Japanese katakana syllabogram. The prime, which was identical to the target, was represented by another hiragana syllabogram in the "Repeated" condition, whereas it was a string of unreadable pseudocharacters in the "Unrepeated" condition. Subjects executed a categorical decision task on the target. Activation was significantly larger for the Repeated condition than for the Unrepeated condition at a time window of 150-250 ms in the right occipital area, 200-250 ms in the bilateral ventral occipitotemporal areas, and 200-250 ms and 200-300 ms in the left and right anterior temporal areas, respectively. These areas have been reported to be related to processing of visual-form/orthography and lexico-semantics, and the enhanced activation supports the hypothesis. However, the absence of the priming effect in the areas related to phonological processing implies that automatic phonological priming effect depends on task requirements.

Phase-compensated averaging for analyzing electroencephalography and magnetoencephalography epochs.

Stimulus-locked averaging for electroencephalography and/or megnetoencephalography (EEG/MEG) epochs cancels out ongoing spontaneous activities by treating them as noise. However, such spontaneous activities are the object of interest for EEG/MEG researchers who study phase-related phenomena, e.g., long-distance synchronization, phase-reset, and event-related synchronization/desynchronization (ERD/ERS). We propose a complex-weighted averaging method, called phase-compensated averaging, to investigate phase-related phenomena. In this method, any EEG/MEG channel is used as a trigger for averaging by setting the instantaneous phases at the trigger timings to 0 so that cross-channel averages are obtained. First, we evaluated the fundamental characteristics of this method by performing simulations. The results showed that this method could selectively average ongoing spontaneous activity phase-locked in each channel; that is, it evaluates the directional phase-synchronizing relationship between channels. We then analyzed flash evoked potentials. This method clarified the directional phase-synchronizing relationship from the frontal to occipital channels and recovered another piece of information, perhaps regarding the sequence of experiments, which is lost when using only conventional averaging. This method can also be used to reconstruct EEG/MEG time series to visualize long-distance synchronization and phase-reset directly, and on the basis of the potentials, ERS/ERD can be explained as a side effect of phase-reset.

Neuroimaging study on brain asymmetries in situs inversus totalis.

Situs inversus totalis (SI) is a rare condition in which all visceral organs are arranged as mirror images of the usual pattern. The objective of this study was to determine whether SI individuals have reversed brain asymmetries. We performed a neuroimaging study on 3 SI subjects and 11 control individuals with normally arranged visceral organs. The language-dominant hemisphere was determined by magnetoencephalography. Left-hemispheric dominance was observed in 1 SI subject and all controls, whereas right-hemispheric dominance was observed in the remaining 2 SI subjects. Statistical analysis revealed that language dominance patterns in SI subjects were different from those in the controls, suggesting that the developmental mechanisms underlying visceral organ asymmetries are related to those underlying functional brain asymmetry. Anatomical brain asymmetries were determined by magnetic resonance imaging. SI subjects had the same planum temporale (PT) asymmetry pattern as the controls, but a reversed petalia asymmetry pattern. The inferior frontal gyrus (IFG) asymmetry pattern varied within both groups, indicating a relationship between the rightward IFG and right-hemispheric language dominance. These results suggest that the developmental mechanisms underlying visceral organ asymmetries are related to those underlying petalia asymmetry but not to those underlying PT and IFG asymmetries, and that brain asymmetries might develop via multiple region-dependent mechanisms.

Neural activations correlated with reading speed during reading novels.

Functional magnetic resonance imaging was used to measure neural activations in subjects instructed to silently read novels at ordinary and rapid speeds. Among the 19 subjects, 8 were experts in a rapid reading technique. Subjects pressed a button to turn pages during reading, and the interval between turning pages was recorded to evaluate the reading speed. For each subject, we evaluated activations in 14 areas and at 2 instructed reading speeds. Neural activations decreased with increasing reading speed in the left middle and posterior superior temporal area, left inferior frontal area, left precentral area, and the anterior temporal areas of both hemispheres, which have been reported to be active for linguistic processes, while neural activation increased with increasing reading speed in the right intraparietal sulcus, which is considered to reflect visuo-spatial processes. Despite the considerable reading speed differences, correlation analysis showed no significant difference in activation dependence on reading speed with respect to the subject groups and instructed reading speeds. The activation reduction with speed increase in language-related areas was opposite to the previous reports for low reading speeds. The present results suggest that subjects reduced linguistic processes with reading speed increase from ordinary to rapid speed.

Early neural activation for lexico-semantic access in the left anterior temporal area analyzed by an fMRI-assisted MEG multidipole method.

To determine the time and location of lexico-semantic access, we measured neural activations by magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) and estimated the neural sources by fMRI-assisted MEG multidipole analysis. Since the activations for phonological processing and lexico-semantic access were reported to overlap in many brain areas, we compared the activations in lexical and phonological decision tasks. The former task required visual form processing, phonological processing, and lexico-semantic access, while the latter task required only visual form and phonological processing, with similar phonological task demands for both tasks. The activation areas observed among 9 or 10 subjects out of 10 were the superior temporal and inferior parietal areas, anterior temporal area, and inferior frontal area of both hemispheres, and the left ventral occipitotemporal area. The activations showed a significant difference between the 2 tasks in the left anterior temporal area in all 50-ms time windows between 200-400 ms from the onset of visual stimulus presentation. Previous studies on semantic dementia and neuroimaging studies on normal subjects have shown that this area plays a key role in accessing semantic knowledge. The difference between the tasks appeared in common to all areas in the time windows of 100-150 ms and 400-450 ms, suggesting early differences in visual form processing and late differences in the decision process, respectively. The present results demonstrate that the activations for lexico-semantic access in the left anterior temporal area start in the time window of 200-250 ms, after early visual form processing.