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To date, electroencephalogram (EEG) has been used in the diagnosis of epilepsy, dementia, and disturbance of consciousness via the inspection of EEG waves and identification of abnormal electrical discharges and slowing of basic waves. In addition, EEG power analysis combined with a source estimation method like exact-low-resolution-brain-electromagnetic-tomography (eLORETA), which calculates the power of cortical electrical activity from EEG data, has been widely used to investigate cortical electrical activity in neuropsychiatric diseases. However, the recently developed field of mathematics “information geometry” indicates that EEG has another dimension orthogonal to power dimension — that of normalized power variance (NPV). In addition, by introducing the idea of information geometry, a significantly faster convergent estimator of NPV was obtained. Research into this NPV coordinate has been limited thus far. In this study, we applied this NPV analysis of eLORETA to idiopathic normal pressure hydrocephalus (iNPH) patients prior to a cerebrospinal fluid (CSF) shunt operation, where traditional power analysis could not detect any difference associated with CSF shunt operation outcome. Our NPV analysis of eLORETA detected significantly higher NPV values at the high convexity area in the beta frequency band between 17 shunt responders and 19 non-responders. Considering our present and past research findings about NPV, we also discuss the advantage of this application of NPV representing a sensitive early warning signal of cortical impairment. Overall, our findings demonstrated that EEG has another dimension — that of NPV, which contains a lot of information about cortical electrical activity that can be useful in clinical practice.

Background: Dementia with Lewy bodies (DLB) is characterized by progressive cognitive decline, fluctuating cognition, visual hallucinations, rapid eye movement sleep behavior disorder, and parkinsonism. DLB is the second most common type of degenerative dementia of all dementia cases. However, DLB, particularly in the early stage, is underdiagnosed and sometimes misdiagnosed with other types of dementia. Thus, it is of great interest investigating neurophysiological markers of DLB. Method: We introduced exact low-resolution brain electromagnetic tomography (eLORETA)-independent component analysis (ICA) to assess activities of 5 electroencephalography (EEG) resting-state networks (RSNs) in 41 drug-free DLB patients. Results: Compared to 80 healthy controls, DLB patients had significantly decreased activities in occipital visual and sensorimotor networks, where DLB patients and healthy controls showed no age dependences in all EEG-RSN activities. Also, we found correlations between all EEG-RSN activities and DLB symptoms. Specifically, decreased occipital α activity showed correlations with worse brain functions related to attention/concentration, visuospatial discrimination, and global cognition. Enhanced visual perception network activity correlated with milder levels of depression and anxiety. Enhanced self-referential network activity correlated with milder levels of depression. Enhanced memory perception network activity correlated with better semantic memory, visuospatial discrimination function, and global cognitive function as well as with severer visual hallucination. In addition, decreased sensorimotor network activity correlated with a better semantic memory. Conclusion: These results indicate that eLORETA-ICA can detect EEG-RSN activity alterations in DLB related to symptoms. Therefore, eLORETA-ICA with EEG data can be a useful noninvasive tool for sensitive detection of EEG-RSN activity changes characteristic of DLB and for understanding the neurophysiological mechanisms underlying this disease.

Highlights • We aimed to detect EEG changes induced by meditative interventions in PTRD subjects. • PTRD subjects exhibited increased gamma activity in the IPL relative to controls. • Changes of delta activity in the precuneus correlated with changes of the QOL scale., Objective Neurophysiological changes related to meditation have recently attracted scientific attention. We aimed to detect changes in electroencephalography (EEG) parameters induced by a meditative intervention in subjects with post-traumatic residual disability (PTRD), which has been confirmed for effectiveness and safety in a previous study. This will allow us to estimate the objective effect of this intervention at the neurophysiological level. Methods Ten subjects with PTRD were recruited and underwent psychological assessment and EEG recordings before and after the meditative intervention. Furthermore, 10 additional subjects were recruited as normal controls. Source current density as an EEG parameter was estimated by exact Low Resolution Electromagnetic Tomography (eLORETA). Comparisons of source current density in PTRD subjects after the meditative intervention with normal controls were investigated. Additionally, we compared source current density in PTRD subjects between before and after meditative intervention. Correlations between psychological assessments and source current density were also explored. Results After meditative intervention, PTRD subjects exhibited increased gamma activity in the left inferior parietal lobule relative to normal controls. In addition, changes of delta activity in the right precuneus correlated with changes in the psychological score on role physical item, one of the quality of life scales reflecting the work or daily difficulty due to physical problems. Conclusions These results show that the meditative intervention used in this study produces neurophysiological changes, in particular the modulation of oscillatory activity of the brain. Significance Our meditative interventions might induce the neurophysiological changes associated with the improvement of psychological symptoms in the PTRD subjects.

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric disease characterized by gait disturbance, cognitive deterioration and urinary incontinence associated with excessive accumulation of cerebrospinal fluid (CSF) in the brain ventricles. These symptoms, in particular gait disturbance, can be potentially improved by shunt operation in the early stage of the disease, and the intervention associates with a worse outcome when performed late during the course of the disease. Despite the variable outcome of shunt operation, noninvasive presurgical prediction methods of shunt response have not been established yet. In the present study, we used normalized power variance (NPV), a sensitive measure of the instability of cortical electrical activity, to analyze cortical electrical activity derived from EEG data using exact-low-resolution-electromagnetic-tomography (eLORETA) in 15 shunt responders and 19 non-responders. We found that shunt responders showed significantly higher NPV values at high-convexity areas in beta frequency band than non-responders. In addition, using this difference, we could discriminate shunt responders from non-responders with leave-one-subject-out cross-validation accuracy of 67.6% (23/34) [positive predictive value of 61.1% (11/18) and negative predictive value of 75.0% (12/16)]. Our findings indicate that eLORETA-NPV can be a useful tool for noninvasive prediction of clinical response to shunt operation in patients with iNPH.

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric disease characterized by gait disturbance, cognitive dysfunction, and urinary incontinence that affects a large population of elderly people. These symptoms, especially gait disturbance, can potentially be improved by cerebrospinal fluid (CSF) drainage, which is more effective if performed at an early stage of the disease. However, the neurophysiological mechanisms of these symptoms and their recovery by CSF drainage are poorly understood. In this study, using exact low-resolution brain electromagnetic tomography-independent component analysis (eLORETA-ICA) with electroencephalography (EEG) data, we assessed activities of five EEG resting-state networks (EEG-RSNs) in 58 iNPH patients before and after drainage of CSF by lumbar puncture (CSF tapping). In addition, we assessed correlations of changes in these five EEG-RSNs activities with CSF tapping–induced changes in iNPH symptoms. The results reveal that compared with 80 healthy controls, iNPH patients had significantly decreased activities in the occipital alpha rhythm, visual perception network, and self-referential network before CSF tapping. Furthermore, CSF tapping–induced changes in occipital alpha activity correlated with changes in postural sway and frontal lobe function. Changes in visual perception network activity correlated with changes in gait speed. In addition, changes in memory perception network activity correlated with changes in Parkinsonian gait features. These results indicate a recruitment of cognitive networks in gait control, and involvement of the occipital alpha activity in cognitive dysfunction in iNPH patients. Based on these findings, eLORETA-ICA with EEG data can be considered a noninvasive, useful tool for detection of EEG-RSN activities and for understanding the neurophysiological mechanisms underlying this disease.

Healthy aging is associated with impairment in cognitive information processing. Several neuroimaging methods such as functional magnetic resonance imaging, positron emission tomography and near-infrared spectroscopy have been used to explore healthy and pathological aging by relying on hemodynamic or metabolic changes that occur in response to brain activity. Since electroencephalography (EEG) and magnetoencephalography (MEG) are able to measure neural activity directly with a high temporal resolution of milliseconds, these neurophysiological techniques are particularly important to investigate the dynamics of brain activity underlying neurocognitive aging. It is well known that age is a major risk factor for Alzheimer’s disease (AD), and that synaptic dysfunction represents an early sign of this disease associated with hallmark neuropathological findings. However, the neurophysiological mechanisms underlying AD are not fully elucidated. This review addresses healthy and pathological brain aging from a neurophysiological perspective, focusing on oscillatory activity changes during the resting state, event-related potentials and stimulus-induced oscillatory responses during cognitive or motor tasks, functional connectivity between brain regions, and changes in signal complexity. We also highlight the accumulating evidence on age-related EEG/MEG changes and biological markers of brain neurodegeneration, including genetic factors, structural abnormalities on magnetic resonance images, and the biochemical changes associated with Aβ deposition and tau pathology.

Background: Tetris has recently expanded its place of activity not only to the original entertainment but also to clinical applications such as prevention of trauma flashback. However, to our knowledge, no studies focused on the cortical activation patterns themselves when playing Tetris in a natural form. This study aimed to investigate the activation patterns in the frontal cortex during naturally-performed Tetris for 90 seconds in 24 healthy subjects using functional near-infrared spectroscopy robust to artifacts by motion and electric devices. We also calculated the correlations of behavioral data with cortical activations, and compared the differences in activations between the high and low performers of Tetris. Results: The results demonstrated that significant activations in the frontal cortex during Tetris play had two factors, each showing a similar activation pattern. One of the factors was distributed over the lateral prefrontal cortex bilaterally, and the other was localized to the right prefrontal cortex. Moreover, in the high performers, the activations of the areas centered on the right dorsolateral prefrontal cortex (DLPFC) were estimated to increase and correlations of the activations between those areas and the other areas decrease compared with the low performers. Conclusions: It is suggested that high Tetris performers might reduce functional connectivity between activations of the areas centered on the right DLPFC and the other areas, and increase the local activations compared with low performers. It would be necessary to consider whether its visuospatial cognitive loads stimulate the appropriate areas of the subject’s brain to effectively utilize Tetris play for clinical interventions.

Recently, cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease (AD) have garnered a lot of clinical attention. To explore neurophysiological traits of AD and parameters for its clinical diagnosis, we examined the association between CSF biomarkers and electroencephalography (EEG) parameters in 14 probable AD patients. Using exact low-resolution electromagnetic tomography (eLORETA), artifact-free 40-sesond EEG data were estimated with current source density (CSD) and lagged phase synchronization (LPS) as the EEG parameters. Correlations between CSF biomarkers and the EEG parameters were assessed. Patients with AD showed significant negative correlation between CSF beta-amyloid (Aβ)-42 concentration and the logarithms of CSD over the right temporal area in the theta band. Total tau concentration was negatively correlated with the LPS between the left frontal eye field and the right auditory area in the alpha-2 band in patients with AD. Our study results suggest that AD biomarkers, in particular CSF Aβ42 and total tau concentrations are associated with the EEG parameters CSD and LPS, respectively. Our results could yield more insights into the complicated pathology of AD.

Objectives: eLORETA (exact low-resolution brain electromagnetic tomography) is a technique created by Pascual-Marqui et al. [Int J Psychophysiol. 1994 Oct; 18(1): 49–65] for the 3-dimensional representation of current source density in the brain by electroencephalography (EEG) data. Kurtosis analysis allows for the identification of spiky activity in the brain. In this study, we focused on the evaluation of the reliability of eLORETA kurtosis analysis. For this purpose, the results of eLORETA kurtosis source localization of paroxysmal activity in EEG were compared with those of eLORETA current source density (CSD) analysis of EEG data in 3 epilepsy patients with partial seizures. Methods: EEG was measured using a digital EEG system with 19 channels. We set the bandpass filter at traditional frequency band settings (1–4, 4–8, 8–15, 15–30, and 30–60 Hz) and 5–10 and 20–70 Hz and performed eLORETA kurtosis to compare the source localization of paroxysmal activity with that of visual interpretation of EEG data and CSD analysis of eLORETA in focal epilepsy patients. Results: The eLORETA kurtosis analysis of EEG data preprocessed by bandpass filtering from 20 to 70 Hz and traditional frequency band settings did not show any discrete paroxysmal source activity compatible with the results of CSD analysis of eLORETA. In all 3 cases, eLORETA kurtosis analysis filtered at 5–10 Hz showed paroxysmal activities in the theta band, which were all consistent with the visual inspection results and the CSD analysis results. Discussion: Our findings suggested that eLORETA kurtosis analysis of EEG data might be useful for the identification of spiky paroxysmal activity sources in epilepsy patients. Since EEG is widely used in the clinical practice of epilepsy, eLORETA kurtosis analysis is a promising method that can be applied to epileptic activity mapping.

We applied rhythmic binaural sound to Parkinson’s Disease (PD) patients to investigate its influence on several symptoms of this disease and on Electrophysiology (Electrocardiography and Electroencephalography (EEG)). We conducted a double-blind, randomized controlled study in which rhythmic binaural beats and control were administered over two randomized and counterbalanced sessions (within-subjects repeated-measures design). Patients ([Formula: see text], age [Formula: see text], stage I–III Hoehn & Yahr scale) participated in two sessions of sound stimulation for 10[Formula: see text]min separated by a minimum of 7 days. Data were collected immediately before and after both stimulations with the following results: (1) a decrease in theta activity, (2) a general decrease in Functional Connectivity (FC), and (3) an improvement in working memory performance. However, no significant changes were identified in the gait performance, heart rate or anxiety level of the patients. With regard to the control stimulation, we did not identify significant changes in the variables analyzed. The use of binaural-rhythm stimulation for PD, as designed in this study, seems to be an effective, portable, inexpensive and noninvasive method to modulate brain activity. This influence on brain activity did not induce changes in anxiety or gait parameters; however, it resulted in a normalization of EEG power (altered in PD), normalization of brain FC (also altered in PD) and working memory improvement (a normalizing effect). In summary, we consider that sound, particularly binaural-rhythmic sound, may be a co-assistant tool in the treatment of PD, however more research is needed to consider the use of this type of stimulation as an effective therapy.

Synaptic dysfunction is a core deficit in Alzheimer's disease, preceding hallmark pathological abnormalities. Resting-state magnetoencephalography (MEG) was used to assess whether functional connectivity patterns, as an index of synaptic dysfunction, are associated with CSF biomarkers [i.e., phospho-tau (p-tau) and amyloid beta (Aβ42) levels]. We studied 12 human subjects diagnosed with mild cognitive impairment due to Alzheimer's disease, comparing those with normal and abnormal CSF levels of the biomarkers. We also evaluated the association between aberrant functional connections and structural connectivity abnormalities, measured with diffusion tensor imaging, as well as the convergent impact of cognitive deficits and CSF variables on network disorganization. One-third of the patients converted to Alzheimer's disease during a follow-up period of 2.5 years. Patients with abnomal CSF p-tau and Aβ42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, and medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by p-tau was associated with impaired axonal integrity of the hippocampal cingulum. We noted that several connectivity abnormalities were predicted by CSF biomarkers and cognitive scores. These preliminary results indicate that CSF markers of amyloid deposition and neuronal injury in early Alzheimer's disease associate with a dual pattern of cortical network disruption, affecting key regions of the default mode network and the temporal cortex. MEG is useful to detect early synaptic dysfunction associated with Alzheimer's disease brain pathology in terms of functional network organization. SIGNIFICANCE STATEMENT In this preliminary study, we used magnetoencephalography and an integrative approach to explore the impact of CSF biomarkers, neuropsychological scores, and white matter structural abnormalities on neural function in mild cognitive impairment. Disruption in functional connectivity between several pairs of cortical regions associated with abnormal levels of biomarkers, cognitive deficits, or with impaired axonal integrity of hippocampal tracts. Amyloid deposition and tau protein-related neuronal injury in early Alzheimer's disease are associated with synaptic dysfunction and a dual pattern of cortical network disorganization (i.e., desynchronization and hypersynchronization) that affects key regions of the default mode network and temporal areas.

BACKGROUND: Idiopathic normal-pressure hydrocephalus (iNPH) is a neuropsychiatric syndrome characterized by the clinical triad of gait disturbance, urinary dysfunction, and cognitive impairment. The aim of the present study was to find specific EEG patterns associated with shunt response in iNPH. METHODS: Twenty five iNPH patients (10 shunt responders and 15 non-responders) were enrolled in this study. We performed current source density (CSD) analysis in several frequency bands (delta: 2-4 Hz, theta: 4-8 Hz, alpha: 8-13 Hz, beta: 13-30 Hz, gamma: 30-60 Hz) using exact Low Resolution Brain Electromagnetic Tomography (eLORETA). CSD distribution was compared between shunt responders and non-responders for each frequency band before and after CSF tap test. RESULTS: Shunt responders showed increased gamma CSD in the left temporal cortex before CSF tapping relative to non-responders. However, after CSF tapping, shunt response was associated with significantly higher CSDs in several frequency bands, specifically theta, alpha, beta and gamma, involving mainly the frontal and temporal areas. Using eLORETA analysis, we were able to identify cortical oscillatory activity before and after CSF tap test related to clinical recovery due to shunt operation in iNPH. CONCLUSION: Our findings support and extend the results of previous studies examining the effects of CSF tap test and shunt operation in patients with iNPH, possibly indicating electrophysiological features of shunt response in this disease. These findings warrant future studies to use EEG for prediction of shunt response in iNPH.

Background The electroencephalography (EEG) abnormalities found in patients with dementia with Lewy bodies (DLB) are conflicting. In this study, we used magnetoencephalography, which has higher spatial resolution than electroencephalography, to explore neurophysiological features of DLB that may aid in the differential diagnosis. Methods Six patients with DLB, 11 patients with Alzheimer's disease, and 11 age-matched normal subjects were recruited. We investigated alterations in the ratio of event-related synchronization (ERS) in the alpha band after eye-closing. Results Although the averaged ratio change of alpha ERS after eye-closing appeared predominantly in the posterior brain regions in all study groups, DLB patients had the weakest ratio change of alpha ERS. In particular, DLB patients exhibited a significantly reduced ratio change of alpha ERS in the bilateral inferior temporal gyrus, right occipital pole, and left parieto-occipital cortex compared to Alzheimer's disease patients or normal controls. Conclusion Our findings indicated that a reduced ratio change of alpha ERS in the posterior brain regions elicited by eye-closing is a brain electromagnetic feature of DLB.

This century is about brain. Not surprisingly, two megaprojects, the “Brain Activity Map Project” (USA) and the “Human Brain Project” (EU) with a total budget over a few billions euros, have been initiated across the Atlantic and mobilized many of the best and most renowned neuroscientists. They both aims to answer open questions for Neuroscience, such as: Is there an underlying functional architecture to the brain’s networks?, What is the functional connectivity diagram of a circuit?, What are the long-range interactions that underlie cognitive functions and behaviour? or What are the paths of information flow?. Such questions are related to the so-called “functional connectivity”, it reflects the statistical interdependencies between two physiological signals, providing information about functional interactions between the corresponding brain regions. Over the last years it has been increasingly used in neuroscience. Specifically, in the study of electrophysiological recordings such as Magnetoencephalography (MEG) and Electroencephalography (EEG).

Objective To explore neurophysiological biomarkers of Alzheimer's disease (AD), we investigated electroencephalography (EEG) of AD patients, and assessed lagged phase synchronization, a measure of brain functional connectivity. Methods Twenty-eight probable AD patients and 30 healthy controls (HC) were enrolled. Forty seconds of artifact-free EEG data were selected and compared between patients with AD and HC. Current source density (CSD) and lagged phase synchronization were analyzed by using eLORETA. Results Patients with AD showed significantly decreased lagged phase synchronization between most cortical regions in delta band relative to controls. There also was a decrease in lagged phase synchronization between the right dorsolateral prefrontal cortex (DLPFC) and the right posterior-inferior parietal lobule (pIPL) in theta band. In addition, some connections in delta band were found to be associated with cognitive function, measured by MMSE. This involved specifically interhemispheric temporal connections as well as left inferior parietal connectivity with the left hippocampus, lateral frontal regions, and the anterior cingulate cortex (aCC). Right temporal connections in delta band were related to global function, as estimated by CDR. No differences were found in CSD analysis between patients and HC. Conclusions Functional connectivity disruptions between certain brain regions, as measured with lagged phase synchronization, may potentially represent a neurophysiological biomarker of AD. Significance Our study indicated that AD and healthy elderly could have the different patterns of lagged phase synchronization.

The impact of neurological and psychiatric diseases on the functional organization of the brain has been a topic of growing interest in the last decade. There is increasing evidence indicating that the characterization of brain activity purely in terms of anatomically segregated responses is not sufficient to explain the complexity of neuropsychiatric disorders such as Alzheimer’s disease, epilepsy, schizophrenia, or autism. Thus, recent studies are looking at brain functional connectivity using neuroimaging and neurophysiological techniques. It is known that a lesion in a brain region considered a hub or key node may cause the loss of a particular brain function supported by a particular brain network, in which that hub plays a crucial role for an efficient communication. This brain integration approach may improve our understanding of symptoms and pathophysiology of neurological and psychiatric diseases, which are currently considered as disconnection syndromes. In addition, this may help clarify answered questions such as how local lesions (e.g., tumors) or focal epilepsy can affect the organization of functional networks or how some diseases are using neural networks to spread their functional and histopathological abnormalities?

Grand average waveforms of changes in [oxy-Hb] (red), [deoxy-Hb] (blue) and [total-Hb] (green) during the Shiritori task. For each channel, the x-axis denotes time from 0 to 160 s and the y-axis denotes activation between −0.8 and 0.8 mM∙mm. The Shiritori task period is marked by two vertical dashed lines at 10 and 100 s. CH, channel. (PDF 830 kb)

In this study we used magnetoencephalography during a modified version of the Sternberg's memory recognition task performed by patients with early Alzheimer's disease (AD), mild cognitive impairment (MCI), and by age-matched healthy controls to identify differences in induced oscillatory responses. For analyses, we focused on the retention period of the working memory task. Multiple-source beamformer and Brain Voyager were used for localization of source-power changes across the cortex and for statistic group analyses, respectively. We found significant differences in oscillatory response during the task, specifically in beta and gamma frequency bands: patients with AD showed reduced beta event-related desynchronization (ERD) in the right central area compared to controls, and reduced gamma ERD in the left prefrontal and medial parietal cortex compared to patients with MCI. Our findings suggest that reduced oscillatory responses over certain brain regions in high frequency bands (i.e., beta, gamma), and especially in the beta band that was significantly different between AD patients and healthy subjects, may represent brain electromagnetic changes underlying visual-object working memory dysfunction in early AD, and a neurophysiological indicator of cognitive decline.

Alpha rhythm is one of the most prominent electromagnetic changes in the brain, and electroencephalography (EEG) alpha reactivity disturbance may sometimes represent an early sign of cerebral dysfunction. Although magnetoencephalography (MEG) has a better spatial resolution than EEG, it has not extensively been used to explore alpha-power change deficits in schizophrenia as a possible neurophysiological marker of the disease. The purpose of this study was to use MEG to identify abnormalities in alpha synchronization induced by eye-closing in schizophrenia patients compared to healthy controls, and to investigate whether alpha reactivity deficits correlate with clinical features of the disorder. MEG data were recorded in 22 schizophrenia patients and 20 age- and gender-matched controls during eyes-open/eyes-closed resting states. Cortical sources of event-related synchronization (ERS) were estimated using multiple source beamformer, and BrainVoyager was used for statistic group analysis. A significant decrease in ERS in the upper alpha band (10-13 Hz) was found in the left posterior temporal region in schizophrenia patients relative to controls, and this activity showed correlation with visual memory scores. This upper alpha ERS deficit may indicate left temporal dysfunction and visual-information processing impairment in schizophrenia, and upon further confirmation it might represent a neurophysiological state marker of the disorder.

Methods: Twelve patients with SLPE and 14 nonpsychotic epilepsy controls participated in this study. Magnetoencephalography was recorded while patients performed a visual working memory (WM) task. Psychopathology was assessed using a fourfactor structure of the Brief Psychiatric Rating Scale, and regression analyses were carried out to examine the relative impact of severity of psychopathology on WM-induced activation of the DLPFC. Results: We found that activation of the WMcompromising DLPFC, as indicated by increased alpha desynchronization in patients with SLPE compared with their non-psychotic counterparts, showed a positive linear correlation with disorganization symptom scores. This association remained significant after controlling for confounding factors, including age, task performance, IQ, and duration of psychosis. Conclusion: Our results indicate that abnormal activation in prefrontal areas engaged during working memory may be critical to domains of psychopathology, in particular disorganized thought-processing in patients with SLPE.

Neuronal cell cycle reentry, which is associated with aberrant tau phosphorylation, is thought to be a mechanism of neurodegeneration in AD. Caffeine is a neuroprotective drug known to inhibit the cell cycle, suggesting that its neuroprotective nature may rely, at least in part, on preventing tau abnormalities secondary to its inhibitory effect on neuronal cell cycle-related pathways. Accordingly, we have explored in the present study the impact of caffeine on cell cycle-linked parameters and tau phosphorylation patterns in an attempt to identify molecular clues to its neuroprotective effect. We show that caffeine blocks the cell cycle at G1 phase in neuroblastoma cells and leads to a decrease in tau phosphorylation; similarly, exposure of postmitotic neurons to caffeine led to changes in tau phosphorylation concomitantly with downregulation of Akt signaling. Taken together, our results show a unique impact of caffeine on tau phosphorylation and warrant further investigation to address whether caffeine may help prevent neuronal death by preventing tau abnormalities secondary to aberrant entry into the cell cycle.

Background: Induced-oscillatory activity is considered a key factor for understanding functional processes in the brain. Magnetoencephalography (MEG) can measure oscillatory activity non-invasively with higher spatial resolution than electroencephalography (EEG). However, MEG has rarely been used to explore functional abnormalities that may represent state markers in patients with Alzheimer's disease (AD). Methods: Thirteen patients with early AD and 14 age-matched normal controls participated in the present study. Magnetoencephalography activity was acquired during eyes-open and eyes-closed states. Alpha event-related synchronization (ERS) after eye closing was calculated and its cortical sources superimposed on each individual's magnetic resonance imaging (MRI) scan. The resulting functional image was converted into a Talairach-transformed anatomical brain image and group comparisons were made. We also assessed correlations between cortical ERS sources showing significant between-group differences in alpha activity and external clinical parameters, especially measures of cognitive function. Results: The averaged alpha ERS after eye closing appeared dominantly in posterior brain regions in both patients with AD and healthy controls. However, there was a significant increase in alpha ERS in frontal regions, maximal over the prefrontal cortex, in patients with AD relative to controls, indicating a frontal shift of the posterior dominant MEG alpha rhythm in AD patients. This frontal ERS source in the alpha band was negatively correlated with Mini-Mental State Examination scores in the AD patient group. Conclusions: The findings indicate that a frontal shift of alpha ERS elicited by an eyes-open/eyes-closed paradigm may be an early brain electromagnetic change in patients with AD, probably representing a physiological state marker of the disease. Furthermore, the results confirm that the beamformer with group comparison analysis is a useful tool with which to explore functional processes in the brain, as indicated by oscillatory activity changes.

The mu rhythm is regarded as a physiological indicator of the human mirror neuron system (MNS). The dysfunctional MNS hypothesis in patients with autistic spectrum disorder (ASD) has often been tested using EEG and MEG, targeting mu rhythm suppression during action observation/execution, although with controversial results. We explored neural activity related to the MNS in patients with ASD, focusing on power increase in the beta frequency band after observation and execution of movements, known as post-movement beta rebound (PMBR). Multiple source beamformer (MSBF) and BrainVoyager QX were used for MEG source imaging and statistical group analysis, respectively. Seven patients with ASD and ten normal subjects participated in this study. During the MEG recordings, the subjects were asked to observe and later execute object-related hand actions performed by an experimenter. We found that both groups exhibited pronounced PMBR exceeding 20% when observing and executing actions with a similar topographic distribution of maximal activity. However, significantly reduced PMBR was found only during the observation condition in the patients relative to controls in cortical regions within the MNS, namely the sensorimotor area, premotor cortex and superior temporal gyrus. Reduced PMBR during the observation condition was also found in the medial prefrontal cortex. These results support the notion of a dysfunctional execution/observation matching system related to MNS impairment in patients with ASD, and the feasibility of using MEG to detect neural activity, in particular PMBR abnormalities, as an index of MNS dysfunction during performance of motor or cognitive tasks.

Summary The purpose of this study is to weigh psychological state, patients’ demographics, seizure-related factors, and medical comorbidity in older adults with epilepsy against the same parameters in younger adults in an attempt to identify best quality of life (QoL) predictors. The Quality of Life in Epilepsy Inventory for Adults (QOLIE-31) and the Beck Depression Inventory-II (BDI-II) were completed by 146 patients with localization-related epilepsy. There was no statistical difference in the QOLIE-31 total score between younger and older adults. Best QoL predictors were BDI-II and seizure frequency, with BDI-II providing more than 3 times the impact of seizure frequency. BDI-II also substantively predicted most QOLIE-31 domains. Additionally, epilepsy duration positively correlated with overall QoL only among older adults. In summary, in younger as well as older adult epilepsy patients, depressive symptoms emerge as the strongest predictor of QoL. However, older adults appear to adapt better to their chronic health problem.

Background: Despite increasing recognition of delirium as a serious complication of physical illness, little has been reported in this area. Interest has been raised in treatment options other than haloperidol, such as atypical antipsychotic agents. Methods: A 2-week open-label trial of risperidone for the treatment of delirium was conducted to assess the efficacy and tolerance of this medication in elderly patients. Twenty-two patients with DSM-IV-defined delirium were investigated. All patients had the hyperactive–hyperalert variant of delirium. Patients received a fixed dose of risperidone (mean 1.5 ± 0.7 mg; range 0.5–3 mg). Delirium was assessed using the Delirium Rating Scale (DRS) at baseline and on Days 1, 3, 5, 7, and 14 after the initiation of risperidone treatment. Clinical and demographic data, as well as risperidone therapy related information, were collected. Results: Delirium resolved in all patients over the course of treatment. The mean period over which delirium resolved was 4.0 ± 2.9 days. The mean DRS score at baseline was 20.7 ± 3.0. The DRS score improved from baseline to Day 1 of treatment and continued to improve until the study end-point. Mild side-effects were present in 27.3% of patients. Stepwise logistic regression identified a decrease of 2 points or higher on the DRS on Day 1 associated with side-effects. There were no significant differences in the response to treatment with the different doses of risperidone used. Conclusion: Our findings indicate that low-dose risperidone (0.5–3.0 mg/day) is effective and safe for the treatment of delirium in elderly patients, and that an early response on Day 1 of treatment may be associated with side-effects in these patients.

Backgrounds: The digit symbol substitution test (DSST) is a clinically useful and widely accepted tool for the detection of various psychiatric disorders. Investigating neural activity during the DSST is useful when considering the relationship between the poor performance on the DSST and neurocognitive deficits. However, obtaining reliable functional imaging of the neural mechanisms associated with this test is challenging due to motion artifacts. Aims: To circumvent this problem, we examined frontal lobe activity during the DSST using multichannel near-infrared spectroscopy, a noninvasive functional imaging technique that does not interfere with the DSST procedure. Methods: Twenty-five healthy volunteers were enrolled in this study. Changes in the concentration of oxygenated hemoglobin (oxyHb) during the DSST were determined bilaterally in 52 measurement points (channels) on the frontal area. Results: We found significant increases in oxyHb in more than 70% of the channels, with the intensity of the increase being more pronounced in the left hemisphere. Several channels showed significant positive correlations between changes in oxyHb and DSST performance. Some of the channels with a significant increase in oxyHb during the DSST did not show a correlation with the DSST performance. Conclusions: Our findings indicate that the DSST could prove useful as a frontal lobe stimulating task. Further examinations of DSST/near-infrared spectroscopy analyses of neural mechanisms in patients with psychiatric and neurological diseases are necessary to assess its effectiveness in clinical practice for the evaluation of neuropsychopathology.

To evaluate the effects of slow repetitive transcranial magnetic stimulation (rTMS) on thalamic pain, the magnetoencephalographic (MEG) signals following eye closing and tactile stimulation were recorded before and after rTMS in two patients. After the application of rTMS, similar neuromagnetic changes were obtained in both patients. Alpha event-related synchronization (ERS) following eyes closing increased and it became more symmetric. Beta ERS following paralytic extremities stimulation, which was hardly observed before rTMS, increased. Beta ERS following non-paralytic extremities stimulation increased as well. Slow rTMS may change oscillatory MEG activity and induce brain plasticity even if the pain cannot be relieved.

Although delusions are quite common symptoms among psychiatric patients, few neuroimaging studies have explored the neural correlates of delusions. In this study we used magnetoencephalography (MEG) to directly image brain activity associated with delusions in acute psychosis of epilepsy patients. Two female patients aged 65 and 68 years with temporal lobe epilepsy were studied. We obtained topographic images of the excess kurtosis (g2), the statistical index of spiky activities, from unaveraged MEG measurements using an analysis called “synthetic aperture magnetometry” (SAM). In both patients, the excess kurtosis (g2) images showed spiky activity over the right inferior parietal cortex during the delusional state. A second MEG measurement after delusions were resolved with antipsychotic medication showed no excess kurtosis image in the right parietal cortex. Our results indicate association of the right inferior parietal region with the experience of delusions in these patients. We suggest that MEG with SAM analysis is useful in the identification of abnormal activity in acute psychotic disorders.

The purpose of our study was to identify the main factors associated with objective noise-induced hearing loss (NIHL), as indicated by abnormal audiometric testing, in Spanish workers exposed to occupational noise in the construction industry. We carried out a prospective study in Tenerife, Spain, using 150 employees exposed to occupational noise and 150 age-matched controls who were not working in noisy environments. The variables analyzed included sociodemographic data, noise-related factors, types of hearing protection, self-report hearing loss, and auditory-related symptoms (e.g., tinnitus, vertigo). Workers with pathological audiograms had significantly longer noise-exposure duration (16.2 ± 11.4 years) relative to those with normal audiograms (10.2 ± 7.0 years; t = 3.99, P < 0.001). The vast majority of those who never used hearing protection measures had audiometric abnormalities (94.1%). Additionally, workers using at least one of the protection devices (earplugs or earmuffs) had significantly more audiometric abnormalities than those using both protection measures simultaneously (Chi square = 16.07; P < 0.001). The logistic regression analysis indicates that the use of hearing protection measures [odds ratio (OR) = 12.30, confidence interval (CI) = 4.36-13.81, P < 0.001], and noise-exposure duration (OR = 1.35, CI = 1.08-1.99, P = 0.040) are significant predictors of NIHL. This regression model correctly predicted 78.2% of individuals with pathological audiograms. The combined use of hearing protection measures, in particular earplugs and earmuffs, associates with a lower rate of audiometric abnormalities in subjects with high occupational noise exposure. The use of hearing protection measures at work and noise-exposure duration are best predictive factors of NIHL. Auditory-related symptoms and self-report hearing loss do not represent good indicators of objective NIHL. Routine monitoring of noise levels and hearing status are of great importance as part of effective hearing conservation programs.

Scopolamine administration may be considered as a psychopharmacological model of Alzheimer’s disease (AD). Here, we studied a group of healthy elderly under scopolamine to test whether it elicits similar changes in brain connectivity as those observed in AD, thereby verifying a possible model of AD impairment. We did it by testing healthy elderly subjects in two experimental conditions: glycopyrrolate (placebo) and scopolamine administration. We then analyzed magnetoencephalographic (MEG) data corresponding to both conditions in resting-state with eyes closed. This analysis was performed in source space by combining a nonlinear frequency band-specific measure of functional connectivity (phase locking value, PLV) with network analysis methods. Under scopolamine, functional connectivity between several brain areas was significantly reduced as compared to placebo, in most frequency bands analyzed. Besides, regarding the two complex network indices studied (clustering and shortest path length), clustering significantly decreased in the alpha band while shortest path length significantly increased also in alpha band both after scopolamine administration. Overall our findings indicate that both PLV and graph analysis are suitable tools to measure brain connectivity changes induced by scopolamine, which causes alterations in brain connectivity apparently similar to those reported in AD.

Neuropsychiatric symptoms are very common in tuberous sclerosis complex (TSC). Autism is present in up to 60% of these patients, and TSC accounts for 1-4% of all cases of autism. In this study, we illustrate a 27 year-old female patient with TSC, autism, and renal angiomyolipomas, in whom everolimus treatment was associated with improvement in behavioral deficits. She took part in an everolimus clinical trial (EXIST-2: ClinicalTrials.gov number NCT00790400) to assess the efficacy of this drug in TSC. It was a randomized, double-blind, placebo-controlled study of everolimus (RAD001) (10 mg/day during 18 months) in the treatment of TSC-related angiomyolipoma. The Japanese version of the Aberrant Behavior Checklist (ABC) and the Pervasive Developmental Disorders - Autism Society Japan Rating Scale (PARS) were used to assess the severity of behavioral deficits. Clinical improvement after everolimus treatment was more remarkable for irritability, stereotypic behavior and inappropriate speech scores on the ABC scale. In addition, stereotypic behavior and lethargy/social withdrawal subscale scores showed an overall reduction of 10 and 8 points, respectively. The severity of autistic symptoms measured with the PARS also showed a marked reduction after treatment. There were no abnormal EEG findings before the treatment and no changes after the treatment. Our findings are consistent with those of animal models proposing that treatment of TSC1 and TSC2 mutant mice with the mTOR inhibitor rapamycin, reversed impaired social interaction. This makes everolimus a promising drug for the treatment of TSC patients with autism. Our findings warrant further investigation in future clinical trials.

Recent functional magnetic resonance imaging (fMRI) studies have shown that functional networks can be extracted even from resting state data, the so called ?Resting State independent Networks? (RS-independent-Ns) by applying independent component analysis (ICA). However, compared to fMRI, electroencephalography (EEG) and magnetoencephalography (MEG) have much higher temporal resolution and provide a direct estimation of cortical activity. To date, MEG studies have applied ICA for separate frequency bands only, disregarding cross-frequency couplings. In this study, we aimed to detect EEG-RS-independent-Ns and their interactions in all frequency bands. We applied exact low resolution brain electromagnetic tomography-ICA (eLORETA-ICA) to resting-state EEG data in 80 healthy subjects using five frequency bands (delta, theta, alpha, beta and gamma band) and found five RS-independent-Ns in alpha, beta and gamma frequency bands. Next, taking into account previous neuroimaging findings, five RS-independent-Ns were identified: (1) the visual network in alpha frequency band, (2) dual-process of visual perception network, characterized by a negative correlation between the right ventral visual pathway (VVP) in alpha and beta frequency bands and left posterior dorsal visual pathway (DVP) in alpha frequency band, (3) self-referential processing network, characterized by a negative correlation between the medial prefrontal cortex (mPFC) in beta frequency band and right temporoparietal junction (TPJ) in alpha frequency band, (4) dual-process of memory perception network, functionally related to a negative correlation between the left VVP and the precuneus in alpha frequency band; and (5) sensorimotor network in beta and gamma frequency bands. We selected eLORETA-ICA which has many advantages over the other network visualization methods and overall findings indicate that eLORETA-ICA with EEG data can identify five RS-independent-Ns in their intrinsic frequency bands, and correct correlations within RS-independent-Ns.

Idiopathic normal pressure hydrocephalus (iNPH) is a syndrome characterized by gait disturbance, cognitive deterioration and urinary incontinence in elderly individuals. These symptoms can be improved by shunt operation in some but not all patients. Therefore, discovering predictive factors for the surgical outcome is of great clinical importance. We used normalized power variance (NPV) of electroencephalography (EEG) waves, a sensitive measure of the instability of cortical electrical activity, and found significantly higher NPV in beta frequency band at the right fronto-temporo-occipital electrodes (Fp2, T4 and O2) in shunt responders compared to non-responders. By utilizing these differences, we were able to correctly identify responders and non-responders to shunt operation with a positive predictive value of 80% and a negative predictive value of 88%. Our findings indicate that NPV can be useful in noninvasively predicting the clinical outcome of shunt operation in patients with iNPH.