Right parietal activation during delusional state in episodic interictal psychosis of epilepsy: a report of two cases.

Magnetoencephalography (MEG) was used to image brain activity associated with delusions in episodic interictal psychosis of epilepsy. Two female patients aged 65 and 68 with temporal lobe epilepsy were studied during and after a delusional state. Topographic images of the excess kurtosis (g2), the statistical index of spikelike activity, were obtained from unaveraged MEG recordings using an analysis called "synthetic aperture magnetometry" (SAM). For both patients, MEG waveforms and excess kurtosis images revealed spiky activity in the right inferior parietal region during the delusional state. A second MEG measurement after delusions were resolved with antipsychotic therapy revealed no excess kurtosis in the right parietal area. Likewise, the sharp waves on MEG recordings disappeared as well. Our results suggest association of the right inferior parietal cortex, including the supramarginal gyrus, with the delusional state of episodic interictal psychosis of epilepsy.

Wavelet-crosscorrelation analysis: Non-stationary analysis of neurophysiological signals.

OBJECTIVE: Wavelet-crosscorrelation analysis is a new application of wavelet analysis used to show the propagation of epileptiform discharges and to localize the corresponding lesions. We have shown previously that this analysis can help predict brain conditions statistically (Mizuno-Matsumoto et al. 2002). Our objective was to assess whether wavelet-crosscorrelation analysis reveals the initiation and propagation of epileptiform activity in human patients. METHODS: The data obtained from three patients with simple partial seizures (SPS) using whole-head magnetoencephalography (MEG) were analyzed by the wavelet-crosscorrelation method. Wavelet-crosscorrelation coefficients (WCC), the coherent structure of each possible pair of signals from 64 MEG channels forvarious periods, and the time lag (TL) in two related signals, were ascertained. RESULTS: We clearly demonstrated both localization of the irritative zone and propagation of the epileptiform discharges. CONCLUSIONS: Wavelet-crosscorrelation analysis can help reveal and visualize the dynamic changes of brain conditions. The method of this analysis can compensate for other existing methods for the analysis of MEG, electroencephalography (EEG) or Elecotrocorticography (ECoG). SIGNIFICANCE: Our proposed method suggests that revealing and visualizing the dynamic changes of brain conditions can help clinicians and even patients themselves better understand such conditions.

SAM(g2) analysis for detecting spike localization: a comparison with clinical symptoms and ECD analysis in an epileptic patient.

SAM(g2) analysis, a combination of synthetic aperture magnetometry (SAM) and excess kurtosis (g2) method, is a novel epilepsy analysis procedure based on a spatial filtering technique. By producing a three-dimensional image of the g2 values and superimposing them onto a patient's MR images, this analysis can automatically estimate spike localization from raw MEG epilepsy signals including spikes. The aim of this study is to examine SAM(g2) analysis using MEG signals of an epileptic patient, whose clinical symptoms of colored elementary visual auras had ceased in accordance with the changes of the estimated localizations of the equivalent current dipoles (ECDs) of the interictal spikes. His visual auras were experienced in 1997, while they ceased in 1999 with effective medication. The patient provided written informed consent for the experimental procedures. The MEG signals were recorded in 1997 and 1999, and were analyzed using both ECD and SAM(g2) analyses. For the MEG signals of 1997, ECD analysis estimated most of the interictal spikes in the right fusiform and inferior temporal gyri, which subserve human color processing. SAM(g2) analysis also estimated them in the same areas. For those of 1999, both ECD and SAM(g2) analyses estimated them in the right transverse gyrus of Heschl. As well as ECD analysis, SAM(g2) analysis successfully estimated the changes of the localizations of the interictal spikes in accordance with the changes of the patient's clinical symptoms, indicating that SAM(g2) analysis is useful for detection of interictal spike localization in epileptic patients.

Transient global amnesia (TGA) in an MEG study.

A patient who had experienced an attack of transient global amnesia (TGA) was examined using neurophysiological methods. Magnetoencephalography (MEG) was performed and the Wechsler Memory Scale-Revised (WMS-R) test was administered at 5 days and at more than a month after the TGA episode. MEG data on neuronal activity obtained while the patient was undertaking a working memory task and during rest were analyzed using the wavelet-crosscorrelation method, which reveals time-lag and information flow between related sites in the brain. The WMS-R memory scores showed dramatic improvement when the test was administered a month following the attack, although no significant changes were observed in EEG, MRI and SPECT data. The MEG study revealed that under a working memory load how the neuron works functionally and the information propagates assembly within the right hemisphere, and that these brain functions were not performed adequately shortly after the TGA attack.

Theta rhythm increases in left superior temporal cortex during auditory hallucinations in schizophrenia: a case report.

Auditory hallucinations (AH), the perception of sounds and voices in the absence of external stimuli, remain a serious problem for a large subgroup of patients with schizophrenia. Functional imaging of brain activity associated with AH is difficult, since the target event is involuntary and its timing cannot be predicted. Prior efforts to image the patterns of cortical activity during AH have yielded conflicting results. In this study, MEG was used to directly image the brain electrophysiological events associated with AH in schizophrenia. We observed an increase in theta rhythm, as sporadic bursts, in the left superior temporal area during the AH states, whereas there was steady theta band activity in the resting state. The present finding suggests strong association of the left superior temporal cortex with the experience of AH in this patient. This is consistent with the hypothesis that AH arises from areas of auditory cortex subserving receptive language processing.

[Understanding of molecular pathogenesis of Alzheimer's disease: implications for drug development].

Recent advances in the knowledge about Alzheimer pathogenesis indicate several tactics for the development of drugs to treat Alzheimer's disease. Firstly, the function of presenilin, the causative gene for most familial Alzheimer's disease, has been demonstrated to be the protease in the Notch signaling system. Presenilin cleaves the transmembrane domain of the C-terminal fragment of the Notch-1 molecule, which is generated by proteolysis by furin-like proteases. APP is also cleaved by presenilin at the gamma cut site, implying that presenilin is gamma-secretase itself or at least closely functioning with gamma-secretase. A recent paper has demonstrated that immunization of APP transgenic mouse with amyloid beta 42 may decrease and prevent amyloid deposition in brain tissue. This unique and novel approach may open the new tactics for developing anti-dementia drugs. Another important finding comes from the identification of the function of prolyl isomerase. It is demonstrated that pin 1, intra-nuclear prolyl isomerase, can restore the microtubule binding capacity of phosphorylated tau, which clearly shows a solid strategy for developing drugs for preventing neuronal degeneration.

Significance of tau phosphorylation and protein kinase regulation in the pathogenesis of Alzheimer disease.

The role of the phosphatidylinositol-3 kinase pathway in the hyperphosphorylation of tau protein was investigated in cultured cells. Human kidney 293T-cells were cotransfected with tau and glycogen synthase kinase-3 (GSK-3) genes or tau and protein kinase B genes. The phosphorylation of tau protein was increased by cotransfection with GSK-3; however, it was decreased by cotransfection with protein kinase B. Human neuroblastoma SY5Y cells were treated with wortmannin, an inhibitor of phosphatidylinositol-3 kinase, and only transient (after 1 hour) activation of GSK-3 and hyperphosphorylation of tau protein were observed. However, continuous inactivation of protein kinase B was observed, suggesting the involvement of protein kinases other than protein kinase B in the phosphorylation and inactivation of GSK-3 after 3 hours. In cells treated with wortmannin, protein kinase C delta fragments were observed, and the protein kinase C activity increased after 3 hours, whereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase-3, inhibited fragmentation of protein kinase C delta and induced continuous activation of GSK-3. It is suggested that fragmentation of protein kinase C delta during the process of apoptosis results in the phosphorylation and the inactivation of GSK-3. Those data suggest that, in Alzheimer disease, more complicated mechanisms are involved in the process of phosphorylation of tau protein predominantly regulated by P13K pathway.

Telemedicine for evaluation of brain function by a metacomputer.

A method of evaluating brain function using the metacomputer concept of the Globus system combined with a message-passing interface is described. The proposed method has the ability to exploit various geographically distributed resources and parallel computing linked to a high-technology medical instrumentation system, magnetoencephalography, to analyze the functional state of the brain. It is envisaged that the method will lead to the realization of an efficient telemedicine system for health care.

Neurobiological basis of behavioral and psychological symptoms in dementia of the Alzheimer type.

Recent dementia studies indicate that behavioral and psychological symptoms of dementia (BPSD) are not merely an epiphenomenon of cognitive impairment, but could be attributed to specific biological brain dysfunction. We describe findings from different research modalities related with BPSD (psychopathological, neuropsychological, neurochemical, and psychophysiological strategies), and attempt to reconcile them into the more integrated form. Characteristics of delusions in dementia patients should be studied in more detail from a psychopathological aspect, aiming for the integration of psychopathology and neurobiology. Imperfect integration of memory function and cognitive function, assigned to the limbic systems and association areas, respectively, may result in BPSD. More intimate collaboration of psychopathological and neurobiological study would be fruitful to promote the research in psychological basis of BPSD. Neurochemical studies indicated that density of extracellular tangles and/or PHF-tau protein have relationships with delusion or misidentification. These changes in neurochemical parameters should be the key to understanding the pathogenesis of BPSD. More importantly, neurochemical and psychological study could be linked by the research in psychophysiology. Computer-assisted electroencephalogram analysis suggests that the right posterior hemisphere shows significant age-associated change earlier than the left in the elderly. Cerebral metabolic rate by positron emission tomography study indicates that paralimbic, left medial temporal, and left medial occipital area are involved in pathogenesis of BPSD in some dementia patients.

A profile analysis of personality disorders: beyond multiple diagnoses.

The authors applied cluster analysis and multidimensional scaling to the analyses of 59 patients with personality pathology. Cluster analysis yielded eight typologies of patients: detached, anankastic, phobic, dramatic, erratic, emotional, milder emotional, and masochistic negativistic. Multidimensional scaling identified the dimensions of classifying patients: anxious rumination versus behavioural acting out, overall severity of personality pathology, and assertiveness versus withdrawal. Considering the distinction between personality disorder (dysfunctional personality) and abnormal personality (extreme personality), the following changes in current classification system are proposed: use of a hierarchy and exclusion criteria in a categorical-type model or use of a personality profile in a dimensional-trait model, in either case, with a dimensional rating for severity of psychopathology to define personality 'disorder'.

Diminished facial expression despite the existence of pleasant emotional experience in schizophrenia.

In order to investigate the relationship between pleasant emotional experience and facial expression (i.e., laughter), mood before and after watching comic film clips, self-rated pleasant emotional experience for each film clip and electromyographic activities of facial muscles involved in laughter while watching film clips were measured for 25 patients with schizophrenia and 20 normal controls. Patients with schizophrenia who showed a significant correlation between self-rated emotional experience and major zygomatic activity were equivalent to normal controls in self-rated emotional experience and in mood after film clips; they had a significant increase in mood scores related with pleasure. Although these patients were thought to have sufficient pleasant emotional experience, they showed significantly low major zygomatic activity as compared to normal controls. It is suggested that these patients have a disturbance in the process of emotional expression rather than emotional experience.

Medial prefrontal cortex generates frontal midline theta rhythm.

Frontal midline theta rhythm (Fm theta) is a distinct theta activity of EEG in the frontal midline area that appears during concentrated performance of mental tasks in normal subjects and reflects focused attentional processing. To tomographically visualize the source current density distributions of Fm theta, we recorded Fm theta by using a 64-channel whole-head MEG system from four healthy subjects, and applied a new analysis method, synthetic aperture magnetometry (SAM), an adaptive beam forming method. Fm theta was observed in the MEG signals over the bilateral frontal regions. SAM analysis showed bilateral medial prefrontal cortices, including anterior cingulate cortex, as the source of Fm theta. This result suggests that focused attention is mainly related to medial prefrontal cortex.

Basic and clinical studies on ApoE gene typing by line probe assay (LiPA) as a biological marker for Alzheimer's disease and related disorders: multicenter study in Japan.

The fundamental reagent capability and clinical significance of ApoE gene typing has been investigated. The result of each test shows that the reagent capability satisfied the expected standard. Four-hundred thirty-nine samples classified into three groups (Alzheimer's disease (AD), other types of dementia and nondementia) were measured to examine the clinical significance. The rate of epsilon 4 genotype of each group was 31.5%, 14.6%, 10.4%, respectively. The AD group had a higher rate than the other groups (p < 0.001). The measurement of ApoE genotype is suggested to be useful as one of the guidelines in the diagnosis of AD.

Abnormal distribution of neurofilament L in neurons with Alzheimer's disease.

Abnormality of cytoskeletal proteins is closely related to the pathology of Alzheimer's disease. As neurofilament proteins are major cytoskeletal components of neurons, abnormality of neurofilaments is proposed in brain with Alzheimer's disease. Free-floating sections of the hippocampus with Alzheimer's disease were studied immunohistochemically, using a polyclonal antibody specifically bound to the tail region of neurofilament L (NF-L). In brains with early onset type of Alzheimer's disease, many neurons and dystrophic neurites were labeled by the antibody, while these observations were not seen in either brains with late onset type or control brains. Double immunohistochemical staining of NF-L and tau protein demonstrated that abnormal deposition of NF-L was not always accompanied with that of tau protein, indicating that the abnormal deposition of NF-L might not occur in parallel with that of tau protein. These observations suggest the involvement of neurofilament proteins on the pathology of Alzheimer's disease in a different way than tau protein.

The 3-dimensional representation of EEG distance by use of Shannon-Gelfand-Yaglom information measure during mental arithmetic.

EEG relationships in delta, theta, alpha and beta frequency bands as well as the whole frequency range among 12 electrode locations during resting and mental arithmetic were examined by use of Shannon-Gelfand-Yaglom information measure (SGY) in 10 normal subjects. The EEG relationships were represented in a 3-dimensional (3-D) feature space with multidimensional scaling (MDS). MDS resulted in an anterior-posterior, a left-right and an upper-lower axis. In all 5 frequency bands, the 12 electrodes on the anterior-posterior and left-right axes resembled their actual positions on the scalp during resting and mental arithmetic. During mental arithmetic, prominent changes in the 3-D representation of electrode sites were visualized for activity. The isolation of left and right mid-temporal locations, together with greater EEG distances between left and right mid-temporal locations, were notable during mental arithmetic, suggesting the simultaneous activation possibly in dominant and non-dominant hemispheres and contralateral influences from left to right mid-temporal locations.

Inter-site EEG relationships before widespread epileptiform discharges.

EEG interactions of the background among locations can start to change just before epileptiform discharges. Such interactions were investigated with relative power contribution analysis based on a multivariate autoregressive model, which permits determination of multiple causal relations of EEGs among locations. EEGs from F3, F4, P3, P4, T3 and T4 were examined in 10 epileptic patients with asymmetric spike and wave complexes (SWCs). A 12.5-s epoch just before SWCs was divided into stationary segments throughout 6 locations with a segmentation method. In segments long before SWCs, most power at each location was generated from its own location. In segments immediately preceding SWCs, contributions from other locations, particularly from the hemisphere with smaller SWCs, increased. Overall EEG relationships among 6 locations were examined by an entropy which measures the uniformness of the spatial distribution of power contribution. The entropy significantly increased gradually toward SWCs. Our findings demonstrated stronger interactions among locations just before epileptiform discharges, suggesting a transitional state from background EEG to epileptiform discharges.

Potential flow of alpha activity in the human electroencephalogram.

The movement of potential field of alpha activity was investigated with a potential flow technique, alpha activity was divided into slow, medium and fast subbands. The peak-to-peak amplitude and source density distribution of each subband was also constructed. The potential flow of medium alpha was from medial to lateral in the anterior region, and from lateral to medial in the posterior region. The flow patterns of slow and fast alpha were more complicated. Similar flow directions formed a group. Different groups met or diverged at discontinuous grid points around the local maxima of potential distribution. The discontinuous points of medium alpha were centered in the parieto-occipital region, and those of slow and fast alpha were more equally distributed over the scalp. Against potential gradients, several groups of similar flow directions participated in the formation of potential field. The generation of potential field was assumed to be controlled widely for medium alpha and locally for slow and fast alpha.