A comparative study of synchrony measures for the early diagnosis of Alzheimer's disease based on EEG.

It is well known that EEG signals of Alzheimer's disease (AD) patients are generally less synchronous than in age-matched control subjects. However, this effect is not always easily detectable. This is especially the case for patients in the pre-symptomatic phase, commonly referred to as mild cognitive impairment (MCI), during which neuronal degeneration is occurring prior to the clinical symptoms appearance. In this paper, various synchrony measures are studied in the context of AD diagnosis, including the correlation coefficient, mean-square and phase coherence, Granger causality, phase synchrony indices, information-theoretic divergence measures, state space based measures, and the recently proposed stochastic event synchrony measures. Experiments with EEG data show that many of those measures are strongly correlated (or anti-correlated) with the correlation coefficient, and hence, provide little complementary information about EEG synchrony. Measures that are only weakly correlated with the correlation coefficient include the phase synchrony indices, Granger causality measures, and stochastic event synchrony measures. In addition, those three families of synchrony measures are mutually uncorrelated, and therefore, they each seem to capture a specific kind of interdependence. For the data set at hand, only two synchrony measures are able to convincingly distinguish MCI patients from age-matched control patients, i.e., Granger causality (in particular, full-frequency directed transfer function) and stochastic event synchrony. Those two measures are used as features to distinguish MCI patients from age-matched control subjects, yielding a leave-one-out classification rate of 83%. The classification performance may be further improved by adding complementary features from EEG; this approach may eventually lead to a reliable EEG-based diagnostic tool for MCI and AD.

Growth site localization of Rho1 small GTP-binding protein and its involvement in bud formation in Saccharomyces cerevisiae.

The Rho small GTP-binding protein family regulates various actomyosin-dependent cell functions, such as cell morphology, locomotion, cytokinesis, membrane ruffling, and smooth muscle contraction. In the yeast Saccharomyces cerevisiae, there is a homologue of mammalian RhoA, RHO1, which is essential for vegetative growth of yeast cells. To explore the function of the RHO1 gene, we isolated a recessive temperature-sensitive mutation of RHO1, rho1-104. The rho1-104 mutation caused amino acid substitutions of Asp 72 to Asn and Cys 164 to Tyr of Rho1p. Strains bearing the rho1-104 mutation accumulated tiny- or small-budded cells in which cortical actin patches were clustered to buds at the restrictive temperature. Cell lysis and cell death were also seen with the rho1-104 mutant. Indirect immunofluorescence microscopic study demonstrated that Rho1p was concentrated to the periphery of the cells where cortical actin patches were clustered, including the site of bud emergence, the tip of the growing buds, and the mother-bud neck region of cells prior to cytokinesis. Indirect immunofluorescence study with cells overexpressing RHO1 suggested that the Rho1p-binding site was saturable. A mutant Rho1p with an amino acid substitution at the lipid modification site remained in the cytoplasm. These results suggest that Rho1 small GTP-binding protein binds to a specific site at the growth region of cells, where Rho1p exerts its function in controlling cell growth.

Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes.

Microinjection of either Ki-rasVal-12 p21 or the GDP-bound form of Ki-ras p21 plus smg GDP dissociation stimulator (GDS), a stimulatory GDP/GTP exchange protein for Ki-ras p21, smg/rap1/Krev-1 p21, and rho p21, into quiescent Swiss 3T3 cells induced DNA synthesis irrespective of the presence or absence of insulin. The guanosine 5'-(3-O-thio)triphosphate (GTP gamma S)-bound form of smg p21B or the GDP-bound form of smg p21B plus smg GDS also induced DNA synthesis but only in the presence of insulin. Either the GDP-bound form of Ki-ras p21 or the same form of smg p21B alone was inactive, but smg GDS alone was slightly active only in the presence of insulin. The morphology of the cells was analyzed by scanning electron, phase-contrast, and confocal laser scanning microscopies. Ki-rasVal-12 p21 induced membrane ruffling irrespective of the presence or absence of insulin. The GTP gamma S-bound form of smg p21B showed the same effect only in the presence of insulin. Either the GDP-bound form of Ki-ras p21, the same form of smg p21B, or smg GDS alone was inactive. Upon microinjection of Ki-rasVal-12 p21, stress fibers markedly decreased and the cells became round and piled up. In contrast, upon microinjection of the GTP gamma S-bound form of smg p21B, stress fibers did not markedly decrease and the cells neither became round nor piled up. These results indicate that both ras p21 and smg p21 are mitogenic in Swiss 3T3 cells but that their actions are slightly different.

Techniques for early detection of Alzheimer's disease using spontaneous EEG recordings.

Alzheimer's disease (AD) is a degenerative disease which causes serious cognitive decline. Studies suggest that effective treatments for AD may be aided by the detection of the disease in its early stages, prior to extensive neuronal degeneration. In this paper, we propose a set of novel techniques which could help to perform this task, and present the results of experiments conducted to evaluate these approaches. The challenge is to discriminate between spontaneous EEG recordings from two groups of subjects: one afflicted with mild cognitive impairment and eventual AD and the other an age-matched control group. The classification results obtained indicate that the proposed methods are promising additions to the existing tools for detection of AD, though further research and experimentation with larger datasets is required to verify their effectiveness.

Estimation of the rising phase of EPSP analyzed by computer simulation of the coding process.

Based on data obtained from intracellular recordings of cat alpha-motoneurons in the stretch reflex, the firing process of these motoneurons was computer-simulated. The impulse response EPSP (IR-EPSP) was simulated to correspond to a monosynaptic mass EPSP elicited by a spindle afferent volley, while the returning potential was simulated to correspond to a potential gradient rising toward an augmenting depolarization of the membrane (augmentative EPSP) after motoneuronal spike generation. The IR-EPSPs were generated by input at random intervals and added to each other, linearly, on the returning potential. As soon as the resultant potential attained the critical threshold level, Vth, motoneuron firing occurred. Then IR-EPSPs were again added to the returning potential until another motoneuron firing occurred. This process was repeated continuously, and the time relation between input and output, lag-time distribution (PT(T], was determined Distribution of the bias potential, PV(V), from which the motoneuron spike triggering EPSP started to rise, was also calculated. The relations between PT(T), PV(V) and a waveform of the IR-EPSP were obtained analytically. The relation indicated that the shape of PT(T) corresponds to a time derivative of the rising phase of the IR-EPSP if the PV(V) distribution is uniform. In this study, we investigated the possibility of making the PV(V) distribution uniform.

Conductivity ratios of the scalp-skull-brain head model in estimating equivalent dipole sources in human brain.

The dipole tracing (DT) method estimates the position and vector dipole moment of an equivalent current dipole by minimizing the mean squared error of the dipole potentials at the surface electrode positions. In the scalp-skull-brain/DT (SSB/DT) method, which we have developed, the head model consists of three compartments of uniform conductors corresponding to the scalp, skull and brain. The accuracy of the calculations are mainly dependent on the ratios of the conductivities of the three compartments. The best result was obtained with the conductivity ratios of 1:1/80:1 for the scalp, skull and brain compartments, respectively.

Dipole-tracing method applied to human brain potentials.

A new computer-aided method was developed to estimate the location of an electric source generator (e.g. a current dipole) in the human brain. Brain activity such as somatosensory evoked potentials was recorded with 21 surface electrodes over the scalp. To solve the inverse problem, it was assumed that only one dipole is elicited at a given time, and that the head is embedded in an infinite and homogeneous conductor. The exact geometry of the human head was measured from 17 slices of CT-images of a real head to arrange a human head model. A dipole with a given moment and location is assumed in the head model. Potential distribution elicited by the dipole is compared with potential distribution which was the actual recorded one. The optimal dipole location was calculated, using the simplex method. Hence, the optimal dipole moment was obtained. The accuracy of estimation as an equivalent dipole was expressed in terms of dipolarity.

Lipoprotein analysis using agarose gel electrophoresis and differential staining of lipids.

We established a strategy to directly measure cholesterol and triglyceride levels of each lipoprotein fraction using a combination of agarose gel electrophoresis and differential staining. The cholesterol and triglyceride levels determined by electrophoresis correlated significantly with those of ultracentrifugation. The correlation coefficients between these methods were, for cholesterol levels 0.975(very low density lipoproteins, VLDL), 0.986(low density lipoproteins, LDL) and 0.965(high density lipoproteins, HDL) and for triglyceride levels 0.994(VLDL), 0.963(LDL) and 0.959(HDL) respectively. Both intra-and inter-assays showed low values of coefficients of variation (CV) (less than 3.57%). We observed a strong linearity between staining and triglyceride concentration. An increased VLDL-cholesterol was observed in type III subjects, a result which enabled distinction between type III and type IIb or type V lipoproteinemia. The method revealed lipoprotein patterns in some samples otherwise unexpected from their corresponding serum lipid parameters. Analyses of these electrophoretic patterns thus provide an effective technique to classify types of hyperlipidemia defined by the WHO. Furthermore, quantitative measurement of chylomicrons, usually difficult, proved to be achievable, providing an additional analysis of postprandial hyperlipidemia and the exact measurement of LDL-cholesterol after diet. Consequently, we recommend this simple and easy method for clinical evaluation of abnormalities in lipoprotein profiles.

Dipole-tracing of 'awareness' attenuating the cortical components of somatosensory evoked potentials.

Using the dipole-tracing method, the source generators of N18, P22 and P40 of the somatosensory evoked potential (SEP) were estimated as the equivalent dipole. After voluntary action of the thumb flexion, no changes were observed in N18 or P40, but the amplitude of P22 was suppressed. The after-effects of intention accompanied by a voluntary action or the subject's awareness that electrical stimulation will be given after the voluntary action were treated as 'awareness'. By subtracting the pure SEP from SEP during 'awareness', it was found that the equivalent dipole of 'awareness' of P22 was located at the same region of pure P22, but the vector was of opposite orientation. 'Awareness' attenuated the perceptive potential of SEP like P22 generated in the cortex.

Estimation of neural architecture in human brain by means of the dipole tracing method.

The electric source locations of interictal spikes recorded with depth electrodes were estimated by the dipole tracing (DT) method. Three-dimensional coordinates of the active surfaces of the depth electrodes and head geometry of the patient were measured from frontal and sagittal X-ray images and by a special device, respectively. The estimated dipole locations were superimposed on MR images of the patients. The dipole locations estimated in the hippocampal or parahippocampal regions successively moved in a small limited region during the interictal spike's peak. It was suggested that an interictal spike is composed of summated equivalent dipoles generated by hypersynchronization of a cluster of neurons, and that the timing of such hyperexcitation is more or less delayed because of electrical propagation along neuronal clusters which might be separated by sclerotic tissues.

Generator mechanisms of epileptic potentials analyzed by dipole tracing method.

A new dipole tracing method, based on a realistic head model, was used to determine dipole locations and vector moments of interictal convexity sharp waves recorded (with conventional EEG technique) from the right fronto-temporal region in a patient with partial complex seizures. When the dipole locations in the head model were compared to MRI scans, the majority of the sharp wave dipoles were found to be located in the right hippocampal area. For individual sharp waves, the hippocampal dipoles moved along tracks corresponding to the vector moment directions, suggesting that the electrical sources of the convexity sharp waves were somato-dendritic currents which spread rapidly from one neuron group to the next in the hippocampal area. Previous long-term subdural recording had shown seizure onset in this area. After right-sided anterior temporal lobectomy including the hippocampus the patient has been seizure-free for three months.

Dipole-tracing of abnormal slow brain potentials after cerebral stroke--EEG, PET, MRI correlations.

A patient with major neurological deficits 5 years after a left cerebral infarction underwent correlative EEG, MRI and PET studies of cerebral blood flow and oxygen metabolism. The EEG showed abnormal slow electroencephalographic activity in the frontopolar region. The intracranial location of the slow electrical activity was estimated, as an equivalent current dipole, by using a newly developed dipole tracing (DT) method. The DT analysis showed that the dipole equivalent of the slow wave is approximately located at the frontal part of the left cingulate gyrus, away from the margins of the infarction and enlarged left lateral ventricle demonstrated by MRI, and in a region with intact oxygen consumption rate. The genesis of the slow wave is discussed.

Forward and inverse problems of EEG dipole localization.

Mathematical procedures are discussed in detail of numerical solutions for obtaining scalp potentials from the electric sources. The finite-element method for an inhomogeneous volume conductor, the boundary-element method for a compartment model, and their hybrid for more general cases are discussed. Construction of the head model and typical estimation of electric conductivity of the compartment model is described, which can reduce errors in estimated dipole location caused by incorrect head geometry. The concept of reciprocity is explained, which is applied to understanding a relation between the electrode configuration and its sensitivity for various source conditions. Typical techniques for solving the inverse problem are reviewed for discrete source models. Methods of estimating accuracy of the dipole location in the presence of noise are discussed, together with some numerical examples. The dipolarity is a goodness-of-fit of the dipole approximation, and lowering of the dipolarity is related to inhomogeneous neuronal activity in the cortex. Finally, a criterion of determining the optimal number of model parameters is given in terms of AIC (Akaike Information Criterion), which is applied to decide the most probable number of equivalent dipoles.

Localization of dipole by boundary element method in three dimensional reconstructed monkey brain.

The boundary element method was applied to 3-dimensionally reconstructed monkey brain to localize a current source generator (dipole) of somatosensory evoked potentials (SEPs) recorded from epidural electrodes under assumption that a brain is electrically homogeneous and is bounded by a high resistant substance (skull). Absolute mean deviation of estimated dipoles from actual dipoles artificially generated by electrical stimulation at known coordinates in the brain were within 1-3 mm. The estimated dipole computed from SEPs by right median nerve stimulation at latency of P10-N10 waves was located in area 3b of the somatosensory hand area in monkey. Our data suggest that this technique of locating dipoles by the boundary element method applied to a reconstructed brain allows accurate determination of the 3-dimensional coordinates of a dipole.

Cortical atrophy in Alzheimer's disease unmasks electrically silent sulci and lowers EEG dipolarity.

Alzheimer's disease (AD) patients show lower dipolarity (goodness-of-fit) for dipole localizations of alpha or other dominant electroencephalography (EEG) frequency components in the occipital cortex. In the present study, we performed computer simulations to discover which of distributions of dipole activity lower dipolarity in a manner similar to that seen in severe AD. Dipolarity was estimated from simulations of various electric dipole generator configurations within the occipital cortex under conditions of widened cortical sulci (a severely demented AD case) or no sulcal widening (a normal subject). The cortical and scalp surfaces, derived from the subjects' MRI's, were assumed to be uniformly electrically conducting. Randomly placed, nonoverlapping lesions ranging from 1 to 4 mm2 per lesion were used in both the normal and AD models to simulate the electrical effect of neuropathological AD lesions. In both models, dipolarity decreased as total lesion size increased. However, the AD model showed lower dipolarity than the normal model for both individual lesion sizes and for larger total lesion sizes. The larger decline in dipolarity in the AD model appears to be due to sulcal widening which unmasks the effect of lesions buried within sulci. These simulations identify a possible mechanism explaining why sulcally-located neuropathological changes plus progressive cortical atrophy in AD brains (and presumably other cortical disorders producing atrophy) alter EEG patterns and dipolarity differently from normal cortex damaged by similar lesions.

Approximating dipoles from human EEG activity: the effect of dipole source configuration on dipolarity using single dipole models.

Dipolarity is the goodness-of-fit of the observed potential distribution with one calculated using specific assumptions about the source of the electrical potential distribution. We used computer simulations to examine the effect of different distributions of sources on their resulting dipolarity values. Electric dipoles were placed in a head-shaped model with uniform conductivity using four different dipole configurations (randomly oriented dipoles, a uniform dipole disk layer, a dipole disk layer with uniformly distributed holes, or one with randomly oriented dipoles). The best-fitting single dipole for each configuration was calculated and the dipolarity was computed as the mean squared error of the electrical potential distributions generated by the actual dipole configuration and by the best-fitting single dipole. The simulations show that: 1) a smooth dipole layer with or without holes gives dipolarities above 99.5% even when extended over areas as large as 1256 mm2; 2) randomly oriented dipoles under a smooth dipole layer also give dipolarities above 99.5%; and 3) randomly oriented and distributed dipoles, even if contained in a small portion of the total area, give dipolarities below 93.0%. These simulations show that inhomogeneity (holes) within a dipole disk layer per se do not lower dipolarity; rather, it is the random orientation and distribution of these dipoles which lowers dipolarity. Furthermore, dipolarity is not lowered by such randomly oriented and distributed dipoles when they are beneath a dipole disk layer.

Source estimation in the human brain from EEG based on the SSB Head Model.

Neuronal activity in the brain cortex is replaced by a small current dipole, and hence the localized electric activities of the cortex are well approximated by equivalent current dipoles. Position and moments of these equivalent dipoles are estimated from the scalp potentials. In this analysis, the head as a conductor is divided into three volumes with uniform electric conductivity: Scalp, Skull and Brain tissue; we call this head model the SSB Head Model. The boundary element method is used in solving this problem and reliability of the final result mainly depends on the arrangement of nodal points on the surfaces of these three regions for numerical calculation, the electric conductivity ratios of the three regions in the model, and the number of electrodes. By means of computer simulation we investigated dependence of errors in the estimated dipole position on these factors. It is found that arrangement of nodal points must be decided adaptively depending on the source position.

Equivalent dipole estimation of spontaneous EEG alpha activity: two-moving dipole approach.

A method of estimating equivalent moving and fixed dipoles from the scalp-recorded EEG alpha waves, with the realistic geometry of the head taken into account, is presented. Twenty-one silver electrodes were used to collect spontaneous EEG alpha waves on the scale. Four models, the single-moving dipole model, the single-fixed dipole model, the two-moving dipole model and the two-fixed dipole model were applied to approximate the EEG alpha field on the scalp. The algorithm, based on a least-squares fit for estimating the moving and the fixed dipoles by using a realistically shaped head model, is described. The numerical accuracy of the algorithm is also evaluated by a computer simulation. It is found that the spontaneous EEG alpha activity observed on the scalp can be represented by two equivalent moving dipoles, simultaneously located separately in the occipital regions of the right and the left hemisphere, at a depth of 4-6 cm beneath the scalp, with a goodness-of-fit of up to 97 per cent for all subjects examined. The excellent fit of the two-moving dipole model to the EEG human alpha activity is also compared with the single-dipole fit.

Urinary and salivary stress hormone levels while performing arithmetic calculation in a noisy environment.

The effects of environmental conditions on stress responses to mental work, were examined by measuring urinary catecholamine and cortisol excretion and salivary cortisol concentrations before, during and after an arithmetic calculation task under 90 dB(A) white noise and quiet conditions. Adrenaline excretion increased similarly during the task under both environmental conditions. The salivary cortisol level was significantly higher than the pre-task level during the task with noise, but not under quiet, conditions. The subjects reported that they felt more irritable when performing the task with noise, than under quiet conditions. The results suggest that environmental conditions may affect on the pattern of hormonal response to mental work, which may be related to psychological states of the subjects.

[Assessment of enlarged left atrium with 99mTc-tetrofosmin SPECT and echocardiography].

This study was performed to clarify the possibility of visualization and quantification with 99mTc-tetrofosmin (Tf) myocardial scintigraphy in cases with a large atrium demonstrated by trans-thoracic echocardiography (TTE). Myocardial SPECT was evaluated in 4 patients with mitral stenosis and 15 patients with mitral regurgitation. Left atrium was identified in 12 out of 19 cases from an antero-posterior projection. The Tf uptake ratio of the left atrium, which was defined as the ratio of ROI count of the left atrium divided by the ROI count of the left ventricle, showed a good correlation with the left atrial area obtained by both trans-thoracic and trans-esophageal echocardiography (r = 0.88 and 0.91, respectively), These data suggest that Tf myocardial SPECT is a useful method of evaluating left atrial enlargement.