Synergy between medical informatics and bioinformatics: facilitating genomic medicine for future health care.

In this paper, we review the results of BIOINFOMED, a study funded by the European Commission (EC) with the purpose to analyse the different issues and challenges in the area where Medical Informatics and Bioinformatics meet. Traditionally, Medical Informatics has been focused on the intersection between computer science and clinical medicine, whereas Bioinformatics have been predominantly centered on the intersection between computer science and biological research. Although researchers from both areas have occasionally collaborated, their training, objectives and interests have been quite different. The results of the Human Genome and related projects have attracted the interest of many professionals, and introduced new challenges that will transform biomedical research and health care. A characteristic of the 'post genomic' era will be to correlate essential genotypic information with expressed phenotypic information. In this context, Biomedical Informatics (BMI) has emerged to describe the technology that brings both disciplines (BI and MI) together to support genomic medicine. In recognition of the dynamic nature of BMI, institutions such as the EC have launched several initiatives in support of a research agenda, including the BIOINFOMED study.

Biomagnetic 3-dimensional spatial and temporal characterization of electrical activity of human stomach.

Biomagnetic measurements are based on the noninvasive recording of magnetic signals produced by biological sources such as nervous system and muscle. The aim of this study was to obtain multichannel magnetic field recordings from the human gastrointestinal tract and to localize the sources of these signals three-dimensionally. The magnetic field was recorded in eight human healthy subjects using a sensor array with 37 superconducting quantum interference devices (SQUIDs); an electrogastrogram was recorded simultaneously. Biomagnetic source localization was carried out with an iterative nonlinear optimization algorithm using the model of an equivalent current dipole (ECD) and correlated to magnetic resonance imaging (MRI) in four volunteers. Magnetogastrograms and electrogastrograms demonstrated a similar frequency distribution with a peak at 3/min. In all subjects the centers of the calculated dipoles plotted vs time showed a characteristic migration across the stomach area. One volunteer demonstrated tachygastric episodes, during which his magnetic field amplitudes increased fivefold and his dipole migration disappeared. In absence of an attack his recordings changed to normal. This demonstrates multichannel magnetic recordings can be used to localize the sources of the biomagnetic field, which could be useful for the understanding of motility disturbances.

Suppression of background brain activity influence in localizing epileptic spike sources from biomagnetic measurements.

The origin of inter-ictal epileptic activity can be localized from the magnetoencephalogram (MEG) using the Equivalent Current Dipole (ECD) as a source model. One problem with such localizations is that in many patients, the localization of an epileptic spike source becomes inaccurate because the epileptic spikes are superimposed by pathologic brain rhythmic activities. This paper proposes to use the spatial coherence of the measured magnetic field caused by the measured magnetic field to suppress its influence in the ECD localization. In the method proposed here, the covariance matrix, which expresses the spatial coherence of the rhythmic magnetic field, is first calculated using a data portion where no spikes exist and rhythmic slow waves are evident. Then, ECD localization is performed by minimizing the least-squares cost function modified by the covariance matrix. Experiments using a computer generated ECD field and rhythmic slow waves measured from a patient suffering from complex partial epilepsy prove the basic effectiveness of the method proposed. Localizations of actual spike sources in the same clinical data are performed, and results indicating the effectiveness of the proposed method are obtained.

MFT in complex partial epilepsy: spatio-temporal estimates of interictal activity.

Magnetic field tomography (MFT) displays three dimensional estimates of the distribution of the primary current density vector, Jp, as extracted from non-invasive, non-contact, magnetoencephalographic (MEG) measurements. MFT was used to study the spatiotemporal evolution of the interictal activity during single spike events of a patient with complex partial epilepsy. The sequences of events of the interictal spikes were analysed in sagittal sections, particularly at the depth of the temporal lobe. It appeared that the left-sided interictal spikes were usually initiated at the cortical level of the left temporal lobe, the activity then propagating to the left amygdaloid and hippocampal formation. However, some focal deep activity in this region was obviously initiated in the contralateral hemisphere.

Localization of evoked neuromagnetic 600 Hz activity in the cerebral somatosensory system.

Upon electrical median nerve stimulation wide-band scalp SEP recordings show a burst of high-frequency low-amplitude wavelets of uncertain origin. Digital high-pass filtering (above 400 Hz) of the primary cortical response ("N20") can separate the burst from the underlying "N20 proper" which itself is known to be generated by excitatory postsynaptic potentials (EPSPs) in area 3b. Here, neuromagnetic multichannel recordings show a close correlation between the spatial field distributions of the magnetic burst and of the magnetic "N20m" proper. It is concluded that somatosensory evoked magnetic high-frequency (600 Hz) wavelets have generators at or near the primary somatosensory cortex. Possible modes of generation comprise repetitive discharges conducted in the terminal segments of thalamocortical axons and postsynaptic contributions from neocortical neurons.

The influence of inhomogeneous volume conductor models on the ECG and the MCG.

The authors investigated the influence of human body inhomogeneities such as the lungs, blood masses and the skeletal muscle layer on the electrical body surface potential and the magnetic field. The surface potentials and magnetic fields are calculated using a boundary element method. As a rule the blood masses have a large influence on both potential and magnetic field amplitude as well as on the potential and magnetic field map orientation, but the influence on the topology of the map is less in the electric case than in the magnetic case. The single-dipole reconstruction was applied to estimate the error caused by neglecting inner inhomogeneities in source localization. The neglect of lungs and blood masses results in a localization error of less than 1 cm in the electric case but more than 1 cm for deep sources at the posterior side of the heart in the magnetic case. The authors tried to assess the influence of the skeletal muscle layer by both an analytical two-layered anisotropic half-space model and the torso extension method. The skeletal muscle layer causes a smoothing effect on the electrical surface potential and to a lesser extent on the magnetic field, leading to an overestimation of the actual source depth of about 1-2 cm. In principle this can be reduced by taking data from all over the thoracic surface. The authors designed experiments for simultaneous measurement of body surface potential and extracorporeal magnetic field from the same subject. The evaluation of data from two patients showing Wolff-Parkinson-White syndrome has shown that localization results from electric potential data and magnetocardiographic data are consistent.

Event-synchronous cancellation of the heart interference in biomedical signals.

A two-pass adaptive filtering algorithm is proposed for cancellation of recurrent interferences such as the heart interference in biomedical signals. In the first pass, an average waveform in one period of the interference is estimated by event-synchronous (QRS-synchronous) averaging of the corrupted signal. In a second pass, an adaptive Schur recursive least squares (RLS) lattice filter is used to cancel the interference by using the event synchronously repeated estimated average waveform of the interference as an artificial reference signal. One key feature of this approach is that the ECG is only used for QRS synchronization and not directly as a reference signal for adaptive filtering. Thus the proposed algorithm can be applied to interference problems where ECG and true interference are almost synchronous but show considerably different waveforms. This is usually the case with the heart interference in biomedical signals. Both off-line and real-time implementations of the event synchronous interference canceller are described. The method is applied to the cancellation of the heart interference in magnetoencephalogram (MEG) signals and to the effective isolation of ventricular extrasystoles (VES) in magnetocardiogram (MCG) signals. Experimental results are shown. The new method typically attenuates the amplitudes of R-wave and T-wave interference components by an amplitude factor of 30 without influencing the MEG events of interest.

Magnetic source localization and morphological changes in temporal lobe epilepsy: comparison of MEG/EEG, ECoG and volumetric MRI in presurgical evaluation of operated patients.

Is MEG source analysis able to precisely locate the primary focal epileptic activity? 22 patients with pharmacoresistant temporal lobe epilepsy were recorded during presurgical evaluation simultaneously with multichannel MEG/EEG and invasive (subdural) electrodes to evaluate the increase of information gained by MEG concerning the localization of focal epileptic activity and lesions. With this systematic study it should become clearer how often MEG can establish a diagnostic bridge between function and morphology. In addition, MEG localization accuracy of focal epileptic activity was to be validated empirically by invasive EEG recordings and postsurgical outcome. Spikes in the MEG were used for magnetic source localization, and the result was combined with magnetic resonance imaging (MRI). All patients definitely suffered from temporal lobe epilepsy and revealed a structural abnormality in MRI. 17 patients with lesions in the temporal lobe were operated meanwhile and became markedly improved or seizure free. In 7 of 8 patients with a tumor and validated operation outcome, a very close correlation of the 3D-magnetic source localization and the border of the tumor in the brain was found (distance less than 10 mm). In 8 of 9 patients with a temporal/hippocampal atrophy and validated operation outcome, dipoles of epileptiform activity were located within the atrophic lobe.(ABSTRACT TRUNCATED AT 250 WORDS)

Multichannel magneto-electroencephalography recordings of interictal and ictal activity.

A lobar or even a intralobar congruence was found when comparing the findings of magnetic source localization with presurgical evaluation (EEG, MRI and intraoperative ECoG) in temporal lobe epilepsy. The first dipolar activity that can be recognized during a spike-wave event (primary focal epileptic activity (PFA)) was localized in temporal neocortical or mesial regions. Further centres of epileptic activity could be localized by the method of spike averaging by correlation. This was interpreted as propagation of the electric activity. The comparison of interictal and ictal MEG localization results showed congruency in a patient with temporal lobe epilepsy. The combination of MEG and MRI helps to build a bridge between morphological and functional localization. MEG can serve as a pointer to discrete lesions in MRI.

Experience with a multichannel system for biomagnetic study.

The components of the biomagnetic multichannel system Krenikon are described. The combination of biomagnetically yielded localizations with anatomic images gained from MR or CT is discussed as well as the enhancement of the signal-to-noise ratio by using a correlation technique. The overall localization accuracy is tested with technical phantoms. With volunteers measurements of auditory, visual and somatosensory evoked fields are performed to evaluate the system performance in vivo. Clinical studies were performed mainly with partners from the Universities of Erlangen-Nünberg and Ulm. The data acquisition time typically is 2-10 min which is tolerable both for the patient and the clinical staff. Electric potentials even with invasive electrodes can be recorded simultaneously with the magnetic fields. MEG gives important information for the presurgical diagnosis of epileptic patients and for the understanding of the epilepsy genesis. With MCG, centres of biologic excitation such as ventricular ectopies or accessory bundles in WPW syndrome have been successfully localized.

Magnetocardiography: three-dimensional localization of the origin of ventricular late fields in the signal averaged magnetocardiogram in patients with ventricular late potentials.

The purpose of this study was to detect ventricular late fields recorded by a biomagnetic multichannel system in patients with ventricular late potential and to determine the site of these ventricular late fields non-invasively in three dimensions. Biomagnetic signals of sinus beats during a 5-min acquisition period simultaneously recorded by a 37-channel system Krenikon were averaged in all channels. Ventricular late fields were determined in each channel according to the algorithm of Simson for ECG data. For the localization process, baseline correction from the averaged non-filtered signals was performed at the end of the QRS complex under visual control. The single current dipole model within the homogeneous half-space was applied. Eight patients post myocardial infarction with ventricular late potentials (four with recurrent sustained ventricular tachycardia) and four healthy individuals were examined. In the normal subjects, no ventricular late fields were detected. However, ventricular late fields were found in all patients, and were localized in six patients within the border zone of myocardial infarction. In the four patients with ventricular tachycardia, a spatial coincidence of the site of origin of ventricular late fields and the site of origin of ventricular tachycardia determined by catheter mapping was found in two. It is concluded that magnetocardiography is able to detect ventricular late fields and can be used to determine their site of origin.

Point and distributed current density analysis of interictal epileptic activity recorded by magnetoencephalography.

Equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions have been applied to interictal multichannel magnetoencephalographic recordings of a patient with complex partial epilepsy (CPE). Averaged signals were used. At certain instances ECD solutions could be found with a very high cross-correlation coefficient between the measurements and the field, produced by the current dipole solution, typically in excess of 0.97. At these instances a highly localized distribution, very close to the ECD location, was obtained from the distributed source analysis. The ECD solution started to move when the distributed source solution began to develop activity at more than one centre. This clearly contrasted with the way the activity of the distributed source solutions changed, which turned out to be highly stable. Stringent selection criteria for using the different solutions therefore seem mandatory, especially in identifying pathological areas and volumes of the human brain.

MEG localization of interictal epileptic focal activity and concomitant stereotactic radiosurgery. A non-invasive approach for patients with focal epilepsy.

Two patients with complex partial epilepsy and tumour of the temporal lobe scheduled for gamma knife radiosurgery were evaluated pre- and postoperatively by multichannel magnetoencephalography (MEG). Centers of epileptic dipole activity found preoperatively disappeared after the focal irradiation as did the epileptic seizures. Thus, to combine stereotactic MEG and gamma knife radiosurgery seems to be a non-invasive alternative to the conventional neurosurgery in focal epilepsy.

Spatial differences of the duration of ventricular late fields in the signal-averaged magnetocardiogram in patients with ventricular late potentials.

Magnetocardiography (MCG) allows one to noninvasively localize cardiac electrical activity in three dimensions. It was the purpose of this study to obtain information about the spatial variations of signal-averaged ventricular late magnetic fields recorded by a biomagnetic multichannel system. Biomagnetic signals of 170-600 heart cycles obtained by the 37-channel system KRENIKON (Siemens Medical Engineering Group) were simultaneously averaged in all channels. The absolute values of the filtered signals (digital, bidirectional, four-pole butterworth, bandpass filter [3-dB range, 40-250 Hz]) were calculated in each channel. The noise level was determined within the TP segment. The onset of the terminal low amplitude signals (TLAS) was defined when the signals became lower than 1/23 of Rmax of the QRS complex for the channel with the largest filtered QRS complex after filtering. The TLAS ended when the signal was lower than twice the standard deviation (2 sigma) above the mean noise level. Ventricular late fields were defined as present when the TLAS had a duration of more than 39 msec. In this study, five patients with ventricular late potentials (four with sustained ventricular tachycardia) and three healthy individuals were examined. Ventricular late fields were detected in the patient group in 2-15 MCG channels with a mean length of 49.6 msec (43-60 msec). The spatial distribution of the ventricular late fields was consistently found to exhibit maximum duration in a certain area. In the normal subjects no ventricular late fields were detected. Thus, MCG is able to detect ventricular late fields and their spatial variations. In addition to the information obtained by signal averaging from the surface ECG, averaging of biomagnetic signals with a multichannel device can reveal spatial inhomogeneity of delayed myocardial excitation.

Ictal and interictal activity in partial epilepsy recorded with multichannel magnetoelectroencephalography: correlation of electroencephalography/electrocorticography, magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography findings.

Ictal and interictal epileptic activity was recorded for the first time by multichannel magnetoencephalography (MEG) in three patients with partial epilepsy. Pre- and intra-operative localization of the epileptogenic region was compared. The interictal epileptic activity was localized at the same region of the temporal or frontal lobe as the ictal activity. Main zones of ictal activity were shown to evolve from the tissue at the centers of interictal activity. Pre- and intra-operative electrocorticography (ECoG) as well as postoperative outcome confirmed localization in the temporal and frontal lobe. Results also correlated with findings from scalp EEG, interictal and ictal single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI). Combined multichannel MEG/EEG recording permitted dipole localization of interictal and ictal activity.

Magnetocardiographic non-invasive localization of accessory pathways in the Wolff-Parkinson-White syndrome by a multichannel system.

Electrical activity can be localized by magnetocardiography (MCG) non-invasively. In this study a 37-SQUID (Super Conducting Quantum Interference Device) sensor multi-channel system (KRENIKON) was used to assess the potential of magnetocardiography to localize accessory pathways with a multichannel system. Seven WPW patients were studied by means of magnetocardiography. Prior to the MCG recordings, the site of the accessory pathway had been determined in all patients by invasive catheter mapping. MR images of the heart were used for anatomical correlation. The magnetocardiographic localization of the accessory pathway corresponded with catheter mapping within 2.1 cm on average (total range: 0-5 cm). This is thus, a promising new method for non-invasive localization of accessory pathways in WPW patients.

[Site and propagation of focal epileptic activity: multichannel MEG/EEG analysis]. / Lokalisation und Propagation fokaler epileptischer Aktivität: Multikanal MEG/EEG Analysen.

Electrophysiological examinations provide the basis for a deeper pathophysiological understanding of focal epileptic activity. In addition to electroencephalography, magnetoencephalography from field measurements is now available for biomagnetic diagnosis. As magnetoencephalography (MEG) is basically better suited for the localization of focal epileptic activity than EEG, an increase in MEG measurements has taken place over the last years. In this study we discuss magnetic source localization which was combined with anatomical 3-D-MR-images and compared with the results of EEG-registration carried out simultaneously and with other investigative procedures of presurgical diagnosis. The results of investigation show that simultaneous magnetic field measurements over one hemisphere of the skull allow localization of sources both in the temporal lobe and in deeper areas of the brain. Furthermore, propagation of epileptic activity can be registered not only in neighbouring areas of the epileptogenic source but also in regions localized deeper in the temporal lobe. This opens new possibilities for presurgical evaluation as well as an understanding of partial and generalized epilepsies. The results of investigation show primary focal epileptic activity neocortex laterally or surrounding a mesio-temporal lesion in all investigated patients with partial (temporal, frontal) and secondary generalized epilepsies. Furthermore, a pattern of propagation of focal epileptic activity which is directed from neocortical-lateral to mediobasal-limbic brain structures is found in most of these patients.

Biomagnetic noninvasive localization of accessory pathways in Wolff-Parkinson-White syndrome.

It was our purpose to assess the clinical relevance of noninvasive magnetocardiographic localization of accessory pathways. Nine patients with Wolff-Parkinson-White (WPW) syndrome were studied. For all of them the site of the accessory pathway was known from invasive catheter mapping. A 37-SQUID (superconducting quantum interference device) sensor multichannel system (KRENIKON) was used, allowing synchronous registration with all channels. The site of the electrophysiological activity at the beginning of the delta wave was determined. Magnetic resonance images of the heart were obtained to correlate the biomagnetically localized activity with the anatomy. Magnetocardiographic localization of the bypass tract corresponded with catheter mapping with a spatial difference of 0-5 cm, 1.8 cm on the average, compared to the results obtained by catheter mapping. Thus, magnetocardiography is a promising new method for noninvasive localization of accessory pathways in WPW patients. This may streamline further invasive procedures.

[Magnetocardiography. Biomagnetic localization of impulse development and transmission of the heart]. / Magnetokardiographie. Biomagnetische Lokalisation von Reizbildung und Erregungsleitung am Herzen.

Magnetocardiography is a non-invasive biomagnetic technique for measuring magnetic fields produced at the surface of the body when the heart is stimulated to beat. The measurement is contact-free and is independent of tissue resistance. For the first time, magnetocardiography employing multi-channel systems permits the accurate, non-invasive localization of accessory conduction pathways and ectopic ventricular activity.

The neocortico to mesio-basal limbic propagation of focal epileptic activity during the spike-wave complex.

In order to localize epileptogenic electrophysiological sources, a multichannel MEG system was used in 3 patients with partial epilepsy during presurgical evaluation. MEG and EEG (including scalp, sphenoidal and intracranial foramen ovale electrodes) were recorded simultaneously during a period of intensive video-EEG monitoring in order to observe single spontaneous spikes. In addition to MRI, SPECT and PET investigations were performed. Electrical activity subsequent to the activity of the epileptic focus could be localized by the MEG after noise reduction using a temporal correlation technique. Simultaneous registration of the magnetic field and the electrical field showed that the source of the primary focal epileptic activity (first period during the total spike wave complex where a dipolar magnetic field pattern is found) is localized in neocortical lateral regions, whereas another focal epileptic activity in a later phase of propagation occurs in temporal mesial regions. In 1 patient (case 1) the primary focal epileptic activity was localized in the surrounding neocortical tissue of an angioma and the middle and inferior temporal gyrus. The second phase of propagation is localized in temporo-basal-mesial regions, including para- and hippocampal structures. The latest center of activity occurred in posterior parts of the gyrus cinguli. In 2 other patients, the primary focal epileptogenic activity was localized at the insula and also spread into temporal basal mesial regions. A multi-modal approach to research of focal epilepsy, combining metabolic, electrical potential, magnetoencephalographic and morphological data, recorded by non-invasive techniques, offers new perspectives for the detection of involved brain regions. The 3-D and time-resolved localization of focal epileptic activity, correlated with the individual anatomy of the human brain, may improve the determination of neuronal populations involved in the individual epileptogenic process, especially in the interaction between temporal or extratemporal neocortex and limbic system.