Pharmacoelectroencephalography Main Editor: W.M. Herrmann (Berlin)

Abstracts Neuropsychobiology 1992:25:61 -82

7th IPEG Symposium, Boca Raton

Oral Presentations Saturday, May 23,1992

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Source Localization of Multichannel EEG Frequency Bands and Pharmaco-EEG Studies D. Lehmann Department of Neurology. University Hospital. Zurich. Switzerland A novel method, the FFT Dipole approximation, permits the analysis of multichannel EEG data so that the intracerebral localiza­ tion of the hypothetical electric sources of the different EEG frequen­ cies can be estimated. The method uses the Fourier-transformed multichannel data to construct a best fit single dipole generator source in terms of phase angles for each frequency point. Thereafter, each field distribution obtained is subjected to a conventional dipole source best fit in terms of amplitudes, as known from evoked poten­ tial studies. The source locations for different frequency bands differ during resting (alpha posterior, delta deeper and anterior: EEG Journal 1992:82:38-44). The source locations of given frequency bands proved sensitive to brain condition changes such as eye opening/ closure, sleep stages, mentation styles, and centrally active com­ pounds (placebo, Pyritinol, diazepam). The technique commends itself to reduce EEG data of unlimited duration and from an unlim­ ited number of channels to three location values for each frequency (band), using a sensitive frequency domain approach. Statistical test­ ing thus becomes straightforward.

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Sleep Recordings from Surface and Depth Electrode Recordings A. Wauquier, A. Boone, G. Willkiams. Y. Choi, M. Rayport Medical College of Ohio. Toledo. Ohio, USA There arc few' reports on sleep recordings from depth electrodes in the human brain. We have the opportunity to study sleep patterns in epileptic patients implanted with depth electrodes for the purpose

of delineating seizure foci prior to eventual surgery. Simultaneous sleep recordings w'ere made for 8-hour periods during two consecu­ tive nights, starting at least four days after surgery. Not surprisingly, sleep patterns were often characterized by low sleep efficiency, because of long periods of wakefulness. Furthermore, there was sleep fragmentation, but different sleep stages, including slow wave sleep and REM sleep, were present. Besides the sleep stage classification based on scoring discrete intervals, wc sought to develop a methodology to assess sleep dynam­ ics. The analysis of the hippocampal formation during REM sleep was of interest in the light of the importance of theta activity in mem­ ory processing, as documented in animal studies. New signal analysis processing technique are being researched which create digital images from EEG signals. Also, one- and two-dimensional Fast Fou­ rier methods are being applied to the EEG signals and images, to allow Fourier analysis of the signal distribution parameters. The results of our analyses to date will be presented.

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Aspects of the Chaotic Structure of Sleep EEG Data J Roeschke Department of Psychiatry, University of Mainz, FRG The time history of the sleep EEG is not predictable over a longer time period. Even if a typical EEG pattern is detectable, it is impossi­ ble to estimate the future behavior of the sleep EEG. In this sense, the unpredictability of the sleep EEG may be considered a basic feature of its stochastical character. Recently, it has become clear that unpre­ dictability does not contradict the causality principle of natural phi­ losophy. Under selected conditions nonlinear dynamic systems gen­ erate ‘deterministic chaos". In this case, such systems show a sensitive dependence on initial conditions, which means that different states of a system, which are arbitrarily close initially will become rnacroscopically separated after sufficiently long times. Regardless of a description of a system's dynamic in terms of differential equations, the behavior of such chaotic systems is not predictable over longer time periods. In this sense the unpredictability of the sleep EEG might be a basic phenomenon of its chaotic character. One of the commonly used methods to investigate the behavior of dynamic systems is to measure the dimensionality (Di) of their attractors in phase space. Every instantaneous state of a system is represented by a single point in the phase space. The sequence of

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May 23-25, 1992 Boca Raton, Fla.

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Qualitative and Quantitative Analysis of Sleep Using Hjorth's Descriptors

Wavelet and EEG Signal Analysis

II. Depoortere Synthelabo Recherche (L.E.R.S.). Bagncux. France In rats as in humans. Hjorth's descriptors (NSD) - 'activity', ‘mo­ bility’ and ‘complexity' - appear to be good tools to evaluate the micro- and macrostructural elements of sleep. In rats, the analysis of the visual and sensorimotor (SM) record­ ings using NSD is sufficient and efficient in differentiating sleep stages. ‘Activity’ distribution over the total recording permits the detection of a global effect on sleep (e.g.. increase after chlorpromazine injection or reduction after Mg2* deficiency). Moreover. SM ‘ac­ tivity' distribution by considering different classes of amplitude allows the characterization o f ‘unstable amplitude segments' (UAS) and to define their frequency during NREM (index) and their per­ centage of NREM (rate). Index and rate of UAS constitute useful parameters to analyze the destabilizing effect of experimental insom­ nia models on sleep and the protective effect of pharmacological treatment (e.g.. zolpidem). In humans, NSD also define the quality and stability of sleep. The ratio of ‘activity/mobility/complexity’ allows the possibility of estab­ lishing different levels of classes in which wakefulness and REM represent the lowest levels in comparison to sleep. Moreover. NSD permit the extraction of unstable elements (phasic events). EEG analysis using NSD offers the possibility to evaluate not only the quantity, but also the quality and stability, of sleep and is a useful tool for pharmaco-EEG studies.

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Classification of EEG Data by Computer Neural Networks B. Kloeppel Department of Mathematics/Computer Science, University of Kassel, Kassel. FRG The first part will review the use of computer neural networks to classify EEG data. The advantages and drawbacks of neural network methods over other classification schemes will be outlined. Main advantages are tolerance against noisy, distorted, or incomplete data

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and the capability to recognize completely different kinds of data simultaneously (multi-sensoric input). The major drawbacks are intractable or at least very time-consuming training of the net and structural problems (e.g.. selection of a feasible network topology). Due to the different kind of data processing, we also sketch the neces­ sary changes in the general method of working. We also present our experience in classifying different EEG types (data from evoked potential and long term EEG) with neural network. This covers two case studies where networks have been trained to discriminate differ­ ent classes of probands. One special topic will be the incorporation of additional information (such as psychological scoring values) as net­ work input (i.e.. multi-sensory network input).

Abstracts

C. Tismer, M. Jobert Department of Biosignal Processing. AFB. Arzneimittelforschung GmbH, Berlin. FRG The Wavelet Transform is a new approach to data processing and is used in such tasks as signal, speech and image processing. The wavelet transform provides ar. elegant alternative to the classical Fourier and Gabor transforms unifying numerous signal processing techniques into a common framework. We provide an overview of die applicability of the wavelet trans­ form to EEG signal analysis. The most important theoretical aspects will be summarized allowing the mathematical background to be simply understood. Examples of applications taken from the EEG field (i.e., sleep and pharmaco-EEG) will be presented and discussed. The wavelet transform is applicable to pattern recognition, biosignal representation and signal parametrization.

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New Approaches in EEG Signal Analysis: Transputer Techniques to Determine On-Line Virtual Electrical Sources in the Human Brain if .M. Herrmann. G. Reseller, G. Ulrich. E. Niestroj Department of Psychiatry’, Free University Berlin. Berlin. FRG A parallel communicating computer processor system (transputer system) has been utilized to determine on-line virtual electrical sources of the human brain. In a trial with 18 subjects, monaural acoustic stimuli were presented to the right and left ear and com­ pared to resting condition. After power spectral analysis, both amplitude maps and power, and coherence comparisons did not show effects of the monaural acoustic stimuli nor could the right and left ear stimulation be dis­ criminated. However, using the transputer support method of deter­ mination of virtual sources, a clear effect could be seen. This example is used to demonstrate that on-line multichannel analysis of peak detection with communicating computer processor systems is a breakthrough in EEG-signal analysis because it fully con­ siders the dynamics and locations and is free of unproven assump­ tions of the EEG signal like ‘stationarity' or ‘stochasticity’.

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such states over time defines a trajectory, which either penetrates the entire phase space or converges to a lower dimensional subset, called attractor. The dimensionality of the attractor estimates the com­ plexity or the degrees of freedom of the investigated system. We find that the more sleep moves to slow-wave sleep, the lower the dimensionality of the sleep EEG which varies between D; = 4.3 (stage IV) and Dj = 6.2 (stage REM). In normal healthy subjects, lorazepam does not alter the dimensionality of slow-wave sleep but that of sleep stages II and REM (at electrode position C,). In schizo­ phrenia. a slightly higher dimensional attractor during sleep stages III and IV was observed. In psychosis, a decrease of the EEG dimension­ ality during stages II and REM was observed.

Global Dimensional Complexity of EEG in Healthy Volunteers .17. Matousek, .17. Pains, A. Berankova, V. Albrecht. Wackermann. I. Dvorak Department of Clinical Neurophysiology. Gothenburg. Sweden and Psychiatric Research Center. Prague, Czechoslovakia The relevance of the theory of deterministic chaos in PEG analy­ sis was studied by its application to selected parts of EEGs obtained in healthy individuals of various ages. Methods. EEGs from the electrodes F7. F8. T3, T4. P3. P4. 01 and 02 (common reference) were recorded under basal conditions (supine position, eyes closed) in 26 healthy individuals of ages 1-71 years. Segments representing EEG sleep stages 0 and I (full wakeful­ ness resp. superficial drowsiness) were defined by visual inspection of the tracings. The multichannel correlation exponent (Corex soft­ ware) was calculated repeatedly, with EEG segments of 10 resp. 40 s length. Additionally, segments with low-voltage muscle artefacts and with sleep activity (stage 3) were also analyzed. Results. (1) EEG signs of drowsiness (sleep stage 1) are associated with increased global dimensional complexity of the signal. An oppo­ site trend, with decreased complexity, can be seen in deeper sleep. (2) The correlation exponent/dimension is relatively independent on the age in healthy individuals older than 11 years. (3) Muscle artefacts in two or more EEG channels cause a substantial decrease of the com­ plexity. (4) Considering the random variability of the results, the use of EEG segments longer than 10 s seems to be necessary'. Discussion and Conclusion. The measurement of global dimen­ sional complexity is an interesting approach to characterize the EEG signal. The method can be employed to summarize the mathematical features of the whole EEG. considering the signal simultaneously derived from several electrode positions on the scalp. As shown in the study, it is possible to detect and define the EEG changes which reflect slight shifts of the vigilance level. According to the previous studies, this type of EEG change is associated with symptoms such as anxiety, hypochondriasis, and depression as well as with side effects of psychotropic drugs. Therefore, the method can be of interest in examining psychiatric patients and in psychopharmacology. The results of analysis are not age-dependent in adults but the study is inconclusive as regards children younger than 11 years. Possible dis­ advantage of the method is its high sensitivity to artefacts.

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Analyzing Pharmacodynamic Effects of Psychotropic Drugs via Spectral Dynamics of EEG V. Albrecht. ./. Honig. M. Paltts. A. Berankova. I. David. I. Dvorak Prague Psychiatric Center, Prague. Czechoslovakia The SPEctral DYnamicS (SPEDYS) measure is introduced to partially bridge the lack of convenient bioavailabilitv measure in the analysis of psychopharmacologic pathways. SPEDYS analyses relate EEG changes to blood concentration (BC). or to changes of psychophysiological variables (PPV) after single dose drug administration. SPEDYS uses pre- and post-drug EEG records that are measured

simultaneously with BC and PPV and converted into spectra. The spectral evolution induced by the drug is parameterized by comput­ ing a distance between pre- and post-drug spectra. Reducing relation between two spectra to one number, the spectral distance, is desirable for the statistical analysis. SPEDYS uses several distances, e.g. the L.p formula giving the distance in V2 or the dimensionless distance (re­ sulting from the Renvi’s entropy), suitable to follow effects in statisti­ cal samples by eliminating interindividual variability due to differ­ ent pre-drug spectra. Using EEG data, the drug is characterized by its spectral kinetic profile (SK.P) providing a time course of spectral dis­ tances. The basic SKP is the time of the maximum SKP. The spectral dynamic profile (SDP) of the drug may be cither the plot of spectral distances against BC or the plot of PPV against spectral distances. Since the SDP conforms typically into loops, a special approach avoiding the traditional correlation analysis to assess dependence between spectral distances and other measured variables is used. Comparison of SPEDYS results with classical frequency band analy­ sis performed in an ethanol-EEG study (14 probands, 8 recordings within 6-hour interval after oral 75 mg/kg administration, with CFF and tremorometry measured) will be described.

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EEG Response to Neuroactive Drugs in Coma as an Early Prognostic Parameter in Severe Cerebral Lesions S.A. Rath Department of Neurosurgery. University of Ulm. Giinzburg. FRG Nowadays, somatosensory evoked potentials (SEP), combined with auditory evoked potentials (AEP) are considered the most reli­ able parameter for the early prognostic evaluation of deeply coma­ tose patients with severe cerebral lesions, and to be more predictive than spontaneous F.EG registration. The response to neuroactive drugs, how'ever. is seldom taken into consideration. In 30 comatose patients with severe head injuries or spontaneous intracranial hem­ orrhages and with raised intracranial pressure, changes in EEG after single intravenous benzodiazepine bolus (midazolam. 7.5 mg) and consecutive antagonist administration (flumazenil. 0.3-0.5 mg) were recorded. If the electroencephalic response was similar to that known from healthy subjects (beta increase, alph and theta decrease), the long­ term outcome after 1-3 years was favorable except in 1 patient who remained severely disabled. All patients who presented with abnor­ mal EEG reactions following midazolam and/or flumazenil died or remained in vegetative state. This was also true in all cases without an increase of fast frequencies after a thiopentone bolus (0.2-0.3 g). The response to ncuroactive drugs was highly predictive in the 6 cases with simultaneous ambiguous SEP findings (bilaterally reduced cortical N 20). Pharmaco-EEG is a test for the integrity of essential brain func­ tions.

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A Neurophysiological and SPECT Study on Tonic Pain

was greater during the procaine infusion, nonetheless these results suggest that lack of responsivity may be a hallmark of extreme chronicity and treatment resistance in chronic schizophrenia.

V. Di Piero, S. Fermenti. U. Sabatini, S. Romeo. P. Pantano.

G. Cruccu, G.L. Lenzi Departments of Neurological Sciences and Psychiatry. University of Rome ‘La Sapienza'. Rome, Italy We studied the involvement of specific brain areas in the percep­ tion of tonic pain by cold water pressure test (CWPT) and its modifi­ cations after diazepam administration in humans by using CEEG and SPECT. Seven right-handed male volunteers underwent two SPECT scans, by Xe-133 inhalation and Tomomatic 564, in a single experi­ mental session. The first scan was performed at rest and the second during immersion of the left hand in cold water (0°C I ). Three sub­ jects were studied again, during CPWT. after IV administration of 10 mg of diazepam. The same protocol was used for CEEG. Subjects experienced a painful sensation during activation, both without and with diazepam administration. We found a CBF increase, after tonic pain activation, in the right sensory-motor (p < 0.05) and frontal areas (p < 0.05) and in the left temporal area (p < 0.02). A similar trend was observed in the right temporal region. After diazepam, there was no more evidence of increased CBF in the right sensorv-motor region. CEEG showed a widespread delta increase, more evident in the frontal areas bilater­ ally. lasting the whole period of stimulation, which was not more evident after diazepam. SPECT and CEEG investigations demonstrate a cortical pattern of activation during tonic painful stimuli which may be modified by diazepam.

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EEG Dimensionality in Untreated Acute Schizophrenics, in Remission, after a Schizophrenic Episode, in Neurotics, and in Controls A/. Koukkon. D. Lehmann..!. Wackermann, I. Dvorak, B. Henggeler University Hospital of Psychiatry. Bern. Switzerland, and Prague Psychiatric Center, Prague, Czechoslovakia The local correlation dimension (dimensional complexity) of the EEG from two brain areas was studied in 15 first-episode acute schizophrenics before medication, 12 other medication-free cases with complete remission after a first schizophrenic episode. 17 neu­ rotics. and 17 controls. The dimensional complexity of the left tem­ poral-parietal and parietal-occipital EEG local gradient recordings was estimated in six conditions using 2()-sec epochs. The temporalparietal EEG complexity differed significantly between the groups (ANOVA p = 0.001): it was higher in acute schizophrenics than nor­ mals (p = 0.004). consistently across all conditions: remitted schizo­ phrenics and neurotics had intermediate values. No differences were seen between groups in the parietal-occipital EEG. Differences between the dimensional complexity of the temporal parietal vs. parietal-occipital EEG were significant between groups, with acutes differing from controls. Thus, the measure of dimensional com­ plexity (the non-integer, fractal correlation dimension) of the EEG in acute never-treated schizophrenics was higher than normal values in one. not in other brain areas. The increased complexity might reflect the loosened organization of schizophrenic thought.

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Department of Psychiatry . Hamilton Psychiatric Hospital. Hamilton. Ont.. Canada Intravenous procaine hydrochloride has been reported to be a selective limbic system activator. Some chronic treatment-resistant schizophrenic patients show moderate improvement when given carbamazcpinc. It was hypothesized that carbamazepine responding schizophrenic patients would show evidence of limbic hvper-excitability reflected in increased high-frequency (3l-50H z) relative power following procaine in comparison to saline conditions. Nor­ mal controls (n = 16) and chronic schizophrenic patients clinically classified as showing some response to carbamazepine (n = 10) and those not responding to carbamazepine (n =12) received procaine to activate the EEG. The patients were examined prior to the trial of carbamazepine therapy. Contrary to the original hypothesis, relative power in the highfrequency band (31-50 Hz) was most pronounced for the control subjects. Carbamazepine responsive schizophrenic patients showed moderate activation while the nonresponsive group showed negligi­ ble high frequency reactivity. Though muscle artifact contamination

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Abstracts

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Electrophysiological Subtyping in Psychiatry E.R. John. L.S. Prichep Department of Psychiatry'. NYU Medical Center, New York. N.Y.. USA We published a series of reports demonstrating that neurometric QEEG and EP variables can be used to construct multiple discrimi­ nant functions which separate patients in various DSM-IIIR catego­ ries from normals, with independently replicated high accuracy. Such evidence does not validate that the 'true structure’ of psychiat­ ric pathophysiology corresponds to the systematic DSM-IIIR frame­ work of nomenclature for psychopathology. The ability to achieve successful separations of this sort simply establishes the existence of reliable electrophysiological correlates of different profiles of clinical symptomatology. To gain other insights into the structure of the pathophysiological profiles of psychiatric patients, we elected to perform uninformed cluster analysis on large samples of psychiatric patients with various DSM-IIIR diagnoses. Clustering was carried out based on a set of 26 variables constructed by selecting 3-4 variables having the most util­

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Procaine Activation in Tegretol Responding and Nonresponding Schizophrenics £>../. Maccrimmon. G.J. Durocher, B.M. Saxena

ity indiscriminaiingcach of eight DSM-IHR categories from normal. First, large samples of patients within each category were separately subjected to clustering. Several distinct subtypes were found within each DSM-II1R category. Afterwards, cluster analysis with the same set of variables was performed on the combined total sample of patients. Many clusters were found which contained patients with different DSM-IIIR diagnoses who appeared to have closely similar pathophysiological profiles. Biological classification may help under­ stand treatment response.

centrations and brain effects. Modeled pharmacokinetic-pharmaco­ dynamic (PK-PD) examinations showed that the drug plasma con­ centration paralleled the change of EEG photic driving power with a specific lag time. A single dose of clozapine increased alpha EEG power follow ing photic driving which bore a nonlinear relationship to plasma clozapine concentrations. We suggested that the EEG did not linearly reflect clozapine blood levels due to differences in physiological processes such as drug perfusion. dilTusion. partitioning, and receptor events. The clinical implications of this new PK-PD pharmaco-EEG will be discussed.

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M.J. Barbanoj, P Anderer, R.M. Anlonijoan, ./. Torrent, 11. Salem, F. Jane. P Teixido Clinical Pharmacology Unit (HSCSP). Department of Pharmacology and Psychiatry (UAB), Barcelona. Spain In a phase 1. double-blind, randomized crossover, placebo-con­ trolled study. 16 young, healthy subjects of both sexes received single oral therapeutically-equivalent’ doses of cetirizine (CTZ. 10 mg), terfenadine (TFD. 120 mg) and loratadinc (LOR, 10 mg) with hydroxizine (HXZ. 25 mg) as positive standard. Measures included peripheral H-l antihistamine activity (intracutaneous histamine ■prick’ test) and CNS effects evaluated by psychometric tests (critical flicker-fusion frequency; simple reaction time: ‘d2’ cancelation task; fine motoric task), self-rating mood scales (symmetrical VAS: unsymmctrical numerical) and pharmaco-EEG brain mapping (PhEEG-bm. 16-channcl EEG. vertical and horizontal EOG channels, with eyes closed) performed before, and after 1,2.4. 6, and 8 h. Peripheral activity showed HXZ and CTZ to have the greatest antihistamine effect. Psychometric tests and self-rating scales did not reveal any significant changes in performance or mood after CTZ. TFD. and LOR in comparison to placebo, while HXZ induced objec­ tive impairment and subjective sedation. Ph-EEG-bm showed not only the greatest reduction in vigilance after HXZ but the possibility to differentiate some of the other drugs from placebo. Therefore, although skills required in every-day activities were not affected by ‘non-sedating’ antihistamines. Ph-EEG-bm could distinguish be­ tween their different capacities to interact with the CNS. pointing out its relevance in accurately assessing central effects.

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Clozapine Concentrations and Changes in Alpha EEG Power Yi Jin. S.G. Potkin Department of Psychiatry and Human Behavior. University of California Medical Center, Orange, Calif., USA Spectra of 24-hour photic driving EEGs following a single dose of 50 mg clozapine (p.o.) in 8 drug-free schizophrenic patients were studied to establish the relationship between plasma clozapine con­

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Influence of Oxazepam and a Kava-Preparation (Piper Methysticum) on Event-Related Potentials in a Parallel Visual Search Paradigm Ileinze, T.F. X!utile . M. Xfatzke. J Steitz Department of Neurology, Medizinische Hochschule Hannover. Hannover. FRG Endogenous components of the event-related potentials (ERPs) exhibit reliable relations to psychological processes and can, there­ fore, be used to characterize psychotropic drugs. Specifically, if one presents complex visual multi-element stimuli requiring the detec­ tion of targets in arrays, anterior and posterior N2 components and a posterior P3 component can be registered, the former tw'o compo­ nents being tied to automatic registration of the features of the stimu­ li, while the latter is associated with final stimulus evaluation. We employed a visual search paradigm in a double-blind study of 75 mg oxazepam (OX). Kava (KA. 300-mg single dose) and placebo of 12 young, healthy males. We observed increased reaction time and decreased detection accuracy (OX): decreased amplitude of anterior N2 component (OX); decreased amplitude of posterior P3 compo­ nent (OX): increased posterior N l component (KA): increased poste­ rior contralateral N2 (KA); and increased posterior P3 amplitude (K.A). This pattern suggests a negative influence of OX on automatic feature registration and stimulus processing resources, while Kava exerts a positive influence on attentional engagement, feature regis­ tration. and stimulus processing.

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Brain Protection of BMS-181168 against Hypoxia: Double-Blind, Placebo-Controlled EEG Mapping Studies in Man II. Salem. //. Sclmlz, IIP. Hrend, W.M. Herrmann, P Anderer. R.C. Shrotriya Department of Psychiatry. School of Medicine, University of Vienna. Vienna. Austria In a double-blind, placebo-controlled trial, antihypoxidotic prop­ erties of BMS-18 1168 (previously BMY 2 1502)- a l-[[l-[2-(trifiuoromethyl)-4-pyrimidinyl)-4-piperidinyl]methyl]-2-pyrrolidinone alle­ viating impairment of learning and memory in the animal - were studied utilizing blood gas analysis and EEG mapping under an experimental hypoxic hypoxidosis. The latter w'as induced by a fixed

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Assessing Acute Adverse Vigilance-Related CNS Effects of 'Non-Sedative' Antihistamines: Relevance of the 'Integrated Approach' in Phase I Studies

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Acute Effects of Beta-Adrenergic Blocking Agents: Quantified EEG (QEEG) and Regional Cerebral Blood Flow (rCBF) G. Rosadini. G. Rodriguez. F. Nobili. F. DeCarli, S. Marenco. L. Malfatto, M. Gambaro, R Testa Center for Cerebral Neurophysiology (CNR) and Department of Internal Medicine-Gastroenterology, University of Genoa. Genoa, Italy Twenty cirrhotic and 4 hypertensive patients (age 23-68 years) were randomly assigned to receive oral placebo. 100 mg atenolol, or 40 mg propranolol in a single-blind study. EEG (14 epicranic elec­ trodes) underwent power spectra analysis; four classical bands were considered either as absolute or relative power. For rCBF (l33Xenon inhalation method: 32 probes) the initial slope index of desaturation curves of tracer was considered. QEEG and rCBF were performed before and 1 h after placebo/ drug administration. In comparison to baseline, no significant QEEG effects were found after cither placebo or propranolol administration, while a slight (t test: p < 0.05) increase of theta band relative power in right occipital and left frontal regions was found after atenolol administra­ tion. rCBF did not change significantly after placebo or propranolol, while atenolol induced a rCBF increase (t-test: p < 0.02) in the right perirolandic region. No significant difference among the three drug groups were observed (ANOVA). Beta-blockers are commonly employed in the therapy of portal and arterial hypertension, both at risk for the development of encephalopathy with different mechanism. Our results, based on combined QEEG and rCBF brain functional exploration, show the lack of adverse effects on cerebral electrical activity and perfusion of tw'o of the most widely employed beta-blockers.

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Abstracts

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Pharmacodynamics of Zopiclone on EEG, ERP Topography and Subjective Mental Rating Scale in Healthy Volunteers II. Yamadera. Y. Tsukahara. M Kato. XI. Kimural. S. Endol. T. Okuma Department of Neuropsychiatry. Nippon Medical School. Tokyo, Japan Zopilone is a non-benzodiazepine drug and categorized as a new generation hypnotic drug. The pharmacodynamics of zopiclone was investigated with EEG and ERP topography, the semantic differ­ ential polarity profile, and response time. Subjects were 10 healthy male volunteers aged 21-23 years. All were right-handed. Double blind crossover trials with placebo con­ trol were conducted in random sequence at interv als of I week. Zopi­ clone (7.5 mg) and placebo were administered as single oral dosages. The test hetterv was carried out before, and I. 3, and 5 h after drug administrations. Peak changes were seen 1 h after drug administration. Zopiclone increased the delta power in frontal leads, alpha in the occipital region, and decreased beta power in centro-frontal region. The aver­ age N 100. N200 and P300 amplitudes showed the greatest decreases. The average P300 latency and response time showed the greatest pro­ longation. The peak effect of suppression on subjective mental rating scale was also seen after I h. These changes were almost gone after 5 h. These ncurophysical and subjective changes w'ere almost parallel with serum concentration of zopiclone.

Poster Presentations Saturday, May 23,1992

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A New Approach for the Parameterisation of PEEG Maps II. Escola. M. Jobert. P. Gaillard Université de Compiègne, Compïègne. France Investigations into the CNS are increasingly performed using color EEG mapping. This technique, however, has important limita­ tions for the analysis of large sets of data. We describe a technique for the parameterisation of pharmaco-EEG maps which permits a reduc­ tion in data and assists the interpretation of pharmacological effects. Moreover, variations in EEG activities can be drawn as a function of time, allowing the description of lime-dependent effects. For the analysis. EEG signals recorded under both RT (reaction time) and RS (resting time) were analyzed in epochs of 10 s. For each epoch, the frequency map was characterized by a set of parameters. Each map was described as a point in a multidimensional space and each scries of maps by clusters in this space. Two types of parameter­ isation are suggested. One is based on the activity recorded from each electrode position: the second was constructed using a grcv-level

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gas combination of 9.8% oxygen (Oi) and 90.2% nitrogen (Ni), equivalent to 6.000 m altitude, which was inhaled for 23 min under normobaric conditions by 16 healthy males in the age range of 23-35 years (mean 27.2 years). After an adaptation session they received, in randomized order, placebo, or 100. 200. or 4 00mg BMS-I81I68. Evaluation of blood gases (POj, PCO;. SO2) and mapping was car­ ried out before and 2. 4. 6 and 8 It after oral dnig administration. Hypoxemia was controlled by drawing artcrialized capillary blood samples from the earlobe after hyperemization of the latter (at 0. 14 and 23 min of the hypoxic gas inhalation) and by oximetry. Blood gas analysis showed a drop in PO; from 98 to 48 mm Hg. in PCO: front 41 to 31 mm Hg. and in SO; from 97 to 80% at 0 and 23 ntin of inhalation, respectively. EEG mapping demonstrated under hvpoxia/placebo conditions an increase of delta/theta. a decrease of alpha, an increase of beta activity as well as a slowing of the centroid of the delta/theta and an increase of the alpha and beta centroid, which suggests a marked deterioration of vigilance. BMS-181168 attenu­ ated significantly in all three doses this hypoxia-induced deteriora­ tion in brain function, as delta/theta decreased, alpha activity increased and the centroid of the combined delta/theta waves w'as accelerated. Time- and dose-efficacy relationships as well as topo­ graphic aspects will be discussed. Our study demonstrates that BMS181168 may be suitable for the treatment of dementia.

matrix. The method has been validated using data obtained from a pharmacological study of diazepam and placebo in 16 subjects. We demonstrate a capacity to display pharmacological effects and spon­ taneous vigilance fluctuations by these methods.

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Analysis of the Scalp Potential Fields and Three-Dimensional Source Localization of Epileptic Activity of the Human Brain Vidor V. Gnezdilsky Burdenko Neurosurgical Institute. Moscow. USSR

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\l. Joberl. P. Juhnig. H. Schulz AFB. Arzneimittclforschung GmbH, Berlin. FRG Pharmacological effects on the central nervous system are de­ scribed using EEG mapping. The statistical evaluation of such inves­ tigations is mostly performed using a T:-statistic. This approach, however, has theoretical limitations in the analysis of pharmacologi­ cal trials using a reduced number of subjects. We present an approach based on a non-paramctric evaluation of the data. The statistical test procedures were validated using data taken from a pharmacological study of 16 subjects. The trial was planned according to a randomized, placebo-controlled, double-blind 2-way cross-over design allowing a comparison between diazepam (X mg) and placebo. EEG signals were sampled from 12 electrode positions during 4 recording sessions (baseline 1.5 h. 3.0 h and 4.0 h post medi­ cation). For the analysis. EEG signals recorded under both RT (reaction time) and RS (resting time) conditions were examined. For each treatment, the frequency activities recorded from each electrode were compared using Wilcoxon signed rank tests. Post-pre differ­ ences were computed and vigilance fluctuations analyzed. We demonstrate the robustness of a non-paramctric approach to the description of pharmacological effects.

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Application of Wavelet Transformation for EEG Signal Analysis M. Joberl. C. Tismer. //. Schulz AFB. Arzneimittclforschung GmbH. Berlin. FRG Spectral analysis of EEG signals involving the Windowed Discrete Fourier Transform (WDFT) has been used for a long time. One dis­ advantage of this approach lies in the choice of a window size to optimize both the frequency and time resolutions. Wavelet transform is a new approach. It is also based on a fre­ quency analysis, but the Fixed scaling of the WDFT is changed into a continuous scaling. Because time and scale are both parameters of the wavelet transform, a two-dimensional representation of the sig­ nal is obtained, where the scaling (or dilation) corresponds to the frequency. We demonstrate the capacity of this method to localize EEG pat­ terns such as sleep spindles or K-complexes both in the time and frequency domains with high resolution. EEG signals recorded dur­ ing PEEG studies are also used to demonstrate relevance of a wavelet oriented analysis. The two-dimensional representation of the signal combined with a color encoding of the amplitude of each point of the transform allows a true description of EEG activity over time.

A method of multistage dipole localization is presented with a preliminary analysis of potential maps ( EEG mapping) to detect zone producing abnormal discharge activity in the brain. Sixty-four pa­ tients with known brain abnormalities and epilepsy were studied. EEG localization results are compared with CT and MRI data. A symmetrical 8-laver model of the head is used. The analysis of the discharge potential fields shows that in 78% of cases they can be approximated by one-dipole model, in 12% with a two-dipole config­ uration. and in 10% the configuration is uncertain. The role of the method of multistage dipole localization for focal and generalized epileptic activity is discussed. We find that the place of recording and the origin of the potentials may not be the same. The lack of coincidence can be connected with the orientation of the discharge source. It is necessary to reconstruct the primary place of generation for correct interpretation of the EEG discharge and slowwave activity. We will demonstrate programs our PC ‘BrainLoc’ - Brain Local­ ization System - for EEG mapping and 3-D EEG source localiza­ tion.

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Simultaneous Registration of EEG Brain Mapping and PET Images M. Boettcher, R.-R. Riedel. C. Pegel, H. Kreiser. W. Herdering. U. Kirchner. U. Strohhusch Institute Experimental Physics. University of Hamburg. FRG It is usual to register EEG brain mapping and PET images sepa­ rately. Our approach makes it possible to record the EEG and PET images simultaneously. The EEGs are recorded with a CATEEMsystem (Pro-Science GmbH: 16+1 channels. ECG. 12bit A/D con­ verter with battery supply. 512 Hz per channel sampling rate). The A/D converter is directly installed at the electronic cap. The digitized EEG signal is transferred to the server by glassfiber optics. For the PET scans, the PENN-PET240H (UGM Medical Sys­ tems) is used and the images are reconstructed into 64 slices with 2 mm spacing. The EEG registration is started 5 min prior to the injection of the Fluor-dcoxy-glucosc and continued during the total examination time together with the PET images which are taken in a multiframe mode with a time-binning of about 3 min. The correlation of the EEG data and the glucose metabolism in the corresponding ROIs of the brain will be presented.

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IMon-Parametric Analysis of Pharmaco-EEG Maps

Differentiation of the Sedative-Hypnotic and Anaesthetic Drug Effects in Rats by Means of Visual and Spectral ECoG Analysis II. Depoortere. M. Decoberi Synthelabo Recherche (L..E.R.S.), Bagncux. France Pharmaco-EEG techniques represent in animals as well as in man an objective approach for the definition of the central action of drugs. In rats, spectral and visual analysis of ECoG recordings can differentiate the various sleep stages and provide a means of studying and comparing the sedative-hypnotic and anaesthetic drug profiles. With general anaesthetics, two types of ECoG waves are ob­ served: ‘monomorphic waves' corresponding to 3 Hz peak energy (midazolam) and spike complexes with isoelectric periods (barbitu­ rates. propofol). In immobilized rats, different types of sleep are induced by various sedative-hypnotics: increase of energy in delta (1 -4 Hz) and 12 - 14 Hz bands (benzodiazepines, zopiclone): increase of energy in delta and 8-12 Hz bands (barbiturates, chlormethiazole. meprobamate); and increase of energy only in delta band (gamma hydroxybutyrate, muscimol). Anti-hypertensive drugs (clonidinelike) differ from sedative-hypnotic drugs by the induction of sleep spindles in the sensorimotor area concomitant to a hypersynchromzed theta rhythm in the visual cortex. Differentiation of the drug effects may also be obtained by the use of specific receptor antago­ nists (e.g. omega (BZD)-. ^-antagonists). On the other hand, pharmaco-EEG techniques can be used to evaluate the sedative potential of drugs, e.g. novel histamine Hi-antagonists. Pharmaco-EEG methods in rats are useful in the differentiation of sedative-hypnotic and anaesthetic drug profiles. These techniques led to the selection of zolpidem, a novel imidazopyridine hypnotic inducing physiological sleep, and helped in the characterization of the non-sedative benzimidazole H|-antagonist, mizolastine.

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Possibility of Using the High-Frequency Electrocorticogram for Preclinical Drug Tests R. Miliauskas. G. Rimsiene Kaunas Medical Academy, Kaunas. Lithuania We have previously shown the advantage of the high-frequency (HF) electrocorticogram (ECoG) of the order of 100 Hz in detecting the general depressant properties of drugs in experimental animals. Other properties of psychotropic drugs reflected in the HF ECoG have now been studied. The main representatives of psychostimu­ lants ((/-amphetamine), antipsychotics (chlorpromazine), anxiolytics (diazepam), cholinomimetics (phvsostigmine). and eholinolytics (atropine) were tested. Other drug classes (antidepressants) and more representatives of the same classes arc under investigation. Experi­ ments were performed on rabbits. The HF ECoG was analyzed by two different methods. A wide range of drug doses was used. Drug effects on the HF ECoG were evaluated on the basis of the criteria of the direction of changes, the degree of changes (according to doseeffect curves), and their time course. The similarities of changes found for drugs of the same class and the differences of changes for different drug classes suggest that putative psychotropic drugs may be classified in preclinical tests using the HF ECoG.

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Effects of Histamine Ht-Antagonists on ECoG Activity in the Rat

Drug-Induced EEG Changes in Primary Brainstem Lesions

M. Decoberi. II. Depoortere Synthelabo Recherche (L.E.R.S.), Bagneux. France

.S’..4. Rath Department of Neurosurgery, University of Ulm. Giinzburg, FRG

Although H, antihistamines are useful in alleviating the symp­ toms of allergic disorders, the major drawback of old-generation anti­ histamines is sedation. In contrast, new generation H|-receptor antagonists are described as free of sedative side effects in humans. We sought to evaluate the central effects of a number of antihista­ mines through the use of spectral and visual ECoG analysis in immo­ bilized rats. Classical antihistamines (dexchlorpheniramine. mepyramine, and cyproheptadine), when administered at a dose of I mg/kg i.p.. induced synchronized ECoG recordings. In contrast, administration of astemizolc. cetirizine. loratadine. mizolastine. and terfenadine at increasing doses (from I to 30 mg/kg i.p. at 30-min intervals) did not produce any sedative effect on the cortical recordings in rats. When given intravenously (3 mg/kg i.v.), however, each drug except mizo­ lastine elicited ECoG sleepiness. Moreover, mizolastine (30 mg/kg

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i.p.) reduced the theta rhythm hypersynchronization induced by local injection of histamine (lOpg) into the ventrolateral posterior hypothalamus without affecting the delta energy in the power spec­ tra. an effect which, in contrast, was increased by mepyramine (10 mg/kg i.p.). These results illustrate the low sedative ability of new-generation Hi-antagonists in rats and reflect their low incidence of sedation at therapeutic doses in humans.

Abstracts

In contrast to supratentorial brain lesions, somatosensory and auditory evoked potentials (SEP/AEP) are less able to reflect the state of cerebral function and to give a good prognostic evaluation in cases of primary brainstem lesions. In 9 deeply comatose patients with such lesions caused by spontaneous hemorrhages, posterior fossa infarctions, or contusions after head injuries, mostly repeated EEG recordings (frequency analysis of electrode locations C3-F3 and C4F4) were performed before and after administration of neuroactive drugs. Whereas the patients with normal response to the administra­ tion of the benzodiazepine midazolam (7.5 mg) and subsequently of its antagonsit flumazenil (0.3-0.5 mg), like in healthy subjects, sur­ vived with more or less physical disability, all those with atypical EEG changes (reduction of fast frequencies, no reversal effect of flu­ mazenil) died within the next days. A Thiopentone bolus of 0.2-0.3 g

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Pharmacological Investigations in the Continuous Word Recognition Paradigm: Influence of Oxazepam and Kava T. /•'. Mimte. H.J. Heime. J. Stein. M. Matzke Department of Neurology. Medizinische Hochschule Hannover. Hannover. FRG If a word list is presented visually with the subjects' task being to distinguish repeated (old) from new words, a reliable difference in the event-related potential (ERP) to the old and new words is observed. Beginning 250 ms poststimulus, the ERP of old words is more positive. This old/new ERP effect is currently interpreted in terms of the modulation of tw'o ERP components: the N400 tied in closely with the evaluation of the semantic aspects of the stimulus, and the P300 associated with later processes. We investigated the ERP effects in the continuous word recognition paradigm (450 words per session. Inter-Stimulus-Interval 2.000 ms. 12 electrode sites) under 75 mg of oxazepam (OX) and 600 mg (daily dose) of Kava (KA) in a placebo-controlled double-blind paradigm in young healthy men. Marked effects of the medication were seen on both recognition performance and ERP. While KA had a bcneficient effect on recognition performance (increase of performance by 4% compared to placebo), OX markedly reduced speed and accuracy of performance. The ERP in the N400 range was reduced in amplitude for both old and new words under OX. while the old/new difference w>as reduced in amplitude. In contrast. KA led to an increase of the old/ new ERP difference. These ERP effects can be used to interpret the amnesic effects of OX, to suggest decreased depth of semantic evaluation and context integration of the stimulus material. The memory enhancing effect of KA suggested by ERP and behavioral data, on the other hand, seems to be located in a later state of stimulus evaluation.

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Mental Loads and Their Reflection in the Power Spectra of Multichannel EEG Recording with CATEEM in Research and Clinical Practice IF. Dimpfel. F. Schober Pro Science Private Research Institute, Linden. FRG Quantitative EEG analysis is a most sensitive method to describe brain activity under varying conditions in neuropharmacological. neuropathological. and psychophysiological research. It is one of a few non-invasive techniques to investigate brain function contin­ uously for longer periods of time. A novel EEG amplifier and D/A conversion unit allows us to record 17 channels of EEG activity with

high immunity to electrical noise. Newly developed efficient meth­ ods of visually controlled, semi-automatic detection and rejection of artifacts were used to select time epochs for spectral analysis. CATEEM provides a linear presentation of frequency analysis on the screen. The color encoding scheme of the spectral distribution in the topographical display allows the detection of subtle changes in frequency content and distribution by presenting maximum contin­ uous information. We monitored the topographical distribution of the frequency content of the human EEG before and after a relaxation period and during mental arithmetic (reaction time measurement, concentra­ tion performance test, intelligence investigation record, recall). Comparison of averaged power density spectra within 6 fre­ quency bands revealed a clear load dependent difference between the period of relaxation and changes in the functional state of the brain with different mental tests. The different states of altered brain activ­ ity were reflected in a particular topographical distribution of the frequency changes with respect to lateralization and frontal-occipital accentuation. Comparison of the different cognitive tests and the relaxation periods show reliable differences in increases in delta and theta activities and decreases in alpha-2 power in frontal cortical regions and increases in occipital regions. We conclude that EEG frequencies van' with mental relaxation in a fashion which is distinct from the functional stale of mental loads and that mental processes can be reliably and quantitatively measured during the action of psychoactive drugs. The combination of pharmaco-EEG with psychometric tests enlarges our knowledge of the correlation between the topographical distribution of EEG-frequencies and different functional states of the brain on the one side and its quantitative and specific modulation by drugs on the other.

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Psychosensorial and Cognitive EEG Mapping (EEGM) in Acute and Remitted Schizophrenic Syndromes Gian F. Marchesi, Berenardo Sanli. Giorgio Pannelli Institute of Psychiatry. University of Ancona. Ancona. Italy We sought to determine if different psvchopathological states and selected psychophysiological functions correspond to different EEG patterns in schizophrenic syndromes. Twenty patients (mean age: 32; range: 19-46 years) with a DSM-lll-R diagnosis of chronic schizo­ phrenia were evaluated. Soon after admission (acute exacerbation) and again before discharge, all patients underwent Andreasen’s SANS and SAPS scales, and an EEG mapping (EEGM) during psychosensorv rest (PSR). and during a cognitive-attentive task (CAT). During PSR. we found tw'o EEGM patterns: ‘normal-like’, only in the moderate paranoid type, having an alpha and beta rhythm, without slow activity; and a ‘slow'’, in catatonic, severe paranoid, and undif­ ferentiated types, having slow activity. In remission, we found an EEGM improvement in both groups (reduction of slow activity, increase of fast activity). Upon discharge, we found slow activity reduction and fast activity increase. EEGM improvement is not directly linked to clinical improvement as evaluated by SANS and SAPS. During CAT. there are some frontal EEGM alterations associ­ ated with disorders of attention and motivation (small increase of fast activity, presence of anterior alpha rhythm, etc.).

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caused an increase of last frequencies, whereas this effect disap­ peared in those patients who did not survive due to deterioration. As the thalamus is important in the generation of barbiturate induced fast activities, this pharmacological test reflects the integrity of tha­ lamic structures.

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P300 in Schizophrenic Outpatients: Effects of Age, Gender, Psychopathology and Neuroleptics G. Juckel, U. Hegerl. A. Muller-Schubert. W. Gaebel. W.M. Herrmann Laboratory of Clinical Psychophysiology. Free University of Berlin. Berlin. FRG A reduced P 3-amplitude of sensory evoked potentials has consis­ tently been found in acute or chronic schizophrenic patients and is discussed as a trait-marker for schizophrenia. However, to use this variable as a trait-marker, the influences of age. gender, psychopa­ thology. or neuroleptic medication should be known. Since interac­ tive effects between these covariables have to be expected, their influence on the P3-amplitude of auditor) event-related potentials was investigated in 88 stabilized and medicated schizophrenic outpa­ tients using multivariate analyses. Within multiple regression analysis, we found no effect of age. but females showed greater P3-amplitudes than males on the P3amplitudc. Residual symptomatology (BPRS-scorcs) was negatively correlated with the P3-amplitude, while neuroleptic dosage (CPZ) had no significant partial-coefficients. However, analysis of perazinc and clozapine plasma levels and longitudinal observations of pa­ tients who stopped medication revealed that the P3-amplitude was reduced by neuroleptics in a direct manner and not indirectly by changing psychopathology. We find that the state-dependent factors ‘psychopathology" and ’neuroleptic medication" have small, but sig­ nificant reducing influence on the P3-amplitude even in stabilized schizophrenic patients, which has to be considered when this vari­ able is used as trait-marker.

In the alcoholics the tangential dipole shows a prominent inten­ sity dependence, while the radial does not. After 1 week withdrawal the ASF-slope of the tangential dipole was twice steeper than before, possibly reflecting the assumed low serotonergic activity in nonintoxicated alcoholics.

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Cognitive Function Test (P300) as a Diagnostic Tool for Psychotic Patients Mohammed Al-Fadel Al-Khani Al-Shareef Poly Clinic, Riyadh. Saudi Arabia This study was carried out to determine the effect of psychotic processes on cognitive function. Eighty-seven patients of both sexes, their age ranges between 18 and 58. diagnosed as having functional psychoses, were studied. Thirty had schizophrenia, 42 had affective psychoses, and 15 had undifferentiated psychoses. They were com­ pared with 40 normal controls. The latency and amplitude of P300 component of ARPs were studied, recorded from Fz. Cz and Pz scalp electrodes, using the Odd-ball target detection paradigm. Results were examined among the patient groups and between each group and normal age-matched controls. P300 latency did not change in any sub-group of patients when it is compared with controls. The amplitude of P300 revealed a signifi­ cant decrease in schizophrenic patients and only a trend to decrease in depressive psychotic patients. We find that P300 amplitude changes are sensitive a test in differ­ entiating schizophrenic patients from other functional psychoses. Some of the interested cases and effect of cultural factors on func­ tional psychoses will also be presented.

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V. Hegerl, G. Juckel, ./. Gallinai. H. Rommelspacher, LG. Schmidt, W.M. Herrmann Laboratory of Clinical Psychophysiology. Free University of Berlin, Berlin. FRG A sleep slope of amplitude/stimulus intensity function (ASFslope) of the auditory evoked NI/P2-component is discussed as an indicator of low central serotonergic ncurotransmission. Persons, who become alcoholics during life, are probably characterized y a pre-existing serotonin deficit. Since ethanol acts like a serotonin ago­ nist, acute intake of ethanol compensates transiently for this deficit. It can be expected, therefore, that intoxicated alcoholics will exhibit a flat ASF-slope. whereas after withdrawal, these patients will show steeper ASF-slopes, because serotonergic activity is then low. Auditory evoked potentials to binaural tones at five intensity lev­ els were recorded in 36 alcoholics before and after withdrawal. The ASF-slopes of the N l/P2-component were determined using dipole source analysis (BESA program by Scherg) in order to separate sub­ components. Starting from our 32 scalp-recorded potentials, source potentials of one tangential and one radial dipole in each hemi­ sphere. located in the primary and secondary' auditory cortex, were calculated in the time range of the N l/P2-component.

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Abstracts

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Effects of Diazepam and the Specific Benzodiazepine Antagonist Flumazenil on Somatosensory Evoked Potentials in Rats A. Todorova Department of Pharmacology and Toxicology. Higher Medical Institute. Sofia. Bulgaria Changes in somatosensory evoked potentials (SEP) of 88 rats were studied following i.v. injection of diazepam (DZP: 0.5. 1 and 5 mg/kg) and flumazenil (FZN: 0.5 and 5 mg/kg). The antagonist effect of FZN towards previously administered DZP was evaluated by SEP, when given in the same dosages. Generally, a peak-latency increase and an amplitude reduction were observed after DZP administration. The low FZN dose led to similar SEP changes. The higher FZN dose resulted in an immediate short-lasting latency decrease of the late cortical potentials and an amplitude reduction delayed in its appearance. According to the obtained data. DZP elic­ ited marked suppressive action mainly on the cortico-cortical pro­ cessing of the sensory' information with milder influence on thalamic level. FZN showed some intrinsic activities with the low dose effects being benzodiazepine-like and ihc higher dose resulting in two over­ lapping opposite actions (initial stimulant and subsequent suppres­ sive). The same FZN doses, applied 30 min after DZP injection.

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Dipole Source Analysis of Auditory Evoked Potentials in Alcoholics

reversed fully or partially (with some dose differences) DZP-induced latency prolongations, whereas FZN could not antagonize signifi­ cantly the DZP effect on the amplitudes. It may be due to the greater DZF influence on the amplitudes.

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Do IMootropics Enhance the Amplitude of Circadian Rhythms in Elderly Subjects? - A Hypothesis

EEG (QPEEG) techniques. Eight healthy young volunteers were administered a single oral dose of risperidone (0.5 mg, 1 mg), halopcridol ( 1 mg), and inert placebo in a randomized cross-over design. EEG was recorded with 8 scalp electrodes according to the Interna­ tional 10/20 system before, and 1.3. 4 and 6 It after drug administra­ tion. Risperidone (0.5 mg) showed a decrease of alpha and an increase of slow and beta activities, so-called "thymoleptic pattern’, while ris­ peridone ( 1 mg) showed a ‘major neuroleptic pattern'.

II. Schulz. M. Joheri AFB. ArzneimittelforschungGmbH Berlin, Berlin, FRG

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Quantitative Pharmaco-EEG of Risperidone N. Sato. T. Kinoshita. Y. Okajima, K. Nobuhara. T. Yagyu. M. Fukushima, T. Kuginuki. M. Saito Department of Neuropsychiatry. Kansai Medical University. Osaka, Japan We sought to evaluate the clinical efficacy of risperidone, a newcompound expected to be effective for both negative and positive symptoms of schizophrenic patients using quantitative pharmaco-

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Quantitative Pharmaco-EEG Study of Y-23684 Y. Okajima. T. Isoiani. K. Nobuhara. T. Yagyu. N. Saito. Y. Ohashi. .17. Fukushima. T. Kuginuki. G.B. Su. T. Kinoshita. M. Saito Department of Neuropsychiatry, Kansai Medical University. Osaka, Japan Y-23684. a benzodiazepino [5.4-c] pyridazine derivative with high affinity for brain benzodiazepine (BZP) receptors, exhibits more potent anti-conflict actions than diazepam in animal experi­ ments in spite of its non-BZP structure. Electrophysiological studies classify Y-23684 as a BZP receptor partial agonist, with side effects (muscle relaxant and narcotic potentiation) less than other BZPs. Y23684 is expected to be an anxio-selective anxiolytic drug. To investigate the clinical effects of Y-23684. we carried out a quantitative pharmaco-EEG study using zero-cross methods. Doses of 0.5. 2. 5 and 20 mg Y-23684 and inert placebo were orally admin­ istered to 6 healthy young volunteers by a single-blind method. EEGs were recorded with 8 scalp electrodes before and 0.5. 3. 6. 24. and 48 h after the drug administration. Y-23684 (2 mg) showed a slight increase of slow activities and a remarkable decrease of alpha activities associated with an increase of fast activities. Y-23684 (5 and 20 mg) exhibited patterns similar to that at 2 mg. but with a greater increase of slow activities than that at lower doses. We suggest that Y-23684 possesses anxiolytic actions in humans.

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Quantitative Pharmaco-EEG Study of Citalopram T. Kuginuku. T. Kinoshita. Y Okajima. A. Saito. T. Isoiani, K. Nobuhara. T. Yagyu. M. Saito Department of Neuropsychiatry. Kansai Medical University. Osaka. Japan Citalopram hydrobromidc (H. Lundbeck, Denmark) is a new antidepressant drug, with serotonin re-uptake inhibiting activity. To determine the clinical effects of citalopram hydrobromide, we car­ ried out quantitative pharmaco-EEG studies using the zero-cross method. Ten healthy male volunteers were given a single 10-. 20- or 30-mg oral dose of citalopram hydrobromidc or placebo in doubleblind cross over design and the scalp EEG was recorded, using the International 10/20 system. Recordings w'erc made before and 1. 3, 4, 6. 24 It after drug administration.

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Old animals and people display reduced amplitudes in circadian rhythms, i.e. rhythmic changes with a period of approximately 24 h. These rhythms may be even more disrupted in patients with Alz­ heimer's disease (AD) [Witting et al„ Biol Psychiatry 1990:27:563— 572], The attention of circadian rhythms in old age may be caused by degenerative changes in the pacemaker systems, for example the suprachiasmatic nucleus (SCN) [Swaab ct al„ Brain Res 1985:342: 37-44] and/or a loss of effectiveness of social zeitgebers. One action of nootropic drugs could be to act on the circadian time-keeping sys­ tem and to enhance the amplitude of circadian rhythms. This assumption is based on the following, preliminary data. The pharmaco-EEG (PEEG) was recorded in 16 elderly subjects (age range: 56-74) before and at the end of 8 weeks treatment with a plant extract of Gingko biloha (50 mg t.i.d.), a putative cognition enhancer. While 8 subjects received active drug treatment, the other 8 subjects wrerc placebo controls. The PEEG was recorded twice on each trial day, once in the evening (between 7:00 and 8:00 p.m.) and once in the early morning (between 4:00 and 5:00 a.m.) after prior sleep deprivation [Schulz et a!., Munch Med Wschr 1991:133(suppl 1):26—29], The reason for this design was to use the PEEG after sleep deprivation and near the circadian trough as a sensitive probe to detect the neurophysiological effects of the treatment. After sleep deprivation, compared to evening baseline, there was an increase in theta power and a decrease of the dominant frequency, both indica­ tions of lowered vigilance. Additionally, under Gingko biloha treat­ ment. delta power increased while power in the alpha and beta bands decreased. Overall the day-night dilTcrences in the PEEG were more pronounced after nootropic drug treatment than under placebo. This suggests that the amplitude of the circadian EEG variation was enhanced by the nootropic drug treatment. Currently, two other PEEG and actometrv studies with normal and demented elderly sub­ jects are being conducted. The results of these studies will be used to test the hypothesis presented here.

While low doses of citalopram hydrobromide showed no changes, high dosage showed an increase in beta activity and a decrease of alpha and slow activities. These EEG changes were not similar to those of other antidepressants, but to those of psychostimulants.

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EEG Mapping and Clinical Results of a Double-Blind Controlled Study of IMicergoline and Placebo in MID and SDAT Patients of Low or Moderate Degree A. Moglia. G. Tedeschi. R. Massettani, R. Rocchi, A. Battaglia. R. Novellini. S. Vahelli. F. Pamparana Universities of Pavia. Naples, Pisa, and Siena and Medical Department. Farmitalia, Milan. Italy To assess the efficacy of niccrgoline (N) 30 mg b.i.d. in the treat­ ment of patients affected by multi-infarct or degenerative senile dementia of mild- to moderate degree, a double-blind placebo (P) controlled study is ongoing in i.3 Italian neurologic centers using a standard pharmaco-EEG protocol. The absolute and relative power of each band of EEG mapping arc analyzed for each electrode and for cerebral areas (left and right anterior, central and posterior area). Some specific neuropsychological tests (Mini Mental State. Randt Memory' Test, Toulouse Pieron and Labyrinth Tests) and rat­ ing scales (SCAG. CGBRS and HRSD) were performed for the clini­ cal evaluation. The preliminary data coming from 4/6 centers and relevant to 54 patients (basal and 3-month c-EEG evaluation) showed that N treat­ ment. particularly in MID patients is associated with an increase of fast activity and with a reduction of slow activity. P induced no change or an opposite pattern of EEG mapping. The evaluation in 44 patients after 6-month treatment confirms the clinical and c-EEG improvement with N observed after 3 months. In agreement with c-EEG evaluation, the clinical overall assess­ ment improves after N. with statistical differences vs. P particularly in some SCAG scale clusters and in the physicians' and patients' jud­ gements.

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Piracetam Influences the Global Dimensional Complexity of Multichannel EEG D. Lehmann. CM. Michel..!. Waekemumn. I. Dvorak Department of Neurology, University Hospital, Zurich. Switzerland Multichannel EEG (K-numbcr of channels), considered as a sequence of momentary field maps, may be viewed as a trajectory in K-dintensional state space. A single value measure of complexity of a brain state trajectory can be estimated, called the global correlation dimension (dimensional complexity). It assesses the ensemble char­ acteristics of all channels. Four 40 s records of 16-channel resting EEGs were obtained in each of four randomized sessions (double­ blind) after a single dose of placebo or 2.4. 4.8 or 9.6 g piracetam in 5 normal subjects. For each record, the global correlation dimension was estimated as the mean of 50 computations with 8.192 point pairs. The results were combined for the two intermediate doses and averaged over records. The correlation dimension decreased (Fried­ man ANOVA at p < 0.02) from placebo (median = 5.89) to low (me­ dian = 5.72) to high dose (median = 5.59). significant between pla­ cebo vs. high dose and low’ vs. high dose. The subtle change of brain global functional state after a single dose of piracetam was reflected by the nonlinear measure of global dimensional complexity of the multichannel EEG.

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A Two-Month Follow-Up of EEG Changes Induced by Glycerophosphorilserine in Vascular Dementia

Pharmaco-EEG Studies on Buspirone, a New Anxiolytic Drug, in High- and Low-Anxious Humans S. Kai. Y. Mizuki, N. Kajimura. M. Suetsttgi, M. Yamada Department of Neuropsychiatry. Yamaguchi University School of Medicine. Ube. Japan Buspirone, a 5-HTla partial agonist, is reported to possess anti­ anxiety effects. The present study was undertaken to clarify the effects of buspirone on EEGs in high- and low-anxious humans. Sub­ jects were 24 healthy male university students divided into two groups, classified by STAl and MAS scores, into high-anxious (n = 12) and low-anxious (n = 12) groups. They were given buspirone 5 or 15 mg or placebo in double-blind, crossover design. Resting EEGs with eyes closed were recorded for I min using monopolar leads, i.e.. Fz-(A1+A2), Cz-(A1+A2). The EEG recordings were performed be­ fore and 1 h after the drug administration. Power spectra were devel­

Abstracts

G. Conti. C. Fornara, C. Lie. T. Localelli, A. Poggi. G. Sirabian, S. Mammi. L. Leocani Department of Neurology, University of Milan, Milan, Italy Glycerophosphorilserine (GFS), a new nootropic drug precursor of phosphatidylserine, seems to play an important role in maintain­ ing the functional properties of cellular membranes. In an open uncontrolled study, we evaluated both the short- and long-term effects of the drug on quantitative EEG (qEEG) of patients with mild to moderate vascular dementia. To be included in the study, patients should have had a Mini-Mental Status Score between 17 and 25 and a Hachinski Ischemic Score over 7. Twenty-four patients, 15 males and 9 females, with a mean age of 69.6 years (range 60-75 years), entered the study. Quantitative EEG and subsequent topographic brain mapping were performed with a QSI 9000 machine (19 leads, biauricular ref­ erence). Short-term EEG changes were evaluated at 0.3 and 24 h in

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oped by a digital computer using the Fast Fourier Transform. The low-anxious group showed a moderate increase of the power values of theta and slow alpha activities. The high-anxious group showed a moderate increase in the power values of theta and slow alpha bands, and an increase of beta activities in a dose-dependent manner. The effects of buspirone on EEG clearly differ between groups defined by severity of anxiety: we believe that buspirone may be considered a new type of anxiolytic.

all patients after a single oral dose of 400 nigGFS. Patients were then subdivided in two groups of 12 subjects, receiving 100 or 200 mg. respectively, for 2 months. EEG examination was performed before and after 15. 30 and 60 days of treatment. Short term EEG changes consisted in an increase of the alpha and a decrease of the delta activities, still present at the 24-hour record­ ing. The same changes were observed in the chronic study, with a maximum at the 15th day and subsequent attenuation, and reaching a plateau at the 30th-day examination. We find that EEG changes induced by GFS have different time profiles for different EEG bands. The clinical meaning of this disso­ ciation has to be clarified.

to 4th hours of the 7-hour recording period. ID-6 have demonstrated a dramatic increase in SWS: the effect augmented from hour to hour reaching its maximum at the 8th hour of the 10-hour recording ses­ sion. As regards P-DS1P. it indicated significant increase in both SWS and PS within the 5th and 7th hours of the 10-hour recording session at a dose of 1.4 nmol/kg. Taking into account the recent data on distribution and co-local­ ization of endogenous DSIP (or DSIP-like peptide) in a rabbit brain and pituitary as well as a role of DSIP in hormonal regulation, we propose that sleep-promoting activity of synthetic DSIP analogs is mediated through such peptides as GRF and CLIP.

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Evaluation of Oxcarbazepine (OXC) and Carbamazepine (CBZ) Effects on the CNS through a Computerized Analysis of Eye Movements G. Zaccara. P.F. Gangemi. S. Massi. R. Zappoli, G .L Limiclo Department of Neurological and Psychiatric Sciences, University of Florence, Florence. Italy The evaluation of the eye movements is an interesting tool for evaluating the subclinical adverse-effect profile of antiepileptic drugs. We performed a double-blind, crossover trial to compare the effects of CBZ and OXC on saccadic and smooth-pursuit oculomotor systems. Six drug-free, healthy male volunteers participated in the study. Each subject was given a single oral dose of CBZ 400 mg and OXC 600 mg at 9:30 a.m. on two separate days. Ocular movements were measured by means of EOG immediately before drug intake and at 2-hour intervals over the following 10 h. OXC caused less impairment of ocular movements than CBZ. In particular, in the saccade tests. CBZ caused more slowing of saccadic peak velocity than OXC (p = 0.07) and the smooth-pursuit percent gain was signifi­ cantly lower after XBZ (p = 0.03).

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Delta Sleep-Inducing Peptide (DSIP): Hypnogenic Activity of IMew Analogs in Rabbits V. Kovalzon. M. Kuntsevich, I. Mikhaleva. I. Prudclienko Severtsov Institute. Moscow. Russia In the course of structure-functional relation study of DSIP. hyp­ nogenic activity of 3 novel structural analogs specified as ID-4. ID-5, and ID-6 with substitutions at the Ala-2 position, as well as phosphoryiated analog P-DS1P [Scr-7, HPO-3JDSIP. have been investi­ gated. Experiments were performed in rabbits with previously im­ planted electrodes and a single cannula into a lateral ventricle. Pep­ tides were dissolved in a saline and injected i.e.v. at 11—12 h a.m.; the procedure was followed by 7-1 Oh of recording using an automatic sleep-analyzer. Otherwise, the same animals treated with a saline were used as controls. The peptide ID-4 at a dose of 7 nmol/kg failed to change signifi­ cantly rabbit sleep in the 7 h following administration. ID-5 at the same dose induced a small increase in SWS percentage within the 3rd

Effects of Indeloxazine Hydrochloride on Sleep in Normal Humans Y. Mizuki. .V. Kajimura. S. Kai. M. Suetsugi, M. Yamada Department of Neuropsychiatry. Yamaguchi University School of Medicine. Ubc. Japan The effects of 40 mg of indeloxazine hydrochloride, a cerebral metabolic enhancer, on sleep were investigated in 6 healthy students. Polygraphic recordings were made for 8 consecutive nights in each subject. An inert placebo was given on the first 3 nights and on the 7th and 8th nights, and 40 mg of indeloxazine was administered on the 4th. 5th and 6th nights. Drug and placebo were administered orally at 21:30 h. and the recording of polysomnograms started at 22:00 h and ended at 8:00 h the next morning. The polysomnograms were evaluated by computerized automatic analysis using the inter­ val histogram method. Indeloxazine prolonged both sleep latency and REM latency, and increased stage-1 sleep, but decreased stages-3. -4. and REM sleep. An increase of REM sleep was observed on the 7th and 8th recovery nights. No obvious changes were shown in the subjective assessments after administration of the drug. These results suggest that the effects of indeloxazine on sleep are similar to those of the tricyclic antide­ pressants.

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Antioxidant Therapy with Disodic Ethylendiaminotetracetic Acid (Na2 EDTA) in Multi-Infarct Dementia Monitored by Dynamic Brain Mapping R.P.P. Marineóla Instituto de Investigación, Buenos Aires, Argentina Free Radical (FR)-mediated pathology is well established and documented in multiple research published data in the past several years, particularly in cerebral-vascular changes as they occur in vas­ cular dementias and other mechanisms of brain aging. The FR-trapping properties of NaiEDTA (a potent antioxidant) as well as its C'a' ’-blocking effect were monitored by Dynamic Brain Mapping (DBM) and QPEEG in a group of 38 patients with documented diag­ nosis of multi-infarct dementia (DSM-I1IR. Computerized Axial Tomography and Hachinski Scores) were compared against agematched normal controls.

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Statistically significant changes in DBM patterns before and I It after the administration of Na;EDTA evaluated by QPEEG have biocquivalent effect of cognitive enhancers, that is. decreased delta and theta activities. Na;EDTA FR-trapping and Ca''-channel-blocking psychopharmacological effect are similar to those of the Caf+ channel blocker nimodipine. Furthermore, it should be considered the heavy metal binding capacity of NaiEDTA to lead and aluminum, common eco­ logical factors involved in the pathogenesis of cerebro-vascular dis­ ease.

medications did not differ from those not on medication. The abnor­ mal findings seemed associated with the primary disorder. These observations support the presence of CNS pathology in chronic, treatment resistant conduct disordered children.

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Psychoactive Drug Use and Dynamic Brain Mapping (DBM) in Children with Chronic Psychiatric Disorders A. Turgay. E. Gordon. M. Vigdor Lafayette Clinic and Green Chimneys. Detroit, Mich.. USA

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Biometric Modelling of Human Retinal Oscillatory Potentials V. Balestra, G. Di Bon. O. Benedetli. IF G. Sannita Institute of Ncurophysiopathology. University Hospital San Martino. Genoa. Italy Retinal oscillator) potentials (OPs) evoked by light stimulation are a sequence of high-frequency wavelets that reflect neural activa­ tion of the inner retina are particularly sensitive to neuroactive drugs. A significant correlation exists between the amplitude and latency measured of consecutive wavelets, with statistical evidence of the clustering of early and late OPs wavelets in two distinct sub­ groups. A model based on a negative feedback system can be devised to describe amplitude and latency data synoptically, regardless of the actual OPs latencv/amplitude values and with low within/between subject variability. The model is characterized by two main impulses (with one a gaussian integer), with median values located at 24.0 and 40 ms after full-field stimulation at 4.5 cs-m and is consistent with the existing dichotomy between early and late OPs wavelets with respect to the stimulus/rcsponse curve, dark or light adaptation, ON and OFF retinal effects, and pathological retinal conditions. Animal and human evidence also exists that early components are sensitive to manipulation of the GABA system, while later OPs wavelets are affected by alterations of glycine transmission. Effects of neuroactive drugs in humans will be reported.

This prospective study involved 100 children in long-term resi­ dential care. The most common psychiatric diagnoses were attention deficit hyperactivity disorder(56). conduct disorder (53). dysthymia (31). and major depression (8). Comorbidity was common. 65 patients were receiving psychoactive medications with 39 patients receiving only one medication, and 8 receiving three medications. Commonly used medications were methylphenidate (36). thiorida­ zine (25) and imipramine ( 15). Dynamic Brain Mapping utilizing HZI software was carried out at HZI in Tarrytown. N.Y. DBM findings were compared to age- and sex-matched 'healthy' controls. The children receiving psychoactive drugs showed more slowing and paroxysmal changes on DBM analy­ sis. Children on multiple drugs showed more pathology than those on only one drug. The elTccts of psychoactive drugs on EEG/DBM in children deserves more attention to differentiate drug effects from primary CNS pathology.

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Computer EEG as a Biological Predictor of Clinical Outcome for Nimodipine Treatment of Dementia Patients T.M. Ilil, E. Eralp. P. LeBars. K.Z. Ilil HZI Research Center. Tarrytown. N.Y.. USA

EEG and Dynamic Brain Mapping in Children with Chronic, Treatment-Resistant Conduct Disorders A. Targay, E. Gordon. M. Vigdor Lafayette Clinic and Green Chimneys. Detroit. Mich.. USA This study involved 53 chronically treatment-resistant conduct disordered children in residential treatment in New York State. DSM-IUR diagnostic criteria and NIMH chronicity of child psy­ chiatric disorders were used. EEG and Dynamic Brain Mapping (DBM) analyses were completed at HZI in Tarrytown. N.Y. Only 9 (17%) patients had normal DBM findings: 44 (83%) were deviant. Fourteen showed slowing, 18 showed generalized or petit mal paroxysmal activity. 12 demonstrated temporal lobe pathology. Prevalence and nature of EEG and DBM pathology was not different in children with comorbid ADHD compared to those without ADHD (p = 0.05). DBM findings for the patients on psychoactive

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Abstracts

Previous studies indicated that patients with dementia, particu­ larly those with severe dementia such as Alzheimer's disease, fre­ quently have abnormal EEG records. In a recent study, we demon­ strated that dementia patients (n = 428) had less alpha activity and more theta and delta activity than age-matched controls. The EEG profiles of drugs in our database that are claimed to be effective in relieving dementia (cognitive activators or nootropics). produce more alpha activity and decrease of slow waves. Thus, the EEG pro­ files of dementia and antidementia drugs show almost mirror image differences. This suggests that dementia patients have a deviation in their electrophysiological pattern that differs from healthy subjects, and that anti-dementia drugs reverse (‘normalize’) these deviations. To test this hypothesis, we conducted a large study wdth a group of 80 dementia patients (DSM-1I1R: 290.00-290-20) in the age range of 45-83 years, of whom 33 patients were male and 47 female. After extensive screening examinations, including CT or MRI. clinical neurological, neurophysiological (Computer EEG, Evoked potential)

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and neuropsychological (Mini-Mental. ADAS. Buschke) tests, pa­ tients were assigned to either nimodipinc or placebo treatment. All patients started treatment at 30 mg or I tablet t.i.d. Those patients who failed to show at least a 1+ improvement on CGI scores after 3 months had their dosages doubled. Examinations were repeated at monthly intervals. CEEG was done for diagnostic purposes during the baseline and during treatment. At baseline, a Test-Dose of study drug (30 mg nimodipine or placebo) was given to each subject as the first dose of the study treatment. Before, and I and 3 h after nimodipinc or place­ bo. a CEEG was done. The CNS effects (CEEG) of drug (or placebo) was classified with HZI CEEG database for therapeutic drug groups (antidepressants, anxiolytics, antipsvchotics. cognitive activators). The CNS response of each of the individual subjects was correlated with the clinical response after 3-9 months treatment. Also the CEEG pattern of each of the patients before and after drug treatment was compared and changes were correlated with the clinical (thera­ peutic) drugs.

The patient's EEG t profile is compared with the EEG profiles of the database drug groups and the least similar (the most different) therapeutic group is selected as the choice of treatment. If the com­ puter selection is in agreement with the clinical selection, the next step is done. The patient's EEG profile is compared with the EEG profiles of all 191 database drugs categorized into 1.146 subgroups (different doses, times etc.). The first three drugs with the most different CEEG profiles (the least similarity coefficient and the highest Euclidian dis­ tance) are selected as the drugs of choice for this individual patient.

Drug Classification Sunday, May 24,1992

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'Right' Drug and 'Right' Patient: Computer-Analyzed EEG and Brain Mapping as a Biological Predictor for Psychotropic Drug Selection and Monitoring T.M. ml. E. Eralp. P. LeBars, K.Z. Itil HZI Research Center. Tarrytown. N.Y., USA The quantitative pharmaco-EEG method has demonstrated that therapeutically equivalent psychotropic drugs elicit very' similar computer-analyzed EEG changes. Different therapeutically effective psychoactive drugs have different CEEG profiles. Using our own lab­ oratories and more than 60 'Beta Site' collaborative centers, we have collected a large amount of multi-lead, multi-frequency CEEG data in healthy subjects and a variety of clinical groups. The analyses of computer EEG data of patients with dementia, schizophrenia, depression, and panic disorder show that each diag­ nostic group has different CEEG profiles, compared to age-matched healthy subjects. Also, the quantitative EEG pattern of each diagnos­ tic group differs from each other. The most interesting finding is that the computer EEG profile of each diagnostic group is almost the mir­ ror image of the drugs which are effective in each diagnostic group. For example, the computer profile of depressed patients, in compari­ son to age-matched healthy subjects, is opposite to the EEG profile of antidepressant drugs (pre-drug vs. post-drug) of the computer EEG database. This suggests that depressed patients have different brain biochemistry than healthy subjects and antidepressants reverse the deviated brain biochemistry' resulting in a 'normalization' of the EEG pattern. Based on these observations, we developed a method for the selection and monitoring of the psychotropic drug treatment for each individual patient. In our method, a multilead, multifrequency (20 bands) CEEG is completed for each patient before treatment is ini­ tiated. This EEG pattern is compared to age-matched healthy male subjects using t statistics. The resulting EEG t profile is compared to the EEG t profiles of the computer EEG database diagnostic groups using Pearson Product Moment Correlation statistics to validate a clinical diagnosis by the electrophysiological findings.

Introduction in Animal Pharmaco-EEG Investigations and History Henk van Riezen C iba-G eigy P h arm aceu ticals. Basel. S w itzerland

Computers allow evolution of a science of human 'pharmacoEEG' from the description of drug effects, by identification of com­ mon EEG features in drugs with similar clinical activities, to predic­ tion of clinical indication of new drugs from EEG spectra obtained from volunteers. While human pharmaco-EEG matured, develop­ ments in animal pharmacology led to identification o f ‘mechanisms of action' in terms of functional changes in brain systems of specific sites and. lately, of synaptic effects or ion channels, paralleling pro­ gress made in brain electrophysiology. Few attempts were made to develop animal pharmaco-EEG methods, although one laboratory reported that animal pharmaco-EEG had been essential in their selection procedures for new drugs. There is. however, a large litera­ ture about the effects of drugs on animal EEG showing that drugs with similar indications have similar electrophysiological effects. Since many more parameters can be measured (depth electrodes) in animals than in man, it is expected that predictions from animal EEG will be as accurate as from human pharmaco-EEG.

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Cortical and Subcortical EEG in Relation to Sleep-Wake Behaviour in Mammalian Species Marike Lancet Max-Planck Institute of Psychiatry. Munich, FRG In humans and several other mammals, a quantitative EEG anal­ ysis has been used to study the regulation of sleep-wake behavior. In all mammalian species studied, cortical EEG recorded during tion-REM sleep (NREMS) is characterized by the occurrence of spin­ dles and high-voltage, slow waves (0.5-4.0 Hz). Furthermore, slowwave activity (SWA) is low at the beginning of a NREM episode and

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S3

it rises in the course of a NREM episode. The rise rate and the maxi­ mal level of SWA are a monotonic function of the duration of prior wakefulness. During REMS, cortical EEG typically exists of lowvoltage. mixed frequencies and in some animals, a prominent theta rhythm is superimposed. Only after a sleep deprivation in some spe­ cies, cortical EEG within REMS changes. Especially, the EEG activ­ ity during wakefulness depends considerably on the behavioral state, on the electrode location, and on the species. On average, cortical EEG within wakefulness consists of low-voltage, mixed frequencies. The few studies done on subcortical EEG clearly show that the electrical activity differs highly between brain regions and between species. However, two recent studies, in which a spectral analysis of subcortical EEG was made, showed that, at least in humans [ I ] and cats [2], the changes occurring in subcortical EEG associated with changes in sleep-wake behavior parallel the general characteristics of cortical EEG described above. 1 2

Dijk D.I. Wieser HG: Intracranial recordings of slow wave activity in man: in Home J (ed): Sleep 1990. Bochum. Ponlenagel Press. 1990. pp3-7. Lanccl M, van Riezen H. Glatt A: Enhanced slow wave activity within nonREM sleep in the cortical and subcortical EEG of the cal after sleep deprivation. Sleep (in press).

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Classification of Psychotropic Drugs in Humans Based on Surface Electrodes in Rats F. Krijzer Department of CNS-Pharmacology, Slovay-Duphar. The Netherlands Based on vigilance controlled ECoG recordings in rats, it has been possible to characterize psychoactive drugs and to predict their clinical efficacy. Fronto-parietal ECoG is recorded during 6-min periods immediately before drug/saline administration and starting at 20 and 45 min after drug/saline. Using power spectral analysis of the ECoG the percentage change in power between 20 and 45 min. and predrug is calculated. After a smoothing procedure, these per­ centages arc used as input for an analysis of variance, followed by a t test and normalization for the degrees of freedom, resulting in ‘nprofiles'. Each drug has its own characteristic n-profilc. but n-profiles of drugs belonging to a certain clinical class have some characteristics in common. Thus, it is possible to discriminate between antidepres­ sant. neuroleptic, anxiolytic, and psychostimulant drug classes based on a visual judgement. Moreover, four subclasses can be recognized within the antidepressant class, two subtypes within the neuroleptic class, and three subtypes within the anxiolytic class. Examples will be shown. Our next step is a classification system based on parameters extracted by a statistical analysis seeking a more powerful prediction. Results from this approach will be shown.

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Pharmaco-EEG Studies by Measuring the Frequency Content of Tele-Stereotactically Recorded Field Potentials in the Rat for the Characterization of Psychotropic Drugs W. Dimpfcl Pro Science Private Research Institute GmbH, Linden, FRG Under the assumption that field potentials recorded from partic­ ular brain areas reflect the net balance of neurotransmittcr activities, the dose- and time-dependent responses induced by intraperitoneal application of psychoactive drugs are quantified by spectral analysis of the electroencephalogram recorded from frontal cortex, hippo­ campus, striatum, and reticular formation in the rat. The actions of different classic and atypical neuroleptics arc char­ acterized by increases of the spectral power in the alpha-1 and beta range, at higher dosages also in the theta range. Antidepressive drugs could be recognized by a general decrease of all frequency ranges in all four brain areas. Amphctaminc-like stimulatory drugs produced de­ creases in power density especially in the alpha-2 and delta ranges, clearly less in theta and beta-1 and virtually none in the alpha-1 or beta-2 frequencies. The injection of different benzodiazepines w'as fol­ lowed by a decrease in delta and alpha-1 frequencies, and by a pro­ nounced dose-dependent increase in beta power density. Hallucina­ tory drugs were characterized by a biphasic response with respect to the frequency content of the field potentials. During the beginning phase an amphetamine-like behavior, characterized by increase of alpha-1 power was typically seen, and in the later periods of analysis (starting from the 3rd hour after injection), a prominent increase of delta power in the frontal cortex was common to all hallucinogenic drugs. With respect to the interpretation of the observed changes. 1 hypo­ thesize that changes in the power of the delta range are achieved with drugs that modulate cholinergic transmission. Predominant theta changes are achieved after drug-dependent interactions of the norad­ renergic transmitter system. Drugs acting on the serotonergic system are likewise shown to change alpha-1 power density, and modulation of the dopaminergic system is followed mainly by changes in alpha-2 power. According to our experience NMDA-receptor induced changes also show a biphasic response in the presence of predominant changes in the beta-1 range. Benzodiazepines acting on the GABAergic system induce changes in beta-2 power. But clearly no transmit­ ter system can be modulated without induction of concomitant changes in one or more other communication systems. Thus, the pat­ tern of changes we observe after the application of psychoactivc drugs reflects the current status of the communication structure and can be used to classify drug actions (at least in the rat). 58

Classification of Psychotropic Drugs Based on Sleep EEG in Rats GeS.F. Ruigt, J. Bdgmver, J. Egberts Department of Neuropharmacology. Organon International SDG, The Netherlands

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Abstracts

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We have developed a large data-base on the effects of psycho­ tropic reference drugs (approximately 160) and potentially new psy­ chotropic drugs on 24-hour EEG-defined rat sleep-waking behavior.

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Classification of Psychotropic Drugs Based on Visually Evoked Responses in Rats Adam Sarkadi Pharmacological Research Center. Chemical Works of G. Richter, Ltd., Budapest, Hungary The photically evoked afterdischarge (PEAD) in the rat is an unspecific phenomenon. From a physiological point of view, this phenomenon is dependent upon the recurrent excitatory-inhibitory system of the lateral geniculate nucleus, modulated mainly by the thalamic reticular nucleus and by limbic, brain-stem and thalamic systems. It has distinct behavioral correlations. PEAD was proposed as a model of petit mal epilepsy by Fleming. Shearer and Bigler in the late 1970s, but (according to the studies reviewed by Bigler) it proved not to be specific for this purpose insofar as all CNS drugs influence PEAD in different ways. Adult male rats are prepared for chronic elcctrophysiological investigation. Six spural disc electrodes made of nichromc wire are placed epidurally: two pairs of electrodes on each visual cortex and tw'o electrodes in frontal bone for reference and ground. The animals are placed in a mirror-walled box and those which show artifact-free background activity (BA) and correct latency and wave shape rela­ tions of visual evoked responses (VER) on flashing light (1/8 s) are accepted for drug effect measurements where one bipolar and one monopolar lead of visual cortex arc used. Forty-five VERs (2 s duration) and 44 periods of BA (4 s duration delayed 2.5 s from flashing light trigger) arc analyzed. Single visual evoked potentials (VEP) and PEADs (VEP associated with afterdis­ charge [AD]) are distinguished within VERs. The occurrence of PEAD is counted, then average duration, average curve integral, and curve integral of averaged AD of PEAD of bipolar lead are calculated and treated as PF.AD-data. The averaged time-domain descriptors (Hjorth-parameters) of BA of both leads are calculated and treated as EEG data. Subjective scores of vigilance, reactivity to handling, reactitivty to acoustic startle stimulus, motility, and moving ability are treated as behavioral data.

Drug is given immediately after the baseline data of 8 animals have been registered, and the effect is measured 0.5. 2 and 4 It later when administered i.p., and 1.3.6 and 24 h later when administered p.o. Paired t values of PEAD and EEG data, and mean score differ­ ences of behavioral data registered in a time vs. baseline data are calculated, then the first two factors of these 15 parameters are derived. This procedure results in the time-effect profiles of a single dose and the dose/time-effect profile when several doses of a drug are administered. The profiles prove to be consistent for neuroleptics (including atypical ones), anxiolytics, and psychostimulants. Factor data of convulsants and anti-convulsants showed opposite patterns.

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Classification of Psychotropic Drugs based on Sleep EEG in Cats R Scherschlicht. ./. Schneeberger Predinical Pharma Research, F. Hoffnian-La Roche. Basel. Switzerland In chronically instrumented cats with electrodes in the brain cor­ tex. hippocampus, and lateral geniculate body, conventional EEG analysis was used to discriminate between wakefulness, rapid eye movement (REM) sleep, and non-REM sleep. Differential effects on the parameters of the sleep-wakefulness cycle w'erc found with com­ pounds of different pharmacological classes. While ligands at the benzodiazepine receptor (BZR) increased REM sleep at very low' doses, they decreased total sleep at higher doses. Opiates decreased total sleep in a dose-dependent manner and this effect was antago­ nized by naltrexone. All agents augmenting the monoaminergic tone such as inhibitors of rcuptake and of nonamine oxidase selectively suppressed REM sleep while inhibitors of acetylcholine esterase aug­ mented this phase of sleep selectively. Agonists at the dopamine-2 receptor at very low doses, which presumably were selective for autoreceptors, augmental total sleep but overproportionally REM sleep. It is concluded that drugs can be systematized by evaluating their effect on the different phases of the sleep-wake continuum within certain limits. The classification may be based on empirical findings as in the case of ligands at the BZR and opiated or on hypotheses such as the reciprocal interaction model of sleep cycle generation involving monoaminergic and cholinergic neurons. In an industrial environment, sleep studies have to be seen in the framework of many different pharmacological models.

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incorporating more than 3,500 24-hour rat placebo recordings. To objectively assess the similarity between test compounds and clini­ cally active reference drugs in this data base, we employ both dis­ criminant analysis and an approach based on artificial neuronal net­ works. Antidepressant drugs can be differentiated from antipsy­ chotic and stimulant drugs and from placebo, and subsets can be made of anxiolytic and stimulant antidepressants. The neuronal net­ work approach show's that similarities between antidepressant drugs may vary considerably and we are investigating whether such differ­ ences correlate with differences in biochemical profiles. We have further identified slcep-stage-dependcnt and sleepstage-independent parts of the EEG pow'er spectrum and found that some drugs alter power spectra without changing the nature of the sleep classification, thereby enabling the characterization of drug effects on slccp-slagc-specific pow er spectra. Other drugs have mixed effects on sleep patterns and pow>er spectra. We still have to deter­ mine whether these additional spectral parameters can be used to identify different subsets of psychotropic drugs.

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Classification of Psychotropic Drugs based on EEG and Performance Test Variables

Based on either EEG and performance tests, the drugs could be classified into five classes. When both EEG and performance test variables were used lor the discrimination, the separation for each drug class was even more pronounced (see table).

W.M. Herrmann Laboratory of Clinical Psychophysiology. Freie Universität Berlin. Berlin. FRG

Discriminative function of EEQ- and performance teat variables Mean probability measures after reclassification of the substance vectors

NEUroleptics

EEG

.1 7

37

.22

PT EEG/PT ANXiolytics

.16

EEG

.1 2

EEG/PT PlAcebos

EEG

.13

.18

.20

.1 5 1

22

EEG/PT ANTidepressants

EEG PT EEG/PT

.7 .1 3

.18

.31

22

27

16

-, 0 1 2 1

.4 2

.1 3

16 1

.13

HUM 110. 111.114 116 R R

l"*y'J EEG 21 Variables relative power in 6 frequency bands and total power (1 5-30 0 Hz) tor three time periods (pre i h post. 3 h posti frequency bands 6*. 8‘ . o ,‘ . a* *V andp.' 0 PT performance tests 18 Variables CFF. critical flicker fusion frequency PL.Pauli, serial additions RTT. simple reaction time to a tone. TAP. tapping maximum speed PB. peg board a psychomotor coordination test AIM aiming Time periods pre. 1 h post. 3 h post 1 3» i EEG/PT. 39 Variables The above mentioned EEG-and PT-variables for three time periods (pre. 1 h post. 3 h post)

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Classification of Psychotropics Based on Brain Mapping Model T M [til, P. LeBars, E. Eralp HIZ Research Center. Tarrytown. N.Y.. USA Research with quantitative pharmaco-EEG has demonstrated that EEG changes, induced by the same psychotropic drugs, are rep­ licable and predictable. Drugs with similar therapeutic properties produce similar computer EEG profiles, while drugs with different therapeutic effects induce different EEG profiles. A database with EEG profiles of drugs can assist in predicting the psychotropic properties of new drugs based on the classification with a database of marketed drugs. Previously, quantitative pharmaco-EEG research was primarily conducted with only a few areasof the brain because of technological limitations and economic considerations. In recent years, thanks to advanced microprocessors, we collected multichannel, multifre­ quency pharmaco-EEG and brain mapping data within our own lab­ oratories and in collaboration with more than 60 ‘beta-site’ centers who use the same EEG data collection and analysis systems. Based on the new drug effect EEG brain mapping database, the follow ing observations can be made. (1) Overall, dnig induced EEG changes are very similar in different parts of the brain. (2) The pre­ viously selected brain areas, such as occipital and parietal leads, are indeed still the best areas to establish CNS action of drugs. (3) The onset and duration of EEG changes induced by drugs show topo­ graphic discrimination. The effects of anxiolytics start from the ante­ rior brain area and spread to posterior w'hile. for example, the effect of neuroleptics start from posterior and spread to anterior brain areas. Antidepressants scent to produce early changes in the temporal area of the brain. (4) In the classification of a new psychotropic with marked effects on vigilance (i.e.. sedation or stimulation) there is no significant difference between single and multiple leads. However, to classify the drugs without significant vigilance effects such as drugs developed by newest receptor models and/or special biochemical properties, multilead EEG analysis is significantly superior than that of single lead. One can improve both statical discrimination from placebo and drug classification when multilead data is used. (5) Multilcad multifrequency pharmaco-EEG proved to be an excellent model to determine bio-availability and bio-equivalency of drugs using ‘classical’ and newly developed pharmaco-dynamic models.

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Several attempts have been made during the history of pharmaco-electroencephalography to discriminate EEG and performance test effects of various psychotropics. Based on EEG and on perfor­ mance test variables, the effects of sedation and stimulation were described, and that sedative neuroleptics, antidepressants and anxio­ lytics could be discriminated from each other. In a prospective trial. 60 healthy male volunteers were grouped in four blocks. 15 subjects per group. In each trial, in randomized cross­ over fashion, one typical neuroleptic, anxiolytic, psychostimulant, antidepressant, and placebo were given. Four randomized placebos and four different substances of each substance class of neuroleptics, anxiolytics, antidepressants, and psychostimulants were used. In addition to EEG, critical dicker fusion frequency (downwards). Pauli serial addition test, simple reaction time to a tone, maximum tapping speed, pegboard. and aiming were used.

Workshop

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Sunday, May 24,1992

Pharmacodynamic Modeling of Anesthetic EEG Drug Effects

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Statistical Analysis for Pharmaco-EEG Studies G. Ferber, Basel. Switzerland. (Chairman); K. Abu Frankfurt. FRG:Æ Gevins, San Francisco. Calif.. USA; G. Koch. Chapel Hill. N.C.. USA; M. Jobert. Berlin. FRG Some statistical peculiarities of pharmaco-EEG studies have their origin in the multiplicity of observations: several parameters are evaluated at several time points and at several locations on the head: and all these data are derived from a crossover design of placebo and possibly several doses of one or more active drugs. For this reason, the classical methods of confirmatory statistics in clinical trials can­ not be carried over in a straightforward manner. While some solu­ tions have been proposed and even applied successfully, more work needs to be done to improve the understanding of these problems and their solutions. In this workshop, strategies for the statistical analysis of a sample pharmac-EEG study will be discussed by bio­ metricians who will address the problems of multiplicity of locations in multichannel recording, of time points in a profile, and of fre­ quency bands of variable width.

Workshop on Pharmacodynamics and Pharmacokinetics Monday, May 25,1992

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Donald R. Slanski Department of Anesthesiology. Stanford University School of Medicine. Stanford. Calif.. USA Anesthetic drugs have diverse and profound effects on the EEG. Over the past 10 years, our laboratory has used quantitative wave­ form analysis methodology to obtain continuous, univariate descrip­ tions of anesthetic drug effects and to use these descriptors as meth­ odology' to understand anesthetic drug clinical pharmacology and correlation of these EEG changes with clinical measures of anesthetic depth. Additionally, with the measurement of anesthetic drug plasma concentrations, it is possible to use pharmacokinetic and pharmacodynamic modeling concepts to relate drug concentration to EEG drug effects. This approach allows one to separate the drug dose-response relationship into its pharmacokinetic and pharmaco­ dynamic components. This methodology allow's one to quantitate CNS sensitivity to anesthetic drugs and examine the effects of age or disease states on CNS response. Quantitative EEG methodology has been successfully applied to various anesthetic drug classes and agents. Intravenous anesthetics: thiopental, ctomidale, methohexital. propofol: opiates: fcntanyl. alfcntanil. sufentanil, morphine: dissociative anesthetics: ketamine and benzodiazepines such as diazepam, midazolam, and lorazépam. Different EEG waveform analyses and univariate descriptive param­ eters are necessary with each class of drug- Fast fourier transforma­ tion with calculation of the spectral edge has been useful for the opiates, aperiodic waveform analysis and calculation of the number of w'aves/s is necessary for the intravenous anesthetics, while ape­ riodic analysis and total voltage is optimal for the bezodiazepines. Using these EEG measures of drug effect, parametric and semiparametric pharmacodynamic modeling approaches can be used to relate drug plasma concentration to EEG drug effect. This approach has been useful to estimate the rate of blood:brain equilibration and CNS sensitivity.

Kinetic-Dynamic Studies of Benzodiazepines: The EEG as a Window to the Brain

The primary clinical actions of the class of drugs known as benzo­ diazepines are generally described as sedative, hypnotic, anxiolytic, amnestic, and anticonvulsant. Advancement of our understanding of within- and between-individual variations in the clinical response to benzodiazepines has always been complicated by the problems inher­ ent in quantitating these outcome variables in a reliable and replica­ ble manner. Quantitative analysis of the EEG. via fast-Fouricr trans­ form or aperiodic analysis, holds considerable promise as an objec­ tive measure of the pharmacodynamic effects of benzodiazepines. In a given individual, fractional frequency density in the "benzodiaze­ pine-sensitive’ range is stable over time and unresponsive to placebo. After acute benzodiazepine administration, density increments are dependent on dose, plasma concentration, and time based on estab­ lished mathematical models. Furthermore, quantitative EEG changes arc closely correlated with corresponding changes in seda­ tion. mood, psvehomotor performance, and memory.

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Application of Semilinear Canonical Correlation to EEG Measurement of Drug Effect Steven L. Shafer. Keith Gregg Department of Anesthesiology. Stanford University School of Medicine. Stanford. Calif.. USA Although the EEG waveform is affected by opioids in a dosedependent manner, much of the information relating the EEG to opioid concentration is irrelevant or redundant. It is desirable to reduce the complex EEG waveform to a univariate component to facilitate modeling the pharmacokinetic-pharmacodynamic relation­ ship. Many univariate EEG components have been used to describe opioid drug effect. All have been ad hoc attempts to quantify the increases in total power and low-frequency activity caused by opioids. Using data from 15 patients given an intravenous infusion of the semisynthetic opioid alfentanil, we have been able to reduce the EEG to a univariate component optimally and identify the uni-

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David.I. Greenblatt Tufts University School of Medicine, Boston, Mass., USA

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Pharmacological Relevance of EEG Effect Parameters in Pharmacokinetic-Pharmacodynamic Studies Jaap W. Mandema. Meindert Danhof Division of Pharmacology, University of Leiden, Center for Bio-Pharmaceutical Sciences. Leiden. The Netherlands The characterization of relationship between pharmacokinetics and pharmacodynamics requires the availability of appropriate and reliable measures of the pharmacological effect. Effect parameters derived from a quantitative analysis of the EEG appear to be per­ fectly suited to characterize such relationships for drugs acting on the central nervous system (CNS). EEG parameters represent many of the characteristics of ideal pharmacodynamic measures being contin­ uous. objective, sensitive, and reproducible. These features provide the opportunity to derive in vivo concentration-effect relationships of psychotropic drugs in individual subjects, which yields important quantitative pharmacodynamic information on potency (EC?»), in­ trinsic efficacy (Emax) and rate of biophase equilibration. The relevance of EEG effect measures with respect to the specific (clinical) effects of the drugs, however, is still a matter of substantial debate. The relevance of the EEG parameters may be evaluated by correlating the pharmacodynamic parameters derived from concentration-EEG effect relationships with those obtained using other effect measures. For a number of benzodiazepines, the concentration-EEG effect relationships were derived in individual rats, using the increase in amplitudes in the 11.5-30 Hz (beta) frequency band as EEG parameter. Large differences in potency (EC?o) and intrinsic efficacy (Emaii) were observed. These differences in potency closely correlated with differences in their affinity for the benzodiazepine receptor in vitro. The large differences in maximal EEG effect observed for the benzodiazepine agonists, partial agonists, antago­ nists and inverse agonists corresponded well w'ith their known differ­ ences in intrinsic efficacy at the GABA-benzodiazepinc receptor. In addition, a close correlation was observed with the pharmacody­ namic parameters (both EC50 and Emax) obtained in an animal model for anticonvulsant activity (the pentylenetetrazol threshold model).

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Abstracts

These comparisons revealed that the EEG parameter studied is indeed a relevant measure of the CNS effects of benzodiazepines, reflecting their interaction with the GABA-benzodiazepine receptor.

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EEG and Clinical Response to Risperidone in Schizophrenic Patients Jan Volavka, Pal Czobor Nathan Kline Institute for Psychiatric Research. Orangeburg. N.Y.. USA This study examined relationships between plasma levels of ris­ peridone (R1SP). EEG changes, and clinical improvement in acutely exacerbated schizophrenic patients (n =18) after an 8-week period of treatment. Two hypotheses were tested: (a) RISP treatment elicits a change in EEG power spectral asymmetry, (b) EEG response to RISP depends on RISP plasma levels, and this relationship is more expressed in patients showing clinical improvement. Blood sampling for plasma RISP levels, psychometric assessments (PANSS). and EEGs were performed at study entry, endpoint of the placebo period (‘baseline’), and twice a month during the treatment phase. EEG response to RISP was estimated by power spectral changes in four frequency bands (delta, theta, alpha, beta) Preliminary analyses provide support for hypothesis (a).

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Quantitative Pharmaco-EEG in Dose-Effect Relationship of Psychotropic Drugs Turan M. ltd HZI Research Center. Inc.. Tarrytown, N.Y.. USA In its final ruling on bioavailability testing, the FDA concluded that ‘other methods', such as ‘acute pharmacological effects' of a drug product, may also be applied for establishing bioavailability particu­ larly if the rate and extent to which a drug’s active ingredient or ther­ apeutic moiety cannot be dircctlv measured at the site of drug action [!]■ The Task Force Committee of the American College of Neuropsvchopharmacology (ACNP) recognized the scientific problems of bioavailability and biocquivalency of psychotropic drugs, since among others, their ‘therapeutic metabolites are unknown’ and their ‘availability’ at the site of action, the brain cannot be directly mea­ sured [2]. The Committee was concerned that psychotropic drugs, which are the most widely used dnig classes in the USA. undergo minimal systematic bioavailability evaluations. The Task Force Committee was particularly worried about psychotropic drugs which arc frequently prescribed to ‘patients who cannot legally consent’. The committee acknowledges that quantitative EEG and pupillographv, which clearly identify whether drugs cross the blood-brain bar­ rier. are the most logical methods in the bioavailabilitv assessment of psychotropic drugs. Using the method of quantitative pharmaco-EEG [3], we estab­ lished two different procedures to determine the pharmacodynamics and dose-effect relationship of psychotropic drugs. We find that ccr-

7th IREG Symposium. Boca Raton

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variate components which are maximally correlated with plasma drug concentration. This was performed using a new statistical tech­ nique. scmilinear canonical correlation. The EEG components were maximally correlated to opioid concentration through a standard pharmacokinetic (triexponential)-pharmacodynamic (sigmoidal) model. Two optimal components were produced from the powers in the EEG frequency spectrum: a weighted average of the logarithms of the powers, and a weighted average of the powers expressed as per­ centages of the total power. Both new components had a median R: of 0.84. compared to median R: ranging from 0.37 to 0.83 for five popular ad hoc components. More importantly, the new components correlated well with plasma opioid concentration in every subject, w'hile the ad hoc components invariable correlated poorly in some subjects. Thus the EEG components identified by semilincar canoni­ cal correlation were more robust than previously identified EEG components in characterizing the effect of opioids on the EEG. Scmi­ linear canonical correlation is a promising new technique for relating EEG effect to plasma drug concentration.

1 2 3

Bioavailability and bioequivalency requirements. Federal Register 42 (5): 1639. January 7, 1977. Final ACNP Task Force Committee Report on Bioavailability and Bio­ equivalency of Psychotropic Drugs. Psychopharm Bull 1980:16:9-12. Itil T: Qualitative pharmaco-eleclrocncephalography: in Itil TM (ed): Psy­ chotropic Drugs and Human E tG . Modern Problems in Pharmaco-Psychiatry 8. Basel. K.arger. 1974.

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Pharmacokinetic and Pharmacodynamic Studies with 2 Isomers of Fenfluramine Utilizing EEG Brain Mapping, Psychometric and Psychophysiological Methods B. Salem, ./. Grunbergcr. P. Anderer. II Sieghart, M.J. Barbanoj. N. Laudignon Department of Psychiatry, School of Medicine. University of Vienna, Vienna. Austria In a double-blind, placebo-controllcd. crossover study, pharma­ cokinetics and -dynamics of single oral doses of 15 or 30 mg d- and 30 mg /-fenfluramine (FEN) were studied as compared with 50 mg chlorpromazine (CPZ) and 20 mg ¿/-amphetamine (AMPI I). Eigh­ teen healthy young volunteers received randomized and weekly oral single doses. Blood sampling for AMPH. FEN. the metabolite nor­ fenfluramine (NORFEN) and prolactin. EEG recordings, psychometry, psychophysiology and evaluation of side effects were carried out at 0. 2. 4. 6. 8 h post-drug. After ¿/-FEN. dose-dependent blood con­ centrations were obtained peaking at 2-4 h. slowly declining thereaf­ ter. NORFEN increased up to the 8th hour. After /-FEN a similar

time-course was obtained with concentrations of the parent com­ pound higher and those of the metabolite lower than after the disomer. ¿/-FEN induced significant and dose-dependent pharntacoEEG changes which were quite different from those of the reference drugs and peaked in the 4th to 6th hours. /-FEN produced only minor changes. C'PZ produced the typical sedative-neuroleptic profile. AMPH the typical psychostimulatory one. Prolactin was only modi­ fied by CPZ. These neurophysiological changes will be compared with psychometric and psychophysiological data.

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Dose-, Time-, and Treatment-Related Quantitative EEG Effects of Anti-Epileptic Drugs IF. O'. San nila Center for Neuroactive Drugs. Institute of Neurophysiopathology. University Hospital San Martino. Genoa. Italy Quantitative EEG effects of antiepileptic drugs (phénobarbital, phenytoin. ethosuximide. Na/Mg-valproate, benzodiazepines, mil­ acemide. lamotrigine) vary qualitatively and in topographic distribu­ tion at nontoxic doses despite their common therapeutic indication. A correlation between EEG effects and drug-plasma concentrations is uncommon and usually restricted to acute administration, with limited consistency across subjects. Phénobarbital and valproic acid are exceptional. Phénobarbital induces comparable increases in EEG fast-fre­ quency components after acute and during long-term treatment which correlate with drug plasma levels. This correlation is evident from the 1st hour after acute administration of doses as low as 50100 mg. but plasma Cnm can precede the maximum EF.G effect with a 2-4-hour hysteresis. Both F.EG effects and plasma concentration are subject to circadian cyclicity. Distinct EEG effects depending either on dose or treatment modality (acute vs. chronic administration) are induced by val­ proate. Fast frequency EEG activity decreases during long-term oral treatment (8.2-13.2 mg/kg/dav), while a higher (14.3-33.4 mg/kg/ day) dose yields the same effect after acute administration. The EEG total power decreases during chronic treatment, while increasing after acute administration, when significant dose/effect and EEG/ plasma level correlations are also evident. These observations are consistent with the indirect mechanisms of valproate anti-epileptic action and the suggested direct inhibition of neural activity observed in in vitro models alter acute administration. Quantitative EEG studies allow inferences about drug dynamics al CNS levels to sup­ plement the information from pharmacokinetic approaches and can concur in generating or supplementing working hypotheses in neuro­ pharmacology.

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tain EEG frequency bands can be used to establish time- and doserelated pharmacodynamic effects of drugs. For anxiolytic drugs 2026 cps activity and average frequency: for anti-depressant drugs 7.513 cps activity: for neuroleptic drugs 1.3-3.5 cps activity: and for cognitive activators 9.0 -10.5 cps activity can be used to establish the pharmacodynamic properties and dose-effect relationship of these drugs. The similarity coefficient of the computer EEG profile of a drug with the composite profile of the same therapeutic drug class of the computer EEG drug database can be used as a ‘bioassay’. Surprising­ ly. while the individual EEG frequency bands do not show correla­ tions with peripheral plasma levels, linear correlations were estab­ lished between plasma levels of individual subjects and similarity coeeficients. The results of three marketed drug studies with an anxiolytic (Valium®), and antidepressant (Sinequan®). a neuroleptic (Navanc®) and one experimental drug (CGS 20625) will be presented to demonstrate the use of QPF.F.G in the assessment of dose-effect rela­ tionships and pharmacodynamic properties.

7th IPEG Symposium. Boca Raton, Florida, May 23-25, 1992. Abstracts.

Pharmacoelectroencephalography Main Editor: W.M. Herrmann (Berlin) Abstracts Neuropsychobiology 1992:25:61 -82 7th IPEG Symposium, Boca Raton Oral...
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