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Methods and Findings in Experimental and Clinical Pharmacology

Vol. 24, Suppl. C, 2002, pp. 97-120

ISSN 0379-0355

Copyright 2002 Prous Science, S.A.

CCC: 0379-0355/2002

http://www.prous.com

Classification and Evaluation of the Pharmacodynamics of

Psychotropic Drugs by Single-Lead Pharmaco-EEG, EEG

Mapping and Tomography (LORETA)

B. Saletu1, P. Anderer1, G.M. Saletu-Zyhlarz1, O. Arnold1 and R.D. Pascual-Marqui2

1Section of Sleep Research and Pharmacopsychiatry, Department of Psychiatry,

University of Vienna, Vienna, Austria; 2The Key Institute for Brain-Mind Research,

University Hospital of Psychiatry, Zurich, Switzerland

SUMMARY

Utilizing computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (EEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ: the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG profiles and maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described in this paper. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects, therapeutic efficacy and pharmacokinetic and pharmacodynamic data will be discussed. In recent times, imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be demonstrated for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently. © 2002 Prous Science. All rights reserved.

INTRODUCTION

As the target organ of psychotropic drugs is the human brain, the

electroencephalogram (EEG) seems to be one of the best methods for classifying

psychopharmacological agents and evaluating their pharmacodynamics. Specifically, it

seems possible to objectively and quantitatively determine if, how, when and at which

dosage a compound produces an effect on the human central nervous system (CNS).

This has been demonstrated since the early days of the EEG by Berger (1), initially by

eye-ball evaluation (2, 3), in the 1960s and 1970s by computer-assisted quantitative analysis of single leads (pharmaco-EEG) (4-10), and from the 1980s onwards by

multilead analysis and subsequent mapping techniques (11-32).

In the last decade, EEG tomography techniques such as low-resolution brain

electromagnetic tomography (LORETA) have been developed. LORETA computes a

unique 3-dimensional electrical source distribution by assuming that the smoothest of

all possible inverse solutions is the most plausible, which is consistent with the

assumption that neighboring neurons are simultaneously and synchronously active

(33, 34). Recently, Pascual-Marqui et al. presented a new implementation, introducing

in addition to the smoothness constraint a neuroanatomical constraint (35). In this

new version, the solution space is restricted to cortical gray matter and the

hippocampus, as determined in the digitized Probability Atlas (Brain Imaging Center, Montreal Neurologic Institute) based on the Talairach human brain atlas. Thus, LORETA

combines the high time resolution of the EEG with a source localization method that

permits a truly three-dimensional tomography of the brain's electrical activity, which

makes it possible to answer questions on where a drug works within the brain.

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Pharmacodynamics may be investigated in both normal volunteers and patients, and

involves all phases of drug development (phase I-phase IV), i.e., from the first

evaluation of effects on the normal human brain to therapeutic monitoring in patients.

In the first instance, a target-oriented biometrical planning (maybe with the inclusion

of a placebo control) and a target-oriented recording, evaluation, processing and

interpretation of the data are requested. The requirements for such investigations have been described by many authors (6, 8-10, 14-16, 36-40) and are delineated in

the Guidelines of the International Pharmaco-EEG Group (41, 42) and in its guidelines

on statistical design and analysis for pharmacodynamic trials (43).

CLASSIFICATION OF PSYCHOTROPIC DRUGS

Representative drugs of the main psychopharmacological classes, such as

neuroleptics, antidepressants, hypnotics, tranquilizers, nootropics/cognition-enhancing

drugs and psychostimulants, induce (compared with placebo) significant changes in

the quantitatively analyzed EEG, which (graphically displayed) result in different

pharmaco-EEG profiles based on single-lead analysis (mostly O2-Cz) and pharmaco-

EEG maps based on multilead analysis. The most typical profiles derived from numerous double-blind, placebo-controlled trials in our laboratory with over 130

different psychotropic substances are shown in Figure 1.

FIG. 1. Schematic pharmaco-EEG profiles of the main psychopharmacological classes. EEG variables are shown in

the abscissae, differences between drug- and placebo-induced changes are indicated in the ordinates (in terms of

t-values). The 0 line represents placebo. Low-potency sedative neuroleptics mainly induce an increase in theta and

delta, a decrease in alpha and a slight increase in superimposed fast beta activities. In contrast, nonsedative high-

potency neuroleptics mainly increase alpha and alpha-adjacent beta-1 activity. Thymoleptics of the amitriptyline

type mainly produce an increase in theta, a decrease in alpha and an increase in superimposed fast beta activity,

while thymeretics/thymoleptics of the desipramine type mainly enhance alpha activity. Anxiolytic sedatives,

including hypnotics and tranquilizers, increase activity in all beta frequency bands and attenuate alpha activity,

while only hypnotics augment slow activities. Nootropics/cognition enhancing drugs decrease delta and theta and

increase alpha and alpha-adjacent beta activity, while psychostimulants mainly augment alpha and beta-1.

Pharmaco-EEG profiles and maps of neuroleptics

With neuroleptics, at least two major subtypes of pharmaco-EEG profiles may be

differentiated after single-dose administration in normal subjects (Fig. 1). One seen

after sedative neuroleptics (such as chlorpromazine, zotepine, zetidoline, clozapine

and dapiprazole, which, apart from exhibiting their antidopaminergic effects also

reveal antiserotoninergic, antiadrenergic, anticholinergic and antihistaminic actions) is

characterized by an increase in delta and theta activity, a decrease in alpha and, less

consistently, an increase in concomitant fast beta activity. The other is observed after

nonsedative neuroleptics (such as haloperidol) and is characterized by a lack of delta

augmentation and an increase in alpha and/or alpha-adjacent beta activity (17, 44,

45). As will be discussed later, these two pharmaco-EEG types may also be observed

in schizophrenic patients after acute treatment. Single-dose administration of 100 mg

fluperlapine, a sedative low-potency neuroleptic, resulted in a concomitant increase in

delta/theta and beta activity, as well as a decrease in alpha activity, while 5 mg of the

high-potency neuroleptic haloperidol produced opposite changes (46). In the early

days of the pharmaco-EEG, different investigators described distinct profiles for

different neuroleptics (8).

Pharmaco-EEG mapping after sedative neuroleptics, such as 50 mg chlorpromazine

(47) or 30 mg chlorprothixene (16), demonstrated an attenuation of total power (1.3-

35 Hz), an increase in absolute delta and theta power and a decrease in alpha and

beta power. It also showed an increase in the relative power in the delta and theta

and a decrease in the alpha and beta bands, as well as a slowing of the centroids of

the delta/theta, alpha, beta and total power spectrum (Fig. 2). Galderisi et al.described the same findings after the sedative atypical neuroleptic clozapine (29). In

contrast, the nonsedative neuroleptic 3 mg haloperidol, did not change total power,

increased absolute and relative theta and beta power, slightly attenuated relative

alpha-1 power and left the centroids unchanged (Fig. 2). Thus, our pharmaco-EEG

maps were in accordance with earlier pharmaco-EEG profiles based on single-lead recordings (O2-Cz). Certain discrepancies, for instance in regard to the increased beta

activity observed after chlorpromazine in single-lead recordings (O2-Cz), could be

resolved by the topograms, as the observed increase in beta activity was only found

over the vertex (obviously due to sleep-related waves), whereas over all other brain

regions there was a decrease.

FIG. 2. Maps on EEG differences between nine representative drugs of the major psychopharmaceutical classes

and placebo after acute oral drug administration (time of pharmacodynamic peak effect mostly 2 h postdrug).

Statistical probability maps (SPM) depict intergroup differences in total power, absolute delta, theta, alpha-1,

alpha-2, beta power; relative delta, theta, alpha-1, alpha-2, beta power and the centroids of the delta/theta,

alpha, beta and total activity (from top to bottom) (bird's view, nose at the top, left ear left, right ear right, white

dots indicate electrode positions). Orange, red and purple colors represent significant (p<0.10, 0.05 and 0.01,

respectively) increases; dark green, light blue and dark blue indicate significant (p<0.10, 0.05 and 0.01,

respectively) decreases as compared with normal controls. Different drug-induced changes are topographically

displayed after single-dose administration of 50 mg chlorpromazine (n=15), 3 mg haloperidol (n=20), 75 mg

imipramine (n=15), 20 mg citalopram (n=20), 30 mg clobazam (n=15), 2 mg lorazepam (n=15), 20 mg d-

amphetamine (n=15), 20 mg methylphenidate (n=20) and 600 mg pyritinol (n=15). While, for instance, 50 mg

chlorpromazine decreases, 600 mg pyritinol increases total power. As can be seen, drugs of different

psychopharmacological classes produce different pharmaco-EEG maps.

EEG maps after single doses of 5 mg haloperidol in schizophrenics with a

predominantly plus symptomatology did not demonstrate any changes in regard to

absolute power and the centroid, while regarding relative power, an occipital

delta/theta increase was seen (18). After 4 weeks of treatment with daily doses of 22

mg, there was an increase in total power as well as in absolute and relative power in

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the delta/theta and alpha bands, while relative beta power and the centroid were

significantly decreased. Single doses of 200 mg remoxipride induced an attenuation of

total power and relative delta/theta power in the same patient type, as well as after 4

weeks of therapy with 400 mg daily, a further decrease in relative delta/ theta power, as well as an acceleration of the centroid, predominantly frontotemporally. Thus,

haloperidol revealed more sedative effects than the benzamide, which was also proven

psychometrically. Recent studies with another benzamide, amisulpride, in relation to

low doses of fluphenazine in minus symptomatology patients, showed after 2 mg

fluphenazine a left occipitotemporal decrease in delta/theta activity and an

acceleration of the centroid, and after 6 weeks, a decrease in delta/theta and an

increase in alpha activity over many brain regions, together with a decrease in beta

activity (48). Single doses of 50 mg amisulpride also induced a delta/theta decrease,

but an increase in beta activity and an acceleration of the centroid, which was also

seen after chronic administration of 100 mg over 6 weeks. Thus, pharmaco-EEG maps demonstrate differences between different neuroleptics that are dependent upon the

baseline as well as the type of patient, and last but not least, on the dose. The

aforementioned differences may be important when it comes to selecting the right

neuroleptic in the right dosage for the right patient. Schizophrenics with

predominantly negative symptoms, for instance, found to be correlated with increased

delta/theta activity (48), may respond better to nonsedative neuroleptics decreasing

delta/theta activity, than to sedative neuroleptics increasing slow activity.

Pharmaco-EEG profiles and maps of antidepressants

With antidepressants, two main types of pharmaco-EEG profiles may be differentiated

(Fig. 1): a thymoleptic (imipramine- or amitriptyline-like) profile, showing a concomitant increase in slow and fast activities and a decrease in alpha activity

(indicating sedative qualities) and a thymeretic (desimipramine-like) profile, mainly

characterized by an alpha increase and a decrease in slow and fast activities

(suggesting activating properties). Imipramine/amitriptyline-type changes were

observed by us after doxepine, amitriptyline-N-oxide and antidepressants of the newer

generation such as maprotiline, binodaline, danitracene and fluvoxamine (49-51).

DMI-type pharmaco-EEG findings were observed after tranylcypromine (49),

nomifensine (52), pirlindol (53, 54), fluoxetine (55), zimelidine (56), sertraline (56),

sercloremine (57), moclobemide and diclofensine (58).

Pharmaco-EEG maps after sedative antidepressants, such as 75 mg imipramine,

demonstrated an attenuation of total power as well as of absolute delta and theta and alpha power, mainly over anterior brain regions. There was also an increase in relative

delta and theta and a decrease in alpha activity almost ubiquitously, while relative

beta was reduced occipitally (Fig. 2). The delta/theta centroid became accelerated, the

total centroid slowed over posterior regions. Similar findings, although with an

increase in beta power, were described by us after venlafaxine, a neuronal uptake

inhibitor of serotonin, nordrenaline and dopamine (in order of decreasing potency)

(59). Itil et al. described an increase in slow waves over frontal and temporal regions

after 50 mg amitriptyline, while over occipital and parietal ones they observed a

marked alpha decrease and an increase in concomitant beta activity, specifically over

central areas (14). Herrmann and Schärer also described an increase in delta activity after 75 mg amitriptyline, reflecting a decrease in vigilance (60). Occipital alpha power

decreased, beta-1 and beta-3 power increased, while absolute beta-2 power

decreased.

In contrast, in our studies, nonsedative antidepressants, such as 20 mg of the SSRI

citalopram, showed an attenuation of total power, a decrease in absolute delta, theta

and alpha-1 as well as an increase in beta power. There was also a decrease in

relative theta and alpha-1 and a pronounced increase in alpha-2 and beta power, as

well as a slowing of the delta/theta and an acceleration of the alpha, beta and total

centroid (Fig. 2). Tianeptine, a new tricyclic antidepressant enhancing serotonin

reuptake, showed slightly activating properties paralleled by a thymopsychic improvement in doses of 12.5 mg. A 25-mg dose produced an activation in the EEG up

to the fourth hour and a sedation thereafter, accompanied by an initial improvement

in the tymopsyche and differential changes (improved mood, decreased vigility), while

the noopsyche was found improved at all times (23).

Pharmaco-EEG profiles and maps of tranquilizers and hypnotics

Anxiolytic sedatives comprise (according to WHO, 1967) both tranquilizers and

hypnotics, as they have certain pharmacological properties in common. Indeed, they

also share features in pharmaco-EEG profiles, as they all decrease total power and

absolute and relative power of alpha activity, increase absolute and relative power of

beta activity, accelerate the centroid and increase the centroid deviation of the total

activity (Fig. 1). Differences between tranquilizers and hypnotics are predominantly observed in the slow activities. Daytime tranquilizers, such as oxazepam (61),

prazepam (62), bromazepam (63) and clobazam (64) do not induce augmentation of

slow waves in the clinical dosage range, even if they are administered in extremely

high doses, such as 75 and 150 mg prazepam (62, 65). Diazepam may also be

counted in this group, although in the resting condition one may sometimes observe

an increase in delta activity. This is of interest as diazepam is clinically used both as a

daytime tranquilizer and as a sleep-inducing drug. On the other hand, there are

benzodiazepines, which, in the low dosage range produce a tranquilizer profile, but in

the higher dosage range a night-time tranquilizer (hypnotic) profile, increasing delta

activity (Fig. 1). This was observed with the benzodiazepines brotizolam, lopirazepam,

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flurazepam (63, 66), flunitrazepam (67), triazolam (68), temazepam (64), cloxazolam

(69) and lorazepam (63, 64).

Pharmaco-EEG maps confirmed this subclassification, as observed, for instance, after

diazepam, clobazam, lorazepam and suriclone (70-73). Daytime tranquilizers, such as

30 mg clobazam, slightly attenuated total power, further decreased absolute and

relative delta, theta and alpha, increased beta power, slowed the delta/theta and beta

centroid and accelerated the total centroid (Fig. 2). Night-time tranquilizers, such as 2

mg lorazepam, markedly attenuated total power, augmented absolute delta and beta

and decreased theta and alpha power, increased relative delta, theta and beta and

decreased alpha power, further slowed the delta/theta centroid and accelerated the

alpha and total centroid (the latter to a smaller extent than the daytime tranquilizer

30 mg clobazam) (Fig. 2). Frontal, central and parietal regions showed most prominent changes, as was noted also by other authors (14, 60). However, the

serotonin-5HT1A

agonist buspirone induced different types of changes, mainly

characterized by an increase in theta power, an acceleration of the centroid of delta

and theta power and no modification of alpha activity, but a slowing of its centroid and

a tendency towards a reduction of beta activity, as well as a slowing of the centroid of

the total activity (74).

Pharmaco-EEG profiles and maps of psychostimulants

Psychostimulants, such as d-amphetamine (75) and methamphetamine (76), but also

pharmacologically unique wake-promoting agents, such as adrafinil and modafinil (77), induce pharmaco-EEG profiles predominantly characterized by an increase in

alpha and alpha-adjacent beta activity, as well as by a tendency towards a decrease in

slow and fast activities (Fig. 1). Contrasting reports in the literature seem to be due to

differences in regard to baseline, dose and even recording conditions (resting EEG [R-

EEG] vs. vigilance-controlled EEG [V-EEG]), which was observed in pharmaco-EEG

mapping investigations (47); while in the V-EEG, total power tended to decrease after

20 mg d-amphetamine (Fig. 2), in the R-EEG it increased significantly. In the V-EEG,

delta/theta power decreased and there was a similar tendency in the alpha power,

while in the R-EEG, a significant decrease in delta/theta power, but increase in alpha

power was noted. In the beta frequencies, absolute power remained unchanged in the V-EEG, while it was augmented in the R-EEG. The total centroid was always

accelerated. Relative delta/theta power decreased specifically in the R-EEG, relative

alpha activity generally remained unchanged in the V-EEG, but increased in the R-

EEG, while relative beta power increased under both recording conditions. Differences

to nootropics seem to lie in the total power, which was reduced after stimulants such

as methylphenidate (Fig. 2) but rather increased after nootropics. This corresponds to

the changes observed with antidepressants of the desimipramine type.

Caffeine (250 mg) induced only minimal changes in pharmaco-EEG maps,

characterized by a decrease in total power and absolute power in the alpha and beta

frequencies (16). The centroid showed a slowing over anterior brain regions, relative power generally remained unchanged. The most prominent finding was the

acceleration of the alpha centroid, also reported by Etevenon et al. (78). Itil et al.described similar findings (14).

Pharmaco-EEG profiles and maps of nootropics or cognition-enhancing drugs

Nootropics or cognition-enhancing drugs generally decrease delta and theta and

increase alpha and alpha-adjacent beta activity compared with placebo (Fig. 1). Drugs

producing such a pharmaco-EEG profile belong to different chemical subclasses, such

as co-dergocrine-mesilate and nicergoline of the ergot alkaloids (79, 80); vincamine;

vinconate; SL 76100 and SL 76188 of the vincamine alkaloids and analogues (75, 81,

82); ifenprodil; tinofedrine; suloctidil of the phenylethanolamines (83); piracetam;

etiracetam and aniracetam of the pyrrolidine derivatives structurally related to gamma-aminobutyric acid (GABA) (84-88); ethophylline of the xanthine derivatives

(85); buflomedil (89); ouabain (g-strophantine) of the cardiac glycosides; and

acrihelline of the cardiac steroids. Further drugs inducing such CNS changes were

piridoxilate (a glyoxilic acid substitute pyridoxine) (90), Actovegin® (a standardized

deproteinized hemoderivative) (91), hexobendine and its combination with

ethophylline and ethamivan (Instenon forte®) (85, 92) and the calcium antagonist

cinnarizine (8, 85).

These nootropic-induced changes are just opposite to EEG alterations in pathological

aging (22) and reflect an improvement in vigilance. Vigilance is defined as the

dynamic state of the total neuronal activity, which determines the availability and

organization of man's adaptive behavior (93).

Pharmaco-EEG maps can demonstrate such changes even more impressively. As can

be seen in Figure 2, 600 mg pyritinol augmented total power, absolute alpha-1 and beta power and decreased alpha-2 power, decreased relative delta/theta and alpha-2

and increased relative alpha-1 power, while the centroid of the delta/theta and total

power was accelerated and the alpha centroid slowed. Ergot alkaloids showed similar

findings regarding absolute power and the centroid, as well as relative power in the

delta/theta frequency, but showed a significant augmentation of relative beta activity

(19). DUP 996 (linopirdine), a novel cholinergic drug, also increased total power and

absolute alpha and alpha-adjacent beta power (20, 94). Studies in patients with age-

associated memory impairment, senile dementia of the Alzheimer type and

multiinfarct dementia, as well as investigations with an experimentally induced



hypoxic hypoxidosis in normal volunteers, support the above-mentioned findings of

vigilance improvement (21, 22, 48, 73, 95-98).

PROBLEMS CONCERNING EEG CLASSIFICATION

Although the classification by pharmaco-EEG methods has been applied successfully even in drugs that had not been identified as psychoactive in animal pharmacology,

one has to be aware of certain problems. The pharmaco-EEG profile itself seems to be

influenced by three factors: i) the drug-specific effect; ii) drug-induced changes in

vigilance; and iii) spontaneous fluctuations in vigilance.

This often explains the similarity between profiles of different psychopharmaceutical

classes, specifically if one does not consider time-efficacy and dose-efficacy relations.

One must further keep in mind that the method is basically empirical, and that data

may be viewed from a different angle as their amount increases. It is of interest that

certain antihistaminics, such as diphenhydramine, produce changes similar to those

induced by antidepressants (AMI-type) (8). Thus, the question arises as to whether

such antidepressant EEG profiles also indicate antihistaminergic or anticholinergic effects, which both drug groups have in common. This presumption has been

confirmed by observations concerning yet another similar profile of a member of a

different drug class, i.e., ketamine, a phencyclidine derivative, utilized as a

dissociative anaesthetic (which is misused as a hallucinogenic drug and also has

anticholinergic effects [99]) or clozapine, an anticholinergic neuroleptic drug. Thus, in

classification attempts, it is important to consider dose-efficacy and time-efficacy

relations, as well as recording conditions (e.g., vigilance-controlled vs. resting state).

Moreover, the pretreatment state of the CNS seems to be an important variable.

TIME-EFFICACY RELATIONS

The time course of the cerebral bioavailability of a psychotropic drug at its target organ --the human brain --can impressively be demonstrated by changes in only one

variable over time (Fig. 3) or based on multivariate statistics utilizing mapping of

MANOVA and subsequent Hotelling T2 test results (Fig. 4). In phase I studies, one has

the possibility of objectively and quantitatively evaluating the onset, maximum and

end of the central effect of a drug. These pharmacodynamic changes can be related to

pharmacokinetic data (see below), but in patients, the evaluation of single-dose

effects may provide valuable insight into the prognostic aspects of a planned

treatment (e.g., beta decrease in schizophrenics, delta decrease in dementia

patients).

FIG. 3. Prediction concerning the equipotency of cloxazolam and the reference drug diazepam by pharmaco-EEG

and subsequent confirmation by long-term clinical trials in generalized anxiety disorder patients (n=2x15). Dose-

and time-related changes in alpha activity (R-EEG, relative power) after single-dose administration in 10 normal

subjects are shown in the upper part of the figure. While placebo does not induce any systematic change,

cloxazolam produces a dose-dependent decrease in alpha activity. This effect starts in the 2nd h, peaks in the 4th h

and can still be seen in the 8th h after oral drug administration. In contrast, 5 mg diazepam produces its maximal

effect in the 2nd h after drug administration. 5 mg diazepam is located between 1 mg and 3 mg cloxazolam

(equipotency C:D is 1:2.5). This prediction of equipotency based on single-dose pharmaco-EEG studies in normals

was confirmed by subsequent clinical trials over 6 months in generalized anxiety disorder patients. The optimal

titrated daily doses of cloxazolam and diazepam after 1, 3 and 24 weeks of treatment are shown. Again, the

relationship is 1:2.5.

DOSE-EFFICACY RELATIONS

Dose-efficacy relations can also be demonstrated on the basis of changes in single



variables, as seen in Figure 3, or based on multivariate techniques such as MANOVAs

with subsequent Hotelling T2 tests and mapping techniques (Fig. 4). By such means,

one gains insight into the minimal centrally effective dose in man, which is important

for later open and double-blind, placebo-controlled trials, in order to avoid complicated

and frustrating investigations in patients. One may also obtain information on changes

in CNS effects from certain dosage points onwards, as for instance the switch of CNS-activating to CNS-inhibitory effects after benzamides or the changes from a daytime to

a night-time tranquilizer profile with benzodiazepines.

FIG. 4. Brain maps showing differences between drug-induced and placebo-induced central effects after 0.1 mg,

0.2 mg and 0.4 mg suriclone and 1 mg alprazolam (left to right comumn, respectively) at hours 1, 2, 3, 6, and 8

(top to bottom row). The vertex view shows nose on the top, occiput on the bottom, left ear to the left and right

ear to the right. Electrode positions are indicated by white dots. Maps are based on Hotelling's T2 obtained from

multivariate tests in repeated measures ANOVA on the relative power of the nine frequency bands [ln

(power%/100-power%) transformations] for each electrode (R-EEG, n=15). The color key shows T2 values with

hot/red color indicating significant differences: larger than 2.96=p<0.10, larger than 4.1=p<0.05 and larger than

7.98=p<0.01. With increasing doses, suriclone exerts an increasing effect on the human brain compared with

placebo, which may be observed topographically first over the vertex, right parietal and temporal regions. The

encephalotropic effects of the single oral doses start as early as in the 1st hour and reach up to the 8th hour. The

reference compound, 1 mg alprazolam, induces most CNS effects.

BIOEQUIPOTENCY

In a similar way as time- and dose-efficacy relations, the bioequipotency of an

experimental compound can be explored and compared with that of a clinically well-

known drug on the market. This is of special importance for determining the dosage in

later clinical drug trials in patients. Without such calculations, the different intensity of the CNS effects of a drug in normal volunteers and patients would pose a great

problem for predicting the optimal single and daily dosages for patients on the basis of

phase I trials in normal volunteers. As can be seen in Figure 3, the equipotent dosage

of the novel cloxazolam to the well-known 5 mg diazepam was found to be 2 mg,

which would result in a dose relationship of cloxazolam:diazepam of 1:2.5 (8). In a

subsequent double-blind, placebo-controlled clinical trial over 6 months in 15

generalized anxiety disorder patients, the psychiatrist could titrate the optimal dosage

of diazepam and cloxazolam. The dosages found in the first, third and 24th week of

treatment for the average, minimal and maximal daily dosage resulted in a dose

equipotency of 1:2.5, which confirmed our pharmaco-EEG predictions (Fig. 3). In a

similar way, the bioequipotency of different galenic formulations, such as a novel

mixed micelle solution of diazepam vs. the standard formulation, can be determined

(Fig. 5).



FIG. 5. Images of topographic differences in relative power changes of 16-20 Hz beta activity between two

differently formulated drugs (mixed micelles vs. standard solution of diazepam 10 mg) given intravenously and

intramuscularly (n=15; V-EEG; A12). While no significant differences between the two formulations could be

observed after intravenous injection, the new mixed micelles solution was superior to the standard solution of

diazepam in the 2nd and even in the 6th hour when given intramuscularly. The greater increase in beta activity

over certain areas indicates a better absorption of the drug in the muscle.

THE RELATIONSHIPS BETWEEN PHARMACOKINETICS AND

PHARMOCODYNAMICS

When exploring pharmacokinetic/-dynamic relationships, important information may

be gained on the penetration of drugs through the blood-brain barrier to the site of

the deep compartment receptor, on receptor binding, "hit-and-run" phenomena and

active metabolites (52, 59). This is of particular interest if there is a time lag between

plasma peaks and pharmacodynamic peak effects, such as that observed after the

administration of nomifensine (Fig. 6). If one plots blood levels and EEG changes in

the usual two-dimensional graphs for kinetic/dynamic comparison, a scatter appears,

suggesting a lack of linear correlation. However, if one shows these points in their

time sequence, a system appears in the scatter, resulting in a loop-shaped curve (hysteresis loop) (Fig. 7). This indicates that the maximal pharmacodynamic effect of

nomifensine is not on the rising but on the descending slope of the kinetic curve. The

larger the area within the loop, the greater the delay between changes in blood levels

and CNS activity.



FIG. 6. Comparison between time-related changes in serum concentrations, EEG and psychometry after oral and

intravenous nomifensine (n=10). Note the time lag between the blood level peak (1st to 2nd hour) and the

maximum pharmacodynamic effect (6th hour).

FIG. 7. Relationship between nomifensine serum levels and total V-EEG changes after 75 mg nomifensine i.v.

Numbers in circles refer to time of measurement (hours postadministration). A loop-shaped curve (hysteresis

loop) indicates that the maximum pharmacodynamic effect is not on the rising but on the descending slope of the

kinetic curve. The hysteresis loop depends upon the penetrability of the blood-brain barrier by psychotropic drugs

and/or active metabolites.

By exploring pharmacokinetic/dynamic relations, we can also discover which of the

investigated pharmacodynamic variables are the most sensitive for indicating drug

effects and whether human behavior changes its type with increasing doses. When

determining plasma concentrations after temazepam and flunitrazepam in ng/ml

temazepam-equivalents by a radio receptor assay, peak plasma levels were observed after both drugs in the first hour, with a rapid decline after temazepam, while after

flunitrazepam plasma levels decreased only slowly. Regression and correlation

analyses between blood levels and EEG or psychometric changes after temazepam

demonstrated that beta activity and the centroid of the EEG were positively correlated

with plasma levels, while alpha activity as well as the psychometric variables

attention, concentration, the alphabetical reaction test score, the Pauli test score,

numerical memory, psychomotor activity, complex reaction, reaction time, flicker

frequency and skin conductance level were negatively correlated with plasma levels

(Table 1). Based on the intercept, it can be concluded that EEG beta activity was the

most sensitive variable, followed by the EEG centroid and EEG alpha activity. Psychometric variables started to deteriorate from a blood level of approximately 250

ng/ml upwards, while below this level an improvement may be expected. In fact,

blood levels higher than 250 ng/ml were seen only after 40 mg temazepam in the first

to the sixth hour and after 20 mg in the first and second hour. Our findings indicate

that 20 and 40 mg temazepam exert sedative, sleep-inducing effects, while 10 mg

show rather tranquilizing properties, which was confirmed by all-night

polysomnographic studies in sleep- disturbed subjects (100, 101).



Maps on the correlation between plasma levels and EEG changes can also lead to a better understanding of the pharmacodynamic effect of a novel compound, as we

demonstrated in a trial comparing CNS effects of a serotonin reuptake inhibiting drug,

fluvoxamine, with those induced by the serotonin uptake enhancing compound

tianeptine (23) (Fig. 8). The higher the tianeptine plasma level, the more pronounced

were both absolute and relative powers in the beta frequency bands, mainly over

frontotemporal regions. Furthermore, the higher the plasma levels, the faster the

centroid and the higher the centroid deviation of the total activity. These findings

indicate a more activating property in tianeptine in the highest dosage range

investigated.

FIG. 8. Correlation maps between changes in the EEG and the concentration of tianeptine in human plasma. Each

of the 36 maps shows the topographic image of correlation coefficients between the tianeptine plasma level and a

specific EEG variable. The upper part of the figure shows 13 correlation maps of absolute power variables, the



middle part of 12 relative power variables and the lower part of 11 centroid and dominant frequency measures.

The 8-color key represents positive (hot/red colors) and negative (cold/blue colors) correlation coefficients.

Significance levels are shown in the insert. The higher the tianeptine plasma level, the more pronounced is both

absolute and relative power in the beta frequency bands, mostly over the fronto-temporal regions. Furthermore,

the higher the plasma levels, the faster the centroid and the higher the centroid deviations of the total activity.

ACUTE VERSUS CHRONIC EFFECT, CHANGES IN NORMAL SUBJECTS AND PATIENTS

In contrast to the abundant knowledge of acute drug effects on brain activity in

normal subjects, there is a lack of data concerning chronic CNS effects. The reason for

this lies mainly in the side effects induced by neuroleptics and antidepressants.

However, with the advent of a new generation of antidepressants, the possibility arose

of studying compounds with a better tolerability over a longer period of time, even in

normal subjects. After 2-week administration of pirlindol, a new nordrenaline uptake

and monoamine oxidase (MAO) inhibitor, we found less effect than after acute dosing

in normal subjects, which suggests adaptation phenomena (53). The latter are well

documented at the receptor level (downregulation). After anxiolytics and nootropics,

we found similar acute and chronic profiles, while after neuroleptics different changes were observed (46).

We found differences in CNS changes induced by a certain drug between normal

volunteers and patients, which may be due not only to different sedation thresholds

(68), but mainly to differences in brain function between untreated patients and

normal subjects, which have been discussed in a separate paper (102).

CNS EFFECTIVENESS AND THERAPEUTIC EFFICACY

The relationship between drug-induced quantitative EEG changes and therapeutic

efficacy can be considered from several points of view.

Some EEG changes are indicative of certain clinical alterations in subsequent clinical trials. There are numerous examples for this relationship in the pharmaco-EEG

literature (6, 53, 68, 103 ). In this instance, the pharmaco-EEG can be seen as a

predictive model in human pharmacology, not unlike the models in animal

pharmacology. This applies if the drug-induced EEG changes in normal subjects are

different from those in patients. This is often the case with EEG changes after

nootropics, suggesting a vigilance improvement in both normally aging subjects and

demented patients (104, 105).

Pharmaco-EEG changes are directly linked to behavioral alterations in both normal

subjects and patients. In various studies we demonstrated that EEG alterations

reflecting a vigilance improvement after acute drug administration in normal elderly

subjects were similar to those observed in geriatric and organic brain syndrome patients, which in turn were associated with clinical improvement (16, 19, 90, 98,

105, 106).

Looking closely at the differences between nine major mental disorder patients and

normal controls in 15 topographically displayed EEG measures and the pharmaco-EEG

maps of the representatives of the major psychopharmacological classes, one may see

that the differences between patients and normal controls are in certain instances

opposite to the changes induced by the drugs compared with placebo. This fact speaks

for a key-lock principle in diagnosis and psychopharmacological treatment of mental

disorders, which has been discussed elsewhere (102). The differences between

generalized anxiety disorder (GAD) patients and normal controls (26), for instance, are opposite to the changes induced by tranquilizers compared with placebo in both

normal subjects (8, 61-66, 68, 73, 79) and patients (106) (Table 2).

Finally, we found acute quantitative EEG changes to be of prognostic value regarding



subsequent therapeutic outcome: the greater the increase in average frequency 2 h

after the administration of single oral doses of 10 mg lorazepam, the more

pronounced the clinical improvement (Zung SAS score) in patients after 3 weeks of

chronic therapy.

PHARMACO-EEG IN THERAPEUTIC MONITORING

Quantitative EEG and brain mapping techniques can be utilized in therapeutic

monitoring of both an individual patient (Fig. 9) and a patient group (Fig. 10), and as a prognostic indicator, as described for neuroleptic- induced EEG changes in

schizophrenics. Negative schizophrenia with increased delta/theta activities, for

instance, should respond better to neuroleptics decreasing slow activity than to those

increasing it (48).

FIG. 9. Brain maps of absolute delta power in a therapy-responsive and a therapy-resistant MID patient (left and

right column, respectively) before (upper row) and after (middle row) 8 weeks of treatment with 20 mg nicergoline

daily as well as statistical probability maps (lower row). The color key represents absolute delta power in V2 or p

values. While the therapy-responsive patient shows a decrease in slow activity (vigilance improvement), the

therapy-resistant patient shows an increase (vigilance deterioration).

FIG. 10. Maps on the effects of nicergoline (8 weeks, 2×30 mg/day; n=18) and placebo (n=22) on different EEG

frequency bands in MID patients. Changes in relative delta/theta, alpha-1, alpha-2 and beta power (top to bottom)

after nicergoline and placebo, compared with baseline, are shown in the left and middle column, respectively, inter

drug differences in the right column. The color key shows t-values; hot colors represent an increase (purple



p<0.01, red p<0.05, ochre p<0.10), cold colors a decrease (dark blue p<0.01, middle blue p<0.05, green-blue

p<0.10). While nicergoline decreases delta/theta and increases alpha-1 and alpha-2 power, after placebo

administration an increase in slow alpha and a decrease in beta power occur. Thus, interdrug comparison shows

that nicergoline produces a decrease in delta/theta and an increase in alpha-2 and beta power, thereby improving

vigilance (Saletu et al., 1995).

In the single case, therapy resistance is indicated by a lack of changes in the EEG after

a certain dosage of a particular drug (Fig. 9). If a patient reacts to a drug clinically, he

also shows changes in his EEG. However, it has to be stressed that differences to a

control population, as for instance expressed in z-values, may still point out the

patient as such. Group differences between therapy-responsive and -resistant patients

have been described by us repeatedly (8).

Of course, there may also be different drug-induced changes in different nosological

subgroups within a certain illness. As we showed with xantinolnicotinate, there were

differences in drug-induced changes, in regard to both type and locations in SDAT and

MID patients (22). While SDAT patients showed, as the most characteristic change, an increase in slow alpha activity over frontal regions, MID patients showed a decrease in

delta and theta activity and an increase in beta activity over fronto-polar regions.

Finally, several studies suggested that quantitative EEG changes after single doses are

of prognostic value in regard to the therapeutic response of patients: the more

pronounced the acceleration of the average frequency 2 h after one acute dose of

lopirazepam, the better the clinical and therapeutic response after 3 weeks of

treatment (68).

IDENTIFYING BRAIN TARGETS OF PSYCHOTROPIC DRUGS BY EEG

TOMOGRAPHY (LORETA)

Imaging of drug effects on regional brain electrical activity by means of EEG tomography in healthy subjects might be used for identifying brain areas

predominantly involved in psychopharmacological action (108, 109).

In a recent double-blind, placebo-controlled, cross-over design study, LORETA

identified brain areas characterized by a change in electrical activity after single oral

doses of representative drugs of four different psychopharmaceutical classes, i.e.,neuroleptics (haloperidol), antidepressants (citalopram), tranquilizers (lorazepam) and

psychostimulants (methylphenidate), compared with placebo.

METHODS

Subjects

Twenty normal volunteers (10 males, 10 females) aged 23-34 years, 18 right-handed, 2 left-handed, were included. The subjects were in good health, totally drug-free and

nonsmokers. They received randomly at weekly intervals single oral doses of placebo,

3 mg haloperidol, 20 mg citalopram, 2 mg lorazepam and 20 mg methylphenidate.

The study was performed in accordance with the relevant guidelines of the Declaration

of Helsinki, 1964, as amended in Tokyo, 1975, Venice, 1983, Hong Kong, 1989, and

Somerset West, 1996. The protocol was approved by the ethics committee of the

University of Vienna, School of Medicine, and the General Hospital of Vienna.

Data acquisition and analysis

A 3-min vigilance controlled EEG and a 4-min resting EEG with eyes closed was

recorded at hours 0, 1, 2, 4, 6 and 8. In addition to 19 EEG channels (Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1 and O2 referenced to

averaged mastoid electrodes), vertical and horizontal electrooculograms (EOG) were

recorded (time constant: 0.3 s; high frequency response: 35 Hz) and digitized one-

line with a sampling frequency of 102.4 Hz. After minimization of ocular artifacts,

automatic artifact identification and recomputation to average reference, spectral

analysis was performed for artifact-free 5-sec epochs, resulting in a frequency

resolution of 0.2 Hz. For each recording, six 5-sec epochs of artifact-free, vigilance-

controlled EEG were included in the analysis. Because different EEG frequencies reflect

different functions, data were digitally filtered into seven frequency bands according to

Kubicki et al. (110): delta (1.5-6 Hz), theta (6-8 Hz), alpha-1 (8-10 Hz), alpha-2 (10-

12 Hz), beta-1 (12-18 Hz), beta-2 (18-21 Hz) and beta-3 (21-30 Hz). Subsequently, LORETA was used to estimate the 3-dimensional intracerebral current density

distribution. LORETA images represent the power in 2394 voxels with a spatial

resolution of 7 mm (35).

Statistical evaluations

Paired-samples t-tests were computed for log-transformed LORETA power at each

voxel to evaluate differences between drug- and placebo-induced changes at different

hours. These voxel-by-voxel t-values were displayed as statistical parametric maps. A

single null hypothesis was tested for 'omnibus' significance (111). The Talairach

coordinates of the highest t-value were determined. If this t-value was significant

(p<0.05), the number of neighboring voxels constituting a suprathreshold region with p<0.05 was calculated and tested for significance by means of a binomial test (112).

If more than one nonconfluent suprathreshold region was found, Bonferroni correction

was performed. On the basis of the Structure-Probability Maps Atlas (113), the

number of significant voxels in each lobe (frontal, parietal, occipital, temporal, limbic



and sublobar), gyrus, and Brodmann area of the left and the right hemisphere was

computed separately for each suprathreshold region.

PHARMACO-EEG TOPOGRAPHY

Maps depicting differences between drug- and placebo-induced alterations in seven

frequency bands according to Kubicki et al. (110) are shown for the pharmacodynamic

peak effects, which for lorazepam and citalopram were in the sixth hour post drug,

and for haloperidol and methylphenidate in the fourth hour post drug (Fig. 11).

Lorazepam (2 mg) induced an increase in delta power, a decrease in theta, alpha and

beta-1 power and an increase in fast beta power. In contrast, 3 mg haloperidol

induced significant increases in delta, fast alpha and beta power. The main effect of 20 mg methylphenidate was an increase in fast alpha and a decrease in fast beta activity.

After 20 mg citalopram, delta and alpha-1 power decreased, whereas alpha-2 and fast

beta power increased. Thus, drugs of different pharmacological classes induced

different pharmaco-EEG maps.

FIG. 11. Significant probability maps (SPMs) showing differences between drug-induced and placebo-induced

central effects after 2 mg lorazepam, 3 mg haloperidol, 20 mg methylphenidate and 20 mg citalopram (n=20

normal healthy subjects) at the time of the pharmacodynamic peak effect (6th hour post drug for lorazepam and

citalopram; 4th hour post drug for haloperidol and methylphenidate). SPMs depict placebo-corrected drug effects in

absolute delta, theta, alpha-1, alpha-2, beta-1, beta-2 and beta-3 power (nose at the top, left ear left, right ear

right, white dots indicate electrode positions). Orange, red and purple colors represent significant increases

(p<0.10, 0.05 and 0.01, respectively); light blue, dark blue and violet indicate significant decreases (p<0.10, 0.05

and 0.01, respectively), as compared to placebo. Lorazepam induces the typical pharmaco-EEG maps of anxiolytic

sedatives, characterized by a decrease in theta, alpha-1 and alpha-2 power as well as an increase in delta, beta-2

and beta-3 power. Haloperidol increases inhibitory delta activity, but predominantly alpha-2 and beta activity,

which reflects activating properties of the drug in this low dosage. Methylphenidate clearly exhibits stimulatory

properties characterized by an increase in alpha-2 and a decrease in beta-2 and beta-3 activity as well as a

tendency towards a decrease in theta activity. Citalopram reveals itself as an activating antidepressant, as alpha-2

and beta power increase and delta, theta and alpha-1 activity decrease.

PHARMACO-EEG TOMOGRAPHY

The results of the voxel-by-voxel statistics showing differences between drug- and

placebo-induced changes in current source density evaluated by LORETA are displayed

as LORETA-images in Figures 12-15 for citalopram, methylphenidate, haloperidol and

lorazepam, respectively. Table 3 summarizes the results of the omnibus significance

test for the different drugs and frequency bands. For significant differences, the predominantly involved hemispheres and lobes are given.



FIG. 12. Effect of 20 mg citalopram on brain electrical activity at the pharmacodynamic peak (6HR-PRE). Images

are based on voxel-by-voxel t-values of differences between drug- and placebo-induced changes for delta and

theta, alpha-1 and alpha-2, and beta-1, beta-2 and beta-3 frequency bands (n=20). Red colors indicate increases,

blue colors decreases compared with placebo. Black arrows indicate the extreme t-value of a significant

suprathreshold region. For the size of the suprathreshold region see Table 1. For each frequency band, axial,

sagittal and coronal slices through the voxel of the extreme t-value at the (X,Y,Z)-Talairach coordinate are

displayed. Structural anatomy is shown in gray scale. (L: left, R: right; A: anterior, P: posterior). Citalopram

induces an increase in absolute delta power in BA4 of the left precentral gyrus, a significant increase in alpha-2

power in BA22 of the right superior temporal gyrus, an increase in beta-1 power in BA21 of the right superior

temporal gyrus, an increase in beta-2 power bilaterally in BA20 of the inferior temporal gyrus and, most

pronouncedly, an increase in beta-3 power, with the maximum bilaterally in BA6. The increase in alpha-2 and beta

power reflects activating properties of the drug.



FIG. 13. Effect of 20 mg methylphenidate on brain electrical activity at the pharmacodynamic peak (4HR-PRE).

Images are based on voxel-by-voxel t-values of differences between drug- and placebo-induced changes for delta

and theta, alpha-1 and alpha-2, and beta-1, beta-2 and beta-3 frequency bands (n=20). For a technical

description of the images see Figure 12. Methylphenidate predominantly induces an alpha-2 augmentation in the

right temporal and limbic lobe, but also left occipitally, temporally and parietally as well as a beta-1 attenuation

left frontally and a delta augmentation in the right temporal, frontal, limbic and sublobar cortices.



FIG. 14. Effect of 3 mg haloperidol on brain electrical activity at the pharmacodynamic peak (4HR-PRE). Images

are based on voxel-by-voxel t-values of differences between drug- and placebo-induced changes for delta and

theta, alpha-1 and alpha-2, and beta-1, beta-2 and beta-3 frequency bands (n=20). For a technical description of

the images see Figure 12. Haloperidol induces a local increase in absolute delta power in the left BA20, followed by

an increase in BA8, a local theta increase in the right BA40, but also left BA20 and medial BA6. The changes,

however, do not reach the suprathreshold level. Haloperidol induces a bilateral alpha-2 augmentation in temporal

regions, an increase in beta-1 power in BA6 and the left BA40, in beta-2 power in the left BA40 and medial BA31,

and in beta-3 power in BA23 in the cingulate gyrus, thereby revealing an activating mode of action in low doses.



FIG. 15. Effect of 2 mg lorazepam on brain electrical activity at the pharmacodynamic

peak (6HR-PRE). Images are based on voxel-by-voxel t-values of differences between

drug- and placebo-induced changes for delta and theta, alpha-1 and alpha-2, and

beta-1, beta-2 and beta-3 frequency bands (n=20). For a technical description of the

images see Figure 12. Lorazepam decreases theta and alpha-1 power ubiquitously,

with extremes seen in BA10 and 11 of the prefrontal cortex. Alpha-2 power is also widely attenuated, which becomes most evident in the left BA37. Beta-1, beta-2 and

beta-3 power shows the most pronounced augmentation in BA6 and 5.



Compared with placebo, drugs of different psychopharmacological classes, such as

tranquilizers, neuroleptics, psychostimulants and antidepressants, induce-- compared

with placebo--different changes in quantitatively analyzed EEG target variables, such

as delta, theta, alpha and beta activity, reflecting differential effects on inhibitory,

normal and excitatory EEG activities. Excitingly, for the first time we were able to

demonstrate on the basis of multichannel EEG recordings and LORETA that drugs of

different psychopharmacological classes affect brain structures differently. For instance, the changes in fast alpha and beta power induced by the tranquilizer

lorazepam predominantly involved brain regions in the left hemisphere, while those

induced by the antidepressant citalopram were located in the right hemisphere.

Interestingly, drug-induced changes in the occipital lobe were only seen in the alpha

frequency band, with the exception of theta activity after lorazepam, which affected all

2394 voxels. Drug-induced changes in the beta frequency bands predominantly

involved voxels located in the frontal and limbic lobes. Finally, drug-induced changes

in the delta frequency range were seen predominantly in the temporal lobe: a right

temporal increase after methylphenidate and a left temporal increase after citalopram.

LORETA IMAGES

Citalopram (antidepressant)

After 20 mg citalopram p.o., LORETA delta power increased left temporally and

frontally (Fig. 12), which had not been seen in the EEG topography (Fig. 11).

Citalopram-induced increases in fast alpha and beta activities were predominantly

observed in right frontotemporal cortical areas (Fig. 12).

In detail, our LORETA findings after 20 mg citalopram demonstrated a widely

distributed increase in beta-3 power, reaching its maximum bilaterally in BA6, a region

involved in motor function, an increase in beta-2 power, reaching its maximum

bilaterally in BA20 of the inferior temporal gyrus, and in beta-1 power in the right

BA21 of the superior temporal gyrus, followed by an alpha-2 augmentation in the right BA22. While BA22 constitutes the auditory association area, there are also projection

fibers to area 21, the origin of the major portion of the bundle of Turk, which also

receives projection fibers from area 20. The results of a predominantly right

hemispheric increase in alpha-2 and beta-1 activity after 20 mg citalopram are in

agreement with the postmortem neurochemical studies of Arato et al. (114), implying

a higher 5HT turnover in the right nondominant affective hemisphere than in the left

cognitive hemisphere (already reported by Flor-Henry [115]). Intravenous

administration of clomipramine induced an increase in the P300 latency of auditory

evoked potentials and a shift to the right in the distribution of the peak values,

resulting in increased activity in the right hemisphere, possibly due to greater

inhibition in the left hemisphere (116). The latter findings were in agreement with a LORETA increase in delta power in the left temporal, frontal and parietal region.

Interestingly, these changes did not reach the level of statistical significance in our

EEG mapping investigations, which even showed a right temporo-occipital decrease in

slow activity, as described by Lader et al. (117). The left temporal and frontal delta

increase observed by us after citalopram was in agreement with a significantly

reduced regional cerebral blood flow measured by SPECT in the anterior and lateral

part of the left temporal cortex as well as the anterior, lateral and posterior part of the

left midfrontal cortex, reported by Van der Linden et al. (118).

Methylphenidate (psychostimulant)

Methlyphenidate (20 mg) p.o. induced a significant increase in LORETA delta power in the basal temporo-frontal brain region and a significant decrease in LORETA beta-1

power in the left prefrontal cortex (Fig. 13). This is of interest because these drug

effects had not been observed in the EEG mapping (Fig. 11). The increase in LORETA

alpha-2 power, however, was in accordance with the EEG-mapping results.

In detail, methylphenidate induced a delta power increase in the right temporal,

frontal, limbic and sublobar cortices, with the maximum seen in the right BA38 of the

superior temporal gyrus. Absolute theta power showed a local decrease in BA22 of the

right insula, constituting an auditory association area. There was an increase in alpha-

2 power, with one suprathreshold region showing its maximum in BA21 of the right

middle temporal gyrus and a second in BA19 of the left precuneus, the seat of vertical and oblique conjugate movements of automatic type. An increase in normal alpha

activity in this region could explain improvement in the connection of area 19 to the

frontal oculomotor center, the sensorimotor cortex and the auditory cortex by long

association bundles. Absolute beta-1 power, however, decreased, with the extreme

seen over BA10 of the prefrontal cortex. There was a local increase in beta-2 power in

BA19 bilaterally in the precuneus and a local decrease in beta-3 power in BA23

belonging to the cingulate gyrus. Volkow et al. demonstrated that single doses of 0.5

mg/kg methylphenidate i.v. tended to decrease the metabolism, as measured by PET

and [11 C] cocaine, while repeated doses (0.5 mg + 0.25 mg/kg) administered i.v. 90

min apart from each other increased it, with the differences reaching the level of

statistical significance in the frontal, parietal and occipital cortices and the hippocampus (119). In our LORETA studies, deactivating properties were reflected by

the aforementioned delta increase, while activating properties were reflected by an

alpha-2 increase in the right temporal and limbic and left occipital, temporal and

parietal cortices.



Haloperidol (neuroleptic)

After 3 mg haloperidol p.o., delta power increased in the left temporal lobe (Fig. 14),

but the changes did not reach statistical significance in the omnibus test and thus did

not constitute a suprathreshold region. However, the haloperidol-induced increases in

fast alpha-2, beta-1, beta-2 and beta-3 power were significant. Alpha-2 power

increased symmetrically in the posterior brain region and beta power increased

medially in the frontal lobe and cingulate gyrus, and laterally in the left

parietotemporal lobe.

In detail, 3 mg haloperidol induced a local increase in delta power in the left BA20,

which projects fibers into BA21, the origin of the major portion of the bundle of Turk. A second maximum was found in BA8, containing a large portion of the frontal

oculomotor field for voluntary conjugate movements of the eyes and cephalogyria.

Absolute theta power showed a maximum increase in the right BA40, a territory

strongly linked with associative functions. A second maximum was seen in the left

BA20 and the medial BA6. An increase in this normal theta activity might improve

loosening of associations. The increase in theta activity in BA6 may be of interest in

connection with extrapyramidal symptoms, as this area is known to be involved in

motor functions and extrapyramidal syndromes. The widespread increase in alpha-2

power, whose maximum was seen in BA21, may be due to the activating properties of

low doses of haloperidol via a blockade of presynaptic dopamine D2 receptors. This

may also be true for the increase in beta-1 power, whose maximum was seen in BA6

and the left BA40. In the latter, beta-2 power also showed a maximum increase,

which is significant as this territory is linked with associative functions. A second

maximum, reaching the suprathreshold region, was seen in BA31 in the medial frontal

gyrus. Finally, beta-3 power showed a maximum increase in BA23 in the cingulate

gyrus, which is part of the limbic system that plays a role in emotional behavior, the

regulation of the autonomic nervous system, learning and memory.

Our LORETA data on haloperidol are of interest in the context of recent LORETA

findings obtained by Pascual-Marqui et al. in acute neuroleptic-naive, first-episode, productive schizophrenics (35). The authors described a discoordinated- or

dissociated-like brain state (120, 121) characterized by a combination of an excess of

frontal inhibitory delta activity, a deficit of anterior-left temporal normal theta and

alpha activity, and an excess of right parietal excitatory beta activity. Prefrontal

functions include executive supervisory and coordinative activity, whose inhibition by

slow electrical activity would be expected to result in a generally decreased

cooperativity. The latter has been shown in schizophrenia by functional imaging

correlation studies (122-126) as increased independence of regional brain processes

and increased dimensional complexity of electrical measures (123, 127, 128). Left

temporal functions related to schizophrenic symptomatology include memory (recall and classification), emotional coordination and linguistic construction functions. Left

temporal areas, where Pascual-Marqui et al. (35) described a decreased activity of the

normal function type (e.g., theta and alpha activity), have repeatedly been found

deficient in functional imaging studies (129). Finally, the right parietal region, showing

an excess of excitatory beta activities, proved to be associated with disturbances of

awareness of the disease (anosognosia), body schema (130), eye movements (131)

and sustained attention (132).

When we investigated haloperidol-induced changes in the regions that in the

investigations of Pascual-Marqui et al. (35) had shown the greatest aberrations, in the

delta, theta and alpha frequency bands we intriguingly found changes opposite to

those described by Pascual-Marqui et al. for schizophrenics as compared with controls (key-lock principle) (102). However, the increase in beta power may reflect activating

properties of low doses of haloperidol in normal volunteers via presynaptic D2 receptor

blockade, as described by us after 2 mg (44).

Lorazepam (anxiolytic)

After 2 mg lorazepam p.o., a decrease in theta and alpha-1 power was observed in all

cortical brain regions. The majority of voxels constituting the suprathreshold region of

alpha-2 power decreases after lorazepam were located in the left hemisphere.

Moreover, changes in beta power were predominantly seen in the left frontal lobe (Fig. 15).

In detail, lorazepam 2 mg induced an ubiquitous decrease in theta and alpha-1 power,

with the maximum changes seen in BA10 and BA11 of the prefrontal cortex. The latter

is involved in mnemonic functions and other higher cognitive functions related to

personality, insight and foresight. By decreasing normal functional theta and alpha

activity, subjects may be more detached from their anxiety-provoking problems and

ambivalence. Alpha-2 power was also widely decreased, most pronouncedly in the left

fusiform gyrus located on the inferior surface of the brain, consisting of the visual

association cortex. This region contains high-order visual association areas that

mediate spatial vision and visual, mnemonic and attentional processes. Indeed, in

earlier studies we measured a decline in attention in normal volunteers (64). Finally, 2 mg lorazepam increased beta-2 and beta-3 activity, predominantly in the left-sided

BA6 and 5, which are known to be involved in motor functions. An increase in beta

spindles there may result in an improvement of aberrant psychomotor behavior in the

patients, but may also explain the decrease in psychomotor performance in volunteers

(64). The beta increase in frontal regions also confirms the LORETA findings of

Nobuhara et al. (133). In a placebo-controlled, parallel-group design study in 32



normal subjects, they described an increase in beta-1 and beta-2 activity in the frontal

cortices, which reflects a binding of diazepam to benzodiazepine/GABA receptors that

occur in high density in the frontal neocortex. However, benzodiazepine receptors are

abundant in neocortical cerebral, cerebellar and limbic cortices (134) and thus it comes

as no surprise that theta and alpha-1 activity was attenuated in all our LORETA

regions. Utilizing PET and 18FDG, De Wit et al. described a reduced global metabolism

after diazepam (135). In contrast, GAD patients were reported to have an increased relative glucose metabolism in the left occipital (BA17), right posterior temporal and

right precentral regions (136). There was no evidence of an asymmetry in the

metabolism in the parahippocampal region, as reported by Nordahl et al. (137), who

by means of FDG showed higher values over the right than over the left side in 12

panic disorder patients, or earlier by Reiman et al. (138). In this context it is of

interest that in our LORETA studies, theta reduction was highest in the left superior

frontal gyrus (tMIN

=-6.03, p<0.01) and almost equally pronounced in both

parahippocampal gyri (tMIN

=-6.01, p<0.01).

What makes our LORETA findings with lorazepam even more exciting is the fact that

they were opposite to recently obtained LORETA differences between GAD patients and

normal controls (102). GAD patients showed an increase in delta and theta (mainly

occipitally), alpha-1 (frontally, occipitally), alpha-2 (frontally) and beta-2 power, while

Somnium®, a combination of 1 mg lorazepam and 25 mg diphenhydramine, induced

just the opposite changes compared with placebo 12 h after the evening dose on top of

4-week chronic administration. Last but not least, in recent correlation studies we

found high correlations between the SAS score and left temporal theta activity, thereby

confirming the observations by Tiihonen et al. of a decreased benzodiazepine receptor

binding in the left temporal pole in GAD patients compared with healthy normal

controls (139). As we also obtained HAMAS and SDS ratings, it is noteworthy to

mention that HAMAS ratings were not correlated with LORETA findings, while the highest correlation coefficients were seen between SDS ratings and delta power in the

left temporal lobe (+0.58, involving 1713 voxels) and theta power in the left temporal

(+0.46), left frontal (+0.45) and right frontal (+ 0.41) lobes. This confirms recent

findings of Conca et al. (140), correlating ratings in depressed patients with FDG and

HMPAO SPECT findings. They described that patients with low anxiety scores

demonstrated a marked dynamic coupling bilaterally for the superior temporal gyrus,

while patients with high anxiety scores showed statistically significant correlations to

regional cerebral blood flow and regional cerebral glucose metabolic rate only in the

left superior temporal gyrus. Buchsbaum et al. (141) and Matthew and Wilson (142)

described that clorazepate and diazepam decreased anxiety and also cerebral blood

flow in both hemispheres. The latter may be reflected in the ubiquitous decrease in global theta and alpha power.

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44. Saletu, B., Grünberger, J., Linzmayer, L., Dubini, A. Determination of pharmacodynamics of the new neuroleptic zetidoline by neuroendocrinologic, pharmaco-EEG, and psychometric studies - Part I. Int J Clin Pharmcol Ther Toxicol

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45. Grünberger, J., Saletu, B., Linzmayer, L., Stöhr, H. Determination of pharmacokinetics and pharmacodynamics of amisulpride by pharmaco-EEG and psychometry. In: Pichot, P., Berner, P., Wolf, R., Thau, K. (Eds.). Psychiatry: The State of the Art. Plenum Press: New York-London 1985, 681-6.

46. Saletu, B., Küfferle, B., Grünberger, J., Anderer, P. Quantitative EEG, SPEM, and psychometric studies in schizophrenics before and during differential neuroleptic therapy. Pharmacopsychiatry 1986, 19: 434-7.

47. Saletu, B., Barbanoj, M.J., Anderer, P., Sieghart, W., Grünberger, J. Clinical-pharmacological study with the two isomers (d-, l-) of fenfluramine and its comparison with chlorpromazine and d-amphetamine: Blood levels, EEG mapping and safety evaluation. Meth Find Exp Clin Pharmacol 1993, 15(5): 291-312.

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49. Saletu, B. Pharmaco-EEG profiles of typical and atypical antidepressants. In:

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50. Saletu, B., Grünberger, J. Zur Klassifikation und Objektivierung der Pharmakodynamik der Antidepressiva. In: Saletu, B., Berner, P. (Eds.). Zyklothymie.

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52. Saletu, B., Grünberger, J., Linzmayer, L., Taeuber, K. The pharmacokinetics of nominfensine. Comparison of pharmacokinetics and pharmacodynamics using computer pharmaco-EEG. Int Pharmacopsychiat 1982, 17: 43-72.

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56. Saletu, B., Grünberger, J., Linzmayer, L. On central effects of serotonin re-uptake inhibitors: Quantitative EEG and psychometric studies with sertraline and zimelidine. J Neural Transmission 1986, 67: 241-66.

57. Saletu, B., Grünberger, J., Linzmayer, L. Early clinical pharmacological studies with sercloremine - a novel antidepressant - utilizing pharmacokinetic, pharmaco-EEG and psychometric analyses. Drug Dev Res 1985, 6: 19-38.

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1984, Freiburg im Breisgau).

59. Saletu, B., Grünberger, J., Anderer, P., Linzmayer, L., Semlitsch, H.V., Magni, G.

Pharmacodynamics of venlafaxine evaluated by EEG brain mapping, psychometry and psychophysiology. Br J Clin Pharmac 1992, 33: 589-601.

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Klinische Pharmakologie, 4th ed. Landsberg: München 1986, 1-71.

61. Saletu, B., Grünberger, J., Linzmayer, L., Nitsche, V. Bestimmung der Psychoaktivität und Langzeitwirkung einer Retardform vom Oxazepam (Anxiolit Retard) mittels Blutspiegel-, quantitativer EEG- und psychometrischer Analysen. Wien Klin

Wochenschr 1978, 90: 382-89.

62. Saletu, B., Grünberger, J., Linzmayer, L., Sieghart, W. Zur zentralen Wirkung hoher Benzodiazepindosen: Quantitative Pharmako-EEG und psychometrische Studien mit Prazepam. In: Hopf, A., Beckmann, H. (Eds.). Forschungen zur Biologischen

Psychiatrie. Springer-Verlag: Berlin-Heidelberg-New York-Tokyo 1984, 271-94.

63. Saletu, B., Grünberger, J., Linzmayer, L., Flener, R. Anxiolytics and beta blockers: Evaluation of pharmacodynamics by quantitative EEG, psychometric and physiological variables. Agressologie 1981, 22: 5-16.

64. Saletu, B., Grünberger, J., Berner, P., Koeppen, D. On differences between 1,5-and 1,4-benzodiazepines: Pharmaco- EEG and psychometric studies with clobazam and lorazepam. In: Hindmarch, I., Stonier, P.D., Trimble, M.R. (Eds.). Clobazam: Human Psychopharmacology and Clinical Applications, International Congress and Symposium

Series, Nr 74. Royal Society of Medicine: London 1985, 23-46.

65. Saletu, B. Zur Bestimmung der Pharmakodynamik alter und neuer Benzodiazepine mittels des Pharmako-EEGs. In: Hippius, H., Engel, R.R., Laakmann, G. (Eds.).

Benzodiazepine: Rückblick und Ausblick. Springer: Berlin-Heidelberg-New York-Tokio

1986, 45-68.

66. Saletu, B., Grünberger, J., Volavka, J., Berner, P. Classification and bioavailability studies with WE 941 by quantitative pharmaco-EEG and clinical analyses. Arzneim

Forsch Drug Res 1979, 29: 700-4.



67. Saletu, B., Grünberger, J., Linzmayer, L., Sieghart, W. On the value of CNS, ANS and behavioral measures in early clinical psychopharmacology. In: Pichot, P., Berner,

P., Wolf, R., Thau, K. (Eds.). Psychiatry: The State of the Art. Plenum Press: New

York-London 1985, 7-12.

68. Saletu, B., Saletu, M., Grünberger, J., Mader, R. Drawing inferences about the therapeutic efficacy of drugs in patients from their CNS effect in normals: Comparative quantitative pharmaco-EEG and clinical investigations. In: Saletu, B., Berner, P.,

Hollister, L. (Eds.). Neuro-Psychopharmacology. Pergamon Press: Oxford 1979, 393-

407.

69. Saletu, B., Matejcek, M., Knor, K., Schneewind, W., Ferner, U. Assessing the psychoactivity of cloxazolam (MT 14-411) by quantitative EEG and psychological studies. Curr Therapeutic Res 1976, 20: 510-28.

70. Saletu, B., Anderer, P., Kinsperger, K., Grünberger, J., Sieghart, W. Comparative bioavailability studies with a new mixed-micelles solution of diazepam utilizing radioreceptor assay, psychometry and EEG brain mapping. Int Clin Psychopharmacol

1988, 3: 287-323.

71. Saletu, B., Grünberger, J., Anderer, P., Barbanoj, M.J. Pharmacodynamic studies of a combination of lorazepam and diphenhydramine and its single components: Electroencephalographic brain mapping and safety evaluation. Curr Therapeutic Res 1988, 44(6): 909-37.

72. Saletu, B., Grünberger, J., Linzmayer, L., Anderer, P. EEG-brain mapping, psychometric and psychophysiological studies on central effects of kavain - a kava plant derivative. Hum Psychopharmacol 1989, 4: 169-90.

73. Saletu, B., Grünberger, J., Linzmayer, L., Semlitsch, H.V., Anderer, P., Chwatal, K.

Pharmacokinetic and -dynamic studies with a new anxiolytic, suriclone, utilizing EEG mapping and psychometry. Br J Clin Pharmacol 1994, 37: 145-56.

74. Barbanoj, M.J., Anderer, P., Antonijoan, R.M., Torrent, J., Saletu, B., Jane, F.

Topographic pharmaco-EEG mapping of increasing doses of buspirone and its comparison with diazepam. Hum Psychopharmacol 1994, 9: 101-9.

75. Grünberger, J., Saletu, B., Linzmayer, L., Stöhr, H. Objective measures in determining the central effectiveness of a new antihypoxidotic SL-76188: Pharmaco-EEG, psychometric and pharmacokinetic analyses in the elderly. Arch Gerontol Geriatr

1982, 1: 261-85.

76. Saletu, B., Grünberger, J., Linzmayer, L. Is amezinium methylsulfate - a new antihypotensive drug - psychoactive? Comparative quantitative EEG and psychometric trials with desipramine and methamphetamine. Curr Therapeutic Res 1980, 28: 800-

26.

77. Saletu, B., Grünberger, J., Linzmayer, L., Stöhr, H. Pharmaco-EEG, psychometric and plasma level studies with two novel alpha-adrenergic stimulants CRL 40476 and 40028 (Adrafinil) in elderlies. New Trends Exp Clin Psychiat 1986, 2: 5-31.

78. Etevenon, P., Peron-Magnan, J.P., Boulenger, J.P., Tortrat, D., Guillou, S.,

Toussaint, M., Gueguen, B., Deniker, P., Zarifan, E. EEG cartography profile of caffeine in normals. Clin Neuropharmacol 1986, 9: 538-40.

79. Saletu, B., Grünberger, J., Linzmayer, L. Classification and determination of cerebral bioavailability of psychotropic drugs by quantitative "pharmaco-EEG" and psychometric investigations (studies with AX-A-411-BS). Int J Clin Pharmacol 1977,

15: 449-59.

80. Saletu, B., Grünberger, J., Linzmayer, L., Anderer, P. Proof of CNS efficacy and pharmacodynamics of nicergoline in the elderly by acute and chronic quantitative pharmaco-EEG and psychometric studies. In: Tognoni, G., Garattini, S. (Eds.). Drug

Treatment in Chronic Cerebrovascular Disorders. Elsevier/North Holland, Biomedical

Press: Amsterdam 1979, 245-72.

81. Saletu, B., Grünberger, J. Zur Pharmakodynamik von Vincamin: Pharmako-EEG und psychometrische Studien bei Alternden. In: Lechner, H. (Ed.). Fortschritte in

Pathophysiologie, Diagnostik und Therapie cerebraler Gefäßkrankheiten. Excerpta

Medica, Amsterdam-Oxford-Princeton 1982, 154-77.

82. Saletu, B., Grünberger, J., Linzmayer, L., Wittek, R. Classification and determination of pharmacodynamics of a new antihypoxidotic drug, vinconate, by pharmaco-EEG and psychometry. Arch Gerontol Geriatr 1984, 3: 127-46.

83. Saletu, B., Anderer, P. Double-blind placebo-controlled quantitative pharmaco-EEG investigations after tinofedrine i.v. in geriatric patients. Curr Therapeutic Res 1980, 28:

1-15.

84. Bente, D. Vigilanz: Psychophysiologische Aspekte. Verh Dtsch Ges Inn Med 1977,

83: 945-52.



85. Saletu, B. Application of quantitative EEG in measuring encephalotropic and pharmacodynamic properties of antihypoxidotic/nootropic drugs. In: Scientific

International Research (Ed.). Drugs and Methods in C.V.D. Proc. Int. Cerebrovascular Diseases, France. Pergamon Press: France 1981, 79-115.

86. Saletu, B. Nootropic drugs and human brain function. In: Wheatley, D. (Ed.).

Stress and the Heart. Raven Press: New York 1981, 327-59.

87. Saletu, B., Grünberger, J. Antihypoxidotic and nootropic drugs: Proof of their encephalotropic and pharmacodynamic properties by quantitative EEG investigations.Prog Neuro-Psychopharmac 1980, 4: 469-89.

88. Saletu, B., Grünberger, J., Linzmayer, L. Quantitative EEG and psychometric analyses in assessing CNS- activity of RO 13-5057 - a cerebral insufficiency improver.Meth Find Exp Clin Pharmacol 1980, 2: 269-85.

89. Saletu, B., Grünberger, J., Linzmayer, L., Stöhr, H. Encephalotropic and psychotropic effects of intravenous buflomedil in the elderly: Double-blind, placebo-controlled pharmaco-EEG and psychometric studies. Int J Clin Pharmacol Res 1984, 4:

95-107.

90. Saletu, B., Grünberger, J., Rajna, P., Stöhr, H. Vigilanzverbesserung bei alternden Menschen: Doppelblinde, placebokontrollierte neurophysiologische und psychometrische Studien mit Pridoxilat. Therapiewoche 1982, 32: 5590-603.

91. Saletu, B., Grünberger, J., Linzmayer, L., Stöhr, H. Zur Funktionsbesserung des alternden Gehirns: Placebokontrollierte Pharmako-EEG- und psychometrische Studien mit einem stoffwechselaktiven Hämoderivat (Actovegin). Z Gerontol 1984, 17: 271-9.

92. Saletu, B., Grünberger, J. Assessment of psychoactivity and pharmacodynamics of a cerebral vasodilating hexobendine-combination by quantitative electroencephalographic and psychometric analyses. Prog Neuro-Psychopharmac 1978,

2: 543-51.

93. Head, H. The conception of nervous and mental energy. II. Vigilance: A physiological state of the nervous system. Br J Psychol 1923, 14: 125-47.

94. Saletu, B., Darragh, A., Salmon, P., Coen, R. EEG brain mapping in evaluating the time-course of the central action of DUP 996 - a new acetylcholine-releasing drug. Br J

Clin Pharmacol 1989, 28: 1-16.

95. Saletu, B., Anderer, P., Semlitsch, H.V., Grünberger, J., Linzmayer, L., Chaudhry, H.R. Amantadine infusions in mild dementia: Acute double-blind placebo-controlled EEG mapping and psychometric studies. Arch Gerontol Geriatr 1992, 15: 43-58.

96. Saletu, B., Grünberger, J., Linzmayer, L., Anderer, P. Dose-response studies with co-dergocrine mesylate under hypoxia utilizing EEG mapping and psychometry.Psychopharmacology 1992, 109: 30-40.

97. Saletu, B., Anderer, P., Fischhof, P.K., Lorenz, H., Barousch, R., Böhmer, F. EEG mapping and psychopharmacological studies with denbufylline in SDAT and MID. Biol

Psychiatry 1992, 32: 668-81.

98. Fischhof, P.K., Saletu, B., Rüther, E., Litschauer, G., Möslinger-Gehmayr, R.,

Herrmann, W.M. Therapeutic efficacy of pyritinol in patients with senile dementia of the Alzheimer type (SDAT) and multi-infarct dementia (MID). Neuropsychobiology 1992,

26: 65-70.

99. Saletu, B., Saletu, M., Brown, M., Stern, J., Sletten, I., Ulett, G.A. Hypno-analgesia and acupuncture analgesia: A neurophysiological reality? Neuropsychobiology 1975, 1:

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