EEG mapping and tomography in drug evaluation




Bernd SALETU, MD
Peter ANDERER, PhD
Gerda M. SALETUZYHLARZ, MD
Department of Psychiatry
and Psychotherapy
Medical University of Vienna
Vienna, AUSTRIA

EEG mapping and tomography in drug evaluation

by B. Saletu, P. Anderer, and G. M. Saletu-Zyhlarz,Austria

By quantitative analysis of electroencephalogram (EEG) recordings on the human scalp, in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping or topography), it is possible to classify psychotropic substances and to objectively evaluate their bioavailability at the target organ, the human brain. Specifically, one can determine at an early stage of drug development whether a drug is effective in the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage(s) it acts, when it acts, and the equipotency of different galenic formulations. This article describes the pharmaco-EEG maps of representative drugs from different psychotropic drug classes, and the EEG maps of various mental disorders. The relationships between pharmacodynamics and pharmacokinetics, acute and chronic drug effects, alterations in normal subjects and patients, and CNS effects and therapeutic efficacy will be discussed. Imaging of the effects of drugs on regional brain electrical activity in both healthy subjects and patients, using EEG tomography such as low-resolution electromagnetic tomography (LORETA), has been used to identify brain areas predominantly involved in psychopharmacological action. LORETA demonstrates that these psychopharmacological classes affect brain structures differently. By considering EEG differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, whereby the drug should normalize the deviant brain function.

Medicographia. 2010;32:190-200 (see French abstract on page 200)

Since Hans Berger’s1 early observations of central drug effects visualized with the newly-developed method of the electroencephalogram (EEG), investigators have been trying to utilize the EEG to classify psychopharmacological agents and evaluate their pharmacodynamics at their target organ—the human brain. Initially, trials consisted of eyeball evaluation,2 then in the 1960s and 1970s, computerassisted quantitative analysis of single lead information (pharmaco-EEG),sup>3-7 and from the 1980s onward, of multi-lead analysis and subsequent mapping techniques.8-24 It became 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). Parallel developments occurred regarding drug effects on event-related potentials and sleep, as well as the search for the neurophysiological correlates of neuropsychiatric disorders. In the last decade, EEG tomography techniques such as low-resolution brain electromagnetic tomography (LORETA) have been developed,25,26 which enable the intracerebral identification of electrical generators of both disease and drug effects.

Figure 1
Figure 1. Electroencephalogram maps
of the differences between nine representative
drugs from the major
psychopharmacological classes and
placebo after acute oral administration
(time of pharmacodynamic peak
effect, mostly 2nd hour post-drug).

Statistical parametric maps depicting intergroup
differences in total, absolute, and relative
power are shown, as well as the centroids
of the delta-theta, alpha, and beta frequency
bands (from top to bottom). Bird’s eye view;
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, P<0.05, and P<0.01,
respectively); dark green, light blue, and dark
blue indicate significant decreases (P<0.10,
P<0.05, and P<0.01, respectively) compared
with placebo. In the columns from left to right,
different drug-induced changes after singledose
administration of chlorpromazine 50 mg
(CPZ50; n=15), haloperidol 3 mg (HAL3;
n=20), imipramine 75 mg (IMI75; n=15), citalopram
20 mg (CIT20; n=20), clobazam 30 mg
(CLB30; n=15), lorazepam 2 mg (LOR2;
n=15), amphetamine 20 mg (AMP20; n=15),
metamphetamine 20 mg (MET20; n=20),
and pyritinol 600 mg (PYR600; n=12) are
topographically displayed. While, for instance,
chlorpromazine 50 mg increases absolute
delta and theta power and decreases alpha
power (CNS sedation), pyritinol 600 mg increases
absolute alpha-1 and beta power
(vigilance improvement).
After reference 27: Saletu B. Pharmacodynamics
and EEG. I. From single-lead pharmaco-
EEG to EEG mapping. In: Saletu B,
Krijzer F, Ferber G, Anderer P, eds. Electrophysiological
Brain Research in Preclinical and
Clinical Pharmacology and Related Fields—
An Update. Copyright © 2000, Facultas
Universitätsverlag.

EEG mapping of different psychotropic drug classes

Our own pharmaco-EEG studies in normal subjects27 demonstrated that a sedative neuroleptic like chlorpromazine 50 mg attenuates total power, increases delta/theta power, and decreases alpha and beta power, with a slowing of all centroids and also of the total centroid (Figure 1). In contrast, the nonsedative neuroleptic haloperidol 3 mg does not change total power, increases delta/theta (predominantly theta), slightly decreases alpha, and increases beta activity, while the centroids remain unchanged.

Sedative antidepressants of the imipramine-amitriptyline type attenuate total power, decrease absolute delta/theta and specifically alpha power, increase relative delta/theta, and decrease relative alpha and to some extent also relative beta power, and slow the total centroid. This is in part contrast to nonsedative antidepressants, since citalopram 20 mg, for instance, also attenuates total power, absolute delta/theta, and alpha power, but increases absolute and relative beta power, slows the delta/theta centroid, and accelerates the alpha and beta centroid, as well as the total centroid.

Daytime tranquilizers such as clobazam 30 mg, decrease total power, absolute and relative delta/theta power, and alpha power, and increase absolute and relative beta power. The delta/theta centroid is slowed, as is partly the beta centroid, while the total centroid is accelerated. Nighttime tranquilizers attenuate total power, decrease absolute and relative alpha power, increase absolute and relative beta power, as well as relative delta/theta power, slow the centroid of delta/theta activity and accelerate that of alpha activity, as well as total activity.

Figure 2
Figure 2. Electroencephalogram
maps of the brain differences
between nine groups of
mental disorder patients and
normal control subjects.

For a technical description of the
maps and the color key, see Figure 1.
Schizophrenics with a predominantly
positive symptomatology (SCH+;
n=18), for instance, exhibit an attenuated
absolute delta and theta power,
while schizophrenics with a predominantly
negative symptomatology
(SCH-; n=30) show an increase. Patients
with major depression (DEP;
n=60), generalized anxiety disorder
(GAD; n=41), agoraphobia (PHO;
n=21), obsessive-compulsive disorder
(OCD; n=12), multi-infarct dementia
(MID; n=24), senile dementia of the
Alzheimer type (DAT; n=24) and alcohol-
dependence (currently abstinent)
(ALC; n=29) show different EEG maps
to normal controls.
After reference 27: Saletu B. Pharmacodynamics
and EEG. I. From
single-lead pharmaco-EEG to EEG
mapping. In: Saletu B, Krijzer F, Ferber
G, Anderer P, eds. Electrophysiological
Brain Research in Preclinical
and Clinical Pharmacology and Related
Fields—An Update. Copyright ©
2000, Facultas Universitätsverlag.

Psychostimulants, such as amphetamine 20 mg, attenuate total power, decrease absolute delta/theta, alpha, and beta power, decrease relative delta/theta power, and increase alpha power. The total centroid is accelerated, while after 20mg amphetamine or 20 mg methylphenidate, differential changes are observed in the centroid of the delta/theta and beta band.

Nootropics and cognition enhancers, such as pyritinol 600mg, augment total power as well as absolute alpha and beta power, attenuate relative delta/theta power and augment relative alpha power, accelerate the centroid of delta/theta activity and slow the centroid of alpha activity, while the total centroid is accelerated. This is consistent with a vigilance-promoting action on the brain.

EEG mapping of different psychiatric disorders

Utilizing standardized recording and analyzing procedures,27 we found that drug-free schizophrenics demonstrated a decrease in alpha activity, an increase in beta activity, and an acceleration of the beta centroid compared with controls, which suggests a state of hyperarousal in schizophrenia.While schizophrenic patients with predominantly negative symptomatology showed bi-temporal and frontal augmentation of delta/ theta, patients with positive symptomatology exhibited an attenuation in these measures (Figure 2). The increase in slow activity suggests an organic factor in the pathogenesis of the negative syndrome. Major depression in the menopause was characterized by a decrease in absolute power in all frequency bands, a tendency toward an augmentation of relative delta/ theta and beta and a decrease in alpha activity, as well as by a slowing of the delta/theta centroid and an acceleration of the alpha and beta centroid, reflecting a decrease in vigilance. Generalized anxiety disorder (GAD) patients with nonorganic insomnia showed increased total, absolute delta/theta, and alpha power, as well as relative alpha power, and decreased relative beta power, neurophysiologically reflecting hypervigilance. This pattern is similar to that of another anxiety disor- der, agoraphobia, with and without panic disorder, which, however, in contrast to GAD, also exhibited augmented beta activity and accelerated delta/theta and alpha centroids. Obsessive- compulsive disorder showed a different pattern of activity, characterized by an attenuation of total and absolute delta/theta and beta power, a decrease in relative delta/theta, and an increase in relative alpha activity, as well as a slowing of the delta/theta centroid. Thus, different anxiety disorders show different electrophysiological patterns.

Demented patients, of both the vascular (multi-infarct dementia) and the degenerative (senile dementia/Alzheimer’s type) subtypes, exhibited a massive augmentation of absolute delta/ theta power, an increase in relative delta/theta, a decrease in alpha and beta power, as well as an acceleration of the delta/ theta and a slowing of the alpha and beta centroids. Thus, both subtypes of dementia show a vigilance decrement, with differences between them lying in the asymmetry indices and in differences between minimum and maximum power. By vigilance, one understands (since Head) the availability and grade of organization of human adaptive behavior, which is in turn dependent on the dynamic state of the neuronal network. The latter can be measured objectively and quantitatively by computerized EEG analysis. Utilizing neuronal network statistics on absolute delta/theta power findings, we correctly classified 90% of demented patients. Alcohol-dependent patients predominantly showed an increase in absolute and relative beta power and a decrease in alpha and delta/theta power, with an additional slowing of delta/theta and acceleration of the beta centroid.

For the classification of an individual psychiatric patient, one may obtain routine EEG maps of 36 EEG variables, and visualize the differences between the measures of the patient and those of a normal control group by plotting them in terms of the number of standard deviations from the norm (z-scores). An increase in delta/theta power, a decrease in alpha and beta power, and a slowing of the total centroid, for instance, suggest dementia. The ideal drug for such a patient would be the one inducing EEG changes opposite to those caused by the disease, and has to be chosen fromone of the aforementioned psychotropic drug classes (key-lock principle).

Figure 3
Figure 3. Differences between representative drugs from the four main psychopharmacological classes and placebo in electroencephalogram low-resolution brain electromagnetic tomography (EEG LORETA) power projected to the inflated cortical surface of 20 normal volunteers.

Viewed from the top and front. Structural anatomy is shown in gray scale. Red colors indicate increases, blue colors decreases in cerebral cortical activity compared with placebo (P<0.05). Acute oral drug administration of the neuroleptic haloperidol 3 mg, the antidepressant citalopram 20 mg, the tranquilizer lorazepam 2 mg, and the psychostimulant methylphenidate 20 mg induces different regional effects on electrophysiological brain function at the time of pharmacodynamic peak (hours 4, 6, 6, and 4, respectively) in the 7 frequency bands shown. After reference 30: Saletu B, Anderer P, Saletu-Zyhlarz GM. Clin EEG Neurosci. 2006;37:66-80. Copyright © 2006, EEG and Clinical Neuroscience Society (ECNS).

EEG tomography (LORETA) identifies target regions of drugs and diseases

One of the shortcomings of EEG mapping is that scalp distributions of EEG power cannot be interpreted directly in terms of brain electrical generators. This problem has been over- come by LORETA, which computes a unique three-dimensional electrical source distribution by assuming that the smoothest of all possible inverse solutions is the most plausible.25 This model assumes that neighboring neurons are simultaneously and synchronously active. In a new implementation, an additional neuroanatomical constraint restricts the solution space 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.26 Thus, LORETA combines the high time resolution of the EEG with a source localization method that permits a truly three-dimensional tomography of brain electrical activity.28

Our own LORETA studies demonstrated that representative drugs of the four main psychopharmacological classes such as haloperidol (neuroleptics), citalopram (antidepressants), lorazepam (tranquilizers), and methylphenidate (psychostimulants), affect brain structures differently (Figure 3, page 193).29,30 Figure 431 demonstrates EEG-LORETA findings after citalopram 20 mg compared with placebo in normal subjects, as well as changes in untreated depressed patients compared with controls. Depressed patients show a significantly decreased LORETA power in the theta and alpha-1 frequency band, and to a smaller extent, regionally decreased delta, beta-1 and beta-2 LORETA power. These findings reflect a deterioration of vigilance, which is the opposite of the vigilance increase induced by citalopram, characterized by an increase in beta-3, beta-2, beta-1, alpha-2 and—to some extent—delta LORETA power. During pretreatment, a negative correlation between LORETA theta power and the Hamilton Rating Scale for Depression (HAM-D) score was observed in the bilateral orbital cortex, the bilateral rostral anterior cingulate cortex, and the right insula cortex; there was a negative correlation between alpha-1 power and the HAM-D score in the right prefrontal cortex. These regions are identical to those Davidson et al32 described as being involved in affectivity and mood disorders. Pizzagalli et al33 reported that depressed patients with a higher theta current source density in the rostral anterior cingulate had a better outcome after 4 to 6 months’ nortriptyline treatment than those without this abnormality. The higher theta activity was interpreted as a cingulate hyperactivity, which was described as being reduced after fluoxetine, along with an increase in regional cerebral blood flow in BA, F9, and F46 and in the posterior cingulate gyrus (BA 31).34 Investigating P300 LORETA changes after S-adenosyl-L-methionine (SAMe) administration compared with placebo in elderly normal subjects, we found the same type of changes in identical regions.35

Figure 4
Figure 4. Surface-rendered lowresolution
brain electromagnetic
tomography (LORETA) images on
differences between menopausal
syndrome patients with depression
(n=60) and normal controls (n=29)
(upper part) compared with LORETA
images on differences between
citalopram 20 mg and placebo
(6 hours–pre; vigilance-controlled
electroencephalogram with eyes
closed) in normal subjects (n=20)
(lower part).

Images are based on voxel-by-voxel t-values
on differences between patients and
controls and between drug-induced and
placebo-induced changes in the delta,
theta, alpha-1, alpha-2, beta-1, beta-2,
and beta-3 frequency bands projected to
the left and right lateral and the medial cortical
surface. Structural anatomy is shown
in gray scale (A, anterior; P, posterior; S,
superior; I, inferior). Red colors indicate increases
and blue colors indicate decreases,
as compared with controls/placebo.
While untreated depressed patients as compared
with normal controls show decreases
in LORETA power, specifically in the theta
and alpha-1 range (vigilance decrement),
citalopram 20 mg as compared with placebo
induces an increase in LORETA power,
predominantly in the alpha-2, beta-2, and
beta-3 bands (vigilance increase).
After reference 31: Saletu B, Anderer P,
Stanek J, Saletu-Zyhlarz GM. EEG-mapping
und EEG-tomographie in der neuropsychopharmakologie.
In: Riederer P, Laux G, eds. Grundlagen der Neuro-Psychopharmakologie.
Ein Therapiehandbuch.
Copyright © 2010, Springer Verlag.

Figure 5
Figure 5. Differences between three doses of ABIO-08/01 and placebo regarding acute, subacute, and superimposed effects on regional electrophysiological brain function analyzed by low-resolution brain electromagnetic tomography (LORETA) in 16 healthy subjects during the eyes-open condition.

Surface-rendered regional electroencephalogram-LORETA differences in seven frequency bands are shown from the top to the bottom. Lateral and medial views from the left and right hemisphere as well as from the bottom are demonstrated from the left to the right. Images depicting statistical parametric maps (SPM) are based on voxel-by-voxel t-values of differences between changes induced by the drug and placebo. Red colors indicate increases, blue colors decreases as compared with placebo. Structural anatomy is shown in gray scale. In the 1st hour of day 1, ABIO-08/01 10 mg induces pronounced sedative effects characterized by an increase in delta/ theta and beta activity, which changes to a decrease in alpha and beta activity in the 6th hour, with similar findings in the 1st and 6th hour after a superimposed dose on day 5. The subacute effect (hour 0, day 5) is mainly characterized by a decrease in alpha-2 and beta source density.
After reference 36: Saletu B, Anderer P, Woltz M et al. Neuropsychobiology. 2009;59:110-122. Copyright © 2009, Karger.

Time-efficacy relationships in drug evaluation

The time course of the cerebral bioavailability of a psychotropic drug at its target organ—the human brain—can be demonstrated by changes in various EEG variables over time (Figure 5)36 or on the basis of multivariate statistics utilizing mapping of multivariate analysis of variance (MANOVA) and subsequent Hotelling’s T2 test results. 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 later), but in patients, the evaluation of single- dose effects may provide valuable insight into the prognostic aspects of a planned treatment (eg, beta decrease in schizophrenics, delta decrease in dementia patients).

Dose-efficacy relationships in drug evaluation

Dose-efficacy relationships can also be determined based on changes in various EEG variables (Figure 5) and multivariate techniques such as MANOVA with subsequent Hotelling’s T2 tests and mapping techniques. By such means, one can gain insight into the minimal centrally-effective dose in humans, which is important for subsequent open or doubleblind 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 onward; for instance, the switch from CNS-activating to CNS-inhibitory effects with benzamides or the changes from a daytime to a nighttime tranquilizer profile with benzodiazepines.

Bioequipotency in drug evaluation

In a similar way to time-efficacy and dose-efficacy relationships, the bioequipotency of an experimental compound can be explored and compared with that of a clinically well-known drug on themarket. This is of special importance for determining the dosage to use in later clinical trials of drugs 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.

Relationships between pharmacokinetics and pharmacodynamics

When exploring pharmacokinetic/pharmacodynamic relationships, important information may be gained on: (i) penetration of drugs through the blood-brain barrier to the site of the deep compartment receptor; (ii) receptor binding; (iii) “hitand-run” phenomena; and (iv) active metabolites.37,38 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 cinolazepam. 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”). This indicates that themaximal pharmacodynamic effect of cinolazepam 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.

By exploring pharmacokinetic/pharmacodynamic relationships, we can also discover which of the investigated pharmacodynamic variables are the most sensitive for indicating drug effects, and whether human behavior changes 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 for both drugs in the 1st hour after administration, with a rapid decline thereafter for temazepam, while flunitrazepam plasma levels decreased only slowly.39 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. 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 upward, while below this level, an improvement can be expected. In fact, blood levels higher than 250 ng/ml were seen only after temazepam 40 mg in the 1st to 6th hour, and after 20 mg in the 1st and 2nd 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.40,41

Figure 6
Figure 6. Correlation maps between electroencephalogram (EEG)
changes 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.
After reference 22: Saletu B, Grünberger J, Anderer P, Linzmayer L, Zyhlarz G.
J Neural Transm. 1996;103:191-216. Copyright © 1996, Springer Verlag.

Maps on the correlation between plasma levels and EEG changes can also lead to a better understanding of the pharmacodynamic effects of a novel compound, for instance tianeptine42—a glutamatergic modulator. The higher the tianeptine plasma level, the more pronounced was both absolute and relative power in the beta frequency bands, mainly over frontotemporal regions (Figure 6).22 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 of tianeptine in the higher investigated dosage range.

Acute versus chronic effect: changes in normal subjects and in 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.

On studying the central effects of ademetionine in both younger and older normal subjects, we found in young volunteers pharmaco-EEG maps that were reminiscent of antidepressants of the thymoleptic type, both after acute and subacute administration.43 In elderly subjects, maps of the thymoleptic type were also observed after acute doses, while after 1 week of daily infusion, a marked increase in total power suggested nootropic drug effects.44 After administration of anxiolytics and nootropics, we found similar acute and chronic profiles, while after neuroleptics, different changes were observed for acute and chronic time frames.45 We found differences between the CNS changes induced by a particular drug in normal volunteers and patients, which may not only be due to different sedation thresholds,46 but more importantly to differences in brain function between untreated patients and normal subjects.46

CNS effectiveness and therapeutic efficacy

The relationship between drug-induced quantitative EEG changes and therapeutic efficacy can be considered fromseveral viewpoints. Some EEG changes are indicative of certain clinical alterations observed in subsequent clinical trials. There are numerous examples of this relationship in the pharmaco- EEG literature.3,47-50 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. Pharmaco-EEG changes are directly linked to behavioral alterations in both normal subjects and patients. In various studies, we demonstrated that EEG alterations reflecting improved vigilance after acute administration of nootropics in normal elderly subjects were similar to those observed in geriatric and organic brain syndrome patients, which in turn were associated with clinical improvement.12,14,51-53

Table
Table.
Electroencephalogram
differences
between insomniac
generalized anxiety
disorder (GAD) patients
and controls in
relation to changes
after anxiolytic (benzodiazepine)
therapy.

+=significant P<0.05 increase; ++ = significant P<0.01 increase; – = significant P<0.05 decrease; – – = significant P<0.01 decrease compared with controls/ placebo.

Figure 7
Figure 7. Low-resolution brain electromagnetic tomography (LORETA) images of differences in regional brain electrical activity between nine schizophrenic patients compared with 36 controls (left), and electroencephalogram differences between acute administration of haloperidol 3 mg and placebo in 20 healthy subjects (right).

Images show voxel-by-voxel t-statistics using LORETA for the delta, theta, alpha-1, and alpha-2 frequency bands. Hyperactivity (excess) in patients is indicated by red, hypoactivity (deficit) by blue. The frequency band is identified in the right upper corner of each set of three orthogonal brain views in Talairach space, sliced through the region of the extreme t-value. Structural anatomy is shown in gray scale (white to black). Left: axial slices, seen from above, nose up; center: sagittal slices, seen from the left; right: coronal slices, seen from the rear. Talairach coordinates: X from left (L) to right (R); Y from posterior (P) to anterior (A); Z from inferior to superior.
The locations of the extreme t-values are given as (X, Y, Z) coordinates in Talairach space, and are graphically indicated by black triangles on the coordinate axes.
Compared with placebo, haloperidol induces changes opposite to the differences between untreated schizophrenics and controls, thereby supporting the hypothesis of a key-lock principle in diagnosis and pharmacotherapy of mental disorders.
After reference 49: Saletu B, Anderer P, Saletu-Zyhlarz GM, Pascual-Marqui RD. Clin EEG Neurosci. 2005;36:108-115. Copyright © 2005, EEG and Clinical Neuroscience
Society (ECNS).

EEG topography and tomography in the diagnosis and therapy of mental disorders— a key-lock principle?

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 representative drugs from the major psychopharmacological classes, one can see that the differences between patients and normal controls are in certain instances opposite to the changes induced by the drugs compared with placebo.49 This fact speaks for a key-lock principle in diagnosis and psychopharmacological treatment of mental disorders. The EEG differences between GAD patients and normal controls,23 for instance, are the opposite of the changes induced by anxiolytic sedatives compared with placebo in both normal subjects and patients (Table, page 197).49,54 This key-lock principle was also found with regard to the aforementioned depression/ citalopram study, as well as in schizophrenia/haloperidol (Figure 7),49 dementia/nicergoline,55 and narcolepsy/modafinil investigations.56 Thus, EEG topography and tomography seem to be valuable instruments not only for early drug evaluation,36 but also for both diagnostic and therapeutic purposes. _

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19. Lehmann D, Wackermann J, Michel CM, Koenig T. Space-oriented EEG segmentation reveals changes in brain electric field maps under the influence of a nootropic drug. Psychiatry Res. 1993;50:275-282.
20. Galderisi S, Mucci A, Bucci P, Mignone ML, Maj M. Multilead quantitative EEG profile of clozapine in resting and vigilance-controlled conditions. Psychiatry Res. 1996;67:113-122.
21. Saletu B, Brandstätter N, Metka M, et al. Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls. Maturitas. 1996;23:91-105.
22. Saletu B, Grünberger J, Anderer P, Linzmayer L, Zyhlarz G. Comparative pharmacodynamic studies with the novel serotonin uptake-enhancing tianeptine and -inhibiting fluvoxamine utilizing EEG mapping and psychometry. J Neural Transm. 1996;103:191-216.
23. Saletu-Zyhlarz GM, Saletu B, Anderer P, et al. Nonorganic insomnia in generalized anxiety disorder. 1. Controlled studies on sleep, awakening and daytime vigilance utilizing polysomnography and EEG mapping. Neuropsychobiology. 1997;36:117-129.
24. Prichep LS, Alper KR, Sverdlov L, et al. Outcome related electrophysiological subtypes of cocaine dependence. Clin Electroencephalography. 2002;33:8-20.
25. Pascual-Marqui RD, Michel CM, Lehmann D. Low resolution electromagnetic tomography: A new method for localizing electrical activity in the brain. Int J Psychophysiol. 1994;18:49-65.
26. Pascual-Marqui RD, Lehmann D, Koenig T, et al. Low resolution brain electromagnetic tomography (LORETA) functional imaging in acute, neuroleptic-naïve, first-episode, productive schizophrenia. Psychiatry Res Neuroimaging. 1999; 90:169-179.
27. Saletu B. Pharmacodynamics and EEG. I. From single-lead pharmaco-EEG to EEG mapping. In: Saletu B, Krijzer F, Ferber G, Anderer P, eds. Electrophysiological Brain Research in Preclinical and Clinical Pharmacology and Related Fields—An Update. Vienna, Austria: Facultas Universitätsverlag; 2000:139-156.
28. Anderer P, Saletu B, Pascual-Marqui RD. Effect of the 5-HT1A partial agonist buspirone on regional brain electrical activity in man: a functional neuroimaging study using low-resolution electromagnetic tomography (LORETA). Psychiatry Research, Neuroimaging. 2000;100:81-96.
29. Saletu B, Anderer P, Saletu-Zyhlarz GM, Arnold O, Pascual-Marqui RD. Classification and evaluation of the pharmacodynamics of psychotropic drugs by single-lead pharmaco-EEG, EEG mapping and tomography (LORETA). Methods Find Exp Clin Pharmacol. 2002;24(suppl C):97-120.
30. Saletu B, Anderer P, Saletu-Zyhlarz GM. EEG topography and tomography (LORETA) in the classification and evaluation of the pharmacodynamics of psychotropic drugs. Clin EEG Neurosci. 2006;37:66-80.
31. Saletu B, Anderer P, Stanek J, Saletu-Zyhlarz GM. EEG-mapping und EEGtomographie in der neuropsychopharmakologie. In: Riederer P, Laux G, eds. Grundlagen der Neuro-Psychopharmakologie. Ein Therapiehandbuch. Vienna, Austria; New York, NY: Springer Verlag; 2010:109-123.
32. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol. 2002;53:545-574.
33. Pizzagalli D, Pascual-Marqui RD, Nitschke JB, et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical topography analysis. Am J Psychiatry. 2001;158:405-415.
34. Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675-682.
35. Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and lowresolution brain electromagnetic tomography. Am J Clin Nutr. 2002;76(suppl): 1162S-1171S.
36. Saletu B, Anderer P, Wolzt M, et al. Double-blind, placebo-controlled, multipleascending- dose study on the pharmacodynamics of ABIO-08/01, a new CNS drug with potential anxiolytic activity. 2. EEG-tomography findings based on LORETA (low-resolution brain electromagnetic tomography). Neuropsychobiology. 2009;59:110-122.
37. Saletu B, Grünberger J, Linzmayer L, Taeuber K. The pharmacokinetics of nominfensine. Comparison of pharmacokinetics and pharmacodynamics using computer pharmaco-EEG. Int Pharmacopsychiatr. 1982;17:43-72.
38. Saletu B, Grünberger J, Taeuber K, Nitsche V. Relation between pharmacodynamics and kinetics: EEG and psychometric studies with cinolazepam and nomifensine. In: Herrmann W, ed. EEG in Drug Research. Stuttgart, Germany; New York, NY: G. Fischer; 1982:89-111.
39. Saletu B, Grünberger J, SieghartW. Pharmaco-EEG, behavioural methods and blood levels in the comparison of temazepam and flunitrazepam. Acta Psychiatrica Scandinavica. 1986;332(suppl):67-94.
40. Saletu B, Grünberger J, Anderer P. Abendliches Fernsehen und Schlaf. Polysomnographische, psychometrische und psychopharmakologische Untersuchungen bei Schlafgestörten (I). Med Welt. 1983;34:829-832.
41. Saletu B, Grünberger J, Anderer P. Abendliches Fernsehen und Schlaf. Polysomnographische, psychometrische und psychopharmakologische Untersuchungen bei Schlafgestörten (II). Med Welt. 1983;34:866-870.
42. Sartorius N, Baghai TC, Baldwin DS, et al. Antidepressant medications and other treatments of depressive disorders: a CINP Task Force report based on a review of evidence. Int J Neuropsychopharmacol. 2007;10(suppl 1):S1-S207.
43. Saletu-Zyhlarz GM, Anderer P, Linzmayer L, et al. Visualizing central effects of S-adenosyl-L-methionine (SAMe), a natural molecule with antidepressant properties, by pharmaco-EEG mapping. Int J Neuropsychopharmacol. 2002; 5:199-215.
44. Saletu B, Anderer P, Linzmayer L, et al. Pharmacodynamic studies on the central mode of action of S-adenosyl-L-methionine (SAMe) infusions in elderly subjects, utilizing EEG mapping and psychometry. J Neural Transm. 2002;109: 1505-1526.
45. Saletu B, Küfferle B, Grünberger J, Anderer P. Quantitative EEG, SPEM, and psychometric studies in schizophrenics before and during differential neuroleptic therapy. Pharmacopsychiatry. 1986;19:434-437.
46. 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. Oxford, UK: Pergamon Press; 1979:393-407.
47. Saletu B, Anderer P, Saletu-Zyhlarz GM, Pascual-Marqui RD. EEG topography and tomography in diagnosis and treatment of mental disorders: evidence for a key-lock principle. Methods Find Exp Clin Pharmacol. 2002;24(suppl D): 97-106.
48. Saletu B, Grünberger J, Saletu M, Mader R, Karobath M. The acute drug effect as predictor of therapeutic outcome: neurophysiological/behavioral correlations during anxiolytic therapy of alcoholics. In: Mendlewicz J, Van Praag HM, eds. Advances in Biological Psychiatry. Vol. 9. Basel, Switzerland: Karger; 1982:67-80.
49. Saletu B, Anderer P, Saletu-Zyhlarz GM, Pascual-Marqui RD. EEG mapping and low-resolution brain electromagnetic tomography (LORETA) in diagnosis and therapy of psychiatric disorders: evidence for a key-lock principle. Clin EEG Neurosci. 2005;36:108-115.
50. Saletu B, Grünberger J. On acute and chronic CNS effects of antidepressants in normals: neurophysiological, behavioral and pharmacokinetic studies with pirlindol. Meth Find Exp Clin Pharmacol. 1985;7:137-151.
51. Fischhof PK, Saletu B, Rüther E, Litschauer G, Möslinger-Gehmayr R, Herrmann WM. Therapeutic efficacy of pyritinol in patients with senile dementia of the Alzheimer type (SDAT) and multi-infarct dementia (MID). Neuropsychobiology. 1992;26:65-70.
52. Saletu B. EEG/EP mapping in neurodegenerative and cognitive disorders. In: Racagni G, Brunello N, Langer SZ, eds. Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Dysfunction. Basel, Switzerland; Paris, France; London, UK; New York, NY; New Delhi, India; Bangkok, Thailand; Singapore; Tokyo, Japan; Sydney, Australia: Karger;1994: 24-30.
53. Saletu B, Saletu M, Grünberger J, Mader R. Spontaneous and drug-induced remission of alcoholic organic brain syndrome. Psychiatry Res. 1983;10:59-75.
54. Saletu B, Saletu-Zyhlarz GM, Anderer P, et al. Nonorganic insomnia in generalized anxiety disorder. 2. Comparative studies on sleep, awakening, daytime vigilance and anxiety under lorazepam plus diphenhydramine (Somnium®) versus lorazepam lone, utilizing clinical, polysomnographic and EEG mapping methods. Neuropsychobiology. 1997;36:130-152.
55. Saletu B, Anderer P, Semlitsch HV. Relations between symptomatology and brain function in dementias: double-blind, placebo-controlled, clinical and EEG/ ERP mapping studies with nicergoline. Dement Geriatr Cogn Disord. 1997;8 (suppl 1):12-21.
56. Saletu M, Anderer P, Saletu-Zyhlarz GM, et al. EEG-tomographic studies with LORETA on vigilance differences between narcolepsy patients and controls and subsequent double-blind, placebo-controlled studies with modafinil. J Neurol. 2004;251:1354-1363.

Keywords: EEG mapping; EEG tomography; LORETA; classification; mental disorder; psychotropic drug; key-lock principle; pharmacodynamics, dose efficacy; time efficacy