IPEG Guidelines for the Recording and Evaluation of Pharmaco-EEG Data in Man

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Neuropsychobiology 2012;66:201220

DOI: 10.1159/000343478

Guidelines for the Recording and Evaluationof Pharmaco-EEG Data in Man:The International Pharmaco-EEG Society (IPEG)

Marc Joberta Frederick J. Wilsonb G S.F. Ruigtc Martin Brunovskyd Leslie S. Prichepe

Wilhelmus H.I.M. Drinkenburgf The IPEG Pharmaco-EEG Guidelines Committee

aInternational Pharmaco-EEG Society, Berlin, Germany; bPharmatherapeutics Precision Medicine, Pfizer Ltd,

Sandwich, UK; cClinical Consultancy for Neuroscience Drug Development, Oss, The Netherlands; dPsychiatric Center, Department

of Psychiatry and Medical Psychology, Charles University, Prague, Czech Republic; eBrain Research Laboratories, Department ofPsychiatry, University School of Medicine, New York, N.Y., USA; fNeuroscience Discovery, Janssen Research and Development,

Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium

data in man. Since the publication of the first pharmaco-EEG

guidelines in 1982, technical and data processing methods

have advanced steadily, thus enhancing data quality and ex-

panding the palette of tools available to investigate the ac-

tion of drugs on the central nervous system (CNS), determine

the pharmacokinetic and pharmacodynamic properties of

novel therapeutics and evaluate the CNS penetration or tox-icity of compounds. However, a review of the literature re-

veals inconsistent operating procedures from one study to

another. While this fact does not invalidate results per se, the

lack of standardisation constitutes a regrettable shortcom-

ing, especially in the context of drug development pro-

grammes. Moreover, this shortcoming hampers reliable

Key Words

-Activity Biomarkers Central nervous system

Cordance Drug development Electroencephalography

Guidelines Pharmacodynamics Pharmaco-EEG

Pharmacokinetics Quantitative

electroencephalography Source localisation

Translatable EEG biomarkers

Abstract

The International Pharmaco-EEG Society (IPEG) presents

updated guidelines summarising the requirements for the

recording and computerised evaluation of pharmaco-EEG

Received: May 14, 2012

Accepted after revision: September 17, 2012

Published online: October 12, 2012

Marc JobertE-Mail publications @ ipeg-society.org

2012 S. Karger AG, Basel0302282X/12/06640201$38.00/0

Accessible online at:www.karger.com/nps

Co-authors (in alphabetical order):

Claudio Babiloni:Department of Biomedical Sciences, University

of Foggia, Foggia, Italy; Peter H. Boeijinga: FORENAP Research and

Development, Rouffach, France; Dominic H. ffytche:Institute of Psy-chiatry, Kings College London, London, UK; Jon Freeman:Brooklyn

Strategic Consulting, New York, N.Y., USA; Joop M.A. van Gerven:

Center for Human Drug Research, Leiden, The Netherlands; Koichi

Hirata: Department of Neurology, Dokkyo Medical University, To-

chigi, Japan; Ulrich Hegerl:Department of Psychiatry, University of

Leipzig, Leipzig, Germany; Toshihiko Kinoshita:Department of Psy-

chiatry, Kansai Medical University, Moriguchi, Osaka, Japan; Verner

J. Knott: Institute of Mental Health Research, University of Ottawa,

Ottawa, Ont., Canada; Fernando H. Lopes Da Silva:Center of Neu-

roscience, Swammerdam Institute for Life Sciences, Amsterdam, The

Netherlands; Milos Matousek: Department of Clinical Neurophysi-

ology, Gteborg, Sweden;Armida Mucci:Department of Psychiatry,

University of Naples SUN, Naples, Italy;Judith F. Nottage:Institute ofPsychiatry, Kings College London, London, UK; Sebastian Olbrich:

Department of Psychiatry, University of Leipzig, Leipzig, Germany;

Bernd Saletu:Department of Psychiatry and Psychotherapy, Medi-

cal University of Vienna, Vienna, Austria; Andrej Stancak:Depart-

ment of Experimental Psychology, Institute of Psychology, Health

and Society, University of Liverpool, Liverpool, UK; Werner K. Strik:

University Hospital for Clinical Psychiatry, Bern, Switzerland; Richard

G. Wise:Cardiff University Brain Research Imaging Centre, School of

Psychology, Cardiff University, Cardiff, UK.


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Jobert et al.Neuropsychobiology 2012;66:201220202

comparisons between outcomes of studies from different

laboratories and hence also prevents pooling of data which

is a requirement for sufficiently powering the validation of

novel analytical algorithms and EEG-based biomarkers. The

present updated guidelines reflect the consensus of a glob-

al panel of EEG experts and are intended to assist investiga-

tors using pharmaco-EEG in clinical research, by providingclear and concise recommendations and thereby enabling

standardisation of methodology and facilitating compara-

bility of data across laboratories.

Copyright 2012 S. Karger AG, Basel

Introduction

Pharmaco-electroencephalography (pharmaco-EEG)concerns the description and the quantitative analysis ofthe effects of substances on the central nervous system

(CNS) by means of neurophysiological and electrophysi-ological methods used within the framework of clinicaland experimental pharmacology, neurotoxicology, thera-peutic research and associated disciplines. For the re-mainder of this article, the acronym pharmaco-EEGstrictly refers to human quantitative electroencephalog-raphy (QEEG) in the context of drug testing. Separateguidelines for pharmaco-sleep studies in man are inpreparation for publication by the International Pharma-co-EEG Society (IPEG). Evoked potentials (EPs)/event-related potentials (ERPs), in which the time-locked EEGsignal resulting from a specific event is examined, repre-

sent another area of study and will be the subject of ded-icated guidelines.

In the 80s and early 90s, several guidelines were pub-lished with the goal to standardise the acquisition andprocessing of data collected in pharmaco-EEG studies[13] or to provide procedural recommendations for therecording and quantitative analysis of EEG activity in re-search contexts [4].

The initial pharmaco-EEG guidelines were comple-mented in 1995 by another guideline paper providing theframework to build standard operating procedures(SOPs), identifying the key components and minimum

requirements for data acquisition, amplification and fil-tering, the validation of hardware and software, artefacttreatment and fast Fourier analysis [5]. This frameworkconstituted the basis for setting up laboratory-specificSOPs. This attempt was driven by the mandatory need forcompliance to good clinical practice, an internationalquality standard launched by the International Confer-ence on Harmonisation (ICH), an international body de-

fining standards that governments can transpose intoregulations for the registration of pharmaceuticals andfor the conduct of clinical trials involving human sub-jects. Good clinical practice requires SOPs to be availableto document all methods and procedures in use duringdrug development.

In parallel, several organisations published recom-mendations and guidelines for the use of EEG in variousclinical fields [68] in an effort to improve standardisa-tion and facilitate the proper utilisation of the techniquein clinical practice.

EEG is a non-invasive method which directly revealsthe spontaneous synchronised postsynaptic neuronalactivity of the human cortex with high temporal resolu-tion. While EEG parameters are among the biomarkerswith the highest heritability [912], they show at thesame time a very high sensitivity to changes in both en-

vironment and internal states (state-modulated traits).

The sensitivity to such factors, which are extraneous tothe objective of many studies, means that a high degreeof quality control and detailed SOPs are required in or-der to decrease the effect of confounders in the analysisof the data.

While pharmaco-EEG has demonstrated its value inthe development of CNS-active compounds in many in-stances, and while validated quantitative methods havebeen available for a long time to study the effects of drugson brain functions in patients and volunteers [13], thereis still reluctance to apply this method in large-scale clin-ical trials or for pivotal drug studies. There are a number

of reasons contributing to this situation:(1) While there is evidence indicating the putative utility

and validity of EEG as a biomarker relevant to a rangeof drug classes covering several therapeutic indica-tions, it has not yet been generally accepted as such.Further, the translatability of pharmaco-EEG signa-tures is not universal across the spectrum of CNS-ac-tive drugs, but depends on the pharmacological mech-anism and the preclinical species used. Hence its useas a translational biomarker for the preclinical screen-ing of compounds and the development of new drugsrequires careful interpretation [14].

(2) Despite the fact that pharmaco-EEG has been used inresearch laboratories for several decades now [15, 16],operating procedures have not yet been standardisedto an extent facilitating reliable comparison of datasetsand results across units, making it difficult (or evenimpossible) to share datasets between sites or to poolresults from different clinical trials.


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IPEG Guidelines for Pharmaco-EEG Data Neuropsychobiology 2012;66:201220 203

(3) This lack of standardisation constitutes a difficult ob-stacle for the design and interpretation of clinical trialsdue to the difficulties in comparing results across theliterature.

(4) The large inter-individual variability observed in EEGrecords, some of which may be attributable to the lack

of standardisation, can be compensated by increasingthe sample size, provided that the behavioural andawareness state of the subjects is tightly controlled.However, trial costs quickly become prohibitive as thesample size increases and hence improvements instandardisation which enable sample size reductionswill make routine application more attractive. Despitethis, EEG is still one of the cheapest of the variousmethods that can be used as a window into the brainsactivity, and also has the advantage that it can feasiblybe integrated into first-in-human studies.

(5) For a long time, the amount of data generated by re-

cording EEG signals from multiple electrodes quicklyoverwhelmed the storage capacity of computers andthe processing techniques were constrained by CPUpower. These limitations have now disappeared as aconsequence of vastly increased computing power andstorage capacities.In this context, one of the crucial steps is to enhance

the standardisation of the operating procedures, not onlyto improve the ability to compare EEG data and resultsgenerated in different laboratories by reducing variancebut also to facilitate the creation of a centralised reposi-tory where a large number of records could be stored and

shared. Such a repository would enable the following en-deavours:(1) Constitute reference datasets (i.e. both the raw EEG

signals recorded against a unipolar reference and thederived parameters) obtained under standardisedconditions from different studies using various drugs(with emphasis on reference drugs and including pla-cebo) and study populations (healthy volunteers andvarious patient populations) under standardised be-havioural conditions, enabling comparative analyses.

(2) Identify EEG parameters and properties that could beexploited as potential (translatable) biomarkers and

quantify their validity on large populations.(3) Facilitate the transition of novel compounds from pre-

clinical to clinical research and development pro-grams by enabling the early comparison of results ob-tained in preclinical screening and early clinical ex-periments, thereby improving the decision-makingprocess as well as de-risking and accelerating the de-velopment of new CNS-active compounds.

Pharmaco-EEG Studies

FundamentalsPharmaco-EEG studies are applicable when there are

indications that a substance may have an effect on theCNS at therapeutic or pharmacologically relevant dose

levels. Pharmaco-EEG studies are indicated in all phasesof clinical research and may answer questions in clinicalpharmacology as well as in therapeutic research. It is theconsistency and nature of the empirical observations cap-tured by the pharmaco-EEG method, particularly in therealm of clinical psychopharmacology, which have estab-lished this technique as a suitable means for a completequantitative description of the effect of a drug on thefunction of the brain in humans [17, 18]. Pharmaco-EEGdata can be exploited to classify psychotropic substances[19, 20] and to assess drug-drug interactions or to moni-tor side effects and toxicity [21]. The use of quantitative

methods for data reduction and statistical analysis pro-vides quantitative descriptions of the direct and indirecteffects of active compounds on brain functions [22] hencegenerating pharmacodynamic (PD) outcome measureswhich, along with separate pharmacokinetic (PK) data(e.g. drug concentration from blood samples), can beused to study the PK-PD relationship [2325].

Pharmaco-EEG studies need to be designed in accor-dance with the objectives of the study (including placebocontrol and/or reference drug and test-retest designwhen indicated, and always keeping the behavioural andawareness state of the subjects under well-controlled

standardised conditions) and require appropriate statis-tical methods adapted to the study design and the inves-tigated hypotheses. Dependent upon the study objec-tives, either patients and/or normal volunteers may beexamined. Although a given psychotropic drug tends toproduce similar and replicable EEG profile changes indifferent populations at the group level, per-subject dif-ferences in EEG response profiles have also been shownto be a useful indicator of the biological variability andtherapeutic potency of a compound. Less potent psycho-tropic drugs often exhibit higher biological variability(as seen in individual EEG response profiles), while more

therapeutically potent compounds (i.e. with low biologi-cal variability) generally produce very similar EEG pro-file changes in the majority of subjects tested [26]. In pa-tient populations, clinical response to drugs has shownto be a source of variation with different patterns ob-served in responders versus non-responders [27, 28].This illustrates the potential utility of EEG for patientselection in clinical trials or as a companion diagnostic


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to certain drug therapies, thus facilitating a personalisedmedicine approach.

All clinical trial programmes must follow the ICHguidelines aimed at ensuring that good quality, safe andeffective medicines are developed and registered in themost efficient and cost-effective manner. These activitiesare pursued in the interest of the consumer and publichealth, to prevent unnecessary duplication of clinical tri-als in humans and to minimize the use of animal testing

without compromising the regulatory obligations of safe-ty and effectiveness. The ICH guidelines cover a broadrange of activities related to drug development [29, 30].

In addition, the responsible investigator should: (a) beacquainted with the literature and techniques of EEGdata processing which are the basis for the interpretationof the results; (b) understand the range of normal andabnormal variability of the neurophysiological methodsused, and (c) be responsible for the planning, organisa-tion and execution of the study.

Subjects

Due to the broad spectrum of neurophysiological do-mains where pharmaco-EEG studies are applicable, it isnot possible to provide an all-inclusive standard for sub-ject-related data which should be collected in pharmaco-EEG trials. The type of subject data to be collected maydepend upon the objectives, targeted population, pathol-ogy (by patients) and other attributes of a specific trial.

The following factors should be considered when com-piling inclusion and exclusion criteria for a particularstudy and documented routinely: demographic data (age,gender, handedness and socioeconomic status); medicalhistory [state of health, prior illnesses, presence of any

metabolic syndrome, hyperglycaemia or thyroid disor-der, use of drugs (including medication and recreationalsubstances, particularly cannabis), sleep quality and be-haviour, and EEG characteristics]; psychiatric history(DSM or ICD diagnoses), and use of tobacco, coffee, tea,energy drinks and alcohol (before and during the days ofexamination). If relevant, more personal characteristicsare to be filed: emotional lability, neuroticism, extraver-

sion/introversion; important psycho-physiological attri-butes such as emotional state (anxiety or fatigue), reac-tion to stress, bladder or bowel problems and menstrualcycle, for example. Where possible, standardised ratingscales should be used to quantify characteristics and sub-jective descriptors should be avoided.

Table 1 summarises the set of subject metadata to berecorded in pharmaco-EEG trials.

Given the profound effect of nicotine, caffeine and al-

cohol consumption on the EEG signal, it is generally rec-ommended to restrict the use of these products in clinicalEEG trials, for instance by excluding subjects if they meetany of the following conditions within the previous 6months: History of regular alcohol consumption exceeding 23

units/day for females and 34 units/day for males [31] History of regular use of tobacco or nicotine-contain-

ing products exceeding the equivalent of 5 cigarettesper day

History of regular consumption of caffeine exceedingthe equivalent of 4 cups of coffee per day, a level that

approximates health-related criteria [32]In addition, subjects should refrain from alcohol and

caffeine for at least 24 h, and from tobacco or nicotineproducts for at least 4 h (preferably 8 h) prior to an EEGrecording.

Stricter exclusion criteria or restrictions may be ap-plied on a study-by-study basis where required.

Phenotyping and/or genotyping of the participants isacquiring increasing importance for safety and PK rea-sons; since drugs can be primarily metabolized throughspecific cytochrome P450 (CYP) isoenzymes, metabolicstatus could be defined accordingly in order to avoid po-

tential accumulation/fast elimination during the wash-out phase, for example. If a drug is known to be subjectto a major genetic polymorphism, studies could be per-formed in panels of participants of known phenotype orgenotype for the polymorphism in question.

In addition, genotyping is becoming relevant for theEEG itself: it has been demonstrated that a low/high nat-ural rhythm can influence the interpretation of the

Demographics Age, gender, handedness

Medical history State of health, prior or current illnesses, psychiatric history

Screening EEG Abnormalities, high/low power

Medication status Current use of drugs, use of drugs in the past 4 weeksUse of alcohol, tobacco, illicit drugs

Table 1.Minimum set of subjectmetadata to be filed in pharmaco-EEGtrials


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EEG response to drugs [33], and studies of twins concludethat the high inter-individual variability in power andpeak frequency is largely genetically determined [912].Today, the best candidate is a gene encoding catechol-O-methyltransferase. According to a recent study [34], theVal158Met polymorphism of the enzyme is highly predic-

tive of individual activity, with the Val allele carriersdisplaying lower peak frequency and lower activitycompared to the Met allele carriers. If this variability islikely to have an effect on a particular study, then suitablesubjects could be selected either by genotyping or byscreening for low/high EEG rhythm. Alternatively, ge-notyping data could be collected for post hoc analysis.

Pharmaco-EEG Data Acquisition

Digital Recording

Digitising is the conversion of an analogue (continu-ous) signal into a digital (discrete) representation (i.e. asequence of numbers). Analogue-to-digital (A/D) con-verters usually have a resolution of 16 bits, meaning thatthe analogue amplitude of each discrete point is repre-sented by a value ranging from 0 to 65,535 (0 to 216 1).The sampling rate (TS) corresponds to the time intervalbetween two subsequent points and determines the reso-lution in time. The sampling frequency (FS) expresses thenumber of samples digitised per second and is the recip-rocal of the sampling rate (FS= 1/TS). With a samplingfrequency of 500 Hz, the resolution in time (s) corre-

sponds to the sampling rate and is given by the reciprocalof the sampling frequency, i.e. 2 ms.

From a theoretical point of view, the sampling fre-quency must be at least twice the highest frequency pres-ent in the signal to be digitised (Nyquist-Shannon sam-pling theorem). Conversely, frequency components high-er than half the sampling frequency (also called Nyquistfrequency, FN= FS/2) must be removed using analoguefilters before digitising to avoid aliasing effects. Errorsintroduced in the digitised signal by aliasing cannot bedetected and corrected afterwards. Because of imperfec-tions in the analogue filters, the sampling frequency is in

practice at least fourfold the analogue filter (anti-alias-ing) cut-off frequency.

From a practical point of view, the following appliesfor pharmaco-EEG studies: Sampling frequency must beat least 500 Hz (i.e. 500 samples per second) and be a mul-tiple of 50 or 64 [e.g. 500 or 512 Hz (currently in neuro-cognitive studies and in epilepsy, EEGs are being record-ed with a wider frequency band to allow the study of high

band components or, more generally, high frequencyoscillations; in this case, sampling has to be at rates 12kHz. This is discussed in the section on High-Frequency() EEG Activity below)]. The A/D converter must have adigital resolution of at least 16 bits and resolve changes inthe EEG below 0.2V. Prior to sampling, an anti-aliasing

low-pass filter set at 70 Hz (with a roll-off of at least 12dB/octave) must be used and the high-pass filter shouldbe set below 0.5 Hz (time constant 12 s; recommended0.01 Hz). Ideally, digital recordings should be made withminimal filtering (as above) and additional filters appliedpost hoc. This enables the effect of the filtering step to beevaluated. In particular, the use of a notch filter (50 or 60Hz) during recording should be avoided as it can poten-tially disguise an electrode problem, while the mainsnoise can be eliminated off-line at the data processingstage.

The electrode impedance (or resistance) should con-

ventionally be maintained below 5 k. However, modernamplifiers with high internal resistances are able to re-cord at higher scalp impedances (e.g. without using con-ductive gel). Similarly, MRI compatible EEG caps haveinbuilt safety resistors that set a minimum impedance ofaround 10 k. In these cases, higher impedance is accept-able, but in all cases it is important to balance impedanceacross electrode sites. The preamplifier input impedancemust be over 100 M. As the rejection of cross-talk be-tween channels is important for coherence or other mea-sures of relationships between electrodes, a cross-talk re-jection of at least 90 dB is required and better is recom-

mended.Comprehensible overviews on technical aspects relat-

ed to the digital recording of EEG signals have been pub-lished elsewhere and provide additional insight on spe-cific details [3537].

CalibrationRecording accuracy (how far the sample varies from

the true signal value) is dependent upon system calibra-tion. The calibration procedure is aimed at testing theperformance of the entire hardware and must be carriedout before each measurement. Calibration is also essen-

tial to achieve a reference potential of known voltageagainst the absolute amplitude of the recorded signals. Topick up possible time-dependent fluctuations of ampli-fiers, due to thermic effects for example, it is recommend-ed to re-check the calibration at the end of each measure-ment session.

Nowadays, most EEG machines have internal hard-ware calibration and the procedure may be carried out


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automatically. Verification is made that the same inputsignals (sine waves with known amplitude and frequen-cy) applied to all channels are present with the same am-plitude at the output of the amplifiers and are subse-quently correctly transmitted to the A/D converter. If in-ternal calibration is not available, then an external device

should be used to generate stable test waves that are re-layed through the electrode sockets.

Ideally, standardised calibration procedures shouldinclude sine waves of stable amplitude (e.g. 100V) at twodifferent frequency ranges (e.g. at 1 and 10 Hz) whetherinternally generated or from an external source. Verifica-tion of the calibration signal should be performed withdigital callipers utilising as long a duration of the calibra-tion signal as possible (e.g. 1 min per frequency). Al-though no definitive data currently exist on the amountof tolerable deviation for pharmaco-EEG signals, a max-imum acceptable variance of82% in signal amplitude at

both frequencies is recommended. Between-channel dif-ferences suggest an amplifier imbalance and channelswith182% variance should be eliminated from analysis.

Electrode PositionsWhile demonstration has been made in the past that

it is possible to trace the effects of specific compoundswith a limited number of electrodes (e.g. using the bipolarfronto-central and occipito-temporal derivations, Fz-Czand Oz-T6), it is no-longer state-of-the-art and inappro-priate for advanced investigations. Instead, a configura-tion of 21 electrodes placed according to the internation-

al 1020 system [38] is the recommended minimal elec-trode configuration. If additional EEG electrodes areused (e.g. for mapping or localisation studies), then theinternational extended 1020 electrode placement sys-tem (also known as 10% system [3941]) should beutilised. The nomenclature of the electrodes must followthese standards.

Many laboratories use electrode caps (as opposed tomeasuring individual electrode positions) for ease of ap-plication of dense electrode arrays. However, cap elec-trode positions only approximate the 1020 locations andare rarely measured accurately. It is important to ensure

that the electrode location does not deviate from the stan-dard when using caps.

As a matter of principle, recording against one refer-ence electrode is recommended (e.g. against Cz, A1andA2) or the arithmetic mean of A1and A2[(A1+ A2)/2] (i.e.a mathematically generated linked-ear or linked-mas-toid reference). Without resistors between them, twolinked electrodes (e.g. A1with A2) connect two brain re-

gions, thereby changing the electrical potential distribu-tion over the scalp. Hence, although the resulting distor-tion of potential may be negligible in many or even mostcases [42], physically linking the electrodes is not recom-mended. A linked reference may also be problematic ifthe impedance of one or other electrode varies differen-

tially during a recording (for example if one of the elec-trodes becomes dislodged). The data must be stored in aformat permitting conversion from the recording refer-ence to any other reference (common average reference,current source derivation or other channels as reference,for example). Active electrode systems can be used inpharmaco-EEG studies provided that active electrodeswould not distort any frequency components in the fre-quency range 0.0540 Hz.

In addition, EOG (electrooculography) must be re-corded (vertical and horizontal, bipolar) to aid in identi-fying artefacts and to correct off line the interference cap-

tured in the EEG using appropriate data processing algo-rithms. The recording of both ECG (electrocardiography)for assessment of the activity of the autonomous nervoussystem and EMG (electromyography) as additional mark-er for vigilance stages or artefacts is recommended. Therecording of other vital parameters, such as blood pres-sure and respiration, is optional.

Environmental ConditionsThere are many environmental factors affecting the

function and activity of the CNS and, as a result, also af-fecting neurophysiologic readouts of brain activity. It is

therefore necessary to control these factors to the bestpossible extent. If deviations from normal, pre-existingor pre-defined conditions are observed, then these shouldbe recorded as metadata. In clinical trials, it is manda-tory to document the degree to which these factors havebeen used as inclusion and exclusion criteria.

Adaptation. EEG measurements are subject and sensi-tive to adaptation effects. Consequently, at least one pre-examination EEG recording (apart from the screeningEEG) should ideally be performed on a separate day tocarry out one (or several) blank or habituationmeasurement(s). Such a procedure allows the subject to

become familiar with the environment, apparatus and re-cording protocol. When this additional subject visit is notfeasible, then a period of acclimation should be includedin the protocol on the study day itself before the actualrecording session is started.

Room. The recording should occur in a separate,sound-attenuated room with constant light (approxi-mately 40 lx), regulated temperature (2023 C/6873F)


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and normal humidity conditions. Intermittent disturb-ing events must be avoided. Random and undefined in-teractions between the subject and the staff during therecording (as for changing the electrode placement orposture, or giving additional instructions or stimulation)should be limited and documented. Typically, clinical

neurophysiology studies are carried out with the subjectsitting in a half-reclined position to reduce neck muscletension and with constant dimmed light (approximately40 lx) and this is recommended in many cases. However,these conditions are not amenable to the presentation ofa task and so resting data acquired in this way will not besuitable for comparison with subsequent task-related re-cordings forming part of the same study. Hence in studiesinvolving both resting and task-related recordings, it isrecommended that resting recordings be made in a situ-ation that exactly replicates the recording conditions tobe used when engaged in tasks (i.e. the subjects should be

comfortably seated in a suitably supportive high-backedchair in an upright position). The ambient light levelshould be maintained at a similar level during resting andtask-related recordings.

Time of Recording. Recording periods should be com-pleted at the same time of the day and under the sameconditions. If possible, having documentation of a sub-jects wake and sleep history (e.g. around 1 week of con-sistent bed- and rise-time) is advisable to assist in recog-nising circadian influences on the EEG (subjects withhighly disrupted sleep should be carefully evaluated andpotentially excluded from the study). Whenever possible,

the recording should preferably occur in the morning(between 9: 00 and 13: 00 h) to avoid interference withmeal times and postprandial vigilance f luctuations. Thisaspect is to be taken into consideration for the design ofstudies with repeated measurements following drug in-take (e.g. at baseline and 1, 2, 4 and 8 h af ter medication).Also the type of food (breakfast and lunch) must be care-fully selected.

Recording ConditionsFor the purpose of standardisation and to ensure that

results obtained in one laboratory can be compared with

results obtained in another, pharmaco-EEG studiesshould be recorded under one or more of the followingconditions:

(1) Vigilance-controlled EEG for 5 min (RT).Duringthis recording session, the subjects must have their eyesopen and the vigilance level should be controlled by asimple continuous performance task (e.g. creating a storyout of given words or solving simple arithmetic prob-

lems), which incorporates a fixation point to minimiseeye movement artefacts. The purpose is to stabilise thevigilance to a relatively narrowly defined level by meansof the continuous mental exercise. The EEG should bemonitored online by an EEG technician and short exter-nal interventions for vigilance stimulation are permissi-

ble if a decrease in vigilance is observed, for instance incase of intrusion of slow-wave activity in the EEG. How-ever, the EEG segments in which the interventions oc-curred are labelled as artefacts and are excluded from theevaluation.

(2) Resting EEG with closed eyes for 5 to 15 min (RSc).During this session, the EEG is recorded with closed eyesand fluctuations of vigilance are permitted without anyrestriction, the purpose of this recording condition beingto examine the variations in vigilance over time. It is es-sential that the instructions should be explicit, such as Sitquietly and keep your eyes closed; there is no task to com-

plete, just relax! Limited external interventions shouldtake place during the session and used only when neces-sary to help maintain consistency of state (e.g. eyes open-ing). Drowsiness EEG patterns or falling asleep are not areason to intervene. While sessions of 5 min yielding aminimum of 2-min artefact-free signal are sufficient toquantify EEG activity and demonstrate pharmacologicaleffects on spectral parameters [43], the recording may beextended to 15 min to assess the regulation of vigilance(CNS arousal) and wakefulness, and to quantify drug-induced changes in these parameters (e.g. sleepiness)[44].

(3) Resting EEG with open and closed eyes for 5 min ineach eye state (RSco).Recordings of this type employ al-ternate periods with eyes open and closed of 1-min dura-tion each in response to commands from the technician.Subjects should face a featureless wall in order to stan-dardise the visual environment and reduce the effect ofeye movements on the EEG during periods with openeyes. No additional vigilance control procedure should beused; in particular, fixation is not recommended as thisin itself constitutes a task. Data in each of the two statesshould be separated prior to processing and the EEG ac-tivity analysed separately for segments with open and

closed eyes.

Important Comments: The task to be used during the vigilance-controlled

condition has deliberately not been tightly defined inorder to encompass the range of currently acceptedpractice. One particular variation is to use a visualperformance task undertaken at a computer terminal,


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which has the benefit of also providing a measure ofperformance whereby epochs surrounding stimuluspresentation and motor response or outside presetlimits of normal reaction time can be excluded fromthe analysis. There are also other accepted proceduresfor maintaining vigilance during EEG recording, in-

cluding the use of a device which is sensitive to musclerelaxation. However, it is important to note that theresults cannot be readily compared when differenttasks or vigilance control methods are used as system-atic differences in both the topography and frequencycomposition of the resulting EEG signals are to be ex-pected. Hence, the method used must always be clear-ly described alongside the results.

Continuous video recording synchronised with theEEG is recommended.

It may not be possible to fully adhere to the standardprocedures in cases where patients are uncooperative

or unable to follow instructions (e.g. psychotic or se-verely demented patients). Any deviations from thestandard must be clearly stated alongside the presenta-tion of the results.

EEG recording should always take place prior to ad-ditional testing (e.g. cognitive paradigms), since vigi-lance might be decreased after exhausting or time-consuming tests.

Since the brain activity indicated by the EEG dependsstrongly on the present level of vigilance [45], care hasto be taken that drug effects on vigilance regulation(e.g. more rapid decline to lower vigilance stages with

sedating drugs) are separated from drug effects onEEG activity within the same vigilance level (e.g. in-crease in frequency).

With measures such as connectivity, phase and coher-ence, there is evidence that more data are necessary toconverge to stable, reliable estimates, and hence therecording duration for any of the conditions may beextended if required to meet the objectives of the study.

ArtefactsArtefact identification and elimination is crucial for

the proper quantitative analysis of EEG records. With op-

timal recording conditions, artefacts are only accidentaland appear infrequently. Artefacts can have various phys-iological origins (ocular, cardiac, muscular, behavioural,sweating and respiratory) and can be identified and/oreliminated either on line during the recording or off line.Special care should be taken in those studies where high-er frequency bands (i.e. and ) are of interest since theEEG signals may be contaminated by muscle activity.

Automated EOG artefact rejection is possible usingappropriate algorithms [4648]. However, when comput-erised algorithms are used, a semi-automatic procedurethat includes additional visual inspection is recommend-ed. Even new approaches such as the independent com-ponent analysis (ICA) used for the detection of eye move-

ment or muscle artefacts [49] should be applied with cau-tion. The risk of excluding components with mixedneurophysiological information of brain activity and ar-tefacts should be minimised by careful inspection of top-ographic maps of the components and by using an appro-priate number of components (equal to the number ofchannels of the input matrix).

Should the investigator doubt the validity of the pro-cedure either because of the large percentage of EEG seg-ments containing artefacts or because the kind of arte-facts could be confused with the treatment effect, then acomparative biometrical evaluation and assessment of

the artefact-free and complete data should follow.

Minimum RequirementsTable 2 summarises the minimum requirements for

the recording of pharmaco-EEG studies.

Pharmaco-EEG Data Processing

Representation in the Time DomainIn the time domain, the variations in potential after

amplification are displayed as a function of time and sig-

nals are usually denoted by a function s(t) [or s(k TS)(with k = 1N) in its digital form]. The representation inthe time domain is used for the visual inspection of EEGcurves and for the evaluation of EEG activity resultingfrom external sensory stimulation for which the positionin time is relative to the time point at which a stimulusoccurs. Thus, time is considered as a variable of the ob-served phenomenon. The detection of patterns or tran-sient activities in the EEG usually relies on processingalgorithms operating in the time domain.

Representation in the Frequency Domain

The transformation of a signal s(t) into the frequencydomain using the fast Fourier transformation (FFT) im-plicitly assumes that s(t) can be split up as a finite sum ofweighted sinusoidal waveforms [denoted as s(f)]. Thenumber of sinusoidal waveforms is dependent upon thewindow size (i.e. the number of points of the input signal)subjected to FFT. The resulting graphical representationdisplays the spectral characteristics of s(t), which is then


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Table 2.Minimum requirements for the recording of pharmaco-EEG studies

EEG recordingequipment

Sampling rate 500 Hz

A/D conversion 16 bits

High-pass filtering 0.5 Hz (0.01 Hz recommended)

Low-pass filtering 70 Hz (roll-off of at least 12 dB/octave)

Notch filter Usage avoided; otherwise 50 or 60 Hz (dependent on the power supply frequency)Pre-amplifier impedance 100 Mat 50 Hz

Common mode rejection 90 dB

Electrodes Electrode impedance Balanced impedance across all electrode sites

Number and placement At least 21 electrodes placed according to the 1020 system or the extended1020 system (10% system) in case >21 electrodes are used

Type Ag/AgCl or equivalent in terms of electrode drift and DC resistance

Montage Monopolar against a common reference

Reference Should be modifiable post hoc, (Cz, A1, A2, average mastoids)

Ground AFzEOG Vertical and horizontal for artefact identification

ECG Recommended

EMG RecommendedExperimentaldesign andconditions

Adaptation It is recommended to make the subject familiar with the recording conditions andprocedures during a separate recording session

Recording environment Sound-attenuated roomConstant dimmed light (approximately 40 lx)or light level defined by the computer monitor used for task presentationConstant room temperature: 2023C (6873F)Any major disturbances should be loggedSubject in a (semi-)reclined comfortable position or in an upright position facing acomputer monitor (for studies that also include a task)

Design Double-blind placebo-controlled cross-over design is recommended for acute studiesin healthy subjectsFor multiple dose and patient studies, the design should be adapted according to theobjectives

Recording time points Baseline and a number of post-drug recording time points to be driven by drug PK; atleast one time point around Tmaxplus at least 3 time points covering the decline in thePK curve (usually multiples e.g. 1, 2, 4 and 8 h)If Thalf12 h, then a 24-hour overnight time point should be considered

Time of day Preferably in the morningCross-over repeat tests should be done at the same clock time and under the sameconditions

Recording conditions RT (5 min vigilance controlled, eyes open)RSc(5- to 15-min resting condition, eyes closed)RSco(10-min resting with alternate eyes open and eyes closed)

Storageconditions

Local storage The proprietary format of each EEG recording equipment

Export/import format European data format plus [see ref. 50 for details]

Signals Raw data without transformation

Automatic artefact rejection is optional


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depicted by peaks in the frequency domain. This kind ofdisplay is generally used for the evaluation of spontane-ous EEG activity for which the position in time of eventshas no direct relevance.

The FFT (as an orthogonal transformation) is essen-tially a mathematical operation performed on time seriesdata which does not alter the information content of thesignal. Neither is any assumption made regarding the na-ture of the data nor any interpretation implied. Withinthe limitations of computational accuracy, the full revers-ibility of the transformation is implicit and given only as

long as numbers are retained in their complex form andnot averaged.

The resolution in the frequency domain depends uponthe sampling frequency (FS) and the number (N) of sam-pling points (size of the signal window) subjected to FFT.This resolution (denoted here as F) is given by the ratio(F = FS/N). Accordingly, the longer the signal window(N), the better the resolution of the frequency content.

When considering the results of an FFT applied to asignal window of N = 2,048 points (a number chosen be-cause it corresponds to 211and facilitates a rounded-offlength) with FS= 512 Hz, thenF = 0.25 Hz, which meansthat the frequency analysis can resolve 0.25 Hz (that isresolve 10.25 vs. 10.50 Hz directly). In this particular

case, the signal window (called epoch) will have a lengthof 4 s.

To reduce the broadband artefact, known as leakage,the signal window must be tapered toward zero at theirinitial and final data points (this tapering is usually doneusing a windowing function). When the FFT is appliedon sequential epochs, then discarding a proportion of thesignal through windowing can lead to differences inspectra depending on the starting point of the epoch se-ries. An alternative that results in a spectrum less sensi-tive to the starting point is to use partially overlappingepochs so that all data are represented.

Although computer-based analysis of scalp-recordedsignals for pharmaco-EEG profiling has utilised a widerange of quantitative techniques, spectral analysis viaFFT is currently the most common method of choice forthe parameterisation of pharmaco-EEG studies.

Non-StationarityMany signals, including EEG, are non-stationary,

which means that they have a time-varying frequencyspectrum, although they can be considered locally sta-tionary over short segments in which the parameters ofinterest vary minimally.

In practice, the choice of the segment length is a trade-off between frequency resolution (which suggests a longerepoch) and ensuring quasi-stationarity (which suggests ashorter epoch). For the pharmaco-EEG, epochs of 2- to10-second duration are used.

Spectral AnalysisThe traditional parameterisation of pharmaco-EEG

activity is largely based on spectral analysis. To this end,the recorded signals are divided into epochs (210 s)which are subjected to spectral analysis using FFT. Thistransformation in the frequency domain and subsequent

computation of the power spectrum allows a first datareduction.

The second step of data reduction consists in the extrac-tion of spectral parameters. The frequency range is subdi-vided into frequency bands, and the spectral performance(area under the curve) is computed for each of them (ex-pressed in V/Hz; square root of absolute power) or usinganother transformation (e.g. the natural logarithm of ab-

Table 3.Frequency ranges for spectral analysis in pharmaco-EEGstudies

Nomenclature Frequency rangeHz

Units of theresults

F 1.5 to


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In the following and for the purpose of example, it willbe assumed that the EEG signals are recorded with a sam-

pling frequency of 500 Hz (FS) and that the spectral pa-rameters are computed for epochs of 4-second length (i.e.2,000 samples), whereby the FFT are computed based on2,048 (211) points, with the individual overlapping epochsbeing tapered digitally toward zero voltage at their initialand final 24 data points. This way, 1 min of EEG record-ing will produce 15 power spectra, each 4-second epochproviding a set of spectral parameters (table 3).

Considering an EEG signal recorded for 5 min underRT or under RScconditions, the 5-min recording is firstdivided into 75 epochs; artefact-marked epochs are elim-inated, and the sets of spectral parameters are calculated.

Then, the strategy for data processing involves two steps(fig. 1):(1) For each spectral parameter, the activity over 5 min is

quantified using the sample mean and its standard de-viation (the median and its quartiles or the trimeancan also be used). This procedure is straightforwardand provides for each measurement point and eachEEG channel a set of spectral values that can be com-pared with others. The main drawback of this ap-proach lies in the fact that it does not allow changesthat may occur during the 5-min recording to be cap-tured [43], e.g. as a result of a sedative effect. This prob-

lem can be addressed by proceeding with a subsequentcomplementary assessment.

(2) The spectral activity at the beginning and at the endof the recording are quantified separately and the re-sults compared. This assessment is particularly usefulto verify the stability of the recording condition (asexpected for RT) or to detect time-dependent changes(especially for RSc).

Typically, the duration of the recording under RScisextended to up to around 15 min to assess the dynamicsof vigilance f luctuations. In this case, the vigilance regu-lation can be explored and vigilance levels assessed overthe whole duration of the recording session, from relaxedwakefulness to sleep onset [6870]. When focusing on

spectral activities only, the recording can be decomposedinto segments of equal length (e.g. 3 min) and the spectralparameters quantified for each segment (fig. 2) using thesample mean and standard deviation or other suitable pa-rameters as described above, following the elimination ofepochs containing artefacts. Then, the results obtainedfor the segments at the beginning, the middle and the endof the recording can be compared to capture time-depen-dent changes.

The processing of EEG signals recorded in the restingstate with alternate periods of RSco requires separatingthe epochs corresponding to the respective eye states

(fig. 3). Off-line treatment of EOG (blink) events occur-ring in the open-eye segments is mandatory and requiresparticular attention (e.g. using ICA or similar filteringtechniques). Then, the spectral parameters can be quan-tified for each eye state separately using the same methodas for the RT and RScrecording conditions (fig. 1). Also,in this case, it is useful to verify the stability of the re-cording through assessment of any time-dependentchanges.

In pharmacological trials aimed at assessing the effectof compounds on the CNS and on the EEG in particular,the study design as well as the selected recording condi-

tions and related processing strategies will be dependentupon the profile of the compound under examination,whereby the hypotheses and targeted parameters will bedefined upfront. Exploratory evaluations, however, mayrequire more flexibility, especially when the potential ef-fects are unknown. When documented and justified, therecording duration and the strategy selected for data pro-cessing can be adjusted if specifically needed for a par-ticular study. However, such deviations may impede theability to compare results with other studies.

Pharmaco-EEG Statistical Analysis

The present guideline paper is not intended to discussthe statistical aspects of the design and analysis of phar-maco-EEG studies and especially of PD studies. To thisend, reference is made to the corresponding IPEG guide-lines [71], which provide a set of recommendations for theinvestigation of the PD characteristics of a compound

10 2 3 4 5

Recording duration (min)

Fig. 1.Processing of 5 min EEG recorded under RT or RSccondi-tions. Spectral activity is analysed over 5 min (A). A comparisonof spectral activity for the segments at the beginning and the endof the recording (B) can be applied to capture time-dependentchanges.


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(e.g. time or dose effects) in the early phases of clinicaldrug development.

In summary, the key factors to consider during theplanning include, but are not limited to, the suitable typeof study design, the determination of the sample size andthe randomisation. In PD studies, the investigator mustaddress the problem of multiplicity of tests resulting

from a profusion of parameters (i.e. inferential statisticalstatements) to which a statistical comparison is applied.Further, the computation of a large number of statisticaltests in a given sample may lead to false conclusions andmust be used careful ly [72]. In a paper published in 1987,Abt [73] distinguishes three levels of statistical approachbased on probability computations: exploratory, descrip-tive and confirmatory statistical analyses. The descrip-

tive data analysis suggests inspection of changes by study-ing the pattern of descriptive p values assessed for allpairwise tests for differences in time or treatment. Thisapproach is particularly useful for the evaluation of topo-graphical changes [74]. Valid alternatives to this methodinclude randomisation and non-parametric permutationanalyses, which are used in brain imaging studies [75, 76],

including EEG source imaging.Sources of multiplicity are several variables, time

points and locations of measurement/observation, andcomparisons of more than two treatments or differentgalenic formulations. Moreover, pharmaco-EEG profilesmay also be examined in relation to behavioural changesassessed with rating scales, neuropsychological evalua-tions and computerised cognitive tests.

10 2 3 4 5 6 7 8 9 10 11 12 13 14 15


Fig. 2.Processing of 15 min EEG recorded under RSc. The variations in spectral activity can be analysed over15 min (C) or over consecutive segments (D). A comparison of spectral activity for segments of 3 min at thebeginning, middle and end of the recording can be applied to capture time-dependent changes (E).

10 2 3 4 5 6 7 8 9 10


eyes open

eyes closed

Fig. 3.Processing of 10 min EEG recorded under RS co. During the recording session, the subject alternates be-

tween states with eyes open and closed every 60 s. The spectral activity is analysed over the 5 segments corre-sponding to (F) and (G) recording periods with eyes open and closed.


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Whilst univariate models generally compare individ-ual variables of between-group or within-subject datas-ets, multivariate statistics assess multiple factors to creatediscriminants. Some methods utilise linear combina-tions of EEG measures with other clinical, cognitive andaffective ratings (neurometric analysis [77]). Methods

based on EEG measures alone are less well developed butshow future promise [78], and this field is advancing rap-idly, driven mainly by the use of such techniques in func-tional MRI (fMRI).

Finally, it should be noted that careful modelling andprecise correlation with independent parameters, such asPK factors, hormonal profile or metabolic status, are oftenneeded to determine the particular electrophysiologicalchange induced by a neuroactive drug, due to the inherentnon-specificity of the electrophysiological effects [79].

Due to the complexity of most statistical analyses re-quired for the evaluation of pharmaco-EEG studies, the

assistance of an experienced statistician is highly recom-mended.

Use of Normative DatabasesWhile not always available, when appropriate norma-

tive data exist [80], the data collected should be subjectedto comparisons (e.g. z-transformation) with a normativedata sample. The power spectrum of the EEG is extreme-ly stable and highly replicable, distinctive for each brainregion in a healthy, normally functioning individual, andis generally independent of cultural, ethnic or racial fac-tors. Therefore, this predictable, known power spectrum

can be used as a normative baseline that specifies the ex-pected electrical activity of the healthy, normally func-tioning human brain across the human lifespan. Devia-tions from these norms can be described as standardscores, providing a reliable and objective metric for ab-normalities of brain electrical activity [8183].

Pharmaco-EEG Advanced Topics

EEG Source LocalisationThe ability to display the time course and localisation

of brain activity based on extracranial measurements re-quires a mathematical solution to the inverse problem forthe computation of images of electric neuronal activitybased on the EEG signals recorded from the electrodes.In general, there is no unique solution to this problem.Inverse solutions critically depend on many a priori as-sumptions, including head models, solution spaces, regu-larisation parameters, the specif ic assumption on current

density distribution and procedures used for statisticalmapping (like normalisation or log transformation) andstatistical thresholds. All these factors have a significantimpact on the results that may vary drastically dependingon the choices made and it is usually impossible to vali-date the correctness of the choices independently. Conse-

quently, it is therefore absolutely necessary that all ofthese parameters and choices are fully presented and thatthe implications of the choices are explicitly discussed.

LORETA (low resolution electromagnetic tomogra-phy) provides 3-dimensional functional imaging of brainelectrical activity based on multichannel surface EEG re-cording without a priori knowledge about the putativenumber of discernible source regions [84, 85]. It is impor-tant to notice that a reliable estimation of EEG sourcesdepends upon the usage of a sufficient number of elec-trodes (at least 19) which are equally distributed. The spa-tial resolution is limited by the distances between elec-

trodes in the input matrix and by the assumption ofsmoothness. LORETA can be used to locate the mostprobable cortica l and subcortical sources for different fre-quency bands, and the time resolution of the EEG data canbe exploited for functional mapping of brain activities,whereby the solution space is restricted to cortical greymatter. Finally, LORETA images can also be computedrelative to normative voxel values, allowing sources to beevaluated as the deviation from age-expected norms.

The empirical validity of LORETA has been estab-lished in a large number of studies [86] covering variousEEG research fields, such as psychiatry [87, 88], neurol-

ogy [89, 90], neuropsychopharmacology [91] and sleepmedicine [92]. Further, the co-registration of LORETAwith other neuroimaging methods has shown good cor-respondence of effects [93, 94]. More recently, LORETAhas been used to evaluate interactive functional dynamicconnectivity in the brain, quantified by coherence andphase synchronization [95].

Despite the limitations of inherently low resolutionand the need for a priori assumptions, source localisationtechniques represent important advances in the utility ofQEEG that are a useful addition to other available func-tional neuroimaging techniques, and EEG-based meth-

ods provide direct information on neuronal activity withhigh temporal but low spatial resolution. In contrast,fMRI has high spatial resolution but low temporal resolu-tion that is confounded by the haemodynamic responsefunction. Magneto-encephalography combines high spa-tial and temporal resolution with a direct measure of ac-tivity but is less well established and not readily available.Also, it is sensitive to tangential and insensitive to radial


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sources, whereas EEG is most sensitive to radial sources,so the techniques may provide different but complemen-tary information on brain activity [96].

CordanceCordance is a QEEG analysis procedure that combines

complementary information from both absolute and rel-ative power from the EEG spectrum, as well as informa-tion from neighbouring electrodes for each scalp elec-trode [97]. It has been reported to have a stronger correla-tion with cerebral perfusion as measured by positronemission tomography (PET) than either absolute or rela-tive power alone [98], potentially providing a physiologicframework for the interpretation of findings.

Cordance has been used to assess neurophysiologicalchanges and treatment outcomes in major depression[99] and to predict the response of treatments in patientswith major depressive disorder [100102] or bipolar de-

pression [103]. Across studies of patients with major de-pressive disorder treated with various antidepressantmedications, decreases in prefrontal cordance 1 weekafter the start of medication have consistently predictedresponse, with overall accuracy ranging from 72 to 88%.Examination of this measure in one randomized, double-blind, placebo-controlled trial has suggested it may be aspecific indicator of medication efficacy but not placeboefficacy [104].

High-Frequency () EEG ActivityOver recent years, there has been considerably in-

creased interest in EEG activities in the frequency do-main above 40 Hz. Prior to 2007, attempts to extract EEGactivity in the band used traditional analysis methods.However, in 2007, Whitham et al. [105] demonstratedthat a considerable proportion of thesignal extracted inthis way disappeared with temporary muscle paralysis.Subsequently, Yuval-Greenberg et al. [106] and Keren etal. [107] showed that most of the power in the widely re-ported induced broad-band peak at 200300 ms after avisual stimulus did not originate in the brain and was infact due to extra-ocular muscle activity during micro-saccades.

Subsequently, methods have been developed to dealwith these tonic scalp and neck muscle and extra-ocularmuscle artefacts, hence enabling the true underlying EEGsignal to be extracted [107109]. These techniques requirerecording specifications that exceed those specifiedabove, including in particular: Increased sampling rate (25 kHz) Higher low-pass filter cut-off (5001,000 Hz)

Improved amplitude resolution (0.1 V or below) Additional EOG electrodes to record fully the extra-

ocular muscle activity Additional electrodes to record exogenous noise (e.g.

power-line noise) for regression-based artefact reduc-tion

Enhanced signal processing techniques are also needed,such as:

Shorter epoch lengths (typically 512 or 256 ms) tomaintain the stationarity assumption of the FFT

ICA- or regression-based methods for removal of ex-ogenous artefacts (e.g. power-line noise or pick-upfrom computer monitors) that would be removed bythe low-pass filter in traditional recordings

ICA-, regression- or model-based methods for remov-al of tonic scalp and neck muscle and extra-ocularmuscle artefacts.This is an area of research in which techniques are de-

veloping rapidly and there is insufficient evidence at pres-ent to determine the optimal recording and analysis tech-niques for high-frequency EEG. However, it is clear thatthe choice of method will quantitatively change the re-sults. Therefore, in studies including high-frequencyEEG, full details of the recording specification and anal-ysis techniques used, especially in relation to the artefactsdiscussed above, must be reported such that other labo-ratories can replicate, and potentially improve upon, theresults, so the field can continue to advance.

In addition, the factor analysis used to define the fre-quency ranges presented in table 3 did not include cover-

age of frequencies above 40 Hz. Hence, until a formal fac-tor analysis is undertaken to include the highfrequencyrange, it is important that studies clearly report the fre-quency bands that have been used. In the absence of anyother information, the following empirically chosen fre-quency ranges are suggested as a starting point for inves-tigators: 30 to !65 (1), 65 to !90 (2), and 90 to !135 Hz(3) [110, 111].

EEG Biomarkers and Translational MedicineWithin the context of drug discovery, the definitions

of a biomarker, clinical endpoint and surrogate endpoint

have been formalised by the Biomarkers DefinitionsWorking Group [112]: A biomarker is a characteristicthat is objectively measured and evaluated as an indicatorof normal biological processes, pathogenic processes, orpharmacologic responses to a therapeutic intervention,whereas a surrogate endpoint is a biomarker that is in-tended to substitute for a clinical endpoint. Put differ-ently, a biomarker is an objectively measured index of


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pharmacological response (or biological process) that isquantifiable, precise and reproducible. Biomarkers maybe used to diagnose or stage disease processes or predictclinical responses to treatments [113]. In the future, im-plementation of panels of relevant biomarkers may welltransform the process of development of new drugs [114].

In the simplest case, EEG can be used as a PD bio-marker reflecting brain activity in healthy subjects with-out reference to a specific therapeutic indication. PK-PDmodelling can thus be undertaken in different species us-ing a similar outcome measure, hence enabling cross-species comparisons of the effects of a drug [115, 116].

While EEG has a long history of evaluation in variousdiseases of the CNS, evidence is only recently accruing ofits putative validity as a useful and reliable biomarker forseveral therapeutic indications [14]. Recent reviews have,for instance, focussed on promising results indicating therelevance of QEEG as a reliable and sensitive biomarker

in many areas, including: Prediction of antidepressant response [104] Early detection of mild cognitive impairment and

Alzheimers disease [117, 118] Application in major neuropathophysiological disor-

ders [119] Characterisation of sleep disturbances in depression

[120] Assessment of vigilance in affective disorders [121] As a marker of genetic risk for attention deficit hyper-

activity disorder [122] As a biomarker for localizing epileptogenic foci in the

brain [123]In addition there is an increasing interest in the use of

ERP biomarkers for characterisation of, for example, thecognitive disturbances in schizophrenia [124] or clinicaldepression [125].

Another important aspect concerns the translatabilityof pharmaco-EEG signatures for the preclinical screen-ing and the development of CNS-active compounds. Thegoal of translational medicine applied to QEEG is tobring brain research from bench to bed and back. Thereare already several examples of successful contribution ofpreclinical EEG-based models in the discovery of psy-

choactive drugs [14, 126, 127]. These EEG models in ani-mals have shown promise in improving the understand-ing of disease mechanisms and therapeutics (e.g. iden-tification of central effects at a functional level andcharacterisation of central effects depending on the psy-choactive class or therapeutic indication) or in studyingthe relationship between animal behaviour and EEG ac-tivity [128]. Recent papers have further shown the valid-

ity of EEG as putative translatable biomarker in depres-sion [129] and Alzheimers disease [130].

The major strength of using EEG in translationalmedicine is that most EEG parameters can be measuredin a similar way in various animal species and humansubjects, using broadly similar paradigms, recording

techniques and signal processing algorithms: these simi-larities not only reflect face validity but also considerableconstruct validity. As similar QEEG methodology is ap-plicable in different species, it has the potential to bridgethe gap between preclinical and clinical research. How-ever, the lack of reliable translational procedures appli-cable to both patients and experimental animal models isan obstacle for the advancement of basic research, the de-termination of the translational validity of the technolo-gy and ultimately the development of new compounds[131] for three main reasons:(1) Lack of standardisation of animal EEG methodology

(e.g. low lead density)(2) Lack of specific guidelines on animal QEEG and phar-

maco-sleep EEG recording(3) Lack of valid animal models for psychiatric diseases.

In this context, it becomes crucial that efforts are madein the standardisation of experimental conditions and inthe development of protocols facilitating the comparisonof data collected in both humans and animals. Such aconcerted harmonisation would also offer the potentialto quickly acquire large databases that could be sharedbetween research groups and hence enable a fuller studyand understanding of translatability, including:

Equivalence of electrode specifications, positioningand montage across species including man

Equivalence of preclinical and clinical paradigms,such as vigilance control for example

Equivalence of spectral bands in different species(both numerically and in terms of species physiology)

Differences between human scalp EEG recordings andpreclinical cortical recordings (including understand-ing differences between gyrencephalics and lissence-phalics)

Equivalence and differences of underlying neurologi-cal processes and drug effects in different species and

strains (from mice to primates)Specific guidelines for preclinical, animal pharmaco-

EEG recording and analysis are in preparation for publi-cation by IPEG. Together with the present guidelines forstudies in man, these will address several of the above is-sues and hence should further contribute to optimisationof the translational value of QEEG.


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Conclusion

QEEG and related methods have the potential to offerreliable biomarkers and will, in view of the recent devel-opments in QEEG technology, play an increasingly im-portant role in all phases of drug development. The eval-

uation and quantification of drug effects in pharmaco-EEG, sleep and EP/ERP studies provide a set of methodsto capture the therapeutic benefits and the potential ad-verse effects that a drug induces in diverse patient popu-lations. By combining various methods and their respec-

tive strengths, it is reasonable to argue that they will pro-vide a more complete characterisation of the spectrum ofpharmacologic CNS responses [132].

In this context, it is mandatory to enhance and stan-dardise methodology and facilitate comparability of dataacross laboratories both in academia and in industry. To

this end, investigators using pharmaco-EEG are urged torefer to and comply with the guidelines presented herewhen designing and conducting studies, and to referencethe present paper when publishing study results.

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Documents

IPEG Guidelines for the Recording and Evaluation of Pharmaco-EEG Data in Man