Journal of Child Psychology and Psychiatry 48:5 (2007), pp 415–435
doi:10.1111/j.1469-7610.2006.01681.x
Annotation: What electrical brain activity tells
us about brain function that other techniques
cannot tell us – a child psychiatric perspective
Tobias Banaschewski1 and Daniel Brandeis2
1
Child and Adolescent Psychiatry, University of Göttingen, Germany; 2Child and Adolescent Psychiatry, and Centre
for Integrative Human Physiology, University of Zürich, Switzerland
Background: Monitoring brain processes in real time requires genuine subsecond resolution to follow
the typical timing and frequency of neural events. Non-invasive recordings of electric (EEG/ERP) and
magnetic (MEG) fields provide this time resolution. They directly measure neural activations associated
with a wide variety of brain states and processes, even during sleep or in infants. Mapping and source
estimation can localise these time-varying activation patterns inside the brain. Methods: Recent EEG/
ERP research on brain functions in the domains of attention and executive functioning, perception,
memory, language, emotion and motor processing in ADHD, autism, childhood-onset schizophrenia,
Tourette syndrome, specific language disorder and developmental dyslexia, anxiety, obsessivecompulsive disorder, and depression is reviewed. Results: Over the past two decades, electrophysiology
has substantially contributed to the understanding of brain functions during normal development, and
psychiatric conditions of children and adolescents. Its time resolution has been important to measure
covert processes, and to distinguish cause and effect. Conclusions: In the future, EEG/ERP parameters will increasingly characterise the interplay of neural states and information processing. They are
particularly promising tools for multilevel investigations of etiological pathways and potential predictors
of clinical treatment response. Keywords: ADHD, anorexia nervosa, anxiety, autism, childhood-onset
schizophrenia, depression, developmental dyslexia, EEG, endophenotypes, ERP, fMRI, neuropsychology, obsessive-compulsive disorder, specific language disorder, tic disorder. Abbreviations: ACC:
anterior cingulate gyrus; ADHD: attention deficit hyperactivity disorder; ASD: autism spectrum disorder;
BOLD: blood-oxygen-level-dependent; CNV: contingent negative variation; COMT: CatecholO-methyltransferase; CPT A-X: (cued) continuous performance test A-X (type); CHRM2: cholinergic
receptor, muscarinic 2; DRD2: D2 receptor gene; EEG: electroencephalogram; ERN: error-related negativity; ERP: event-related potential; fMRI: functional Magnetic Resonance Imaging; GABRA2: GABA-A
receptor gene; LDAEP: loudness-dependent amplitude change of auditory evoked ERP; MDD: major
depressive disorder; MEG: magnetoencephalogram; MMN: mismatch negativity; NIRS: Near Infrared
Spectroscopy; PET: Positron Emission Tomography; REM: rapid eye movement; RP: readiness potential
(or Bereitschaftspotential); SSRI: selective serotonine reuptake inhibitor.
Electrophysiological and magnetencephalographic
methods allow non-invasive monitoring of brain
processes in real time. Their supreme time resolution captures even fast neural events and highfrequency oscillations, and permits functional brain
imaging at millisecond resolution through source
analysis of high density maps. As a consequence,
they can directly measure the full spatio-temporal
dynamics of neural activation (see: methodological
section) associated with a wide variety of cognitive
processes and their development, and can be used
repeatedly without problems in longitudinal studies
and even during sleep or in infants (for reviews see:
Picton et al., 2000; Picton & Hillyard, 1988; Taylor &
Baldeweg, 2002). Over the past two decades,
electrophysiology has increasingly been used for
investigating the biological substrates of psychiatric
disorders.
The aim of this paper is to illustrate the current
state of the art of electrophysiological brain imaging
(here: EEG and ERP) in child and adolescent psychiatry. It will be shown how this research has con-
tributed substantially to our understanding of brain
states and functions in normal development, and of
deviations in psychiatric conditions occurring in
childhood or adolescence.
The paper starts with an introduction to methodological issues and contrasts advantages and
disadvantages of electroencephalogram (EEG) and
event-related potentials (ERP) methodology with
those of other neuroimaging techniques and neuropsychology. Secondly, recent advances of EEG/ERP
research in the domains of attention, executive
functions, perception, memory, language, emotion,
and motor processing are reviewed. This selective
review is not comprehensive, but rather aims to
illustrate the key issues through exemplary findings
in child psychiatry, focusing on ERP research. The
selection of studies was based (a) on the presence of
findings that contribute to theoretical controversies
or clinical treatment issues, (b) on the quality of the
samples investigated and the analyses used, and (c)
on whether a paper clearly illustrates specific
methodological strengths or weaknesses of EEG/
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416
Tobias Banaschewski and Daniel Brandeis
ERP research. We only included those studies with
adults which were exemplary and lacked an analogous equivalent in child psychiatric findings.
In an outlook, the annotation will then give
examples how electrophysiological parameters have
been (or may be) used to predict pharmacological
treatment response and to identify endophenotypes
for multilevel investigations of etiological pathways.
Methodology
The EEG measures brain electrical activity as
recorded from electrodes placed on the scalp. It directly reflects neural mass action, and mainly synchronised postsynaptic potentials of aligned neurons
such as pyramidal cells in cortex. Such spatiotemporal synchronisation of neural networks results
in net polarisation of extended brain regions, which
may be transient, slow, or oscillatory. The largest
EEG potentials are generated by cortical sources
which vary in depth and orientation, reflecting the
cortical folding. The attenuation of EEG activity with
depth is moderate, and far less than for the MEG.
The clinical routine of auditory brain stem potential
recordings demonstrates that even activity from
small and deep subcortical structures is reliably
detected in the scalp EEG after averaging (see below).
In contrast, action potentials are unlikely to contribute to the scalp EEG, because their fields are
radially symmetric around the axons and thus cancel at some distance despite their large amplitude.
Although an influential model has related surface
polarity of slow ERPs to neural inhibition (positivity,
as during the frontocentral NoGo P300) or activation
(negativity, as during the pre-central CNV) of nearby
cortical regions (Birbaumer, Elbert, & Canavan,
1990), tomographic source models of brain electrical
activity (Pascual-Marqui, Michel, & Lehmann, 1994;
Strik, Fallgatter, Brandeis, & Pascual-Marqui, 1998)
and fMRI correlates of slow ERPs (Hinterberger et al.,
2003) indicate a more complex relationship between
the local polarity of scalp maps, which strongly
depends on local cortical folding, and the underlying
distributed neural networks which may involve a
distributed pattern of activations and deactivations.
EEG waveforms generally are classified according
to their dominant frequency (see Table 1), amplitude, shape, and the sites of scalp distribution
(topography).
The EEG frequency composition is highly heritable
(van Beijsterveldt & van Baal, 2002). It reflects the
state of development and wakefulness, along with
modulations due to state regulation and arousal.
The magnetoencephalogram (MEG) measures the
corresponding magnetic fields with sensors around
the head. Although electric and magnetic fields are
typically closely related, the MEG is insensitive to
radial brain sources and skull conductivities, and
less sensitive to deep sources, thus (compared to
EEG recording) providing a more selective view of the
same neural mass activity.
ERP are changes in the ongoing EEG or MEG
which are time-locked (i.e., stimulus- or responselocked) and phase-locked (i.e., time-locked and with
the same polarities) to perceptual, cognitive, and
motor processes. They are typically extracted from
the ongoing electroencephalogram by means of signal averaging (see glossary). Averaging not only
eliminates the spontaneous background EEG, but
also those event-related EEG modulations which are
not phase-locked as ‘noise’. Other techniques can
also characterise such event-related modulations of
specific frequencies (event-related synchronisation
or desynchronisation), stimulus-induced phaselocking (i.e., stability of the evoked EEG rhythms
independently of amplitude measures), or the power
(i.e., the ‘strength’) within defined frequency bands of
the spontaneous EEG.
ERP consist of characteristic sequences of components or ‘microstates’ (i.e., time segments with a
stable topographical distribution of brain electrical
activity) that span a continuum between early
activity primarily determined by the physical characteristics of the eliciting stimulus (latency range
<250 ms), and later components (latency range
Table 1 Overview of EEG frequency bands, their topography, developmental and functional characteristics, and exemplary findings
EEG
Frequency bands
Topography
Developmental
characteristics
Functional state
Exemplary findings
Delta (<4 Hz)
Theta (4–7 Hz)
Predominant during neonatal
period & early childhood
e.g., sleep, decreased vigilance
ADHD: increased slow wave
activity
Cholinergic muscarinic receptor gene related to theta and
delta event-related oscillations
Alpha (8–12 Hz)
Posterior
Increases until early
adolescence
e.g., relaxation
Beta (13–30 Hz)
Frontal
Continues to mature
until adulthood
e.g., concentration,
neuronal excitability
Associated with GABA-A
receptor polymorphism
Risk for alcohol
dependence associated
with increased beta
ADHD: EEG subtype
with increased beta
Gamma (30–70 Hz)
e.g., feature binding
Considerable heritability
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Annotation: What electrical brain activity tells us about brain function
>250 ms) dominated by cognitive rather than physical characteristics of the stimuli (Brandeis & Lehmann, 1986; Picton & Hillyard, 1988). These
components are characterised by their topography,
polarity and amplitude, by their latency, and their
functional significance (see Table 2a and 2b for an
overview).
Mapping the scalp topographies of electric potentials or current source densities (also called surface
Laplacians, acting as spatial high pass filters emphasising localised components) gives important
clues to the intracranial generators of brain electrical
activity which determine map topography. Topographically stable micro-states usually coincide with
the conventional component peaks. Separate measures of map topography and of map strength (i.e.,
Global Field Power) provide a simplified description
of the map (Brandeis, Vitacco, & Steinhausen, 1994;
Lehmann, 1987).
Brain sources of scalp recorded ERP can be estimated from EEG or MEG topographies through source
modelling. However, the inverse problem (i.e., calculating sources from the known scalp distribution)
allows for multiple solutions which fit the data
equally well. Their validity can be considerably improved by allowing not only focal (e.g., dipole based)
417
but also distributed (tomographic) solutions, and by
taking neurophysiological and anatomical constraints into account (Michel et al., 2004; Pascual
Marqui, 2002; Pascual-Marqui et al., 1999). Absolute localisation errors for focal sources are usually around 1 cm and remain well below 2 cm even
for deep sources. Due to their complementary sensitivities, combined EEG and MEG recordings further facilitate source localisation (Fuchs et al.,
1998). See Figure 1.
EEG/ERP and neuropsychology
Performance data alone can only give indirect clues
about covert processing. Different covert mechanisms leading to similar overt performance may appear indistinguishable, and deviant covert information
processing may precede overt performance deficits
or even underlie normal performance. In addition,
many tasks tap more than one latent dimension of
functioning (Banaschewski et al., 2005).
Thus, the construct validity (i.e., do they measure
what they mean to measure) of neuropsychological
tasks is often uncertain. In contrast, EEG/ERP
studies can reveal both psychophysiological precursors and correlates of poor performance, and meas-
Figure 1 Time course, scalp distribution, and sources of an ERP. The activity (GFP curve, top) peaks at 380 ms with
the NoGo P300 to O-not X trials in the CPT O-X following smaller visual evoked potential components. The maps
(middle, red positive, blue negative potentials, scaled to maximum) demonstrate a stable central positivity and
increasing prefrontal negativity during the NoGo P3 at 330, 380 and 430 ms. The sources (bottom, maximal activity
in yellow and indicated by cursors in slices) suggest anterior cingulate cortex (ACC) activation progressing towards
increasingly anterior brain locations. Grand mean 48-channel ERP data of 12 young adult controls from an ongoing
study. Children show a similar but shorter and less prominent NoGo P300, leading to less reliable source localization.
Source tomography with standardised sLORETA, assuming SNR 10; Pascual Marqui, 2002
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Journal compilation ! 2006 Association for Child and Adolescent Mental Health.
418
Tobias Banaschewski and Daniel Brandeis
ure covert attention even in the absence of an overt
response (Brandeis et al., 1998; van Leeuwen et al.,
1998). Moreover, EEG/ERP parameters can index
processing of task-irrelevant, distracting or unattended stimuli, and may be recorded even during
sleep, unconsciousness, or in infants. They may
indicate whether task performance reflects the same
underlying processes across development and in
various populations. Thus, EEG/ERP studies
increasingly are being used (a) to illuminate the
content validity of neuropsychological tests by
revealing the modular architecture of more complex
neuropsychological constructs, (b) to test alternative
models and (c) to constrain psychological theories.
EEG/ERP and other imaging techniques
Neuroimaging techniques based on cerebral blood
flow or metabolism excel at spatial resolution, but
lack the genuine and high temporal resolution provided by EEG/ERP to reveal the exact timing,
sequencing or oscillation frequency of covert brain
processes and their neural substrates. In addition,
neuroimaging methods such as NIRS, fMRI or PET
reflect delayed metabolic consequences of the neural
activity while the latter is measured directly by EEG/
MEG.
The native time resolution of EEG/MEG (vs. fMRI)
and the native spatial resolution of fMRI (vs. EEG/
MEG) continue to differ by an order of magnitude.
Some authors also caution that they reflect different
aspects of neural processing operating at different
time scales, which can at best provide converging
evidence, and thus require integration through
models rather than through direct fusion (Horwitz &
Poeppel, 2002). On the other hand, progress in both
event-related fMRI (faster temporal sampling and
deconvolution) and in EEG/MEG (denser spatial
sampling and source tomographies) source imaging
has brought together the effective spatio-temporal
resolution of these methods. Recent multimodal
animal research has established that local EEG and
fMRI responses are closely coupled during visual
stimulation (Logothetis, Pauls, Augath, Trinath, &
Oeltermann, 2001), and multimodal (EEG-fMRI)
human studies demonstrate statistical correspondence (Brem et al., 2006; Vitacco, Brandeis, PascualMarqui, & Martin, 2002). Such multimodal research
also highlights the fact that the accurate localisation
with fMRI is necessary, but not sufficient to the understanding of brain function unless complemented
by the high temporal resolution of EEG/MEG, because initial and re-entrant brain activation in the
same brain region occurs within less than 100 ms
and cannot be disentangled by the low time resolution of fMRI alone (Noesselt et al., 2002). Recent
developmental work combining EEG and fMRI in the
same subjects is particularly relevant in this context.
These studies illustrate the importance and the
sensitivity of EEG-based measures in a develop-
mental context, and provide intriguing evidence for a
two-stage model of late maturation. The distribution
of networks for visual, motor and even reading
functions (as measured by fMRI) seems largely
established before adolescence, but fine-tuning of
specific neural networks in terms of specialisation
and processing speed (as measured by ERPs) and the
deactivation of non-specific ‘default’ networks
(measured by both ERPs and fMRI) continue beyond
adolescence (Brem et al., 2006; Bucher et al., in
press; Halder et al., in press).
The temporal and spatial features of the adult EEG
are linked through the distinct topographies and
sources of the EEG frequency bands, with the most
occipital and superior locations for alpha and the
most frontal and inferior locations for delta (Michel,
Henggeler, & Lehmann, 1992a; Michel, Lehmann,
Henggeler, & Brandeis 1992b). How distributed
neuronal networks correlate with the EEG frequency
bands is becoming increasingly clear through simultaneous EEG-fMRI recordings. This method has
provided an impressive verification that EEG frequency bands indeed reflect activity of cortical and
subcortical networks hypothesised to be involved in
regulation of attention and arousal, respectively;
higher frequencies are related to localised cortical
activation, while lower frequencies are more related
to deactivation or inhibition. Increased occipital alpha
activity during the resting state has been mapped
onto increased thalamic and decreased occipital,
temporal, and frontal fMRI activity in adults (Goldman, Stern, Engel, & Cohen, 2002; Moosmann et al.,
2003), and mainly increased frontal (dorsal medial)
and posterior (cingulate and precuneus) fMRI activity with increased beta at occipital leads (Laufs et al.,
2003).
Importantly, the EEG can characterise functional
states directly through absolute calibrated measures
of amplitude in the time or frequency domain. Such
calibrated measures are not possible with BOLD
(blood-oxygen-level-dependent) fMRI, which can only
characterise the differences between states, and requires calibration with regard to yet another state
(Davis, Kwong, Weisskoff, & Rosen, 1998). Absolute
calibrated measures of brain activity can also be
obtained by other imaging techniques such as PET.
However, PET applications in child psychiatry are
particularly limited due to the use of radioactive
markers, along with the high cost and technical
demands.
Brain functions and applications – EEG
Resting state, activation
The EEG changes with age and state of activation.
Maturation is accompanied by a reduction of the
slower components, whereas drowsiness and cerebral dysfunction both produce slowing. The typical
resting EEG is recorded during relaxed wakefulness
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Annotation: What electrical brain activity tells us about brain function
with closed eyes. Its main feature in adults is usually
the alpha rhythm, which emerges during early
childhood, increasing in frequency and responsiveness. Clinically, relaxed wakefulness reflects a particularly important state of controlled attention and
arousal, and is easily and reliably reproduced in a
wide range of patient groups and ages. The corresponding EEG has repeatedly been shown to discriminate between patients and controls. Long-term
stability (5 years) of the individual frequency-power
profiles in eight-year-old healthy children (Woerner,
Rothenberger, & Lahnert, 1987) indicates that these
profiles may be useful for genetic studies on controlled attention and arousal.
The EEG can measure brain function not only
across a wide range of maturational and developmental states, but also during both wakefulness and
sleep. As an essential indicator of sleep stages and
cycles, the EEG provides unique information
regarding altered sleep physiology in psychiatric
disorders specific to certain sleep stages such as the
disturbance of rapid eye movement (REM) sleep in
depression, which is associated with metabolic
increases in paralimbic and prefrontal networks
(Nofzinger et al., 2004). Sleep structure may also be
affected in children with ADHD, with an increased
duration of the absolute REM sleep and increased
number of sleep cycles (Kirov, Pillar, & Rothenberger,
2004). Since spectral and topographic sleep EEG
features in adults also show striking intraindividual
stability (Buckelmüller, Landolt, Stassen, & Achermann, 2006; Finelli, Achermann, & Borbely, 2001),
these measures may help to search for genes underlying functional aspects of undisturbed human sleep.
The typical EEG frequency analyses translate the
high time resolution into a high frequency resolution.
Numerous studies demonstrate that this frequency
resolution is essential to characterise arousal, state
regulation, and clinical features. Findings from EEGbased schizophrenia research can illustrate this
point. Drug-naı̈ve first-episode adult schizophrenic
patients exhibit increased slow as well as reduced
medium frequency activity, with both dysfunctions localised in a similar frontal network (PascualMarqui et al., 1999). Such an increase of slow frontal
EEG activity also occurs in active tasks, where it results in increased variability of frontal ERPs, and has
been interpreted as noise in prefrontal transmission
under genetic control (Winterer et al., 2004). More
refined topographic microstate analyses also reveal
prominent developmental stages during adolescence
(Koenig et al., 2002), and deviant state-transitions in
the sub-second time range in adult patients with
schizophrenia (Lehmann et al., 2005).
Because EEG frequencies characterise both
development and arousal or attention, EEG studies
are well suited to characterise developmental attention disorders such as ADHD (attention deficit
hyperactivity disorder). Extensive EEG research has
also related subtypes of ADHD to developmental
419
models. The spontaneous or resting EEG of ADHD
children is characterised by increased slow, and decreased fast activity (reviewed in Barry, Clarke, &
Johnstone, 2003a; Brandeis, 2000). The increased
slow activity is most prominent in children with
hyperkinetic disorder (HD) or ADHD-combined, but
is also found in ADHD children of the inattentive
subtype. This slow activity has a frontocentral distribution, although group differences are most
prominent over posterior regions and reliably discriminate ADHD children from controls. This type of
EEG deviation could be compatible with models
implicating maturational lag1 or underarousal in
ADHD. However, at least one subtype of ADHD which
is characterised by impulsivity and increased frontal
beta activity does not fit this developmental lag
scheme (Clarke, Barry, McCarthy, & Selikowitz,
2001). Further investigations of these subtypes in
terms of their clinical utility would appear promising.
The resting EEG abnormalities also show developmental continuity, i.e., increased slow posterior
activity continues to distinguish adolescents and
adults with ADHD from age-matched normal (Bresnahan, Anderson, & Barry, 1999) and clinical controls (Bresnahan & Barry, 2002). They are thus hard
to reconcile fully with developmental lag models.
In conclusion, EEG provides easy access to reliable measures of normal and deviant arousal and
state regulation across a wide age range including
infancy, where other functional brain mapping
methods are of limited use. EEG studies also clarify
that clinical deficits often affect multiple EEG frequency bands, and thereby reflect functional deficits
in several distinct networks evident at the same time.
Such conclusions cannot be drawn using methods
with lower time-frequency resolution. Table 1 provides an overview of EEG frequency bands, their
topography, developmental and functional characteristics, and exemplary findings discussed above.
Brain functions and applications – ERP
Automatic stimulus processing and attentional
orienting
A main strength of ERPs is their ability to resolve the
split-second time course of information processing.
ERPs have been used to determine whether incoming
sensory information is selected at initial, early (latency range 100–250 ms) or at later (latency range
>250 ms) stages of processing, i.e., before or after
1
If markers of developmental psychopathology also characterise an earlier stage of normal development, maturational lag
becomes a plausible explanation. However, if such markers are
not typical for a normal child of any age, the pattern instead
suggests a deviation of development. If a marker of developmental psychopathology does not normalise with maturation,
a developmental lag hypothesis can no longer explain the
finding (Rothenberger, Banaschewski, Siniatchkin, & Heinrich, 2003).
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420
Tobias Banaschewski and Daniel Brandeis
Table 2a Overview of exemplary early ERP components, their topography, developmental latency, functional significance, generators, corresponding exemplary findings and their specificity
Early ERPs
Component
(modality)
P50 (auditory)
N1, N170 (visual)
Topography
Latency (msec)
Central
40–80 post-stimulus
Posterior temporal
140–200 post-stimulus
Functional
significance
Refractory reduction
of P50 amplitude in
a paired auditory
stimuli paradigm
¼>preattentive
sensory inhibition
of irrelevant inputs
Early attentional orienting &
stimulus evaluation
Face processing, expertise
Generators
Exemplary
findings
Schizophrenia: abnormally
large S2/S1 amplitude
ratio ¼>impaired sensory
input control
Specificity
Low
N2
Frontal
200–400
post-stimulus
Response
monitoring
& response
inhibition
Visual N1: extrastriate visual
cortices, ventral occipitotemporal cortices
ADHD: increased in CPT
¼>deviant orienting
Autism spectrum disorder:
delayed to faces ¼>slowing
of face processing
ADHD, conduct
problems: reduced
in Stop task
¼>impaired
inhibition
Low
Low
stimulus properties are fully analyzed. ERPs have
demonstrated that the early stages of auditory and
visual information processing can be altered by
attention (Mangun, Hillyard, & Luck, 1992), even in
young healthy children (Taylor & Khan, 2000;
Yordanova, Banaschewski, Kolev, Woerner, & Rothenberger, 2001).
In ADHD children, already the early information
processing stages related to the initial orienting and
stimulus evaluation are altered (Brandeis et al.,
1998; Jonkman et al., 1997; Kemner et al., 1996;
Oades, 1998; Robaey, Breton, Dugas, & Renault,
1992; Steger, Imhof, Steinhausen, & Brandeis, 2000;
van Leeuwen et al., 1998; Yordanova et al., 2000).
Brain mapping indicates that children with ADHD
exhibit increased early automatic attentional orienting (increased N1) before failing to allocate sufficient attentional resources in further processing
stages (reduced P300, central processing, motor
output) (Brandeis et al., 2002a). This finding converges with shorter latencies of early auditory ERPs
around 100 ms (Oades, 1998; Satterfield, Schell, &
Nicholas, 1994), and with a deviant topography of
the visual N1 at around 200 ms in a stop task2 in
children with ADHD (Brandeis et al., 1998; Pliszka,
2
The Stop task is a reaction time task where Stop signals occasionally follow the Go signals and require inhibition of ongoing responses.
Mismatch negativity
(MMN)
Frontocentral
120–250
post-stimulus
Preattentive auditory
discrimination &
sensory memory.
Elicited by deviants
in an unattended
repetitive auditory
sequence
(Frontal &)
supratemporal
auditory cortices
Language impairment,
dyslexia & dyslexia
high risk: reduced
MMN to tone and
speech deviants
¼>phonetic
processing deficit
Schizophrenia:
reduced or
prolonged frequency
& duration MMNs
¼>impaired memory
traces
Low
Liotti, & Woldorff, 2000); the latter results also
indicate that a failure in early orienting and preparatory mechanisms can precede and partly determine
subsequent processing.
In adult schizophrenia, abnormal early sensory
processing is reflected by less refractory reduction
(less habituation) of the P50 amplitude of auditory
ERP (Myles-Worsley, Ord, Blailes, Ngiralmau, &
Freedman, 2004). A recent meta-analysis confirmed
that the P50 effect in schizophrenia has a large effect
size (Cohen’s d ¼ 1.5), similar to the most robust
findings reported in neuroimaging and neuropsychology in schizophrenia (for a meta-analysis
see: Bramon, Rabe-Hesketh, Sham, Murray, &
Frangou, 2004). Correspondingly, there is electrophysiological evidence for reduced latent inhibition
in adult schizophrenic patients (increased N100
amplitudes to irrelevant stimuli), indicating a deficit
in learning to ignore irrelevant stimuli (Kathmann,
von Recum, Haag, & Engel, 2000).
Furthermore, ERP studies indicate that adult
patients with schizophrenia are profoundly impaired
in the ability to recognise complete objects based on
fragmentary information, a process termed perceptual closure, as reflected by a strongly reduced visual
P100 (Doniger, Foxe, Murray, Higgins, & Javitt,
2002).
Recordings of auditory evoked potentials found
difficulties in anorectic patients modulating auditory
! 2006 The Authors
Journal compilation ! 2006 Association for Child and Adolescent Mental Health.
Frontocentral
100 after error
Error evaluation &
conflict monitoring
Sensitive to mood and
personality variables
ACC; modulated by
DLPFC & dopamine
ADHD, schizophrenia:
reduced ERN
¼>attenuated ACC
activity and reduced
control;
ADHD: diminished
sensitivity to internal
feedback, enhanced
sensitivity to external
negative feedback
Low
Latency (msec)
Functional
significance
Generators
Exemplary
findings
Specificity
Error-related negativity (ERN)
Topography
Component
(modality)
Late ERPs
Oddball-P3, Cue P3: attentional
allocation, stimulus evaluation &
context updating
Nogo-P300 amplitude, anteriorisation:
response control
P3a: novelty orienting
NogoP3: ACC, DLPFC, parietal cortices
cue P300: posterior attention networks
P3a: inferior parietal & prefrontal
regions; reflects phasic noradrenergic
activity
ADHD, schizophrenia: reduced target
P300 amplitude and Nogo-P300
anteriorisation pure ADHD: reduced
cue P3 ¼>attentional problems
ADHD + conduct problems: more
pronounced deficits in Nogo P3
¼>inhibitory problems
Alcohol & substance abuse:
Schizophrenia: oddball P300
topography with right-shift ¼ left
hemisphere attenuation
P3 associated with: quantitative trait
loci at chromosome 2, 5, 6, 17
and with DRD2, COMT, CHRM2
polymorphisms
None (except topography)
300–800 post-stimulus
P3a, Nogo-P3: frontocentral;
Cue-P3, oddball P3: centroparietal
P300
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Low
ADHD: reduced CNV
ADHD: LRP
attenuations;
Patients with
simple tics deviant
RP & other motor
potentials
Low
SMA, motor cortices
Cognitive preparation,
time estimation and
working memory
Contingent negative
variation (CNV)
SMA, motor cortices
Initial bilaterally
centrally symmetric,
then lateralised
over motor cortex
RP starts 1000,
LRP 200–500 prior
to movement
Motor preparation
Readiness potential
(RP); lateralised RP (LRP)
Low
Aphasia: attenuated/
delayed N400
Anterior medial temporal
lobes
Semantic language
processing, contextual
integration
400 post-stimulus
Centroparietal
N400
Table 2b Overview of exemplary late ERP components, their topography, developmental latency, functional significance, generators, corresponding exemplary findings and their specificity
Annotation: What electrical brain activity tells us about brain function
421
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Tobias Banaschewski and Daniel Brandeis
stimuli adequately at the subcortical level during
starvation, indicating dysfunctions at a subcortical
level (brainstem) and a transitory functional uncoupling of cortical versus subcortical neuronal
systems; these deficits persisted even after gaining
weight (Miyamoto, Sakuma, Kumagai, Ichikawa, &
Koizumi, 1992; Rothenberger, Blanz, & Lehmkuhl,
1991; Rothenberger, Dumais-Huber, Moll, &
Woerner 1995a).
In summary, ERP studies demonstrate that fast
perceptual and attentional functions that occur
within the initial 150 ms of information processing
are affected in ADHD, schizophrenia and anorexia
nervosa, even though different early processing deficits characterise these three disorders. The examples illustrate that the time resolution of EEG/ERPs
is essential to clarify how altered activation in sensory systems (which is also found in fMRI studies,
e.g., for adolescents with ADHD, Rubia, Smith,
Brammer, Toone, & Taylor, 2005) reflects a primary
information processing problem, and not a secondary, late consequence of altered cognitive or emotional evaluation.
Executive functions, attention, inhibition, motor
processes and motivation
Later attentional and executive functions can be
measured through the P300 type components following targets in numerous tasks. The P300 components have been linked to attentional allocation,
stimulus evaluation and context updating processes
of working memory (Polich & Herbst, 2000). Reduced
P300 amplitudes are a robust finding in a variety of
psychiatric disorders in adults, including schizophrenia (Bramon et al., 2004), increased risk for alcohol and substance abuse (Carlson, Katsanis,
Iacono, & Mertz, 1999; Porjesz et al., 2005). In children similar P300 reductions are present in children
at risk for schizophrenia (Schreiber, Stolz-Born,
Kornhuber, & Born, 1992), and in ADHD (Brandeis
et al., 2002a; reviewed in: Barry, Johnstone, &
Clarke, 2003b; Brandeis, 2000; Klorman, 1991), as
well as in a number of other disorders. P300
attenuation is usually measured for correctly detected targets only and is therefore not just a correlate
of poor performance. While the much-replicated
P300 attenuation in schizophrenia is not disorderspecific, the right-shift of the P300 topography due
to a left-sided amplitude reduction (found in adult
patients) appears rather specific, and correlated with
left temporal gray matter loss (McCarley et al., 2002;
Salisbury et al., 1998; Strik, Fallgatter, Stoeber,
Franzek, & Beckmann, 1996a).
The specific brain functions underlying inattention, impulsivity and impaired response control can
be separated with adequate ERP tasks, for example
the cued continuous performance test (CPT A-X)
which yields different P300 components to cue, target, and NoGo stimuli.
In ADHD children, impaired attention is reflected
in a reduction of the P300 to cues which signal that
the next stimulus may be a target. This finding (van
Leeuwen et al., 1998) was replicated in multicentre
studies (Banaschewski et al., 2003; Brandeis et al.,
2002a; van Leeuwen et al., 1998). Importantly, these
attentional deficits occur without concomitant responses or performance deficits, temporally precede
inhibitory or executive control, predict subsequent
performance (Banaschewski et al., 2003; van Leeuwen et al., 1998), and do not depend on age and sex
(Brandeis et al., 2002a). These covert attention deficits are more pronounced in ADHD children without than in those with comorbid externalising
behaviour problems, despite a more severe psychopathology in the latter group (Albrecht, Banaschewski, Brandeis, Heinrich, & Rothenberger, 2005;
Banaschewski et al., 2003). Electrophysiological
evidence thus supports conclusions from recent
family studies that the comorbid condition represents a separate pathological entity as considered in
the ICD-10 classification system, rather than a sum
of deficits from both pure disorders (Faraone,
Biederman, Mennin, Russell, & Tsuang, 1998).
Tomographic source solutions converge to posterior cue P300 sources (Brandeis et al., 2002a; Herrmann & Fallgatter, 2004; van Leeuwen et al., 1998).
This finding contrasts with the predominance of
frontal deficits in metabolic studies of ADHD, and
suggests under-activation of the posterior attention
system in ADHD children, and an involvement of
central noradrenergic networks as the cue P300 is
substantially modulated by this transmitter system.
Further deficits of ADHD children during behaviourally silent waiting and preparation periods are
implicated by reduced amplitudes of the contingent
negative variation (CNV) component (Dumais-Huber
& Rothenberger, 1992; Hennighausen, SchulteKörne, Warnke, & Remschmidt, 2000; Perchet, Revol, Fourneret, Mauguiere, & Garcia-Larrea, 2001).
This component has been related to several brain
processes implicated in ADHD, such as selective
preparation, time estimation (Elbert, Ulrich, Rockstroh, & Lutzenberger, 1991; Pouthas, Garnero,
Ferrandez, & Renault, 2000) and working memory
(McEvoy, Smith, & Gevins, 1998). While specific
motor preparation (LRP) is also reduced in children
with ADHD (Steger et al., 2001), the core deficits
(e.g., attenuated P3) were shown not to be timelocked to motor output processing stages, but rather
to increase with central factors such as coordination demands (Steger et al., 2001; Steger et al.,
2000).
Inhibitory control deficits as reflected by reduced
Nogo P300 are also found in children with ADHD
(Brandeis, van Leeuwen, Steger, Imhof, & Steinhausen, 2002b; Fallgatter et al., 2004; Rubia, Oosterlaan, Sergeant, Brandeis, & v Leeuwen, 1998).
However, these are preceded by state regulation
deficits (Brandeis et al., 1998; Pliszka et al., 2000) or
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Annotation: What electrical brain activity tells us about brain function
accompanied by executive control deficits, particularly at slow event rates (Wiersema, van der Meere,
Roeyers, Van Coster, & Baeyens, 2006). All these
findings implicate a more general state or response
regulation problem in ADHD (Banaschewski et al.,
2004). Unlike the covert attentional deficits, response control deficits are more prominent in children with comorbid externalising disorders.
Consistent with this suggestion, most ERP studies
have found that children with ADHD have a normal
enlargement of their N2 component in Nogo as compared to Go trials during GoNogo tasks (Banaschewski et al., 2004; Fallgatter et al., 2004;
Fallgatter, 2001; Overtoom et al., 1998, 2002; Wiersema et al., 2006); interestingly, this enlargement has
specifically been associated with inhibition (Eimer,
1993; Falkenstein, Hoormann, & Hohnsbein, 1999;
Jodo & Kayama, 1992; Kok, 1986; Pfefferbaum, Ford,
Weller, & Kopell, 1985; Sasaki, Gemba, & Tsujimoto,
1989; Sasaki et al., 1996; Schroger, 1993).
In contrast, the subsequent Nogo-P300 and its anteriorisation (a topographic measure of how much it is
anterior to the go-P300) are reduced in children
(Brandeis et al., 2002b; Fallgatter et al., 2004) and
adults with ADHD (Fallgatter et al., 2005). This NogoP300 seems to reflect more general processes of response and conflict control beyond inhibition, and
seems to be related to activations of the anterior cingulate cortex, and additional frontal and parietal
regions in adults (e.g., Carter et al., 2000; Falkenstein
et al., 1999; Fallgatter et al., 2001, 2004). Similarly,
both attentional and inhibitory deficits are seen for
ADHD children performing the Stop task, as their
reduced activity to Go-signals precedes an attenuated
right frontal N2-activity to Stop-signals (Albrecht
et al., 2005; Brandeis et al., 1998; Pliszka et al., 2000).
Control deficits in psychiatric disorders are also
evident from altered ERP activity to performance
errors and feedback. The initial error related
frontocentral negativity (ERN) peaks 100 ms after
motor onset. It has been associated with performance monitoring, conflict inhibition and error processing (for a review in adults: Falkenstein,
Hoormann, Christ, & Hohnsbein, 2000), localised to
the anterior cingulate gyrus (ACC), and is modulated
by lateral prefrontal cortex and the dopaminergic
system (e.g., Carter et al., 2000; Dehaene, Posner, &
Tucker, 1994). The development of conflict and error
processing is reflected in major differences between
children, adolescents and adults regarding the time
course of concomitant brain activation (Davies, Segalowitz, & Gavin, 2004; Hogan, Vargha-Khadem,
Kirkham, & Baldeweg, 2005; Rueda, Posner, Rothbart, & Davis-Stober, 2004).
The ERN amplitude is sensitive to mood and personality variables (Luu, Collins, & Tucker, 2000),
especially when correct responses are rewarded
and/or incorrect responses are punished (Dikman &
Allen, 2000), suggesting that affective and motivational processes may significantly influence pro-
423
cesses of performance monitoring and conflict
processing. Consistent with this, frontocentral
negativities with ACC sources are also involved in
processing feedback signals during guessing and
gambling in adults (Gehring & Willoughby, 2002;
Nieuwenhuis, Holroyd, Mol, & Coles, 2004).
In children with ADHD, one study found the ERN
during STOP task performance to be markedly reduced, suggesting a deficit in cognitive control processes (Liotti, Pliszka, Perez, Kothmann, & Woldorff,
2005). However, another study indicated that children with ADHD may have a normal ERN, but may
suffer from abnormal response strategy adjustments,
reflected in deviant ERP activity following the ERN
(diminished error positivity), suggesting reduced
evaluation of the error (Wiersema, van der Meere, &
Roeyers, 2005). Studies recording ERP associated
with feedback processing (feedback-related negativity) in children with ADHD found diminished sensitivity to internal feedback (internal error signals,
predicting the likelihood of an error) during a time
production task (van Meel, Heslenfeld, Oosterlaan,
Luman, & Sergeant, 2005a), suggesting problems in
assigning relative motivational significance to negative outcomes rather than in differentiating between
favourable and unfavourable outcomes. In contrast,
children with ADHD showed an enhanced sensitivity
to external negative feedback during a guessing
paradigm despite similar behavioural responses (van
Meel, Oosterlaan, Heslenfeld, & Sergeant, 2005b). An
enhanced ERN in patients with obsessive-compulsive
disorder (OCD) suggests that the clinical features in
OCD are related to hyper-functioning error and action-monitoring processes (Hajcak & Simons 2002;
Johannes et al., 2001).
In schizophrenia, ERP studies in adults have
documented diminished frontal response control
through reduced Nogo anteriorisation (Fallgatter &
Muller, 2001) and deviant neural processes involved
in response inhibition (Kiehl, Smith, Hare, & Liddle,
2000). Correlations of Nogo-P300 and fMRI data
suggest that adult patients with schizophrenia and
healthy subjects use different neural structures to
inhibit responses (Ford et al., 2004). Auditory P300
amplitude abnormalities in adults have indicated
high-level cognitive dysfunctions that do not originate from potential preceding impairments at lower
information processing levels (van der Stelt, Frye,
Lieberman, & Belger, 2004; van der Stelt, Lieberman, & Belger, 2005).
Several child psychiatric disorders are also characterised by movement problems (e.g., ADHD, tic
disorders, autistic stereotypies, developmental coordination disorder). Therefore, the neural dynamics
of normal and pathological movement in the developing child are of special interest, and may even have
clinical potential for training of deviant movement
regulation in the light of recent ERP evidence for
rapid plasticity of motor activation in adults (Halder
et al., 2005).
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424
Tobias Banaschewski and Daniel Brandeis
With ERPs, it is even possible to study the covert
process of motor preparation with the readiness potential (RP) preceding movement onset. This slowly
increasing precentral negativity peaks around the
onset of a voluntary movement. Its initial bilateral
phase is followed by the lateralised readiness potential (LRP), which is contralateral to the movement
and considered to reflect the output of the response
selection stage (Coles, 1989; Eimer, 1998). A consistently negative pre-central RP can only be registered by age ten (Chiarenza, Papakostopoulos,
Giordana, & Guareschi-Cazzullo, 1983). Recent
developmental work combining ERP with fMRI also
indicates that the basic motor network is established
around age 9, and that topographic changes of motor
ERPs beyond this age may result from increasing
deactivation of a non-specific, task-irrelevant default
network with age (Halder et al., in press). Since the
RP, as a voluntary ERP, is usually missing before a
tic (Hallett, 2001) and tics can be seen during all
sleep stages (Rothenberger et al., 2001), these motor
phenomena seem to be non-voluntary. Hence,
electrophysiology is at the moment the only method
which may contribute empirical evidence to further
clarify the issue of voluntary vs. involuntary aspects
of movements. Also, earlier RP studies first suggested that patients with tic disorder may develop
frontal premotor compensatory mechanisms to control for their tics (Rothenberger, 1982). This
assumption was recently supported indirectly by
studies with MRI (Leckman, Vaccarino, Kalanithi, &
Rothenberger, 2006) and is in line with the fact that
the frontally increased RP normalises after successful treatment of the tics with neuroleptics (Rothenberger, 1990).
ADHD children exhibit a more bilateral RP distribution as well as an attenuation of both LRP and
P300. This suggests parallel problems in motor
preparation and attention or coordination (Rothenberger, 1995b; Steger et al., 2000) which could not
be measured by other methods.
In conclusion, specific ERP tests allow detailed
mapping of the information processing sequence of
attentional, inhibitory and premotor brain functions
for state regulation and response control. Nonspecific deficits of control functions with attenuated
ACC activity characterise several disorders including
comorbid ADHD + CD and schizophrenia, while
deficits of premotor functions and posterior attentional networks are prominent in tic disorders and
pure ADHD, respectively.
Perception, face processing, emotion
Neural correlates of face recognition in the occipitotemporal brain, including the bilateral fusiform and
right superior temporal cortices, specialised for
faces, are indexed by the N170 (Henson et al., 2003).
This component can be used to assess developmental changes of face recognition already during
postnatal development (de Haan & Nelson, 1999;
Taylor, Edmonds, McCarthy, & Allison, 2001); its
recording does not require verbal responses, and it
is more sensitive in assessing facial recognition in
infants than the traditional behavioural measure of
looking time (de Haan & Nelson, 1997).
ERP studies reveal a slowing of face processing (by
20 ms) in young children with autism spectrum
disorder (ASD), as reflected in N170 latency
(McPartland, Dawson, Webb, Panagiotides, & Carver, 2004). These children’s ERP amplitudes also fail
to differentiate familiar from unfamiliar faces,
although they distinguish familiar from unfamiliar
objects, suggesting that autism is associated with
face recognition impairment early in life (Dawson
et al., 2002). Furthermore, 3–4-year-old children
with ASD show a disordered pattern of neural responses to emotional stimuli (Dawson, Webb, Carver,
Panagiotides, & McPartland, 2004).
In contrast, fMRI studies failed to find consistent
differences between adults with autism spectrum
disorder and normal controls in fusiform gyrus activation during face processing (Hadjikhani et al.,
2004; Hubl et al., 2003).
This example does indicate that structure and
overall activation can be basically intact, even
though the timing of the processes involved may be
impaired; thus, measuring brain functions with a
high time resolution can be crucial. Early interventions that enhance social attention should result in
changes in brain activity that are reflected in ERP to
face stimuli, and those children showing the greatest
social improvement should exhibit more normal
brain activity.
ERP indices confirm the presence of an attentional
bias for negative stimuli in anxiety, as high-anxious
adults show significantly larger amplitudes in the
early CNV during vigilance towards negative stimuli
(Carretie, Mercado, Hinojosa, Martin-Loeches, &
Sotillo, 2004). In contrast to behavioural data, the
ERP data indicate that threat-related faces elicit
faster and stronger early ERP responses in highanxious than in low-anxious adults (Bar-Haim,
Lamy, & Glickman, 2005).
Anxious children also show higher ERP amplitudes than their controls, probably reflecting difficulties in the effortful regulation of negative emotion
(Lewis & Stieben, 2004; Lewis, Lamm, Segalowitz,
Stieben, & Zelazo, 2006). Correspondingly, atypical
EEG patterns of frontal brain activation have been
found in anxious school children (Baving, Laucht, &
Schmidt, 2002). These findings indicate that EEG
studies may contribute to the understanding of the
development and the neuronal underpinnings of
emotion regulation in children.
Sensory memory and language
Auditory memory traces are measured through the
MMN, a frontally negative ERP component with a
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Journal compilation ! 2006 Association for Child and Adolescent Mental Health.
Annotation: What electrical brain activity tells us about brain function
latency of 120 to 250 ms that is elicited by deviations
of sound in a repetitive auditory sequence. It can be
considered as an outcome of an automatic ‘comparison process’ that contrasts incoming auditory input
against the memory traces of the preceding sounds,
and it is a valuable tool for investigating very early
pre-attentive auditory discrimination and sensory or
‘echoic’ memory even in infants and children (e.g.,
Cheour, Leppanen, & Kraus, 2000; Näätänen, 1990).
Auditory ERPs have been used to study mechanisms of early language acquisition (Baldeweg, Richardson, Watkins, Foale, & Gruzelier, 1999;
Leppänen & Lyytinen, 1997). Thus, the development
of language-specific memory traces has been demonstrated by the age of 1 year (Cheour et al., 1998),
although considerable topographic ERP differences
remain between children and adults (Maurer, Bucher, Brem, & Brandeis, 2003b). Auditory ERPs have
been applied in the investigation of specific language
impairment and related disorders, and for identifying children at risk, as they may reveal immaturity or
deficits of auditory processing even when behavioural thresholds look normal (Bishop & McArthur,
2005).
In developmental dyslexia, ERP studies documented that neurophysiological correlates of word
recognition are significantly attenuated (Brandeis
et al., 1994; Schulte-Körne, Deimel, Bartling, & Remschmidt, 2004). Abnormalities of the MMN correlated with the degree of phonological impairment
(Baldeweg et al., 1999; Kraus et al., 1996), pointing
to a selective processing deficit at an earlier phonetic
level as a possible source of the difficulties in learning to read, while at a later lexical level information
seems to be processed normally (Bonte & Blomert,
2004). Several groups studied auditory ERPs to
speech sounds in infants with and without a genetic
risk for dyslexia. All of them found significant group
differences, although the ERP deviance varied with
the speech test and the infants’ age. Infants at risk
had larger responses to standard sounds (more
right-central negativity after 400 ms) by the age of
6 months (Pihko et al., 1999), larger response (more
right frontal positivity after 300 ms) to deviants by
the age of 2 weeks (Leppänen et al., 1999), and
essentially absent mismatch responses to subtle
speech contrasts by the age of 2 months (van Leeuwen et al., 2006). Children at risk for dyslexia continue to show altered mismatch responses to subtle
tone and speech deviants when they start learning to
read, with a less left lateralised mismatch response
to speech stimuli implicating phonological deficits
(Maurer, Brem, Bucher, & Brandeis, 2003a). Longitudinal studies confirm that infants’ ERPs to
speech sounds also predict (in a statistical sense)
their subsequent language development, such as
verbal memory at age 5 (Guttorm et al., 2005) or
reading skills at age 8 (Molfese, 2000).
Although MMN abnormalities indicative of
auditory processing deficits have also been reported
425
in various other disorders (for reviews: Cheour
et al., 2000; Näätänen & Escera, 2000), the
underlying sensory memory impairments may be
specific for a given disorder. Thus, dyslexics exhibit
MMN attenuations mainly to subtle speech and
frequency deviance (Baldeweg et al., 1999), while
schizophrenic patients, or those at high risk for
schizophrenia due to microdeletion in the 22q11.2
gene, have reduced MMNs to large frequency and
especially duration deviants (adolescents: Baker,
Baldeweg, Sivagnanasundaram, Scambler, &
Skuse, 2005; adults: Javitt, Grochowski, Shelley, &
Ritter, 1998; Michie et al., 2000; Oades, DittmannBalcar, Zerbin, & Grzella, 1997), suggesting different deficits in preattentive auditory processing
in schizophrenic patients and individuals with
dyslexia.
The processing of language at the semantic and
syntactic level is indexed by several ERP components. The N400 is considered to be a sensitive index
of semantic processing reflecting neural mechanisms of semantic integration into context. It has been
localised to the anterior medial temporal lobe
(McCarthy, Nobre, Bentin, & Spencer, 1995). ERP
data indicate that both lexical expectations facilitating early phonological processing and mechanisms of semantic priming facilitating integration into
semantic context are already present in 19-montholds (Friedrich & Friederici, 2004). Syntactic violations elicit an early left anterior negativity and a late
centroparietal positivity called P600 in 3-year-old
children (for a review see: Friederici, 2005).
These findings demonstrate that ERP studies (in
contrast to fMRI) are particularly well suited to track
very early language development, and to detect
language processing deficits ranging from simple
automatic sensory memory to high-level syntactic
functions.
Brain functions and applications – single trial
analyses
Intraindividual variability – ADHD
Although computationally demanding, single-trial
analyses are important to investigate the degree of
trial-to-trial variability that may characterise different clinical syndromes. A single-trial analysis of low
frequency ERP components (Heinrich et al., 2001)
suggested that children with ADHD allocate more
attentional resources for an adequate performance
with time-on-task, supporting a sustained attention
deficit in ADHD, which is not consistently found
using neuropsychological tasks (van der Meere,
1996; van Leeuwen et al., 1998). Moreover, large
variability in component amplitudes and latencies
between single-trial ERP, suggestive of greater
variability in the extent and timing of latent cognitive
processing stages, has been found in ADHD (Lazzaro
et al., 1997), matching reaction time results
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426
Tobias Banaschewski and Daniel Brandeis
(Drechsler, Brandeis, Foldenyi, Imhof, & Steinhausen, 2005; Kuntsi & Stevenson, 2001).
Outlook
EEG/ERP parameter – potential predictors of
treatment response?
The intensity (i.e., loudness)-dependent amplitude
change of auditory evoked ERP has been suggested
as an indicator of the level of central serotonergic
neurotransmission in adults (Hegerl, Gallinat, &
Juckel, 2001; Strobel et al., 2003). This parameter
has potential clinical value since subgroups of patients with a serotonergic dysfunction can be identified and can be treated more specifically. In
depressed patients, a significant relationship between strong LDAEP, indicating low serotonergic
function, and a favourable response to SSRI has
been found. Additionally, there is evidence that the
LDAEP is a predictor of favourable response to a
preventive lithium treatment in adult patients with
affective disorders, and of responsiveness to reboxetine treatment in major depression (Hegerl et al.,
2001; Linka, Muller, Bender, Sartory, & Gastpar,
2005). In adult schizophrenic patients, a prospective
longitudinal study has demonstrated the predictive
value of auditory P300-amplitudes on clinical outcome in terms of social functioning (Strik, Fallgatter,
Stoeber, Franzek, & Beckmann, 1996b).
Electrophysiological measures also reflect changes
in the pattern of brain activations due to training.
Short-term attention training had a specific effect on
the scalp distribution of the ERPs that resembled the
effect of maturation, thus supporting the direction of
the behavioural data showing more adult-like performance after training (Rueda, Rothbart, McCandliss, Saccomanno, & Posner, 2005). Positive
behavioural and specific neurophysiological effects
of neurofeedback training of slow cortical potentials
has been demonstrated in children with ADHD
(Heinrich, Gevensleben, Freisleder, Moll, & Rothenberger, 2004).
Future studies will have to show whether objective
and reliable tools like ERP combined with genetic
markers can be used to predict individual patients’
treatment response even better.
EEG/ERP parameter – potential endophenotypes for
multilevel investigations of etiological pathways?
Many psychiatric disorders are probably best conceptualised as clinically and etiologically heterogenous conditions with differentiable pathways
linking specific putative causes to clinical phenotypes (Banaschewski et al., 2005). The still limited
knowledge of etiological and pathogenic mechanisms
is a major barrier for the development of selective
treatments for specific subgroups of patients. Efforts
to clarify the disorders’ molecular genetic basis have
often been hindered by an inability to detect nonclinically penetrant carriers of the predisposing
genes and by uncertainties concerning the nature of
the non-genetic influences and the extent of locus
heterogeneity.
Thus, ideally, molecular genetic studies should
not be performed on psychiatric diagnostic categories alone, but also on quantitative neurobiological
measures or markers (i.e., intermediate phenotypes,
or endophenotypes) of the genetic risk to develop
psychiatric disorders which are also associated with
the psychopathological symptoms (Castellanos &
Tannock; 2002; de Geus, 2002; Gottesman &
Shields, 1973; Tsuang & Faraone, 2000). This
endophenotype approach is an alternative method
for disentangling phenotypic variation that may
facilitate the identification and functional characterisation of susceptibility genes and other etiologic
factors in etiologically complex disorders, because
endophenotypes are less complex and more proximal
to gene function than either diagnostic categories or
neuropsychological measures (Almasy, 2003). This
approach has the advantage of providing insight into
the underlying pathogenic mechanisms and can help
to disentangle the pathways through which genes
may exert their influences on neuropsychological
parameters and behavioural symptoms.
Quantitative electrophysiological markers of
human information processing and psychopathology
are thus reliably detected throughout childhood and
adolescence, and differentiate between cases, highrisk relatives and controls. Furthermore, they show a
higher heritability than neuropsychological variables, suggesting that they may provide potentially
useful endophenotypes. Unfortunately, heritability of
fMRI measures has still to be determined; a recent
study found that prefrontal cortex activation is sensitive to genetic vulnerability for ADHD (Durston,
Mulder, Casey, Ziermans, & van Engeland, in press).
Considerable heritability for EEG band power has
been found for both slow and fast activities in both 5year-old children (averaging .81 for theta and .73 for
beta) and adults (averaging .89 for theta and .86 for
beta). For ERP, the estimated mean heritability is
60% for P300 amplitude and 51% for P300 latency,
depending to some extent on task conditions (van
Beijsterveldt & van Baal, 2002). A substantial proportion of genetic influences on P300 amplitude may
be explained by strong heritability of theta and delta
oscillations elicited during cognitive processing of
stimuli contributing to P300 (Anokhin et al., 2001;
Yordanova & Kolev, 1996). Functionally, P300 activity in adults has been associated with quantitative
trait loci at chromosomes 2, 5, 6 and 17 (Porjesz
et al., 2005) and with specific genes involved in
dopamine transmission (DRD2 polymorphism, Hill et
al., 1998; COMT polymorphism, Gallinat et al.,
2003).
The utility of quantitative electrophysiological
measures as endophenotypes of disinhibitory dis-
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Journal compilation ! 2006 Association for Child and Adolescent Mental Health.
Annotation: What electrical brain activity tells us about brain function
orders, including alcoholism, has recently been
illustrated in adults by the Collaborative Study on
the Genetics of Alcoholism. The association between
GABA-A receptor gene GABRA2 (the gene encoding
the alpha2 subunit), EEG beta frequency and the
risk for alcohol dependence in adults (Covault, Gelernter, Hesselbrock, Nellissery, & Kranzler, 2004;
Edenberg et al., 2004) suggests that this gene affects
the predisposition to develop alcohol dependence
through influences on the level of neural excitability.
Furthermore, a cholinergic muscarinic receptor gene
on chromosome 7 (CHRM2) was shown to be related
to the theta and delta event-related oscillations
underlying P300 to target stimuli and also to the
clinical diagnoses of alcoholism and depression
(Jones et al., 2004; Wang et al., 2004).
For ADHD, such specific pathophysiological
pathways have still to be identified. Taken together,
ERP findings indicate that children with ADHD suffer from a more general regulation problem, including deficits of attentional orienting and response
preparation and response monitoring, than just from
a response inhibitory deficit causing secondary deficits in other executive functions as proposed by
Barkley (1998). Hence, ERP could differentiate the
cognitive-motor problem best, compared to neuropsychology and other methods. Further, ERP paradigms have differentiated children with ADHD with
and without comorbid conduct disorder or tic disorder (Banaschewski et al., 2003, 2004; Rothenberger et al., 2000; Yordanova, Dumais Huber,
Rothenberger, & Woerner, 1997; Yordanova, Heinrich, Kolev, & Rothenberger, in press), indicating
that the presence of comorbidity in ADHD may alter
brain electrical correlates specifically, without necessarily affecting the level of overt behavioural
performance. Meanwhile, the idea of multiple developmental pathways to ADHD has been articulated
and developed in several recent theory papers
(Banaschewski et al., 2005; Nigg, Blaskey, Stawicki,
& Sachek, 2004a; Nigg, Goldsmith, & Sachek,
2004b; Sonuga-Barke, 2003).
Conclusions/summary
Electrophysiological parameters provide a noninvasive method to monitor spatio-temporal activation in the brain during sensory, cognitive, affective,
attentional and motor information processing as well
as during state regulation in real time. They can
reliably be reproduced in a wide range of patient
groups and across a wide age range, even in infants,
and during both wakefulness and sleep, and they
can give indices of covert, pre-attentive or pre-motor
processes. This makes them ideal for studies of brain
function during normal and deviant child development. Their excellent time-frequency resolution has
proven particularly useful to clarify whether multiple
deficits follow and cause each other, or are present
427
simultaneously, which is not possible with slower
metabolic methods. At the same time, the advances
in source resolution now allow genuine dynamic
neuroimaging with EEG/ERP.
Over the past two decades, the functional significance of many EEG and ERP parameters has become
biologically more meaningful and better grounded in
neurosciences. EEG/ERP research has contributed
substantially to the understanding of brain processes and functions in normal development and their
deviations in child and adolescent psychiatric conditions. They have helped to clarify whether overt
task performance reflects the same underlying processes throughout development and in various disorders (e.g., response inhibition in schizophrenia)
and to illuminate the content validity of neuropsychological tests by revealing the modular architecture of more complex neuropsychological
constructs (e.g., inhibition, attention), to test alternative models of information processing (e.g., allor-none or discrete stage models3 vs. continuous
models) and to constrain psychological theories.
EEG/ERP research on ADHD, indicating the
occurrence of a sequence of multiple activation deficits of posterior and anterior attentional networks
within a subsecond range, may serve as an illustration; attentional focusing and orienting deficits,
temporally and causally preceding inhibitory or
executive control, were found to predict subsequent
performance during CPT-AX performance.
However, the issues of specificity of findings
associated with certain disorders and the impact of
comorbid disorders still needs to be addressed. Few
EEG and ERP studies have investigated the impact
of comorbid disorders using a full factorial design, to
allow separation of effects of comorbid disorders and
their interaction (for an exception see: Banaschewski
et al., 2003, 2004), and some of the most reliable
deficits are not specific for one disorder. In addition,
only few EEG- or ERP-based deficits have been replicated across a wide age range. Studies on children
and adolescents are still largely lacking. Given these
limitations, the clinical use of EEG/ERP as a tool for
individual diagnoses of child psychiatric disorders is
clearly not warranted at this stage.
Because some EEG/ERP measures are substantially heritable and developmentally stable, they are
particularly promising endophenotype candidates
that may disentangle phenotypic variation (e.g.,
ADHD with vs. without comorbid externalising
behaviour) and facilitate the identification and
functional characterisation of susceptibility genes
and other etiologic factors in etiologically complex
disorders. This may help to pave the way for the
3
All-or-none or discrete stage models of information processing assume – in contrast to continuous models – that partially
processed information cannot be used by further processing
stages, respectively that information processing on a later
stage cannot start until a prior stage is completed.
! 2006 The Authors
Journal compilation ! 2006 Association for Child and Adolescent Mental Health.
428
Tobias Banaschewski and Daniel Brandeis
identification of prognostic predictors for (psychopathological) developmental processes and the design of selective treatments for specific diagnostic
subgroups of patients and families.
Correspondence to
T. Banaschewski, University of Göttingen, Child and
Adolescent Psychiatry, von-Siebold-Str. 5, D-37075
Göttingen, Germany; Tel: 0049-551-396727; Fax:
0049-551-398120; Email: [email protected]
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Glossary
Construct validity: Construct validity means that the measure appropriately reflects the concept which it
intends to measure
Current source density: CSD emphasises localised components and estimates the local current density
flowing perpendicular to the skull through the scalp, without an influence of the reference. CSD maps depict
the second spatial derivative (‘the curvature’) of the potential field (units are voltage-per-meter squared). CSD
is derived by the mathematical Laplacian operator, which acts as spatial high pass filter.
Generators: Neural structures (focal sources or distributed networks) that produce the specific brain
electrical activity
Global field power: Measure of map ‘strength’ in microvolts, computed as the spatial standard deviation
Inverse problem: Calculating unknown brain sources from the known scalp distribution (allows for multiple
solutions which fit the data equally well)
Phase-locking: Synchronisation of ERPs or EEG rhythms to events (or to other rhythms) in terms of their
timing (time-locked) and polarity but independent of their absolute amplitudes
Power: ‘Strength’ (amplitude squared) within defined frequency bands of the spontaneous EEG
Map: Topographical distribution (‘landscape’) of quantities such as potential, CSD or power reflecting brain
electrical activity at the scalp
Microstates: Time segments with a stable topographical distribution of brain electrical activity
Signal averaging: Method for improving the signal-to-noise (S/N) ratio of phase-locked signals by calculating the average of several signals at corresponding time points, typically time- and phase-locked to
repeated stimuli event
Time-locked: Synchronisation with constant latencies between events, e.g., a certain cognitive process and
EEG power changes or ERPs
! 2006 The Authors
Journal compilation ! 2006 Association for Child and Adolescent Mental Health.