Clinical EEG and Neuroscience

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Event-Related Potentials in Psychiatry

Oliver Pogarell, Christoph Mulert and Ulrich Hegerl
Clin EEG Neurosci 2007 38: 25
DOI: 10.1177/155005940703800108

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CLINICAL EEG and NEUROSCIENCE
Event-Related Potentials in Psychiatry
Oliver Pogarell, Christoph Mulert and Ulrich Hegerl
Kev Words
Alzheimer’s Disease
CNV
Depression
Event-Related Potentials
LDAEP
MMN
P50
P300
Psychiatry
Schizophrenia
Sensory Gating
ABSTRACT
Electrophysiological assessments of psychiatric disor-
ders have produced a number of promising, highly replica-
ble findings and thus carry the potential of becoming clini-
cally utilizable in the diagnostic or prognostic evaluation of
psychopathological conditions. The procedures involved
are rather complex technically and the interpretation of the
findings require a combined neurophysiological and clinical
expertise. On the other hand, electrophysiological tech-
niques are in general non-invasive and relatively inexpen-
sive, and neurophysiology laboratories are widely available
in the clinical setting.
Among these techniques, event-related potentials
(ERPs) are of major interest in psychiatry, particularly
since these tools can indicate cortical neuronal dysfunc-
tions, which play a major role in various neuropsychi-
atric disorders.
INTRODUCTION
Decades ago reports on event-related potentials
(ERPs) such as Contingent Negative Variation (CNV)’ and
P300* stimulated the interest of both psychiatrists and psy-
chologists in these neurophysiology techniques. ERPs in
psychiatry, however, did not gain comparable clinical rele-
vance as early sensory evoked potentials in neurology, and
rather remained a tool for basic research.
Regarding clinical applicability ERP studies were ham-
pered by the fact that most of these parameters were diag-
nostically unspecific and not reliable enough to be useful
for the individual patient. On the other hand, the relation-
ship between ERPs and circumscribed cognitive functions
was another attractive approach. For example, interesting
25
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02007 VOL. 38 NO. 1
correlations between late evoked positivities and memory,
N400 and semantic processes, or the latencies of ERPs
and the timing of cognitive processes have been
described. This research is of considerable interest for
testing information processing models in cognitive psy-
chology because ERPs might be useful indicators of cog-
nitive processes and dysfunctions not accessible to
behavioral testing. Concerning psychiatry, this approach
may deepen the understanding of pathophysiology in a
wide range of psychiatric disorders. Nevertheless, it is
unlikely that such studies will lead to results with broad
clinical relevance.
In recent years the focus of ERPs research in psychia-
try has shifted to other fields. A unique advantage of ERPs
is the fact that cortical function and reactivity can be
assessed with high temporal resolution (e.g., as compared
to functional MRI) in both a sensitive and noninvasive man-
ner. This offers the possibility to monitor changes of brain
function, e.g., during medication with psychotropic drugs
by serial recordings. Another promising approach is to
study ERP parameters as indicators of central neurochem-
ical function and as predictors of the patients’ responses to
psychopharmacotherapy, since ERPs directly reflect post-
synaptic effects of cortically released neurotransmitters
(e.g., GABA, glutamate) and indirect modulatory effects of
neuromodulators (e.g., serotonin, acetylcholine) on cortical
neuronal function. ERP parameters indicating the function
of neurochemical systems would be of considerable clini-
cal value due to the fact that subgroups of patients with
certain neurochemical dysfunctions could be identified and
could be treated more specifically. The increasing knowl-
edge about anatomical structures and cellular processes
underlying event-related potentials and methodological
advances in ERP data analysis may help to bridge the gap
between ERPs and basic physiological processes.
The P300 event related potential
P300 is a positive ERP which occurs with a latency of
about 300 ms after presentation of task relevant stimuli
Oliver Pogarell, Christoph Mulert, Ulrich Hegerl are from the Department
of Psychiatry, Division of Clinical Neurophysiology, Ludwig-Maximilians-
University of Munich.
Address requests for reprints to Oliver Pogarell. MD, Dept. of Psychiatly,
Div. of Clinical Neurophysiology,Ludwig-Maximilians-Universityof Munich,
Nussbaumstr.7, D-80336 Munich, Germany.
Email: oliver.pogarell@med.uni-muenchen.de
CLINICAL EEG and NEUROSCIENCE
and which is related to psychological aspects like cogni-
tion or attention (information processing). There are at
least two distinct P300 subcomponents which overlap at
the scalp. The P3b has a more centro-parietal distribution
and corresponds to the classical P300 recorded within an
oddball paradigm after rare and task relevant events. The
P3a occurs after novel events independently of task rele-
vance and is characterized by a more frontal distribution,
a shorter latency and a fast habituation. These subcompo-
nents reflect functionally different processes. Whereas the
P3a has been interpreted as an orienting response, the
P3b was related to psychological constructs such as con-
trolled information processing, the information content of
the event, memory processes, the reorganization of an
internal expectancy model ("context updating") or the
"context closure."3
The physiological interpretation of P300 is limited by
the fact that knowledge about the neuronal structures and
processes involved in the generation of P300 are still insuf-
ficient. However, knowledge has increased considerably in
the last years. lntracerebral recordings in patients with
epilepsy have shown that the parietal and temporal cortex
are involved in the generation of the auditory P3b.
Concerning P3a the superior temporal plane, the associa-
tion cortices, limbic structures, and frontal as well as pre-
frontal cortices appear to play a major role.4-6 With local
recording, the hippocampus shows the largest P300.
However, because the hippocampus is an electrically
closed field, this structure probably does not contribute in a
relevant manner to the P300 recorded at the scalp.
A further progress in this respect might be the simulta-
neous recording of ERPs under functional magnetic reso-
nance imaging (fMRI). Both fMRl and EEG are comple-
mentary methods for the analysis of brain activity with
each method having its strength where the other one has
limits: the spatial resolution in the range of millimeters in
fMRl and the time resolution in the range of milliseconds
in EEG.
Mulert et al7 have shown that high quality EEG record-
ings are feasible inside the scanner with adequate elimina-
tion of artifacts (e.g., originating from MR gradients) from
the EEG signal. Therefore, not only an optimal temporal
resolution of brain activity (as recorded via ERPslEEG from
the scalp) but also a precise spatial allocation of the under-
lying structures has been made possible.
Regarding the neurochemical background, it is widely
accepted that P300 potentials recorded at the scalp result
from intracortical currents induced by postsynaptic poten-
tials. Neuronal cortical processing is influenced by cortical-
ly released modulatory neurotransmitters (serotonin,
dopamine, noradrenaline, and acetylcholine). Therefore it
is not surprising that these transmitters are also related to
P300. Because of the close interaction between the differ-
ent neuromodulatory systems, a highly specific relationship
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between P300 parameters and a certain neuromodulator
cannot be expected. Most consistent are the results con-
cerning P300 and the cholinergic system. Anticholinergic
interventions induce a latency increase and amplitude
reduction of P300 whereas the opposite is observed afler
choline agonists.8-15 This is in line with the robust finding
that Alzheimer's disease, which is associated with cholin-
ergic hypofunction, is associated with reduced amplitude
and prolonged latency of P300.
Influences of the noradrenergic and the dopaminergic
system on P30016-19 have also been described. The sero-
tonergic system appears to play only a minor role for the
generation of the P300.12.20
P 300 in psychiatric disorders
Schizophrenia
The heterogeneity of schizophrenic disorders regarding
symptomatology, course and outcome is expected to
reflect heterogeneity of various underlying pathophysiolog-
ical processes. In this respect physiological parameters
could be helpful to define subgroups that are more homo-
geneous not only concerning clinical and therapeutic vari-
ables but also the pathophysiological mechanisms. With
respect to schizophrenic disorders P300 is among the
most intensively studied ERPs.
It is a robust finding that the P300 amplitude is smaller
in schizophrenic patients than in healthy controls. This has
been demonstrated in acutely ill, remitted, medicated and
unmedicated patients.21-26 Neuroleptics have only a rela-
tively small effect on P300 amplitudes, which is supported
by studies comparing patients with high versus low plasma
levels of neuroleptics or by a longitudinal study in patients
who discontinued neuroleptic treatment27
The amplitude reduction of the auditory P300 in schiz-
ophrenic patients is not merely reflecting state dependent
aspects but also has to be considered as a trait marker.
This is supported by studies showing that the reduction of
P300 amplitude is not influenced in a relevant manner by
neuroleptic medication and can also be found in remitted
schizophrenics.22 Furthermore, children of schizophrenic
parents and other subjects at risk of developing schizo-
phrenia showed P300 abnormalities. Studies in children of
schizophrenic parents showed a prolongation of P300
latencies (auditory oddball paradigm) andlor smaller P300
amplitudes as compared to matched controIs.28
It has been postulated that patients with a neurodevel-
opmental schizophrenia form a subgroup characterized by
poor premorbid adjustment with cognitive disturbances,
early and insidious onset, a chronic and deteriorating
course of the disease, negative symptoms and a tenden-
cy to develop tardive dyskinesia.2g There are several stud-
ies supporting the assumption that schizophrenic patients
with small P300 correspond to this subgroup of schizo-
phrenics. In a study on stabilized schizophrenic patients
the subgroup with a small P300 showed more residual
CLINICAL EEG and NEUROSCIENCE
symptoms, more perinatal complications, poor premorbid
adjustment and a higher risk of developing tardive dyski-
nesia. The majority of patients showing tardive dyskinesia
at the time of the recording also presented with a small
P300. Even more interesting is the finding that patients
who developed tardive dyskinesias during a 2 years fol-
low-up period had already significantly smaller P300 at the
beginning of the prospective study.30 A small P300 has
been found to predict nonresponse to neuroleptics con-
cerning positive symptoms and a prolonged P300 latency
has been found to predict non-response concerning neg-
ative symptorns.23 Similarly, Strik et a131-33 found that
patients with a "cycloid psychosis" (according to the clas-
sification by Leonhard), which is characterized by a favor-
able therapeutic response and long-term prognosis, have
no reduction of P300 amplitude or even an increase in
amplitude compared to healthy subjects. Furthermore, in
studies on stabilized schizophrenic outpatients it is a quite
consistent finding that patients with small P300 have more
residual symptoms, mainly negative symptoms and
thought disorders.
P300 and psychopathology
For the evaluation of the relationship between P300
and psychopathology, it is of crucial importance to inde-
pendently study stabilized patients and acutely psychotic
patients. In stabilized patients, it is a quite consistent find-
ing that P300 amplitude is negatively correlated with resid-
ual symptoms. This association does not reflect state
dependent effects of residual symptoms on P300 but
rather the poor outcome of a subgroup of patients with
small P300. This interpretation is supported by a study of
schizophrenic patients, retested after 9 months. Here the
intra-individual changes of psychopathology were not relat-
ed to the corresponding changes of P300 amplitude.27
However, the P300 component reflects both trait and
state aspects such as psychopathology. Several studies on
acutely psychotic patients reported positive correlations
between P300 amplitudes and the severity of positive
symptoms. However, the literature is not entirely consistent
on this issue, which can be explained by differences in the
severity of the acute symptomatology. It has to be expect-
ed that patients with severe acute symptoms leading to
impaired attention, will have difficulties to cooperate and to
perform the P300 oddball paradigm.34-36
In summary, a small P300 in schizophrenic patients
has been found to be a vulnerability marker characterizing
a subgroup of patients with a poor premorbid adjustment,
an enhanced risk of developing tardive dyskinesia, more
residual symptoms and a poor outcome. Concerning the
evaluation of the relationship between psychopathology
and P300, it is of importance to control the studies for
remitted versus acutely psychotic patients, predominance
of positive versus negative symptoms and to differentiate
the P300 subcomponents P3a and P3b.
27
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Affective disorders
An amplitude reduction of P300 has been found in
depressed patients although the literature is not consistent
on this issue. Some authors found changes of P300 only in
a subgroup of patients, mainly in those with severe or psy-
chotic depression.37,38
It is a replicated finding that patients with depressive dis-
orders with suicide attempts showed smaller P300 ampli-
tudes than depressive patients without suicide attempts. In
addition a correlation has been reported between acute sui-
cidality and P300 amplitude.39A convincing explanation for
this relationship has not been given up to now.
Alzheimer's disease
P300 is an interesting instrument for studying
Alzheimer's disease, because latency and amplitude of
P300 are closely related to cognitive processes and to
cholinergic function. Furthermore P300 is cortically generat-
ed and Alzheimer's disease impairs especially cortical func-
tioning. It is therefore not surprising that Alzheimer's dis-
ease is related in a consistent manner with smaller P300
amplitudes and prolonged P300 latencies. Such changes
can be observed even in patients with mild Alzheimer's dis-
ease.40.41In studies, comparing demented patients with psy-
chiatric and neurological patients without dementia, the
specificity of P300 latencies was above 80 % whereas the
sensitivity was relatively poor, ranging between 15 and
80%. As expected, studies with more severely demented
patients reported higher sensitivities. Auditory P300 laten-
cies were superior to visual P300 latencies concerning the
recognition of patients with Alzheimer's disease.
In a prospective, confirmatory study to evaluate the clin-
ical relevance of the P300 in the early diagnosis of AD,
Frodl et aid2 investigated patients with AD, mild cognitive
impairment (MCI) and healthy controls (HC) using P300
assessments with dipole source analysis. The authors
could demonstrate that the amplitudes of temporo-basal
dipoles (equivalent to the P3b subcomponent) were statisti-
cally significantly decreased in AD as compared to both HC
and MCI. Furthermore, the latencies of superior temporal
dipoles (equivalent to P3a) were significantly prolonged in
AD compared with HC. The significant differences remained
stable afler stratification of the patients regarding the sever-
ity of the disease: Even patients with mild AD showed
marked, significant reductions in P300 amplitudes. The
sensitivity and specificity for the differentiation of AD
patients and HC using temporo-basal P300-amplitudes and
superior temporal P3004atencies were as high as 86.7%,
and 88.5%, respectively, which is comparable to other
(often less validated) biological diagnostic markers in AD.
The P300 is related to cholinergic neurotransmission
and may therefore be useful to identify subgroups with a
more circumscribed cholinergic dysfunction. This subgroup
may turn out to show a favorable response to a treatment
with cholinesterase inhibitors.
CLINICAL EEG and NEUROSCIENCE
In addition, P300 as a non-invasive instrument might
be a useful method for the assessment of changes in cor-
tical function during follow-up by serial recordings.
Regarding treatment monitoring, i.e., detection of neu-
robiological effects of pharmacotherapy with choline
esterase inhibitors (CEI) in AD, Thomas et a143 could
demonstrate in a study of 60 subjects with AD treated with
either the choline esterase inhibitors donepezil or rivastig-
mine or with vitamine E, that only the treatment with CEI
(both rivastigmine or donepezil) led to a significant
decrease in P300 latencies, which was correlated to a clin-
ical improvement of cognitive performance. The data have
been replicated after stratification of the subjects according
to severity of the dementia.44
In a study by another group on 40 patients with moder-
ate AD who underwent a 12 week controlled treatment with
either CEI or placebo medication, the investigators could
provide preliminary evidence for the value of P300 meas-
urements regarding prediction of treatment response.45
The subjects received electrophysiological evaluations
(P300, auditory oddball paradigm, dipole source analysis)
during a 12 week double-blind, placebo-controlled treat-
ment with donepezil. Treatment response (as assessed by
a maintenance or improvement in scoring on dementia rat-
ing scales) was analyzed after stratification of donepezil
and placebo patients according to highllow P300 ampli-
tudes at baseline. In this study there was a significant
association between the P300 parameters at baseline and
the mean change in ADAS-cog scores after 12 weeks on
treatment: patients with high P300 amplitudes at baseline
showed a statistically significant better treatment response
after 12 weeks on verum medication. The corresponding
analyses in the placebo group did not show statistically sig-
nificant differences.
Thus these studies provide preliminary evidence that
the event-related P300 might represent a reliable, non-
invasive and clinically practicable auxiliary tool, offering
complementary information on brain functional aspects.
The data on P300 in patients with Alzheimer's dementia
show that ERPs may provide useful tools not only for diag-
nosis but also for treatment monitoring andlor prediction of
treatment response in cognitive dysfunction.
Contingent negative variation (CNV)
CNV is a negative potential that slowly develops in the
time-interval between a warning stimulus and a related
imperative stimulus, which requires a motor or mental
response. When longer time-intervals are used between
the warning and the imperative stimulus (inter-stimulus
interval: 3-8 sec.) an initial CNV (iCNV) with a more frontal
distribution and a terminal CNV (tCNV) with a maximum
over central regions can be distinguished. Empirical as well
as theoretical arguments indicate that this negativity is
related to the depolarization of apical cortical dendrites and
to an enhanced cortical excitability. This interpretation is
28
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supported by the more recent observation that the reaction
time to sensory stimuli falling in the phase of the develop-
ing negativity is shorter and the evoked neuroelectric
response is larger as compared to stimuli falling outside of
this negativity.4647 CNV has originally been related to
expectancy. However, it depends on several unspecific
psychological factors such as attention or motivation. A
clear relation to psychological constructs is difficult. One
reason is the fact that CNV is not a uniform component.
Concerning iCNV, an overlap of late effects of the warning
stimuli to processes related to the imperative stimulus have
to be considered, and concerning tCNV, there may be an
overlap between non-motoric pre-imperative processes
(e.g., anticipation) and the Bereitschaftspotential48 related
to the preparation of a motor response.
In schizophrenic patients it is a quite consistent finding
that CNV at central regions is reduced. An interesting obser-
vation has been that in schizophrenic patients, especially in
the acute psychotic state, the CNV after the imperative stim-
ulus is not going down to baseline or is going down more
slowly. This post imperative negative variation (PINV), how-
ever, is not specific for schizophrenia, but has also been
found in other psychiatric disorders, such as dementia or
mania. In patients with affective disorders a reduction of
CNV has been reported although it is controversial, whether
or not this reduction is state dependent or a trait marker. It is
of interest that depressed patients with an enhanced risk of
suicide have a smaller CNV and a larger PINV than
depressed patients without enhanced risk of suicide.3949
Mismatch negativity (MMN)
MMN is a negativity over fronto-central brain regions
with a latency of 250 ms, which develops after stimuli that
are deviant with regard to physical stimulus properties
(e.g., loudness, duration, frequency). MMN is mostly
shown as the difference wave between the response to the
frequent and the deviant stimuli. This component is inde-
pendent of attention and seems to reflect a largely auto-
matic deviance detecting process of sensory cortex. In the
auditory modality the MMN is generated mainly by the
supratemporal cortex.%The sum activity of this structure is
oriented perpendicularly to the cortical surface and is
therefore projecting to frontal electrodes. This explains the
frontal distribution of the MMN. Animal experiments have
shown that the MMN is blocked by competitive as well as
non-competitive NMDA-receptor antagonists whereas ear-
lier obligatory components are not influenced by such
drugs.51 This indicates that MMN depends on the current
flow induced by the opening of cortical NMDA-channels
and therefore on glutamatergic neurotransmission. The
evaluation of the specificity of this relationship is difficult at
the moment. It has been observed that histamine-recep-
tors also influence the MMN.52
Medicated and unmedicated schizophrenic patients
showed a reduction of the MMN.53-56 This indicates that a
CLINICAL EEG and NEUROSCIENCE
neurophysiological deficit in schizophrenia can be found
already at the level of the sensory cortex and not only
involves association cortices and limbic structures. This
finding is also of interest considering the hypothesis of glu-
tamatergic hypofunction in schizophrenic disorders. This
glutamatergic hypofunction could be an explanation for the
reduction of the MMN, because the relevance of NMDA-
receptor function for the electrogenesis of MMN has been
shown in animal experiments.
MMN responses were related to negative but not to
positive symptoms and correlated with neuropsychological
impairrnents.”.j7 Since MMN reflects a basal detection
mechanism for deviant sensory events, a dysfunction in
this process could be the physiological correlate for the
reduced reactivity to external stimuli in schizophrenic
patients with negative symptoms. A recent study showed
that MMN deficits are linked to global impairments in every-
day functioning in patients with schizophrenia. MMN
seems to represent a core neurophysiological dysfunction
and might therefore be useful as a measure for predicting
the functional 0utcome.58 In addition, mismatch negativity
generation has been reported to be impaired in subjects at
risk for the later development of psychosis.jg
P50 sensory gating
P50 sensory gating paradigms have been extensively
used in patients with schizophrenia, where various degrees
of abnormalities and deficits have been described.aa63
Sensory gating means the pre-attentional habituation of
responses to repeated stimuli of the same sensory quality.
In normal controls there is an inhibition of responsiveness
to these repetitive stimuli. The P50 wave is the event relat-
ed potential used for the assessment of sensory gating. The
decrease or inhibition of this component upon a second of
a pair of stimuli serves as the neurophysiological correlate
of activated inhibitory mechanisms to block out irrelevant,
meaningless or redundant stimuli.
Most patients with schizophrenia have an impairment
of P50 sensory gating, i.e., a diminished P50 reduction in
the respective paradigms. Human and animal studies have
suggested that alterations of cholinergic (nicotinic) recep-
tors might be the neurochemical background of sensory
gating deficits in schizophrenia.60,@-68P50 sensory gating
abnormalities in schizophrenia have just recently been
extensively reviewed by Potter et a1.61 There is a large body
of literature; however, the presented data are not overall
consistent regarding clinical correlates, medication effects,
control for confounding effectors, etc. There is strong evi-
dence of an association of P50 data with measures of vig-
ilance and attention, whereas there are no clear and explic-
it correlations with the severity of clinical schizophrenic fea-
tures such as positive or negative symptoms. Regarding
treatment effects, it has been shown, mainly in open
uncontrolled studies, that P50 sensory gating deficits are
unchanged under typical neuroleptic medication, whereas
29
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atypical antipsychotics seem to improve this neurophysio-
logical parameter.@-71Among the second generation
antipsychotics, clozapine has been shown to even nor-
m a k e P50 rati0s.69~71.72Besides schizophrenics, subjects
with prodromal symptoms and at risk for the development
of schizophrenia have been shown to present with
impaired sensory gating,~aand P50 gating deficits appear
to be a genetic trait in schizophrenia patients that is also
found in first degree relatives.63.74-76
In conclusion, the P50 sensory gating paradigm is an
important research tool for the investigation of patients with
schizophrenia and their relatives, since it reflects essential
functions of information processing protecting the brain
from overflow and that might be disturbed in psychosis.
However, more research is required in terms of the clinical
significance of P50 impairments and their improvements
upon different types of medication.
The intensity dependence of
auditory evoked potentials (IDAEP)
Interindividual differences in the intensity dependence
of sensory evoked potentials were first investigated within
the augmentinglreducing concept proposed for evoked
potentials by Buchsbaum and Silverman.77 In these studies
mainly visual evoked potentials (VEP) were used. A flat or
negative slope of the amplitude stimulus intensity function
(reducing) was seen as reflecting a central mechanism
regulating the sensitivity in all sensory modalities and pro-
tecting the organism from sensory overstimulation. This
general augmentinglreducing concept has been criticized,
because the augmentinglreducing characteristic was
shown to depend on many methodological aspects such as
the parameterization of the intensity dependence, the
recording site or the intensity range or modality of the stim-
uli.i*-m Converging arguments from clinical and preclinical
studies support the hypothesis that the loudness depend-
ence of the auditory evoked NllP2 response (LDAEP) is
regulated by the level of central serotonergic neurotrans-
mission.^^ More specifically, animal studies suggest that
inhibition or activation of the serotonergic neurons in the
dorsal raphe nucleus influence the loudness dependence
in the primary but not in the secondary auditory cortex.82.83
With dipole source analysis or tomographic current source
density analysis activity of the primary and secondary audi-
tory cortex can (at least in parts) be separated.64.85
Recently, with functional magnetic resonance imaging
(fMRI) loudness dependence could be demonstrated main-
ly for the primary and only to a lesser degree for the sec-
ondary auditory cortex.86.87
In clinical studies an increased LDAEP has been
shown in MDMA users,~8.89and in patients with borderline
personality disorder,w indicative of a serotonergic dysfunc-
tion in these subjects. In depressed patients a high LD
before drug treatment has been associated with a favor-
able response to serotonergic medication.gi-~3
CLINICAL EEG and NEUROSCIENCE
Regarding the validation of the assumed serotonergic
properties of LDAEP in vivo combined studies with Single
Photon Emission Computed Tomography (SPECT) using
the monoaminergic (serotonergic and dopaminergic) radi-
oligand p-CIT, a marker of Serotonin- and Dopamintrans-
porters (SERT, and DAT) have been performed. SPECT
and (3-CIT allow to semiquantitatively assess SERT and
DAT availabilities within the brainstemlpons (SERT) and in
the striatum (DAT). In such studies it has been demonstrat-
ed that the loudness dependence was highly significantly
correlated with both nuclear imaging markers of the sero-
tonergic and dopaminergic system, which is a first direct in
vivo evidence that LDAEP is associated with central
monoaminergic function in psychiatric patients.%
The observation that allelic variants of the serotonin
transporter gene differ with respect to the LD further sup-
ports the hypothesis of an association between the sero-
tonergic system and neurophysiological measures.95
Nevertheless, the complexity of central monoaminergic
systems, which are strongly interconnected and show
interactions between different neurochemical subdivisions,
has to be taken into account. Therefore, only a relative
specificity of this indicator for certain functional aspects,
e.g., in terms of the serotonergic system can be expected.
In spite of these limitations, the studies on psychiatric
patients treated with serotonergic agents suggest that the
loudness dependence of the NllP2 activity may well be
clinically useful for a more carefully directed individual
pharmacotherapy in neuropsychiatry.96
Affective disorders
Reports in the literature as well as own results indicate
that a pronounced LDAEP predicts a favorable response to
SSRl treatment. Paige et a197 reported that depressed
patients who responded to SSRl had a strong LDAEP (P2-
component) before starting medication. During medication,
no reduction of the LDAEP was observed. These findings
were supported by using a dipole source analysis of
LDAEP. Depressed patients responding to SSRl (sertra-
line, paroxetine) had a stronger LDAEP ( N I P 2 compo-
nent) at baseline, i.e., before starting medication.93 This
indicates that the LDAEP could give valuable information
to the clinician concerning the probability of individual
response to SSRl in depressed patients. It remains unclear
whether or not LDAEP predicts response or nonresponse
specifically to SSRl or also to alternative therapies. Paige
30
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02007 VOL. 38 NO. 1
et alga reported that a strong LDAEP also predicts favorable
response to the noradrenergic and dopaminergic agent
buproprion, which supports the predictive quality of the
LDAEP concerning response to antidepressants whereas
the specificity of this tool concerning serotonergic antide-
pressants remains to be elucidated.
Lithium has serotonin-agonistic effects:$ which are sup-
posed to be relevant for its acute antidepressant and anti-
manic as well as its relapse preventing effects. Therefore, it
can be assumed that especially those patients with low
serotonergic function, indicated by a strong LDAEP, will be
lithium responders. Several studies consistently reported
that patients with a strong intensity dependence of sensory
evoked potentials (VEP, SEP) are responders to acute anti-
depressive or antimanic lithium therapy.77.iw-’02
These findings have stimulated research on the predic-
tive quality of LDAEP concerning clinical response to pre-
ventive lithium treatment. Predictors of response or nonre-
sponse to preventive lithium medication would be especial-
ly valuable, because of the high rate of nonresponse (up to
45%), the long observation time needed to evaluate clini-
cal response and the risks of long-term lithium medication.
In our laboratory, Hegerl et al found that patients with affec-
tive psychoses responding to preventive lithium medication
were indeed characterized by a strong LDAEP.103 Patients
were classified as responders, when they had no recur-
rence leading to hospitalization under lithium during the
preceding 5 years. This finding was replicated in another
retrospective study: responders to preventive lithium treat-
ment were again characterized by a significantly stronger
LDAEP.lo4
CONCLUSION
ERPs are unique tools for evaluating the reactivity of cor-
tical neuronal activity in psychiatric patients. Due to a close
relationship between ERPs and cortical release of neuro-
transmitters, ERPs are at least in part useful indicators of
neurochemical dysfunction. Therefore, these techniques
might contribute to the prediction of response to pharma-
cotherapy or monitoring changes in brain function during
psychopharmacotherapy. These approaches have led to
consistent results, which are not only of value for the devel-
opment of pathogenetic models or to establish a sub classi-
fication of psychiatric disorders, but also are of relevance for
clinical and therapeutic decisions in psychiatric practice.
CLINICAL EEG and NEUROSCIENCE
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