Auditory Change Detection in Schizophrenia

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BMC Psychiatry
BioMed Central
Open Access
Research article
Auditory change detection in schizophrenia: sources of activity,
related neuropsychological function and symptoms in patients with
a first episode in adolescence, and patients 14 years after an
adolescent illness-onset
Robert D Oades*1, Nele Wild-Wall1,2, Stephanie A Juran1,2, Jan Sachsse1,
Ljubov B Oknina1,3 and Bernd Röpcke1
Address: 1Biopsychology Group, University Clinic for Child and Adolescent Psychiatry, Virchowstr. 174, 45147 Essen, Germany, 2Institute for
Occupational Physiology, University of Dortmund, Ardeystr.67, 44139 Dortmund, Germany and 3Institute of Higher Nervous Activity &
Neurophysiology, Burdenco Neurosurgery Institute, Butlerova Str. 5a, Moscow, Russia
Email: Robert D Oades* –; Nele Wild-Wall –; Stephanie A Juran –;
Jan Sachsse –; Ljubov B Oknina –; Bernd Röpcke –
* Corresponding author
Published: 08 February 2006
BMC Psychiatry2006, 6:7
Received: 01 September 2005
Accepted: 08 February 2006
This article is available from:
© 2006Oades et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: The event-related brain response mismatch negativity (MMN) registers changes in auditory stimulation
with temporal lobe sources reflecting short-term echoic memory and frontal sources a deviance-induced switch in
processing. Impairment, controversially present at the onset of schizophrenia, develops rapidly and can remain
independent of clinical improvement. We examined the characteristics of the scalp-recorded MMN and related these to
tests of short-term memory and set-shifting. We assessed whether the equivalent dipole sources are affected already at
illness-onset in adolescence and how these features differ after a 14-year course following an adolescent onset. The
strength, latency, orientation and location of frontal and temporal lobe sources of MMN activity early and late in the
course of adolescent-onset schizophrenia are analysed and illustrated.
Methods: MMN, a measure of auditory change-detection, was elicited by short deviant tones in a 3-tone oddballpresentation and recorded from 32 scalp electrodes. Four dipole sources were placed following hypothesis-led
calculations using brain electrical source analysis on brain atlas and MR-images. A short neuropsychological test battery
was administered. We compared 28 adolescent patients with a first episode of schizophrenia and 18 patients 14 years
after diagnosis in adolescence with two age-matched control groups from the community (n = 22 and 18, respectively).
Results: MMN peaked earlier in the younger than the older subjects. The amplitude was reduced in patients, especially
the younger group, and was here associated with negative symptoms and slow set-shifting. In first-episode patients the
temporal lobe sources were more ventral than in controls, while the left cingular and right inferior-mid frontal sources
were more caudal. In the older patients the left temporal locus remained ventral (developmental stasis), the right
temporal locus extended more antero-laterally (illness progression), and the right frontal source moved antero-laterally
Conclusion: From the start of the illness there were differences in the dipole-model between healthy and patient
groups. Separate characteristics of the sources of the activity differences showed an improvement, stasis or deterioration
with illness-duration. The precise nature of the changes in the sources of MMN activity and their relationship to selective
information processing and storage depend on the specific psychopathology and heterogeneous course of the illness.
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BMC Psychiatry 2006, 6:7
The detection of a change in ongoing ambient auditory
stimulation is an important preliminary requirement for
the conscious organisation of an adaptive response to a
significant event. The unusual sound could be an unexpected tone in a well-known piece of music, or the telephone ringing during a conversation. The change is
detected automatically, but the altered behaviour requires
controlled information processing beyond detection. The
brain’s response on detecting deviance is registered by an
event-related potential (ERP) called mismatch negativity
(MMN). This is recorded by subtracting the ERPs after a
series of similar stimuli from that elicited by the unexpected tone. The procedure requires no task, and is thus
well-suited for study in patients with schizophrenia. But
what parts of the brain generate MMN activity and what
mechanisms are involved?
Sources of neuronal activity have been reported for the
auditory cortices and the frontal lobe [1,2]. The frontal
sources lie in the right inferior/mid-frontal and left anterior cingulate gyri [3,4]. This is consistent with functional
imaging of the activity generated by dissonant tones in
music [5]. The activity of these sources represents the registration of a change and the mechanism for switching to
a new mode of information processing [6,7]. Sources in
the superior temporal lobe represent the short-term sensory memory trace for the currently usual sound [8,9].
This sensory memory has many features in common with
an auditory working memory [10]. Information in working memory is organised in the inferior frontal region [11]
where activity closely covaries with that in the superior
temporal areas in imaging studies of auditory memory
(e.g. in same-different judgments [12,13]). Like the phonological loop in working memory [14], the auditory sensory trace can be reactivated for 11–15 seconds after a
stimulus [15]. A monitoring function is widely attributed
to both working memory and to the automatic process
underlying MMN [16], for which a supervisory attention
system [17] and a store are essential parts [18]. There is
much evidence for impaired auditory [19] and non-verbal
working memory in schizophrenia [20], but are both the
memorial (temporal lobe) and switching (frontal lobe)
components of MMN also impaired? If so, then an examination of the sources should show how the impairment
is expressed. Associations with conventional neuropsychological indicators of working memory and switching
were explored..
A reduced MMN is widely reported in patients with schizophrenia with or without antipsychotic medication [2123]. In contrast, borderline or non-significant reductions
are reported for depressed and bipolar patients [23,24],
and MMN with a normal amplitude was recorded in
obsessive compulsive disorders [25]. Significant [26] or
nonsignificant [27] decreases described at onset may get
more severe after a longer illness [24,27-29]. They are
often more marked in patients with non-paranoid or negative symptoms [27,30] and without hallucinatory or
delusory symptoms [31]. Such negative features (e.g. flataffect, alogia, social withdrawal, avolition) correlate with
the severity of working memory difficulties [32].
Initial studies of MMN sources with magnetoencephalography (MEG: [33,34]) and ERP and imaging techniques
(e.g. [35,36]) suggest impaired left-sided locations and
source strengths. But these have concentrated on the temporal rather than the frontal lobe. As suggested above,
such temporal lobe changes would be expected if the
reduced MMN amplitude reflects in part impaired superior temporal function in categorization [37], sound identification [38] and auditory working-memory processes
[39]. But if the supervisory attention system is also
impaired, the frontal sources of activity may be altered.
Evidence from MMN topography [40,41] and source
modelling [42] has implicated frontal generator impairments in schizophrenia, and that in the early stages of illness there may be some further deterioration of these
impairments reflecting illness-progression [42].
In this current report two groups of patients were selected
to examine the hypotheses of there being impaired frontal
sources and a progressive deterioration with course in
schizophrenia. Patients were either experiencing their first
episode as adolescents, or had been diagnosed initially in
adolescence 14 years before. (It has been suggested that an
onset in adolescence can lead to a severer course of illness
[43].) We sought to explain the topographic pattern of
MMN activity with brain electrical source analysis locating
dipoles bilaterally in the frontal and temporal lobes based
on published models [3,42]. This procedure describes 4
features (locus, orientation, strength and latency) for each
of the 4 dipoles that could differ between groups. We concentrate on the MMN generated by stimuli of different
durations for which impairments are frequently reported,
and may even be impaired in the patients’ relatives [44],
making it a candidate for an endophenotype of change
detection processes.
The study protocol was reviewed and approved by both
the board of the University of Essen Psychiatry Clinics and
the Ethics Committee of the Faculty of Medicine according to the criteria of the Declaration of Helsinki (00-21357-Y). After the procedures had been described all subjects and care-givers gave written informed consent. A
first-episode of DSM-IV schizophrenia was diagnosed in
28 adolescent inpatients (early-onset: EOS) on the basis
of a clinical interview and hospital records first on the
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BMC Psychiatry 2006, 6:7
Table 1: Characteristics of two groups of patients with schizophrenia and two groups of healthy comparison subjects (means and
standard deviations)
EOS (N = 28)
Gender m/f
Mean Age (y)
Socio-economic status**
DSMIV diagnosis:
Ratings per question+
Medication (CPZ)#
[N, Atypical/Mixed/Typical]
[N, without Medication]
Mean cigarettes/day/smoker
[Non-smokers: N, %])##
27R, 1M
C-EOS (N = 22)
21R, 1L
S-14Y (N = 18)
16R, 1M, 1L


[14, 50%]
[20, 91%]
C-14Y(N = 18)
14R, 3M, (1 missing)

[7, 39%]
[16, 89%]
*Edinburgh inventory [91](-100/-50 (left- [L]), -50/+50 (mixed- [M]), +50/+100 (right-handed [R]). ** Parent occupation, scale 1–6 [92] (EOS vs. CEOS, t40 = 3.6, P < .01). ***Short-IQ (information, arithmetic, digit-symbol, block-design [50]: patients3 days, and 13 were examined without medication (Table 1). Assessment of the positive and negative symptoms in patients [49], SCID-II interviews and testing took place in the same week. Neuropsychological testing included a short IQ (4 WAIS sub-tests [50]), trail-making, digit-span forwards and backwards, logical memories, and visual reproduction. ERP measurements An auditory oddball sequence (3 sinusoidal tones, 76 dBspl) was presented over 1600 trials. There was a pseudorandom sequence of standards (800 Hz, 80 ms, 10 ms rise/fall, p = 80%), frequency deviants (600 Hz, p = 10%) and duration deviants (40 ms, p = 10%) with each deviant preceded by at least one standard (stimulus onset asynchrony 850–1050 ms, mean 950 ms). During 4 blocks of 200 trials (passive auditory condition) subjects performed a simple visual red/green circle discrimination on a PC (50:50; subtending 3.8° at 1.5 m, changing at random every 1100 ms). Responses to the green target alternated between hands between blocks. Tone detection is not suppressed during various concurrent visual processes [51], nonetheless the stimulus onsets were controlled so as not to coincide. Four further audio-visual trial-blocks were presented with response to the frequency deviant (active auditory condition). This permitted an analysis of duration-deviant MMN in a state of attention to the auditory modality. Page 3 of 14 (page number not for citation purposes) BMC Psychiatry 2006, 6:7 average-reference recomputed offline. A band-pass filter was set at 0.1–100 Hz. Data were digitised with 16-bit resolution, sampled at 500 Hz and stored on a hard disk. Records were epoched separately for each tone type with 100 ms prestimulus baseline and linear detrended. A 30 Hz low-pass filter (24 dB/octave) was used offline. Figure The recorded patients age-matched 18], central blue) 1(EOS from during part controls [N 7of the frontal =the 28], passive (C-EOS figure red; and auditory 2S-14Y illustrates [N mastoid =[N 22], condition =the electrodes green, 18], MMN orange) C-14Y waveforms for and [N = The central part of the figure illustrates the MMN waveforms recorded from 7 frontal and 2 mastoid electrodes for patients (EOS [N = 28], red; S-14Y [N = 18], orange) and age-matched controls (C-EOS [N = 22], green, C-14Y [N = 18], blue) during the passive auditory condition. The inserts show the waveforms elicited by the standard and the duration deviant tones recorded from FCz in the younger (top) and older subject groups (bottom). They illustrate the N1 peaks over 50 ms before the MMN peak. Nearly 50 ms after the MMN peak, in the deviant waveform, is a peak probably belonging to the N2/N2b family that contributes to the later part of the double-peak form in the subtraction-waveform. An EEG was recorded (Neuroscan, El Paso) from 31 tin electrodes (Fpz, Fz, Cz, Pz, Oz, FCz, CPz, F3, F7, F4, F8, FT7, FT8, C3, C4, P3, P4, CP3, CP4, T3, T4, T5, T6, TP7, TP8, M1, M2) in an electrode cap (Electro-Cap International: modified 10–20 system) with impedance <5 k?. A vertical EOG was recorded from the supra-orbital ridge of the right eye and a horizontal EOG from the outer canthus of the right and left eye to monitor blink-and eye-movements for rejection of artefacts (>50 µV) in EOG leads.
Electrodes were referenced to linked-earlobes and the

ERP data analysis
The MMN waveform was derived by subtracting the ERP
to standard tones from those elicited by the durationdeviant. Peaks were sought automatically from 90 to 225
ms after stimulus-onset. The MMN was averaged across
blocks for each group and the mean amplitude was computed in successive 30 ms windows from average-refenced
data (105–135–165–195–225 ms) for the active and passive condition, respectively. An initial repeated-measures
analysis of variance (ANOVA) was carried out for 4 subject
groups (between subject factor group) using data from 29
electrodes. The 135–165 and 165–195 ms windows covering the MMN peak (factor window), where inspection
showed there to be potential group differences (Figure 1),
were analysed by an ANOVA on the data from an array of
12 electrodes. The electrodes were arranged in two withinfactors of 3 saggital chains (factor side: i.e. left; F3, FC3,
C3, CP3: midline Fz, FCz, Cz, CPz: right; F4, FC4, C4,
CP4)) and 4 coronal rows (factor row:frontal; fronto-central; central; centro-parietal). This reduced the degrees of
freedom that were also adjusted with the GreenhouseGeisser epsilon. The MMN in the active condition as well
as the latency were analysed by ANOVAs using the same
factors (for the latter excluding the factor window). Where
significant main effects or interactions involved more
than two factor levels, additional ANOVAs were carried
out to test simple effects. The influence of antipsychotic
medication was examined with ANOVA and Spearman
correlations in the EOS group. Exploratory correlations
were sought for 3 sets of MMN measures (frontal, mastoid
and dipole-moments) with the CGI sum scores, the main
clusters of SANS/SAPS symptoms, and neuropsychological measures of processes putatively related to MMN
measures (digit-span, trail-making)[52,53]. Trends are
described at P < .05 and type-1 corrected correlations at P < .002. MMN source analysis Brain electrical source analysis (BESA) using a four-shell head-model [54] was used to compute dipoles based on the average-referenced ERP from 20 ms before to 40 ms after the MMN peak. Modelling requires iterative fitting of the dipole location and orientation in a spherical headmodel until the difference between the recorded and the calculated surface data is minimised (least square fit [55]). Efficacy was enhanced by seeding with previously published solutions [3,42,56]. The goodness of fit is expressed Page 4 of 14 (page number not for citation purposes) BMC Psychiatry 2006, 6:7 MANOVA including the 4-level factor dipole as well as the between-subject factor group. The x, y, and z-coordinates of each dipole [57] and the phi and theta orientation angles were compared with post-hoc F-Tests. Group differences of peak dipole-strength and latency were determined by univariate ANOVAs using a 2-level betweensubject factor for the younger and older groups and a 4level within-subject factor dipole (left/right, frontal/temporal lobe loci).

Demographic, clinical, performance and ERP measures
are presented in Tables 1, 2, 3. There were no group differences for hit rates on the visual vigilance control task,
although the S-14Y group responded slower than the controls (F3,79 = 5.8, P < .01). Slow reaction times were confirmed for S-14Y patients in the auditory task (F3,79 = 3.9, P < .02). Here both patient groups made fewer hits than their comparison groups (F3,81 = 10.8, P < .01: Table 2). Figure 2components Principle temporal topographic lobe variance dipoles were confirmed necessary that bilateral to explain frontal >98%and
of the
Principle components confirmed that bilateral frontal and
temporal lobe dipoles were necessary to explain >98% of …
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