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Lateral asymmetry and reduced forward masking effect in early brainstem auditory
evoked responses in schizophrenia
Johan Källstrand
a
, Sara Fristedt Nehlstedt
a
, Mia Ling Sköld
a
, Sören Nielzén
a,b,
⁎
a
SensoDetect AB, Lund, Sweden
b
Department of Clinical Neuroscience, Section of Psychiatry, Lund, Sweden
abstractarticle info
Article history:
Received 25 March 2011
Accepted 30 August 2011
Keywords:
Schizophrenia
Brainstem
Auditory brainstem response
Forward masking
Lateral asymmetry
Diagnosis
Individuals diagnosed with schizophrenia show deficiencies of basic neurophysiological sorting mechanisms.
This study further investigated this issue, focusing on the two phenomena, laterality of coding and auditory
forward masking. A specific audiometric method for use in psychiatry was the measuring set up to register
brain stem audiograms (ABRs). A sample of 49 schizophrenic patients was compared with three control
groups consisting of healthy reference subjects (n= 49), attention deficit hyperactivity disorder (ADHD) pa-
tients (n=29), Asperger syndrome (AS) patients (n=13) and drug-induced psychotic patients (n=14).
Schizophrenic patients showed significant abnormal laterality of brainstem activity in wave II of the auditory
brainstem response (ABR) in comparison with all other study groups. Forward masking effects in the superior
olive complex were coded significantly differently by schizophrenic patients compared to control groups ex-
cept for the AS group. The results suggest deficits in the coding of auditory stimuli in the lower parts of the
auditory pathway in schizophrenia and indicate that increased peripheral lateral asymmetry and forward
masking aberrances could be neurophysiological markers for the disorder.
© 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Schizophrenia is a severe illness that affects about 1% of the popu-
lation (Jablensky, 2000), and symptoms include, for example, delu-
sions, hallucinations, disorganized thinking, avolition and cognitive
impairment. Schizophrenic symptoms are characterized by disconti-
nuity, which may be due to dysfunctional integration among neuro-
nal systems (Friston, 1999).
Abnormal brain lateralization, including structural and functional
asymmetries, has been widely reported for schizophrenic patients
(Sommer et al., 2001). Decreased right-ear advantage, increase of
non-right-handedness, altered language lateralization and reduced
cerebral dominance have all been implicated in schizophrenia (Sommer
et al., 2001; Dragovic and Hammond, 2005). In addition to disturbed
asymmetry in cortical structures, abnormal lateralization has also
been shown in lower brain areas, i.e. the brainstem. It has been reported
that schizophrenic patients lack the functional medial olivocochlear
asymmetry found in healthy individuals, and show increased evoked
otoacoustic emission intensity in the right ear (Veuillet et al., 2001).
Magnetic resonance imaging (MRI) findings show a significantly smal-
ler volume of the right inferior colliculus (Kang et al., 2008) as well as
smaller thalamic volumes on the right side (Andreasen et al., 1994)in
schizophrenic patients. These two brainstem structures are both
involved in mediating auditory sensory gating processes. Interesting-
ly, auditory hallucinations are associated with neural activation in
right inferior colliculus and right thalamus (Shergill et al., 2000)
in a study that identified an extensive network of cortical and sub-
cortical areas associated with auditory hallucinations.
Sensory processing difficulties have been widely reported in
schizophrenia, and particularly impaired auditory sensory processing
is a prominent feature in schizophrenia (Rabinowicz et al., 2000;
Javitt, 2009). Psychoacoustic phenomena such as streaming, i.e., orga-
nizing the sounds into “streams”(Nielzén and Olsson, 1997), restoration
of missing sounds (Olsson and Nielzén, 1999b), and contralateral induc-
tion (Olsson and Nielzén, 1999a), where the perception of a sound's lo-
calization is affected by a second sound, have previously been shown by
this group to be abnormal in schizophrenic patients. Schizophrenic pa-
tients also exhibit abnormalities in several auditory event-related po-
tential (ERP) measures. Reduced P300 response (Roth et al., 1980;
Javitt et al., 1995; Turetsky et al., 1998), reflecting central attentional
processing and working memory, and abnormal mismatch negativity
(MMN) (Javitt et al., 1994, 1995; Näätänen and Kähkönen, 2009),
reflecting pre-attentive auditory information processing, are well
established findings in schizophrenia. Consistently reported findings
also include decreased P50 inhibition (Adler et al., 1982; Freedman et
al., 1983; Ward et al., 1996) and diminished prepulse inhibition (PPI)
of the acoustic startle response (Braff et al., 1978), two measures of neu-
ronal inhibition. These deficits are suggested to involve impaired sen-
sory gating, e.g., inability to filter the inflow of information.
Furthermore, auditory forward masking has been shown to be aberrant
Psychiatry Research 196 (2012) 188–193
⁎Corresponding author at: Department of Clinical Neuroscience, Section of Psychiatry,
Lund, Sweden. Tel.: +46 733528056.
E-mail address: soren.nielzen@med.lu.se (S. Nielzén).
0165-1781/$ –see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2011.08.024
Contents lists available at SciVerse ScienceDirect
Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres
for schizophrenic patients (Källstrand et al., 2002). Auditory forward
masking refers to the reduced ability to detect a stimulus when preced-
ed by a masking sound and is thought to involve adaptation or habitu-
ation (Recanzone and Sutter, 2008).
The auditory brainstem response (ABR) is stated to be an objective
technique that measures the electrical activity of the subcortical
nerve cells along the auditory pathway upon auditory stimulation.
The ABR wave pattern consists of up to seven positive peaks, desig-
nated waves I–VII, and is recorded within 10 ms following stimula-
tion onset. Wave I is generated in the distal portion of the eighth
cranial nerve, wave II is generated by the proximal portion of the
eighth nerve as it enters the brainstem, wave III arises from second-
order neuron activity at the level of the auditory pons, wave IV is be-
lieved to originate from pontine third-order neurons in the superior
olivary complex (SOC), whereas wave V is thought to arise from the
inferior colliculus (Muncie and McCandless, 2011). Advantages with
this technique include that it does not depend on the level of con-
sciousness nor the cooperation of the subject and it is not affected
by general anesthetics (Chiappa, 1997; Terk and Kveton, 2007). Ab-
normal ABR patterns including missing peaks, prolonged latencies
and reduced amplitudes have been reported in schizophrenia (Haya-
shida et al., 1986; Lindström et al., 1987; Igata et al., 1994), predomi-
nantly in subgroups correlated with clinical symptoms. However,
contradicting studies have reported no differences in ABR patterns in
schizophrenic patients (Pfefferbaum et al., 1980; Brecher and Beglei-
ter, 1985). The heterogeneous results provided by traditional ABR
studies may, in part, be explained by different patient criteria,
small patient groups and technical variations. However, the contra-
dicting results also indicate that it may be difficult to detect brain-
stem pathologies accompanying the complex auditory dysfunctions
with a basic tw o-dimensional approach, such as studying ABR latencies
and amplitudes in response to simple click sounds. In line with this, rou-
tine ABR procedures have not satisfactorily been able to divert differ-
ent psychiatric patient groups as, for example, prolonged latencies is a
common finding among neuropsychiatric diagnosis groups such as au-
tism spectrum or Asperger syndrome (AS) disorders (Wong and
Wong, 1991; Maziade et al., 2000) and attention deficit hyperactivity
disorder (ADHD) (Lahat et al., 1995; Puente et al., 2002). Therefore, a
more elaborate approach was taken in this study, using more complex
sound stimulation and data analysis.
The aim of this study was to investigate auditory lateralization
functions and forward masking abilities of schizophrenic patients
compared with age- and gender-matched healthy controls, as well
as clinical control groups reportedly having sensory and perceptual
dysfunctions. These two processes have been shown by us and others
(Sommer et al., 2001; Veuillet et al., 2001; Källstrand et al., 2002)to
be altered in schizophrenia, and in the present study a more sophisti-
cated approach was applied in order to further clarify the underlying
mechanisms behind such deficits.
2. Methods
2.1. Subjects
Participating subjects included schizophrenic patients (n=49; 32 males, 17 females;
age range 20–62, mean age (± standard deviation [S.D.]) 41.6± 10.7 years) recruited
from threedifferent clinicsin Sweden. All patients met the diagnostic criteriaof Diagnostic
and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) for schizophrenia and
were stated to clearly fulfill a typical schizophrenic symptom profile by senior psychia-
trists. At thetime of ABR testing, all but four schizophrenic subjects were undergoingneu-
roleptic treatment. Patients with additional presence of other psychiatric diagnoses,
organic brain disease and/or ongoing drug or alcohol abuse were excluded. Healthy con-
trols (n= 49;32 males, 17 females;age range 20–71, meanage (± S.D.) 39.4± 12.1 years)
with matching age and gender were recruited from a pool of subjects earlier used in the
validation of the technicalsetting. Three additional groups of controlsubjects were includ-
ed in the study sinceschizophrenia symptoms may overlap withother diagnoses: patients
diagnosedwith ADHD (n= 29; 15 males, 14 females; age range 19–64, mean age (±S.D.)
36.1± 12.6 years), patients diagnosed with AS (n=13; 10 males, 3 females; age range
26–53, mean age (±S.D.) 38.4± 8.8 years) and patients suffering of drug-induced
psychosis (n=14; 9 males, 5 females; age range 18–55, mean age 32). ADHD patients
had no medication at the time of testing, as individuals on methylphenidate were tested
after washout(N24 h). Of the AS patients, three were taking selective serotonin reuptake
inhibitorsand one was taking a selective norepinephrine reuptakeinhibitor. All diagnostic
groups consisted of patientswith clinical DSM-IV diagnoses that had been observed for at
least 1 year in specialized psychiatric care.Patients with additional presenceof other psy-
chiatric diagnoses were excluded. Patients were recruited from a total of six different
clinics.
Hearing ability and control ABRs were investigated by an audiologist to exclude
subjects with hearing disabilities from the study. Two subjects were excluded due to
hearing disabilities. In addition, two subjects were excluded due to interrupted mea-
surement, one due to inability to sit still during measurement and three due to equip-
ment malfunction. There were no significant differences in the proportion of
handedness between groups. A formal consent was ascertained in accordance with
the requirements of the ethical committee at the University of Lund, Sweden (document
number 353/2006).
2.2. Stimuli and apparatus
A square-shaped click pulse was used as a probe for both the control ABR condition
and the auditory forward masking setup. The probe had a duration time of 0.000136 s
and a rise and fall time of 0.000023 s. The individual clicks of the stimulus train had an
interstimulus interval (ISI) from onset to onset of 0.192 s. In the forward masking par-
adigm the square-shaped click pulse is preceded by a masker. A 1500 Hz low-pass fil-
tered noise (Butterworth filter) was used as the masker. The duration of the masking
noise was 0.015 s including the 0.004 s rise and fall time, and the gap between masker
and target stimulus was 0.012 s. The time interval onset to onset of click in the forward
masking setup was 0.192 s. Three different forward masking conditions were applied
(FM
1
,FM
2
and FM
3
) where the level of the masker was 64, 70 or 76 dB sound pressure
level (SPL), respectively. The square-shaped click pulse was presented to the subjects
with an intensity level of 80 dB SPL. All stimuli were presented through SensoDetect
Brainstem Evoked Response Audiometry® (SensoDetect, Lund, Sweden). The evoked
potentials were recorded using the GN Otometrics' Chartr EP ABR recording equipment
(GN Otometrics, Taastrup, Denmark). TTL trigger pulses coordinated the sweeps with
the auditory stimuli. In each condition (control condition and three different forward
masking conditions) the stimuli were repeated until a total of 1024 accepted evoked
potentials for each ear had been collected. Each ABR waveform represents an average
of the responses to 1024 stimulus presentations. Aberrant activity, such as extremely
high amplitudes due to extraordinary movements, was rejected using the standard setup
GN Otometrics' Chartr software. Sound levels were calibrated using a Bruel and Kjaer
2203 sound level meter and Type 4152 artificial ear (Bruel and Kjaer S&V Measurement,
Naerum, Denmark). All stimuli were constructed using the MATLAB Signal Processing
Toolbox (The MathWorks, Inc., Natick, MA, USA) and presented using a Denon
DCD-685 compact disc player (Denon Electronics,Mahwah,NJ,USA).Theoutputof
the CD player was connected to TDH-50P headphones withModel 51 cushions (Tele-
phonics, Farmingdale, NY, USA). Presentations were made binaurally with the stimuli
in phase over headphones.
2.3. Testing procedure
All tests were performed in a quiet darkened room. Participants were comfortably
seated in an armchair in a resting position. Surface electrodes were attached to the
skin over the mastoid bones behind the left and right ear, with a ground electrode
and a reference electrode placed on the vertex and forehead, respectively. Before the
test session, the procedure was fully explained to the test subject and the click sounds
were presented beforehand to aquaint him/her with the stimuli. Absolute impedances
and interelectrode impedance were measured before and after the experiments to verify that
electrode contact was maintained (below 5000 Ω).Thesubjectswereinstructedtorelax
with their eyes closed and were permitted to fall asleep. The test required no active partici-
pation other than being subjected to sound stimulation. The subjects were tested one at a
time and the duration of the testing procedure was 40 min.
2.4. Data analysis
2.4.1. Lateral asymmetry
In order to measurelateral symmetryfor each test person,non-parametric correlation
coefficients between leftand right square-shapedclick pulse audiogramswere computed.
Thus, Spearman's rhos were calculated for seven consecutive time windows, starting
at 0.6 ms and each representing activity in microvolts within 1.2 ms. The windows
comprised 160 data points for each side. The time frame for the windows was chosen
in order to obtain the best fit of standard peaks. In this way, each window included
only one peak in the majority of the recorded audiograms. The rho-values were then
used for non-parametric group comparisons (Mann Whitney Utest).
2.4.2. Forward masking
The forward masking sound stimuli had the square-shaped click as target stimulus
preceded by no masker (FM
0
) or a masker of 64, 70 or 76 dB (FM
1
,FM
2
or FM
3
). In
total, eight ABR waveforms were obtained from each test subject (four left and four
right) and the left and right were averaged. We studied the k-values, k=Δy/Δx, of the
activities for the troughs to peaks in the brainstem audiograms. Amplitude (Δy) and
189J. Källstrand et al. / Psychiatry Research 196 (2012) 188–193
latency (Δx), both evidently reciprocally affected in forward masking (Ananthanarayan
and Gerken, 1987), are considered in such a measure. The k-values were calculated be-
tween the consecutive minimum and maximum points in each defined time window
(Fig. 1). Thus six values were obtained from each ABR waveform, corresponding to
waves I–VI, respectively. At first masking effects were defined for healthy individuals,
i.e., these measures were analyzed in the non-diagnostic reference group and were
found to be homogeneous making them suitable for further comparisons. The masking
effect in each time window was expressed as the slope of the regression line of the k-
values derived from the four different stimulations. The regression coefficient βwas cal-
culated for each subject and each wave according to
β¼
∑mi−P
mðÞki−
P
k
∑mi−P
mðÞ
2
where the k-values kfor the four masking conditions FM
0
,FM
1
,FM
2
and FM
3
were the y
values and the numbers of the order of the masking conditions m(0, 1, 2 or 3) were the
xvalues.
This relationship cannot be assumed to be fully linear but is ordinally stepwise de-
creasing with increased masking in the group of healthy subjects. In this way, a mea-
sure of forward masking was obtained. In order to evaluate the usefulness of this
measure, the masking regressions for each peak and the four stimulation conditions
were studied in the group of healthy controls. The slopes of the masking regression
lines were found to be negative in more than 90% of the healthy subjects regarding
peaks II to V. For peaks I and VI the slopes were still homogeneous but not below
zero. Thus, this expression of the effect of forward masking in different parts of the
brainstem was considered a useful way of comparing the study groups.
3. Results
Fig. 2 shows averaged left and right side ABR waveforms of psychi-
atrically healthy (Fig. 2a) and schizophrenic individuals (Fig. 2b), re-
spectively. All wave peaks are clearly discernible. In addition to a
tendency toward reduced amplitudes of peaks II and V in the schizo-
phrenic group, the asymmetry in peak II is clearly different between
the two groups. Lateral correlation coefficients (Spearman's rho) for
each of the seven time intervals, as described in Section 2, are
shown in Fig. 2c. The only time interval rendering significant differ-
ences for the schizophrenic group against all other groups was the
1.8- to 3.0- ms window, reflecting activity in the peak II region (all
Mann Whitney U-test comparisons, pb0.05). Over 90% of the healthy
controls had a correlation value higher than + 0.5, whereas 70% of the
schizophrenic patients, on the contrary, had values below + 0.5 (data
not shown). Furthermore, the time windows 4.2–5.4 ms and 6.6–
7.8 ms rendered analogous significant differences between the
schizophrenic group and the group of healthy controls (pb0.001
and pb0.01, respectively) and the schizophrenic group in comparison
with the ADHD group (pb0.01 and pb0.05, respectively).
Forward masking effects were calculated for each of the six peaks
I–VI in the ABR waveforms for all subjects. The forward masking ef-
fects were expressed as the regression coefficients of the inclination
k-values as described in Section 2. The progression of the forward
masking effect with increasing noise was evident in healthy individ-
uals regarding the majority of peaks (data not shown). This was
found to exist in more than 90% of the healthy subjects. Thus, this
method of expressing forward masking was well suited for purposes
of comparisons between groups. As is shown in Fig. 3, the masking ef-
fect at the level of SOC was significantly lower in the schizophrenia
group as compared to all other groups (pb0.01) except the Asperger
group (n.s.). Regarding masking effects in other peaks, no significant
group differences were found (data not shown).
4. Discussion
The main finding of this study is that significant aberrances were
found in the peripheral parts of the brainstem of schizophrenic pa-
tients. Subcortical abnormalities have been identified in several stud-
ies including magnetic resonance imaging (Nopoulos et al., 2001;
Kang et al., 2008), otoacoustic emissions (Veuillet et al., 2001) and
post-mortem brain studies (Kreczmanski et al., 2007; Barley et al.,
2009). The present study further identifies subcortical abnormalities
in schizophrenia, as auditory deficits at the levels of two specific
brainstem structures are found.
Previous ABR studies have shown contradictory results regarding
brainstem aberrances in schizophrenia in general. ABR abnormalities
such as absence of peaks, prolonged latencies and/or reduced ampli-
tudes have been found in several studies (Hayashida et al., 1986;
Lindström et al., 1987; Lindström et al., 1990; Igata et al., 1994),
whereas other studies report no differences in ABR patterns between
schizophrenic patients and healthy controls (Pfefferbaum et al., 1980;
Brecher and Begleiter, 1985). Tendencies toward reduced amplitudes
and prolonged latencies were observed in the present study, but
these measures were not the primary focus of the study.
The finding of increased lateral asymmetry in schizophrenia, as
indexed by lower correlation between left and right ABR waveforms,
was significantly differentiated schizophrenic patients from each and
all control groups in the region reflecting the proximal portion of the
eighth nerve. This is in the proximity of cochlear nucleus as well. At
this level the first lateral crossing-over in the afferent auditory path-
way is made, as second-order neurons within the cochlear nuclei
cross over to terminate on third-order neurons in the contralateral
superior olivary complex, the nuclei of the lateral lemniscus or the in-
ferior colliculus (Biacabe et al., 2001). This implies a disturbance in
schizophrenic patients at the level of the first lateral crossing over
in the afferent auditory pathway. Such an early processing deficit
may influence further ascending auditory processing and may result
in coding deficiencies in the bottom-up networks. Perhaps, the audi-
tory misperceptions and hallucinations that are characteristic fea-
tures of schizophrenia originate from early brainstem dysfunctions.
Previous studies have shown that ABR abnormalities in schizophrenic
patients are correlated with clinical symptoms and test performance
(Hayashida et al., 1986; Igata et al., 1994). Furthermore, auditory hal-
lucinations were associated with abnormal patterns of language
Fig. 1. Explanatory figure displaying the calculations of βvalues computed with ordinal number of masking (m) as independent variable and k-values derived from troughs and
peaks in ABRs as dependent variables.
190 J. Källstrand et al. / Psychiatry Research 196 (2012) 188–193
asymmetry in a dichotic listening study in schizophrenic patients
(Green et al., 1994), suggesting that abnormal lateral asymmetry
may be involved in generating hallucinations.
The current study also showed a lower degree of forward masking
among the schizophrenic patients. They showed irregularities in seri-
al masking stimulation whereas 90% of the non-schizophrenic sub-
jects (93 of 105) had a regular masking progression in the SOC
region. This finding was, however, only observed in peak IV, reflecting
SOC activity. Previous studies on forward masking have suggested
that peripheral adaptation is involved at the level of auditory nerve fi-
bers (Harris and Dallos, 1979) and the cochlear nucleus (Boettcher et
al., 1990; Kaltenbach et al., 1993), although a role for the cortex also is
proposed (Calford and Semple, 1995; Brosch and Schreiner, 1997).
The present study shows that the decreased forward masking effect
observed in schizophrenic patients is localized to the SOC region.
The SOC is a specific neuronal organization that handles sensory
input as the first processing stage of binaural interactions.
Forward masking disabilities have in our research previously been
documented in schizophrenia, as the schizophrenic subjects did not
detect a square-shaped click stimulus in the presence of a preceding
masker at the same levels as matched controls (Källstrand et al.,
2002). In the present study, the forward masking effect is, in contrast,
less pronounced among schizophrenic patients as compared to the
control groups. However, coding deficits in the lower part of the audi-
tory pathway, as identified in the current study, most probably have
secondary effects at the perceptual level. Such effects may manifest
themselves as a decreased ability to detect target stimuli. Secondly,
the study design differs between the two studies as the former
Fig. 2. Averaged ABR curves from left (dotted curve) and right (solid curve) sides of healthy controls (a) and schizophrenic patients (b) upon stimulation with square-shaped click
pulses. In (c) correlations between left and right sides in the seven time intervals of 1.2 ms in the ABR curves of schizophrenic patients and the four control groups are shown. The
yaxis in figure c displays Spearman rho values of the curves when split in 160 points/time window. * pb0.05, ** pb0.01, *** pb0.005, **** pb0.001 Mann- Whitney Utest.
Fig. 3. Box plot of the regression coefficient βcomputed with ordinal number of masking as independent variable and k-value as dependent variable. Negative βvalues indicate a
reduction of activity in SOC, constituting a normal forward masking effect. * pb0.05, ** pb0.01, *** pb0.005, **** pb0.001 Mann- Whitney Utest.
191J. Källstrand et al. / Psychiatry Research 196 (2012) 188–193
study is based on the subjects verbally indicating if they could hear
the target stimulus, in contrast to this study where the response to
the stimuli in presence of a masker was measured objectively using
the ABR technique. The previous results may therefore, at least to a
larger extent, be explained by secondary processing at higher brain
locations.
The finding of a decreased masking effects in the SOC region
among schizophrenic patients suggests an altered, less active inhibi-
tory system in schizophrenia. This is in line with previous findings
of deficiencies in inhibition, sensory gating and filtering mechanisms
that are well established in schizophrenia research (Braff et al., 1992;
Braff, 1993; Adler et al., 1982). Interestingly, the decreased forward
masking abilities differentiated schizophrenic patients against all
other comparison groups except the Asperger syndrome group,
indicating that this deficiency is shared with Asperger syndrome
patients. However, the Asperger syndrome control group only included
13 test subjects, so this needs to be further investigated. Furthermore,
forward masking deficits at the SOC level have previously been demon-
strated in Asperger syndrome patients by this group (Källstrand et al.,
2010) and abnormal neuronal morphology is reported in autism spec-
trum disorders (Kulesza et al., 2011), highlighting the importance of
the SOC region in auditory dysfunctions in this group. A further notion
is that the SOC projects heavily onto the CN, which could indicate that
a common developmental lesion could at least in part include both de-
ficiencies here revealed.
This study has some limitations. Firstly, some of the studied
groups are small, making influence of background factors impossible
to check. A second limitation of the study is that neither clinical rating
scales nor psychological tests to corroborate diagnoses were included.
Finally, the number of neuroleptic- naïve patients was limited. However,
these limitations do not preclude the possibility of drawing conclusions
because of the very great impact of these diseases on neurophysiolog-
ical functioning, even under pharmacotherapy.
In conclusion, this study further supports the idea of early subcor-
tical lesions in schizophrenia (Singh et al., 2004) and auditory brain-
stem abnormalities may contribute to the clinical representation of
the disease. Interestingly, the two identified measures combined
yield sensitivity and specificity over 75% for the schizophrenic diag-
nose in this sample (data not shown). In combination with other neu-
rophysiological measures, this figure may ultimately meet to
clinically useful levels for diagnostic and therapeutic control
purposes.
References
Adler, L.E., Pachtman, E., Franks, R.D., Pecevich, M., Waldo, M.C., Freedman, R., 1982.
Neurophysiological evidence for a defect in neuronal mechanisms involved in sen-
sory gating in schizophrenia. Biological Psychiatry 17, 639–654.
Ananthanarayan, A.K., Gerken, G.M., 1987. Response enhancement and reduction of the
auditory brain-stem response in a forward-masking paradigm. Electroencephalog-
raphy and Clinical Neurophysiology 66, 427–439.
Andreasen, N.C., Arndt, S., Swayze II, V., Cizadlo, T., Flaum, M., O'Leary, D., Ehrhardt, J.C.,
Yuh, W.T., 1994. Thalamic abnormalities in schizophrenia visualized through mag-
netic resonance image averaging. Science 266, 294–298.
Barley, K., Dracheva, S., Byne, W., 2009. Subcortical oligodendrocyte- and astrocyte-
associated gene expression in subjects with schizophrenia, major depression and
bipolar disorder. Schizophrenia Research 112, 54–64.
Biacabe, B., Chevallier, J.M., Avan, P., Bonfils, P., 2001. Functional anatomy of auditory
brainstem nuclei: application to the anatomical basis of brainstem auditory evoked
potentials. Auris, Nasus, Larynx 28, 85–94.
Boettcher, F.A., Salvi, R.J., Saunders, S.S., 1990. Recovery from short-term adaptation in
single neurons in the cochlear nucleus. Hearing Research 48, 125–144.
Braff, D.L., 1993. Information processing and attention dysfunctions in schizophrenia.
Schizophrenia Bulletin 19, 233–259.
Braff, D., Stone, C., Callaway, E., Geyer, M., Glick, I., Bali, L., 1978. Prestimulus effects on
human startle reflex in normals and schizophrenics. Psychophysiology 15, 339–343.
Braff, D.L., Grillon, C., Geyer, M.A., 1992. Gating and habituation of the startle reflex in
schizophrenic patients. Archives of General Psychiatry 49, 206–215.
Brecher, M., Begleiter, H., 1985. Brain stem auditory evoked potentials in unmedicated
schizophrenic patients. Biological Psychology 20, 199–228.
Brosch, M., Schreiner, C.E., 1997. Time course of forward masking tuning curves in cat
primary auditory cortex. Journal of Neurophysiology 77, 923–943.
Calford, M.B., Semple, M.N., 1995. Monaural inhibition in cat auditory cortex. Journal of
Neurophysiology 73, 1876–1891.
Chiappa, K.H., 1997. Evoked Potentials in Clinical Medicine. Lippincott-Raven Pub-
lishers, Philadelphia.
Dragovic, M., Hammond, G., 2005. Handedness in schizophrenia: a quantitative review
of evidence. Acta Psychiatrica Scandinavica 111, 410–419.
Freedman, R., Adler, L.E., Waldo, M.C., Pachtman, E., Franks, R.D., 1983. Neurophysio-
logical evidence for a defect in inhibitory pathways in schizophrenia: comparison
of medicated and drug-free patients. Biological Psychiatry 18, 537–551.
Friston, K.J., 1999. Schizophrenia and the disconnection hypothesis. Acta Psychiatrica
Scandinavica 99 (Suppl. 395), 68–79.
Green, M.F., Hugdahl, K., Mitchell, S., 1994. Dichotic listening during auditory halluci-
nations in patients with schizophrenia. The American Journal of Psychiatry 151,
357–362.
Harris, D.M., Dallos, P., 1979. Forward masking of auditory nerve fiber responses. Jour-
nal of Neurophysiology 42, 1083–1107.
Hayashida, Y., Mitani, Y., Hosomi, H., Amemiya, M., Mifune, K., Tomita, S., 1986. Auditory
brain stem responses in relation to the clinical symptoms of schizophrenia. Biological
Psychiatry 21, 177–188.
Igata, M., Ohta, M., Hayashida, Y., Abe, K., 1994. Missing peaks in auditory brainstem re-
sponses and negative symptoms in schizophrenia. The Japanese Journal of Psychi-
atry and Neurology 48, 571–578.
Jablensky, A., 2000. Epidemiology of schizophrenia: the global burden of disease and
disability. European Archives of Psychiatry and Clinical Neuroscience 250,
274–285.
Javitt, D.C., 2009. Sensory processing in schizophrenia: neither simple nor intact.
Schizophrenia Bulletin 35, 1059–1064.
Javitt, D.C., Steinschneider, M., Schroeder, C.E., Vaughan Jr., H.G., Arezzo, J.C., 1994. De-
tection of stimulus deviance within primate primary auditory cortex: intracortical
mechanisms of mismatch negativity (MMN) generation. Brain Research 667,
192–200.
Javitt, D.C., Doneshka, P., Grochowski, S., Ritter, W., 1995. Impaired mismatch negativ-
ity generation reflects widespread dysfunction of working memory in schizophre-
nia. Archives of General Psychiatry 52, 550–558.
Källstrand, J., Montnémery, P., Nielzén, S., Olsson, O., 2002. Auditory masking experi-
ments in schizophrenia. Psychiatry Research 113, 115–125.
Källstrand, J., Olsson, O., Nehlstedt, S.F., Sköld, M.L., Nielzén, S., 2010. Abnormal audito-
ry forward masking pattern in the brainstem response of individuals with Asperger
syndrome. Neuropsychiatric Disease and Treatment 6, 289–296.
Kaltenbach, J.A., Meleca, R.J., Falzarone, P.R., Myers, S.F., Simpson, T.H., 1993. Forward
masking properties of neurons in the dorsal cochlear nucleus: possible role in
the process of echo suppression. Hearing Research 67, 35–44.
Kang, D.-H., Kwon, K.W., Gu, B.-M., Choi, J.-S., Jang, J.H., Kwon, J.S., 2008. Structural ab-
normalities of the right inferior colliculus in schizophrenia. Psychiatry Research
164, 160–165.
Kreczmanski, P., Heinsen, H., Mantua, V., Woltersdorf, F., Masson, T., Ulfig, N., Schmidt-
Kastner, R., Korr, H., Steinbusch, H.W., Hof, P., Schmitz, C., 2007. Volume, neuron
density and total neuron number in five subcortical regions in schizophrenia.
Brain 130, 678–692.
Kulesza Jr., R.J., Lukose, R., Stevens, L.V., 2011. Malformation of the human superior
olive in autistic spectrum disorders. Brain Research 1367, 360–371.
Lahat, E., Avital, E., Barr, J., Berkovitch, M., Arlazoroff, A., Aladjem, M., 1995. BAEP stud-
ies in children with attention deficit disorder. Developmental Medicine and Child
Neurology 37, 119–123.
Lindström, L., Klockhoff, I., Svedberg, A., Bergström, K., 1987. Abnormal auditory brain-
stem responses in hallucinating schizophrenic patients. British Journal of Psychia-
try 151, 9–14.
Lindström, L.H., Wieselgren, I.-M., Klockhoff, I., Svedberg, A., 1990. Relationship be-
tween abnormal brainstem auditory-evoked potentials and subnormal CSF levels
of HVA and 5-HAA in first-episode schizophrenic patients. Biological Psychiatry
28, 435–442.
Maziade, M., Mérette, C., Cayer, M., Roy, M.-A., Szatmari, P., Côte, R., Thivierge, J., 2000.
Prolongation of brainstem auditory-evoked responses in autistic probands and
their unaffected relatives. Archives of General Psychiatry 57, 1077–1083.
Muncie, L., McCandless, D.W., 2011. Auditory brainstem response. In: McCandless, D.W.
(Ed.), Kernicterus, Contemporary Clinical Neuroscience, 0. HumanaPress c/o Springer
Science+Business media, New York, pp. 175–187.
Näätänen, R., Kähkönen, S., 2009. Central auditory dysfunction in schizophrenia as
revealed by the mismatch negativity (MMN) and its magnetic equivalent
MMNm: a review. The International Journal of Neuropsychopharmacology 12,
125–135.
Nielzén, S., Olsson, O., 1997. Perceptual grouping due to pitch and amplitude in hallu-
cinating schizophrenics. Psychopathology 30, 140–148.
Nopoulos, P.C., Ceilley, J.W., Gailis, E.A., Andreasen, N.C., 2001. An MRI study of mid-
brain morphology in patients with schizophrenia: relationship to psychosis, neu-
roleptics, and cerebellar neural circuitry. Biological Psychiatry 49, 13–19.
Olsson, O., Nielzén, S., 1999a. Contralateral induction by frequency spectrum in hallu-
cinating schizophrenics. Psychiatry Research 87, 65–75.
Olsson, O., Nielzén, S., 1999b. Perceptual restoration of missing sounds in a group of
hallucinating schizophrenics. Perceptual and Motor Skills 89, 315–326.
Pfefferbaum, A., Horvath, T.B., Roth, W.T., Tinklenberg, J.R., Kopell, B.S., 1980. Auditory
brain stem and cortical evoked potentials in schizophrenia. Biological Psychiatry
15, 209–223.
Puente, A., Ysunza, A., Pamplona, M., Silva-Rojas, A., Lara, C., 2002. Short latency and
long latency auditory evoked responses in children with attention deficit order. In-
ternational Journal of Pediatric Otorhinolaryngology 62, 45–51.
192 J. Källstrand et al. / Psychiatry Research 196 (2012) 188–193
Rabinowicz, E.F., Silipo, G., Goldman, R., Javitt, D.C., 2000. Auditory sensory dysfunction
in schizophrenia: imprecision or distractibility. Archives of General Psychiatry 57,
1149–1155.
Recanzone, G.H., Sutter, M.L., 2008. The biological basis of audition. Annual Review of
Psychology 59, 119–142.
Roth, W.T., Pfefferbaum, A., Horvath, T.B., Berger, P.A., Kopell, B.S., 1980. P3 reduction in
auditory evoked potentials of schizophrenics. Electroencephalography and Clinical
Neurophysiology 49, 497–505.
Shergill, S.S., Brammer, M.J., Williams, S.C., Murray, R.M., McGuire, P.K., 2000. Mapping
auditory hallucinations in schizophrenia using functional magnetic resonance im-
aging. Archives of General Psychiatry 57, 1033–1038.
Singh, S.M., McDonald, P., Murphy, B., O'Reilly, R., 2004. Incidental neurodevelopmen-
tal episodes in the etiology of schizophrenia: an expanded model involving epige-
netics and development. Clinical Genetics 65 (6), 435–440 (Jun).
Sommer, I., Aleman, A., Ramsey, N., Bouma, A., Kahn, R., 2001. Handedness, language
lateralization and anatomical asymmetry in schizophrenia. British Journal of Psy-
chiatry 178, 344–351.
Terk, A.R., Kveton, J.F., 2007. Clinical evaluation of hearing loss. In: Gumpert, E. (Ed.),
Clinical Otology. Thierne Publishers, Inc., New York, pp. 174–182.
Turetsky, B.I., Colbath, E.A., Gur, R.E., 1998. P300 subcomponent abnormalities in
schizophrenia: I. Physiological evidence for gender and subtype specific differ-
ences in regional pathology. Biological Psychiatry 43, 84–96.
Veuillet, E., Georgieff, N., Philibert, B., Dalery, J., Marie-Cardine, M., Collet, L., 2001. Ab-
normal peripheral auditory asymmetry in schizophrenia. Journal of Neurology,
Neurosurgery, and Psychiatry 70, 88–94.
Ward, P.B., Hoffer, L.D., Liebert, B.J., Catts, S.V., O'Donnell, M., Adler, L.E., 1996. Replica-
tion of a P50 auditory gating deficit in Australian patients with schizophrenia. Psy-
chiatry Research 64, 121–135.
Wong, V., Wong, S.N., 1991. Brainstem auditory evoked potential study in children
with autistic disorder. Journal of Autism and Developmental Disorders 21,
329–340.
193J. Källstrand et al. / Psychiatry Research 196 (2012) 188–193
