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Lateral asymmetry and reduced forward masking effect in early brainstem auditory evoked response in schizophrenia


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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) patients (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 except 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.
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Lateral asymmetry and reduced forward masking effect in early brainstem auditory
evoked responses in schizophrenia
Johan Källstrand
, Sara Fristedt Nehlstedt
, Mia Ling Sköld
, Sören Nielzén
SensoDetect AB, Lund, Sweden
Department of Clinical Neuroscience, Section of Psychiatry, Lund, Sweden
abstractarticle info
Article history:
Received 25 March 2011
Accepted 30 August 2011
Auditory brainstem response
Forward masking
Lateral asymmetry
Individuals diagnosed with schizophrenia show deciencies of basic neurophysiological sorting mechanisms.
This study further investigated this issue, focusing on the two phenomena, laterality of coding and auditory
forward masking. A specic 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 decit hyperactivity disorder (ADHD) pa-
tients (n=29), Asperger syndrome (AS) patients (n=13) and drug-induced psychotic patients (n=14).
Schizophrenic patients showed signicant 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 signicantly differently by schizophrenic patients compared to control groups ex-
cept for the AS group. The results suggest decits 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) ndings show a signicantly 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 identied an extensive network of cortical and sub-
cortical areas associated with auditory hallucinations.
Sensory processing difculties 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), reecting central attentional
processing and working memory, and abnormal mismatch negativity
(MMN) (Javitt et al., 1994, 1995; Näätänen and Kähkönen, 2009),
reecting pre-attentive auditory information processing, are well
established ndings in schizophrenia. Consistently reported ndings
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 decits are suggested to involve impaired sen-
sory gating, e.g., inability to lter the inow of information.
Furthermore, auditory forward masking has been shown to be aberrant
Psychiatry Research 196 (2012) 188193
Corresponding author at: Department of Clinical Neuroscience, Section of Psychiatry,
Lund, Sweden. Tel.: +46 733528056.
E-mail address: (S. Nielzén).
0165-1781/$ see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
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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 IVII, 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 difcult 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 nding among neuropsychiatric diagnosis groups such as au-
tism spectrum or Asperger syndrome (AS) disorders (Wong and
Wong, 1991; Maziade et al., 2000) and attention decit 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 decits.
2. Methods
2.1. Subjects
Participating subjects included schizophrenic patients (n=49; 32 males, 17 females;
age range 2062, 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 fulll a typical schizophrenic symptom prole 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 2071, 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 1964, mean age (±S.D.)
36.1± 12.6 years), patients diagnosed with AS (n=13; 10 males, 3 females; age range
2653, mean age (±S.D.) 38.4± 8.8 years) and patients suffering of drug-induced
psychosis (n=14; 9 males, 5 females; age range 1855, 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
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 signicant 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 l-
tered noise (Butterworth lter) 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
and FM
) 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 articial 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
coefcients 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 t 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
) or a masker of 64, 70 or 76 dB (FM
or FM
). 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) 188193
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 dened time window
(Fig. 1). Thus six values were obtained from each ABR waveform, corresponding to
waves IVI, respectively. At rst masking effects were dened 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 coefcient βwas cal-
culated for each subject and each wave according to
where the k-values kfor the four masking conditions FM
and FM
were the y
values and the numbers of the order of the masking conditions m(0, 1, 2 or 3) were the
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 coefcients (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 signicant differ-
ences for the schizophrenic group against all other groups was the
1.8- to 3.0- ms window, reecting 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 4.25.4 ms and 6.6
7.8 ms rendered analogous signicant 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
IVI in the ABR waveforms for all subjects. The forward masking ef-
fects were expressed as the regression coefcients 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 signicantly 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 signicant
group differences were found (data not shown).
4. Discussion
The main nding of this study is that signicant aberrances were
found in the peripheral parts of the brainstem of schizophrenic pa-
tients. Subcortical abnormalities have been identied 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 identies subcortical abnormalities
in schizophrenia, as auditory decits at the levels of two specic
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 nding of increased lateral asymmetry in schizophrenia, as
indexed by lower correlation between left and right ABR waveforms,
was signicantly differentiated schizophrenic patients from each and
all control groups in the region reecting the proximal portion of the
eighth nerve. This is in the proximity of cochlear nucleus as well. At
this level the rst 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 rst lateral crossing over
in the afferent auditory pathway. Such an early processing decit
may inuence further ascending auditory processing and may result
in coding deciencies 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 gure 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) 188193
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 nding was, however, only observed in peak IV, reecting
SOC activity. Previous studies on forward masking have suggested
that peripheral adaptation is involved at the level of auditory nerve -
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 specic neuronal organization that handles sensory
input as the rst 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 decits in the lower part of the audi-
tory pathway, as identied 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 gure 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 coefcient 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) 188193
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
The nding 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 ndings
of deciencies in inhibition, sensory gating and ltering 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 deciency 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 decits 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-
ciencies here revealed.
This study has some limitations. Firstly, some of the studied
groups are small, making inuence 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 identied measures combined
yield sensitivity and specicity over 75% for the schizophrenic diag-
nose in this sample (data not shown). In combination with other neu-
rophysiological measures, this gure may ultimately meet to
clinically useful levels for diagnostic and therapeutic control
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... Several audiological, neurological and psychiatric abnormalities can be detected using ABR [3]. Using quantified electrophysiological methods for detecting neuropsychiatric diseases, sensitivity and intraindividual variability are key factors for clinical usefulness [4]. ...
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Auditory Brainstem Responses have previously been reported to be aberrant in patients with neuropsychiatric diagnoses. In this study, 88 subjects from Sweden and 72 subjects from Bolivia were tested using a test battery of sound stimuli. The Gaussian Naïve Bayes AI classification model was used for analyzing traits and predicting diagnosis. The test proved to have both high sensitivity and specificity. The results were consistent with previous studies where similar outcomes have been shown in other populations. Abstract Background
... In contrast to previously reported EEG biomarkers, auditory brainstem responses to clicks (click ABRs) reflect the earliest stages of auditory processing. Click ABRs represent a manifestation of the beginning of auditory processing within the auditory peripheral pathway from the cochlea to the rostral brainstem (Henry, 1979;Legatt, 2015); features of click ABRs are sensitive to abnormalities in various psychiatric disorders (Baghdassarian et al., 2018;Brecher and Begleiter, 1985;Källstrand et al., 2012;Manouilenko et al., 2017;Sköld et al., 2014). Click ABRs have distinct waveform morphology that is captured using scalp-recorded EEG, with responses occurring within 10 ms of the presentation of brief acoustic stimuli (i.e., clicks). ...
Patients with schizophrenia have impairments in early auditory system functioning that relate to clinical, cognitive, and psychosocial functioning. Some neurophysiological biomarkers of auditory information processing are sensitive to and predictive of clinically relevant outcomes following auditory-based targeted cognitive training (TCT) in schizophrenia. It is not known, however, whether schizophrenia patients show abnormalities at the earliest stage of sensory processing reflecting the integrity of the ascending auditory pathway at the level of the brainstem, or whether such abnormalities can serve as biomarkers. This study aimed to determine whether click-evoked auditory brainstem responses (click ABRs) are 1) abnormal in schizophrenia patients relative to healthy comparison subjects (HCS), 2) acutely sensitive to or predictive of TCT response, and 3) associated with clinically relevant symptoms. We also sought to determine whether 4) click ABRs show adequate psychometric reliability. Click ABRs were examined in 52 patients with schizophrenia and 32 HCS. Patients were randomized to either TCT (n = 32), which comprised 30 hours of training, or treatment as usual (TAU; n = 23). Patients showed intact click ABRs relative to HCS and click ABRs did not change significantly after 1 or 30 hours of TCT. Exploratory analyses revealed modest relationships between click ABRs and baseline measures of positive symptoms and speech-in-noise perception; acute changes in ABRs were modestly related to improvements on measures of cognition independent of treatment. ABR measurements showed adequate internal consistency indicating their suitability for cross-sectional studies of individual differences, but poor test-retest reliability indicating poor suitability for clinical trials. In contrast to a growing literature demonstrating the utility of later cortical neurophysiological measures for translational research, the present findings indicate that brainstem-mediated responses are intact in schizophrenia and are not sensitive to or predictive of clinical changes in the context of TCT. These data provide guidance for establishing future neurophysiology-guided interventions in schizophrenia.
... Further region-of-interest weight map analysis indicated that the time points selected by the algorithm as most relevant in the classification were actually outside of the 50-250 ms interval, although all spatiotemporal voxels contribute globally to the prediction. The N100 and MMN are the most widely studied neurophysiological markers in schizophrenia, but abnormalities have also been reported in other event-related potential components, namely decreased attenuation of the P50 auditory evoked potential, which is considered a measure of neuronal inhibition (Källstrand et al., 2012). Reduced amplitude and increased latency of the P300 have also been consistently reported in schizophrenia patients and correlates with the degree of MMN reduction (Javitt et al. 1995;Ford et al., 2010;Brown et al., 2013). ...
Schizophrenia is a complex psychiatric disorder, typically diagnosed through symptomatic evidence collected through patient interview. We aim to develop an objective biologically-based computational tool which aids diagnosis and relies on accessible imaging technologies such as electroencephalography (EEG). To achieve this, we used machine learning techniques and a combination of paradigms designed to elicit prediction errors or Mismatch Negativity (MMN) responses. MMN, an EEG component elicited by unpredictable changes in sequences of auditory stimuli, has previously been shown to be reduced in people with schizophrenia and this is arguably one of the most reproducible neurophysiological markers of schizophrenia. EEG data were acquired from 21 patients with schizophrenia and 22 healthy controls whilst they listened to three auditory oddball paradigms comprising sequences of tones which deviated in 10% of trials from regularly occurring standard tones. Deviant tones shared the same properties as standard tones, except for one physical aspect: 1) duration-the deviant stimulus was twice the duration of the standard; 2) monaural gap-deviants had a silent interval omitted from the standard, or 3) inter-aural timing difference, which caused the deviant location to be perceived as 90° away from the standards. We used multivariate pattern analysis, a machine learning technique implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo) to classify images generated through statistical parametric mapping (SPM) of spatiotemporal EEG data, i.e. event-related potentials measured on the two-dimensional surface of the scalp over time. Using support vector machine (SVM) and Gaussian processes classifiers (GPC), we were able classify individual patients and controls with balanced accuracies of up to 80.48% ( p -values = 0.0326, FDR corrected) and an ROC analysis yielding an AUC of 0.87. Crucially, a GPC regression revealed that MMN predicted global assessment of functioning (GAF) scores (correlation = 0.73, R ² = 0.53, p = 0.0006)
... 4,5 With respect to the neural substrates underlying these impairments, histological studies have focused on the auditory cortex, for which structural and molecular alterations have been identified. 6 However, evidence from neuroimaging 7,8 and neurophysiological studies [9][10][11][12][13] suggest that deficits may be present at earlier levels along the auditory pathway. ...
Aberrant processing of auditory stimuli is a prominent feature of schizophrenia (SZ). Prior studies have chronicled histological abnormalities in the auditory cortex of SZ subjects, but whether deficits exist at upstream, subcortical levels has yet to be established. En route to the auditory cortex, ascending information is integrated in the inferior colliculus (IC), a highly gamma amino butyric acid (GABA) ergic midbrain structure that is critically involved in auditory processing. The IC contains a dense population of parvalbumin-immunoreactive interneurons (PVIs), a cell type characterized by increased metabolic demands and enhanced vulnerability to oxidative stress. During development, PVIs are preferentially surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures that promote redox homeostasis and excitatory/inhibitory balance. Moreover, in SZ, deficits in PVIs, PNNs, and the GABA synthesizing enzyme, glutamic acid decarboxylase (Gad67), have been extensively documented in cortical regions. Yet, whether similar impairments exist in the IC is currently unknown. Thus, we compared IC samples of age- and sex-matched pairs of SZ and unaffected control subjects. SZ subjects exhibited lower levels of Gad67 immunoreactivity and a decreased density of PVIs and PNNs within the IC. These findings provide the first histological evidence of IC GABAergic abnormalities in SZ and suggest that SZ-related auditory dysfunction may stem, in part, from altered IC inhibitory tone.
... Previous studies have demonstrated that the brainstem is involved in the development of psychotic disorders 70 and may be associated with auditory hallucinations. 71 Our results suggest that the disorganized relationship between interoception and sensory processing may be one possible reason for the more severe symptoms observed in patients with SOC. ...
A phenomenon in schizophrenia patients that deserves attention is the high comorbidity rate with obsessive-compulsive disorder (OCD). Little is known about the neurobiological basis of schizo-obsessive comorbidity (SOC). We aimed to investigate whether specific changes in white matter exist in patients with SOC and the relationship between such abnormalities and clinical parameters. Twenty-eight patients with SOC, 28 schizophrenia patients, 30 OCD patients, and 30 demographically matched healthy controls were recruited. Using Tract-based Spatial Statistics and Probabilistic Tractography, we examined the pattern of white matter abnormalities in these participants. We also used ANOVA and Support Vector Classification of various white matter indices and structural connection probability to further examine white matter changes among the 4 groups. We found that patients with SOC had decreased fractional anisotropy (FA) and increased radial diffusivity in the right sagittal stratum and the left crescent of the fornix/stria terminalis compared with healthy controls. We also found changed connection probability in the Default Mode Network, the Subcortical Network, the Attention Network, the Task Control Network, the Visual Network, the Somatosensory Network, and the cerebellum in the SOC group compared with the other 3 groups. The classification results further revealed that FA features could differentiate the SOC group from the other 3 groups with an accuracy of .78. These findings highlight the specific white matter abnormalities found in patients with SOC.
Background Attention-deficit hyperactivity disorder (ADHD), characterized by periods of inattention, overactivity, and impulsiveness, is the most prevalent neurodevelopmental disorder among children. Auditory Brainstem Response (ABR) is a technique in which clickshaped sounds elicit potentials that are recorded from electrodes placed on a patient’s skull. Extant research indicates that ABR is frequently affected in neurodevelopmental disorders such as ADHD. Methylphenidate (MPH), a psychostimulant, is often prescribed to children with ADHD as a first-line pharmacological treatment. The aim of this study was to explore the effects of Methylphenidate treatment on previously observed amplitude alterations in the ABR of patients with ADHD. Methods We recruited 32 drug-naïve children and adolescents (19 males and 13 females; mean age 11 years) diagnosed with ADHD and 35 health controls (15 males and 20 females; mean age 12 years). The ADHD group was treated with Methylphenidate, and ABR was recorded before treatment and at a steady state of medical treatment. Results Medicated ADHD patients exhibited increased activity in the right side ABR in Wave VI. Conclusions A significant increase in activity was found in a part of the ABR thought to correspond to the thalamic area in medicated ADHD patients compared to the same area of non-medicated ADHD patients. The results add to the growing body of research suggesting that specific ABR peaks correlate to certain psychiatric symptoms.
Attention-deficit hyperactivity disorder (ADHD) is a common chronic neurodevelopmental disorder characterized by symptoms of inattention, overactivity, and/or impulsiveness. The prevalence of ADHD varies in different settings and there have been voices raised to call for more objective measures in order to avoid over- and underdiagnosing of ADHD. Auditory Brainstem Response (ABR) is a method where click shaped sounds evoke potentials that are recorder from electrodes on the skull of a patient. The aim of this study was to explore possible alterations in the ABR of 29 patients with ADHD compared to 39 healthy controls. We used a forward masked sound. We found differences in ABR that correspond to the thalamic area. The thalamus seems to play an active role in regulation of activity level in ADHD. More research is needed to draw any further conclusions on using ABR as an objective measurement to detect ADHD.
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Background Hearing impairment is a risk factor for schizophrenia. Patients with 22q11.2 Deletion Syndrome (22q11.2DS) have a 25-30% risk of schizophrenia, and up to 60% also have varying degrees of hearing impairment, primarily from middle ear inflammation. The Df1/+ mouse model of 22q11.2DS recapitulates many features of the human syndrome, including schizophrenia-relevant brain abnormalities and high inter-individual variation in hearing ability. However, the relationship between brain abnormalities and hearing impairment in Df1/+ mice has not been examined. Methods We measured auditory brainstem responses (ABRs), cortical auditory evoked potentials, and/or cortical parvalbumin-positive (PV+) interneuron density in over 70 adult mice (32 Df1/+, 39 wild-type). We also performed longitudinal ABR measurements in an additional 20 animals (13 Df1/+, 7 wild-type) from 3 weeks of age. Results Electrophysiological markers of central auditory excitability were elevated in Df1/+ mice. PV+ interneurons, which are implicated in schizophrenia pathology, were reduced in density in auditory cortex but not secondary motor cortex. Both auditory brain abnormalities correlated with hearing impairment, which affected approximately 60% of adult Df1/+ mice and typically emerged before 6 weeks of age. Conclusions In the Df1/+ mouse model of 22q11.2DS, abnormalities in central auditory excitability and auditory cortical PV+ immunoreactivity correlate with hearing impairment. This is the first demonstration of cortical PV+ interneuron abnormalities correlating with hearing impairment in a mouse model of either schizophrenia or middle ear inflammation.
Zusammenfassung Die aktuellen Klassifikationssysteme zur Einordung psychiatrischer Störungsbilder gehen primär von einer kategorialen Typologie aus und beschreiben diese als distinkte nosologische Entitäten. Eine eher dimensionale Betrachtungsweise erlaubt hingegen die Beschreibung eines graduierten Übergangs zwischen Pathologien wie auch zwischen Normalität und Pathologie von psychischen Phänomenen und Symptomen . Am Beispiel der akustischen Halluzinationen als häufigste Form der Wahrnehmungsstörungen werden in der vorliegenden Arbeit psychiatrisch-psychopathologische und theoretische Standpunkte für das Für und Wider einer dimensionalen Einordnung psychischer Symptomatik skizziert. Trotz der bestehenden und kontrovers diskutierenden Zweifel an der Gleichartigkeit von realen Wahrnehmungen und akustischen Halluzinationen zugrundeliegenden mentalen Ereignisse, finden sich viele Hinweise für ein Kontinuum halluzinatorischer Symptome in der psychisch gesunden Bevölkerung bis hin zu schizophrenen Patienten. Studien, welche die neurophysiologischen Mechanismen akustischer Halluzinationen auch bei gesunden Probanden mit Stimmenhören im Vergleich zu schizophrenen Patienten untersuchen, könnten zur weiteren Differenzierung beitragen.
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Abnormal auditory information processing has been reported in individuals with autism spectrum disorders (ASD). In the present study auditory processing was investigated by recording auditory brainstem responses (ABRs) elicited by forward masking in adults diagnosed with Asperger syndrome (AS). Sixteen AS subjects were included in the forward masking experiment and compared to three control groups consisting of healthy individuals (n = 16), schizophrenic patients (n = 16) and attention deficit hyperactivity disorder patients (n = 16), respectively, of matching age and gender. The results showed that the AS subjects exhibited abnormally low activity in the early part of their ABRs that distinctly separated them from the three control groups. Specifically, wave III amplitudes were significantly lower in the AS group than for all the control groups in the forward masking condition (P < 0.005), which was not the case in the baseline condition. Thus, electrophysiological measurements of ABRs to complex sound stimuli (eg, forward masking) may lead to a better understanding of the underlying neurophysiology of AS. Future studies may further point to specific ABR characteristics in AS individuals that separate them from individuals diagnosed with other neurodevelopmental diseases.
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This special issue focuses on the theme of sensory processing dysfunction in schizophrenia. For more than 50 years, from approximately the time of Bleuler until the early 1960s, sensory function was considered one of the few preserved functions in schizophrenia (Javitt1). Fortunately, the last several decades have brought a renewed and accelerating interest in this topic. The articles included in the issue range from those addressing fundamental bases of sensory dysfunction (Brenner, Yoon, and Turetsky) to those that examine how elementary deficits in sensory processing affect the sensory experience of individuals with schizophrenia (Butler, Kantrowitz, and Coleman) to the question of how sensory-based treatments may lead to improvement in remediation strategies (Adcock). Although addressing only a small portion of the current complex and burgeoning literature on sensory impairments across modalities, the present articles provide a cross-section of the issues currently under investigation. These studies also underscore the severe challenges that individuals with schizophrenia face when trying to decode the complex world around them.
Schizophrenic patients exhibit impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have well-described neurobiologic bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize patients with schizophrenic spectrum disorders. In this context, the startle response is particularly interesting, because it is a cross-species response to strong stimuli that is plastic or alterable using experimental and neurobiologic manipulations. Thirty-nine medicated schizophrenic patients and 37 normal control subjects were studied in a new electromyography based startle response paradigm in which both prepulse inhibition (an operational measure of sensorimotor gating) and habituation (the normal decrease in response magnitude to repeated stimuli over time) can be separated and assessed in one test session. The results indicate that schizophrenic patients have extensive deficits in both intramodal and cross-modal sensorimotor gating and a trend to show acoustic startle habituation deficits. The deficit in prepulse inhibition of startle amplitude exhibited by schizophrenic patients was evident when an acoustic prepulse stimulus preceded either an acoustic or a tactile startle stimulus. No deficit was observed in the prepulse-induced facilitation of startle latencies, indicating that the failure of gating was not due to a failure of stimulus detection. These findings suggest centrally mediated deficits in sensorimotor gating in schizophrenic patients.
Background: Impaired P300 (P3) generation is one of the most robust indices of brain dysfunction in schizophrenia. This study investigates the integrity of cognitive eventrelated potentials that precede P3 in an "oddball" paradigm to determine the earliest stages at which auditory information processing is impaired in schizophrenia. Methods: Cognitive event-related potential components including mismatch negativity (MMN), N2, and P3 were recorded from subjects with chronic schizophrenia who were receiving medication (n=20), from those who were withdrawn from drug treatment (n=11), and from healthy volunteers (n=11) during an auditory oddball paradigm. Recordings were made in both passive and active response conditions. The MMN, N2, and P3 amplitudes were compared across groups and the degree of MMN deficit was correlated with the degree of P3 reduction as a function of diagnostic group. Results: Schizophrenic subjects showed severe impairments in the generation of MMN and N2 as well as P3. Across groups, the decrement in MMN amplitude correlated significantly with the decrement in P3 amplitude. There were no significant between-group differences in MMN topography. Conclusions: The present study demonstrates that the neurophysiological deficits associated with schizophrenia, as reflected in cognitive event-related potential generation, are pervasive, extending even to the level of the sensory cortex. Mismatch negativity indexes the functioning of an automatic alerting mechanism designed to stimulate individuals to explore unexpected environmental events. Dysfunction of this mechanism may contribute to the deficit state associated with schizophrenia.
Auditory brainstem responses (ABRs) were examined in 30 schizophrenic patients and 29 normal subjects. The psychotic symptoms were assessed by the Brief Psychiatric Rating Scale (BPRS) and the Scale for Assessment of Negative Symptoms (SANS) in the patients. At least one of the waves I, II or III was found missing on either side at 80 dBHL (hearing level) in 8 (27%) of the patients but in only one (3%) of the normal subjects. There was a significant association between the missing peaks and the BPRS negative symptom cluster or the total score of the SANS. These results suggest that some schizophrenics, especially those with negative symptoms, have an abnormality of input processing of auditory information in the lower brainstem.
Graham (1975) demonstrated that a weak prestimulus could effectively inhibit or facilitate the eyeblink component of the startle reflex in humans, depending on the temporal duration of the prestimulus. This study had three goals: 1) to replicate the findings of Graham, 2) to establish the reliability of this phenomenon by a test-retest comparison, and 3) to compare the eyeblink reflex response of normal subjects with schizophrenic subjects. Seven prestimulus durations of continuous tone (from 0 to 2000 msec) were presented to 20 normal subjects and the results confirmed that maximal inhibition of eyeblink amplitude occurred in the 120 msec prestimulus condition. Increased amplitude occurred nonsignificantly when the prestimulus lasted for 2000 msec. On retest, 14 normal subjects showed a significant degree of reliability. When 20 normal subjects were compared to 12 schizophrenic subjects, significant differences in eyeblink response were found for blink amplitude and latency in the 60 msec prestimulus condition. This change is consistent with information processing “overload” theories of sensory overstimulation in schizophrenia. The blink reflex is a rather stable phenomenon and is probably altered in schizophrenia and/or by antipsychotic medication.
Mismatch negativity (MMN) is a cognitive, auditory event-related potential (AEP) that reflects preattentive detection of stimulus deviance and indexes the operation of the auditory sensory (‘echoic’) memory system. MMN is elicited most commonly in an auditory oddball paradigm in which a sequence of repetitive standard stimuli is interrupted infrequently and unexpectedly by a physically deviant ‘oddball’ stimulus. Electro- and magnetoencephalographic dipole mapping studies have localized the generators of MMN to supratemporal auditory cortex in the vicinity of Heschl's gyrus, but have not determined the degree to which MMN reflects activation within primary auditory cortex (AI) itself. The present study, using moveable multichannel electrodes inserted acutely into superior temporal plane, demonstrates a significant contribution of AI to scalp-recorded MMN in the monkey, as reflected by greater response of AI to loud or soft clicks presented as deviants than to the same stimuli presented as repetitive standards. The MMN-like activity was localized primarily to supragranular laminae within AI. Thus, standard and deviant stimuli elicited similar degrees of initial, thalamocortical excitation. In contrast, responses within supragranular cortex were significantly larger to deviant stimuli than to standards. No MMN-like activity was detected in a limited number to passes that penetrated anterior and medial to AI. AI plays a well established role in the decoding of the acoustic properties of individual stimuli. The present study demonstrates that primary auditory cortex also plays an important role in processing the relationships between stimuli, and thus participates in cognitive, as well as purely sensory, processing of auditory information.
Autistic spectrum disorders (ASD) comprise a continuum of psychosocial disorders clinically characterized by social difficulties, impaired communication skills and repetitive behavioral patterns. Despite the prevalence of ASD, the neurobiology of this disorder is poorly understood. However, abnormalities in neuronal morphology, cell number and connectivity have been described throughout the autistic brain. Further, there is ample evidence that auditory dysfunction is a common feature of autism. Our preliminary investigation of neuronal morphology in the auditory brainstem of individuals with ASD focused on the medial superior olive (MSO) and revealed that neurons in this region were significantly smaller and rounder than in controls. In this report, we expand our investigation to examine all nuclei within the human superior olivary complex (SOC), an important auditory brainstem center. We examine neuronal morphology and neuronal number in four control (average age=15 years) and 9 autistic brains (average age=15 years). This detailed investigation supports our previous descriptions of the MSO, and also reveals significant dysmorphology in five other SOC nuclei. Moreover, we provide evidence of a consistent and significant decrease in the number of SOC neurons in the autistic brain. Our studies implicate an extensive malformation of the auditory brainstem in the hearing and language difficulties in individuals with ASD. The results from this investigation suggest that neonatal testing of auditory function may aid in the identification of individuals with ASD earlier than presently possible.