Lateral asymmetry and reduced forward masking effect in early brainstem auditory
evoked responses in schizophrenia
, Sara Fristedt Nehlstedt
, Mia Ling Sköld
, Sören Nielzén
SensoDetect AB, Lund, Sweden
Department of Clinical Neuroscience, Section of Psychiatry, Lund, Sweden
Received 25 March 2011
Accepted 30 August 2011
Auditory brainstem response
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.
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: email@example.com (S. Nielzén).
0165-1781/$ –see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
Contents lists available at SciVerse ScienceDirect
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.
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
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
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
) 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
) or a masker of 64, 70 or 76 dB (FM
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
where the k-values kfor the four masking conditions 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.
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).
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
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
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