Article
The Neural Substrates of Impaired Prosodic Detection in
Schizophrenia and its Sensorial Antecedents
David I. Leitman, Ph.D.
Matthew J. Hoptman, Ph.D.
John J. Foxe, Ph.D.
Erica Saccente, B.S.
Glenn R. Wylie, Ph.D.
Jay Nierenberg, M.D.
Maria Jalbrzikowski, B.A.
Kelvin O. Lim, M.D.
Daniel C. Javitt, M.D., Ph.D.
Objective: Individuals with schizophrenia show severe deficits in their ability to
decode emotions based upon vocal inflection (affective prosody). This study examined neural substrates of prosodic dysfunction in schizophrenia with voxelwisebased analysis of diffusion tensor magnetic resonance imaging (MRI).
Method: Affective prosodic performance
was assessed in 19 patients with schizophrenia and 19 comparison subjects with
the Voice Emotion Identification Task
(VOICEID), along with measures of basic
pitch perception and executive processing (Wisconsin Card Sorting Test). Diffusion tensor MRI fractional anisotropy
scores were used for voxelwise correlation
analyses. In a follow-up experiment, performance on a nonaffective prosodic perception task was assessed in an additional
cohort of 24 patients and 17 comparison
subjects.
Results: Patients showed significant deficits in VOICEID and Distorted Tunes Task
performance. Impaired VOICEID performance correlated significantly with lower
fractional anisotropy values within primary and secondary auditory pathways,
orbitofrontal cortex, corpus callosum,
and peri-amygdala white matter. Impaired Distorted Tunes Task performance
also correlated with lower fractional
anisotropy in auditory and amygdalar
pathways but not prefrontal cortex. Wisconsin Card Sorting Test performance in
schizophrenia correlated primarily with
prefrontal fractional anisotropy. In the follow-up study, significant deficits were observed as well in nonaffective prosodic
performance, along with significant intercorrelations among sensory, affective prosodic, and nonaffective measures.
Conclusions: Schizophrenia is associated with both structural and functional
disturbances at the level of primary auditory cortex. Such deficits contribute significantly to patients’ inability to decode
both emotional and semantic aspects of
speech, highlighting the importance of
sensorial abnormalities in social communicatory dysfunction in schizophrenia.
(Am J Psychiatry 2007; 164:1–9)
S
chizophrenia is associated with deficits in the ability
to decode emotion based upon modulation of intonation
(affective prosody) (1, 2). Such deficits, along with disturbances in facial affect recognition, contribute substantially
to impaired social and global outcome in schizophrenia (3,
4). Traditionally, such deficits have been attributed to generalized neurocognitive dysfunction, particularly involving
processes such as executive function and working memory
(5) as well as limbic dysfunction (6). More recently, however, specific contributions of auditory processing deficits
have been noted as well, with deficits in simple tone
matching correlating with deficits in prosodic identification (4). These findings predict both sensory-level and cognitive-level contributions to impaired prosodic processing.
This study investigates the neural substrates of impaired
auditory emotion detection with a combined behavioral
and structural imaging approach.
Neuroanatomical abnormalities in schizophrenia have
been extensively documented and shown to involve both
white and gray matter structures (e.g., references 7, 8). In
order to further evaluate the neural substrates of im-
Am J Psychiatry 164:3, March 2007
paired prosodic processing in schizophrenia, voxelwise
correlation analyses were performed relative to magnetic
resonance diffusion tensor imaging studies. Diffusion
tensor imaging is sensitive to white matter disturbances
in schizophrenia and has previously been used to evaluate structure-function correlations within frontal cortical
regions (7–9). To our knowledge, this is the first study to
evaluate structure-function relationships within audio
sensory brain regions in schizophrenia with diffusion tensor imaging.
Diffusion tensor imaging studies are classically analyzed with fractional anisotropy, a parameter that reflects
the relative diffusion of water parallel to the long axis of
structural boundaries, such as axonal membranes or myelin, relative to diffusion perpendicular to those boundaries
(9). Reduced fractional anisotropy in schizophrenia is
thought to reflect either axonal or myelin-related pathology (9), both of which have been documented in schizophrenia (10). Reduction in fractional anisotropy may also
reflect disorganization of fiber bundles (“disconnectivity”), although in areas of crossing fibers, such disconnecajp.psychiatryonline.org
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IMPAIRED PROSODIC DETECTION IN SCHIZOPHRENIA
tivity may lead to paradoxical increases in fractional
anisotropy (11).
Regardless of underlying etiology, fractional anisotropy
has proved effective for evaluating structure-function relationships. For example, increased impulsivity has been
found to correlate selectively with reduced fractional
anisotropy in inferior frontal white matter (12, 13),
whereas impairments in executive processing have been
found to correlate selectively with reduced fractional
anisotropy in anterior prefrontal regions (14, 15). Impairments in visual processing have been found to correlate
selectively with reduced fractional anisotropy in optic radiations (16).
In this study, we analyzed relationships between regional fractional anisotropy in schizophrenia patients and
healthy comparison subjects and performance on two separate tasks: the Distorted Tunes Task (17), which measures
the ability to detect incorrect notes within common melodies, and the Voice Emotion Identification Task (VOICEID)
(2), which measures the ability to decode emotions based
upon tone of voice. The Distorted Tunes Task was originally developed to assess genetic contributions to musical
pitch perception abilities and shows high heritability
within families (17). The VOICEID task has been used by
ourselves (4) and others (2, 3), and it is highly sensitive to
affective prosodic perception deficits in schizophrenia.
In the brain, auditory projection paths begin at the level
of the medial geniculate nucleus and project to the primary auditory cortex (Heschl’s gyrus, A1) through superolaterally projecting thalamocortical (acoustic) radiations.
From the auditory cortex, fibers project to higher brain regions along both ventral and dorsal divisions of the arcuate fasciculus (18). The ventral stream is primarily involved in acoustic feature analysis (19), whereas the dorsal
stream is thought to process spatial and spectral motion
(20), including speech (19).
Affective prosodic comprehension can be conceptualized as involving a “three-stage processing chain” that begins with sensation (stage 1) in the primary auditory cortex and continues with integration (stage 2) within ventral
aspects of the temporal cortex and the superior temporal
sulcus. There, aspects of the acoustical information are
tagged as affective. Processing proceeds finally to the cognitive stage (stage 3) in inferior frontal regions, where this
information is evaluated both semantically and contextually (reviewed in reference 21).
The present study used two specific tasks—the Distorted Tunes Task and the VOICEID—to evaluate functioning of sensation and integration phases of affective
prosodic comprehension. We have previously demonstrated that individuals with schizophrenia show deficits
in auditory sensory-level performance, as reflected in impaired tone-matching ability (22), as well as reduced auditory event-related potential generation (23). For this study,
we hypothesized that joint impairments in Distorted
2
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Tunes Task and VOICEID performance in patients would
correlate significantly with reduced fractional anisotropy
primarily in basic auditory brain regions (i.e., acoustic radiations) that subserve sensation and that VOICEID impairments would show additional correlations in ventral
and dorsal stream projection regions that subserve integration and cognitive evaluation.
As a control condition, we evaluated correlations between fractional anisotropy and performance levels on the
Wisconsin Card Sorting Test, a widely used, visually based
test of executive/prefrontal performance that would not be
expected to show correlations with auditory sensory regions. In a prior study, an increased perseverative error rate
on the Wisconsin Card Sorting Test was found to correlate
with reduced fractional anisotropy in specific regions of
the cingulum (14). Here, patterns of voxelwise correlations
to the Wisconsin Card Sorting Test were compared to patterns observed for the Distorted Tunes Task/VOICEID.
To characterize the further extent of prosodic processing dysfunction in schizophrenia, a follow-up study examined the integrity of nonaffective prosodic processing,
such as the ability to distinguish statements from questions (declarative versus interrogative prosody) or to distinguish between alternative meanings based upon which
syllables within a sentence are emphasized (stress prosody). We hypothesized that impairments in pitch perception, which were statistically associated with impaired affective prosodic performance (i.e., emotion recognition
deficits) in a prior study (4), might also be correlated with
impairments in the ability to make even nonaffective discriminations, such as the ability to differentiate statements and questions (i.e., declarative versus interrogative
intent) based upon tone of voice. Furthermore, such findings would provide convergent evidence for the contribution of sensorial abnormalities to social communicatory
disturbances in schizophrenia.
Methods
Experiment 1
Participants. Nineteen patients (one woman) meeting DSM-IV
criteria for either schizophrenia (N=17) or schizoaffective disorder (N=2) participated in this study. Diagnoses were based upon
the Structured Clinical Interview for DSM-IV (SCID) with all available clinical information used. Twelve patients were receiving
only second-generation antipsychotics (primarily risperidone or
olanzapine), two patients were receiving clozapine, two patients
were receiving only traditional antipsychotics (haloperidol), and
three patients were receiving combination treatment. The mean
chlorpromazine equivalency dose was 1298.3 mg/day (SD=
780.4). The mean illness duration was 15.7 years (SD=8.7). The
clinical ratings of patients followed the methods described previously (4). The patients had a mean rating of 35.5 (SD=7.1) on the
Brief Psychiatric Rating Scale and a mean rating of 32.5 (SD=12.8)
on the Schedule for the Assessment of Negative Symptoms.
The healthy comparison group consisted of 19 (six women) staff
volunteers or individuals who responded to local advertisements.
The comparison subjects had a mean age of 36 years (SD=9). The
healthy subjects and the patients differed significantly in mean IQ
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LEITMAN, HOPTMAN, FOXE, ET AL.
Behavioral Measures. Behavioral measures included the Voice
Emotion Identification Test (VOICEID) (2), which consists of 21
spoken sentences conveying one of six different emotions (happiness, anger, fear, sadness, surprise, or shame), the Distorted
Tunes Task (17), which consists of 26 popular tunes of which 17
are rendered melodically incorrect by changing the pitch of specific notes within the tune, and the Wisconsin Card Sorting Test
(24). For the VOICEID and the Distorted Tunes Task, the primary
dependent measure was percentage of stimuli identified correctly. For the Wisconsin Card Sorting Test, which was administered to patients only, the perseverative error rate was used as a
primary dependent measure. All behavioral tasks were presented
through a stereo player at a comfortable hearing level. For all subjects, behavioral task data were collected within 6 months of magnetic resonance imaging (MRI) acquisition.
MRI. Scanning was performed on a 1.5-T Siemens Vision system
(Erlangen, Germany) at the Nathan Kline Institute Center for Advanced Brain Imaging. Three main sequences were acquired: a
magnetization prepared rapidly acquired gradient echo scan
(TR/TE=11.4/4.9 msec, matrix=256×256, field of view=300 mm,
number of excitations=1, 1.17-mm slice thickness, 172 slices, no
gap), a turbo spin echo scan (TR=5000 msec, TE=22/90 msec, matrix=256×256, field of view=224 mm, number of excitations=1, 5mm slice thickness, 26 slices, no gap), and a diffusion tensor imaging sequence. The diffusion tensor imaging sequence has been
described elsewhere (25) ( TR/TE=6000/100 msec, matrix=
128×128 (interpolated to 256×256), field of view=240 mm, 5-mm
slice thickness, 20 slices, no gap) and employs a double echo
pulse to minimize eddy current effects (26). The sequence entailed four acquisitions of six diffusion-weighted images (b=1000
s/mm2) for 20 slices. In addition, two acquisitions without diffusion weighting (b=0 s/mm2) were acquired.
Fractional anisotropy was calculated with custom software.
The b=0 images were corrected for susceptibility-induced distortion and were transformed into Montreal Neurological Institute
space with methods described elsewhere (13, 27). Images were
matched to a template in Montreal Neurological Institute space,
and the final voxel size was 2×2×2 mm3. A white matter mask was
computed from the mean spatially normalized patient fractional
anisotropy image with a nonparametric image segmentation algorithm (28) and was applied to all of the standardized images.
This approach limited the voxels to white matter and resulted in
fewer statistical comparisons, thereby lowering the probability of
false positive tests.
After transformation into Talairarch space, the images were
masked such that only voxels with data present for all subjects
were included in the analyses. This ensured that missing data,
which would have zero values, would not drive correlations.
Statistical Analysis. Between-group comparisons of prosodic
(VOICEID) and pitch (Distorted Tunes Task) performance were
performed with repeated-measures analysis of variance. Spearman correlation coefficients were used to measure the relationship between task performances within groups.
For neuroimaging data, a voxelwise correlation approach was
used similar to that of Baudewig et al. (29), with thresholds as described previously (13, 15). This approach protects against false
Am J Psychiatry 164:3, March 2007
FIGURE 1. Behavioral Task Performance Between Comparison Subjects and Schizophrenia Patientsa
Comparison
subjects (N=19)
Schizophrenia
patients (N=19)
100
Mean (±SD) Pecent Correct
(112, SD=9, versus 95, SD=16; t=3.9, df=32, p<0.001) and grades
achieved (16 years, SD=2, versus 11, SD=3; t=6.05, df=36, p<0.001).
The local institutional review boards approved all experimental procedures, and all subjects provided written informed consent after study procedures were explained fully. The participants
received $10/hour for participation.
All subjects except one patient were right-handed, as assessed
by methods described previously (4). Within this group, 12 of 19
patients and seven of 19 healthy comparison subjects had been in
a prior study (4).
80
*
**
60
40
20
0
Distorted
Tunes Task
Voice Emotion
Identification
a
Effect sizes (d) for Distorted Tunes Task and VOICEID were SD=1.2
and SD=1.6, respectively. Dashed lines represent chance performance levels.
*p<0.01.**p<0.001.
positive correlations with voxels that are significant at p≤0.05 that
are grown from a seed voxel with a significance value of p<0.005.
To supplement these criteria, only clusters with more than 11
contiguous voxels were considered significant. To assess areas of
shared correlation across tasks, maps of each task-fractional
anisotropy correlation cluster were overlaid, and a new map representing overlap regions (identically thresholded for each task)
was generated.
Our voxelwise correlation analysis was two-tailed; nevertheless, we focused a priori only on correlations in which worse performance correlated with fractional anisotropy reductions.
Experiment 2
Participants. The participants consisted of 24 patients with
schizophrenia (three women) meeting DSM-IV criteria for either
schizophrenia (N=21) or schizoaffective disorder (N=3) and 17
healthy volunteers (three women). Healthy subjects and patients
were of similar age (mean=37.8 years, SD=10.2, versus mean=
32.5, SD=10.6) but differed in verbal IQ (mean=109.7, SD=10.4,
versus mean=94.1, SD=7.5; t=4.4, df=33, p>0.001) and education
(mean=16, SD=1, versus mean=11, SD=2; t=–7.5, df=35, p>0.001).
The patients were receiving typical and/or atypical antipsychotic
medication (chlorpromazine dose: mean=1373 mg/day, SD=829).
Behavioral Measures. In addition to the VOICEID (2), the Distorted Tunes Task (17), and the Wisconsin Card Sorting Test (24),
nonaffective prosody was assessed with Weintraub’s Sentence
Discrimination and Semantic Comprehension Tasks (30):
Twenty-five pairs of semantically neutral sentences, such as “Jack
climbed the mountain,” were repeated after a brief delay. Seventeen of the pairs differed because of either stress (where stressed
emphasis shifted between the subject and object of the sentence)
or declarative/interrogative differences. Eight pairs were identical. The subjects were asked whether the sentences were said in
the same or a different manner. The score reflected percent correct. Additionally, scores were broken down into percent correct
for stress and declarative/interrogative distinctions.
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IMPAIRED PROSODIC DETECTION IN SCHIZOPHRENIA
FIGURE 2. Fractional Anisotropy Map at the Level of the Medial Geniculate Nucleus and the Primary Auditory Cortex (Heschl’s Gyrus) (Top Left), Fiber Pathways at the Level of the Ventral Stream (top right), and Three-Dimensional Voxelwise Correlation Map for VOICEID Performance in Schizophrenia Patients (Bottom)a,b,c
Auditory Radiations at the Level
of the Medial Geniculate Nucleus
Auditory Radiations at the Level of A1
y
z
x
x=medial-lateral
y=superior-inferior
z=anterior-posterior
Fractional Anisotropy Level
Voxelwise Correlations Between Voice Emotion Identification and Fractional Anisotropy in Schizophrenia Patients
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
60
80
100
Voice Emotion Identification
(percent correct)
a A magnified view showing acoustic radiations that project superolaterally from the medial geniculate nucleus to Heschl’s gyrus (right).
b Magnified view showing medial lateral (red) radiations to Broca’s area branching off the superior arcuate fibers (green).
c Within-patient scatterplot and correlation values between fractional anisotropy levels from auditory radiations and VOICEID performance.
The Semantic Comprehension Task consisted solely of 16 utterances, expressing either declarative (eight utterances) or interrogative (eight utterances) intent. The subjects were asked
whether the speaker posed a question or a statement. The score
reflected percent correct.
Data Analysis. Between-groups effects across all auditory measures were assessed with multivariate analysis of variance, with
post hoc contrasts for specific measures (t tests). In the event of
ceiling or floor effects, Mann-Whitney nonparametric measures
were employed. Nonparametric signal detection analyses used A’
(31) and B” (32) as measures of sensitivity and bias, respectively.
Correlation matrices between nonaffective and affective prosody, as well as pitch perception, were calculated within the patient group only and submitted to principal components analysis.
Principal components analysis, factor selection, and rotation
were conducted on eigenvalues≥1 (see reference 4). All statistical
tests were two-tailed, with alpha≤0.05 and computed with JMP
software (SAS Institute, Cary, N.C.).
4
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Results
Experiment I
Behavioral Results. The patients showed significantly
impaired performance across both tests (F=56.6, df=1,
36, p<0.001) (Figure 1). The group-by-task interaction
was nonsignificant (F=2.5, df=1, 36, p<0.13). Distorted
Tunes Task and VOICEID scores were significantly correlated both across groups (rs=0.55, N=38, p<0.001) and
within the patient group alone (rs=0.54, N=19, p<0.02)
but were not significantly correlated for comparison subjects (rs=0.25, N=19, p<0.30). For patients, poorer Wisconsin Card Sorting Test performance (increased perseverative errors) correlated with poorer VOICEID (rs=–
0.55, N=17, p<0.02) but not Distorted Tunes Task (rs=–
0.23, N=17, p<0.34) performance. Additionally, among
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LEITMAN, HOPTMAN, FOXE, ET AL.
FIGURE 3. Voxelwise Correlation Maps in Schizophrenia Patients for Dorsal and Ventral Auditory Pathways for Voice Emotion Identification (A), Distorted Tunes Task (B), and Wisconsin Card Sorting Test (C) (D–F) and Voxelwise Correlation Maps
for Cingulate Fasciculus (G)a
Prefrontal/Cingulate
Auditory Pathways
Cingulate
middle
Voice Emotion
Identification
Corpus
callosum
A1
A
Medial geniculate nucleus
D
Orbitofrontal
cortex
Splenium
of corpus
callosum
Orbitofrontal
cortex
Distorted Tunes Task
B
E
C
F
Wisconsin Card
Sorting Test
Overlap Between Voice
Emotion Identification
and Distorted Tunes Task
Wisconsin Card
Sorting Test
Dorsal stream
Ventral stream
G
Anterior cingulate
Amygdala
a
Arrows indicate periamygdala correlations.
patients, medication dosage did not correlate with neuropsychological measures (all p>0.22).
Structural Correlations Within Patients. VOICEID. As
predicted, impaired VOICEID performance was significantly correlated with fractional anisotropy in regions lying between the auditory thalamus (medial geniculate nucleus) and the primar y auditor y cor tex (acoustic
radiations, Figure 2, top). These regions are known to contain auditory radiations from Montreal Neurological Institute space to A1 (Figure 2, bottom). In addition to these regions, significant correlation clusters were observed
bilaterally along the ventral and dorsal auditory pathway
in temporal and frontal white matter (Figure 3A). Other areas in which correlation clusters were observed include
Am J Psychiatry 164:3, March 2007
the corpus callosum splenium and body, as well as the
posterior commissure and the right cingulum (Figure 3D).
Clusters were also observed adjacent to both left and right
amygdala medial laterally (Figure 4, left). Additional areas
of significant correlation included white matter in Brodmann’s regions 44, 45, 46, and the orbitofrontal cortex
(Figure 3). R2 values for each region are shown in Table 1.
Distorted Tunes Task. Also as predicted, the pattern of
correlations of fractional anisotropy with the Distorted
Tunes Task closely resembled the pattern of correlation
with VOICEID (Figure 3B) (see Table 1). Regions of overlap
included primary auditory radiations, dorsal and ventral
stream auditory projections (Figure 3), and the amygdala
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IMPAIRED PROSODIC DETECTION IN SCHIZOPHRENIA
FIGURE 4. Principal Components Analysis on Correlations Between Pitch Perception and Nonaffective Prosody Performance in Schizophrenia Patientsa
100
Component 1
Component 2
Semantic
Comprehension
Task (0.59)
Semantic
Comprehension
Task (0.61)
0.48*
0.43*
Sentence
Discrimination
Task (0.82)
–0.41*
Wisconsin
Card Sorting
Test (0.95)
0.39
Semantic Comprehension Task
(percent correct)
Social Communication Disturbance
Distorted
Tunes Task
(0.77)
75
50
25
0
20
35
50
65
80
Voice Emotion Identification
(percent correct)
a
Schematic diagram of interrelationship between nonaffective prosody measures, pitch perception, and executive processing (left). Values inside circles represent factor rotation, while values outside circles represent Pearson correlation coefficients between indicated measures. The
Sentence Discrimination and Distorted Tunes Tasks rely exclusively on component 1 (sensory processing), the Wisconsin Card Sorting Test relies exclusively on component 2 (executive processing), and the Semantic Comprehension Task relies on both components. On the right, the
Semantic Comprehension Task by affective prosody (VOICEID).
*p<0.05.
TABLE 1. R2 Values for Pitch (Distorted Tunes Task) and Affective Prosody (Voice Emotion Identification Task) Performance and Fractional Anisotropy Levels Within Dorsal and
Ventral Auditory Streams and Anterior Cingulate Regions
of Interest
Region of Interest/R2
Right ventral stream
(x=36, y=–21, z=–7a)
Right dorsal stream
(x=44, y=–4, z=15a)
Left ventral stream
(x=36, y=–21, z=–7a)
Left dorsal stream
(x=–47, y=–11, z=19a)
Right anterior commissure
(x=–47, y=–11, z=19a)
Voice
Emotion
Identification
Task
0.55**
Distorted
Tunes
Task
0.34**
Wisconsin
Card
Sorting Test
0.07
0.45**
0.31*
0.04
0.38**
0.36**
0.03
0.37**
0.42**
0.16
0.01
0.01
0.43**
a
Talairarch coordinates of region of interest locations for betweengroups analysis.
*p≤0.01. **p≤0.005.
(Figure 4, left). However, no correlations were observed in
regions 44, 45, or 46 or in the orbitofrontal cortex.
Wisconsin Card Sorting Test. As opposed to the Distorted Tunes Task and the VOICEID, no significant correlations of fractional anisotropy with the Wisconsin Card
Sorting Test were observed in regions of the acoustic radiations or along either dorsal or ventral auditory radiations
(Figure 3C) (see Table 1). Moreover, there were no significant areas of overlap between Wisconsin Card Sorting Test
and VOICEID correlations (Figure 3A, Figure 3C). Significant correlation clusters were observed between the Wisconsin Card Sorting Test perseverative error scores and
6
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fractional anisotropy in white matter in the regions of the
right anterior cingulate gyrus (Figure 3F). Even in frontal
regions, however, little overlap was observed between correlation clusters for the VOICEID and the Wisconsin Card
Sorting Test. Finally, in contrast to the VOICEID and the
Distorted Tunes Task, no correlations in the vicinity of the
amygdala were observed (Figure 3G).
Experiment 2
The patients performed significantly worse than the
comparison subjects across all prosodic measures (Table
2) with no significant group-by-task interaction (p>0.50).
On the Sentence Discrimination Task, the patients showed
significant decrements in performance on interrogative/
declarative items as well as stress items (all p<0.01).
Within nonaffective prosody measures, the patients
were significantly less sensitive (A’) on both the Sentence
Discrimination Task (mean=0.86, SD=0.19, versus mean=
0.98, SD=0.32) and the Semantic Comprehension Task
(mean=0.83, SD=0.17, versus mean=0.98, SD=0.03) in detecting differing prosody or interrogative intent respectively (p<0.001). However, there were no significant differences in terms of bias (B”) in the Sentence Discrimination
Task (mean=0.54, SD=0.14, versus mean=0.68, SD=0.11)
(p>0.50) or in the Semantic Comprehension Task (mean=
0.37, SD=0.60, versus mean=0.72, SD=0.67) (p>0.08).
An examination of the interrelationship among prosody
measures, pitch perception, and executive processing using principal components analysis (Figure 4, left) yielded
only two criteria-meeting components, which when rotated revealed that the Distorted Tunes Task and the Sentence Discrimination Task loaded exclusively onto the first
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LEITMAN, HOPTMAN, FOXE, ET AL.
TABLE 2. Performance (% correct) on Indicated Tasks for 24 Schizophrenia Patients and 17 Healthy Comparison Subjects
Schizophrenia Patients
Measure 1a
Nonaffective prosody
Sentence Discrimination Task
Sentence Discrimination Task: stress subfactor
Semantic Comprehension Task (interrogative/declarative)
Affective prosody
Voice emotion identification (VOICE-ID)
Voice emotion discrimination (VOICEDIS)
Perceptual processing
Distorted Tunes Task
a Between-group multivariate analysis of variance
b Calculated after Cohen’s (1988) conventions.
Comparison Subjects
Mean
SD
Mean
SD
t (df=34)
Effect size
(d)b
79.8
79.1
79.2
20.6
26.5
16.3
98.1
99.5
96.3
2.5
2.0
5.9
–3.8†
–3.5†
–3.9†
1.4
1.1
1.4
41.3
70.0
14.7
13.8
64.1
84.9
13.5
5.3
–5.0**
–4.0**
1.6
1.4
88.7
17.1
69.7
19.0
3.1*
1.1
across measures (F=46.6, df=4, 31, p<0.0001.)
*p<0.05, between-group t test. **p<0.001, between-group t test. †p<0.001, Mann-Whitney U test.
component (0.77 and 0.82, respectively) and the Wisconsin Card Sorting Test onto the second (0.95). The Semantic
Comprehension Task, however, loaded significantly on
both components (component 1=0.59, component 2=
0.61). Correlations between affective prosody and their
nonaffective counterparts were highly significant (Semantic Comprehension Task by VOICEID [r=0.64, N=24,
p<0.001], Sentence Discrimination Task by VOICEDIS [rs=
0.61, N=21, p<0.004]) (Figure 4).
Finally, patient performance on nonaffective prosody
measures did not significantly correlate with illness duration or medication dosage (all p>0.20).
Discussion
Emotion recognition deficits are associated with poor
social and global functional outcome in schizophrenia (3,
4, 33), yet neural correlates have been investigated to only
a limited degree. This study used a combined behavioral
and voxelwise investigation to localize areas of potential
relevance to impaired auditory prosodic processing. Significant correlations were observed between prosodic
processing deficits and regions (e.g., prefrontal, periamygdalar) that are classically associated with neurocognitive dysfunction in schizophrenia (6). However, prominent deficits were also observed with reduced fractional
anisotropy in regions such as the primary auditory radiations and the dorsal and ventral auditory streams, suggesting that impairments in voice emotion recognition arise
from sensory-level disturbance in schizophrenia as well.
Thus, these findings support our prior observations of
processing deficits within, rather than across, sensory modalities (4) and suggest that functional and structural deficits within early sensory regions contribute to the overall
pattern of cognitive dysfunction in schizophrenia.
In this study, structure-function relationships were assessed with voxelwise diffusion tensor imaging analysis. In
contrast with volumetric approaches targeting gray matter
regions, diffusion tensor imaging provides a measure of
integrity of white matter tracts in the brain, which in turn
may serve as a measure of dysconnectivity or dysmyelination within specific brain pathways (7, 8). Fractional
Am J Psychiatry 164:3, March 2007
anisotropy reductions in schizophrenia have been observed across brain regions, consistent with underlying reductions in oligodendrocytic markers (10). Furthermore,
regionally specific correlations have already been observed for several well-validated measures (12, 13). Within
this study, for example, reduced Wisconsin Card Sorting
Test performance in schizophrenia correlated with reduced fractional anisotropy within the cingulate fasciculus, consistent with prior investigations in the field (14), as
well as functional brain imaging studies (34). In contrast,
no significant correlations were observed in auditory regions. Using the present approach, we have also previously demonstrated significant associations between verbal declarative memory, attention, and fractional
anisotropy in task-relevant regions attesting to the regional specificity of the current analysis approach (15).
The primary finding of this study was that reduced performance on the Distorted Tunes Task and the VOICEID
correlated independently with reduced fractional anisotropy in brain regions containing primary auditory radiations from the medial geniculate nucleus of the thalamus
to Heschl’s gyrus and subsequent dorsal and ventral
stream auditory projections. Additional areas of commonality included the genu and splenium of corpus callosum
and the middle cingulate gyrus, consistent with lesion and
neuroimaging studies implicating these regions in musical
pitch and affective prosodic processing (19, 35, 36). Correlation clusters lateral to the amygdala were also observed
in both tasks. As such, these findings indicate significant
contributions of low-level auditory processing deficits to
higher-order failures of neurocognition in schizophrenia.
In addition to areas of commonality, we also observed
differences in correlation patterns between the pitch and
prosodic tasks, particularly in the frontal cortex. Here, prosodic correlations extended more anteriorally to Brodmann’s areas 44, 45, and 46, which are implicated particularly in speech perception (19) (Figure 2, bottom). Other
areas involved in the affective evaluation of speech, such
as the prefrontal and orbitofrontal cortex (21), also
showed significant prosody-fractional anisotropy but not
pitch-fractional anisotropy correlations (Figures 2, bottom; Figure 3B). The somewhat greater severity of proajp.psychiatryonline.org
7
IMPAIRED PROSODIC DETECTION IN SCHIZOPHRENIA
sodic versus pitch identification deficits observed in our
patient group may reflect the greater extent of brain involvement engaged by the prosodic identification task.
The finding of sensory-level correlations in patients
with schizophrenia is consistent with well-replicated deficits in auditory processing that have been demonstrated
with both electrophysiological (e.g., reference 37) and behavioral (e.g., reference 22) approaches. Structural imaging studies of the auditory primary cortex are conflicting
with some (38)—but not all (39)—studies, finding reduced
volume of superior temporal auditory regions. However,
postmortem changes analogous to those observed in the
prefrontal cortex have been demonstrated in the auditory
cortex as well (40), supporting auditory cortical involvement in the pathophysiology of schizophrenia.
In our second experiment, large effect size deficits
(d>1.1) were observed in nonaffective prosodic perception
and were correlated with deficits in affective prosodic perception. Thus, for instance, the subjects had difficulty in
differentiating statements and questions based upon tone
of voice, just as they had difficulty in differentiating sad
from happy utterances. Both types of deficits are related to
impaired pitch-perception abilities, suggesting significant
audiosensory antecedents. These findings indicate that
dysprosodia, rather than being associated purely with
emotional perceptual disturbances in schizophrenia, affects broader aspects of cognitive and social communicatory functioning.
Presented in part at the 12th annual meeting of the Society for Cognitive Neuroscience, New York, May 5–8, 2005. Received April 3,
2006; revisions received July 12 and Sept. 5, 2006; accepted Sept. 28,
2006. From the Program in Cognitive Neuroscience and Schizophrenia and the Cognitive Neurophysiology Laboratory, Nathan S. Kline Institute for Psychiatric Research; the Program in Cognitive Neuroscience, the City College of the City University of New York, New York;
the Department of Psychiatry, New York University School of Medicine, New York; the Department of Psychiatry, University of Minnesota, Minneapolis, Minn.; and the Clinical Research Division, Nathan
Kline Institute, Orangeburg, N.Y. Address correspondence and reprint
requests to Dr. Javitt, Program in Cognitive Neuroscience in Schizophrenia, Nathan S. Kline Institute for Psychiatric Research, 140 Old
Orangeburg Rd., Orangeburg, NY 10962; javitt@nki.rfmh.org (e-mail).
All authors report no competing interests.
Supported in part by NIMH grants NRSA F1-MH-067339 (to Dr. Leitman), K02-MH-01439 and R01-MH-49334 (to Dr. Javitt), R01-MH64783 (to Dr. Hoptman), R01-MH-060662 (to Dr. Lim), and a Translational Research Scientist Award from the Burroughs Welcome Fund
(to Dr. Javitt).
The authors thank Dr. Denis Drayna for the use of his Distorted
Tunes Test and Drs. Kerr and Neale for the use of their Voice Emotion
Identification Task.
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