The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents.

Abstract

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 voxelwise analysis of diffusion tensor magnetic resonance imaging (MRI).
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 valves 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.
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.
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.

Full text

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Am J Psychiatry 164:3, March 2007
1
Article
ajp.psychiatryonline.org
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 schizophre-
nia show severe deficits in their ability to
decode emotions based upon vocal in-
flection (affective prosody). This study ex-
amined neural substrates of prosodic dys-
function in schizophrenia with voxelwise-
based analysis of diffusion tensor mag-
netic resonance imaging (MRI).
Method: Affective prosodic performance
was assessed in 19 patients with schizo-
phrenia and 19 comparison subjects with
the Voice Emotion Identification Task
(VOICEID), along with measures of basic
pitch perception and executive process-
ing (Wisconsin Card Sorting Test). Diffu-
sion tensor MRI fractional anisotropy
scores were used for voxelwise correlation
analyses. In a follow-up experiment, per-
formance on a nonaffective prosodic per-
ception task was assessed in an additional
cohort of 24 patients and 17 comparison
subjects.
Results: Patients showed significant defi-
cits in VOICEID and Distorted Tunes Task
performance. Impaired VOICEID perfor-
mance correlated significantly with lower
fractional anisotropy values within pri-
mary and secondary auditory pathways,
orbitofrontal cortex, corpus callosum,
and peri-amygdala white matter. Im-
paired Distorted Tunes Task performance
also correlated with lower fractional
anisotropy in auditory and amygdalar
pathways but not prefrontal cortex. Wis-
consin Card Sorting Test performance in
schizophrenia correlated primarily with
prefrontal fractional anisotropy. In the fol-
low-up study, significant deficits were ob-
served as well in nonaffective prosodic
performance, along with significant inter-
correlations among sensory, affective pro-
sodic, and nonaffective measures.
Conclusions: Schizophrenia is associ-
ated with both structural and functional
disturbances at the level of primary audi-
tory cortex. Such deficits contribute signif-
icantly to patients’ inability to decode
both emotional and semantic aspects of
speech, highlighting the importance of
sensorial abnormalities in social commu-
nicatory dysfunction in schizophrenia.
(Am J Psychiatry 2007; 164:1–9)
Schizophrenia is associated with deficits in the ability
to decode emotion based upon modulation of intonation
(affective prosody) (1, 2). Such deficits, along with distur-
bances in facial affect recognition, contribute substantially
to impaired social and global outcome in schizophrenia (3,
4). Traditionally, such deficits have been attributed to gen-
eralized neurocognitive dysfunction, particularly involving
processes such as executive function and working memory
(5) as well as limbic dysfunction (6). More recently, how-
ever, specific contributions of auditory processing deficits
have been noted as well, with deficits in simple tone
matching correlating with deficits in prosodic identifica-
tion (4). These findings predict both sensory-level and cog-
nitive-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-
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 evalu-
ate 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 ten-
sor imaging.
Diffusion tensor imaging studies are classically ana-
lyzed 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 mye-
lin, relative to diffusion perpendicular to those boundaries
(9). Reduced fractional anisotropy in schizophrenia is
thought to reflect either axonal or myelin-related pathol-
ogy (9), both of which have been documented in schizo-
phrenia (10). Reduction in fractional anisotropy may also
reflect disorganization of fiber bundles (“disconnectiv-
ity”), although in areas of crossing fibers, such disconnec-

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IMPAIRED PROSODIC DETECTION IN SCHIZOPHRENIA
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tivity may lead to paradoxical increases in fractional
anisotropy (11).
Regardless of underlying etiology, fractional anisotropy
has proved effective for evaluating structure-function re-
lationships. 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). Impair-
ments in visual processing have been found to correlate
selectively with reduced fractional anisotropy in optic ra-
diations (16).
In this study, we analyzed relationships between re-
gional fractional anisotropy in schizophrenia patients and
healthy comparison subjects and performance on two sep-
arate tasks: the Distorted Tunes Task (17), which measures
the ability to detect incorrect notes within common melo-
dies, 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 origi-
nally 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 pri-
mary auditory cortex (Heschl’s gyrus, A1) through supero-
laterally projecting thalamocortical (acoustic) radiations.
From the auditory cortex, fibers project to higher brain re-
gions along both ventral and dorsal divisions of the arcu-
ate fasciculus (18). The ventral stream is primarily in-
volved 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 conceptual-
ized as involving a “three-stage processing chain” that be-
gins with sensation (stage 1) in the primary auditory cor-
tex 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 cog-
nitive stage (stage 3) in inferior frontal regions, where this
information is evaluated both semantically and contextu-
ally (reviewed in reference 21).
The present study used two specific tasks—the Dis-
torted Tunes Task and the VOICEID—to evaluate func-
tioning of sensation and integration phases of affective
prosodic comprehension. We have previously demon-
strated that individuals with schizophrenia show deficits
in auditory sensory-level performance, as reflected in im-
paired tone-matching ability (22), as well as reduced audi-
tory event-related potential generation (23). For this study,
we hypothesized that joint impairments in Distorted
Tunes Task and VOICEID performance in patients would
correlate significantly with reduced fractional anisotropy
primarily in basic auditory brain regions (i.e., acoustic ra-
diations) that subserve sensation and that VOICEID im-
pairments would show additional correlations in ventral
and dorsal stream projection regions that subserve inte-
gration and cognitive evaluation.
As a control condition, we evaluated correlations be-
tween 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 re-
gions. 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 pat-
terns observed for the Distorted Tunes Task/VOICEID.
To characterize the further extent of prosodic process-
ing dysfunction in schizophrenia, a follow-up study exam-
ined the integrity of nonaffective prosodic processing,
such as the ability to distinguish statements from ques-
tions (declarative versus interrogative prosody) or to dis-
tinguish between alternative meanings based upon which
syllables within a sentence are emphasized (stress pros-
ody). We hypothesized that impairments in pitch percep-
tion, which were statistically associated with impaired af-
fective 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 dis-
criminations, such as the ability to differentiate state-
ments and questions (i.e., declarative versus interrogative
intent) based upon tone of voice. Furthermore, such find-
ings would provide convergent evidence for the contribu-
tion 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 disor-
der (N=2) participated in this study. Diagnoses were based upon
the Structured Clinical Interview for DSM-IV (SCID) with all avail-
able 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 previ-
ously (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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(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 experimen-
tal procedures, and all subjects provided written informed con-
sent 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).
Behavioral Measures. Behavioral measures included the Voice
Emotion Identification Test (VOICEID) (2), which consists of 21
spoken sentences conveying one of six different emotions (happi-
ness, 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 spe-
cific 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 cor-
rectly. For the Wisconsin Card Sorting Test, which was adminis-
tered 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 sub-
jects, behavioral task data were collected within 6 months of mag-
netic 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 Ad-
vanced 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, ma-
trix=256×256, field of view=224 mm, number of excitations=1, 5-
mm slice thickness, 26 slices, no gap), and a diffusion tensor im-
aging 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 en-
tailed four acquisitions of six diffusion-weighted images (b=1000
s/mm2) for 20 slices. In addition, two acquisitions without diffu-
sion weighting (b=0 s/mm2) were acquired.
Fractional anisotropy was calculated with custom software.
The b=0 images were corrected for susceptibility-induced distor-
tion 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 al-
gorithm (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. Spear-
man correlation coefficients were used to measure the relation-
ship 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 de-
scribed previously (13, 15). This approach protects against false
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 rep-
resenting overlap regions (identically thresholded for each task)
was generated.
Our voxelwise correlation analysis was two-tailed; neverthe-
less, we focused a priori only on correlations in which worse per-
formance 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 Dis-
torted 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. Seven-
teen 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 identi-
cal. The subjects were asked whether the sentences were said in
the same or a different manner. The score reflected percent cor-
rect. Additionally, scores were broken down into percent correct
for stress and declarative/interrogative distinctions.
FIGURE 1. Behavioral Task Performance Between Compar-
ison Subjects and Schizophrenia Patientsa
aEffect sizes (d) for Distorted Tunes Task and VOICEID were SD=1.2
and SD=1.6, respectively. Dashed lines represent chance perfor-
mance levels.
*p<0.01.**p<0.001.
Mean (±SD) Pecent Correct
Distorted
Tunes Task
Voice Emotion
Identification
0
20
40
60
80
100
Comparison
subjects (N=19)
Schizophrenia
patients (N=19)
*
**

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The Semantic Comprehension Task consisted solely of 16 ut-
terances, expressing either declarative (eight utterances) or inter-
rogative (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 mea-
sures 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 pros-
ody, as well as pitch perception, were calculated within the pa-
tient 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.).
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 corre-
lated 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 sub-
jects (rs=0.25, N=19, p<0.30). For patients, poorer Wis-
consin Card Sorting Test performance (increased perse-
verative 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
FIGURE 2. Fractional Anisotropy Map at the Level of the Medial Geniculate Nucleus and the Primary Auditory Cortex (He-
schl’s Gyrus) (Top Left), Fiber Pathways at the Level of the Ventral Stream (top right), and Three-Dimensional Voxelwise Cor-
relation Map for VOICEID Performance in Schizophrenia Patients (Bottom)a,b,c
aA magnified view showing acoustic radiations that project superolaterally from the medial geniculate nucleus to Heschl’s gyrus (right).
bMagnified view showing medial lateral (red) radiations to Broca’s area branching off the superior arcuate fibers (green).
cWithin-patient scatterplot and correlation values between fractional anisotropy levels from auditory radiations and VOICEID performance.
x
z
x=medial-lateral
y=superior-inferior
z=anterior-posterior
y
Auditory Radiations at the Level of A1
Auditory Radiations at the Level
of the Medial Geniculate Nucleus
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
Fractional Anisotropy Level
Voice Emotion Identification
(percent correct)
0.0
0
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patients, medication dosage did not correlate with neu-
ropsychological measures (all p>0.22).
Structural Correlations Within Patients. VOICEID. As
predicted, impaired VOICEID performance was signifi-
cantly correlated with fractional anisotropy in regions ly-
ing between the auditory thalamus (medial geniculate nu-
cleus) and the primary auditory cortex (acoustic
radiations, Figure 2, top). These regions are known to con-
tain auditory radiations from Montreal Neurological Insti-
tute space to A1 (Figure 2, bottom). In addition to these re-
gions, significant correlation clusters were observed
bilaterally along the ventral and dorsal auditory pathway
in temporal and frontal white matter (Figure 3A). Other ar-
eas in which correlation clusters were observed include
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 Brod-
mann’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
FIGURE 3. Voxelwise Correlation Maps in Schizophrenia Patients for Dorsal and Ventral Auditory Pathways for Voice Emo-
tion Identification (A), Distorted Tunes Task (B), and Wisconsin Card Sorting Test (C) (D–F) and Voxelwise Correlation Maps
for Cingulate Fasciculus (G)a
aArrows indicate periamygdala correlations.
Dorsal stream
Ventral stream
Anterior cingulate
Auditory Pathways
A
B
C
D
E
F
G
Voice Emotion
Identification
Overlap Between Voice
Emotion Identification
and Distorted Tunes Task
Distorted Tunes Task
Wisconsin Card
Sorting Test
Wisconsin Card
Sorting Test
Prefrontal/Cingulate
Amygdala
Orbitofrontal
cortex
Corpus
callosum
Cingulate
middle
Orbitofrontal
cortex
Medial geniculate nucleus
A1
Splenium
of corpus
callosum

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(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 Dis-
torted Tunes Task and the VOICEID, no significant correla-
tions of fractional anisotropy with the Wisconsin Card
Sorting Test were observed in regions of the acoustic radi-
ations or along either dorsal or ventral auditory radiations
(Figure 3C) (see Table 1). Moreover, there were no signifi-
cant areas of overlap between Wisconsin Card Sorting Test
and VOICEID correlations (Figure 3A, Figure 3C). Signifi-
cant correlation clusters were observed between the Wis-
consin Card Sorting Test perseverative error scores and
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 cor-
relation 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 de-
tecting differing prosody or interrogative intent respec-
tively (p<0.001). However, there were no significant differ-
ences 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 us-
ing principal components analysis (Figure 4, left) yielded
only two criteria-meeting components, which when ro-
tated revealed that the Distorted Tunes Task and the Sen-
tence Discrimination Task loaded exclusively onto the first
FIGURE 4. Principal Components Analysis on Correlations Between Pitch Perception and Nonaffective Prosody Perfor-
mance in Schizophrenia Patientsa
aSchematic diagram of interrelationship between nonaffective prosody measures, pitch perception, and executive processing (left). Values in-
side 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 re-
lies 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.
Social Communication Disturbance
100
Semantic Comprehension Task
(percent correct)
Voice Emotion Identification
(percent correct)
0
25
50
75
2035 506580
Component 1Component 2
Semantic
Comprehension
Task (0.59)
Sentence
Discrimination
Task (0.82)
Distorted
Tunes Task
(0.77)
Semantic
Comprehension
Task (0.61)
Wisconsin
Card Sorting
Test (0.95)
–0.41*0.43*
0.48*
0.39
TABLE 1. R2 Values for Pitch (Distorted Tunes Task) and Af-
fective Prosody (Voice Emotion Identification Task) Perfor-
mance and Fractional Anisotropy Levels Within Dorsal and
Ventral Auditory Streams and Anterior Cingulate Regions
of Interest
Voice
Emotion
Identification
Task
Right ventral stream0.55**
(x=36, y=–21, z=–7a)
Right dorsal stream0.45**
(x=44, y=–4, z=15a)
Left ventral stream0.38**
(x=36, y=–21, z=–7a)
Left dorsal stream0.37**
(x=–47, y=–11, z=19a)
Right anterior commissure0.01
(x=–47, y=–11, z=19a)
aTalairarch coordinates of region of interest locations for between-
groups analysis.
*p≤0.01. **p≤0.005.
Region of Interest/R2
Distorted
Tunes
Task
0.34**
Wisconsin
Card
Sorting Test
0.07
0.31*0.04
0.36**0.03
0.42**0.16
0.010.43**

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component (0.77 and 0.82, respectively) and the Wiscon-
sin 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 (Seman-
tic 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 dura-
tion 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. Sig-
nificant correlations were observed between prosodic
processing deficits and regions (e.g., prefrontal, peri-
amygdalar) that are classically associated with neurocog-
nitive dysfunction in schizophrenia (6). However, promi-
nent deficits were also observed with reduced fractional
anisotropy in regions such as the primary auditory radia-
tions and the dorsal and ventral auditory streams, suggest-
ing 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 mo-
dalities (4) and suggest that functional and structural defi-
cits within early sensory regions contribute to the overall
pattern of cognitive dysfunction in schizophrenia.
In this study, structure-function relationships were as-
sessed 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 dysmyelina-
tion within specific brain pathways (7, 8). Fractional
anisotropy reductions in schizophrenia have been ob-
served across brain regions, consistent with underlying re-
ductions in oligodendrocytic markers (10). Furthermore,
regionally specific correlations have already been ob-
served for several well-validated measures (12, 13). Within
this study, for example, reduced Wisconsin Card Sorting
Test performance in schizophrenia correlated with re-
duced fractional anisotropy within the cingulate fascicu-
lus, 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 re-
gions. Using the present approach, we have also previ-
ously demonstrated significant associations between ver-
bal declarative memory, attention, and fractional
anisotropy in task-relevant regions attesting to the re-
gional specificity of the current analysis approach (15).
The primary finding of this study was that reduced per-
formance on the Distorted Tunes Task and the VOICEID
correlated independently with reduced fractional anisot-
ropy in brain regions containing primary auditory radia-
tions from the medial geniculate nucleus of the thalamus
to Heschl’s gyrus and subsequent dorsal and ventral
stream auditory projections. Additional areas of common-
ality 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). Corre-
lation 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, pro-
sodic correlations extended more anteriorally to Brod-
mann’s areas 44, 45, and 46, which are implicated particu-
larly 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, bot-
tom; Figure 3B). The somewhat greater severity of pro-
TABLE 2. Performance (% correct) on Indicated Tasks for 24 Schizophrenia Patients and 17 Healthy Comparison Subjects
Schizophrenia Patients
Mean
Nonaffective prosody
Sentence Discrimination Task79.8
Sentence Discrimination Task: stress subfactor79.1
Semantic Comprehension Task (interrogative/declarative)79.2
Affective prosody
Voice emotion identification (VOICE-ID)41.3
Voice emotion discrimination (VOICEDIS)70.0
Perceptual processing
Distorted Tunes Task88.7
aBetween-group multivariate analysis of variance across measures (F=46.6, df=4, 31, p<0.0001.)
bCalculated after Cohen’s (1988) conventions.
*p<0.05, between-group t test. **p<0.001, between-group t test. †p<0.001, Mann-Whitney U test.
Measure 1a
Comparison Subjects
Mean
t (df=34)
Effect size
(d)b
SDSD
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
14.7
13.8
64.1
84.9
13.5
5.3
–5.0**
–4.0**
1.6
1.4
17.169.719.03.1*1.1

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IMPAIRED PROSODIC DETECTION IN SCHIZOPHRENIA
ajp.psychiatryonline.org
sodic versus pitch identification deficits observed in our
patient group may reflect the greater extent of brain in-
volvement engaged by the prosodic identification task.
The finding of sensory-level correlations in patients
with schizophrenia is consistent with well-replicated defi-
cits in auditory processing that have been demonstrated
with both electrophysiological (e.g., reference 37) and be-
havioral (e.g., reference 22) approaches. Structural imag-
ing 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 involve-
ment 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 per-
ception. 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, af-
fects broader aspects of cognitive and social communica-
tory functioning.
Presented in part at the 12th annual meeting of the Society for Cog-
nitive 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 Schizophre-
nia and the Cognitive Neurophysiology Laboratory, Nathan S. Kline In-
stitute for Psychiatric Research; the Program in Cognitive Neuro-
science, the City College of the City University of New York, New York;
the Department of Psychiatry, New York University School of Medi-
cine, New York; the Department of Psychiatry, University of Minne-
sota, 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 Schizo-
phrenia, 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. Leit-
man), K02-MH-01439 and R01-MH-49334 (to Dr. Javitt), R01-MH-
64783 (to Dr. Hoptman), R01-MH-060662 (to Dr. Lim), and a Transla-
tional 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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