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Selective Deficits in Prefrontal Cortex Function in Medication-Naive Patients With Schizophrenia
Deanna M. Barch, PhD;
Cameron S. Carter, MD;
Todd S. Braver, PhD;
Fred W. Sabb, BA;
Angus MacDonald III, MA;
Douglas C. Noll, PhD;
Jonathan D. Cohen, MD, PhD
Arch Gen Psychiatry. 2001;58:280-288.
ABSTRACT
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Background Previously we proposed that dorsolateral prefrontal cortex (PFC) supports
a specific working memory (WM) subcomponent: the ability to represent and
maintain context information necessary to guide appropriate task behavior.
By context, we mean prior task-relevant information represented in such a
form that it supports selection of the appropriate behavioral response. Furthermore,
we hypothesized that WM deficits in schizophrenia reflect impaired context
processing due to a disturbance in dorsolateral PFC. We use functional magnetic
resonance imaging to examine PFC activation in medication-naive, first-episode
patients with schizophrenia during a WM, task-isolating context processing.
Methods Fourteen first-episode, medication-naive patients with schizophrenia
and 12 controls similar in age, sex, and parental education underwent functional
magnetic resonance imaging during performance of an A-X version of the Continuous
Performance Test.
Results Patients with schizophrenia demonstrated deficits in dorsolateral PFC
activation in task conditions requiring context processing but showed intact
activation of posterior and inferior PFC. In addition, patients demonstrated
intact activation of the primary motor and somatosensory cortex in response
to stimulus processing demands.
Conclusions These results demonstrate selectivity in dorsolateral PFC dysfunction
among medication-naive first-episode patients with schizophrenia, suggesting
that a specific deficit in PFC function is present at illness onset, prior
to the administration of medication or the most confounding effects of illness
duration. Furthermore, these results are consistent with the hypothesis that
WM deficits in patients with schizophrenia reflect an impairment in context
processing due to a disturbance in dorsolateral PFC function.
INTRODUCTION
DISTURBANCES in prefrontal cortex (PFC) functioning have long been implicated
in schizophrenia and have been linked to working memory (WM) deficits.1 Working memory is typically defined as the ability
to temporarily maintain and manipulate information on-line.2
Several lines of research support a link between PFC and WM dysfunction in
schizophrenia3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19
(for contrasting evidence, see the articles by Manoach et al17
and Fletcher et al20). However, many studies
have examined large areas of PFC, combining subregions that may be functionally
distinct.9, 13, 15, 16
Thus, it is not clear whether all or only certain subregions of PFC show disturbed
patterns of cognition-related activation in schizophrenia. Additionally, most
functional imaging studies have chosen tasks based on their sensitivity to
frontal lobe dysfunction (eg, Wisconsin Card Sorting Test)16, 19
or used tasks that tap multiple components of WM,9, 14, 15
making it difficult to determine which specific processes are disturbed in
schizophrenia.
Considerable controversy exists about what functions specific regions
of PFC carry out in support of WM. Several researchers have argued that ventral
regions (ie, Brodmann area [BA] 44, BA 45, and BA 47) subserve pure maintenance
functions, whereas dorsolateral (DL) PFC (ie, DLPFC; BA 46, BA 9) is involved
in manipulating the contents of WM.21, 22, 23
In contrast, Goldman-Rakic24 has argued that
DLPFC supports the maintenance of information. Our hypothesis regarding DLPFC
function combines elements of both views. Specifically, we have proposed that
DLPFC supports a subcomponent of WM: the ability to represent and maintain
context information necessary to guide appropriate task behavior.25, 26 By context, we mean prior task-relevant
information represented in a form that supports selection of the appropriate
response. Context representations can include instructions, specific prior
stimuli, or the result of processing a sequence of prior stimuli (eg, a sentence).
Thus, we believe that DLPFC plays a role in manipulation by recoding information
into context representations. However, we believe that context representations
are also actively maintained in DLPFC, a hypothesis supported by prior imaging
work.27 We have also hypothesized that WM deficits
in schizophrenia reflect impaired context processing due to disturbed DLPFC
function.26 In behavioral studies, we have
observed a highly selective pattern of schizophrenic deficits in task conditions
sensitive to context processing.28, 29, 30
However, we have not yet determined whether context processing deficits in
schizophrenia are associated with a selective disturbance in DLPFC function.
The current study, using functional magnetic resonance imaging (fMRI),
examined PFC activation in medication-naive first-episode patients with schizophrenia
during a WM task-isolating context processing: a version of the A-X Continuous
Performance Test (AX-CPT).25, 27, 29, 30
In the AX-CPT, subjects are presented with a sequence of letters and instructed
to respond to a prespecified probe (X) only if it follows a particular contextual
cue (A). Target (A-X) trials occur frequently (70%), producing (1) a prepotent
tendency to make a target response to an X, and (2) an expectancy to make
a target response following an A. Thus, context processing can be selectively
probed in 2 types of nontarget trials, B-X and A-Y (B and Y refer to the letters
used other than A and X). In B-X trials, context is required to inhibit the
prepotent tendency to make a target response to the X. In A-Y trials, the
context creates an expectancy that an X will occur next, leading to a tendency
to false alarm to the probe. Thus, the same failure to represent and maintain
context should manifest as an increase in B-X false alarms but no change,
or even a decrease, in A-Y false alarms. The B-Y trials serve as a control
since performance is unaffected by context processing. We manipulated contextual
memory demands by varying the delay between the cue and probe (Figure 1).25, 27, 29, 30
Our task design allowed us to provide internal activation standards among
patients,15 which are needed to establish the
validity of fMRI findings in schizophrenia. Specifically, we used event-related
methods to track the dynamics of activation during each trial (Figure 1) and identify sensory and motor regions that exhibited
transient activation associated with stimulus presentation and/or response
execution.
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Figure 1. Experimental design. This diagram
shows a timeline of the events occurring in each trial in the short and long
delay blocks and the timing of scan acquisitions. ITI indicates intertrial
interval.
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Based on prior work,25, 29, 30
we first predicted that patients would show behavioral evidence of selective
cognitive deficits involving the active maintenance of context. Second, we
predicted that cognitive deficits in patients would manifest in the neuroimaging
data as a failure to show increased activity in DLPFC during the long delay.27 In contrast, we predicted that patients would show
intact delay-related activation of posterior and inferior PFC (ie, BA 44,
BA 45). This latter hypothesis was based on findings suggesting that patients
with schizophrenia are not impaired while performing short-term memory tasks
that primarily require verbal rehearsal of items,29, 31
a process commonly associated with the function of BA 44 and BA 45.32 Lastly, we predicted that patients would show normal
activation in motor and somatosensory regions associated with response demands,
providing evidence of intact basic somatosensory and motor processing.
PATIENTS AND METHODS
PARTICIPANTS
Participants were 12 healthy controls and 14 medication-naive first-episode
patients with schizophrenia. Controls were recruited through advertisements
and evaluated using the nonpatient version of the Structured Clinical Interview
for DSM-III-R.33 All
patients were neuroleptic naive and recruited if they were experiencing any
type of psychotic symptom (ie, hallucination, delusion, thought disorder)
and it was their first psychiatric hospitalization or contact with outpatient
psychiatric services. Patients were scanned as soon as possible after initial
contact, typically within 1 to 2 days. Patients were followed longitudinally
and confirmed to have a diagnosis of schizophrenia 6 months after their participation
in this study. Diagnoses were confirmed by diagnostic conference, including
information from the Structured Clinical Interview for DSM-III-R,33 administered by trained
research personnel, and thorough medical record review. In addition, the Brief
Psychiatric Rating Scale,34 the Global Assessment
Scale, and the Scales for the Assessment of Positive and Negative Symptoms
were used to evaluate symptom severity (Table 1). Ratings were completed by trained research team personnel,
blind to task performance, who regularly participated in evaluation sessions
to insure reliability. All ratings were made within 1 week of testing.
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Table 1. Clinical and Demographic Characteristics*
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Participants were excluded for (1) age (older than 50 years or younger
than 14 years); (2) Wechsler Adult Intelligence Scale–Revised full scale
IQ lower than 70; (3) non-English native language; (4) lifetime diagnosis
of substance dependence or substance abuse within 1 month of testing; (5)
neurologic disorders or family history of hereditary neurologic disorder;
or (6) pregnancy. Potential controls were excluded if they had (1) lifetime
history of axis I disorder or first order family history of a psychotic disorder
or (2) treatment with any psychotropic medication within 6 months of testing.
Controls were similar to patients regarding age, sex, race, and father's education
(as a proxy for socioeconomic status). t Tests indicated
that controls did not differ from patients with schizophrenia on any of these
variables (Table 1). All participants
were right-handed and signed informed consent forms in accordance with the
University of Pittsburgh, Pittsburgh, Pa, institutional review board.
COGNITIVE TASK
Single letters were presented centrally on a visual display. Trials
lasted 10 seconds and included a cue, a delay period, a probe, and an intertrial
interval (ITI). Cue and probe durations were 0.5 seconds. In long delay trials,
the cue-probe interval was 8 seconds, and the ITI was 1 second. In short delay
trials this was reversed, with a 1-second cue-probe interval and an 8-second
ITI to control general factors (eg, pace of the task). Subjects responded
to every stimulus with their dominant hand, pressing one button for targets
and an adjacent button for nontargets. Eleven patients and 8 controls performed
the task continuously for blocks made up of 10 trials. The remaining 3 patients
and 4 controls performed the task continuously for blocks of 12 trials. Between
each block there was a brief delay, allowing the subject to rest, and the
hemodynamic response to recover. Six blocks were run for each of the 2 delay
conditions, pseudorandomly ordered to control for the confounding effects
of time on task, head movement, and scanner drift.
IMAGE ACQUISITION
Scanning took place using a whole-body scanner (1.5T GE Signa; General
Electric Medical Systems, Milwaukee, Wis) and standard head coil in the University
of Pittsburgh Medical School, Pittsburgh, Pa, MR Research Center. Sixteen
slices (3.75 mm3 voxels) were acquired parallel to the anterior
commissure-posterior commissure (AC-PC) line. Functional scans were acquired
using a spiral-scan pulse sequence.35 In 11
patients and 8 controls, we used a 2-shot spiral sequence (TR [time to repetition],
1250 milliseconds; TE [time to echo], 35 milliseconds; flip, 40°; field
of view, 24 cm), with scanning synchronized with stimulus presentation so
that a set of 16 slices was acquired 4 times during each 10-second trial (Figure 1). In the other 3 patients and 4
controls, we used a 4-shot spiral sequence (TR, 640 milliseconds; TE, 35 milliseconds;
flip, 40°; field of view, 24 cm); which allowed 8 slices to be acquired
every 2.5 seconds. Scanning was again synchronized with stimulus presentation
so that 4 scans of 8 slice locations were acquired during each 10-second trial
(Figure 1). A first set of 8 locations
was scanned for 3 trials, followed by 2 additional sets of 8 different locations,
each scanned for 3 trials. Slice acquisition order was counterbalanced across
subjects and blocks. Individual subject analyses did not indicate differences
between results with the 2- and 4-shot sequences, so data from these 2 sequences
were combined in the analyses presented in the "Imaging Data" section. T1-weighted
structural scans were performed in the same planes as the functional scans
for anatomic localization and coregistration of images across subjects.
IMAGE ANALYSIS
Images were movement corrected using a 6-parameter rigid body translation,
coregistered to a common reference brain using a 12-parameter algorithm36 and smoothed using a 3-dimensional Gaussian filter
(8-mm full with half maximum) to accommodate between-subject differences in
anatomy.
DATA ANALYSIS
Reaction time (RT) and accuracy (normalized using an arcsine transformation37) for behavioral data acquired during scanning were
analyzed using analyses of variance (ANOVAs) with group as a between-subject
factor and trial type and delay as within-subject factors. We also examined
a more specific measure of sensitivity to context, referred to as d'-context, which computes d'38
from A-X hits and B-X false alarms. Since d'-context compares responses
to X in the presence of contextual cues indicating a target response (A-X)
with a nontarget response (B-X), it provides a more focused measure of sensitivity
to context.
For the fMRI data, we conducted group analyses using voxel-wise ANOVAs
with subject as a random factor, group as a between-subject factor (control
vs patients), and both scan (scans 1-4 within each trial) and delay (short
vs long) as within-subject factors. In theory, one could examine all possible
main effects and interactions in this design. However, our a priori hypotheses
focused on regions demonstrating 1 of the following 4 patterns. (1) The first
pattern was a main effect of delay, designed to identify regions responding
to the context memory manipulation, by identifying voxels demonstrating greater
activity in the long- than short-delay condition. If a region demonstrated
a main effect of delay, planned contrasts were conducted to confirm that this
effect was significant for both controls and patients. (2) The second pattern
was a group x delay interaction. If a region demonstrated such an interaction,
planned contrasts were conducted to confirm that the interaction reflected
a significant delay effect in at least 1 of the groups. (3) The third pattern
was a main effect of scan. This effect was designed to identify regions showing
significant responses to motor and sensory processes, which should be transient
events with a specific hemodynamic response shape. Thus, we only examined
regions showing a main effect of scan, the activity of which also demonstrated
an event-related time course that reflected greater signal during scans 2
and 3 than scans 1 and 4 (taking into account the well-characterized lag in
hemodynamic response that results in peak activation occurring approximately
5 seconds after stimulus onset39, 40).
To identify such time courses, we conducted planned contrasts on voxels showing
a main effect of scan using inverse quadratic contrast weights (-1,
1, 1, -1). The signal values for each of 4 scans are multiplied by their
corresponding contrast weights and then summed for each subject. If activity
during scans 2 and 3 is significantly greater than activity during scans 1
and 4, then the summed value is significantly greater than 0 (tested using
a t test against 0).41
As with the main effect of delay, additional planned contrasts were then conducted
on any such region to confirm that the inverse quadratic effects of a scan
were significant in both patients and controls. (4) The fourth pattern was
a group x scan interaction, with planned contrasts conducted to confirm
that the interaction reflected a significant scan effect in at least 1 of
the groups. Voxel-wise statistical maps were generated for each pattern and
then thresholded for significance using a cluster-size algorithm42
that protects against an inflation of the false-positive rate with multiple
comparisons. A cluster-size threshold of 8 voxels and a per-voxel 
of .01 was chosen, corresponding to a corrected image-wise false-positive
rate of 0.01. Regions showing such effects were overlaid onto the reference
structural image and transformed to standard stereotactic space using computer
software (Analysis of Functional NeuroImages; R.W. Cox, Medical College of
Wisconsin, Milwaukee).43 We also conducted
individual subject analyses (using ANOVAs treating trial as a random factor)
to locate regions showing a main effect of delay, using the same significance
threshold as the group analyses. These analyses were conducted to insure that
any failures to obtain PFC activation in the group analyses among patients
did not reflect increased heterogeneity of the location of activation in PFC.
RESULTS
BEHAVIORAL DATA
The accuracy of ANOVA (Table 2)
did not reveal significant main effects of group (F1,24 = 2.18, P = .11) or delay (F1,24 = 0.3, P>.10) but did indicate a significant trial type main effect (F3,72 = 4.6, P = .005), which was moderated
by a group x trial type interaction (F3,72 = 3.49, P = .02). As predicted, planned contrasts indicated that
this interaction reflected (1) worse performance on B-X trials (t24 = 2.65, P = .01) and (2) better
performance on A-Y trials for patients (t24 = 2.96, P = .007); and (3) no B-Y differences
(t24 = 0.92, P
= .37). The RT ANOVA (Table 2)
indicated main effects of group (F1,24 = 6.5, P = .02; patients slower than controls), delay (F1,24 =
8.9, P = .006; long delay slower), and trial type
(F3,72 = 26.8, P<.001). Again, the
trial type main effect was moderated by a group x trial type interaction
(F3,72 = 3.8, P<.01). Planned contrasts
indicated that this interaction reflected (1) slower B-X RTs for patients
(t24 = 2.2, P
= .037), (2) no significant differences on A-Y RTs (t24 = 1.6, P = .12), (3) slower B-X than A-Y
RTs in patients (t24 = 2.6, P = .016), and (4) slower A-Y than B-X RTs in controls (t24 = 2.6, P = .47). The group
x trial type x delay interactions for accuracy and RT did not
reach significance. However, we did find the predicted interaction with delay
in d'-context (Table 2).
The d'-context ANOVA indicated main effects of group (F1,24
= 5.4, P = .029) and delay (F1,24 = 18.1, P<.001) and a group x delay interaction (F1,24 = 4.1, P = .05). Planned contrasts indicated
no significant differences between patients and controls at the short delay
(t24 = 1.0, P
= .33) but significantly decreased d'-context among patients at the
long delay (t24 = 3.2, P = .004).
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Table 2. Behavioral Data*
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IMAGING DATA
We first examined regions showing a main effect of delay. In the group
analysis, we observed a network of WM-related regions21
showing this effect (Table 3).
Planned contrasts indicated that most of these regions demonstrated significant
delay effects in both groups, including bilateral inferior/posterior frontal
cortex (Figure 2), right parietal
cortex, and the anterior cingulate. The 2 right temporal regions demonstrated
significant delay effects in patients but marginally significant effects in
controls (P<.10). Individual subject analyses
provided similar results (Table 3).
Most patients and controls displayed delay-related activity in anterior cingulate,
bilateral inferior frontal, and right parietal cortex, though fewer individual
subjects displayed significant activity in the temporal regions.
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Table 3. Regions Exhibiting Significant Delay-Related Activity
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Figure 2. Prefrontal cortex (PFC) regions
showing main effect of delay. The functional magnetic resonance image (fMRI)
shows PFC regions active in long delay relative to short delay blocks with
significant effects in both controls and patients. Insets plot the signal
for healthy controls (n = 12) and patients with schizophrenia (n = 14) separately
as a percent change from the short delay condition. BA indicates Brodmann
area.
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As predicted, only 1 brain region displayed a significant group x
delay interaction. This was located in DLPFC (Table 3 and Figure 3),
and planned contrasts revealed significantly greater activity in the long
compared with short delay among controls (t11 = 3.6, P<.005) but not in patients (t13 = 1.6, P>.10).
Moreover, among controls, the temporal dynamics of activity indicated a sustained
response over the delay period (manifested as no main effect of scan in the
long delay condition, F3,33 = 1.81, P>.15),
consistent with the interpretation that this region is actively maintaining
the context information provided by the cue. One possibility for this is that
patients with schizophrenia did demonstrate DLPFC activation in response to
the delay manipulation but simply in a different area than controls. However,
no other regions anywhere in the brain demonstrated a group x delay
interaction with a significant delay effect in patients. Furthermore, analyses
examining delay effects in patients with schizophrenia alone did not reveal
any significant activity in DLPFC, though they did reveal activation in the
bilateral inferior/posterior frontal cortex, parietal cortex, anterior cingulate,
and temporal cortex, consistent with the main effect of delay analyses presented
in the section. In addition, individual subject analyses indicated that 10
of 12 controls displayed significantly greater activity in the long compared
with short delay in DLPFC, while only 6 of 14 patients did (Table 3).
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Figure 3. Dorsolateral prefrontal cortex
(DLPFC) region showing group x delay interaction. Functional magnetic
resonance image (fMRI) shows DLPFC region demonstrating group x delay
interaction. Insets plot the signal for healthy controls (n = 12) and patients
with schizophrenia (n = 14) separately as a percent change from the first
scan of the short delay condition. BA indicates Brodmann area.
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We did not predict that DLPFC activity would interact with trial type,
even though we did predict and find such interactions in the behavioral data.
This is because we believe that the behavioral trial type interaction reflects
the fact that the same deficit in maintaining context information can lead
to worse (eg, more B-X errors) and better performance (eg, fewer A-Y errors).
Thus, reduced DLPFC activation should be present during all trial types at
the long delay, even though its behavioral manifestations may differ across
trial types. We were able to examine trial type effects in those individuals
scanned with the 2-shot spiral sequence (n = 19), though the AX-CPT design
provided only a small number of trials for each nontarget trial type. Consistent
with our predictions, the DLPFC did not show a further interaction with trial
type (P>.25).
We next examined regions showing significant effects of scan within
trial. As given in Table 4 and Figure 4, controls and patients showed response-related
activation of motor and somatosensory cortex, with similar amplitude and dynamics.
Three additional regions showed a group x scan interaction (Table 4). One region (left posterior frontal
cortex) demonstrated significant inverse quadratic effects of scan within
trial among patients but not controls, while the other 2 (right inferior frontal
and posterior cingulate) showed such effects among controls but not patients.
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Table 4. Regions Exhibiting Significant Scan-Related Activity
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Figure 4. Representative regions demonstrating
significant effects of functional magnetic resonance imaging (fMRI) within
trial. Insets plot the signal for healthy controls (n = 12) and patients with
schizophrenia (n = 14) separately as a percent change from the first scan.
BA indicates Brodmann area.
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A potential criticism of fMRI studies in schizophrenia is that increased
movement among patients creates artifacts that impair the detection of cortical
activation. To explore this possibility, we analyzed the 12 estimated movement
parameters (pitch, roll, yaw, X, Y, and Z for absolute and image-to-image
movement). Patients differed significantly from controls only on average absolute
pitch (t24 = 2.03, P = .05) due primarily to increased movement in 2 patients. When these
patients were removed, no significant group differences in movement remained
(P>.10 for all parameters), but the behavioral (eg,
d'-context group x delay interaction; F1,22 = 4.6, P = .04) and imaging effects (eg, DLPFC group x delay
interaction; F1,22 = 14.7, P = .001) remained
significant. We also examined signal-to-noise ratios in each slice of the
imaging data. There were significant signal-to-noise ratio reductions among
patients but only in more inferior slices (ie, slices 11-14, Z = +7-18 mm),
well below the regions of interest in either PFC or parietal cortex.
A second criticism of fMRI studies in schizophrenia is that the poorer
behavioral performance on the part of patients confounds the interpretation
of observed activation differences.9, 17
To address this concern we looked at DLPFC activation in a subset of 8 controls
and 8 patients roughly matched for performance based on d'-context at
the long delay (mean [SD]: controls, 3.14 [0.62]; patients, 3.10 [0.41]).
The DLPFC group x delay interaction remained significant in this subset
of patients and controls (F1,16 = 11.25, P
= .004).
COMMENT
The pattern of results obtained in the current study were consistent
with our hypothesis that patients with schizophrenia have a specific impairment
in the ability to actively represent and maintain context information due
to an underlying neurophysiological disturbance in DLPFC. Specifically, patients
with schizophrenia demonstrated a specific pattern of both better (fewer A-Y
errors) and worse behavioral performance (more B-X errors), suggestive of
a deficit in the ability to actively represent and maintain context information.
In addition, patients with schizophrenia demonstrated a selective deficit
in the ability to appropriately activate DLPFC in response to demands for
the maintenance of context. Our results suggested that the observed differences
between controls and patients were not due to increased movement or reduced
signal-to-noise ratios in the patient data. Since this study was conducted
in first-episode medication-naive patients, we can conclude that DLPFC deficits
are present at the onset of the first acute exacerbation in this illness and
are not due to current or previous medication effects. More importantly, our
findings suggest that PFC disturbances among patients with schizophrenia,
at least first-episode medication-naive patients, may be somewhat anatomically
specific. In particular, we found that more posterior and inferior regions
of PFC, such as BA 44, were relatively functionally intact in our sample of
patients with schizophrenia, providing critical "internal activation standards"
against which to interpret decreased DLPFC activation among patients with
schizophrenia. Patients also showed intact response-related activation of
motor and somatosensory cortex, with amplitude and dynamics similar to controls.
Such results raise the question of the functional significance of activation
in DL vs inferior regions of PFC and have implications for normal cognitive
function as well as for the nature of cognitive impairments in schizophrenia.
Activation of BA 44 is frequently found in neuroimaging studies of language
and verbal WM.32, 45, 46, 47
This activity has typically been interpreted as reflecting articulatory planning
and covert rehearsal processes.32, 47, 48, 49
As such, normal activation in BA 44 among patients is consistent with prior
research, suggesting that patients are not impaired while performing tasks
for which explicit rehearsal is sufficient to drive performance (eg, span
tasks).31, 50 However, the AX-CPT
is qualitatively different from some traditional WM tasks. In many such tasks,
an articulatory or phonologically based representation of stimuli may be sufficient
for correct performance. For example, in the digit-span task, the representation
of the digits must be actively maintained in a form that allows them to be
correctly repeated back without error. Thus, an ideal representation for this
task would be an articulatory or phonologically based one. In contrast, in
the AX-CPT, such articulatory or phonologically based representations may
be useful or even necessary but not sufficient for correct performance. Instead,
performance is critically dependent on transforming the cue into a representational
form that carries information regarding the cue's implications for future
stimulus evaluation and response, which we refer to as a context representation. For example, following a B cue, representing
the stimulus in a phonological or articulatory form may not be sufficient.
What is also needed is an interpretation of a B cue as indicating that a subsequent
X should be associated with a nontarget rather than a target response. It
is the representation and maintenance of information in this contextual code
that we feel best characterizes the function of DLPFC25
and which we believe is a key function that is impaired in schizophrenia.26
Although our results suggested impaired DLPFC activation but relatively
intact activation of BA 44 in patients with schizophrenia, we should note
that some prior studies have found disturbed activation of BA 44 in this illness.
In particular, a recent study by Stevens et al51
using word and tone span tasks found hypoactivation of a number of inferior/posterior
PFC regions, such as BA 44, BA 6, and BA 45. There are a number of differences
between the current study and the study of Stevens and colleagues that may
have contributed to the differences in our results. First, and perhaps most
importantly, the patients in the study by Stevens and coauthors had received
long-term medication, while ours were medication-naive first-episode patients.
As such, in future research, it will be important to determine whether illness
duration and/or medication effects influence the integrity of BA 44 and BA
45 in schizophrenia. Second, the tasks used in the study by Stevens et al51 placed a heavy demand on covert rehearsal, as noted
by the authors themselves, and may not have strongly tapped the context processing
component of WM. Consistent with this task analysis, Stevens and colleagues
did not find activation of DLPFC among controls in their study. In contrast,
the AX-CPT task used in the current study was specifically designed to tap
context processing and may have only placed a moderate demand on covert rehearsal.
Thus, another possibility is that the magnitude of BA 44 and BA 45 dysfunction
demonstrated by patients with schizophrenia is related to the degree to which
the task taxes or is critically dependent on covert rehearsal, a hypothesis
that can be investigated in future cognitive and neuroimaging studies. Although
we believe our results are consistent with the hypotheses outlined in the
introduction, we should also note some limitations of the current study. First,
our patients were experiencing their first contact with the psychiatric system
and had not yet experienced any potential confounding effects of antipsychotic
medications or repeated hospitalizations. However, prodromal symptoms of schizophrenia
can sometimes appear years before the onset of the first acute psychotic episode.
Thus, we cannot rule out the possibility that our results may have been influenced
by subtle effects of this prodromal period. Second, we did not match our patients
and controls on variables such as IQ. This was a deliberate choice, as it
has been argued that the development of schizophrenia itself may influence
IQ and that matching groups on IQ can lead to nonrepresentative groups of
both patients and controls.52 Nonetheless,
in future work it will be important to determine how variables such as IQ
are related to both context-processing deficits and DLPFC dysfunction in schizophrenia.
Lastly, we have interpreted the results of our study as reflecting disturbances
in the ability to represent and maintain context. However, the results of
this study itself cannot rule out an alternative interpretation, namely that
patients have a deficit in actively maintaining any type of information, not
just context representations, over a delay. This alternative hypothesis is
consistent with the proposals of Goldman-Rakic1, 24
regarding the function of DLPFC and with data showing deficits on delayed
matched to sample tasks among patients with schizophrenia.6, 53
To arbitrate between these alternatives, future research will need to directly
compare the role of DLPFC in the maintenance of contextual vs noncontextual
information and determine the critical parameters influencing WM deficits
in schizophrenia.
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
This work was supported by grants from the National Institute of Mental
Health (NIMH), Bethesda, Md, and NIMH center grant 2 P50 MH45156-09 (Dr Cohen).
Presented in part at the International Congress on Schizophrenia Research,
Albuquerque, NM, April, 1999, and the Society for Neurosciences Conferences,
Miami, Fla, September, 1999.
We thank Judy Johnstonbaugh, BA, Brittany Lourea, BA, Grace Nah, BA,
and Greg Nickliss, BA, for their invaluable assistance in the conduct of this
study.
From the Department of Psychology, Washington University, St Louis,
Mo (Drs Barch and Braver); Department of Psychiatry, University of Pittsburgh,
Pittsburgh, Pa (Drs Carter and Cohen and Mr MacDonald); Department of Psychology,
Princeton University, Princeton, NJ (Mr Sabb and Dr Cohen); and the Department
of Biomedical Engineering, University of Michigan, Ann Arbor (Dr Noll).
Corresponding author and reprints: Deanna M. Barch, PhD, Department
of Psychology, Campus Box 1125, 1 Brookings Dr, Washington University, St
Louis, Mo 63130 (e-mail: dbarch{at}artsci.wustl.edu).
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