Article
Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 173
of these cognitive impairments to neural function is not
clear. For example, impairments in the function of tem-
poral lobe memory systems, prefrontal lobe executive
regions, or visual and attention networks could underlie
working memory defi cits in psychotic major depression.
Working memory tasks require the temporary mainte-
nance and manipulation of information as well as sustained
attention. The neurofunctional system subserving verbal
working memory has been studied extensively in healthy
comparison subjects using functional MRI (fMRI). Studies
consistently show that the dorsolateral prefrontal cortex,
typically in Brodmann’s area 46, sustains activation during
the delay periods in which individuals hold information in
working memory (11) and suppresses activation to nonrel-
evant stimuli (12). The sustained attention and target detec-
tion component of a working memory task often activates
a right hemisphere attention system, including regions of
the temporoparietal cortex and inferior and middle frontal
gyri. This network is consistently activated during detection
of task-relevant stimuli, especially when they are infrequent
(13). In the left hemisphere, the inferior parietal region is
believed to be part of a storage buffer for verbal information
An estimated 5%–20% of patients with major depres-
sion experience psychotic symptoms, including halluci-
nations and delusions (1, 2). Psychotic major depression is
associated with more severe psychomotor symptoms and
guilt (3, 4), signifi cantly greater impairment, longer illness
duration, and greater likelihood of recurrence compared
with nonpsychotic major depression (1, 5, 6). However,
the severity of a depressive episode does not necessarily
determine whether psychotic features will be present (7).
Unfortunately, psychotic major depression is frequently
misdiagnosed (8), which can deter effective treatment.
A better understanding of the brain pathophysiology
underlying psychotic major depression can lead to earlier
detection and more effective treatments. Neuropsycho-
logical data from our lab have shown that patients with
psychotic major depression have greater cognitive impair-
ment than do patients with nonpsychotic major depres-
sion or healthy comparison subjects on tests of working
memory, verbal memory, and psychomotor speed but
not on tests of simple verbal attention (9), which implies
abnormal brain circuits associated with memory encod-
ing and executive function (10). However, the relationship
(Am J Psychiatry 2011; 168:173–182)
Amy Garrett, Ph.D.
Ryan Kelly, B.S.
Rowena Gomez, Ph.D.
Jennifer Keller, Ph.D.
Alan F. Schatzberg, M.D.
Allan L. Reiss, M.D.
Objective: The authors sought to bet-
ter understand the neural circuitry asso-
ciated with working memory defi cits in
psychotic major depression by examining
brain function during an N-back task.
Method: Study subjects were 16 patients
with psychotic major depression, 15 pa-
tients with nonpsychotic major depres-
sion, and 19 healthy comparison subjects.
Functional MRI data were collected while
participants responded to letter stimuli
that were repeated from the previous trial
(1-back) or the one before that (2-back).
Results: Relative to the healthy compari-
son group, both the psychotic and non-
psychotic major depression groups had
signifi cantly greater activation in the right
parahippocampal gyrus during the 2-back
task, and the psychotic major depression
group showed this overactivation during
the 1-back task as well. The nonpsychotic
major depression group showed signifi -
cantly lower activation than other groups
in the right dorsolateral prefrontal cortex
and greater activation than the healthy
comparison group in the superior occipi-
tal cortex. The psychotic major depres-
sion group was unique in showing greater
activation than both other groups in the
right temporoparietal junction, a cluster
that also demonstrated connectivity with
activation in the left prefrontal cortex.
Conclusions: The psychotic major de-
pression group showed aberrant parahip-
pocampal activation at a lower demand
level than observed in nonpsychotic ma-
jor depression. While the nonpsychotic
major depression group showed abnor-
malities in frontal executive regions,
the psychotic major depression group
showed abnormalities in temporoparietal
regions associated with orienting to unex-
pected stimuli. Considering the functional
connectivity of this cluster with left dor-
solateral prefrontal cortex regions, these
fi ndings may refl ect neural compensation
for sensory gating defi cits in psychotic
major depression.
Aberrant Brain Activation During a Working Memory
Task in Psychotic Major Depression
This article is the subject of a CME course (p. 227)
BRAIN ACTIVATION DURING WORKING MEMORY IN PSYCHOTIC MAJOR DEPRESSION
174 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011
symptoms. Patients were excluded if they had active suicidality,
obsessive-compulsive disorder, or bipolar disorder or had abused
substances or received ECT within the past 6 months. All par-
ticipants were allowed to continue their psychiatric medications
but were required to maintain a stable medication regimen for at
least 1 week before the study.
Healthy comparison subjects, recruited through advertise-
ments, had to score less than 6 on the HAM-D, have no psychotic
symptoms, and have no current or past axis I diagnoses according
to SCID criteria.
Exclusion criteria for all participants included major medical
illness, history of seizures or head injury, pregnancy or lactation,
age <18 years, or use of estrogen supplements or birth control pills.
The study included 22 patients with psychotic major depression,
21 patients with nonpsychotic major depression, and 24 healthy
comparison subjects. All participants gave written informed
consent and received $250 for their participation. The study was
approved by the Institutional Review Board of Stanford University.
The N-Back Task
Participants performed an N-back task during image acquisi-
tion. The task had three types of alternating blocks: four 1-back,
four 2-back, and six control (“press for Z”) blocks. For all blocks,
a succession of uniform-size single letters was presented, in both
upper- and lowercase. Each letter was presented for 500 msec,
with a 1,500 msec intertrial interval showing a fi xation cross. Each
block contained 12 letters and lasted for 24 seconds. Brief instruc-
tions were shown for 4 seconds at the beginning of the block
(e.g., “Press for 1-back”). During the 1-back blocks, participants
pressed the button when the current letter matched the one pre-
sented one trial back, e.g., a repeated letter such as A—A. During
2-back blocks, participants pressed the button when the current
letter matched the one presented two trials back, e.g., in a “sand-
wich” pattern such as A—B—A. During the “press for Z” blocks,
participants pressed the button whenever the current letter was
a Z. Participants pressed with the right index fi nger on a hand-
held button box. Stimuli were projected onto a screen and viewed
through a mirror attached to the head coil. All participants prac-
ticed the task before the scan. The scan lasted 7 minutes and 48
seconds, during which 232 frames were acquired. The E-Prime
software program (www.pstnet.com) was used to present the task
and collect responses.
fMRI Data Acquisition and Processing
Images were acquired on a 3-T General Electric (GE) Signa
scanner using a standard GE whole-head coil (Lx platform, gradi-
ents 40 mT/m, 150 T/m/sec; GE Medical Systems, Milwaukee). A
custom-built head restraint system and foam padding prevented
head movement. A high-order shim (31) reduced blurring and sig-
nal loss from fi eld inhomogeneities. Twenty-eight axial slices (4
mm thick, 0.5 mm skip) parallel to the anterior and posterior com-
missures and covering the whole brain were imaged using a T
2
*-
weighted spiral pulse sequence (32) (repetition time=2,000 msec,
echo time=30 msec, fl ip angle=80°, interleave=1, fi eld of view=200
mm2, matrix=64×64, inplane spatial resolution=3.125 mm2).
fMRI data were processed using SPM5 (www.fi l.ion.ucl.ac.uk/
spm). Images were realigned to the third volume. Image distortion
and spin history errors caused by abrupt motions were repaired by
interpolation from the nearest unaffected volumes. These methods
were implemented in the ArtRepair toolbox for SPM (http://cibsr.
stanford.edu/tools/ArtRepair/ArtRepair.htm). Data were normal-
ized to the Montreal Neurological Institute (MNI) echo-planar
image template and resampled to a 2-mm3 matrix using sinc inter-
polation. Data were smoothed with a 4-mm full width at half maxi-
mum Gaussian fi lter and high-pass fi ltered at 120 seconds.
Individual statistics were computed using a fi xed-effects model
and a block design comparing 1-back with press for Z, and 2-back
(14). The hippocampus is also active during the delay period
of a working memory task, but the parahippocampal gyrus,
in contrast, is activated during the encoding and recogni-
tion parts of the working memory task and predicts success-
ful long-term memory encoding (15).
Because of the widespread brain circuitry involved,
patients with various psychiatric disorders have been found
to show abnormal brain activation during working memory
tasks. Patients with nonpsychotic major depression show
abnormal prefrontal function during a verbal working mem-
ory task, which emphasizes the importance of comparing
patients with psychotic and nonpsychotic major depres-
sion (16–22). Because patients with schizophrenia also
display defi cits in working memory, several neuroimaging
studies have found dorsolateral prefrontal cortex defi cits in
schizophrenia relative to comparison subjects (23–25) and
to patients with nonpsychotic major depression (24, 26),
which suggests a common substrate for working memory
defi cits across diagnoses but with greater severity in schizo-
phrenia. Given that psychotic major depression involves
symptoms of both nonpsychotic major depression and
schizophrenia, these patients may share common defi cits
in executive function. However, because high cortisol levels
in psychotic major depression (9) are likely to affect hippo-
campal and parahippocampal systems as well, defi cits in
medial temporal lobe regions may differentiate psychotic
major depression from nonpsychotic major depression.
In this study, we investigated the neural correlates of a
verbal working memory task in patients with psychotic
major depression in order to better understand the brain
circuitry underlying working memory defi cits in psy-
chotic major depression. Patients with nonpsychotic
major depression and healthy comparison subjects were
included to differentiate between depressive subtypes
as well as between these subtypes and unaffected indi-
viduals. We predicted that the psychotic major depres-
sion group would show a unique pattern of activation that
refl ects abnormalities in medial temporal lobe and pari-
etal regions and similarities to the nonpsychotic major
depression group in prefrontal regions.
Method
Participants
Participants were recruited from outpatient psychiatric clinics
at Stanford University and through advertisements in the sur-
rounding communities. Patients with psychotic and nonpsychotic
major depression were diagnosed with the Structured Clinical
Interview for DSM-IV (SCID) (27), and diagnoses were confi rmed
by the treating psychiatrist when available. Patients had to score
at least 18 on the 21-item Hamilton Depression Rating Scale
(HAM-D) (28) and at least 7 on the Thase Core Endogenomorphic
Scale (29) to verify signifi cant depressive and endogenous symp-
toms, respectively. Patients with psychotic major depression had
to score at least 5 on the positive symptom subscale of the Brief
Psychiatric Rating Scale (BPRS; 30). All patients met DSM-IV
criteria for current unipolar major depressive episode. Patients
with nonpsychotic major depression had no history of psychotic
GARRETT, KELLY, GOMEZ, ET AL.
Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 175
with press for Z. Group t tests used a random-effects model to
examine activation within and between each group. A dual-signif-
icance corrected threshold of height at p=0.01 and cluster extent
at p=0.01 was used within groups. To determine the location of
signifi cant clusters, coordinates were fi rst converted to the Talai-
rach template using the mni2tal function (http://imaging.mrc-
cbu.cam.ac.uk/imaging/MniTalairach), and then brain regions
were localized using the Talairach Daemon software (http://www.
talairach.org/client.html) and also visually inspected by an expe-
rienced neuroimager (A.G.).
A multivariate analysis of variance was conducted in SPM5
using the independent factor group and the repeated factor task
(1-back minus press for Z, and 2-back minus press for Z). Gender
and response time were used as covariates (see below). A thresh-
old of p=0.001, extent=10 defi ned signifi cant activation that dif-
fered among the three groups across task conditions (main effect
of group). Mean activation levels (t-scores) were extracted from
signifi cant clusters using MarsBar (http://marsbar.sourceforge.
net/). Between-group t tests were then performed using SPSS
(http://www.spss.com/) with a corrected signifi cance threshold
of p=0.0125 (or p=0.05/4 regions tested).
A connectivity analysis was conducted using the Psychophysi-
ological Interaction module of SPM5. This post hoc analysis
located brain regions functionally associated with the temporo-
parietal junction region in the psychotic major depression group.
The temporoparietal junction cluster that was signifi cantly
increased in the psychotic major depression group was used as
the seed region. For each participant, a 6-mm3 box was placed on
the maximum voxel in the cluster. The average time course of the
voxels that surpassed threshold (p=0.01) was extracted. A multi-
ple regression identifi ed voxels showing a signifi cant interaction
between that time course and the 2-back-press-for-Z contrast for
each participant. A random-effects analysis combined individual
results into a group result using a cluster-corrected threshold of
dual height and extent at p=0.01.
Results
Data for fi ve participants with psychotic major depres-
sion, two with nonpsychotic major depression, and three
healthy comparison subjects were excluded because of
response box failure resulting in N-back task accuracy
below 50%. Scan data from one patient with psychotic
major depression, four patients with nonpsychotic major
depression, and two healthy comparison subjects were
excluded because of movement artifacts during more than
20% of the scan. This left 16 participants in the psychotic
major depression group, 15 in the nonpsychotic major
depression group, and 19 in the healthy comparison group.
Table 1 summarizes participants’ clinical and demo-
graphic characteristics. There were no group differences
in age, handedness, or years of education, but the groups
differed in gender distribution. The groups had similar IQ,
as measured by full-scale estimates of premorbid intellec-
tual functioning.
The patients for whom medication data were available
had established antidepressant medication regimens
with no changes; the psychotic major depression group
(N=6) had an average of 20.3 weeks of antidepressant use
(range=3–56, SD=19.9) and 9.8 weeks of antipsychotic use
(range=5–26, SD=9.2). The nonpsychotic major depres-
sion group (N=9) had an average of 42.6 weeks of antide-
pressant use (range=4–156, SD=56.4).
N-Back Task Performance Results
All participants performed the task with a high degree
of accuracy (Table 1). Response time for the 2-back task
was different between groups, and further comparisons
showed that this was due to signifi cantly slower response
time in the nonpsychotic major depression group com-
pared to the healthy comparison group (p=0.002),
even when controlling for group differences in gender
(p=0.007). Therefore, all comparisons with the nonpsy-
chotic major depression group during the 2-back task
included response time as a covariate.
fMRI Results
Tables 2 and 3 list regions that were signifi cantly acti-
vated during the 1-back and 2-back tasks within each
group. All three groups activated regions typically associ-
ated with verbal working memory tasks, such as the left
supramarginal gyrus, left inferior frontal gyrus, and left
and right inferior parietal lobe.
Between-Group Analysis of Variance
Four clusters of activation were signifi cant (Figure 1).
Activation in the right parahippocampal gyrus was sig-
nifi cantly greater during both the 1-back and 2-back
tasks in the psychotic major depression group relative to
the healthy comparison group. The nonpsychotic major
depression group showed greater parahippocampal acti-
vation during the 2-back task relative to the comparison
group. The nonpsychotic major depression group showed
signifi cantly less activation in the right dorsolateral pre-
frontal cortex during the 2-back task relative to both
groups and greater occipital cortex activation relative to
the healthy comparison group during both tasks. The psy-
chotic major depression group had signifi cantly greater
activation in the right temporoparietal junction during
the 2-back task relative to both the nonpsychotic major
depression and healthy comparison groups and nonsig-
nifi cantly greater activation during the 1-back task.
An important question is whether differences between
the psychotic and nonpsychotic major depression groups
can be attributed solely to differences in severity of depres-
sive symptoms. However, group differences in brain acti-
vation did not change when covaried for HAM-D score.
Also, we attempted to better understand the infl uence of
medication on our results by examining brain activation
in medicated compared with unmedicated participants.
Only the nonpsychotic major depression group contained
a suffi cient number of unmedicated participants to per-
form this analysis. With the group divided into unmedi-
cated (N=6) and medicated (N=9) subgroups, none of the
regions were signifi cantly different between subgroups.
Connectivity Results
The psychophysiological interaction analysis was con-
ducted to better understand functional circuits involv-
ing the temporoparietal junction during the 2-back task.
Results showed that activation in a single large cluster in
BRAIN ACTIVATION DURING WORKING MEMORY IN PSYCHOTIC MAJOR DEPRESSION
176 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011
TABLE 1. Clinical, Demographic, and Task Performance Measures, by Group, in a Study of the Neural Circuitry Associated
With Working Memory Defi cits in Psychotic Major Depression
Measure
Psychotic Major
Depression Group (N=16)
Nonpsychotic Major
Depression Group (N=15)
Healthy Comparison
Group (N=19)
Mean SD Mean SD Mean SD
Age (years) 34.13 10.68 39.81 12.74 34.85 12.54
Education (years) 16.25a 3.72 14.40 1.40 15.95 2.15
IQb 111.56 9.40 104.00 10.63 111.28 9.35
Hamilton Depression Rating Scale (21-item) scorec 27.88 3.52 24.20 3.30 0.58 0.84
Brief Psychiatric Rating Scale scored 28.75 5.36 15.73 2.71 0.42 0.69
Brief Psychiatric Rating Scale positive symptom
subscoree 8.38 3.70 0.13 0.35 0.00 0.00
Length of current depressive episode (weeks) 165.8f 198.4 155.5g 217.1
Task performance
1-Back
% Correct 97.25 1.13 96.41 1.20 97.26 1.05
Response time 581.7 28.24 650.0 29.96 556.7 26.35
2-Back
% Correct 98.47 2.84 99.03 0.38 99.77 0.33
Response timeh 629.6 30.28 683.9 32.13 559.7 28.26
N % N % N %
Femalei 7 43.8