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Dysfunctional Cortico-Basal Ganglia-Thalamic Circuit and Altered

Hippocampal-Amygdala Activity on Cognitive Set-Shifting in Non-
Neuropsychiatric Systemic Lupus Erythematosus

Article  in  Arthritis & Rheumatology · December 2012

DOI: 10.1002/art.34660 · Source: PubMed

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Dysfunctional Cortico–Basal Ganglia–Thalamic Circuit
and Altered Hippocampal–Amygdala Activity on
Cognitive Set-Shifting in Non-Neuropsychiatric
Systemic Lupus Erythematosus
Tao Ren, Roger Chun-Man Ho, and Anselm Mak
Objective. To explore sequential brain activities
throughout cognitive set-shifting, which is critical to
understanding the basic pathophysiology of cognitive
dysfunction, in patients with new-onset systemic lupus
erythematosus (SLE) without neuropsychiatric symp-
toms.
Methods. Fourteen patients with new-onset SLE
but without neuropsychiatric symptoms and 14 healthy
controls matched for age, sex, education level, and
intelligence quotient with the patients performed a
cognitive set-shifting task derived from the Wisconsin
Card Sorting Test while they were undergoing event-
related functional magnetic resonance imaging of the
brain. Blood oxygen level–dependent signals were com-
pared between different stages of cognitive set-shifting
in the lupus patients and in the healthy subjects.
Results. Lupus patients and healthy subjects
demonstrated comparable cognitive function perfor-
mance, but the cortico–basal ganglia–thalamic–cortical
circuit and amygdala–hippocampus coupling, which
were involved in response inhibition and active
forgetting–learning dynamics, respectively, were demon-
strated to be compromised in patients with SLE. More-
over, an increase in contralateral cerebellar–frontal
activity was found to compensate for the compromised
Supported by the Ministry of Education, Singapore (Tier 1
Academic Research grant R-172-000-164-112).
Tao Ren, PhD student, Roger Chun-Man Ho, MBBS,
MMed(Psych), DPM, MRCPsych, Anselm Mak, MMedSc, MBBS,
MD, FRCP(Edin): National University of Singapore Yong Loo Lin
School of Medicine, Singapore.
Address correspondence to Anselm Mak, MMedSc, MBBS,
MD, FRCP(Edin), National University of Singapore, Division of
Rheumatology, Department of Medicine, University Medicine Clus-
ter, Level 10, NUHS Tower Block, 1E Kent Ridge Road, Singapore
119228. E-mail: anselm_mak@nuhs.edu.sg.
Submitted for publication May 18, 2012; accepted in revised
form July 31, 2012.
4048
ARTHRITIS & RHEUMATISM
Vol. 64, No. 12, December 2012, pp 4048–4059
DOI 10.1002/art.34660
© 2012, American College of Rheumatology
cortico–basal ganglia–thalamic–cortical circuit in lupus
patients in order to maintain their cognitive test perfor-
mance as comparable to that of the healthy subjects.
Conclusion. Our study revealed significant differ-
ences in the sequential brain signals during cognitive
set-shifting between patients with SLE without neuro-
psychiatric symptoms and healthy subjects. The results
prompt further in-depth investigation for the functional
neural basis of cognitive dysfunction involving the
aforementioned neural circuits and compensatory path-
ways in patients with SLE.
Systemic lupus erythematosus (SLE) is a chronic
and multisystemic autoimmune disorder characterized
by protean clinical manifestations. Neuropsychiatric
SLE (NPSLE) is one of the most common manifesta-
tions of lupus, and it has hindered improvements in the
survival of these patients over the last 5 decades (1). Of
the various symptoms of NPSLE, cognitive impairment,
which primarily affects attention, planning, reasoning,
working memory, and executive function, has been
frequently described (2). It is evident that the cognitive
functioning of patients with NPSLE is inferior to that of
lupus patients without neuropsychiatric symptoms and
that of healthy individuals (3,4), as they demonstrate
poorer performance in a number of domains of cognitive
function testing, in particular, attention, information
processing, learning, memory, and executive function
(3–5).
Real-time functional magnetic resonance imag-
ing (fMRI) of the brain while subjects were performing
cognitive function tasks revealed that brain activities,
which were manifested by blood oxygen level–
dependent (BOLD) signals, were significantly altered in
patients with NPSLE as compared with healthy subjects
(6,7). However, since these fMRI studies involved lupus
fMRI AND COGNITIVE SET-SHIFTING IN SLE
patients with neuropsychiatric manifestations, the find-
ings failed to give insights as to whether the real-time
brain activities in lupus patients without clinically overt
neuropsychiatric symptoms were altered. Such knowl-
edge is particularly relevant because it is currently
believed that lupus patients, even those without clinically
obvious neuropsychiatric symptoms, perform poorer
cognitively on neuropsychiatric tests than do healthy
individuals (4,8,9).
Until recently, we used brain fMRI to evaluate
the event-related brain activities of lupus patients with-
out neuropsychiatric symptoms (10). Using the Wiscon-
sin Card Sorting Test (WCST) for assessing neural
activities corresponding to response selection and feed-
back evaluation, which evaluate the performance of
goal-directed tasks and strategic planning skills of exec-
utive function, respectively, lupus patients without neu-
ropsychiatric symptoms demonstrated significantly in-
creased brain activities in regions that enhanced event
anticipation, attention, and working memory during RS
to compensate for their poor strategic planning as a
result of deactivated brain regions involved in motor
planning, decision-making, sensory integration, error
detection, and conflict processing (10). Very recently, a
study performed by another group of investigators using
a different functional imaging protocol demonstrated
attenuated brain activities in the cerebellum, posterior
cingulate, and the adjacent precuneus in the default
mode network in lupus patients without neuropsychiat-
ric manifestations (11). While both of these studies
demonstrated altered brain signals in certain anatomic
regions of the brain in lupus patients without neuropsy-
chiatric symptoms, it is pathologically more relevant to
map the functional abnormalities that occur in neural
circuits by analyzing sequential activation of the brain
while patients are going through various sequential
stages of cognitive function testing.
The WCST, which is primarily regarded as a
unitary system for evaluating executive function that
recruits cognitive processes as a whole during task
performance, has been increasingly used to identify the
neural basis of different cognitive stages of executive
function. Using tailored set-shifting tasks derived from
the original WCST (12), the modified version of the
WCST was able to demonstrate that the prefrontal
cortex, hippocampus, and striatum were sequentially
involved across cognitive set-shifting processes in a
stage-specific manner (12–15). We therefore undertook
this fMRI study using the modified WCST to explore
brain activities across all stages of cognitive set-shifting
processes in patients with new-onset SLE who did not
4049
have clinically overt neuropsychiatric symptoms. Our
goal was to map the potential functional abnormalities
in neural circuits by analyzing event-related sequential
activation of the brain.
PATIENTS AND METHODS
Study participants. Patients with new-onset SLE who
satisfied the American College of Rheumatology classification
criteria for the disease (16) were recruited from the Lupus
Clinic of the National University Hospital, Singapore. SLE
disease activity was measured with the Systemic Lupus Ery-
thematosus Disease Activity Index (SLEDAI) (17), and assays
for serum levels of complement components 3 and 4 and
anti–double-stranded (anti-dsDNA) antibodies were carried
out in the hospital laboratory. Healthy subjects recruited from
staff working at the National University of Singapore were
individually matched with the lupus patients in terms of age,
sex, education level, and intelligence quotient (IQ). Each
participant’s IQ was evaluated with the Wechsler Abbreviated
Scale of Intelligence (WASI), which comprises verbal, perfor-
mance, and the full IQ.
Participants were ineligible for this study if they were
left-handed, were not proficient in English, had a history of
neurologic disorders, had symptoms of anxiety and/or depres-
sion (Hospital Anxiety and Depression Scale score ⱖ8), (18)
had a history of a psychiatric disorder or treatment with
psychotropic medications, or were positive for antiphospho-
lipid antibodies. Written informed consent was obtained from
the study participants, and the study was approved by the ethics
committee at our institution.
Wisconsin Card Sorting Test. All participants were
instructed to perform the computer-based modified WCST.
Prior to the test, all participants underwent training to ensure
satisfactory comprehension of the sorting criteria. During
response selection (RS), 4 cards appeared along the top of a
blue screen as a reference and remained unchanged as the test
ensued. On each trial, a candidate card that appeared at the
center bottom of the blue screen was to be matched according
to 1 of the 3 rules (color, number, or shape) with 1 of the
reference cards, as randomly generated by the program (Fig-
ure 1). Participants were given 4 seconds to respond, after
which either a bar would appear under the selected reference
card or else the words “too late” would appear on the blue
screen, which signified trial termination, and the test would
move on to the next trial. After the 4-second selection time,
fixation display of a white cross would appear at the center of
the blue screen. After another 5 seconds, feedback would
appear on the screen as “Right” or “Wrong,” indicating a
correct or incorrect card selection, respectively. The feedback
stimulus would appear for 500 msec, during which feedback
evaluation (FE) was allowed, and then the display would
change to fixation until the inception of the next trial.
The identified rule remained unchanged for a random
3–5 successive correct feedbacks until another rule was ran-
domly generated. Appearance of the first negative feedback
(NF) after successive correct feedbacks signaled a “shift” event
for the study subject to abandon previously prepotent rule and
search for a new rule, subsequent negative feedback (second
4050
Figure 1. Sample sequence of the modified Wisconsin Card Sorting Test, showing the course of cognitive set-shifting. RS ⫽ response selection;
PF ⫽ positive feedback; NF ⫽ negative feedback. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/
journal/10.1002/(ISSN)1529-0131.
NF), if applicable, would serve as a “generate” event to identify
the correct rule. The first positive feedback (PF) in a series of
correct feedbacks was regarded as an “update” event to
register the newly confirmed cognitive set in memory, while
subsequent positive feedback (second PF) served as a “main-
tain” event to keep the prevailing rule until a signal was
received to shift to another rule.
Each scanning session consisted of 5 runs, and each
run lasted for 8 minutes. Figure 1 shows a sample sequence
from the modified WCST. During the performance of the
WCST and concomitant imaging, the sequence of the “shift,”
“generate,” “update,” and “maintain” events was kept constant
throughout the course of the WCST, while the predefined time
interval of the imaging sequence was entirely independent of
the WCST event sequence.
Image acquisition. Functional imaging was performed
with a Siemens Symphony 1.5T MRI scanner. A blipped
gradient-echo echo-planar imaging sequence was applied for
functional imaging, using the following parameters: repetition
time 3,000 msec, flip angle 90°, field of view 192 ⫻ 192 mm,
and pixel matrix 64 ⫻ 64. Each run contained 156 whole-brain
acquisitions in a plane parallel to the line between the anterior
and posterior commissures on the sagittal scout images, using
the following parameters: 32 oblique axial slices of 3 mm
thickness, 0.3-mm gap between slices, with descending inter-
leaved slice acquisition. T1-weighted anatomic reference im-
ages were acquired using a magnetization-prepared rapid
gradient-echo sequence, as follows: pixel matrix 256 ⫻ 256,
field of view 206 ⫻ 206 mm, 80 slices of 2 mm thickness, and
in the coronal plane.
Image processing and statistical analysis of the BOLD
signal. Image processing and analyses were performed using
the software Brain Voyager QX (version 2.1; Brain Innova-
tions). Preprocessing steps, including slice scan-time correc-
tion, motion correction, spatial smoothing (8-mm full-width
half-maximum) and linear trend removal, were performed
REN ET AL
prior to statistical mapping of brain activation during the fMRI
paradigm. Functional images were subsequently registered to
the T1-weighted images, and the realigned images were trans-
formed into Talairach space.
Beta-score maps were computed in the Talairach space
using a random-effects general linear model. This model was
constructed with separate regressors relative to a fixation
baseline, convolved with a canonical hemodynamic response
function peaking at 6 seconds after initiation of card stimulus
or feedback, for RS and FE. Jittering of the fixation intervals
between the FE and the subsequent RS facilitated event
deconvolution (15). A region of interest (ROI) was computed
by analyzing the effect contrasts of the 2 categorical task
factors, class (positive/negative) and order (first/subsequent),
for both the RS and the FE. Significant clusters and peak
voxels that survived a false discovery rate (a statistical method
for correcting for multiple comparisons) of q ⬍ 0.05 were
reported (19). The cluster threshold was calculated with the
Cluster-Level Statistical Threshold Estimator tool in the Brain
Voyager QX software package.
Statistical analysis. Results are expressed as the
mean ⫾ SD except where indicated otherwise. Data from
healthy controls and SLE patients were compared by Mann-
Whitney U test for continuous variables and by chi-square test
for categorical variables. P values (2-tailed) less than 0.05 were
considered significant. All statistical analyses were performed
with the PASW Statistics software (version 18; SPSS).
RESULTS
Characteristics of the study participants and
performance on the WCST. Fourteen patients with
new-onset SLE and 14 healthy controls matched to the
patients in terms of age, sex, education level, and IQ
fMRI AND COGNITIVE SET-SHIFTING IN SLE
Table 1. Demographic and clinical characteristics and WCST performance of the study participants*
Demographic and clinical characteristics
Age, years
Sex, no. female/male
Education level, years
Full IQ
C3, mg/dl (normal 85–185)
C4, mg/dl (normal 10–50)
Anti-dsDNA, IU (normal ⬍20)
SLEDAI
Prednisolone, mg/day
WCST performance
No. of rules identified
No. of errors per rule
Reaction time, msec
* Except where indicated otherwise, values are the mean ⫾ SD or the mean ⫾ SD (range). WCST ⫽
Wisconsin Card Sorting Test; SLE ⫽ systemic lupus erythematosus; IQ ⫽ intelligence quotient;
anti-dsDNA ⫽ anti–double-stranded DNA; SLEDAI ⫽ Systemic Lupus Erythematosus Disease Activity
Index.
were recruited. Upon recruitment, the majority of the
SLE patients had active lupus, as indicated by low serum
levels of C3 and C4 and a high serum level of anti-
dsDNA. Two patients had SLEDAI scores ⱕ4, indicat-
ing low levels of disease activity, while the other 12
patients had SLEDAI scores ⬎4. With regard to perfor-
mance on the WCST, the SLE patients and controls
were comparable in terms of the number of rules
identified, the number of errors per rule, and the
reaction time. Table 1 summarizes the demographic
features, clinical data, and WCST performance data of
the study participants.
Signals on fMRI during response selection after
negative feedback versus after positive feedback. Fol-
lowing the rule-shift signal, brain regions that yielded
greater activation during RS after the first NF as com-
pared with the RS after the first PF (RS after first NF ⬎
RS after first PF) implied involvement in response
inhibition of the previously prepotent rule and the need
to search for a new rule. In healthy control subjects,
significantly activated BOLD signals were found in both
middle frontal gyri, the left medial frontal gyrus, the left
inferior parietal lobule, the right angular gyrus, the right
middle occipital gyrus, the right middle temporal gyrus,
the left fusiform gyrus, the right claustrum, the right
globus pallidus (GP), and both thalami. The GP and
thalami, being the critical components of the cortico–
basal ganglia–thalamic–cortical circuit, were involved in
response inhibition and change in behavioral set (20,21).
In patients with SLE, besides brain activation in
various regions within the frontal and parietal lobes, the
declive of the cerebellar vermis was activated while
signals in the right GP and thalami were concomitantly
4051
SLE patients (n ⫽ 14) Healthy controls (n ⫽ 14)
39.38 ⫾ 13.9 34.07 ⫾ 14.4
12/2 12/2
14.43 ⫾ 3.4 13.43 ⫾ 3.4
96.23 ⫾ 15.6 100.43 ⫾ 11.0
70.46 ⫾ 25.0 (28–103) –
15.42 ⫾ 10.9 (3–38) –
132.50 ⫾ 111.3 (1–250) –
9.93 ⫾ 5.7 –
15.32 ⫾ 18.4 –
19.54 ⫾ 3.5 19.50 ⫾ 3.0
3.04 ⫾ 2.5 2.51 ⫾ 0.7
1,679.01 ⫾ 411.3 1,808.51 ⫾ 228.8
absent. However, activated BOLD signals in the right
parahippocampal gyrus and left posterior cingulate were
elicited during the condition contrast of the RS after the
first NF ⬍ RS after the first PF, which was absent in the
healthy controls, implying that SLE patients required
additional activity in these 2 regions to boost reconfigu-
ration of the response strategy for adapting to a new
rule. The brain activation profiles of healthy controls
and SLE during RS after the first NF versus after the
first PF are shown in Table 2 and Figure 2.
Signals on fMRI during negative feedback versus
positive feedback. Regions that showed greater activa-
tion at the second NF as compared with the second PF
(second NF ⬎ second PF) reflected involvement in
generating the identity of a new rule instead of keeping
the prevailing one. In healthy controls, both middle
frontal gyri, the left medial frontal gyrus, the precentral
gyrus, and both inferior parietal lobules were activated
during this condition. In lupus patients, the right supe-
rior frontal gyrus, the bilateral middle frontal gyri, the
right inferior parietal lobule, the left superior parietal
lobule, the left cingulate gyrus, and the right claustrum
were activated instead.
Brain regions that were activated in the second
PF as compared with the second NF (second PF ⬎
second NF) signified their contribution to maintain the
established rule rather than to generate the identity of a
new rule. During this condition, healthy controls had
involvement of their right precentral gyrus, right precu-
neus, left inferior parietal lobule, left middle temporal
gyrus and both hippocampi, left amygdala, right poste-
rior cingulate, left anterior cingulate, and left cingulate
4052 REN ET AL

Table 2. Region of interest during RS and FE in healthy controls and patients with SLE*
Talairach

Brain region x y z Hemisphere BA

Healthy controls
RS after first NF ⬎ RS after first PF 1 Middle frontal gyrus 41 25 30 R 9
(response inhibition) 2 Middle frontal gyrus ⫺34 50 6 L 10
3 Medial frontal gyrus ⫺1 19 45 L 8
4 Angular gyrus 32 ⫺56 39 R 39
5 Inferior parietal lobule ⫺37 ⫺56 42 L 40
6 Middle occipital gyrus 30 ⫺83 ⫺3 R 18
7 Middle temporal gyrus 50 ⫺32 0 R 21
8 Fusiform gyrus ⫺37 ⫺56 ⫺9 L 37
9 Globus Pallidus 14 ⫺2 3 R –
10 Thalamus 12 ⫺7 9 R –
11 Thalamus ⫺10 ⫺8 9 L –
12 Claustrum 29 19 0 R –
RS after first NF ⬍ RS after first PF No significant voxels
RS after second NF vs. RS after second PF No significant voxels
Second NF ⬎ second PF 13 Precentral gyrus ⫺43 1 30 L 6
(generation of new rule identity) 14 Middle frontal gyrus 29 49 3 R 10
15 Middle frontal gyrus ⫺37 50 3 L 10
16 Medial frontal gyrus ⫺1 19 45 L 8
17 Inferior parietal lobule 35 ⫺56 42 R 7
18 Inferior parietal lobule ⫺43 ⫺44 42 L 40
Second NF ⬍ second PF 19 Precentral gyrus 32 ⫺29 57 R 4
(maintenance of established rule) 20 Anterior cingulate ⫺7 43 ⫺6 L 32
21 Posterior cingulate 5 ⫺50 18 R 30
22 Cingulate gyrus ⫺10 ⫺20 39 L 24
23 Precuneus 14 ⫺44 51 R 7
24 Inferior parietal lobule ⫺49 ⫺26 27 L 40
25 Postcentral gyrus 56 ⫺23 21 R 40
26 Middle temporal gyrus ⫺52 ⫺2 ⫺9 L 21
27 Middle temporal gyrus ⫺46 ⫺59 9 L 39
28 Hippocampus 29 ⫺29 ⫺9 R –
29 Hippocampus ⫺27 ⫺29 ⫺9 L –
30 Amygdala ⫺19 ⫺11 ⫺13 L –
First NF vs. first PF No significant voxels
First NF vs. second NF No significant voxels
First PF vs. second PF No significant voxels
Patients with SLE
RS after first NF ⬎ RS after first PF 31 Superior frontal gyrus ⫺31 55 15 L 10
(response inhibition) 32 Middle frontal gyrus 32 10 51 R 6
33 Middle frontal gyrus 29 49 3 R 10
34 Middle frontal gyrus ⫺49 25 27 L 46
35 Superior parietal lobule ⫺31 ⫺68 51 L 7
36 Inferior parietal lobule 44 ⫺56 45 R 40
37 Inferior parietal lobule ⫺37 ⫺50 42 L 40
38 Inferior parietal lobule ⫺55 ⫺47 48 L 40
39 Thalamus ⫺16 ⫺8 6 L –
40 Claustrum 29 22 3 R –
41 Declive of cerebellar vermis 35 ⫺62 ⫺21 R –
42 Declive of cerebellar vermis 5 ⫺74 ⫺18 R –
RS after first NF ⬍ RS after first PF 43 Posterior cingulate ⫺7 ⫺47 21 L 30
(reconfiguration of RS) 44 Parahippocampal gyrus 23 ⫺14 ⫺15 R 28
RS after second NF vs. RS after second PF No significant voxels
Second NF ⬎ second PF 45 Superior frontal gyrus 29 49 12 R 10
(generation of new rule identity) 46 Middle frontal gyrus 41 34 30 R 9
47 Middle frontal gyrus ⫺31 58 6 L 10
48 Middle frontal gyrus ⫺46 25 24 L 46
49 Cingulate gyrus ⫺4 28 33 L 32
50 Superior parietal gyrus ⫺37 ⫺59 54 L 7
51 Inferior parietal gyrus 41 ⫺53 45 R 40
52 Claustrum 29 19 0 R –
fMRI AND COGNITIVE SET-SHIFTING IN SLE 4053

Table 2. (Cont’d)
Talairach

Brain region x y z Hemisphere BA

Second NF ⬍ second PF 53 Precentral gyrus 50 ⫺2 6 R 6
(maintenance of established rule) 54 Paracentral lobule ⫺19 ⫺38 54 L 5
55 Anterior cingulate ⫺7 31 ⫺9 L 32
56 Hippocampus 29 ⫺26 ⫺12 R –
First NF vs. first PF No significant voxels
First NF vs. second NF No significant voxels
First PF vs. second PF No significant voxels

* RS ⫽ response selection; FE ⫽ feedback evaluation; SLE ⫽ systemic lupus erythematosus; BA ⫽ Brodmann area; NF ⫽ negative feedback; PF ⫽
positive feedback.

gyrus (limbic system). In lupus patients, limbic involve- brain activation in healthy controls and SLE for second
ment in rule maintenance occurred only in the right NF versus second PF are described in Table 2 and
hippocampus and left anterior cingulate. Regions of Figure 2.

Figure 2. Composite general linear model of the blood oxygen level–dependent activation pattern seen on functional magnetic resonance imaging
in healthy control subjects and patients with new-onset systemic lupus erythematosus (SLE) during the condition contrasts of response selection (RS)
after the first negative feedback (NF) ⬎ RS after the first positive feedback (PF) as well as the second NF ⬎ the second PF. Red/yellow areas indicate
activation; green/blue areas indicate deactivation. Images are numbered according to the brain region numbering shown in Table 2.
4054
DISCUSSION
We found that the cortico–basal ganglia–
thalamic–cortical circuit, which is involved in response
inhibition, was dysfunctional in lupus patients, even if
they did not manifest clinically overt neuropsychiatric
symptoms. To compensate for the dysfunction of the
circuit in the lupus patients, the contralateral cerebellar
and frontal areas of the brain were activated. Addition-
ally, lupus patients showed altered activities at the
amygdala and hippocampus while they tried to maintain
prepotent rules during cognitive set-shifting.
While experiencing the maximum cognitive de-
mand for withholding the previous prepotent rule and
the response inhibition throughout the cognitive set-
shifting processes, healthy subjects showed increased
brain activation in the right middle frontal gyrus, the
right GP, and both thalami in a synchronous pattern
across the cognitive set-shifting processes (Figure 3A).
The dorsolateral prefrontal cortex is involved in working
memory, in the switching of cognitive sets, and in the
inhibitory control of the prepotent response (20,22).
Since the right middle frontal gyrus belongs to the
dorsolateral prefrontal cortex, it implies that it partici-
pates in conditions that require functional working
memory and switching of cognitive sets. Furthermore, it
was previously proposed that response suppression re-
quired the functional integrity of the prefrontal cortex,
basal ganglia, and thalami. Functionally, these 3 regions
form the cortico–basal ganglia–thalamic–cortical circuit
that was believed to coordinate the function of the
cortical regions involved (21–25).
Studies have identified the indirect pathway that
connected these regions, showing that the cortex, stria-
tum, external segment of the GP, subthalamic nucleus,
internal segment of the GP, thalami, and cortex were
involved sequentially in implementing response suppres-
sion and in changing the behavioral set (26). However,
we did not observe brain activation at the right GP and
right thalamus in patients with SLE when the cognitive
demand for inhibitory response control was dominant,
implying that information flow from the striatum to the
thalamus was compromised, which resulted in the deficit
of response control in SLE patients under this circum-
stance. Although the left thalamus was still activated in
the lupus patients, the magnitude of the activation signal
in the same region was lower than that in the healthy
controls (Figure 3B).
Besides its role in the response inhibition circuit,
a number of lesion studies have shown that the GP is one
of the important neural components that mediate exec-
REN ET AL
utive cognitive function (27,28). For example, patients
with advanced Parkinson’s disease were unable to shift
attention after undergoing bilateral pallidotomy (29).
Similarly, disturbance of metabolism in the thalamus was
demonstrated in children with Sturge-Weber syndrome
(30), of which cognitive dysfunction is one of the most
common symptoms. Therefore, the absence of activity in
the right GP and right thalamus in our lupus patients
suggests that they had impaired response inhibition and
reduced capability for behavioral change secondary to
dysfunction of the cortico–basal ganglia–thalamic–
cortical circuit.
Notably, the absence of brain activation at the
right GP and right thalamus as mentioned above was
coupled with an increase in brain activity at the declive
of the right cerebellar vermis in lupus patients. A few
anatomic, physiologic, and neuroimaging studies dem-
onstrated that cerebellar damage led to impairment of
executive function, spatial cognition, language, and per-
sonality change (31). On the other hand, overreliance on
cerebellar activities was demonstrated in patients with
schizophrenia, alcoholism, and cocaine abuse during
evaluation of working memory, verbal working memory,
and executive control, respectively (32–35). In our study,
the increased activity in the right cerebellum was cou-
pled with activation of the left prefrontal cortex (left
superior frontal gyrus and middle frontal gyrus) in lupus
patients. This activation pattern is reminiscent of in-
creased brain activation in the left frontal–right cerebel-
lar circuit in alcoholics during verbal memory testing
(34), which is consistent with the observations that
cerebellar activation often occurs in conjunction with
contralateral frontal lobe activation (35). In our study,
analysis of brain activities at the declive of the cerebellar
vermis and the left middle and superior frontal gyri
revealed a rather similar activation pattern during the
course of cognitive set-shifting (Figure 3C), further
implying the conjugated role of the right cerebellum and
left frontal regions during different stages of cognitive
set-shifting.
Cerebellar activities, coupled with brain activa-
tion in the contralateral frontal areas, have been sug-
gested to compensate for articulatory and inhibitory
controls in patients with alcoholism and cocaine abuse,
respectively, in order to maintain normal cognitive func-
tion (34,35). Taken together with another recent finding
of the cerebellum–basal ganglia interconnections in an
anatomic study performed in primates (36), we postu-
lated that in patients with SLE, the increased right
cerebellar activities and its coupled left prefrontal activ-
ities may serve to compensate for the dysfunction of
fMRI AND COGNITIVE SET-SHIFTING IN SLE 4055

Figure 3. Brain signal changes across the cognitive set-shifting process. A, Cortico–basal ganglia loop activity in healthy control subjects. B, Left
thalamus activity in healthy controls and patients with new-onset systemic lupus erythematosus (SLE). C, Cerebellar–contralateral frontal activity
in SLE patients. The Talairach x, y, and z coordinates for the right declive of the cerebellar vermis are shown in the key to C to distinguish the two
graphs. Red/yellow areas indicate activation; green/blue areas indicate deactivation. Numbered images at the bottom correspond to the numbered
␤ score graphs at the top. Values are the mean and images are the composite of 14 healthy control subjects and 14 SLE patients. NF ⫽ negative
feedback; RS ⫽ response selection; PF ⫽ positive feedback. Color figure can be viewed in the online issue, which is available at
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.
4056
inhibitory control secondary to the compromised
cortico–basal ganglia–thalamic–cortical circuit in order
to maintain the performance of the set-shifting tasks.
Consistent with the findings of other functional imaging
studies, the compensatory activations that aided the
dysfunctional cortico–basal ganglia–thalamic circuit
found in our study illustrate the adaptability and plas-
ticity of the brain to recruiting neural networks to serve
those functions that have been damaged. For example,
in order to maintain performance levels, generalized
brain activations were demonstrated in subjects with
age-related degeneration in motor performance of the
hands (37). Relevant to SLE, a few recent studies
demonstrated generalized brain activation in lupus pa-
tients during the performance of neuropsychological
tasks (6,7,10,38). Importantly, compensatory BOLD sig-
nal intensity decreased in lupus patients with disease
duration of ⬎10 years, suggesting that compensatory
activations may decrease when irreversible neuron dam-
age has set in (38).
When being challenged to adapt to a new rule
during cognitive-set shifting, the right parahippocampal
gyrus and left posterior cingulate were activated in SLE
patients in order to reconfigure their response strategy
and to adapt to a new rule, whereas among the healthy
controls, no significant brain activities in these two
regions were observed. The altered activities of the
posterior cingulate and parahippocampus were consis-
tent with two recently published studies in SLE patients
without NPSLE and in patients with schizophrenia
(11,39), which suggested that there was attenuation of
the intrinsic default mode network, episodic memory
problem, and related cognitive deficits. The default
mode network is regarded as a resting state of brain
function and is involved in the planning of future events
and ongoing information processing.
The condition contrast second NF ⬎ second PF
indicated brain regions where involvement of new rule
generation dominated the maintenance of an estab-
lished rule. In healthy controls, both hippocampi were
deactivated during this condition contrast, indicating
their involvement in maintaining an identified rule. Most
brain regions that contributed more to rule generation
than to rule maintenance in SLE patients and healthy
subjects overlapped, suggesting that brain activities un-
derlying this cognitive process remained intact in lupus
patients. Further analysis revealed that activities of both
hippocampi initially decreased during the “generate”
event, when the identity of the new rule was unknown.
Subsequently, during the “update” and “maintain”
events, while the new rule was identified and maintained
REN ET AL
in memory, both hippocampi were activated. This find-
ing is consistent with the putative role of the hippocam-
pus in set-shifting, in which decreased hippocampal
activity at the generation event would facilitate active
forgetting of the previous rule and a shift to a new
cognitive set, while the subsequent increased hippocam-
pal activity at the update and maintenance events would
enhance learning of the new rule to guide ensuing trials
(15). Interestingly, the left amygdala appeared to follow
a synchronous activity pattern with both hippocampi
across all stages of set-shifting (Figure 4A).
The neural activity underlying FE has been pro-
posed as a result of the response to reward or punish-
ment of the feedback stimulus (14). Hippocampal activ-
ities appear to be reinforced and maintained by the
amygdala through the generation of rewards (40), sug-
gesting the coupled role of the amygdala and the hip-
pocampus in set-shifting processes observed in our
study. However, involvement of the left hippocampus
and left amygdala in rule maintenance was absent in our
SLE patients, implying a compromise of the active
forgetting–learning dynamics in set-shifting despite the
fact that the right hippocampus was still required to
maintain the established rule in a pattern similar to that
in healthy controls (Figure 4B). As in patients with SLE,
altered amygdala and hippocampal activities within the
default mode network have been demonstrated in pa-
tients with depression and Alzheimer’s disease (41,42).
These findings may signify a potential common patho-
logic basis of the disrupted forgetting–learning dynamics
that involves the amygdala and hippocampi in patients
with SLE, depression, and dementia.
While further mechanistic evaluation is required
to explain the BOLD signal changes, especially those
involved in hippocampus–amygdala coupling, and the
absence of BOLD signals in the hippocampus and
amygdala in our patients with SLE, the well-investigated
anti–N-methyl-D-aspartate (NMDA) receptor antibod-
ies and anti–ribosomal P antibodies may be potentially
contributory. The NMDA receptors are mainly ex-
pressed in the neurons of the hippocampi and amygdala.
Under physiologic conditions, the neurotransmitter glu-
tamate activates the receptors and mediates learning
and memory by manipulating synaptic plasticity (43). In
animal models, antagonizing the NR2 subunit of the
NMDA receptor (anti-NR2 antibody) led to impaired
memory and learning (43). Because anti-NR2 is present
in the serum and cerebrospinal fluid of NPSLE patients
(43), a potential pathogenetic role of anti-NR2 antibody
in cognitive dysfunction has been advocated (44). In-
deed, anti-NR2 purified from lupus patients was able to
fMRI AND COGNITIVE SET-SHIFTING IN SLE 4057

Figure 4. Brain signal changes in the hippocampus and amygdala across the cognitive set-shifting process. A, Hippocampal and amygdala activity
in healthy control subjects. B, Right hippocampal activity in healthy controls and patients with new-onset systemic lupus erythematosus (SLE).
Red/yellow areas indicate activation; green/blue areas indicate deactivation. Numbered images at the bottom correspond to the numbered ␤ score
graphs at the top. Values are the mean and images are the composite of 14 healthy control subjects and 14 SLE patients. NF ⫽ negative feedback;
RS ⫽ response selection; PF ⫽ positive feedback. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.
com/journal/10.1002/(ISSN)1529-0131.

induce cognitive impairment, memory deficits, and hip-
pocampal neurotoxicity in BALB/c mice (45,46). It was
recently shown that anti-NR2 antibody exerted its cyto-
toxic effects on neurons by increasing intracellular cal-
cium levels through inhibition of the binding capacity of
zinc at the zinc-binding site of the NMDA receptor,
resulting in reduced cell viability (47).
As for the anti–ribosomal P antibodies, a clinical
study in the 1980s demonstrated that the serum titer of
anti–ribosomal P antibodies was selectively raised in
lupus patients with active psychosis, although not all
subsequent studies were able to replicate the associa-
tions between the antibodies and psychosis as well as
depression in patients with SLE (48). Nevertheless,
induction of autoimmune depression in C3H/HeJ mice
by intracerebroventricular injection of affinity-purified
anti–ribosomal P antibodies revealed that the antibodies
bound specifically to the pyramidal cell layer and dentate
gyrus of the hippocampus and other areas of the limbic
system that could be significantly counteracted by anti-
idiotypic antibodies to anti–ribosomal P antibodies (49).
This study has a few limitations. First, the sample
size is relatively small. However, sample sizes of this
magnitude have consistently demonstrated sufficient
sensitivity of BOLD signals to achieve statistical signif-
icance (14,15). Second, patients with SLE were given
prednisolone treatment at the time of the fMRI scan,
and the possible effects of medication on BOLD signals
may confound the interpretation of our results. Since the
majority of patients underwent fMRI scanning within
2 months of the diagnosis of SLE, with a mean ⫾ SD
exposure to initial immunosuppressive therapy of
36.86 ⫾ 35.5 days (range 8–143 days) prior to the scan,
the effect of treatment on BOLD signals should be
minimal.
In summary, our findings demonstrate that pa-
tients with SLE, even without clinically overt neuropsy-
chiatric symptoms, had abnormal sequential brain activ-
4058
ities involving the basal ganglia, hippocampi, and amyg-
dala, which indicated a compromised cortico–basal
ganglia–thalamic–cortical circuit and hippocampus–
amygdala coupling in comparison with healthy subjects.
These results translate into a potential compromise in
response inhibition and the active forgetting–learning
dynamics in lupus patients. Moreover, patients with SLE
demonstrated overreliance on the cerebellar–contralateral
frontal conjunction activities to compensate for the dys-
function of the compromised cortico–basal ganglia–
thalamo–cortical circuit. While scientifically, our results
highlight a potential pathologic brain network, which
should prompt further investigation into the functional
neuropathophysiology of cognitive dysfunction in pa-
tients with SLE, the practical clinical implication is that
physicians who treat lupus patients may need to be aware
of their potential reluctance to change their existing
knowledge and adapt to new information, such as in
situations where pharmacologic treatment and lifestyle
need to be modified for the optimization of disease
control and the prevention of organ damage.
ACKNOWLEDGMENT
We would like to thank Dr. Steven Graham for pro-
fessional assistance regarding data acquisition, control recruit-
ment, teaching, and initial analyses.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Mak had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Ren, Ho, Mak.
Acquisition of data. Ren, Ho, Mak.
Analysis and interpretation of data. Ren, Mak.
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