A JOURNAL OF NEUROLOGY
Reduced functional connectivity in a
right-hemisphere network for volitional
ocular motor control in schizophrenia
Peichi Tu,1,2Randy L. Buckner,2,3,4,5,6Lilla Zollei,4Kara A. Dyckman,2Donald C. Goff2and
Dara S. Manoach2,5
1 Institute of Neuroscience, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan
2 Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
3 Department of Psychology and Center for Brain Science, Harvard University, Cambridge, MA, USA
4 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
5 Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA
6 Howard Hughes Medical Institute, Chevy Chase, MD, USA
Correspondence to: Dara S. Manoach,
Departments of Psychiatry,
Massachusetts General Hospital and Harvard Medical School,
149 13th St., Room 1.111,
Charlestown, MA 02129,
Patients with schizophrenia consistently show deficient performance on tasks requiring volitional saccades. We previously
reported reduced fractional anisotropy in the white matter underlying right dorsal anterior cingulate cortex in schizophrenia,
which, along with lower fractional anisotropy in the right frontal eye field and posterior parietal cortex, predicted longer
latencies of volitional saccades. This suggests that reduced microstructural integrity of dorsal anterior cingulate cortex white
matter disrupts connectivity in the right hemisphere-dominant network for spatial attention and volitional ocular motor control.
To test this hypothesis, we examined functional connectivity of the cingulate eye field component of this network, which is
located in dorsal anterior cingulate cortex, during a task comprising volitional prosaccades and antisaccades. In patients with
schizophrenia, we expected to find reduced functional connectivity, specifically in the right hemisphere, which predicted
prolonged saccadic latency. Twenty-seven medicated schizophrenia outpatients and 21 demographically matched healthy con-
trols performed volitional saccades during functional magnetic resonance imaging. Based on task-related activation, seed
regions in the right and left cingulate eye field were defined. In both groups, the right and left cingulate eye field showed
positive correlations with the ocular motor network and negative correlations with the default network. Patients showed reduced
positive functional connectivity of the cingulate eye field, specifically in the right hemisphere. Negative functional connectivity
of the right cingulate eye field predicted faster saccades, but these relations differed by group, and were only present in
controls. This pattern of relations suggests that the coordination of activity between ocular motor and default networks is
important for efficient task performance and is disrupted in schizophrenia. Along with prior observations of reduced white
matter microstructural integrity (fractional anisotropy) in schizophrenia, the present finding of reduced functional connectivity
suggests that functional and structural abnormalities of the right cingulate eye field disrupt connectivity in the network for
spatial attention and volitional ocular motor control. These abnormalities may contribute to deficits in overcoming prepotency in
the service of directing eye gaze and attention to the parts of the environment that are the most behaviourally relevant.
doi:10.1093/brain/awp317Brain 2010: 133; 625–637 |
Received August 11, 2009. Revised October 16, 2009. Accepted October 28, 2009
? The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: email@example.com
Keywords: saccadic eye movements; schizophrenia; anterior cingulate cortex; fMRI; executive control
Abbreviations: CEF=cingulate eye field; fMRI=functional magnetic resonance imaging; FSL=Functional MRI of the Brain Software
Library; MNI=Montreal Neurological Institute
Patients with schizophrenia consistently show performance deficits
on tasks requiring volitional saccades (Manoach et al., 2002;
Calkins et al., 2003; Harris et al., 2006; Radant et al., 2007)
that are associated with abnormal activation of the anterior
cingulate cortex (Crawford et al., 1996; Camchong et al., 2008;
Polli et al., 2008). The anterior cingulate cortex is a large and
heterogeneous region that can be partitioned on the basis of
cytoarchitecture, function and both structural and functional
connectivity (Devinsky et al., 1995; Bush et al., 2000; Koski and
Paus, 2000; Margulies et al., 2007). Here, we focus on the dorsal
anterior cingulate cortex, which is structurally (Pandya et al.,
1981; Morecraft et al., 1993) and functionally (Koski and Paus,
2000; Margulies et al., 2007) connected to premotor, motor and
ocular motor regions, consistent with its putative role in providing
top-down control of motor (Miller and Cohen, 2001) and ocular
motor (Johnston et al., 2007) responses. More specifically, the
posterior part of the dorsal anterior cingulate cortex has been
labelled the cingulate eye field (CEF) based on its involvement in
tasks requiring volitional saccadic control (Paus et al., 1993;
Gaymard et al., 1998; Pierrot-Deseilligny et al., 2004). In mon-
keys, stimulation of the dorsal bank of cingulate sulcus, ventral to
the supplementary eyefield,
Godschalk, 1989). In humans, lesions of the posterior dorsal
anterior cingulate cortex increase antisaccade errors (Milea et al.,
2003) and prolong the latencies of both prosaccades and
antisaccades (Gaymard et al., 1998).
Using diffusion tensor imaging, Manoach et al. (2007a)
reported reduced microstructural integrity, measured as fractional
anisotropy, of the white matter underlying the dorsal anterior
cingulate cortex of the right hemisphere in schizophrenia, which,
along with lower fractional anisotropy in the white matter under-
lying the right frontal eye field and the right posterior parietal
cortex, predicted longer latencies of volitional saccades. These
three regions comprise the key cortical components of a right
hemisphere dominant network for the spatial distribution of atten-
tion and eye gaze (Mesulam, 1981, 1990; Gitelman et al., 1999),
which are tightly linked (Klein and McCormick, 1989; Corbetta
and Shulman, 2002; Hunt and Kingstone, 2003; Moore et al.,
2003). These findings support the hypothesis that in schizophre-
nia, anterior cingulate cortex abnormalities compromise the func-
tion of the distributed network critical for spatial attention and
volitional ocular motor control. Here, to evaluate this hypothesis
further, we examined functional MRI (fMRI) measurements of
functional connectivity of the CEF during the performance of
volitional saccades in individuals with schizophrenia compared
with healthy controls. Functional connectivity MRI (Biswal et al.,
1995; Fox and Raichle, 2007; Van Dijk et al., in press) has proven
to be a powerful method for evaluating network dysfunction in
neuropsychiatric disorders (Buckner et al., 2008; Greicius, 2008;
Calhoun et al., 2009). We hypothesized that patients with
specifically of the right CEF, during saccadic performance and
that this would be associated with prolonged saccadic latencies.
The schizophrenia sample comprised 27 out-patients recruited from
an urban community mental health centre. Twenty-five had been
maintained on stable doses of a variety of anti-psychotic medications
for at least 6 weeks; 24 took atypical agents (risperidone, aripiprazole,
clozapine, olazapine and quetiapine) and one took prolixin. Two
patients had discontinued their anti-psychotic medications at least
6 weeks prior to the study. No patient took anti-cholinergic medica-
tions and nine took diverse adjunctive medications for anxiety, agita-
tion and/or concurrent mood disturbance. Diagnosis was confirmed
with the Structured Clinical Interview in the Diagnostic and Statistical
Manual of Mental Disorders (SCI-DSM)-IV (First et al., 1997). Clinical
status was characterized with the Brief Psychiatric Rating Scale (Overall
and Gorham, 1962), the Positive and Negative Syndrome Scale (Kay
et al., 1987) and the Scale for the Assessment of Negative Symptoms
(Andreasen, 1983). (Table 1 provides demographic information and
clinical ratings.) Twenty-one healthy control participants, screened to
exclude those witha personal
(SCIDSM-Non-patient edition, First et al., 2002) or a family history
of schizophrenia spectrum disorders, were recruited from the commu-
nity with poster and website advertisements.
Participants were screened to exclude substance abuse or depen-
dence within the past 6 months, a history of head injury resulting in
a sustained loss of consciousness and/or cognitive sequelae, neurolog-
ical illness, and any disorder affecting cerebral metabolism. Groups did
not differ in age, gender, handedness as measured by the modified
Edinburgh Handedness Inventory (Oldfield, 1971; White and Ashton,
1976), or parental education. The study was approved by the Partners
Human Research Committee and the Central Office Research Review
Committee of the Massachusetts Department of Mental Health.
All participants gave written informed consent after the experimental
procedures had been fully explained.
historyof mental illness
The paradigm consisted of a pseudorandom series of prosaccades and
antisaccades. Prosaccades are the prepotent response of looking
towards a suddenly appearing visual stimulus, while antisaccades
require inhibition of the prepotent prosaccade and the generation of
the novel behaviour of looking in the opposite direction (Hallett,
1978). Since prosaccade and antisaccade trials were inter-mixed and
both required participants to respond according to an instructional cue,
both trial types required volitional saccades.
Prior to scanning, the task was explained and participants practiced
in a mock scanner. Participants were encouraged to respond as quickly
and accurately as possible. In addition to a base rate of pay, they
received 5 cents for each correct response, an incentive intended to
enhance attention and motivation. Each run of the task consisted of a
Brain 2010: 133; 625–637P. Tu et al.
pseudorandom sequence of prosaccade and antisaccade trials that
were balanced for right and left movements. Figure 1 provides a
graphic depiction of the task and a description of task parameters.
Randomly inter-leaved with the saccadic trials were intervals of fixa-
tion lasting 2, 4 or 6s. The fixation trials provided a baseline for anal-
yses of task-related activation and their variable length introduced
‘temporal jitter’, which optimizes the analysis of rapid presentation
event-related fMRI designs (Buckner et al., 1998; Burock and Dale,
2000; Miezin et al., 2000). Participants performed six runs of the task,
each lasting 5min 22s, with short rests between runs. The total exper-
iment lasted about 40min and generated a total of 211 prosaccade
trials, 211 antisaccade trials and 80 fixation intervals.
Stimulus display and eye tracking
Displays of the eye movement task were generated using the
Vision Shell programming platform, and back-projected with a Sharp
XG-2000 colour LCD projector (Osaka, Japan) onto a screen at the
rear of the bore that was viewed by the participant via a mirror on the
head coil. Vision Shell triggered the scanner to begin acquiring data.
The ISCAN fMRI Remote Eye Tracking Laboratory (ISCAN, Burlington,
MA, USA) was used to sample eye position at a rate of 60Hz during
scanning. Stimuli presented by Vision Shell were digitally encoded and
relayed to ISCAN as triggers that were inserted into the eye position
Eye position data were scored in MATLAB (Mathworks, Natick, MA,
USA) using a partially automated programme that determined the
directional accuracy of each saccade with respect to the required
response and the latency from target onset. Saccades were identified
as horizontal eye movements with velocities exceeding 47?/s. The
onset of a saccade was defined as the point at which the velocity of
the eye movement first exceeded 31?/s. Only trials with saccades in the
desired direction and latencies over 130ms were considered correct,
and only correct saccades were included in the latency analyses. The
cutoff of 130ms excluded anticipatory saccades, which are executed
too quickly to be a valid response to the appearance of the target
(Fischer and Breitmeyer, 1987). Error rate and latency of correct trials
were compared using repeated measures ANOVA with factors for
group (schizophrenia, control), condition, (antisaccade, prosaccade)
and their interaction. Error rate was logit transformed in all analyses.
Images were acquired with a 3.0T Siemens Trio whole body
(Siemens Medical Systems, Erlangen, Germany). Head stabilization
was achieved with cushioning, and all participants wore earplugs
(29 dB rating) to attenuate noise. Automated shimming procedures
were performed and scout images were obtained. Two high-resolution
structural images were acquired in the sagittal plane using a high
resolution 3D magnetization prepared rapid gradient echo sequence
(repetition time, 2530ms; echo spacing, 7.25ms; echo time, 3ms; flip
angle 7?; field of view, 256mm; matrix, 256?256) with an in-plane
resolution of 1 and 1.3mm slice thickness. T1- and T2-weighted struc-
tural images, with the same slice specifications as the blood oxygen
level dependent scans, were obtained to assist in registering functional
and structural images.
T2?-weighted sequence (repetition time/echo time/Flip=2000ms/
30ms/90?; field of view, 200mm; matrix, 64?64). Twenty contigu-
ous horizontal slices, parallel to the inter-commissural plane (voxel size:
3.13?3.13?5mm), were acquired inter-leaved.
motion (Thesen et al., 2000). Prospective acquisition correction adjusts
slice position and orientation in real time during data acquisition to
reduce motion-induced effects on magnetization history.
usinga gradient echo
Analyses of functional data
Functional scans were corrected retrospectively for motion using the
Analysis of Functional NeuroImages algorithm (Cox and Jesmanowicz,
CEF seed region definition
We defined the CEF using both Montreal Neurological Institute (MNI)
anatomical criteria for anterior cingulate cortex and fMRI activation
during the performance of volitional saccades. In the averaged func-
tional data of all participants, unbiased to participant group, we com-
puted the contrast of all correct trials versus fixation at 4s, which is the
time of peak ocular motor response (Polli et al., 2005). This analysis
was conducted using FreeSurfer Functional Analysis Stream software
(Burock and Dale, 2000). Motion-corrected functional scans were
intensity normalized, and smoothed using a 3D 8mm full width at
half maximum Gaussian kernel. For each participant, finite impulse
response estimates (Burock and Dale, 2000; Miezin et al., 2000) of
the event-related haemodynamic responses were calculated for four
trial types (correct and error prosaccades and antisaccades) at 12 time
points with an interval of 2s (corresponding to the repetition time),
ranging from 4s before the start of a trial to 18s after the start.
Table 1 Means, standard deviations, and group comparisons of demographic data and rating scale scores for patients
Participant characteristics Healthy controls (n=21)Schizophrenia patients (n=27)tP
Level of severity
Age of onset
Length of illness (years)
BPRS=Brief Psychiatric Rating Scale; PANSS=Positive and Negative Syndrome Scale; SANS=Scale for the Assessment of Negative Symptoms.
Reduced connectivity in schizophreniaBrain 2010: 133; 625–637 |
To obtain estimates of the haemodynamic responses in the averaged
group data, individual contrast images were registered to the MNI152
atlas with the Functional MRI of the Brain Software Library (FSL;
www.fmrib.ox.ac.uk/fsl) using the same registration matrix as the
functional connectivity analysis, and activation was examined using a
random effects model. As in prior studies of this paradigm (Polli et al.,
2005; Manoach et al., 2007b), we observed significant task-related
activation in dorsal anterior cingulate cortex at 4s (corrected for
multiple comparisons based on 10000 Monte Carlo simulations of
synthesized white Gaussian noise using a P-value of 40.05 and the
smoothing, resampling and averaging parameters of the functional
analyses). Right and left CEF seed regions were defined as spheres
of 4mm radius around the peak voxels (Fig. 2).
Functional connectivity pre-processing
The motion corrected functional scans were registered to the MNI152
atlas (Collins et al., 1994) using FSL. Additional pre-processing steps,
described in previous reports (Fox et al., 2005; Vincent et al., 2006;
Van Dijk et al., in press), were: (i) spatial smoothing using a Gaussian
kernel of 6mm full-width at half-maximum; (ii) temporal filtering
(0.009Hz5f50.08Hz); (iii) removal of spurious or non-specific
sources of variance by regression of the following variables: (a) the
six movement parameters computed by rigid body translation and
rotation in preprocessing, (b) the mean whole brain signal, (c) the
mean signal within the lateral ventricles and (d) the mean signal
within a deep white matter region of interest. The first temporal deriv-
atives of these regressors were included in the linear model to account
for the time-shifted versions of spurious variance. Regression of each
of these signals was computed simultaneously and the residual time
course was retained for the correlation analysis.
Functional connectivity analysis
Blood oxygen level dependent time courses of the right and left CEF
seed regions were based on the average signal across voxels. A
Pearson correlation map was created for the time course of each
seed region and all of the other voxels in the brain. To avoid auto-
correlation, a sphere of 10mm radius around the voxel at the centre of
the seed was excluded from analysis. The correlation map of each
participant was converted to a map of z-scores using a Fisher’s z
transform (Vincent et al., 2006).
Figure 1 Saccadic paradigm with idealized eye position traces. Saccadic trials lasted 4000 ms and began with an instructional cue at the
centre of the screen. For half of the participants, orange concentric rings were the cue for a prosaccade trial (A) and a blue cross was the
cue for an antisaccade trial (B). These cues were reversed for the rest of the participants. The cue was flanked horizontally by two small
green squares of 0.2?width that marked the potential locations of stimulus appearance, 10?left and right of centre. These squares
remained on the screen for the duration of each run. (C) At 300ms, the instructional cue was replaced by a green fixation ring at the
centre of the screen, of 0.4?diameter and luminance of 20cd/m2. After 1700ms, the ring shifted to one of the two target locations, right
or left, with equal probability. This was the stimulus to which the participant responded by either making a saccade to it (prosaccade) or to
the square on the opposite side (anti saccade). The green ring remained in the peripheral location for 1000ms and then returned to the
centre, where participants were also to return their gaze for 1000ms before the start of the next trial. Fixation intervals were simply a
continuation of the fixation display that constituted the final second of the previous saccadic trial.
Brain 2010: 133; 625–637 P. Tu et al.
We first examined positive and negative CEF functional connectivity
in the averaged data of all participants using a false discovery rate
threshold of P50.001. Based on this analysis, we created four
masks: positive and negative functional connectivity for the right
and left CEF. For each participant, we derived a single value for
each mask by averaging the z-scores for the correlation coefficients
across all the voxels in the mask. Using these ‘global functional
connectivity’ values, we compared groups using repeated measures
ANOVAs with factors of group, hemisphere and their interaction.
To determine whether there were regionally specific group differ-
ences in functional connectivity, we also compared groups at each
voxel in the brain. The group difference map was thresholded at
P50.001 and a cluster-wise threshold of P50.05 was used to control
for multiple comparisons.
Correlations of CEF functional connectivity with
The association between CEF functional connectivity and saccadic
latency, adjusting both variables for age, was investigated using
multiple regression analyses. For these regressions, global functional
connectivity (see above) was the dependent variable and saccadic
latency and age were covariates. An interaction term (latency by
group) was included in the model to test whether the slope of the
relation differed by group. The mean latency of correct prosaccades or
antisaccades was the covariate of interest. Age was regarded as a
potential confound given the documented relation of age with
decreased functional connectivity (Andrews-Hanna et al., 2007;
Damoiseaux et al., 2007; Sambataro et al., 2008) and increased
saccadic latency (Munoz et al., 1998).
Effect of anti-psychotic medications
To estimate the effect of medication on functional connectivity and to
determine whether group differences and correlations with behaviour
remained significant when this effect was statistically controlled,
we regressed functional connectivity measures on anti-psychotic
medication dose as measured by chlorpromazine equivalent (Woods,
2003) for each mask. We adjusted the estimates of functional
connectivity by subtracting the product of the slope of the regression
and chlorpromazine equivalent from activation for each region of
interest in each participant with schizophrenia. These adjusted
functional connectivity measures for patients and the original measures
for controls were entered into the group comparison and correlation
analyses described above.
Two controls and one patient were missing latency data due to
technical problems). The groups did not differ significantly in the
Figure 2 CEF seed regions displayed on coronal and sagittal views of the averaged structural MRI image of study participants registered
to the MNI152 atlas (Collins et al., 1994). Top row=left CEF: Brodmann’s area 24, –8, 8, 50; bottom row=right CEF, Brodmann’s area
32, 12, 16, 38.
Reduced connectivity in schizophrenia Brain 2010: 133; 625–637 |
latency of correct saccades [F(1,42) =0.80, P=0.38], regardless of
the task [Group?Task: F(1,42)
Participants with schizophrenia made significantly more errors
than controls [F(1,46) =12.55, P=0.001], and compared with
controls, they made disproportionately more errors on antisaccade
than prosaccade trials [Group?Task: F(1,46) =7.19, P=0.01;
=1.89, P=0.18] (Fig. 3).
CEF functional connectivity in the combined groups
Positive functional connectivity was similar for the right and left
CEFs (Fig. 4). For both seeds, the strongest correlation was with
the homologous region of the other hemisphere, as in a previous
study (Margulies et al., 2007). Significant correlations were
also observed bilaterally in premotor and ocular motor regions,
including the frontal and supplementary eye fields, posterior pari-
etal cortex, supplementary motor area and pre-supplementary
motor area. Additional regions showing correlations were bilateral
Supplementary Table S1 for a complete list of regions).
The right and left CEF were both negatively correlated with regions
that comprise the default network (Shulman et al., 1997; Gusnard
et al., 2001; Mazoyer et al., 2001; Raichle et al., 2001; Buckner
et al., 2008) including: the ventromedial prefrontal cortex, rostral
anterior cingulate cortex, posterior cingulate gyrus, angular gyrus
and superior temporal sulcus and gyrus. Negative correlations,
given our pre-processing step of whole brain signal regression,
must be interpreted with caution (see Discussion section, Chang
and Glover, 2009; Murphy et al., 2009).
Group comparisons of CEF functional connectivity
Positive global functional connectivity
The main effects of group [F(1,46) =1.29, P=0.26] and hemi-
sphere [F(1,46) =2.96, P=0.09] were not significant, but there
was a significant group by hemisphere interaction [Fig. 4A;
F(1,46) =5.92, P=0.02]. As predicted, compared with controls,
patientsshowed reduced positivefunctional connectivity
Figure 3 Bar graphs of performance by group and task
measured as mean and standard errors of (A) latency of
correct saccades and (B) error rate. HC=healthy controls;
SZ=schizophrenia; PS=prosaccade; AS=antisaccade. Asterisks
denote statistical significance.
Figure 4 Regions showing significant (false-discovery rate
corrected P50.001) positive and negative functional
connectivity with left and right CEF in the combined group data
displayed on the lateral and medial inflated cortical surfaces.
Brain 2010: 133; 625–637P. Tu et al.
t(46)=0.25, P=0.80; Fig. 5a]. In addition, patients showed signif-
icant leftward asymmetry of functional connectivity [t(26) =2.78,
P=0.01], while controls showed no significant asymmetry [t(20)
Negative global functional connectivity
Neither the main effect of group [F(1,46) =0.006, P=0.94] nor
hemisphere [F(1,46) =0.24, P=0.63] was significant, but the
group by hemisphere interaction was [F(1,46) =6.57, P=0.01],
reflecting the different patterns of hemispheric asymmetry by
group (Fig. 5b). As was the case with positive functional connec-
tivity, patients showed a trend to leftward asymmetry of negative
contrast, controls showed a significant rightward asymmetry of
negative functional connectivity
groups did not differ significantly, however, in negative functional
connectivity in either hemisphere [right: t(46)=1.42, P=0.16; left:
t(46) = 1.15, P=0.25].
Regionally specific group differences in functional connectivity
Relative to controls, patients showed significantly reduced func-
tional connectivity of the right CEF with the left thalamus, right
pre-supplementary motor area and right anterior insula (Fig. 6 and
Table 2). There were no significant group differences in the
functional connectivity of the left CEF.
Relations of global CEF functional connectivity with
Positive functional connectivity did not correlate with saccadic
latency in the combined group (all P’s40.3). However, greater
negative functional connectivity of the right CEF predicted faster
prosaccade and antisaccade latencies (Table 3 and Fig. 7). These
relations differed by group, significantly for prosaccades, and at a
trend level for antisaccades (Table 3). These group differences
reflected that controls showed strong and significant relations
(P’s40.01), while in patients the slopes of the relations were
On an exploratory basis, we also examined the correlations of
CEF functional connectivity with error rate. Neither positive nor
negative CEF functional connectivity significantly correlated with
either antisaccade or prosaccade error rate in the combined group.
Control analyses with functional connectivity measure-
ments adjusted for chloropromazine equivalent
In patients, chloropromazine equivalent was not significantly
related to functional connectivity in any mask (all P’s50.42).
Adjusting functional connectivity measurements for chloroproma-
zine equivalents in patients did not substantially alter the findings
of either the group comparisons or the correlations with behaviour
(i.e. all significant findings remained). That the findings were
unchanged reflects that the slopes of the relations of functional
connectivity measurements to chloropromazine equivalent were all
very low (510?4), and consequently the adjusted functional
connectivity values were very close to the original ones.
Compared with controls, patients with schizophrenia showed
reduced positive functional connectivity of the CEF, specifically
in the right hemisphere, during the performance of volitional
saccades. In both groups, the CEFs showed positive functional
connectivity with premotor and ocular motor regions, including
the frontal eye field and the posterior parietal cortex. This pattern
of connectivity is similar to that observed in a previous study that
placedseeds in posteriordorsalanteriorcingulate cortex
Figure 5 Bar graphs of (A) positive functional connectivity and
(B) negative functional connectivity divided by group and
hemisphere. Correlations are expressed as z-scores with
standard error bars. HC=healthy controls; SZ=schizophrenia.
Asterisks denote statistical significance.
Reduced connectivity in schizophreniaBrain 2010: 133; 625–637 |
(Margulies et al., 2007), and is consistent with the putative role of
this region in providing top-down control of structures generating
ocular motor responses (Johnston et al., 2007). Dorsal anterior
cingulate cortex, the frontal eye field and posterior parietal
cortex are the key cortical components of the right hemisphere
dominant network for spatial attention (Mesulam, 1981, 1990;
Gitelman et al., 1999) and volitional ocular motor control, which
are tightly linked (Klein and McCormick, 1989; Corbetta and
Shulman, 2002; Hunt and Kingstone, 2003; Moore et al., 2003),
with the paralimbic anterior cingulate cortex providing a map of
motivational salience. In schizophrenia, reduced connectivity of
this network might compromise inter-regional communication
and thereby contribute to deficits on tasks requiring volitional
ocular motor control, a consistent finding in the schizophrenia
literature (Gooding and Basso, 2008). The finding of a selective
reduction of right CEF positive functional connectivity comple-
ments our prior observation of reduced microstructural integrity
of the white matter underlying the right dorsal anterior cingulate
cortex (Manoach et al., 2007a). Together, these findings,
along with those of prior studies showing abnormal dorsal anterior
cingulate cortex activation during volitional saccades in schizo-
phrenia (Crawford et al., 1996; Camchong et al., 2008; Polli
et al., 2008), suggest that functional and structural abnormalities
of the right CEF disrupt connectivity and function in the network
for spatial attention and volitional ocular motor control in
Unlike the other cortical components of the ocular motor
network (i.e. frontal, parietal, and supplementary eye fields,
McDowell and Clementz, 2001), there is abundant evidence of
structural abnormalities of the anterior cingulate cortex in schizo-
phrenia. In addition to grey matter reductions (Ohnuma et al.,
1997; Goldstein et al., 1999; Sigmundsson et al., 2001; Suzuki
et al., 2002; Kuperberg et al., 2003; Ha et al., 2004; Yamasue
et al., 2004; Mitelman et al., 2005), there are reports of reduced
fractional anisotropy of the cingulum bundle (Agartz et al., 2001;
Ardekani et al., 2003; although for negative reports see,
Buchsbaum et al., 1998; Foong et al., 2002; Burns et al., 2003;
Kubicki et al., 2003; Sun et al., 2003; Wang et al., 2004; Hao
et al., 2006), and volume reductions in the white matter under-
lying anterior cingulate cortex (McDonald et al., 2005; Mitelman
et al., 2005). There is histopathological evidence of disturbances in
between the anterior cingulate cortex and connected regions
(Benes, 1993, 2000). The anterior cingulate cortex is comprised
of several subregions with distinct cytoarchitecture, patterns of
connectivity and contributions to cognition (Devinsky et al.,
1995; Bush et al., 1998; 2000; Whalen et al., 1998; Margulies
et al., 2007). Dorsal anterior cingulate cortex contributes to the
performance volitional saccades in healthy individuals (Polli et al.,
2005), while showing abnormal activity in patients with schizo-
phrenia (Polli et al., 2008)
(Camchong et al., 2008). The present findings add to this
and their unaffected relatives
Figure 6 Statistical maps of regionally specific group differences in the positive functional connectivity of the right CEF displayed on the
averaged structural MRI image of study participants registered to the MNI152 atlas (Collins et al., 1994). Schizophrenia participants
showed reduced functional connectivity in the (a) left thalamus, (b) right pre-supplementary motor area (SMA), and (c) right anterior
Table 2 Regionally specific group differences in the functional connectivity of right CEF
StructuresBrodmann’s area Peak coordinates Peak tCluster sizeCWP HC FC values SZ FC values
SMA=supplementary motor area; CWP=cluster-wise probability level; HC=healthy controls; SZ=schizophrenia; FC=functional connectivity. Cluster size is expressed as
the number of voxels.
Brain 2010: 133; 625–637P. Tu et al.
literature by demonstrating a specifically localized and lateralized
abnormality of anterior cingulate cortex functional connectivity
which, along with the prior diffusion tensor imaging findings
(Manoach et al., 2007a), suggests functional and structural
dysconnectivity in a distributed network for spatial attention and
volitional ocular motor control.
The reductions of right CEF functional connectivity in schizo-
phrenia were most pronounced in the left thalamus, right
pre-supplementary motor area and right anterior insula. The
thalamus did not show significant functional connectivity with
CEF in the combined group data, but is known to project to
pre-supplementary motor area and anterior insula, which both
showed positive functional connectivity with CEF in the combined
group data, receive projections from the dorsal anterior cingulate
cortex (Pandya et al., 1981; Morecraft et al., 1993). Anterior
insula and dorsal anterior cingulate cortices are hypothesized to
be components of a right hemisphere dominant network that
re-orients attention to behaviourally relevant events (Corbetta
and Shulman, 2002). The pre-supplementary motor area, which
borders the supplementary eye field and CEFs (Nachev et al.,
2008), is thought to contribute to volitional ocular motor control.
Activation of the pre-supplementary motor area has been asso-
ciated with volitional rather than exogenously generated action
(Nachev et al., 2008) and with switching responses during eye
movement paradigms (Isoda and Hikosaka, 2007). It shows
greater preparatory activation in response to cues to perform an
antisaccade compared with prosaccade (Curtis and D’Esposito,
2003) and right pre-supplementary motor area has been shown
to have greater functional connectivity with the frontal eye field
during the performance of antisaccades compared with prosac-
pre-supplementary motor area is theorized to interact with
ocular motor structures to establish a preparatory set when
higher level cognitive control is required (Curtis and D’Esposito,
2003; Miller et al., 2005). Thus, reduced connectivity between the
right CEFand both the right
pre-supplementary motor area in schizophrenia may contribute
to poorer performance on tasks that require one to reorient spatial
attention and eye gaze volitionally.
Basedon thisevidence, the
Figure 7 Scatter plots of the age-corrected regressions of
negative functional connectivity (FC) of the right cingulate eye
field on (A) antisaccade latency and (B) prosaccade latency by
group. Regression lines are given for controls (HC) and patients
(SZ) separately. Only for controls is negative functional
connectivity of the right CEF related to saccadic latency.
Table 3 Regression analyses of negative CEF connectivity on saccadic latency with the interaction term of latency by group,
and within group regressions
Region of interest Within group
Latency Latency by group Controls Patients
CEF=cingulate eye field; AS=antisaccade; PS=prosaccade; *P50.05.
Reduced connectivity in schizophreniaBrain 2010: 133; 625–637 |
In our prior diffusion tensor imaging study, reduced fractional
anisotropy underlying the dorsal anterior cingulate cortex, as well
as lower fractional anisotropy in frontal eye field, and posterior
parietal cortex of the right hemisphere predicted longer latencies
of volitional saccades in schizophrenia (Manoach et al., 2007a).
These relations suggest that abnormally reduced microstructural
integrity of the white matter underlying dorsal anterior cingulate
cortex in schizophreniacompromised
thereby contributing to slower performance of volitional saccades.
Based on this finding, we predicted that reduced positive func-
tional connectivity of the right CEF in schizophrenia would also
be associated with prolonged saccadic latencies. This prediction
was not borne out. Instead, negative functional connectivity
(i.e. anti-correlations) of the right CEF predicted faster latencies
of both prosaccades and antisaccades, but this relation differed by
group and was only present in controls. Since the negative mask
primarily comprised default network regions, this relation may
reflect a reciprocal relationship between activation in the ocular
motorand default networks
This interpretation is compatible with the current theory of default
network function and with activation findings using a range of
cognitive tasks, including the saccadic paradigm of the present
Default network regions commonly show deactivation during
task performance (Shulman et al., 1997; Binder et al., 1999;
Mazoyer et al., 2001; Raichle et al., 2001; Buckner et al.,
2008). Using the same saccadic paradigm employed here, we
previously reported that correct antisaccade trials were accompa-
nied by task-induced deactivation of default network regions and
error trials were marked by a failure of task-induced deactivation
in healthy individuals (Polli et al., 2005). Coincident with
task-induced deactivation, the CEFs showed increased activation
during correct trials, which in the right hemisphere, correlated with
a lower antisaccade error rate. These fMRI findings support the
hypothesis that a reciprocal pattern of activation between default
network regions and the right CEF optimizes the performance of
between the dorsal anterior cingulate cortex and default network
regions have been reported during a range of cognitive tasks
(Drevets and Raichle, 1998; Bush et al., 2000).
In the present study, patients differed significantly from controls
in that the relations of negative functional connectivity with
saccadic latency were absent. They also differed significantly in
the asymmetry of negative functional connectivity of the CEF,
with controls showing significant rightward asymmetry and
patients showing a trend towards leftward asymmetry. These find-
ings suggest that the coordination of activity between the right
hemisphere dominant ocular motor control network and the
default network is important for efficient task performance and
is disrupted in schizophrenia. These findings resonate with existing
evidence of abnormalities of default network function during task
performance in schizophrenia patients (Garrity et al., 2007; Kim
et al., 2009) and their relatives, including reduced suppression of
default network activity during working memory that predicted
less accurate performance and reduced negative functional con-
nectivity of the default network with lateral prefrontal cortex
(Whitfield-Gabrieli et al., 2009).
that optimizes performance.
Several methodological limitations and alternative conceptualiza-
tions of our findings merit consideration. First, our schizophrenia
samplewas limitedto patients
anti-psychotic medications. Dopaminergic medications have been
found to modulate fMRI measures of cortico–striato–thalamic
functional connectivity, with the anti-psychotic sulpiride increasing
functional connectivity (Honey et al., 2003). While it would be
difficult to account for such lateralized functional findings
(and structural findings in the prior report, Manoach et al.,
2007a) on the basis of medications, and statistically controlling
for dosage as measured by chloropromazine equivalents did not
alter the findings, the effects of anti-psychotic medications on
functional connectivity are still largely unknown and we cannot
exclude the possibility that medications contributed to our
In addition, we failed to support our prediction, based on
diffusion tensor imaging findings (Manoach et al., 2007a), that
like reduced fractional anisotropy in the dorsal anterior cingulate
white matter, reduced positive functional connectivity of the right
CEF in schizophrenia would also be associated with prolonged
saccadic latencies. This may reflect the different measurements
used by these two studies. While fractional anisotropy indexes
white matter microstructure, including myelination (Beaulieu,
2002; Harsan et al., 2006), functional connectivity indexes corre-
lations in the blood oxygen level dependent signal in grey matter
structures. Thus, we interpreted the observed correlations between
fractional anisotropy and saccadic latency in schizophrenia to
reflect the well-established role of white matter myelin thickness
and axon diameter in determining conduction velocity. Functional
connectivity during task performance instead reflects inter-regional
coordination, which may depend, in part, on white matter integ-
rity, but is also influenced by other factors. The present findings
suggest that coordination between the default and ocular motor
networks plays a bigger role in performance variability than
coordination within the ocular motor control network.
Another issue concerns our interpretation of negative functional
connectivity. Based on the existing literature (Drevets and Raichle,
1998; Bush et al., 2000; Fox et al., 2005; Fransson, 2006) and an
fMRI study of the same task showing that deactivation in default
network regions was coincident with increased activation in dorsal
anterior cingulate cortex (Polli et al., 2005) the negative correla-
tions raise the possibility of reciprocal patterns of brain activity.
However, negative correlations can be an artefact of global signal
regression techniques such as those applied here (Chang and
Glover, 2009; Murphy et al., 2009; Van Dijk et al., in press).
Based on these prior studies, we expect that if we did not use
global signal regression, the relative patterns of connectivity would
be preserved, but the negative sign would no longer be present.
Regardless of the direction of the correlations, the relations of
right CEF functional connectivity with task performance differed
significantly by group reflecting that they were significant in con-
trols and absent in patients. This suggests that the coordination of
activity in the volitional ocular motor control network and the
regions that collectively comprise the default network is important
for efficient task performance and is disrupted in schizophrenia.
This finding is consistent with a growing literature suggesting that
dyscoordination of activity between the default network and
with chronic exposureto
Brain 2010: 133; 625–637P. Tu et al.
task-active networks compromises cognitive function in schizo-
phrenia (Buckner et al., 2008; Whitfield-Gabrieli et al., 2009).
Finally, although similar networks are identified by analyses of
task-based and resting-state functional connectivity, there is
evidence that task alters functional connectivity (Van Dijk et al.,
2010). Similar to some prior studies in schizophrenia (Garrity et al.,
2007; Kim et al., 2009; Whitfield-Gabrieli et al., 2009), we exam-
ined functional connectivity while participants performed a specific
task. Therefore, we do not know whether similar abnormalities
would also be present during rest.
In summary, the present findings demonstrate reduced func-
tional connectivity of the CEF, specifically in the right hemisphere,
during the performance of volitional saccades in schizophrenia.
Along with our prior observation of reduced microstructural integ-
rity of the white matter underlying the right dorsal anterior
cingulate cortex (Manoach et al., 2007a), the present findings
suggest that functional and structural right CEF abnormalities dis-
rupt connectivity and function in a distributed network for spatial
attention and volitional ocular motor control. These abnormalities
may contribute to the consistently observed deficits on tasks
requiring volitional ocular motor control in schizophrenia. More
generally, disrupted connectivity in this network may compromise
the ability to overcome prepotency in the service of directing eye
gaze and attention to the parts of the environment that are the
most behaviourally relevant. These findings suggest a neural basis
for the deficits in the control of visual spatial attention that
characterize schizophrenia (Luck and Gold, 2008).
Advanced Multimodal Neuroimaging Training Program (R90
MH67720, F32 MH082514); National Alliance for Research on
Schizophrenia and Depression; Mental Illness and Neuroscience
Discovery (MIND) Institute; Howard Hughes Medical Institute;
National Institute for Biomedical Imaging and Bioengineering
(R01EB006758); National Institute for Neurological Disorders and
Stroke (R01 NS052585-01); Ellison Medical Foundation; National
Center for Research Resources (P41RR14075).
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