Psychiatry Research: Neuroimaging 265 (2017) 7786

Contents lists available at ScienceDirect

Psychiatry Research Neuroimaging

journal homepage: www.elsevier.com/locate/psychresns

Plasticity of prefrontal cortex connectivity in schizophrenia in response to MARK

antisaccade practice

Amanda L. Rodrigue1, Benjamin P. Austin2, Jennifer E. McDowell
Department of Psychology, University of Georgia, Athens, GA, USA

A R T I C L E I N F O A BS T RAC T

Keywords: People with schizophrenia exhibit diculties in cognitive control that are often attributed to decits in
Cognitive control prefrontal cortex (PFC) circuitry. Practice paradigms have been used to improve these PFC-mediated decits.
FMRI The neural consequences of practice on task-based PFC activation have been addressed. Eects on task-based
Psychophysiological interaction PFC connectivity, however, are largely unknown. We recruited people with schizophrenia and controls to
practice antisaccades, a measure of PFC-mediated cognitive control that is disrupted in people with
schizophrenia. Subjects performed antisaccades during functional magnetic resonance imaging (fMRI) before
and after eight days of antisaccade practice. A group (schizophrenia, controls) time (pre-, post-test) repeated
measures ANOVA on the results of a psychophysiological interaction (PPI) analysis was used to evaluate
changes in PFC connectivity; a similar model was used to evaluate changes in antisaccade behavior. After
practice, antisaccade behavior improved and PFC connectivity with insular/temporal regions (involved in
bottom-up orienting processes) increased in the schizophrenia group. The level of connectivity at post-test in
the schizophrenia group was similar to that seen at pre-test in controls and positively correlated with
antisaccade performance. Increases in connectivity between bottom-up and top-down regions may underlie
behavioral improvements in people with schizophrenia after cognitive control practice.

1. Introduction dependent (BOLD) signal coupled with improved behavioral perfor-

Cognitive control involves top-down processes that are important to
daily functioning and includes operations like attention, inhibition, and
working memory. People with schizophrenia often exhibit poor per-
formance on a variety of cognitive control paradigms. These decits are
not only correlated with problems in social functioning (Bellack et al.,
1999; Liddle, 2000), but are more predictive of clinical outcomes than
other symptoms of psychosis (Minzenberg and Carter, 2012).
Given such detrimental eects, eort has focused on remediating
cognitive control disruptions in schizophrenia. One technique is via
practice or repeated, frequent performance of cognitive control tasks.
Practice improves cognitive control behavior (Chein and Schneider,
2005) and alters the function of underlying neural circuitry (Chein and
Schneider, 2005; Kelly et al., 2006), especially prefrontal cortex (PFC).
PFC function is of particular interest given its putative support of
cognitive control abilities (Koechlin et al., 2003; Miller, 2000) and its
hallmark disruption in schizophrenia (Braver et al., 1999; Callicott
et al., 2000). Studies using functional magnetic resonance imaging
(fMRI) report practice-induced decreases in PFC blood oxygen level
mance in both healthy people (Garavan et al., 2000; Koch et al., 2006)
and people with schizophrenia (Koch et al., 2007, 2010). BOLD signal
decreases are interpreted as less reliance on controlled processes and
increases in eciency of control regions like the PFC (Kelly and
Garavan, 2005). Other studies in people with schizophrenia report
practice-induced increases in PFC activation; these studies, however,
either use a generalized cognitive remediation paradigm (where
patients are taught skills rather than given practice on a particular
task) (Bor et al., 2011; Wykes et al., 2002), and/or show no practice-
related improvements in behavioral performance in the schizophrenia
group (Bor et al., 2011).
Although PFC activation is important for successful task perfor-
mance, PFC connectivity is also important. Connectivity analyses
identify regions of the brain whose BOLD signal time series are
correlated with one another. Temporal correlations across brain
regions are indicative of synchronous neural ring and shared infor-
mation processing (Rissman et al., 2004). Evidence of practice-induced
changes in connectivity is sparse in schizophrenia even though it has
signicant implications for changes in brain activation (Bchel and

Corresponding author.
E-mail address: jemcd@uga.edu (J.E. McDowell).
1
Department of Psychology, University of Georgia, Psychology Building, 125 Baldwin St., Athens, GA 30602, USA.
2
Permanent address: Department of Medicine, School of Medicine and Public Health, 2500 Overlook Terrace, Madison, WI 53705, USA.

http://dx.doi.org/10.1016/j.pscychresns.2016.09.004
Received 30 March 2016; Received in revised form 10 August 2016; Accepted 11 September 2016
Available online 12 September 2016
0925-4927/ 2016 Elsevier Ireland Ltd. All rights reserved.
A.L. Rodrigue et al. Psychiatry Research: Neuroimaging 265 (2017) 7786

Friston, 1997; Fletcher et al., 1999) and cognitive control disruptions increased error rates similar to those with schizophrenia. There also are
in the disorder (Camchong et al., 2011; Fornito et al., 2011; Meyer- additional reports of disruptions in both structural (Manoach et al.,
Lindenberg et al., 2005). In healthy people, two studies show increases 2007) and functional (Tu et al., 2010) connectivity in the right
in resting state functional connectivity in fronto-parietal networks in hemisphere related to antisaccades in people with schizophrenia.
response to cognitive training (Jolles et al., 2013; Mackey et al., 2013), We hypothesized that antisaccade practice in the schizophrenia
suggesting practice strengthens connections between PFC and regions group would improve performance and alter pre-test connectivity
typically recruited for cognitive control tasks. In people with schizo- disruptions between rMFG and bottom-up regions that are typically
phrenia, Schlsser et al. (Schlsser et al., 2009) report increases in responsible for successful antisaccade performance. We also hypothe-
functional connectivity between PFC and task-relevant regions during sized that regions changing connectivity patterns over time in the
stimulus overlearning in a delayed match to sample paradigm; after schizophrenia group would show a positive relationship with antisac-
practice, the connectivity patterns in schizophrenia more closely cade behavior measures at post-test. For comparison purposes, we also
resembled those of controls. This study, however, looked at repeated collected healthy controls. Furthermore, to evaluate the transferability
exposure over a single scanning session with under an hour of practice. of antisaccade practice to other aspects of cognitive control, subjects
Also, the intention of practice was to learn a specic set of stimuli, not completed two additional transfer tasks: a specic transfer task (an
to enhance cognitive control per say. Practice paradigms that are not alternate cognitive control-related ocular motor task) and a general
designed to elicit overlearning and/or those involving longer practice transfer task (a cognitive control task that does not involve eye
periods (days to weeks) may be more ecologically valid in evaluating movements).
the plasticity of PFC connectivity (Kelly and Garavan, 2005).
The current study used BOLD fMRI to measure changes in PFC 2. Methods
connectivity in response to extended practice (eight days) of a cognitive
control task. We specically investigated changes in task-based con- 2.1. Subjects
nectivity (as in Schlsser et al. (2009)), meaning connections that
became stronger during cognitive control task states. The targeted Subject characteristics are listed in Table 1. Subjects were 15 people
cognitive control task was an antisaccade task. Antisaccades require with schizophrenia and 16 age and gender matched controls recruited
individuals to direct the eyes to the mirror image location of a suddenly from the community with yers and newspaper/internet ads. People
appearing peripheral visual stimulus. This ocular motor response with schizophrenia also were recruited from regional mental health
requires several cognitive control operations and successful perfor- centers and given the Structured Clinical Interview for DSM-IV-TR
mance is positively correlated with performance on other cognitive (First, 2002a) for diagnosis conrmation. Individuals with schizophre-
control measures (Hutton et al., 2004; Miyake et al., 2000). Dorsal nia were chronic (average illness duration of 15 yrs.), taking multiple
lateral PFC (DLPFC), particularly the middle frontal gyrus (MFG), is an medications (except one subject), and had a typical age of onset (early
important node of antisaccade circuitry as it mediates goal mainte- 20s). All but two were outpatients; one was not currently in treatment
nance and inhibition of the pre-potent glance toward the visual cue and the other was in residential care. The schizophrenia group did not
(Everling and Johnston, 2013; Hussein et al., 2014; Hwang et al., dier from controls on IQ (as assessed using the Information subtest of
2014). The DLPFC provides top-down modulation of sensory (visual the WAIS IV; t(28)=0.40, p=0.69), but had slightly lower education
cortex) and sensory-motor cortical regions (frontal and supplementary level (high school equivalent vs. part college; t(29)=2.5, p=0.02).
eye elds), as well as subcortical regions (basal ganglia and thalamus). Controls were given the Non-Patient Edition of the Structured
In fact, pre-stimulus activity in DLPFC predicts the success of correctly Clinical Interview for DSM-IV-TR (First, 2002b) and the Schizotypal
performing an antisaccade (DeSouza et al., 2003; Ford et al., 2005) and Personality Questionnaire (SPQ) (Raine, 1991) to rule out psychiatric
is correlated with pre-stimulus activity in bottom-up regions such as disorders. Subjects from both groups reported no current drug or
visual cortex (Hamm et al., 2012). alcohol abuse, history of head trauma, or contraindications for MRI.
People with schizophrenia make more antisaccade errors (glance Subjects completed informed consent approved by the University of
toward the peripheral cue instead of away), take longer to initiate Georgia Institutional Review Board and were paid for their participa-
correct antisaccades (Ettinger et al., 2004, 2006; McDowell et al., 1999; tion.
Reilly et al., 2014), and under activate regions of antisaccade circuitry,
including the DLPFC (Camchong et al., 2008; McDowell et al., 2002; Table 1
Tu et al., 2006). These decits are present despite intact performance Subject characteristics.
on visually guided prosaccades (glances toward the cue) (Clementz
et al., 1994; Crawford et al., 1998; Ettinger et al., 2006; Smyrnis et al., Schizophrenia N=15 Control N=16
2004; Thaker et al., 1989), indicating that the eye movement system Age (yrs.) 37 (11) 37 (12)
itself is not impaired. Antisaccade disruptions are also seen to a lesser Gender (N Males) 9 10
extent in unaected rst-degree relatives, making them candidate Education level 4 (1.2) 3 (1.3)
endophenotypes for the disorder (Calkins et al., 2007; Camchong Information 18 (6.7) 17 (7.0)
SAPS 8.6 (3.2) N/A
et al., 2008; McDowell et al., 1999; Reilly et al., 2014). The dependency
SANS 10.6 (5.1) N/A
of antisaccade tasks on the DLPFC and its consistent disruption in Age of onset (yrs.) 23 (6.1) N/A
schizophrenia and their relatives makes them a useful model to Illness duration (yrs.) 15 (10.4) N/A
measure practice-related changes in cognitive control behavior and Medication
connectivity of the PFC. Furthermore, given the positive relationship Anti-psychotic (typical, atypical, both) 1, 10, 2 0
Anti-convulsant 4 0
between antisaccade performance and other cognitive operations, it Anti-depressant 9 0
may be likely that antisaccade practice eects may transfer to other Anti-anxiety 2 0
cognitive control tasks. Polypharmacy 10 0
Within this framework, we specically evaluated changes in con-
nectivity between the right MFG and the rest of the brain during an Cells show means (std. dev.) except for gender and medication, which show N. Education
level was assessed with the SCID (1=grade 6 or less; 2=grade 712 w/o graduation;
antisaccade task before and after antisaccade practice. BOLD signal
3=high school graduation or equivalent; 4=part college; 5=2-year college graduate; 6=4-
activation of the MFG during antisaccades is often lateralized to the year college graduate; 7=part-graduate school 8=graduate school graduate). One control
right hemisphere (DeSouza et al., 2003; Ford et al., 2005; Manoach was missing a score on the Information subtest. One subject was missing SAPS and two
et al., 2007), although lesions in both left and right DLPFC result in subjects were missing SANS scores. One schizophrenia subject was undedicated.

78
A.L. Rodrigue et al.
2.2. Antisaccade task
An antisaccade task was used in two session types: pre-/post-test
scanner sessions and practice sessions. Eye movements during scanner
sessions were recorded using an MRI compatible MEye Track LR from
Sensorimotor Instruments (SMI Inc., Berlin, Germany). Eye move-
ments during practice sessions were recorded outside the scanner
environment with one of two eye tracking systems using headband
mounted infrared cameras: an Eyelink II (SR Research Ltd., Ottawa,
Ontario, Canada) or an Eye Trak (model 310, Applied Science
Laboratories, Waltham, Massachusetts, USA). For both session types,
eye movement recordings were digitized at 500 Hz and observed
continuously throughout the session using a monitor visible to the
experimenter.
The task was performed in a blocked design: 6 blocks of anti-
saccades (7 trials in each block; 28 s duration) alternating with 7 blocks
of xation (28 s duration). Antisaccade blocks were indicated with a
2.5 blue cue. For each trial within antisaccade blocks, the blue cue
started in a central position, disappeared, and reappeared in a
peripheral location ( 8 or 16). Subjects were instructed to look
at the central cue and to direct a glance to the mirror image location
(opposite direction, same distance from center) when the cue jumped
to the periphery. Task parameters were identical for scanner sessions
and practice sessions except for the timing of central xation during
antisaccade blocks. Central xation during scanner sessions was
maintained at a constant value, whereas central xation during practice
sessions was pseudo-randomly jittered (See Fig. 1). Fixation blocks
were indicated with a 2.5 pink cue.
2.3. Transfer tasks
Two other types of cognitive control tasks that were not practiced
were evaluated at pre- and post-test to determine whether the eects of
antisaccade practice would transfer to other tasks. Transfer tasks were
chosen based on their dependence on prefrontal functioning (Mansouri
et al., 2006; Milea et al., 2005; Pierrot-Deseilligny et al., 2003), like the
antisaccade task. A specic transfer task was an ocular motor delayed
Antisaccade Task
Antisaccade Block (28s)
7 Trials
2400ms (pre-/post-test)
2150ms-2650ms (practice)
200ms
1400ms
Time (6min 4s)
Fig. 1. Antisaccade Task Design and Parameters. The task was performed in a blocked design with blocks of antisaccades alternating with blocks of xation. Arrows inside the black
boxes indicate correct location of gaze and were not present during the task.
79
Psychiatry Research: Neuroimaging 265 (2017) 7786
response task (ODRT), which is similar to an antisaccade task but
requires a higher working memory component. In this study, subjects
focused on a central xation cross and after a pseudo-randomized ITI,
a 1 blue cue ashed briey (100 ms) at one of four peripheral locations
( 8 or 16). Subjects were instructed to maintain focus on the
central xation cross and remember the location of the peripheral cue
during a 4000 ms delay period. At the end of the delay period, the
xation cross was extinguished and subjects were instructed to look
towards the remembered location as quickly and accurately as possible.
A response period of 1500 ms was then given, followed by a feedback
cue (1 pink) to indicate the correct location of gaze. The ODRT was
conducted in the same laboratory setting and with the same equipt-
ment as that used for the anitsaccade practice sessions.
The general transfer task was the Wisconsin Card Sorting Task
(WCST), a test of problem solving and set-shifting. In this task, subjects
match response cards to key cards based on rules that change
throughout the task. Subjects must use right or wrong feedback
after each trial to learn the desired rule and switch to a dierent rule
once it has changed. We used a computerized version of the WCST with
standardized instructions (Heaton, 1981).
2.4. Imaging parameters
Imaging was performed at the Bio-Imaging Research Center at the
University of Georgia with a GE Excite HD 3.0 T MRI scanner
(Milwaukee, Wisconsin). A parallel imaging calibration (ASSET,
FOV=30 cm, slice thickness 6.0 mm, 31 slices, scan time 6.0 s) was
used to measure the magnetic eld in the presence of the participant
followed by a fast 3D T1-weighted structural scan to determine the
angle of acquisition along the AC-PC line (BRAVO protocol: ASSET
factor=2.0, echo time [TE]=4.6 ms, repetition time [TR]=10.8 ms, ip
angle=13, number of excitations [NEX]=0.5, matrix=352224, eld of
view [FOV]=24 cm [resulting in an in-plane resolution of 0.681.07],
slice thickness of 1.2 mm, frequency direction A/P, 150 slices, scan
time 3 min 7 s, bandwidth=25 kHz, phase FOV=1, time to inversion
[prep time]=450 ms). Data collection also included acquisition of an
additional T1-weighted scan to obtain a high resolution image of
Fixation Block (28s)
A.L. Rodrigue et al.
subjects brain anatomy (fast spoiled gradient echo [FSPGR] protocol;
TE=Min-Full, TR=7.8 ms, ip angle=20, NEX=1, matrix=256256,
FOV=24 cm [resulting in an in-plane resolution of 0.93750.9375],
slice thickness of 1.2 mm, frequency direction A/P, 150 slices, scan
time 6 min 20 s, bandwidth=31.25 kHz, phase FOV=0.7, prep time
450 ms). A T2*-weighted scan was collected to measure the BOLD
signal associated with the antisaccade task (oblique prescription,
gradient echo echo-planar imaging pulse sequence [EPI] with data
points in k-space sampled line by line: matrix=6464, FOV=22 cm
[resulting in an in-plane resolution of 3.43753.4375], slice thickness
of 4 mm, TE=30 ms, TR=2000 ms with a singleshot interleave, ip
angle=90, 33 slices, scan time 6 min 12 s, frequency direction R/L,
bandwidth=250 kHz, phase FOV=1, NEX=1, ramp-sampling turned
on, ASSET (acceleration factor)=2.0 pH). The T2* weighted scan began
with four null repetitions (not included in the analysis) to allow
magnetization to stabilize at steady state equilibrium.
2.5. Procedure
Subjects participated in a two week trial: 2 antisaccade scanning
sessions (pre-test and post-test) separated by eight days of antisaccade
practice (four days each week). On the rst day of the trial, subjects
completed the pre-test scanning session. Upon arrival, subjects were
given instructions regarding the antisaccade task and were positioned
in the scanner with their heads stabilized. Subjects viewed antisaccade
stimuli through a dual mirror box (16 cm above the eyes) on a screen at
their feet (174 cm from the nasion). After magnetic eld calibration,
the BRAVO protocol was used to identify the AC-PC line, which was
then used to orient slices in the oblique plane for the T2*-weighted
scan. Subjects performed one run of an antisaccade task (42 trials)
during the T2*-weighted scan followed by the collection of the
remaining high resolution T1-weighted scan.
Subjects returned for eight practice sessions over the next twelve
days - no subject went more than two days without practice. Practice
sessions were conducted outside the scanner environment in a quiet,
dark room. Subjects were reminded of task instructions and seated
70 cm from a CRT stimulus monitor using a chin bar to minimize head
movement. Subjects then completed three runs of an antisaccade task
(126 total trials) with short breaks between each run. After completing
eight practice sessions, subjects returned for the post-test scanning
session, which was conducted with identical procedures and equipment
as the pre-test scanning session. The specic (ODRT) and general
(WCST) transfer tasks were performed in the same laboratory setting
as the practice sessions and were administered in separate testing
sessions before the pretest and after the posttest scanning session.
2.6. Analysis
2.6.1. Antisaccades
Antisaccade performance from both the scanning and practice
sessions were scored using a program in MATLAB (The Mathworks
Inc., Natick, MA). Trials were excluded if there was no saccade, if there
was a pre-saccade blink (from 350 ms prior to the appearance of the
peripheral stimulus), or if there was a saccade faster than 90 ms
(considered anticipatory and not visually guided). Trials were scored
for direction (a glance toward or away from the peripheral stimulus)
and reaction time (time in ms between peripheral stimulus presenta-
tion and start of saccade). Antisaccade behavior measures for each
subject included error rate (number of incorrect trials/ total number of
scorable trials100) and average correct reaction time.
Due to technical diculties, one subject (a control) was missing
behavior measures at pre-test and ve subjects (three schizophrenia
and two controls) were missing behavior measures at post-test. One
control was missing behavior measures at both pre- and post-test.
Subjects with missing data suciently performed the antisaccade task
in the scanner, as noted by the experimenter. Additionally, two subjects
80
Psychiatry Research: Neuroimaging 265 (2017) 7786
(both in the schizophrenia group) missed one practice day, one on Day
2 and one on Day 7. All other subjects completed all eight practice days.
Error rates and average correct reaction times for both scanner and
practice sessions obtained from the MATLAB program were evaluated
with a linear mixed model approach implemented in SPSS with group
(schizophrenia and control) and time (pre- and post-test) as xed
factors; time was treated as a repeated measure. Using a linear mixed
model analysis allows utilization of all available data by accounting for
unbalanced designs and missing values (Cnaan et al., 1997;
Gueorguieva and Krystal, 2004).
2.6.2. Transfer tasks
For the specic transfer task, ODRT performance was scored with a
similar MATLAB-script and rules as those used for the antisaccade
task; error rates and correct reaction times were calculated for each
subject. In the ODRT, an error is an initial glance toward the peripheral
cue either at its onset or at any time during the delay period (i.e. before
the oset of central xation). Correct reaction time is the time it takes
from the oset of xation and the start of the saccade towards the
remembered location on error free trials. Dierences across groups and
time were evaluated with a 22 repeated measures ANOVA.
For the general transfer task, WCST performance was scored using
standard computerized software. One schizophrenia subject did not
have WCST data and three control subjects were missing post-test
WCST. We focus on three WCST measures: number of categories
completed, percent perseverative errors, and percent perseverative
responses. These measures are related to general conceptual and
problem solving abilities (Paolo et al., 1995) and are impaired in
people with schizophrenia (Berman et al., 1995). To evaluate dier-
ences across groups and time and to account for missing data, we
implemented the same linear mixed model analysis that was used in
the antisaccade analyses.
2.6.3. Imaging
The imaging analysis included 15 people with schizophrenia and 16
controls and was performed with Analysis of Functional NeuroImages
(AFNI) (Cox, 1996) software. Three-dimensional datasets were created
from individual DICOM les for the antisaccade run. Preprocessing of
functional images included despiking, slice timing correction, registra-
tion to a representative volume for movement, alignment of functional
data to anatomy, smoothing with a 4 mm full-width at half-maximum
(FWHM) Gaussian lter, and scaling each voxel to a mean of 100 as in
(Camchong et al., 2006; Dyckman et al., 2007).
To evaluate task-based functional connectivity of the PFC, we
performed a psychophysiological interaction (PPI) analysis (Friston
et al., 1997). PPI analyses provide information about how connectivity
between brain regions change in a context-dependent way. Results
return changes in functional connectivity between a seed region and
target regions across two task states (e.g. antisaccade compared to
xation). Our seed region was the right middle frontal gyrus (rMFG)
because of its disruption during antisaccade performance (as measured
by fMRI) in people with schizophrenia (Camchong et al., 2008;
McDowell et al., 2002). We dened the rMFG seed as an anatomical
region of interest (ROI) with the Talairach-Tournoux atlas (TT-
Daemon) using AFNI (Cox, 1996).
For the PPI analysis, we followed the approach of McLaren et al.
(McLaren et al., 2012) and constructed three regressors for each
subject: one representing the time course of the rMFG seed (average
time course extracted using the anatomical ROI as a mask), one
representing the task design (taken from the design matrix), and one
representing the interaction (product of the previous two time courses).
All three regressors were then entered into a standard GLM analysis
along with motion regressors obtained from the alignment procedure
to account for movement-related signal change. Focus was placed on
the interaction regressor, which after the GLM, returns a connectivity
change value for each voxel. This represents the change in connectivity
A.L. Rodrigue et al.
between the voxel and the rMFG seed when performing the antisaccade
task compared to xation. Positive values indicate increases in
connectivity with the rMFG during antisaccade task blocks, whereas
negative values indicate decreases in connectivity during antisaccade
task blocks.
To assess changes before and after practice, two PPI analyses (pre-
and post-test) were performed using the same rMFG seed as suggested
by OReilly et al. (2012). A 22 repeated measures ANOVA was
performed on the results of the two PPI analyses with group (schizo-
phrenia and controls) and time (pre- and post-test) as factors. To test
the hypothesis that practice alters disrupted connectivity patterns seen
in those with schizophrenia at pre-test, we focused on the interaction
eect in order to identify regions that both diered between groups and
changed over time. To evaluate the relationship between antisaccade
performance and connectivity after practice, we correlated the average
connectivity values in regions showing an interaction eect with
antisaccade behavior measures (error rate and reaction time).
3. Results
3.1. Behavior
3.1.1. Antisaccades
Scanner session results are summarized in Table 2. After practice,
error rates were lower in both groups, but the schizophrenia group had
signicantly higher error rates than the control group at both time
points. Practice had dierential eects on correct reaction time
between the two groups. The schizophrenia group's reaction times
did not dier between pre- and post-test, whereas the control group
exhibited faster reaction times at post-test compared to pre-test.
Antisaccade variables did not dier between rightward and leftward
saccades.
Practice session results showed a similar pattern as those seen
across the 2 scanning sessions (see Fig. 2): the schizophrenia group
exhibited lower error rates over time but maintained consistent
reaction times, whereas the control group exhibited slight decreases
in error rates and faster reaction times. Separate group by time mixed
model analyses of error rate and reaction time did not reveal a
signicant overall main eect of time (ER: F(7, 215)=0.98, p=0.44;
RT: F(7, 215)=1.3, p=0.22), although within each group the simple
eect of time was trend level for error rate in the schizophrenia group
(F(7, 215)=1.7, p=0.09) and signicant for RT in the control group
(F(7, 215)=2.7, p=0.01).
3.1.2. Transfer tasks
Results of the two transfer tasks that were not practiced, ODRT and
WCST, are listed in Table 3. For the ODRT, both groups exhibited
Table 2
Antisaccade behavior results.
Control
Pre-Test Post-Test
Total Sample N=15 N=15
Error Rate (%) 33 (24) 25 (21)
n=14 n=14
Group Eect
Time Eect
Interaction Eect
Reaction Time (ms) 279.3 (92) 239.1 (56)
n=14 n=13
Group Eect
Time Eect
Interaction Eect
Group means (Std. dev.) and significance tests for the linear mixed models analysis on antisaccade behavior measures. Respective n's for each mixed model analysis are under the group
means. Bolded results indicate signicance at p0.05.
81
Psychiatry Research: Neuroimaging 265 (2017) 7786
signicantly faster reaction times and made fewer errors after anti-
saccade practice. For the WCST, there was a main eect of time,
however, only the control group improved WCST performance after
antisaccade practice. The groups did not signicantly dier on any of
the ODRT or WCST measures at pre-test, although there were some
signicant dierences at post-test.
3.2. Imaging
The 22 ANOVA evaluating the changes in connectivity between
the rMFG and the rest of the brain identied two regions showing an
interaction eect. Both regions were located in the left hemisphere and
included the insula, extending to the superior temporal gyrus (STG),
and the middle temporal gyrus (MTG), both of which had a similar
pattern of connectivity (See Fig. 3.). First, the schizophrenia and
control groups exhibited signicant changes in connectivity over time
(SZ: Insula/STG F(1, 29)=17.0, p < 0.0001, MTG F(1, 29)=10.5,
p=0.003; C: Insula/STG, F(1, 29)=20.6, p < 0.0001, MTG F(1, 29)
=6.7, p=0.02). Second, the schizophrenia group at pre-test exhibited a
connectivity value close to 0, however, controls exhibited a positive
connectivity value between these regions and the rMFG (Insula/STG
F(1, 29)=19.0, p < 0.001; MTG F(1, 29)=15.7, p < 0.001). Third, the
schizophrenia group at post-test had a positive connectivity value in
both regions, similar to that seen at pre-test in the control group
(Insula/STG F(1, 29)=0.01, p=0.94; MTG F(1, 29)=0.08, p=0.78).
In the schizophrenia group, post-test connectivity was signicantly
correlated with antisaccade performance such that higher connectivity
values were associated with fewer antisaccade errors (see Fig. 4; r(12)
=0.68, p=0.02). A similar trend level correlation was seen in the MTG
(r(12)=0.52, p=0.08). There were no signicant relationships between
post-test connectivity and antisaccade behavior measures in the control
group.
4. Discussion
The current study recruited people with schizophrenia and controls
to take part in 2-weeks of antisaccade practice to evaluate eects on
task-based PFC connectivity. Evidence from practice studies with
controls suggest that saccadic performance along with its underlying
neural circuitry is somewhat plastic (Dyckman and McDowell, 2005;
Lee et al., 2013). Connectivity disruptions are frequently reported as
possible underlying causes of cognitive control problems in schizo-
phrenia (Camchong et al., 2011; Fornito et al., 2011; Meyer-
Lindenberg et al., 2005), although few studies have evaluated changes
in task-based PFC connectivity and its relationship to improvements in
behavioral performance after cognitive control practice.
This study used antisaccades, as they are measures of cognitive
Schizophrenia
Pre-Test Post-Test
N=15 N=15 F (df) p
53 (29) 42 (31)
n=15 n=13
4.8 (29) 0.04
4.6 (27) 0.04
0.4 (27) 0.55
291.6 (50) 295.7 (68)
n=14 n=12
2.2 (30) 0.14
0.8 (25) 0.38
4.2 (25) 0.05
A.L. Rodrigue et al. Psychiatry Research: Neuroimaging 265 (2017) 7786

Antisaccade Behavior during Practice

60 300
C
SZ
55
* *
* *
280
*
50
*
260

Reaction Time (ms)

45
Error Rate (%)
40 240
*
35 * * * * 220
30
200
25

20 180

0 0
D1 D2 D3 D4 D5 D6 D7 D8 D1 D2 D3 D4 D5 D6 D7 D8

Practice Day
Fig. 2. Practice Session Results. Points show average error rate (SE) on the left and average correct reaction time (SE) on the right for each group during each day of practice. An
asterisk above a data point indicates that it is signicantly dierent from D1. C=Control, SZ=Schizophrenia.

control commonly used in schizophrenia research to asses PFC-
mediated cognitive control decits (Ettinger et al., 2004, 2006;
McDowell et al., 2002, 1999). Pre-test results support these putative
decits with higher error rates and disrupted PFC function in people
with schizophrenia compared to controls. After practice, antisaccade
behavioral performance improved and connectivity patterns that were
disrupted at pre-test in schizophrenia were normalized. Two regions
showed increased connectivity to the positive range at post-test in the
schizophrenia group and were similar to that seen in controls at pre-
test. The sign of the connectivity value denes the nature of the
relationship between the seed region (rMFG) and target regions
(Insula/STG, MTG) during task states of interest (antisaccade blocks).
Positive values indicate signicant increases in connections from
xation blocks to antisaccade blocks, whereas values close to 0 indicate
no signicant change in connectivity from xation blocks to antisac-
cade blocks. Given these interpretations, the insula and temporal
regions were not specically involved with antisaccades in the schizo-
phrenia group at pre-test, however, after practice, connectivity of these
regions with the PFC increased during antisaccade blocks.
Regions identied in our analyses were a combination of those
involved in bottom-up sensory and top-down cognitive control pro-
cesses. Both the STG and the MTG are bottom-up regions involved in
attention, attention shifting, and spatial orienting, especially when
targets are unexpected (Corbetta et al., 1998; Corbetta and Shulman,
2002; Grosbras et al., 2005). This is supported by brain imaging studies
showing greater activation of these regions during visually triggered
eye movements, like prosaccades, compared to antisaccades (Corbetta
et al., 1998; Doricchi et al., 1997; Grosbras et al., 2005; Haller et al.,
2008; Krat, 2012). These regions are further modulated by the
amount of volition needed for a task and are activated during
prosaccades and antisaccades, but not during exploratory saccades
(Kan et al., 2008). The insula has been implicated in the process of
inhibition (Leung and Cai, 2007; Wager et al., 2005) due to the large
number of reciprocal connections with the PFC and inferior parietal
cortex (Andersen et al., 1990; Augustine, 1996), both central nodes of
antisaccade circuitry. Insula activation is observed during both anti-
saccade and no go trials (Brown et al., 2006), which require anti-
saccade-like inhibition but without a saccadic response. It has been
suggested that fronto- insular connections may serve as the mechanism
underlying suppression of extrastriate activity (more apparent during
prosaccades and antisaccade errors) in response to irrelevant visual
stimuli (Perry and Zeki, 2000). When looking at changes that occurred

Table 3
Effect of practice on transfer tasks.

Means (Std. dev.) Simple time effects Overall time effect

Control Schizophrenia Control Schizophrenia

Pre-test Post-test Pre-test Post-test

ODRT n=16 n=16 n=15 n=15 F (df) p F (df) p F (df) p

Error Rate (%) 33 (23) 21 (15) 35 (20) 24 (17) 5.3 (29) 0.03 4.1 (29) 0.05 9.4 (29) 0.005
Correct Reaction Time (ms) 323 (80) 277 (40) 379 (82) 331 (63)a 5.2 (29) 0.03 5.3 (29) 0.03 10.5 (29) 0.003
WCST n=16 n=13 n=14 n=14
Categories Completed 5 (2.1) 6 (0.5) 4 (2.2) 4 (1.9) 3.1 (27) 0.08 1.4 (26) 0.26 4.3 (27) 0.05
Perseverative Errors (%) 13 (10) 7 (2) 25 (21) 23 (24)a 5.4 (28) 0.03 0.45 (27) 0.51 4.5 (28) 0.04
Perseverative Responses (%) 15 (12) 7 (3) 29 (29) 28 (32)a 5.2 (28) 0.03 0.14 (27) 0.71 4.5 (28) 0.07

Results related to changes over time in the 22 repeated measures ANOVA (ODRT) and the linear mixed model analysis (WCST). Bolded results indicate significant time effect at p <
0.05

Trend level time eect p < 0.10.
a
Signicant group eect: control vs. schizophrenia, p < 0.05; Simple main eect: slower ODRT correct reaction time, greater % perseverative error and % perseverative responses in
the schizophrenia group compared to the control group at post-test, p < 0.05.

82
A.L. Rodrigue et al. Psychiatry Research: Neuroimaging 265 (2017) 7786

Insula/ Superior Temporal Gyrus

x=34 mm L
0.12

0.10 n.s.

C o n n e c tiv ity ( r )
0.08
* *
0.06
0.04

0.02

0.00

-0.02 C
SZ
-0.04
Pre-Test Post-Test Pre-Test Post-Test

Middle Temporal Gyrus

0.12 n.s.

0.10 *
* *

C o n n e c t i v it y ( r )
x=38 mm 0.08

0.06

0.04
Interaction Clusters X Y Z Cluster Size
(voxels) 0.02

L. Insula/ -30 -17 16 246 0.00

Superior Temporal Gyrus
-0.02 C
L. Middle Temporal Gyrus -38 -57 24 84 SZ
-0.04
Pre-Test Post-Test Pre-Test Post-Test

Fig. 3. Interaction Results. Two regions showing an interaction eect from the grouptime ANOVA (shown at p=0.03). Regions are displayed on a 3D rendered brain of an individual
subject in radiological orientation (right is left, left is right) with the surface of the temporal lobe removed. Region colors correspond to graph colors. Bar graphs show mean connectivity
change values (SE) for each region at pre- and post-test for each group. The table reports center of mass coordinates and number of voxels within the cluster for each region in Talairach
space. C=Control, SZ=Schizophrenia. * Group- and time-wise signicant dierences. Signicant dierence from 0.

only in the schizophrenia group after practice, we found connectivity

Insula/ Superior Temporal Gyrus changes in extrastriate and primary visual regions similar to the insula
(see Supplementary Fig. 1.). Stronger connections between these
100 bottom-up regions along with the insula could form a PFC-mediated
C r = 0.07
SZ network that reduces the impact of irrelevant visual information and
r = -0.67*
Antisaccade Error Rate (%)

contributes to the inhibition of visually driven responses as is necessary

80 during antisaccade tasks. We saw some evidence of this in the
schizophrenia group, who after practice, had a signicant relationship
between PFC connectivity with insular/temporal regions and antisac-
60
cade error rate, with stronger connections associated with fewer errors.
Results also are consistent with other studies that nd disrupted
40 frontal connectivity in schizophrenia (Tu et al., 2010; Wadehra et al.,
2013) that is strengthened or enhanced with practice-related para-
digms (Schlsser et al., 2009). Disrupted connectivity is indicative of
20 impaired integration of functional signals across the brain and plays a
role in disrupted cognitive control behavior (Wadehra et al., 2013). We
found connectivity changes between the right PFC and regions located
0
in the left hemisphere, although at rest, these regions are typically
-0.15 -0.10 -0.05 0.00 0.05 0.10 0.15
included in bilateral networks (Damoiseaux et al., 2006). There is
Post-Test Connectivity (r) evidence that functional disruptions may be predominant in the left
hemisphere in schizophrenia (Gur and Chin, 1999; Heckers et al.,
Fig. 4. Brain/ Behavior Correlation. Correlation between Insula/STG connectivity
2002; Ke et al., 2010), possibly explaining the laterality of our results.
change values and antisaccade error rate for schizophrenia (black) and control (gray)
groups at post-test. Stronger connectivity with the rMFG was associated with fewer Furthermore, Penads et al. (2013) found that cognitive remediation
antisaccade errors in schizophrenia. * Signicance at p < 0.05. increases white matter integrity (as measured by fractional anisotropy)
in cross hemispheric tracts, which in turn, increases information

83
A.L. Rodrigue et al.
transfer between hemispheres. Although structural connections were
not addressed in this study, this may be a possible mechanism
underlying the observed changes in functional connections between
the rMFG and left insular/temporal regions. Normalization of brain
measures after cognitive control practice, as in our study, has also been
reported by a recent meta-analysis (Ramsay and MacDonald, 2015),
although it focused on brain activation rather than brain connectivity.
In terms of activation, there were no dierences between the
control and schizophrenia groups at pretest in either the rMFG (PPI
seed) or the two interaction clusters (Insula/STG, MTG) (See
Supplemental Figure 2.). Changes in connectivity, therefore, were
independent of any disruptions in brain activation between the two
groups at pre-test. After practice, the schizophrenia group did show
decreases in activation in all three regions (although this was not
signicant in the Insula/STG region). This is consistent with Schlsser
et al. (2009), who found stronger activation decreases in schizophrenia
(compared to controls) coupled with enhanced task based- connectivity
after repeated performance of a cognitive control task. They suggested
that increases in task-based connectivity were a reection of the need
to dampen inecient levels of activation present before practice.
Although the schizophrenia group in our study did not show diering
levels of activation compared to controls at pre-test, they did exhibit
signicantly impaired antisaccade behavior as evidenced by more
errors. Activation in the schizophrenia group, therefore, could still be
considered inecient since they were activating the same amount as
controls but with less behavioral benet.
Similar to previous studies, our control group exhibited changes in
behavior (Dyckman and McDowell, 2005) and brain measures (Lee
et al., 2013) after practice. These changes took the form of increased
eciency with lower error rates coupled with faster reaction times at
post-test. Increased behavioral eciency coupled with reduced con-
nections between the PFC and insular/temporal regions could indicate
that, for the control group, antisaccades were becoming more auto-
matic. Automaticity may make the connections between top-down
control regions and bottom-up sensory regions unnecessary. This is
supported by Unsworth et al. (2011), who showed that with extensive
practice, antisaccade performance can become just as automatized as
prosaccade performance with similar behavioral metrics in each task.
While error rate also decreased in the schizophrenia group, we did not
observe any changes in reaction time. It is likely that baseline
dierences in behavioral performance as well as schizophrenia-related
disruptions in circuitry function contributed to the dierential eects
of practice on the two groups.
Lastly, there is a question of whether the eects of antisaccade
practice would transfer to other cognitive tasks. This seems possible
given decreases in ODRT error rate and reaction time in both groups to
a similar extent as those observed for antisaccade performance. We
also saw increases in the number of categories completed and decreases
in the percent of perseverative errors and responses, all indicators of
better WCST performance. WCST changes, however, were only ob-
served in the control group, and should be interpreted with caution
since there are signicant practice eects on WCST measures (Bartels
et al., 2010) that are independent of cognitive control practice.
Additionally, it is possible that without additional intervention, anti-
saccade transfer eects in schizophrenia may be limited to tasks that
are more closely related to those that are practiced.
One limitation to this study is that schizophrenia subjects were
taking a variety of psychotropic medications at the time of testing. Poor
antisaccade performance is independent of medication status (Reilly
et al., 2014), however, and is found in both rst episode and non-
medicated individuals (Harris et al., 2006; Hutton et al., 1998, 2004)
and their non-psychotic relatives (Calkins et al., 2004; Camchong et al.,
2008). Another limitation is missing behavioral data from some
subjects. Despite not being able to acquire digitized behavioral data,
we knew subjects were engaged in the task via observation of the eye
from a camera. Finally, we did not collect a group of subjects that
84
Psychiatry Research: Neuroimaging 265 (2017) 7786
performed the pre- and post-test scanning sessions without participat-
ing in the practice sessions because of limited resources. While this is
an important consideration, antisaccade performance in adulthood is
relatively stable in both controls (Ettinger et al., 2003; Klein and Berg,
2001) and people with schizophrenia (Calkins et al., 2003). Antisaccade
error rate also is familial in psychosis with moderate heritability (h2 as
high as 0.32) (Reilly et al., 2014), making antisaccade tasks more trait-
like than typical tests of cognitive control.
Practice of a cognitive control task (antisaccades) may alter PFC-
mediated behavior and brain connectivity in schizoprhenia despite
similar levels of brain activation as controls at pre-test. Additionally,
stronger connectivity at post-test in the schizophrenia group was
associated with fewer errors in cognitive control. These results
emphasize the importance of evaluating changes in brain connectivity
in addition to traditional methods of evaluating changes in brain
activation after cognitive control practice. A more complete picture of
practice related changes may contribute to understanding mechanisms
underlying cognitive control disruptions in schizophrenia and reme-
diating them may improve overall cognition and the ability to perform
daily functions, which could signicantly improve the quality of life for
people with the disorder.
Contributors
Amanda Rodrigue performed the analysis and wrote the manu-
script. Benjamin Austin designed the study and collected the data.
Jennifer McDowell designed the study and contributed to manuscript
writing.
Conict of interest
This work was funded by the NIH (MH076998).
Role of the funding source
This work was funded by the NIH (MH076998). The funding source
had no involvement in data collection, analysis, data interpretation,
report writing, or publication submission.
Acknowledgments
This work was funded by the NIH (MH076998). We would also like
to thank the UGA Biomedical Research Center and the Franklin
Foundation Neuroimaging Training Fellowship, whose facilities and
funds helped support this research.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in the
online version at http://dx.doi.org/10.1016/j.pscychresns.2016.09.
004.
References
Andersen, R., Asanuma, C., Essick, G., Siegel, R., 1990. Corticocortical connections of
anatomically and physiologically dened subdivisions within the inferior parietal
lobule. J. Comp. Neurol. 296, 65113.
Augustine, J.R., 1996. Circuitry and functional aspects of the insular lobe in primates
including humans. Brain Res. Rev. 22, 229244.
Bartels, C., Wegrzyn, M., Wiedl, A., Ackermann, V., Ehrenreich, H., 2010. Practice eects
in healthy adults: a longitudinal study on frequent repetitive cognitive testing. BMC
Neurosci. 11, 1.
Bellack, A.S., Gold, J.M., Buchanan, R.W., 1999. Cognitive rehabilitation for
schizophrenia. Schizophr. Bull. 25, 257274.
Berman, K.F., Ostrem, J.L., Randolph, C., Gold, J., Goldberg, T.E., Coppola, R., Carson,
R.E., Herscovitch, P., Weinberger, D.R., 1995. Physiological activation of a cortical
network during performance of the Wisconsin Card Sorting Test: a positron emission
tomography study. Neuropsychologia 33, 10271046.
Bor, J., Brunelin, J., d'Amato, T., Costes, N., Suaud-Chagny, M.-F., Saoud, M., Poulet, E.,
A.L. Rodrigue et al.
2011. How can cognitive remediation therapy modulate brain activations in
schizophrenia?: an fMRI study. Psychiatry Res.: Neuroimaging 192, 160166.
Braver, T.S., Barch, D.M., Cohen, J.D., 1999. Cognition and control in schizophrenia: a
computational model of dopamine and prefrontal function. Biol. Psychiatry 46,
312328.
Brown, M.R., Goltz, H.C., Vilis, T., Ford, K.A., Everling, S., 2006. Inhibition and
generation of saccades: rapid event-related fMRI of prosaccades, antisaccades, and
nogo trials. Neuroimage 33, 644659.
Bchel, C., Friston, K., 1997. Modulation of connectivity in visual pathways by attention:
cortical interactions evaluated with structural equation modelling and fMRI. Cereb.
Cortex 7, 768778.
Calkins, M.E., Curtis, C.E., Iacono, W.G., Grove, W.M., 2004. Antisaccade performance is
impaired in medically and psychiatrically healthy biological relatives of
schizophrenia patients. Schizophr. Res. 71, 167178.
Calkins, M.E., Dobie, D.J., Cadenhead, K.S., Olincy, A., Freedman, R., Green, M.F.,
Greenwood, T.A., Gur, R.E., Gur, R.C., Light, G.A., Mintz, J., Nuechterlein, K.H.,
Radant, A.D., Schork, N.J., Seidman, L.J., Siever, L.J., Silverman, J.M., Stone, W.S.,
Swerdlow, N.R., Tsuang, D.W., Tsuang, M.T., Turetsky, B.I., Bra, D.L., 2007. The
consortium on the genetics of endophenotypes in schizophrenia: model recruitment,
assessment, and endophenotyping methods for a multisite collaboration. Schizophr.
Bull. 33, 3348.
Calkins, M.E., Iacono, W.G., Curtis, C.E., 2003. Smooth pursuit and antisaccade
performance evidence trait stability in schizophrenia patients and their relatives. Int.
J. Psychophysiol. 49, 139146.
Callicott, J.H., Bertolino, A., Mattay, V.S., Langheim, F.J.P., Duyn, J., Coppola, R.,
Goldberg, T.E., Weinberger, D.R., 2000. Physiological dysfunction of the dorsolateral
prefrontal cortex in schizophrenia revisited. Cereb. Cortex 10, 10781092.
Camchong, J., Dyckman, K.A., Chapman, C.E., Yanasak, N.E., McDowell, J.E., 2006.
Basal ganglia-thalamocortical circuitry disruptions in schizophrenia during delayed
response tasks. Biol. Psychiatry 60, 235241.
Camchong, J., Dyckman, K.A., Austin, B.P., Clementz, B.A., McDowell, J.E., 2008.
Common neural circuitry supporting volitional saccades and its disruption in
schizophrenia patients and relatives. Biol. Psychiatry 64, 10421050.
Camchong, J., MacDonald, A.W., Bell, C., Mueller, B.A., Lim, K.O., 2011. Altered
Functional and Anatomical Connectivity in Schizophrenia. Schizophr. Bull. 37,
640650.
Chein, J.M., Schneider, W., 2005. Neuroimaging studies of practice-related change: fMRI
and meta-analytic evidence of a domain-general control network for learning. Cogn.
Brain Res. 25, 607623.
Clementz, B.A., McDowell, J.E., Zisook, S., 1994. Saccadic system functioning among
schizophrenia patients and their rst-degree biological relatives. J. Abnorm. Psychol.
103, 277.
Cnaan, A., Laird, N., Slasor, P., 1997. Tutorial in biostatistics: using the general linear
mixed model to analyse unbalanced repeated measures and longitudinal data. Stat.
Med. 16, 23492380.
Corbetta, M., Akbudak, E., Conturo, T.E., Snyder, A.Z., Ollinger, J.M., Drury, H.A.,
Linenweber, M.R., Petersen, S.E., Raichle, M.E., Van Essen, D.C., Shulman, G.L.,
1998. A common network of functional areas for attention and eye movements.
Neuron 21, 761773.
Corbetta, M., Shulman, G.L., 2002. Control of goal-directed and stimulus-driven
attention in the brain. Nat. Rev. Neurosci. 3, 201215.
Cox, R.W., 1996. AFNI: software for analysis and visualization of functional magnetic
resonance neuroimages. Comput. Biomed. Res. 29, 162173.
Crawford, T.J., Sharma, T., Puri, B.K., Murray, R.M., Berridge, D.M., Lewis, S.W., 1998.
Saccadic eye movements in families multiply aected with schizophrenia: the
Maudsley Family Study. Am. J. Psychiatry 155, 17031710.
Damoiseaux, J., Rombouts, S., Barkhof, F., Scheltens, P., Stam, C., Smith, S.M.,
Beckmann, C., 2006. Consistent resting-state networks across healthy subjects. Proc.
Natl. Acad. Sci. 103, 1384813853.
DeSouza, J.F., Menon, R.S., Everling, S., 2003. Preparatory set associated with pro-
saccades and anti-saccades in humans investigated with event-related FMRI. J.
Neurophysiol. 89, 10161023.
Doricchi, F., Perani, D., Incoccia, C., Grassi, F., Cappa, S.F., Bettinardi, V., Galati, G.,
Pizzamiglio, L., Fazio, F., 1997. Neural control of fast-regular saccades and
antisaccades: an investigation using positron emission tomography. Exp. Brain Res.
116, 5062.
Dyckman, K.A., McDowell, J.E., 2005. Behavioral plasticity of antisaccade performance
following daily practice. Exp. Brain Res. 162, 6369.
Dyckman, K.A., Camchong, J., Clementz, B.A., McDowell, J.E., 2007. An eect of context
on saccade-related behavior and brain activity. NeuroImage 36, 774784.
Ettinger, U., Kumari, V., Crawford, T.J., Davis, R.E., Sharma, T., Corr, P.J., 2003.
Reliability of smooth pursuit, xation, and saccadic eye movements.
Psychophysiology 40, 620628.
Ettinger, U., Kumari, V., Crawford, T.J., Corr, P.J., Das, M., Zachariah, E., Hughes, C.,
Sumich, A.L., Rabe-Hesketh, S., Sharma, T., 2004. Smooth pursuit and antisaccade
eye movements in siblings discordant for schizophrenia. J. Psychiatr. Res. 38,
177184.
Ettinger, U., Picchioni, M., Hall, M.-H., Schulze, K., Toulopoulou, T., Landau, S.,
Crawford, T.J., Murray, R.M., 2006. Antisaccade performance in monozygotic twins
discordant for schizophrenia: the Maudsley twin study. Am. J. Psychiatry 163,
543545.
Everling, S., Johnston, K., 2013. Control of the superior colliculus by the lateral
prefrontal cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20130068.
First, M.B., Spitzer, R.L., Miriam, Gibbon, Williams, Janet B.W., 2002a. Structured
Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient
Edition. (SCID-I/P). Biometrics Research. New York State Psychiatric Institute, New
85
Psychiatry Research: Neuroimaging 265 (2017) 7786
York.
First, M.B., Spitzer, Robert L., Miriam, Gibbon, Williams, Janet B.W., 2002b. Structured
Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient
Edition. (SCID-I/NP). Biometrics Research. New York State Psychiatric Institute,
New York.
Fletcher, P., Bchel, C., Josephs, O., Friston, K., Dolan, R., 1999. Learning-related
neuronal responses in prefrontal cortex studied with functional neuroimaging.
Cereb. Cortex 9, 168178.
Ford, K.A., Goltz, H.C., Brown, M.R., Everling, S., 2005. Neural processes associated with
antisaccade task performance investigated with event-related FMRI. J.
Neurophysiol. 94, 429440.
Fornito, A., Yoon, J., Zalesky, A., Bullmore, E.T., Carter, C.S., 2011. General and specic
functional connectivity disturbances in rst-episode schizophrenia during cognitive
control performance. Biol. Psychiatry 70, 6472.
Friston, K., Buechel, C., Fink, G., Morris, J., Rolls, E., Dolan, R., 1997.
Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 6,
218229.
Garavan, H., Kelley, D., Rosen, A., Rao, S.M., Stein, E.A., 2000. Practice-related
functional activation changes in a working memory task. Microsc. Res. Tech. 51,
5463.
Grosbras, M.-H., Laird, A.R., Paus, T., 2005. Cortical regions involved in eye movements,
shifts of attention, and gaze perception. Hum. Brain Mapp. 25, 140154.
Gueorguieva, R., Krystal, J.H., 2004. Move over anova: progress in analyzing repeated-
measures data andits reection in papers published in the archives of general
psychiatry. Arch. Gen. Psychiatry 61, 310317.
Gur, R.E., Chin, S., 1999. Laterality in functional brain imaging studies of schizophrenia.
Schizophr. Bull. 25, 141156.
Haller, S., Fasler, D., Ohlendorf, S., Radue, E., Greenlee, M., 2008. Neural activation
associated with corrective saccades during tasks with xation, pursuit and saccades.
Exp. Brain Res. 184, 8394.
Hamm, J.P., Sabatinelli, D., Clementz, B.A., 2012. Alpha oscillations and the control of
voluntary saccadic behavior. Exp. Brain Res. 221, 123128.
Harris, M.S., Reilly, J.L., Keshavan, M.S., Sweeney, J.A., 2006. Longitudinal studies of
antisaccades in antipsychotic-naive rst-episode schizophrenia. Psychol. Med. 36,
485494.
Heaton, R., 1981. Wisconsin Card Sorting Test: Manual. Psychological Assessment
Resources, Odessa, FL.
Heckers, S., Go, D., Weiss, A.P., 2002. Reversed hemispheric asymmetry during simple
visual perception in schizophrenia. Psychiatry Res.: Neuroimaging 116, 2532.
Hussein, S., Johnston, K., Belbeck, B., Lomber, S.G., Everling, S., 2014. Functional
specialization within macaque dorsolateral prefrontal cortex for the maintenance of
task rules and cognitive control. J. Cogn. Neurosci. 26, 19181927.
Hutton, S., Crawford, T.J., Puri, B., Duncan, L.-J., Chapman, M., Kennard, C., Barnes, T.,
Joyce, E., 1998. Smooth pursuit and saccadic abnormalities in rst-episode
schizophrenia. Psychol. Med. 28, 685692.
Hutton, S.B., Huddy, V., Barnes, T.R., Robbins, T.W., Crawford, T.J., Kennard, C., Joyce,
E.M., 2004. The relationship between antisaccades, smooth pursuit, and executive
dysfunction in rst-episode schizophrenia. Biol. Psychiatry 56, 553559.
Hwang, K., Ghuman, A.S., Manoach, D.S., Jones, S.R., Luna, B., 2014. Cortical
neurodynamics of inhibitory control. J. Neurosci. 34, 95519561.
Jolles, D.D., Van Buchem, M.A., Crone, E.A., Rombouts, S.A., 2013. Functional brain
connectivity at rest changes after working memory training. Hum. Brain Mapp. 34,
396406.
Kan, S., Misaki, M., Koike, T., Miyauchi, S., 2008. Dierent modulation of medial
superior temporal activity across saccades: a functional magnetic resonance imaging
study. Neuroreport 19, 133137.
Ke, M., Zou, R., Shen, H., Huang, X., Zhou, Z., Liu, Z., Xue, Z., Hu, D., 2010. Bilateral
functional asymmetry disparity in positive and negative schizophrenia revealed by
resting-state fMRI. Psychiatry Res.: Neuroimaging 182, 3039.
Kelly, A.C., Garavan, H., 2005. Human functional neuroimaging of brain changes
associated with practice. Cereb. Cortex 15, 10891102.
Kelly, A.C., Hester, R., Foxe, J.J., Shpaner, M., Garavan, H., 2006. Flexible cognitive
control: eects of individual dierences and brief practice on a complex cognitive
task. Neuroimage 31, 866886.
Klein, C., Berg, P., 2001. Four-week test-retest stability of individual dierences in the
saccadic CNV, two saccadic task parameters, and selected neuropsychological tests.
Psychophysiology 38, 704711.
Koch, K., Wagner, G., von Consbruch, K., Nenadic, I., Schultz, C., Ehle, C., Reichenbach,
J., Sauer, H., Schlsser, R., 2006. Temporal changes in neural activation during
practice of information retrieval from short-term memory: an fMRI study. Brain Res.
1107, 140150.
Koch, K., Wagner, G., Nenadic, I., Schachtzabel, C., Roebel, M., Schultz, C., Axer, M.,
Reichenbach, J.R., Sauer, H., Schlosser, R.G., 2007. Temporal modeling
demonstrates preserved overlearning processes in schizophrenia: an fMRI study.
Neuroscience 146, 14741483.
Koch, K., Wagner, G., Schachtzabel, C., Schultz, C., Sauer, H., Schlsser, R.G., 2010.
Association between learning capabilities and practice-related activation changes in
schizophrenia. Schizophr. Bull. 36, 486495.
Koechlin, E., Ody, C., Kouneiher, F., 2003. The architecture of cognitive control in the
human prefrontal cortex. Science 302, 11811185.
Krat, C., Schwarz, N., Chi, L., Li, Q., Schaeer, D., Rodrigue, A., Pierce, J., Dykman, K.,
McDowell, J., 2012. The Location and Function of Parietal Cortex Supporting of
Reexive and Volitional Saccades, A Meta-analysis of over a Decade of Functional
MRI Data, Parietal Cortex: Anatomy, Functions and Disorders. Nova Science
Publishers, Hauppauge, NY.
Lee, J., Park, C., Dyckman, K.A., Lazar, N.A., Austin, B.P., Li, Q., McDowell, J.E., 2013.
A.L. Rodrigue et al.
Practice-related changes in neural activation patterns investigated via wavelet-based
clustering analysis. Hum. Brain Mapp. 34, 22762291.
Leung, H.-C., Cai, W., 2007. Common and dierential ventrolateral prefrontal activity
during inhibition of hand and eye movements. J. Neurosci. 27, 98939900.
Liddle, P.F., 2000. Cognitive impairment in schizophrenia: its impact on social
functioning. Acta Psychiatr. Scand. 101, 1116.
Mackey, A.P., Singley, A.T.M., Bunge, S.A., 2013. Intensive reasoning training alters
patterns of brain connectivity at rest. J. Neurosci. 33, 47964803.
Manoach, D.S., Ketwaroo, G.A., Polli, F.E., Thakkar, K.N., Barton, J.J., Go, D.C., Fischl,
B., Vangel, M., Tuch, D.S., 2007. Reduced microstructural integrity of the white
matter underlying anterior cingulate cortex is associated with increased saccadic
latency in schizophrenia. Neuroimage 37, 599610.
Mansouri, F.A., Matsumoto, K., Tanaka, K., 2006. Prefrontal cell activities related to
monkeys success and failure in adapting to rule changes in a Wisconsin Card Sorting
Test analog. J. Neurosci. 26, 27452756.
McDowell, J.E., Myles-Worsley, M., Coon, H., Byerley, W., Clementz, B.A., 1999.
Measuring liability for schizophrenia using optimized antisaccade stimulus
parameters. Psychophysiology 36, 138141.
McDowell, J.E., Brown, G.G., Paulus, M., Martinez, A., Stewart, S.E., Dubowitz, D.J.,
Bra, D.L., 2002. Neural correlates of rexation saccades and antisaccades in normal
and schizophrenia subjects. Biol. Psychiatry 51, 216223.
McLaren, D.G., Ries, M.L., Xu, G., Johnson, S.C., 2012. A generalized form of context-
dependent psychophysiological interactions (gPPI): a comparison to standard
approaches. Neuroimage 61, 12771286.
Meyer-Lindenberg, A.S., Olsen, R.K., Kohn, P.D., et al., 2005. REgionally specic
disturbance of dorsolateral prefrontalhippocampal functional connectivity in
schizophrenia. Arch. Gen. Psychiatry 62, 379386.
Milea, D., Lobel, E., Lehricy, S., PIERROT-DESEILLIGNY, C., Berthoz, A., 2005.
Cortical mechanisms of saccade generation from execution to decision. Ann. N. Y.
Acad. Sci. 1039, 232238.
Miller, E.K., 2000. The prefontral cortex and cognitive control. Nat. Rev. Neurosci. 1,
5965.
Minzenberg, M.J., Carter, C.S., 2012. Developing treatments for impaired cognition in
schizophrenia. Trends Cogn. Sci. 16, 3542.
Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A., Wager, T.D.,
2000. The unity and diversity of executive functions and their contributions to
complex frontal lobe tasks: a latent variable analysis. Cogn. Psychol. 41, 49100.
OReilly, J.X., Woolrich, M.W., Behrens, T.E.J., Smith, S.M., Johansen-Berg, H., 2012.
Tools of the trade: psychophysiological interactions and functional connectivity. Soc.
Cogn. Aect. Neurosci. 7, 604609.
Paolo, A.M., Trster, A.I., Axelrod, B.N., Koller, W.C., 1995. Construct validity of the
WCST in normal elderly and persons with Parkinsons disease. Arch. Clin.
Neuropsychol. 10, 463473.
Penads, R., Pujol, N., Cataln, R., Massana, G., Rametti, G., Garca-Rizo, C., Bargall,
N., Gast, C., Bernardo, M., Junqu, C., 2013. Brain eects of cognitive remediation
therapy in schizophrenia: a structural and functional neuroimaging study. Biol.
Psychiatry 73, 10151023.
86
Psychiatry Research: Neuroimaging 265 (2017) 7786
Perry, R., Zeki, S., 2000. The neurology of saccades and covert shifts in spatial attention.
Brain 123, 22732288.
Pierrot-Deseilligny, C., Mri, R., Ploner, C., Gaymard, B., Demeret, S., Rivaud-Pechoux,
S., 2003. Decisional role of the dorsolateral prefrontal cortex in ocular motor
behaviour. Brain 126, 14601473.
Raine, A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on
DSM-III-R criteria. Schizophr. Bull. 17, 55555564.
Ramsay, I.S., MacDonald, A.W., 2015. Brain correlates of cognitive remediation in
schizophrenia: activation likelihood analysis shows preliminary evidence of neural
target engagement. Schizophr. Bull., sbv025.
Reilly, J.L., Frankovich, K., Hill, S., Gershon, E.S., Keefe, R.S., Keshavan, M.S., Pearlson,
G.D., Tamminga, C.A., Sweeney, J.A., 2014. Elevated antisaccade error rate as an
intermediate phenotype for psychosis across diagnostic categories. Schizophr. Bull.
40, 10111021.
Rissman, J., Gazzaley, A., DEsposito, M., 2004. Measuring functional connectivity
during distinct stages of a cognitive task. Neuroimage 23, 752763.
Schlsser, R., Koch, K., Wagner, G., Schultz, C., Rbel, M., Schachtzabel, C.,
Reichenbach, J., Sauer, H., 2009. Intensive practice of a cognitive task is associated
with enhanced functional integration in schizophrenia. Psychol. Med. 39,
18091819.
Smyrnis, N., Malogiannis, I.A., Evdokimidis, I., Stefanis, N.C., Theleritis, C., Vaidakis, A.,
Theodoropoulou, S., Stefanis, C.N., 2004. Attentional facilitation of response is
impaired for antisaccades but not for saccades in patients with schizophrenia:
implications for cortical dysfunction. Exp. Brain Res. 159, 4754.
Thaker, G., Kirkpatrick, B., Buchanan, R.W., Ellsberry, R., Lahti, A., Tamminga, C., 1989.
Oculomotor abnormalities and their clinical correlates in schizophrenia.
Psychopharmacol. Bull. 25, 491497.
Tu, P., Yang, T., Kuo, W., Hsieh, J., Su, T., 2006. Neural correlates of antisaccade decits
in schizophrenia, an fMRI study. J. Psychiatr. Res. 40, 606612.
Tu, P., Buckner, R.L., Zollei, L., Dyckman, K.A., Go, D.C., Manoach, D.S., 2010.
Reduced functional connectivity in a right-hemisphere network for volitional ocular
motor control in schizophrenia. Brain 133, 625637.
Unsworth, N., Spillers, G.J., Brewer, G.A., McMillan, B., 2011. Attention control and the
antisaccade task: a response time distribution analysis. Acta Psychol. (Amst.) 137,
90100.
Wadehra, S., Pruitt, P., Murphy, E.R., Diwadkar, V.A., 2013. Network dysfunction during
associative learning in schizophrenia: increased activation, but decreased
connectivity: an fMRI study. Schizophr. Res. 148, 3849.
Wager, T.D., Sylvester, C.-Y.C., Lacey, S.C., Nee, D.E., Franklin, M., Jonides, J., 2005.
Common and unique components of response inhibition revealed by fMRI.
Neuroimage 27, 323340.
Wykes, T., Brammer, M., Mellers, J., Bray, P., Reeder, C., Williams, C., Corner, J., 2002.
Eects on the brain of a psychological treatment: cognitive remediation therapy:
functional magnetic resonance imaging in schizophrenia. Br. J. Psychiatry 181,
144152.