HHS Public Access

Author manuscript
Autism Res. Author manuscript; available in PMC 2016 July 14.
Author Manuscript

Published in final edited form as:

Autism Res. 2015 April ; 8(2): 123135. doi:10.1002/aur.1398.

Developmental Changes in Brain Function Underlying Inhibitory

Control in Autism Spectrum Disorders
Aarthi Padmanabhan, Krista Garver, Kirsten OHearn, Natalie Nawarawong, Ran Liu, Nancy
Minshew, John Sweeney, and Beatriz Luna
Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania (A.P., K.G., K.O., N.N.); Psychology,
Carnegie Mellon University, Pittsburgh, Pennsylvania (R.L.); Psychiatry and Neurology, University
Author Manuscript

of Pittsburgh Medical School, Pittsburgh, Pennsylvania (N.M.); University of Texas Health Science
Center, Psychiatry and Pediatrics, Dallas, Texas (J.S.); Psychiatry and Psychology, University of
Pittsburgh, Pittsburgh, Pennsylvania (B.L.)

Abstract
The development of inhibitory controlthe ability to suppress inappropriate actions in order to
make goal-directed responsesis often impaired in autism spectrum disorders (ASD). In the
present study, we examined whether the impairments in inhibitory control evident in ASD reflect
in partdifferences in the development of the neural substrates of inhibitory control from
adolescence into adulthood. We conducted a functional magnetic resonance imaging (fMRI) study
on the anti-saccade task, a probe of inhibitory control, in high-functioning adolescents and adults
with ASD compared to a matched group of typically developing (TD) individuals. The ASD group
Author Manuscript

did not show the age-related improvements in behavioral performance from adolescence to
adulthood evident in the typical group, consistent with previous behavioral work. The fMRI results
indicated that much of the circuitry recruited by the ASD group was similar to the TD group.
However, the ASD group demonstrated some unique patterns, including: (a) a failure to recruit the
frontal eye field during response preparation in adolescence but comparable recruitment in
adulthood; (b) greater recruitment of putamen in adolescence and precuneus in adolescence and
adulthood than the TD group; and (c) decreased recruitment in the inferior parietal lobule relative
to TD groups. Taken together, these results suggest that brain circuitry underlying inhibitory
control develops differently from adolescence to adulthood in ASD. Specifically, there may be
relative underdevelopment of brain processes underlying inhibitory control in ASD, which may
lead to engagement of subcortical compensatory processes.
Author Manuscript

Keywords
autism; fMRI; inhibitory control; antisaccade; development; adolescence

Address for correspondence and reprints: Aarthi Padmanabhan, Laboratory of Neurocognitive Development, Loeffler Building, Room
108, 121 Meyran Avenue, Pittsburgh, PA 15213. padmanabhana@upmc.edu.
Supporting information
Additional Supporting Information may be found in the online version of this article at the publishers web-site:
Figure S1. Schematic of single subject and group data analysis steps. Images for the single subject analysis were taken from a
representative participant.
Table S1. Medication status of ASD participants.
 Padmanabhan et al. Page 2

Introduction
Author Manuscript

Autism spectrum disorders (ASD) are a class of neurodevelopmental disorders characterized

in part by atypical brain development, which may lead to abnormalities in cognitive
behaviors. In typical development, substantial improvements in inhibitory control of
behavior and the brain systems that underlie it continue from adolescence into early
adulthood [Luna, Garver, Urban, Lazar, & Sweeney, 2004; Velanova, Wheeler, & Luna,
2008, 2009]. Inhibitory control, defined as the ability to suppress automatic but
inappropriate responses in favor of a goal-directed behavior [Bjorklund & Harnishfeger,
1995; Dempster, 1992] may be a likely candidate for cognitive differences in ASD, though
the results are mixed, suggesting that deficits may be paradigm specific [Goldberg et al.,
2005; Ozonoff & Strayer, 1997; Ozonoff, Strayer, McMahon, & Filloux, 1994; Schmitz et
al., 2006] [Agam, Joseph, Barton, & Manoach, 2010; Luna, Doll, Hegedus, Minshew, &
Sweeney, 2007; Minshew, Luna, & Sweeney, 1999; Ozonoff & Strayer, 1997; Russell, 1997]
Author Manuscript

or highlight the need to study the development of these processes [Luna et al., 2007;
Solomon et al., 2014]. As adolescence is a time of significant change in brain and behavior
[Spear, 2000], the transition from adolescence to adulthood has become focus of
investigation and represents a potential window of plasticity in the brain, which may be
impacted in ASD.

On the inhibitory tasks shown to differ in ASD, studies have demonstrated that both children
and adults with ASD have poorer performance than matched typical controls, suggesting
that abnormalities may persist throughout development [Agam et al., 2010; Goldberg et al.,
2002; Luna et al., 2007; Minshew et al., 1999; Mosconi et al., 2009; Solomon et al., 2014].
One index of inhibitory control, the anti-saccade(AS) task, is a well-established oculomotor
paradigm that has previously been used to model the developmental trajectory of inhibitory
Author Manuscript

control through adolescence into adulthood [Fischer, Biscaldi, & Gezeck, 1997; Fukushima,
Hatta, & Fukushima, 2000; Klein & Foerster, 2001; Luna et al., 2001, 2004; Munoz,
Broughton, Goldring, & Armstrong, 1998; Velanova et al., 2008, 2009]. During the AS task,
participants must suppress an automatic reaction to a peripheral stimulus and generate a
planned oculomotor response in the opposite direction. Prior evidence has suggested that TD
adults and adolescents engage a widely distributed set of brain regions during performance
of the AS task, including cortical and subcortical regions such as the frontal, supplementary,
and parietal eye fields (FEF, SEF, and PEF, respectively), basal ganglia, dorsolateral
prefrontal cortex (DLPFC), and cerebellum [for review, see Munoz & Everling, 2004]. Our
previous fMRI studies using the anti-saccade task to examine normative development
indicate significant developmental changes in brain function supporting anti-saccade
performance and improved error processing. [Luna et al., 2001; Velanova et al., 2008, 2009].
Author Manuscript

Robust inhibitory control deficits on the AS task have been documented in adults with ASD
[Agam et al., 2010; Luna et al., 2007; Minshew et al., 1999; Mosconi et al., 2009; Thakkar
et al., 2008]. Adults with ASD demonstrate worse performance, decreased recruitment of the
anterior cingulate cortex (ACC) and the FEF following correct trials, and reduced functional
connectivity between the ACC and premotor regions compared to typical adults [Agam et
al., 2010; Thakkar et al., 2008]. This is consistent with other inhibitory control tasks that
result in reduced activation and functional connectivity in ACC, PFC, and posterior parietal

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 3

regions, in adults with ASD relative to typically developed individuals [Kana, Keller,
Author Manuscript

Minshew, & Just, 2007; Schmitz et al., 2006; Solomon et al., 2009]. We previously
examined the development of inhibitory control behavior in ASD using the AS task in a
cross-sectional sample from childhood to adulthood. The results indicated that despite
performing worse than typically developing individuals in both adolescence and adulthood,
the group with ASD showed significant age-related improvements similar to typically
developing individuals [Luna et al., 2007]. That is, individuals with ASD show parallel
improvements in inhibitory control through adolescence but do not catch up with typically
developing peers. These behavioral findings suggest that similar brain maturation processes
may be occurring in ASD from adolescence to adulthood, but to date, little is known about
the development of the neural substrates of inhibitory control in ASD.

Identifying the neural substrates of the developmental delays, arrests, and abnormalities in
ASD will provide insight into limitations in inhibitory control, and help to identify time
Author Manuscript

points during which intervention will be particularly successful. Furthermore, assessing

developmental changes into adulthood will identify cognitive deficits that may be late
appearing and highlights how the final stage of development may deviate from typical
development.

In the present study, we examined the neural correlates of the AS task in adolescents and
adults diagnosed with ASD relative to age and IQ-matched typically developing adolescent
and adult participants using functional magnetic resonance imaging (fMRI). Similar to our
previous behavioral results [Luna et al., 2007], we predicted that the ASD group would show
age-related improvements in anti-saccade performance from adolescence to adulthood
similar to the typically developing group. However, we had no directional hypotheses for the
interaction between age group and diagnosis group, given the lack of previous studies in this
Author Manuscript

area.

Methods
Participants
Forty-two participants were recruited for the study, 14 typical adults (ages 1831, M = 23.4
(+ / 4.0); two females), and nine typical adolescents (ages 1217, M = 13.9 (+ / 1.4); two
females) (CON groups) and eight adults with ASD (ages 1933, M = 24.9 (+ / 6.9), and
eleven adolescents with ASD (ages 1317, M = 15.1 (+ / 1.2); two females) (ASD groups).
The Autism Diagnostic Interview-Revised [Lord, Rutter, & Couteur, 1994] and the Autism
Diagnostic Observation Schedule-General [Lord et al., 2000; Lord, Rutter, & Goode, 1989]
were used to diagnose ASD. Diagnosis was confirmed by expert clinical opinion (NJM).
Author Manuscript

Potential subjects were excluded if known to have an associated disorder such as tuberous
sclerosis or fragile-X syndrome. All participants were required to have full scale and verbal
IQ scores of 80 or above (Table 1). Medication status of the ASD participants is reported in
Supporting Information Table S1. All participants were free of medications known to affect
eye movements and had no history of seizure disorder.

There were no significant differences between groups in IQ (WASI) (Adult CON: 109.5 + /
13.9, Adult ASD: 98.9 + / 13.9, Adolescent CON: 109.7 + / 10.1, Adolescent ASD:

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 4

106.2 + / 12.1, Ps > .05). All but one participant were right handed. CON individuals had
Author Manuscript

no personal or first-degree relative history of neurological disease or neuropsychiatric illness

as determined by interview. Vision was normal (as stated by the participant or guardian for
minor participants) or corrected to normal using MRI compatible glasses or contact lenses.
Experimental procedures for this study complied with the Code of Ethics of the World
Medical Association (1964 Declaration of Helsinki) and the Institutional Review Board at
the University of Pittsburgh. Subjects were paid for their participation in the study. All
participants and guardians provided informed consent prior to participation.

Paradigm
Participants performed an event-related task, which included AS and visually guided
saccade (VGS) trials. Immediately prior to scanning, participants were trained on the AS and
VGS tasks in a training room outside the scanner. During the AS trials, a red central fixation
Author Manuscript

cross appeared on the screen for 2.5 sec signaling participants to prepare for presentation of
the target stimulus. When the red cross disappeared, a peripheral target appeared at an
unpredictable location on the horizontal meridian at 3, 6, or 9 degrees of visual angle to the
left and right of the center fixation cross for 2.5 sec. Participants were instructed not to look
at the stimulus, but instead make an eye movement to the mirror location. Peripheral target
location was randomized within each run. During the VGS trials, participants were presented
with a green fixation cross and instructed to look toward the peripheral stimulus when it
appeared. These VGS trials were randomly interspersed between the AS trials (Fig. 1).

To uniquely estimate the hemodynamic response for the preparatory and response phases of
the AS trials, our experimental design included additional AS partial catch trials,
randomly inserted along with jittered intertrial intervals [Ollinger, Corbetta, & Shuldman,
2001; Ollinger, Shulman, & Corbetta, 2001]. This approach ensured that there were a
Author Manuscript

sufficient number of independent linear equations to separately estimate the Blood-Oxygen-

Level Dependent (BOLD) response associated with the preparatory and saccade response
phases of each AS trial. The catch trials consisted of the presentation of a red central fixation
cross, with no following target. The intertrial fixation period was uniformly distributed and
jittered between intervals of 2.5, 5, or 7.5 sec and consisted of a white cross on a black
background that subjects were instructed to fixate on in between trials. This allowed us to
isolate activation specific to the fixation period when the inhibitory processes begin prior to
making a correct inhibitory response [Everling, Dorris, & Munoz, 1998; Everling,
Spantekow, Krappmann, & Flohr, 1998]. The three trial types (prep only, whole AS, whole
VGS) were presented in a random order, separated by the intertrial intervals. Participants
performed two functional runs of the task (duration = 6 min 50 sec each) for a total of 34 AS
trials, 16 VGS trials, and 18 catch AS trials.
Author Manuscript

Eyetracking
Eye movement measurements during the scan using a long-range optics eye-tracking system
(Model R-LRO6, Applied Science Laboratories, Bedford, MA). Nine-point calibrations
were performed at the beginning of the session. Stimuli were presented using E-Prime
(Psychology Software Tools, Inc., Pittsburgh, PA) projected onto a flat screen positioned
behind the magnet. Participants viewed the screen using a mirror mounted on the head coil.

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 5

Eye-movement data were analyzed and scored offline using ILAB [Gitelman, 2002] in
Author Manuscript

conjunction with an in-house scoring program. The behavioral variables of interest were
error rates for AS and VGS trials (the number of accurate eye movements/ total number of
scorable trials). A correct response in the VGS task was one in which the first eye movement
during the saccade response epoch was made toward the peripheral cue. A correct response
in the AS task was one in which the first eye movement during the saccade response epoch
was made toward the mirror location of the peripheral cue and extended beyond a 2.5
degrees/visual angle central fixation zone. Inhibitory errors occurred when the first saccade
during the saccade response epoch was directed toward the suddenly appearing peripheral
stimulus that they were to ignore and exceeded the 2.5 degrees/visual angle central fixation
zone.

Image Acquisition
Author Manuscript

Imaging data were acquired using a 3.0 Tesla whole-body MR scanner (SIGNA; General
Electric Medical Systems, Milwaukee, WI) with echo-planar imaging capability and a
commercial head radiofrequency coil. The following gradient echo echo-planar acquisition
parameters were used: echo time = 25 ms; repetition time = 2,500 ms; single shot; full k
space; 64 64 acquisition matrix with field of view = 20 20 cm3, voxel dimension = 3.125
3.125 6 mm. Twenty-three 5-mm axial slices were prescribed with a 1-mm gap in order
to image the whole brain. The first four volumes in each run were discarded to allow
stabilization of longitudinal magnetization. A three-dimensional spoiled gradient recalled
(SPGR) pulse sequence with 124 slices (6 mm each) was used to acquire structural images
in the axial plane. These anatomical images were used to register to functional images and to
localize regions of activation.

Image Preprocessing
Author Manuscript

Imaging data were preprocessed using FSL (Functional MRI of the Brain (FMRIB)
Software Library; [Smith et al., 2004]. Our preprocessing procedures included the following:
SPGR images were warped into Talairach space [Talairach & Tournoux, 1988] using a 12-
parameter affine transformation in FSL [Jenkinson & Smith, 2001]. Functional images were
first slice-time corrected, adjusting for interleaved slice acquisition. Images were then rigid-
body motion corrected by aligning all volumes with the volume acquired in the middle of
the fMRI session. Rotational and translational head movement estimates were calculated.
Following brain extraction, functional images were affine registered and warped to structural
SPGR images in Talairach space [Talairach & Tournoux, 1988]. Images were resampled to
voxel sizes of 3 3 3 mm. No subjects were excluded due to motion: instead the temporal
derivative of the relative displacement from the middle volume for each run was calculated
Author Manuscript

for each volume in the x, y, and z directions. Magnitude of the velocity was then calculated
by taking the square root of the sum of squares of the x, y, and z components for each
volume. Volumes with a velocity of over 1.2 mm/TR were removed from subsequent
analyses. Participant groups did not differ in number of volumes removed due to excessive
motion (P > 0.05). Total number of volumes removed for each group were the following:
Adult ASD: 2, Adult CON: 1, Teen ASD: 15, Teen CON: 8. Images were then spatially
smoothed with a 5 mm full-width at half maximum Gaussian smoothing kernel, and high-

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 6

pass filtered (sigma = 30 sec) to remove low frequency drift. Finally, data from each run
Author Manuscript

were scaled to a mean of one hundred.

Image Analyses
Analysis and Visualization of Functional Neuroimages (AFNI, Bethesda, MD, USA)
software [Cox, 1996] was used for individual subject deconvolution, followed by group
analyses (see Supporting Information Fig. S1). Deconvolution methods followed steps
delineated by Ward [2002]. Our model consisted of three orthogonal regressors of interest;
the preparatory period of the AS (catch and correct trials only), the correct AS saccade
response, and the correct VGS trials, as well as regressors for incorrect AS and VGS trials.
Linear and nonlinear trends and six motion parameters were also included as nuisance
regressors. A unique estimated impulse response function for each regressor of interest was
determined by a weighted linear sum of sine basis functions, multiplied by data determined
Author Manuscript

least squares estimated beta weights. The estimated impulse response function reflects the
estimated BOLD response to a type of trial after controlling for variations in the BOLD
signal due to other regressors. We specified the duration of the estimated response (AS prep
and response: 20 sec; VGS: 24 sec post stimulus onset), a sufficient time window for the
hemodynamic response to peak and return to baseline [Boynton, Engel, Glover, & Heeger,
1996; Buckner, 1998; Dale & Buckner, 1997]. This procedure produced one-time course
estimate per voxel per condition of interest. No assumptions about the specific shape of the
BOLD response were made beyond using zero as the start point. The finite impulse response
method and deconvolution allowed for comparison of the shapes of the estimated time
courses at several different time points in order to choose the peak time point. This approach
allowed us to characterize potential differences (if any) in the shape of the response related
to development or ASD that an assumed response shape via the classical hemodynamic
Author Manuscript

response modeling might miss. Goodness-of-fit statistics were calculated including partial F-
statistics for each regressor and t-scores comparing each of the 5 estimated beta weights
(from each basis function) with zero.

For group analyses, impulse response function values associated with AS prep and response
epochs from each subject were entered into voxel-wise linear mixed effects models (one for
prep and one for saccade), with subjects as a random factor and time course values (prep
and saccade: 6 time points) as a within-group factor, and age-group (adolescents, adults)
and diagnosis group (patients, controls) as between-group fixed factors. The resulting
statistical map produced main effect of time maps that were used as base images from
which functional regions of interest (ROIs) were defined (Figures 3 and 5). The main effect
of time map reveals all the regions that demonstrate a significant modulation of signal from
baseline across groups and conditions within each epoch, making this approach unbiased
Author Manuscript

with respect to the effects of interest across groups. Prior research suggests that this method
is reliable in delineating the basic circuitry recruited for the AS task Velanova et al., 2008,
Geier et al., 2010. We also ran a second linear mixed effects model including estimated time
points associated with correct VGS trials only in order to delineate the circuitry involved in
eye movement control.

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 7

The main effect of time map was corrected for multiple comparisons using a combination of
Author Manuscript

cluster size and individual voxel probabilities, with the parameters determined by a Monte
Carlo simulation using AFNIs AlphaSim program. This analysis specified that 23
contiguous voxels (27 mm3 voxels) along with a single-voxel threshold of P < 0.001 was
required to achieve a corrected, cluster-level alpha value of 0.05, and these regions were
designated as clusters. Next, peak voxels within these significant clusters that were more
than 12 mm apart in the corrected main effect of time map were identified using an
automatic search algorithm. Twelve-millimeter diameter spheres were then centered on these
peak voxels, resulting in a sphere map. Finally, a conjunction of the sphere map and the
corrected main effect of time map yielded a functional ROI map, with each ROI consisting
of at least 23 contiguous voxels. The resulting ROI map was used as a mask for
subsequently extracting time course values for each participant.

We focused our analyses on functionally defined clusters that fell within the boundaries of a
Author Manuscript

priori anatomical regions of interest that are known to be involved in oculomotor control.
These included the SEF adjacent to the paracentral lobule, the FEF on the superior aspect of
the precentral sulcus, the PEF on the inferior parietal sulcus, the putamen, the ACC, and the
DLPFC [Curtis & Connolly, 2008; Luna et al., 1998] (Table 2).

Mean estimated time courses from each participant were extracted from each ROI of
interest. The values from these mean estimated time courses at each time point for each
subject response were entered into a repeated measures analysis of variance (ANOVA) using
age group and diagnosis group as between-subjects factors and time as a within-subject
factor. Below, we report regions that demonstrated significantly different modulations across
time by age group, diagnosis group, and/or an age group by diagnosis group interaction. We
also ran regression analyses with peak time course values for each subject response using
Author Manuscript

age as a continuous variable, and diagnosis group as a categorical variable and report any
significant effects as a linear function of age below. In Figures 4 and 6, we show graphs of
average peak time course values for each group.

Results
Behavior
We ran an ANOVA with two factors (age group and diagnosis) on performance (percent
correct values). There was a significant main effect of age group, and an age group by
diagnosis interaction. The CON group performed significantly better than the ASD group
(t40 = 2.325, P = 0.025). Collapsed across diagnosis groups, there was no effect of age
group (t40 = 1.999, P = 0.052). Planned comparison two tailed t-tests revealed that AS
Author Manuscript

performance improved significantly between CON adolescents and CON adults (t21 = 2.384,
P = .027) but not between ASD adolescents and ASD adults (t17 = .122, P = .904).
Adolescents in the ASD group performed similarly to the CON adolescent group (t18 = .
192, P = .85). In contrast, adults with ASD performed significantly worse than adults in the
typical group (t20 = 3.356, P = .003), consistent with prior findings [Agam et al., 2010;
Luna et al., 2007; Mosconi et al., 2009; Thakkar et al., 2008] (Fig. 2). When considering age
as a continuous variable, there was no significant effect of age or diagnosis group, or age by

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 8

diagnosis group interactions. No differences were found between any of the groups in VGS
Author Manuscript

error rates.

Imaging Results
VGSAll groups similarly recruited a widely distributed set or regions during the VGS
trials including the cortical eye fields (FEF, SEF, and PEF) and subcortical regions (caudate,
putamen, thalamus). There were no diagnosis or age group effects.

AS response preparationDuring the preparatory period of correct whole trials and

all catch trials, all four participant groups similarly recruited a distributed set of brain
regions known to support AS response preparation, including the FEF, SEF, DLPFC and IPL
(Fig. 3). Across diagnosis groups, in the SEF, adults demonstrated greater activation than
adolescents (F6,240 = 2.219, P = .042) (Fig. 4). In the left FEF, a significant age group by
Author Manuscript

diagnosis group interaction (F6,228 = 2.468, P = .024) revealed that the ASD adolescents
demonstrated reduced activation relative to the ASD adults (F6,102 = 2.687, P = .018) and
CON adolescent (F6,108 = 2.925, P = .011) groups (Fig. 4). Secondary regression analyses
confirmed the age effect in SEF ( = 0.015, t = 2.433, P = 0.020), showing linear increases in
activation with age. In the left FEF, there were no significant effects when considering age as
a continuous variable.

AS responseAll groups recruited a set of regions known to be involved in making a

correct AS response including the FEF, SEF, IPL, DLPFC, and striatum (Fig. 5). A
significant age group effect was observed in SEF (F8,304 = 3.305, P = .001), with adults
demonstrating increased activation relative to adolescents in both ASD and typical groups
(Fig. 6I). A significant age group effect was also observed in left FEF (F8,304 = 2.080, P = .
038), again with CON and ASD adults demonstrating increased activation relative to CON
Author Manuscript

and ASD adolescents (Fig. 6I). In left precuneus, there was a significant main effect of
diagnosis (F8,304 = 2.532, P = .011), revealing that individuals with ASD displayed
increased activation relative to the typical groups (Fig. 6II). In the left putamen, a diagnosis
group by age group interaction (F8,304 = 2.452, P = .014) indicated that adolescents with
ASD demonstrated increased activation relative to typical adolescents and adults with ASD
(Fig. 6III). In right IPL, there was a significant age group by diagnosis group interaction
(F8,304 = 11.819, P = .0000), revealing an age-related increase in activation in the CON
group but not in the ASD group (Fig. 6III). There were no significant effects when
considering age as a continuous variable in SEF, FEF, IPL, precuneus, or putamen.

Secondary analysesWe ran secondary analyses using equal groups (eight

participants in each group) that were matched for age and IQ to ensure that our findings for
Author Manuscript

AS performance and in the right IPL were not due differences in group sizes. These results
revealed a significant effect of group on performance (F3,28 = 3.504, P = 0.028). Post-hoc
tests confirmed that adult ASD participants performed significantly worse than adult CON
(t14 = 2.867, P = 0.012). Adolescent ASD participants performed similarly to Adolescent
CON (t14 = 0.096, P = 0.925) and Adult ASD participants (t14 = .118, P = 0.908).
Adolescent CON participants performed significantly worse than Adult CON participants

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 9

(t14 = 2.689, P = 0.018). In right IPL, we also found a significant age-group by diagnosis
Author Manuscript

interaction (F8,224 = 7.33, P = 0.01).

Discussion
We aimed to characterize age-related differences in inhibitory control in ASD during
adolescence and adulthood. We used the AS task, which reliably shows a protracted
maturation through adolescence and a behavioral deficit in ASD [Goldberg et al., 2002;
Luna et al., 2001, 2007]. Overall, our findings suggest that brain development continues
between adolescence and adulthood in individuals both with and without ASD, as expected
on the basis of behavior.

While the ASD adolescent group performed at equivalent levels to the CON adolescent
group, there were no changes between adolescence and adulthood in ASD, which was unlike
Author Manuscript

our previous behavioral findings [Luna et al., 2007]. The CON groups showed characteristic
age-related improvements in AS performance (e.g. [Geier, et al., 2010; Luna et al., 2001;
Padmanabhan, 2011; Velanova et al., 2008]). The lack of age-related improvement in
behavior in the ASD group suggests that development is delayed or arrested. The current
study employed an interleaved paradigm, mixing VGS trials with AS trials, adding a task-
switching component to the task. Prior research has suggested that mixing VGS and AS
trials results in worse AS performance relative to pure blocks of AS trials [Cherkasova,
Manoach, Intriligator, & Barton, 2002; Manoach et al., 2002; Reuter, Herzog, & Kathmann,
2006]. This added complexity may have particularly affected age-related improvements in
individuals with ASD and suggests particular limitations in higher order cognitive processes
may be delayed or arrested.

Contrary to prior research showing brain activation differences during VGS trials in ASD
Author Manuscript

relative to TD [Takarae, Minshew, Luna, & Sweeney, 2007], we found no VGS differences
across diagnostic groups. This difference from previous work may be due to the fact that this
task had a basic sensorimotor task (VGS) in the context of a more cognitively demanding
inhibition task, which engages the same sensorimotor regions, but may require more effort in
processing. Our findings of similar VGS performance and activation patterns between ASD
and TD mirror recent findings demonstrating that, in the context of AS trials, VGS
performance and brain activation is similar in ASD [Agam et al., 2010]. Prior research has
also suggested that cortical eye movement control regions such as the FEF are recruited to a
higher degree for inhibitory processes (AS) relative to sensorimotor processes (VGS), and
disruptions in FEF and pre-supplementary motor area (SMA) have been found to impair
inhibitory control while keeping simple saccadic processes intact [Muggleton, Chen, Tzeng,
Hung, & Juan, 2010].
Author Manuscript

All participant groups recruited a largely similar network of relevant brain regions during
both the preparation and response components of AS trials, including the FEF, SEF, IPL,
ACC, and DLPFC, suggesting that the core circuitry required for making inhibitory
responses is in place by adolescence and is functional in ASD. However, there were distinct
age and diagnosis group differences in activation during both the preparatory and saccade
response phases of the task that are discussed in detail below.

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 10

Three major patterns of differences were observed in brain activation during AS trials
Author Manuscript

relative to baseline fixation. First, results revealed that the right IPL demonstrated an age
group by diagnosis group interaction, mirroring the behavioral findings, providing evidence
for distinct developmental trajectories between ASD and typically developing individuals.
Second, the ASD groups demonstrated increased activation in precuneus relative to typical
groups, suggesting increased reliance on attention-specific mechanisms to perform the task.
Third, results showed thatin adulthoodboth ASD and typical groups demonstrated
increased recruitment relative to their adolescent counterparts in FEF and SEF, suggesting
parallel age related change between diagnosis groups.

Although the typical groups demonstrated an age-related increase in lateral IPL activation,
the ASD groups did not. This finding mirrored the behavioral findings of a lack of
developmental improvement in AS performance in ASD relative to typically developing
individuals. The lateral IPL has been previously associated with AS generation and in
Author Manuscript

transforming sensory information to a motor plan [Barash & Zhang, 2006]. The ASD groups
recruited this region to a lesser degree than the typical groups during correct anti-saccades,
which may point to a general deficit in sensorimotor programming resulting in more errors
overall. These results remained significant even with smaller group sizes, suggesting that
they are unlikely to be due to unequal groups.

Furthermore, the groups with ASD demonstrated increased recruitment of left precuneus
relative to the typical groups during the generation of a voluntary response. The precuneus
has direct connections to regions of the IPL that are involved in visuo-spatial processing
[Andersen, Asanuma, Essick, & Siegel, 1990; Leichnetz, 2001; Selemon & Goldman-Rakic,
1988], as well as the SMA and dorsal premotor areas [Cavada & Goldman-Rakic, 1989;
Petrides & Pandya, 1984] including oculomotor regions such as the FEF [Cavanna &
Author Manuscript

Trimble, 2006; Leichnetz, 2001; Leichnetz & Goldberg, 1988; Leichnetz & Gonzalo-Ruiz,
1996; Tian & Lynch, 1996a, 1996b]. Evidence suggests that the precuneus is engaged when
attending to visuospatial tasks [Berman et al., 1999] and the response phase of the AS task
[Brown, Goltz, Vilis, Ford, & Everling, 2006; Brown, Vilis, & Everling, 2007]. In the
current study, increased reliance on the precuneus suggests the ASD group may rely on
attention-related circuitry to generate a voluntary response as a compensatory mechanism
for possible limitations in utilizing the cortical eye fields, specifically the IPL. The
precuneus is also part of the putative default-mode network (a network of regions that are
suppressed during goal-directed processes) [Raichle & Snyder, 2007]. Thus, it is also
possible that a failure to attenuate default mode activation hampers inhibitory control
performance.
Author Manuscript

Both ASD and typical groups showed age-related increased activation in SEF during
response preparation, and SEF and FEF during the generation of the AS. Single-cell
recordings demonstrate that neurons in the SEF and FEF are active prior to making correct
AS responses, suggesting that these regions support planned responses and that response
preparation is an essential component in the AS task [Schlag & Schlag-Rey, 1987].
Furthermore, the SEF and FEF have connections to oculomotor regions in the superior
colliculus, with direct routes for planning eye movements [De Weijer et al., 2010; Everling
& Munoz, 2000; Huerta & Kaas, 1990; Shook, Schlag-Rey, & Schlag, 1990]. Neurons in the

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 11

FEF are also engaged during response preparation, supporting the ability to inhibit saccade
Author Manuscript

motor neurons in the superior colliculus, thus stopping the prepotent motor response to the
target [Munoz & Everling, 2004; Schall, Stuphorn, & Brown, 2002].

Our previous developmental studies have shown increased recruitment of SEF and FEF with
age across blocks of AS trials, paralleled with developmental differences in performance
[Luna et al., 2001]. Although prior event-related fMRI studies have demonstrated that
adolescents do not differ from adults in recruitment of cortical eye fields during correct trials
[Velanova et al., 2008], the added demand of task-switching in the current task may have
tapped into a process that is not yet mature in typical adolescent populations. Furthermore,
the parallels in age-related increases in the recruitment of FEF and SEF during correct AS
responses from adolescence to adulthood in both typical and ASD groups suggest that some
brain maturational processes underlying AS performance may be preserved in ASD.
Author Manuscript

In the FEF, adolescents with ASD demonstrated decreased preparatory activation relative to
the other three participant groups. This suggests a maturational delay in recruiting key
inhibitory regions required to perform successful anti-saccades, as ASD adults showed the
same magnitude of activation as CON adults. However, given that this activation difference
in the FEF was found during correct AS trials and adolescents with ASD demonstrated the
same level of performance as typical adolescents, compensatory mechanisms may have been
recruited to perform at equivalent levels. Adolescents with ASD demonstrated increased
engagement of putamen during correct AS trials relative to adults with ASD and typical
adolescents. The putamen has direct projections to the FEF and is integral to oculomotor
processing [ODriscoll et al., 1995; Petit et al., 1993]. Increased activation in the putamen in
the adolescent ASD group may reflect a compensatory process in order to overcome
possible delayed development in cortical (i.e., FEF) control in order to generate a successful
Author Manuscript

AS response. There is little fMRI evidence showing activation differences in putamen in

ASD, with one study linking reduced activation in putamen with repetitive behavior
symptoms and verbal fluency in ASD [Kenworthy et al., 2013]. However, converging lines
of research from PET and structural MRI have suggested that the putamen may be a locus of
dysfunction in ASD. Adults with ASD have also demonstrated decreased glucose
metabolism in putamen [Haznedar et al., 2006] and decreased white matter connectivity
strength between putamen and prefrontal cortex in ASD relative to typical individuals
[Langen et al., 2011]. Individual differences in putamen shape have previously been
correlated with deficits in motor skills in ASD [Qiu, Adler, Crocetti, Miller, & Mostofsky,
2010] and differences in putamen volume with repetitive and stereotyped behavior [Estes et
al., 2011, Hollander et al., 2005]. There is however, a lack of developmental studies in this
area, with one study showing differences in rates of change over age in putamen volume in
Author Manuscript

individuals with ASD relative to typically developing individuals between childhood and
early adulthood [Langen et al., 2009].

Conclusions
The present study was a cross-sectional study. Our results as such provide indirect evidence
of developmental changes, which in the future may benefit from a longitudinal approach
with a larger cohort especially given known variation in this spectrum. Furthermore, the

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 12

number of trials per condition limited our ability to look at AS error versus correct trials.
Author Manuscript

Given prior results suggesting limitations in AS circuitry in ASD, such as the dorsal ACC
[Agam et al., 2010] that are involved in error processing over adolescence, an interesting
future direction would be to explore this further in ASD. While the sample size is also a
limitation, given the scarcity of developmental studies of inhibitory control in ASD that
currently exist in the literature, the results from the present study can inform future work in
this area.

We demonstrate that inhibitory control is affected in ASD and that age related change in
both brain function and behavior from adolescence to adulthood may be distinct relative to
typically developing individuals. These results suggest that there are underlying limitations
in ASD in the ability to recruit the optimal circuitry to support inhibitory control.
Furthermore, individuals with ASD may not show the optimal transitions in brain function
through adolescence evident in typical maturation. Lastly, much of the circuitry supporting
Author Manuscript

cognitive control was intact in ASD changes. Taken together, the results suggest that the
well-delineated circuitry underlying the AS task is recruited in ASD, but specific
refinements in the underlying circuitry evident in typically developing individuals may be
compromised in ASD. Furthermore, age related change in AS performance and underlying
brain function in key areas such as the FEF and IPL may be affected in ASD.

Acknowledgments
We thank Melanie Wilds for assistance with participant recruitment and data collection. We also thank all
participants and families who volunteered for this study.

References
Author Manuscript

Agam Y, Joseph RM, Barton JJ, Manoach DS. Reduced cognitive control of response inhibition by the
anterior cingulate cortex in autism spectrum disorders. Neuroimage. 2010; 52:336347. DOI:
10.1016/j.neuroimage.2010.04.010 [PubMed: 20394829]
Andersen RA, Asanuma C, Essick G, Siegel RM. Corticocortical connections of anatomically and
physiologically defined subdivisions within the inferior parietal lobule. The Journal of Comparative
Neurology. 1990; 296:65113. [PubMed: 2358530]
Barash S, Zhang M. Switching of sensorimotor transformations: Antisaccades and parietal cortex.
Novartis Foundation Symposium. 2006; 270:5971. [PubMed: 16649708]
Berman RA, Colby CL, Genovese CR, Voyvodic JT, Luna B, et al. Cortical networks subserving
pursuit and saccadic eye movements in humans: An fMRI study. Human Brain Mapping. 1999;
8:209225. [PubMed: 10619415]
Bjorklund, DF.; Harnishfeger, KK. The evolution of inhibition mechanisms and their role in human
cognition and behavior. In: Dempster, FN.; Brainerd, CJ., editors. Interference & inhibition in
cognition. San Diego, CA: Academic Press, Inc; 1995. p. 141-173.
Boynton GM, Engel SA, Glover GH, Heeger DJ. Linear systems analysis of functional magnetic
Author Manuscript

resonance imaging in human V1. The Journal of Neuroscience. 1996; 16:42074221. [PubMed:
8753882]
Brown MR, Goltz HC, Vilis T, Ford KA, Everling S. Inhibition and generation of saccades: Rapid
event-related fMRI of prosaccades, antisaccades, and nogo trials. Neuroimage. 2006; 33:644659.
[PubMed: 16949303]
Brown MR, Vilis T, Everling S. Frontoparietal activation with preparation for antisaccades. Journal of
Neurophysiology. 2007; 98:17511762. [PubMed: 17596416]
Buckner RL. Event-related fMRI and the hemodynamic response. Human Brain Mapping. 1998;
6:373377. [Clinical Trial Randomized Controlled Trial]. [PubMed: 9788075]

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 13

Cavada C, Goldman-Rakic PS. Posterior parietal cortex in rhesus monkey: II. Evidence for segregated
corticocortical networks linking sensory and limbic areas with frontal lobe. The Journal of
Author Manuscript

Comparative Neurology. 1989; 287:422445. [PubMed: 2477406]

Cavanna AE, Trimble MR. The precuneus: A review of its functional anatomy and behavioural
correlates. Brain: A Journal of Neurology. 2006; 129(Pt 3):564583. [Research Support, Non-U.S.
Govt Review]. [PubMed: 16399806]
Cherkasova MV, Manoach DS, Intriligator JM, Barton JJS. Antisaccades and task-switching:
Interactions in controlled processing. Experimental Brain Research. 2002; 144:528537. [PubMed:
12037637]
Cox RW. AFNI: Software for analysis and visualization of functional magnetic resonance
neuroimages. Computers and Biomedical Research. 1996; 29:162173. [PubMed: 8812068]
Curtis CE, Connolly JD. Saccade preparation signals in the human frontal and parietal cortices. Journal
of Neurophysiology. 2008; 99:133145. [PubMed: 18032565]
Dale AM, Buckner RL. Selective averaging of rapidly presented individual trials using fMRI. Human
Brain Mapping. 1997; 5:329340. [PubMed: 20408237]
De Weijer AD, Mandl RC, Sommer IE, Vink M, Kahn RS, Neggers SF. Human fronto-tectal and
Author Manuscript

fronto-striatal-tectal pathways activate differently during anti-saccades. Frontiers in Human

Neuroscience. 2010; 4:41. [PubMed: 20631846]
Dempster FN. The rise and fall of the inhibitory mechanism: Toward a unified theory of cognitive
development and aging. Developmental Review. 1992; 12:4575.
Estes A, Shaw DW, Sparks BF, Friedman S, Giedd JN, Dawson G, Dager SR. Basal ganglia
morphometry and repetitive behavior in young children with autism spectrum disorder. Autism
research : official journal of the International Society for Autism Research. 2011; 4:212220. DOI:
10.1002/aur.193 [PubMed: 21480545]
Everling S, Dorris MC, Munoz DP. Reflex suppression in the anti-saccade task is dependent on
prestimulus neural processes. Journal of Neurophysiology. 1998; 80:15841589. [PubMed:
9744965]
Everling S, Munoz DP. Neuronal correlates for preparatory set associated with pro-saccades and anti-
saccades in the primate frontal eye field. Journal of Neuroscience. 2000; 20:387400. [PubMed:
10627615]
Author Manuscript

Everling S, Spantekow A, Krappmann P, Flohr H. Event-related potentials associated with correct and
incorrect responses in a cued antisaccade task. Experimental Brain Research. 1998; 118:2734.
[PubMed: 9547075]
Fischer B, Biscaldi M, Gezeck S. On the development of voluntary and reflexive components in human
saccade generation. Brain Research Brain Research Reviews. 1997; 754:285297.
Fukushima J, Hatta T, Fukushima K. Development of voluntary control of saccadic eye movements. I.
Age-related changes in normal children. Brain & Development. 2000; 22:173180. [PubMed:
10814900]
Geier CF, Terwilliger R, Teslovich T, Velanova K, Luna B. Immaturities in reward processing and its
influence on inhibitory control in adolescence. Cereb Cortex. 2010; 20:16131629. DOI: 10.1093/
cercor/bhp225 [PubMed: 19875675]
Gitelman DR. ILAB: A program for postexperimental eye movement analysis. Behavior Research
Methods, Instruments, & Computers: A Journal of the Psychonomic Society, Inc. 2002; 34:605
612.
Goldberg MC, Lasker AG, Zee DS, Garth E, Landa RJ, Tien A. Deficits in the initiation of eye
Author Manuscript

movements in the absence of a visual target in adolescents with high functioning autism.
Neuropsychologia. 2002; 40:20392049. [PubMed: 12208001]
Goldberg MC, Mostofsky SH, Cutting LE, Mahone EM, Astor BC, et al. Subtle executive impairment
in children with autism and children with ADHD. Journal of Autism & Developmental Disorders.
2005; 35:279293. [PubMed: 16119469]
Haznedar MM, Buchsbaum MS, Hazlett EA, LiCalzi EM, Cartwright C, Hollander E. Volumetric
analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients
with autism spectrum disorders. American Journal of Psychiatry. 2006; 163:12521263. [PubMed:
16816232]

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 14

Hollander E, Anagnostou E, Chaplin W, Esposito K, Haznedar MM, Licalzi E, Buchsbaum M.

Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol
Author Manuscript

Psychiatry. 2005; 58:226232. [PubMed: 15939406]

Huerta MF, Kaas JH. Supplementary eye field as defined by intracortical microstimulation:
Connections in macaques. The Journal of Comparative Neurology. 1990; 293:299330. [PubMed:
19189718]
Jenkinson M, Smith S. A global optimisation method for robust affine registration of brain images.
Medical Image Analysis. 2001; 5:143156. [PubMed: 11516708]
Kana RK, Keller TA, Minshew NJ, Just MA. Inhibitory control in high-functioning autism: Decreased
activation and underconnectivity in inhibition networks. Biological Psychiatry. 2007; 62:198206.
[PubMed: 17137558]
Kenworthy L, Yerys BE, Weinblatt R, Abrams DN, Wallace GL. Motor demands impact speed of
information processing in autism spectrum disorders. Neuropsychology. 2013; 27:529536. DOI:
10.1037/a0033599 [PubMed: 23937483]
Klein C, Foerster F. Development of prosaccade and antisaccade task performance in participants aged
6 to 26 years. Psychophysiology. 2001; 38:179189. [PubMed: 11347863]
Author Manuscript

Langen M, Leemans A, Johnston P, Ecker C, Daly E, Murphy CM, Murphy DG. Fronto-striatal
circuitry and inhibitory control in autism: Findings from diffusion tensor imaging tractography.
Cortex; a journal devoted to the study of the nervous system and behavior. 2011; doi: 10.1016/
j.cortex.2011.05.018
Langen M, Schnack HG, Nederveen H, Bos D, Lahuis BE, et al. Changes in the developmental
trajectories of striatum in autism. Biological Psychiatry. 2009; 66:327333. [PubMed: 19423078]
Leichnetz GR. Connections of the medial posterior parietal cortex (area 7 m) in the monkey. The
Anatomical Record. 2001; 263:215236. [Comparative Study]. [PubMed: 11360237]
Leichnetz GR, Goldberg ME. Higher centers concerned with eye movement and visual attention:
Cerebral cortex and thalamus. Reviews of Oculomotor Research. 1988; 2:365429. [Review].
[PubMed: 3153653]
Leichnetz GR, Gonzalo-Ruiz A. Prearcuate cortex in the Cebus monkey has cortical and subcortical
connections like the macaque frontal eye field and projects to fastigial-recipient oculomotor-
related brainstem nuclei. Brain Research Bulletin. 1996; 41:129. [Comparative Study Research
Support, U.S. Govt, Non-P.H.S.]. [PubMed: 8883912]
Author Manuscript

Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, et al. The autism diagnostic observation
schedule-generic: A standard measure of social and communication deficits associated with the
spectrum of autism. Journal of Autism and Developmental Disorders. 2000; 30:205223.
[PubMed: 11055457]
Lord C, Rutter M, Couteur AL. Autism diagnostic interview-revised: A revised version of a diagnostic
interview for caregivers of individuals with possible pervasive developmental disorders. Journal of
Autism and Developmental Disorders. 1994; 24:659685. [PubMed: 7814313]
Lord C, Rutter M, Goode S. Autism diagnostic observation schedule: A standardized observation of
communicative and social behavior. Journal of Autism and Developmental Disorders. 1989;
19:185212. [PubMed: 2745388]
Luna B, Doll S, Hegedus SJ, Minshew N, Sweeney J. Maturation of executive function in autism.
Biological Psychiatry. 2007; 61:474481. [PubMed: 16650833]
Luna B, Garver KE, Urban TA, Lazar NA, Sweeney JA. Maturation of cognitive processes from late
childhood to adulthood. Child Development. 2004; 75:13571372. [PubMed: 15369519]
Author Manuscript

Luna B, Thulborn KR, Munoz DP, Merriam EP, Garver KE, et al. Maturation of widely distributed
brain function subserves cognitive development. Neuroimage. 2001; 13:786793. [PubMed:
11304075]
Luna B, Thulborn KR, Strojwas MH, McCurtain BJ, Berman RA, et al. Dorsal cortical regions
subserving visually-guided saccades in humans: An fMRI study. Cerebral Cortex. 1998; 8:4047.
[PubMed: 9510384]
Manoach DS, Lindgren KA, Cherkasova MV, Goff DC, Halpern EF, et al. Schizophrenic subjects show
deficient inhibition but intact task switching on saccadic tasks. Biological Psychiatry. 2002;
51:816826. [PubMed: 12007456]

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 15

Minshew NJ, Luna B, Sweeney JA. Oculomotor evidence for neocortical systems but not cerebellar
dysfunction in autism. Neurology. 1999; 52:917922. [PubMed: 10102406]
Author Manuscript

Mosconi MW, Kay M, DCruz AM, Seidenfeld A, Guter S, et al. Impaired inhibitory control is
associated with higher-order repetitive behaviors in autism spectrum disorders. Psychological
Medicine. 2009; 39:15591566. [PubMed: 19154646]
Muggleton NG, Chen CY, Tzeng OJ, Hung DL, Juan CH. Inhibitory control and the frontal eye fields.
J Cogn Neurosci. 2010; 22:28042812. DOI: 10.1162/jocn.2010.21416 [PubMed: 20044887]
Munoz DP, Broughton JR, Goldring JE, Armstrong IT. Age-related performance of human subjects on
saccadic eye movement tasks. Experimental Brain Research. 1998; 121:391400. [PubMed:
9746145]
Munoz DP, Everling S. Look away: The anti-saccade task and the voluntary control of eye movement.
Nature Reviews Neuroscience. 2004; 5:218228. [PubMed: 14976521]
ODriscoll GA, Alpert NM, Matthysse SW, Levy DL, Rauch SL, Holzman PS. Functional
neuroanatomy of antisaccade eye movements investigated with positron emission tomography.
Proceedings of the National Academy of Sciences of the United States of America. 1995; 92:925
929. [PubMed: 7846080]
Author Manuscript

Ollinger JM, Corbetta M, Shuldman GL. Separating processes within a trial in event-related functional
MRI: Part II. Neuroimage. 2001; 13:218229. [PubMed: 11133324]
Ollinger JM, Shulman GL, Corbetta M. Separating processes within a trial in event-related functional
MRI: Part I. Neuroimage. 2001; 13:210217. [PubMed: 11133323]
Ozonoff S, Strayer DL. Inhibitory function in nonretarded children with autism. Journal of Autism and
Developmental Disorders. 1997; 27:5977. [PubMed: 9018582]
Ozonoff S, Strayer DL, McMahon WN, Filloux F. Executive function abilities in autism and Tourette
syndrome: An information processing approach. Journal of Child Psychology and Psychiatry.
1994; 35:10151032. [PubMed: 7995842]
Padmanabhan A, Geier CF, Ordaz SJ, Teslovich T, Luna B. Developmental changes in brain function
underlying the influence of reward processing on inhibitory control. Dev Cogn Neurosci. 2011;
1:517529. DOI: 10.1016/j.dcn.2011.06.004 [PubMed: 21966352]
Petit L, Orssaud C, Tzourio N, Salamon G, Mazoyer B, Berthoz A. PET study of voluntary saccadic
eye movement in humans: Basal ganglia-thalamocortical system and cingulate cortex involvement.
Author Manuscript

Journal of Neurophysiology. 1993; 69:10091017. [PubMed: 8492144]

Petrides M, Pandya DN. Projections to the frontal cortex from the posterior parietal region in the
rhesus monkey. The Journal of Comparative Neurology. 1984; 228:105116. [PubMed: 6480903]
Qiu A, Adler M, Crocetti D, Miller MI, Mostofsky SH. Basal ganglia shapes predict social,
communication, and motor dysfunctions in boys with autism spectrum disorder. Journal of the
American Academy of Child and Adolescent Psychiatry. 2010; 49:539551. [PubMed: 20494264]
Raichle ME, Snyder AZ. A default mode of brain function: A brief history of an evolving idea.
Neuroimage. 2007; 37:10731082.
Reuter B, Herzog E, Kathmann N. Antisaccade performance of schizophrenia patients: Evidence of
reduced task-set activation and impaired error detection. Journal of Psychiatric Research. 2006;
40:122130. [Research Support, Non-U.S. Govt]. [PubMed: 16459170]
Russell, J. Autism as an executive disorder. New York: Oxford University Press; 1997.
Schall JD, Stuphorn V, Brown JW. Monitoring and control of action by the frontal lobes. Neuron.
2002; 36:309322. [PubMed: 12383784]
Schlag J, Schlag-Rey M. Evidence for a supplementary eye field. Journal of Neurophysiology. 1987;
Author Manuscript

57:179200. [PubMed: 3559671]

Schmitz N, Rubia K, Daly E, Smith A, Williams S, Murphy DG. Neural correlates of executive
function in autistic spectrum disorders. Biological Psychiatry. 2006; 59:716. [PubMed:
16140278]
Selemon LD, Goldman-Rakic PS. Common cortical and subcortical targets of the dorsolateral
prefrontal and posterior parietal cortices in the rhesus monkey: Evidence for a distributed neural
network subserving spatially guided behavior. Journal of Neuroscience. 1988; 8:40494068.
[PubMed: 2846794]

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 16

Shook BL, Schlag-Rey M, Schlag J. Primate supplementary eye field: I. Comparative aspects of
mesencephalic and pontine connections. The Journal of Comparative Neurology. 1990; 301:618
Author Manuscript

642. [PubMed: 2273101]

Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, et al. Advances in functional and
structural MR image analysis and implementation as FSL. Neuroimage. 2004; 23(Suppl 1):S208
S219. [PubMed: 15501092]
Solomon M, Ozonoff SJ, Ursu S, Ravizza S, Cummings N, et al. The neural substrates of cognitive
control deficits in autism spectrum disorders. Neuropsychologia. 2009; 47:25152526. [PubMed:
19410583]
Solomon M, Yoon JH, Ragland JD, Niendam TA, Lesh TA, Fairbrother W, Carter CS. The
development of the neural substrates of cognitive control in adolescents with autism spectrum
disorders. Biol Psychiatry. 2014; 76:412421. DOI: 10.1016/j.biopsych.2013.08.036 [PubMed:
24209777]
Spear LP. Neurobehavioral changes in adolescence. Current Directions in Psychological Science.
2000; 9:111114.
Takarae Y, Minshew NJ, Luna B, Sweeney JA. Atypical involvement of frontostriatal systems during
Author Manuscript

sensorimotor control in autism. Psychiatry Research. 2007; 156:117127. [PubMed: 17913474]

Talairach, J.; Tournoux, P. Co-planar stereotaxic atlas of the human brain. New York: Thieme Medical
Publishers; 1988.
Thakkar KN, Polli FE, Joseph RM, Tuch DS, Hadjikhani N, et al. Response monitoring, repetitive
behaviour and anterior cingulate abnormalities in autism spectrum disorders (ASD). Brain: A
Journal of Neurology. 2008; 131(Pt 9):24642478. [PubMed: 18550622]
Tian JR, Lynch JC. Corticocortical input to the smooth and saccadic eye movement subregions of the
frontal eye field in cebus monkeys. Journal of Neurophysiology. 1996a; 76:27542771. [PubMed:
8899643]
Tian JR, Lynch JC. Functionally defined smooth and saccadic eye movement subregions in the frontal
eye field of cebus monkeys. Journal of Neurophysiology. 1996b; 76:27402753. [PubMed:
8899642]
Velanova K, Wheeler ME, Luna B. Maturational changes in anterior cingulate and frontoparietal
recruitment support the development of error processing and inhibitory control. Cerebral Cortex.
2008; 18:25052522. [PubMed: 18281300]
Author Manuscript

Velanova K, Wheeler ME, Luna B. The maturation of task set-related activation supports late
developmental improvements in inhibitory control. Journal of Neuroscience. 2009; 29:12558
12567. [PubMed: 19812330]
Ward, BD. Deconvolution analysis of fMRI time series data: documentation for the AFNI software
package. 2002. Available at: http://afni.nimh.nih.gov/pub/dist/doc/manual/3dDeconvolve.pdf
Author Manuscript

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 17
Author Manuscript
Author Manuscript

Figure 1.
Anti-saccade (AS) task schematic. A red fixation cross appeared for 2.5 sec. A peripheral
light appeared for 2.5 sec during which participants were instructed to generate a saccade to
its mirror location.
Author Manuscript
Author Manuscript

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 18
Author Manuscript
Author Manuscript

Figure 2.
Behavioral results. Anti-saccade (AS) performance (% correct) for adolescents (left) and
adults (right) in both CON (solid line, open circles) and ASD groups (dashed line, closed
circles). *P < .05. Error bars denote standard error.
Author Manuscript
Author Manuscript

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 19
Author Manuscript
Author Manuscript
Author Manuscript

Figure 3.
Activation map for main effect of time during response preparation epoch collapsed across
age group and diagnosis group. Threshold set at P < .001(corrected). Right side of image =
right brain.
Author Manuscript

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 20
Author Manuscript
Author Manuscript

Figure 4.
Peak values from time courses during response preparation. Error bars represent + / 1
standard error of the mean. For visualization purposes, filled black circles indicate location
Author Manuscript

of the masks above slices of the Analysis and Visualization of Functional Neuroimages
(AFNI) Talairach atlas, drawn using AFNI. The circles do not reflect the actual shape of the
mask.
Author Manuscript

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 21
Author Manuscript
Author Manuscript

Figure 5.
Activation map for main effect of time during anti-saccade (AS) response epoch collapsed
Author Manuscript

across age group and diagnosis group. Threshold set at P < .001(corrected). Right side of
image = right brain.
Author Manuscript

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Padmanabhan et al. Page 22
Author Manuscript
Author Manuscript
Author Manuscript

Figure 6.
Peak values from time courses showing regions that demonstrated an effect during anti-
Author Manuscript

saccade (AS) response. See materials and methods for how data were extracted. Error bars
represent + / 1 standard error of the mean. For visualization purposes only, filled black
circles indication location of the masks are schematically shown above slices of the Analysis
and Visualization of Functional Neuroimages (AFNI) Talairach atlas, drawn using AFNI.
The circles do not reflect the actual shape of the mask.

Autism Res. Author manuscript; available in PMC 2016 July 14.

 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Table 1

Demographic Information

ASD CON

Adolescent Adult Adolescent Adult

n = 11 n=8 n=9 n = 14
Padmanabhan et al.

Males 9 8 7 12
Right handed, n (%) 36 (88)
Mean (SD) Mean (SD) Mean (SD) Mean (SD) ANOVA P
Age (years) 15.10 (1.19) 24.88 (6.94) 13.89 (1.36) 23.36 (3.99) 0.797
Full scale IQ 108.10 (10.94) 98.88 (13.93) 109.71 (10.13) 109.53 (6.63) 0.925
ADOS
Communication 4.50 (1.58) 4.38 (1.41)
Social 9.50 (2.27) 10.5 (1.69)
Total 14.00 (4.43) 14.88 (2.53)
ADI
Social 23.90 (3.28) 19.38 (4.87)
Communication 18.20 (3.42) 15.25 (4.33)
Restricted, repetitive behaviors 6.30 (2.45) 6.25 (1.98)
Abnormal 3.4 (1.43) 2.62 (1.60)

dashes mean not relevant (CON individuals were not administered the ADOS or ADI).

Autism Res. Author manuscript; available in PMC 2016 July 14.

Page 23
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Table 2

Region Locations and Characteristics for Significant Regions of Interest During Preparatory and Outcome Anti-saccade (AS) Epochs

Talairach coordinates

Region BA x y z Epoch Max F

L. FEF 6 22 5 55 Prep 57.1
Padmanabhan et al.

SEF 6 1 1 49 Prep 49.8

L. FEF 6 22 11 55 Outcome 51.2
SEF 6 4 1 49 Outcome 49.9
R. IPL 39, 40 32 59 40 Outcome 50.1
L.Precuneus 17, 18 1 62 28 Outcome 27.6
L.Putamen N/A 19 4 7 Outcome 29.3

FEF, frontal eye field; SEF, supplementary eye field; IPL, inferior parietal lobule; IPL, inferior parietal lobule; L, left; R, right; BA, Brodmanns Area.

Autism Res. Author manuscript; available in PMC 2016 July 14.

Page 24