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Individuals with Autism Spectrum Disorder (ASD) seem to have difficulties looking others in the eyes, but the substrate for this behavior is not well understood. The subcortical pathway, which consists of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic face processing. A specific component of this pathway – i.e., the amygdala – has been shown to be abnormally activated in paradigms where individuals had to specifically attend to the eye-region; however, a direct examination of the effect of manipulating the gaze to the eye-regions on all the components of the subcortical system altogether has never been performed. The subcortical system is particularly important as it shapes the functional specialization of the face-processing cortex during development. Using functional MRI, we investigated the effect of constraining gaze in the eye-region during dynamic emotional face perception in groups of participants with ASD and typical controls. We computed differences in activation in the subcortical face processing system (superior colliculus, pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals with ASD show abnormally high activation in the subcortical system, which may be at the basis of their eye avoidance in daily life.
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Scientific RepoRts | 7: 3163 | DOI:10.1038/s41598-017-03378-5
Look me in the eyes: constraining
gaze in the eye-region provokes
abnormally high subcortical
activation in autism
Nouchine Hadjikhani
1,2, Jakob Åsberg Johnels2,3, Nicole R. Zürcher1, Amandine Lassalle1,4,
Quentin Guillon5, Loyse Hippolyte6, Eva Billstedt2, Noreen Ward1, Eric Lemonnier7 &
Christopher Gillberg2
Individuals with Autism Spectrum Disorder (ASD) seem to have diculties looking others in the eyes,
but the substrate for this behavior is not well understood. The subcortical pathway, which consists
of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic
face processing. A specic component of this pathway – i.e., the amygdala – has been shown to be
abnormally activated in paradigms where individuals had to specically attend to the eye-region;
however, a direct examination of the eect of manipulating the gaze to the eye-regions on all the
components of the subcortical system altogether has never been performed. The subcortical system
is particularly important as it shapes the functional specialization of the face-processing cortex during
development. Using functional MRI, we investigated the eect of constraining gaze in the eye-region
during dynamic emotional face perception in groups of participants with ASD and typical controls.
We computed dierences in activation in the subcortical face processing system (superior colliculus,
pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze
constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals
with ASD show abnormally high activation in the subcortical system, which may be at the basis of their
eye avoidance in daily life.
Individuals with autism spectrum disorder (ASD) oen report that looking in the eyes of others is uncomfortable
for them, that it is terribly stressful, or even that ‘it burns’ (e.g. ref. 1). Although traditional theoretical accounts of
ASD have interpreted lack of eye contact and other social diculties as indicators of interpersonal indierence to
others2, rst hand reports from verbal people with ASD would rather suggest that the underlying problem may be
one of socio-aective oversensitivity. Some have even proposed that the amygdala may be hyper-reactive in ASD,
resulting in a painfully intense (social) world3. As of yet, however, the evidence pertaining to this fundamental
issue is limited and mixed. For instance, others have reported what was interpreted as a passive social insensitivity
to the eyes of others in a small sample of two year children with autism4.
e presence of a subcortical pathway, conveying rapid emotional information via magnocellular inputs from
the retina to the superior colliculus, the pulvinar and nally to the amygdala, has been shown in rodents (e.g.
ref. 5), in primates (e.g. ref. 6), in blindsight patients (refs 711 for review see ref. 12) and in healthy volunteers
undergoing subliminal emotional stimulation13, 14. Recently, this fast pathway for emotion was directly evidenced
for the rst time with intracranial electrophysiological data in the human amygdala15.
e subcortical system is involved in face processing, in particular in face detection16, and it is the starting
point for the development of face specialization. It modulates cortical processing and is sensitive to direct gaze
1MGH/Martinos Center for Biomedical Imaging, Harvard Medical School, Boston, USA. 2Gillberg Neuropsychiatry
Center, Gothenburg University, 41119, Gothenburg, Sweden. 3Section for Speech and Language Pathology,
Gothenburg University, 41119, Gothenburg, Sweden. 4Autism Research Centre/Department of Psychiatry,
Cambridge University, Cambridge, CB2 8AH, UK. 5Lyon Neuroscience Research Center, Brain Dynamics and
Cognition Team, Lyon, France. 6Service de Génétique Médicale, University of Lausanne, Lausanne, Switzerland.
7CRA, Limoges, France. Correspondence and requests for materials should be addressed to N.H. (email: nouchine@
Received: 20 October 2016
Accepted: 27 April 2017
Published: xx xx xxxx
Scientific RepoRts | 7: 3163 | DOI:10.1038/s41598-017-03378-5
(ref. 17 for review, see ref. 18). Newborns’ looking preferences are presumed to be mediated by the subcortical
pathway over the rst months, and help the normal maturation of the visual cortical areas involved in face per-
ception. is pathway has been thought to be specic for threat, and although fearful face stimuli may serve as
optimal stimuli for the subcortical face processing network19, it was shown in a blindsight patient that it could
also convey other, positive emotions20. Moreover, it is known that the subcortical pathway has broad, indirect
implications in the adequate execution of social actions through motivation-based attention selection19.
Research on the involvement of subcortical brain areas during emotion processing in ASD has yielded mixed
ndings, with some studies showing absent engagement of subcortical brain regions during emotional face pro-
cessing (e.g. ref. 21), while others have shown enhanced involvement of these areas2224. One potentially explan-
atory factor to these mixed ndings is eye contact25 – that is, whether the subjects attended to eye region of the
face stimuli in the experiments or not. Indeed, Dalton et al. showed that amygdala activation in ASD children
was correlated with spontaneous variations in time spent looking in the eyes of the face26. is suggests that some
level of experimental control over participants’ gaze patterns may be critical for characterizing the neural sub-
strate of emotional face processing in ASD27. No previous study has directly examined the eect of looking in the
eyes on subcortical pathway activation in ASD. Nevertheless, Tottenham et al.28 demonstrated using an elegant
paradigm that when ASD participants had to engage in a task that involved detecting a shape placed in the le
or the right eye of faces, they showed heightened amygdala activity compared with controls, and that those who
in natural settings had the least eye-movements towards the eyes were exhibiting the highest amygdala response
when gaze was experimentally driven towards the eyes. In addition, Perlman et al.29 found, in a study conducted
with 12 participants with ASD and 7 controls, that the level of amygdala activity in ASD participants was lower in
a free viewing mode compared to controls, but that activity was modulated by experimental manipulation of gaze
pattern towards the nose and eyes.
e meaning of direct eye-contact depends on the facial expression of the person, in terms of emotional
valence; for instance, a smiling face with a direct gaze is engaging, while an angry face with a direct gaze signals
a potential threat3034. Neutral faces are more ambiguous, and they can be perceived as emotionally negatively
valenced3539 and even threatening in socially anxious individuals40, 41. ASD participants have been shown to have
reduced naturally occurring eye-contact to neutral faces, associated with higher threat ratings for these faces28.
Finally, fearful faces have been shown to automatically attract attention in the eye-region42. We decided to exam-
ine neutral, happy, angry and fearful faces in our paradigm, and to include all emotions in the analyses to conrm
that this is indeed meaningful. In particular, we tested the hypotheses that in each region of the face-processing
subcortical pathway, there would be (1) within the ASD group, increased activation in response to constrained
viewing (CROSS; i.e. the eye region) compared with the free-viewing (NO-CROSS) condition, and (2) between
groups, individuals with ASD would have more activation relative to controls in the constrained (CROSS) view-
ing condition, and that (3) this eect would be the most marked for fear.
e aim of the present study was to specically examine the eect of constraining gaze in the eye-region on acti-
vation of the subcortical system in participants with ASD (n = 23) and in matched controls (CON, n = 20), and to
test the hypothesis that looking in the eyes would activate rapid emotion-processing pathways in ASD. We used
the exact same dynamic facial emotional stimuli in a free-viewing condition and in a condition where participants
were specically asked to look at a cross situated in the eye-region, presented in two separated, counterbalanced
runs. (see supplementary information for details).
We dened anatomical ROIs in the superior colliculus, the pulvinar nucleus of the thalamus, and the amyg-
dala, and compared the level of activation for the free-viewing condition (NO-CROSS) and the constrained
condition (CROSS) in these ROIs. Le and right amygdala were considered separately as there is evidence for
an asymmetric engagement of this structure during face and emotion processing (e.g. refs 4345). Initially, a 2
(Group: ASD, CON) by 4 (Emotion: Neutral, Happy, Angry, Fear) by 2 (Condition: NO-CROSS, CROSS) by 4
(ROI: le amygdala, right amygdala, pulvinar, superior colliculus) mixed factorial analysis of variance (ANOVA)
was performed. e full four-way interaction proved signicant (F1,6.41 = 2.22, p = 0.038, ηp2 = 0.051), which moti-
vates the next step in the analyses where separate ANOVAs for each ROI with planned comparisons between and
within groups for each emotion and for each condition were carried out. In addition, we tested that regardless of
emotion, within the ASD group, there would be increased activation in response to constrained viewing (CROSS;
i.e. in the eye region) compared with the free-viewing (NO-CROSS) condition, and that between group, individ-
uals with ASD would have more activation relative to controls in the constrained (CROSS) viewing condition.
In the superior colliculus and both amygdalae, ASD and controls had the same amount of activation in the
free-viewing condition, but the ASD group had abnormally high activation compared to controls when con-
strained to look in the eyes of neutral and emotional faces. In the pulvinar, ASD participants had higher activation
than controls for both freeviewing and constrained viewing, with exception of angry where, when forced to look
into the eyes, there was no signicant dierence between groups (Fig.1) (see supplementary information for
details). Within the ASD group, the eect of adding a xation cross in the eye-region was most evident in both
amygdalae where activation patterns that were consistently higher compared with the NO-CROSS condition.
We then tested the hypothesis that the size of the eect for the between group comparison in the CROSS
condition would be the most important for FEAR. We computed Cohen’s d for each ROI and for each condi-
tion, and found that the maximum eect size was always for the FEAR condition (see supplementary informa-
tion for details).
Finally, we tested that autism symptom severity, as measured by AQ, would be positively correlated with acti-
vation in the subcortical system in ASD, and found such a correlation for FEAR in all subcortical areas, and for
NEUTRAL in three of the four areas, in the free-viewing condition. See supplementary information for details.
Scientific RepoRts | 7: 3163 | DOI:10.1038/s41598-017-03378-5
Our data demonstrate that constraining individuals with ASD to look into the eyes of dynamic faces expressing
dierent emotions results in aberrant activation of the subcortical pathway, such that higher activation was found
generally in the ASD group. An abnormality of the subcortical system in autism during face processing was rst
hypothesized by Senju and Johnson25, and our data not only conrm this hypothesis, but specify it to a considera-
ble degree: our direct comparison of the same dynamic facial expression seen freely or with a xation cross is the
most direct evidence of the mechanisms by which direct eye-contact may be experienced as stressful in autism.
ASD participants had higher pulvinar activation than controls in both conditions, and it seems that activity
in this structure is less consistently modulated by eye contact. e pulvinar can be considered as a central fore-
brain hub and its input from the superior colliculus may be critical in shaping the functional specialization of the
cortex during early development (for review, see ref. 46). One of the roles of the pulvinar is to lter distracting
stimuli47, and recently morphological alterations of this structure have been reported in ASD, with an expanded
surface area48. e thalamic hyperactivation evidenced here has been hypothesized as one of the substrates of
higher-order social cognition decits in ASD, potentially through its dysregulatory impact on the dorsolateral
prefrontal cortex49. e role of the pulvinar in both the higher-order cognitive and the basic socio-aective prole
in ASD will need to be examined in future studies.
As could be expected from previous studies (e.g. ref. 26), the eect of constraining gaze in the eyes had the
strongest eect for ASD in the amygdala, and although group dierences were most marked for fearful faces, the
dierence between free and constrained gaze was also remarkable for happy faces. is shows that the subcorti-
cal system in ASD over-reacts not only to threat-related stimuli, but also to stimuli that should be considered as
positively engaging and socially rewarding.
Our ndings deepen our understanding of the mechanisms at play in the social decits of individuals with
autism. Traditional accounts have suggested that ASD is characterized by a fundamental lack of interpersonal
interest2; however, the results of our study align with other recent studies showing oversensitivity to socio-aective
stimuli (e.g. refs 50, 51). In everyday life, such oversensitivity may lead to attempts to decrease one’s arousal levels,
and rst-hand reports suggest that simply avoiding to attend to the eyes of others is one common strategy among
Figure 1. Descriptive plots of the ANOVA for each of the four ROIs. Panel A: Superior colliculus; Panel B:
Pulvinar; Panel C: Le amygdala; Panel D: Right amygdala. Each panel shows the results obtained for neutral,
happy, angry and fear faces. ASD participants are shown in white, controls (CON) in black. Values represented
indicate mean ± SEM. Signicant dierences are indicated by red symbols (~trend, *p < 0.05; **p < 0.01;
***p < 0.001).
Scientific RepoRts | 7: 3163 | DOI:10.1038/s41598-017-03378-5
individuals with ASD1. Such a strategy is unlikely, however, to come without costs, since the eyes carry important
interpersonal and deictic information during social interaction and communication, and eye-avoidance may
result in cascading eects leading to improper development of the social brain.
Limitations. ere are several limitations in this work. First, we did not collect eye-tracking data in the
scanner, and hence we never directly correlated subcortical brain activation with the amount of time spent in the
eye-region26. However, while interesting, the relative merits of that approach should not be overstated. Indeed,
abnormal gaze patterns in ASD during spontaneous face viewing has been demonstrated repeatedly, and although
not all studies nd evidence of reduced eye gaze in ASD samples, more robust dierences in how they distribute
their attention within the central areas of the face has been described52, 53. Moreover, while there are current devel-
opments in xation-based54 and event-related55 fMRI, challenges still exists when trying to associate a hemod-
ynamic response (that lasts ca 10 seconds) with xation-based metrics (which averages 300 msec during scene
Second, we only tested constrained gaze with a face, and not with a blank screen or with non-face stimuli,
so part of our results may be due to a general eect of constraining gaze. One can perhaps expect that xating
a cross might introduce some level of cognitive control in the task. Future research should use free-viewing vs.
constrained gaze for non-face stimuli as well, so as to better determine whether part of the eect observed can
be attributed to this factor. Still, there are to our knowledge no theoretical or empirical reasons to predict an
enhanced activation of the face-specic subcortical system following a xed gaze in general.
ird, although we and others have plenty of clinical evidence for the notion that many individuals with ASD
nd eye contact stressful, no research study, including the one presented, have actually linked subjective reports
of discomfort with neural activity patterns during eye gaze. is would be an important area of future research
(though one also needs to hold in mind the potential limitations of self-reports in a condition that is very oen
associated with alexithymia)56.
Finally, as is most oen done in this kind of technically challenging studies, we only examined participants
with normal intelligence, so we do not know whether these results generalize to the full spectrum of ability in the
ASD population. We hope that further studies using less invasive techniques such as eye-tracking with galvanic
skin response will help us investigate a wider range of ASD individuals.
Despite these caveats, the results have potential clinical implications: during behavioral therapy, forcing indi-
viduals with autism to look in the eyes might be counterproductive and elicit more anxiety - however, by not
looking at the eyes, the person with ASD will continue to miss critical social information, and somehow one has
to help them to gather all these important cues. One possible strategy could consist in progressively habituating
individuals with ASD to look into the eyes, analogous to the way surgeons habituate to look at open bleeding bod-
ies, and then in incentivizing them to look at the eyes, nding a way to make eye contact somehow less stressful.
Participants. All procedures were in accordance with the Declaration of Helsinki and were approved locally
by the Lausanne University Hospital Ethics Committee. Written informed consent was obtained from all adult
participants and from all parents of participating children, before the start of the study. In addition, all children
participants gave their oral assent to partake in the study.
Twenty-ve ASD participants were enrolled in the study. Only participants (ASD and CON) who had an
estimated absolute mean displacement of less than 2 mm as reported by FLS MCFLIRT and who responded 75%
or more to the monitoring procedure that we used to track if the participants paid attention were included. Two
ASD subjects were excluded from the data analysis due to excessive movement (n = 1) or for not performing
the task during the scan (n = 1). us, 23 ASD participants (21 males, 22.6 years ± 1.8 (mean age ± SEM), range
10.6–40.7) were included in the nal analysis.
Participants with ASD were all diagnosed by experienced clinicians certied reliable for research purposes
who used the DSM IV-TR criteria57, together with the Autism Diagnostic Interview-Revised (n = 17)58 or the
Diagnostic Interview for Social and Communication Disorders (DISCO) version 10 or 1159 (n = 5), and the
Autism Diagnostic Observation Schedule module 4 (n = 15) or module 3 (n = 3)60. Of the 23 participants, 16 had
a diagnosis of autism, 5 of Asperger Syndrome and 2 of PPD-NOS.
Twenty-ve healthy control participants (CON) were enrolled in the study. ey had no history of psychiatric
or neurological disorders. Five subjects were excluded from the data analysis due to excessive movement (n = 3)
or for not performing the task during the scan (n = 2). us, 20 control participants (17 males, 23.3 years ± 1.8
(mean age ± SEM), range 12.7–42.9) were included in the nal analysis.
Intelligence Quotient (IQ) scores were obtained using the Wechsler Nonverbal Scale of Ability (WNS)61 or the
Wechsler Abbreviated Scale of Intelligence (WASI)62. All participants had normal IQ (ASD: 112.9 ± 3.3; CON:
113.4 ± 2.4 (mean ± SEM)). ASD and CON participants were matched for age and IQ. (p > 0.7).
Participants also completed the Autism-Spectrum Questionnaire63, 64. (ASD: 26.8 ± 1.4; CON: 13.3 ± 1.5
(mean ± SEM)). ASD had signicantly higher scores than CON (p < 0.001).
Anxiety levels were evaluated with the State-Trait Anxiety Inventory (STAI)65 in 12 ASD and 15 CON adults
(data were not collected for 5 ASD adults), and the Revised Children’s Manifest Anxiety Scale RCMAS in 6 ASD
and 5 CON children66. e groups did not dier on these scores (ASD STAI trait: 53.33 ± 12.46; CON STAI trait:
46.13 ± 6.78, t-test: p = 0.09; RCMAS score ASD: 55.00 ± 11.31; CON: 54.60 ± 6.87 T test: p = 0.94).
Experimental design. Twenty-four movies were created from the NimStim database67 representing morphs
of facial expressions from NEUTRAL to FEAR, HAPPY or ANGER with Morph Age Pro (Creaceed). Each movie
lasted for 5 seconds, and consisted of a dynamic morph lasting 3 seconds, followed by 2 seconds of the nal emo-
tional expression. Morphs of NEUTRAL were also created by creating a le-to-right morph between mirror
Scientific RepoRts | 7: 3163 | DOI:10.1038/s41598-017-03378-5
images of neutral faces, in order to also have a dynamic component in this condition. Two versions of these
movies were created, with one version containing a red xation cross in the region of the eyes. e NimStim
database does not allow to publish the identities that we used in the experiment, but we created a representative
example from one of the authorized identities that can be consulted in the supplementary material. In addition,
a red xation cross was present for 1 second between each movie at the same location, and periods of FIXATION
were presented for 6 seconds at the beginning and at the end of each run, as well as for 3 seconds 7 times during
each run interspersed between the blocks of emotional faces. Each participant viewed both versions (CROSS and
NO-CROSS) during the scanning session (that also comported other tasks not reported in the present manu-
script). e order of the CROSS and NO-CROSS versions was counterbalanced across participants, so that about
half of them saw the stimuli with NO-CROSS rst. Participants were instructed to carefully look at the videos
and, in order to monitor their attention, to press a button every time they saw a blue cross between the stimuli,
which happened 4 times during CROSS and 4 times during NO-CROSS. e stimuli presented during CROSS
and NO-CROSS were identical, the only dierence was the presence of a xation cross during the CROSS version.
Each block lasted 48 seconds. ere were 8 blocks (2 for each emotion) and within one block, here were 8 stimuli
(all dierent identities) for a total of 16 stimuli per condition.
Imaging data acquisition and analysis. Anatomical and functional MR images were collected in all
participants with a 12-channel RF coil in a Siemens 3 T scanner (Siemens Tim Trio, Erlangen). T1-weighted
anatomical images were acquired using an ME-MPRAGE (176 slices; 256 × 256 matrix; 1 × 1 × 1 mm voxels,
echo time (TE): TE1: 1.64 ms, TE2: 3.5 ms, TE3: 5.36 ms, TE4: 7.22 ms; repetition time (TR): 2530 ms; ip angle
7°). Functional data were obtained using an echo planar imaging (EPI) sequence (47 AC-PC slices, 3 × 3 × 3 mm
voxels, 64 × 64 matrix; FOV: 216; TE: 30 ms; TR: 3000 ms; ip angle 90°) lasting 384 seconds.
Functional MRI data processing, as well as preprocessing was carried out using FSL Non-brain tissue
was removed from high-resolution anatomical images using Christian Gaser’s VBM8 toolbox for SPM868 and fed
into feat. Data were motion-corrected using MCFLIRT and motion parameters added as confound variables to
the model. Participants with motion exceeding 2mm were excluded from further processing (1 ASD, 3 controls).
Paired t-test within each group comparing average head movements in the CROSS and NO-CROSS conditions
were not signicant (ASD: t22 = 1.55, p = 0.135; CON: t19 = 0.77, p = 0.447). Unpaired t-tests between group for
each condition were not signicant either (NO-CROSS: t41 = 0.83, p = 0.41; CROSS: t41 = 1.26, p = 0.21). Residual
outlier timepoints were identied using FSL’s motion outlier detection program and integrated as additional con-
found variables in the rst-level General Linear Model (GLM) analysis. Preprocessing included spatial smooth-
ing using a Gaussian kernel of 8 mm, grand-mean intensity normalization and highpass temporal ltering with
sigma = 50.0 s.
Subject-level statistical analysis was carried out for the contrasts [NEUTRAL > FIXATION],
[HAPPY > FIXATION], [ANGRY > FIXATION and [FEAR > FIXATION] using FILM with local autocorrela-
tion correction for both the CROSS and the NO-CROSS runs. Registration to high-resolution structural images
was carried out using FLIRT. Registration to MNI standard space was then further rened using FNIRT nonlinear
registration. Group-level analyses for each condition were performed using mixed eects GLM analysis using
FLAME 1 + 2 with automatic outlier detection.
e regions of interest (ROIs) in the subcortical system were anatomically dened and consisted of the le and
right amygdala (from the Harvard-Oxford Subcortical atlas), the superior colliculus and the pulvinar nucleus of
the thalamus. For each subject, the value of the maximum contrast of parameter estimate (COPE) was extracted
for the four structures and the four contrasts of interest, using the FSL Featquery tool in FSL.
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This work was supported by the Swiss National Science Foundation (PP00P3-130191 to NH), the Centre
d’Imagerie BioMédicale (CIBM) of the University of Lausanne (UNIL), as well as the Foundation Rossi Di
Montalera, the LifeWatch Foundation, the AnnMarie and Per Ahlqvist Foundation, the Torsten Soderberg
Foundation and the Swedish Science Council. e funders had no role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the
manuscript. We want to thank Ophélie Rogier for her help in data acquisition, Karine Métrailler and Carole
Burget for their support in participant’s recruitment and administrative assistance, and Anthony Lissot and
Torsten Ruest for their help in data analysis.
Author Contributions
N.H., J.Å.J. and N.R.Z. designed the research and wrote the manuscript. L.H., E.B. performed the
neuropsychological testing of participants. E.L., C.G. performed the diagnosis of ASD participants. A.L., Q.G.,
N.W., and C.G. contributed to editing the manuscript.
Additional Information
Supplementary information accompanies this paper at doi:10.1038/s41598-017-03378-5
Competing Interests: e authors declare that they have no competing interests.
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The pulvinar is the largest thalamic nucleus in primates and one of the most mysterious. Endeavors to understand its role in vision have focused on its abundant connections with the visual cortex. While its connectivity mapping in the cortex displays a broad topographic organization, its projections are also marked by considerable convergence and divergence. As a result, the pulvinar is often regarded as a central forebrain hub. Moreover, new evidence suggests that its comparatively modest input from structures such as the retina and superior colliculus may critically shape the functional organization of the visual cortex, particularly during early development. Here we review recent studies that cast fresh light on how the many convergent pathways through the pulvinar contribute to visual cognition.
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It has been suggested that some cortically blind patients can process the emotional valence of visual stimuli via a fast, subcortical pathway from the superior colliculus (SC) that reaches the amygdala via the pulvinar. We provide in vivo evidence for connectivity between the SC and the amygdala via the pulvinar in both humans and rhesus macaques. Probabilistic DTI tractography revealed a streamlined path that passes dorsolaterally through the pulvinar before arcing rostrally to traverse above the temporal horn of the lateral ventricle and connect to the lateral amygdala. To obviate artifactual connectivity with crossing fibres of the stria terminalis, the stria was also dissected. The putative streamline between the SC and amygdala traverses above the temporal horn dorsal to the stria terminalis and is positioned medial to it in humans and lateral to it in monkeys. The topography of the streamline was examined in relation to lesion anatomy in five patients who had previously participated in behavioral experiments studying the processing of emotionally valenced visual stimuli. The pulvinar lesion interrupted the streamline in two patients who had exhibited contralesional processing deficits and spared the streamline in three patients who had no deficit. Although not definitive, this evidence supports the existence of a subcortical pathway linking the SC with the amygdala in primates. It also provides a necessary bridge between behavioral data obtained in future studies of neurological patients, and any forthcoming evidence from more invasive techniques, such as anatomical tracing studies and electrophysiological investigations only possible in non-human species. Copyright © 2014, Journal of Neurophysiology.
Objective: Two hypotheses, gaze aversion and gaze indifference, are commonly cited to explain a diagnostic hallmark of autism: reduced attention to others' eyes. The two posit different areas of atypical brain function, different pathogenic models of disability, and different possible treatments. Evidence for and against each hypothesis is mixed but has thus far focused on older children and adults. The authors evaluated both mechanistic hypotheses in two sets of experiments at the time of initial diagnosis. Method: Eye-tracking data were collected in 86 2-year-olds: 26 with autism, tested at initial diagnosis; 38 matched typically developing children; and 22 matched developmentally delayed children. In two experiments, the authors measured response to direct and implicit cueing to look at the eyes. Results: When directly cued to look at the eyes, 2-year-olds with autism did not look away faster than did typically developing children; their latency varied neither categorically nor dimensionally by degree of eye cueing. Moreover, direct cueing had a stronger sustained effect on their amount of eye-looking than on that of typically developing children. When presented with implicit social cues for eye-looking, 2-year-olds with autism neither shifted their gaze away nor more subtly averted their gaze to peripheral locations. Conclusions: The results falsify the gaze aversion hypothesis; instead, at the time of initial diagnosis, diminished eye-looking in autism is consistent with passive insensitivity to the social signals in others' eyes.
Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits while age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence while hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset.