Pr Marie Schaer Université de Genève - 1er congrès national de l'autisme
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Comment l’eye-tracking et l’imagerie cérébrale permettent de mesurer
les trajectoires de développement des jeunes enfants avec un TSA
Pr Marie Schaer
Université de Genève
1er congrès national de l’autisme, 10 novembre 2018
National Center of Competences in Research
Plan de la présentation 1. Généralités 2. Intervention Précoce 3. Recherche 4. Perspectives
Les troubles du spectre autistique: un retrait social…
… et des intérêts restreints
Quelles interventions thérapeutiques pour l’autisme?
‣ Il n’existe pas de
traitement
médicamenteux
ciblant les symptômes
de l’autisme
‣ Les interventions les
plus efficaces à ce
jour sont
comportementales
Le temps compte…
Intervenir précocement est primordial
‣ Une intervention précoce et
intensive permet:
de diminuer les symptômes
de l’autisme
d’améliorer la communication
d’améliorer les compétences
cognitives
d’améliorer durablement le
fonctionnement au quotidien,
p.ex. meilleure intégration
scolaire
FIGURE 2 Dawson et al., 2010
Toutes les études confirment les bénéfices deARTICLES
l’intervention précoce
Randomized, Controlled Trial of an Intervention for
Toddlers With Autism: The Early Start Denver Model
AUTHORS: Geraldine Dawson, PhD,a,b,c Sally Rogers, WHAT’S KNOWN ON THIS SUBJECT: Previous studies on the
PhD,d Jeffrey Munson, PhD,e,f Milani Smith, PhD,e Jamie efficacy of early behavioral intervention for improving outcomes
Winter, PhD,e Jessica Greenson, PhD,e Amy Donaldson, for preschool-aged children with autism have yielded promising
PhD,g and Jennifer Varley, MSe
510067
2013
AUT0010.1177/1362361313510067AutismKlintwall et al.
results. However, no randomized clinical trials of early
aAutism Speaks; bDepartment of Psychiatry, University of North developmental behavioral intervention designed for toddlers with
Carolina, Chapel Hill, North Carolina; cDepartment of Psychology,
eUniversity of Washington Autism Center, Center on Human
autism have been conducted to date.
Development and Disability, and fDepartment of Psychiatry and
Behavioral Sciences, University of Washington, Seattle, WHAT THIS STUDY ADDS: This study assessed the efficacy of the
Washington; dMIND Institute, Department of Psychiatry, Early Start Denver Model, a comprehensive developmental
Article
University of California Davis, Sacramento, California; and behavioral intervention, for improving outcomes of toddlers with
gDepartment of Speech and Hearing Science, Portland State
ASD. The intervention, which was initiated when children were Autism
University, Portland, Oregon
KEY WORDS Narrowing the gap: Effects of intervention
less than 21⁄2 years, resulted in significant improvements in IQ,
language, adaptive behavior, and autism diagnosis.
0(0) 1–11
© The Author(s) 2013
Reprints and permissions:
on developmental trajectories in autism
autism, behavioral intervention, cognitive function,
developmental outcomes, early intervention sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1362361313510067
ABBREVIATIONS aut.sagepub.com
ASD—autism spectrum disorder
ESDM—Early Start Denver Model
ABA—applied behavior analysis abstract
Lars Klintwall, Sigmund Eldevik and Svein Eikeseth
NEW RESEARCH
A/M—assess and monitor
PDD—pervasive developmental disorder OBJECTIVE: To conduct a randomized, controlled trial to evaluate the
NOS—not otherwise specified efficacy of the Early Start Denver Model (ESDM), a comprehensive de-
MSEL—Mullen Scales of Early Learning velopmental behavioral intervention, for improving outcomes of tod-
ADOS—Autism Diagnostic Observation Schedule
VABS—Vineland Adaptive Behavior Scales dlers diagnosed with autism spectrum disorder (ASD).
Long-Term Outcomes of Early Intervention in 6-Year-Old AbstractMETHODS: Forty-eight children diagnosed with ASD between 18 and 30
RBS—Repetitive Behavior Scale
This trial has been registered at www.clinicaltrials.gov months
Although still of age were
a matter randomly
of some assigned
debate, theretois1 of 2 groups: body
a growing (1) ESDM inter-
of research supporting Early and Intensive Behavioral
Children With Autism Spectrum Disorder
(identifier NCT00090415).
vention, which is based on developmental and applied behavioral analytic
Intervention as the intervention of choice for children with autism. Learning rate is an alternative to change in standard
www.pediatrics.org/cgi/doi/10.1542/peds.2009-0958 principles andmeasure
deliveredinbystudies
trained oftherapists and parents for 2 years;rates
or can be displayed graphically as developmental
scores as an outcome early intervention. Learning
doi:10.1542/peds.2009-0958 (2) referral
trajectories, which are to community providers for intervention
easy to understand and avoid commonly
some of available in
the counter-intuitive properties of changes in standard
Annette Estes, PhD, Jeffrey
Accepted for publication Jul 17, 2009 Munson,
the community.
PhD , Sally J. Rogers, PhD , Jessica Greenson, PhD ,
scores. The data used in this analysis were from 453 children with autism, previously described by Eldevik et al. Children
Address correspondence to Geraldine Dawson, PhD, AutismJamie Winter,
receiving RESULTS:
Early PhD
and , Geraldine
Compared
Intensive with Dawson,
children
Behavioral who PhDcommunity-intervention,
received
Intervention exhibited significantly steeper developmental trajectories than
Speaks, 4120 Bioinformatics Building, University of North
Carolina, Chapel Hill, North Carolina. E-mail: gdawson@ children inchildren who received
the control group,ESDM
in bothshowed significantand
intelligence improvements in IQ, adap- However, there was a considerable variability
adaptive behaviors.
autismspeaks.org tivelearning
in individual behavior,rates
and autism
within diagnosis.
the group Tworeceiving
years afterEarly
entering
andintervention,
Intensive Behavioral Intervention. This variability could
Objective: We prospectively examined evidence
partly be explained
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). for
the ESDM groupthe
by the with
onintensity the community-intervention-as-usual
average improved 17.6 standard
of the treatment, scorebypoints
partly (1 SD: 15
children’s (COM)
intake group.quotient age-equivalents. Age
intelligence
sustained effects of early intervention based on
Copyright © 2009 by the American Academy of Pediatricsat intake did
anot
points) follow-
compared
co-vary with The
with 7.0 2 groups
points
learning inrate. were not group
the comparison significantly different in terms of
relative to base-Un consortium suisse en intervention précoce
‣ 5 centres universitaires ont combiné
leurs efforts pour évaluer l’efficacité
de l’intervention précoce
‣ Chaque centre propose une
intervention précoce, intensive et
scientifiquement validée
‣ Mandat de l’OFAS de mesurer le
Basel UKBB GSR (Peter Weber / Bettina
résultat de l’intervention précoce en
•
Tillman)
autisme, ayant aboutit à une
recommandation du Conseil • Basel KJPK (Klaus Schmeck / Evelyn
Herbrecht)
Fédéral et à la prise en charge d’un
forfait de prestations d’intervention • Lugano EOC (Gian Paolo Ramelli)
précoce par l’AI • Zürich KJPDZH (Ronnie Gundelfinger)
‣ Actuellement, 130 enfants ont été • Genève OMP (Stephan Eliez / Marie Schaer /
recrutés Hilary Wood de Wilde)L’intervention précoce en Suisse
‣ Après une année d’intervention:
Diminution de la sévérité des symptômes
autistiques, particulièrement réduction du
déficit dans les interactions sociales et la
communication
Augmentation significative des compétences
de communication
Tendance à un gain cognitif
ADOS - Score global de sévérité ADOS - Affect social Vineland - Communication
p=0.0008*** p=0.001**
VABS-II - Communication (SS)
p=0.0013** 8 75
8
ADOS - Total Severity Score
ADOS - Social Affect
7 70
7
6 65
6
5 5 60
4 4 55
V1 V2 V1 V2 V1 V2
Visits Visits Visits
n=59L’expérience de Genève en intervention précoce
L’intervention précoce à Genève, dirigée par Hilary Wood de Wilde
‣ Depuis 2010, les CIPAs (Centre d’Intervention Précoce en Autisme) offrent une
intervention intensive suivant le Early Start Denver Model (Rogers & Dawson, 2010)
‣ Ce programme suit la motivation et les intérêts de l’enfant, et renforce la
communication réciproque entre le psychologue et l’enfant par un focus sur les
affects positifs
‣ 20h de thérapie par semaine, 5 jours par semaine, pour une durée de 2-2.5 ans
‣ Actuellement, 36 enfants âgés de 1 à 4 ans bénéficient de cette approche
http://www.pole-autisme.chL’intervention précoce à Genève, dirigée par Hilary Wood de Wilde
‣ Un programme
très structuré mais ludique
individualisé pour chaque enfant
qui vise à développer l’envie de l’enfant d’entrer en contact, augmenter ses
capacités de communication, de partage d’intérêts, et son autonomie dans
la vie quotidienneFrançois Robain
Mesurer la réponse au traitement
‣ Plus l’intervention commence tôt et est intensive, meilleur est le bénéfice
‣ Cela souligne l’importance d’établir un diagnostic très précoce, ce qui n’est
pas toujours facile sur la seule base des symptômes
*p = 0.03154
Percentage
50 p = 0.03591
(%)
*R2 = 0.08888 100
R2 = 0.1253
du score ADOS
Gain cognitif (%QI)
0
Delta DQ
50
SS Total Diminution
2 3 4 5
-50
0
Réduction
2 3 4 5
-100 âge au débutage
Child's duattraitement
T1 Child'sduage
âge au début at T1
traitement
-50
* *
Réduction de la sévérité des symptômes autistiques après un an Gain cognitif après un an
n = 50 enfants avec TSA âgés 1.6 à 5 ans (3 ans en moyenne); tout type de traitements confondus
Robain et al., in prepLa Boussole, un centre dirigé par Martina Franchini
‣ Un nouveau programme de soutien au
développement précoce pour les enfants à
risque d’autisme ou de troubles associés
pour les tout-petits (A quel âge peut-on diagnostiquer l’autisme?
Age des premières interrogations des parents
2007 2017
Avant Avant Avant
11 mois 24 mois 4% 6 mois
20% 20%
20%
44%
Après
26%
18 mois 36% Entre 11 et Avant 30% Avant
18 mois 18 mois 12 mois
‣ 56% des parents identifient des ‣ 76% des parents identifient des
signes avant l’âge de 18 mois signes avant l’âge de 18 mois
Chawarska et al., JADD 2007 Matheis et al., 2017, Dev Neurorehab
‣ Malgré que les parents s’inquiètent de plus en plus tôt, les cliniciens manquent d’outils
fiables pour augmenter leur certitude dans le diagnostic avant l’âge de 15-24 moisComment les outils de recherche peuvent-ils nous aider à diagnostiquer plus tôt et à mieux comprendre l’autisme?
L’hypothèse de la motivation sociale
Réduction de
l’orientation sociale
Déprivation en
expériences sociales
Réduction des opportunités Diminution de
pour un apprentissage “l’apprentissage social”
cognitif adéquat
Déficit de spécialisation des régions
Développement incomplet cérébrales concernées par le
du potentiel cognitif traitement de l’information sociale
(résumée par Chevallier et al., TICS 2012)an head- and eye-turning responses to the three stimuli are shown in
3. Separate ANOVAs (Subjects x Treatments) were applied and revealed
Développement typique de l’orientation sociale
wing.
turning
46.3, df = 2, 46, p < .OOOl. A Tukey test (alpha = 0.05) was then used
Déjà dans les premières heures après la A partir de 33 semaines de
mine the critical differences (in degrees) between responses to the three
naissance, le nouveau-né s’oriente vers
With q = 3.44 the critical difference was found to be 6.2”. Thus responses
grossesse, les foetus s’orientent
des stimuli qui ressemblent à des visages déjà vers des stimuli qui ressemblent
. Mean head and eye turning for the face, scrambled and blank stimuli. à des visages
s 40
‘3
m
g 30
a
c
8 20
0
5
= 10
0
Q Q Q
Face Scrambled Blank
Johnson et al., Cognition 1991 Figure 2. The Mean
Reid et al., of
Number Current Biology
Fetal Head 2017
Turns to the Stim
The mean number of head turns made toward (left two bars) and aMesurer l’orientation sociale avec l’eye-tracking
Projet de recherche en
autisme, Genève Ami Klin & Warren Jones60 60
95% CI
50 50
LETTER
Fixation time (%)
Fixation time (%)
Eyes
Orientation
40
sociale chez des enfants qui développent
Mouth
un TSA
40
doi:10.1038/nature12715
30 30
Attention
20
to eyes is present but in decline in 20
RESEARCH LETTER
2–6-month-old infants later diagnosed with autism
10 Body 10
1,2,3 1,2,3
Warren Jones & Ami Klin
Object
0 a b 0
2 3 4 5 6 9 12 1,2
15 18 24 2 3 c 4 5
Deficits in eye contact have been a hallmark of autism since the Data were collected at 10 time points: at months 2, 3, 4, 5, 6, 9, 12, 15,
Age as
condition’s initial description3. They are cited widely (months)
a diagnostic 18 and 24. We studied 110 infants, enrolled as risk-based cohorts:
feature4 and figure prominently in clinical instruments5; however, n 5 59 at high-risk for ASD (full siblings of a child with ASD19) and
e f
the early onset of these deficits has not been known. Here we show in n 5 51 at low-risk (without first-, second- or third-degree relatives g
a prospective longitudinal studyEyes
70 that infants later diagnosed with with Mouthat 36 months. For details
70ASD). Diagnostic status was ascertained
autism spectrum disorders (ASDs)
60 ASDdecline in eye fixa- on60
TD exhibit mean study design, clinical characterization of participants, and experi-
tion from 2 to 6 months of age, a pattern not observed in infants who mental procedures, see Methods and Supplementary Information.
Fixation time (%)
50 50
Of the high-risk infants, 12 met criteria for ASD20 (10 males, 2 females),
do not develop ASD. These observations mark the earliest known
6 mois, diagnostiqué 619mois, développement
indicators of social disability in infancy, but also falsify a prior indicating a conversion rate of 20.3% . One child from the low-risk
40
hypothesis: in the first months of life, this basic mechanism of social plus 40 tard
cohort avec
was also un with
diagnosed TSAASD. Given the small typique
number of girls
adaptive action—eye looking—is not immediately diminished in in30
30
the ASD group, we constrained current analyses to males only, 11
infants later diagnosed with ASD; instead, eye looking appears to ASD (10 from the high-risk cohort and 1 from the low-risk), and 25
begin at normative levels prior to decline. The timing of decline typically
20 20 developing (all from the low-risk cohort).
highlights a narrow developmental window and reveals the early
Des courbes de croissance de
At each testing session, infants viewed scenes of naturalistic care-
10 F(1,34) = 11.9, key role in giver
P =a 0.002 10 interaction (Fig. 1a, b) while their visual
F(1,34) = scanning
0.002, P was=measured
0.965
derailment of processes that would otherwise have l’engagement social visuel
canalizing typical social development. Finally, the observation of with eye-tracking equipment. The 36 typically developing and ASD
0 0
a children viewed
2 3 in
this decline 4 5eye6 fixation—rather
9 12 than15 outright
18 absence—offers
24 2 3 4 2,384
5 6 trials9ofASD
video
12 scenes.
typique pourraient être utilisées 15 18 24
ge in fixatioin
promising opportunity for early intervention that could build on d 100 Control comparisons tested for between-group differences
e 100 in atten-
4
pour dépister l’autisme
the apparent preservation of mechanisms subserving reflexive ini- tion4to task and completion of procedures. There were no between-
group80differences in duration of data collected per child 80 (typically
2 orientation towards the eyes.
tial
Autism Spectrum Disorders (ASDs) affect approximately 1 in every 2 60 5 71.25 (27.66) min, ASD 5 64.16 (30.77) min,
developing 60
data given
0
88 individuals6. These disorders are lifelong, believed to be Jones
congenital, mean (standard deviation), with t34 5 0.685, P 5 0.498; two-sample
& Klin,asNature
0 40 2013
s (%)
–2 are among the most highly heritable of psychiatric conditions .
and 7 t-test with 34 degrees of freedom, equal variances); or 40 in the distri-Martina Franchini
Vers de nouvelles méthodes de diagnostic:
Mesurer l’intérêt social avec l’eye-tracking
Garçon contrôle, 24 mois
Preference for biological vs non-biological motion
The figure aside shows that the
Control
toddlers who demonstrated a
Time spent on biological motion
ASD
visual preference for dynamic
100% geometric objects compared
to biological motion were
80%
exclusively toddlers with ASD.
60% However, one toddler with ASD
40% Preferential interest
for geometric objects Garçon avec autisme, 23 mois
had a strong preference for
biological motion. To further
20% understand this phenomenon, we
examined whether this high
0 interest in people was related to
0 12 24 36 48 60 72 84
the severity of autistic symptoms
Age (in months) in this patient.
For that purpose, we examined
Time spent on biological motion
Control the relationship between the
100% ASD visual preference for biological
motion and the ADOS score at
80% different domains.
60% As shown aside, the only toddler
with ASD with high interest for
40% biological motion was also the
one with lower impairment in
20% communication and lower severity
in the ADOS reciprocical social
0
0 2 4 6 8 interaction domain.
Paradigme inspiré de Pierce et al., 2011 ADOS Communication Score This “particularly social” toddler
with ASD was diagnosed with
ion
severe autism at 11 months ofMartina Franchini
Un déficit d’intérêt social dans l’autisme?
Preference for biological vs non-biological motion
Au moment du diagnostic:
Time spent on biological motion Moins d’intérêt
Control
The figure aside shows that the
ASDsocial chez
toddlers les
who demonstrated a Après une année:
visual preference for dynamic
enfants avec TSA, geometric
mais La variabilité d’intérêt social prédit l’évolution
biological avec
100% objects compared
to motion were
80%
une grande hétérogénéité
exclusively toddlers with ASD.
Change in ADOS severity after one year
60% However, one toddler with ASD 50% R=-0.67
had a strong preference for
Preferential interest
40%
biological motion. To further
for geometric objects
p=0.001
Percentage of time spent on biological motion
20% understand this phenomenon, we
pFrançois Robain
Prédicteurs de la réponse au traitement
‣ Même si la mise en place précoce du traitement reste le
facteur le plus prédicteur d’une évolution favorable,
l’orientation sociale est un facteur spécifique de l’enfant qui
module la réduction des symptômes
ADOS (%)
*p = 0.03154
ADOS (%)
du scorePercentage
p = 0.0592 p = 0.03591
50
Percentage
*R2 = 0.08888 R2 = 0.09054 100
50 R2 = 0.1253
(%QI)
0
du score
Delta DQ
50
SS Total Diminution
Gain cognitif
2 3 4 5 0
SS Total Diminution
20
Preference for biological vs non-biological 40
motion 60 80 100
The figure aside shows that the
Control
toddlers who demonstrated a
Time spent on biological motion
ASD
-50 100%
visual preference for dynamic
0
-50
geometric objects compared
Réduction
to biological motion were
2 3 4 5
Réduction
80%
exclusively toddlers with ASD.
60% However, one toddler with ASD
40% Preferential interest had a strong preference for
for geometric objects biological motion. To further
Child's age at T1
âge au débutage
duattraitement âge au début du traitement
20% understand this phenomenon, we
-50
examined whether this high
-100 Child's T1 degré
Sociald’orientation sociale
Orienting at start
0
-100 Age (in months)
interest in people was related to
0 12 24 36 48 60 72 84
the severity of autistic symptoms
in this patient.
For that purpose, we examined
Time spent on biological motion
Control the relationship between the
100% ASD visual preference for biological
motion and the ADOS score at
80% different domains.
1. Précocité de l’intervention
60% As shown aside, the only toddler
1. Précocité de l’intervention 2. Orientation sociale à T1
with ASD with high interest for
40% biological motion was also the
one with lower impairment in
20% communication and lower severity
in the ADOS reciprocical social
0
0 2 4 6 8 interaction domain.
ADOS Communication Score
This “particularly social” toddler
with ASD was diagnosed with
Time spent on biological motion
severe autism at 11 months of
*
100% Control age and already benefitted from
ASD 10 months of specific social
80% enrichment. At the time of
* *
evaluation, he did not meet the
60%
full criteria for autism diagnosis
40% but only for autism spectrum
disorder. This case report lends
20% support to the fact that socially
enriched therapies can help to
0 interest children in people and
0 2 4 6 8 10 12
lower the severity of their
ADOS Reciprocical Social Interaction Score communication impairments.
The tight relationship between
symptom severity and interest
Time spent on biological motion
Control
ASD for geometric object may however
100% not to hold true for all domains, as
Réduction de la sévérité des symptômes autistiques après un an
the visual preference seems less
80%
Gain cognitif après un an
predictive of the severity of
60%
repetitive behaviors.
Although very preliminary and
40% based on the limited sample size
collected to date, we are convinced
20%
that these results are highly
0 promising to uncover the
0 1 2 3 mechanisms by which the
Sample of the video stimuli, shown to ADOS Repetitive Behaviors Score severity of symptoms can be
children using the eye-tracking device
for a total duration of 2 minutes.
lowered in children diagnosed
with autism.
n = 50 enfants avec TSA âgés 1.6 à 5 ans (3 ans en moyenne); tout type de traitements confondus
Robain et al., in prepUn déficit primaire dans le système cérébral de la récompense?
‣ L’intégrité des connections
du système de la
récompense est directement
corrélée à l’intensité des
difficultés sociales
CSD overlaid on the Fractional Anisotropy map
CSD on the Fractional Anisotropy map Tractographic reconstruction from VTA to accumbens using spherical ROIs in MNI space
d circuits and childhood autism | 2800141; 2795–2805
BRAIN 2018: | 2799
BRAIN 2018: 141; 2795–2805 K. Sup
Downloaded from https://academic.oup.com/brain/article-abstract/141/9/2795/5
re 2 Mesolimbic reward pathway in children with ASD and typically developing children. Using analytical procedures illustrated
Supekar, Kochalka, Schaer et al, Brain 2018
. 1, white matter tracts connecting the NAc and the VTA, the major subcortical nodes of the mesolimbic rewardFigure
cted in each child in both cohorts. Six exemplar participants (three ASD, three typically developing) from thewith
3 Structural
pathway,
ASD.
primary (A)and
cohort, Density
six
deficits in mesolimbic reward pathway and its association with social interaction impairments in c
could be reliably
of the NAc-VTA tracts was significantly lower in children with ASD compared to typically developing childrenwere presented with the same visual stimuli in the same order.
Holger Sperdin
were rechecked and electrodes were readjusted where needed
second block was then acquired (animated cartoon; animated
condition of interest: dynamic social images). The experimen
tracking to ensure children were looking at the screen. The w
Les réseaux cérébraux du traitement de l’information sociale
hour. We used stringent criteria and only participants with th
subsequent analysis.
Eye-tracking measurements
Eye-tracking data were recorded with the TX300 Tobii eye-trac
of 300 Hz). In order to analyse and quantify differences in visua
bioRxiv preprint first posted online Aug. 30, 2017; doi: http://dx.doi.org/10.1101/180703. The copyright holder for this preprint (which was n
peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
‣ La diminution de l’intérêt social a un
impact sur le développement des
régions du cerveau spécialisée dans Figure 6. Exemplar single time frame of the normative gaze pattern for each group on one random time fram
for an individual participant. The face has been blurred on purpose to preserve anonymity but was fully visible
le traitement de l’information sociale
experiment.
DOI: https://doi.org/10.7554/eLife.31670.012
Sperdin et al. eLife 2018;7:e31670. DOI: https://doi.org/10.7554/eLife.31670
Sperdin et al., eLife 2018Nada Kojovic
Quelles conséquences d’une réduction de l’orientation sociale?
Développement typique Un garçon avec trouble du spectre de
(n=19, 3.8±1.3 ans) l’autisme (5 ans)
‣ Les interactions sociales sont complexesDes “normes” de cognition sociale
2 3%
a ge :
av e r
100%
Congruence
Proximity
50%
17% av
era
0% ge
0 50 100 150 : 3%
Time(s)
Kojovic et al., in preparationDes “normes” de cognition sociale
Décours temporel de
l’enregistrement du regard Correlations avec les
100%
mesures cliniques
60%
from norm
Congruence
60%
Proximity from norm
40%
50% 40%
Proximity
20%
17% R2=0.265 20%
Kernel density estimation
0%
0% distribution estimates R =0.265p=0.001 2
0 5 5010 15
100 15020 p=0.001
optimally the deviation of every
Expressive Time(s)
language single point from
(VABS-II)
0%
5 a 10 15 20
Expressive language (VABS-II)
multifocal distribution
60% 60%
Proximity from norm
Proximity from norm
40% 40%
20% 20%
R2=0.225 R2=0.273
p=0.004 p=0.001
0% 0%
40 60 80 100 120 40 60 80 100 120
Communication (VABS-II) Socialization (VABS-II)
Kojovic et al., in preparationReem Jan
Traitement de la scène sociale à l’âge de 4 ans
Moins d’activation des régions dorsofrontales dans le groupe avec TSA
pourrait refléter une moindre compréhension de la séquence et structure des
interactions sociales
Plus d’activation des régions pariétales supérieures suggère que les enfants
avec un TSA traitent cette scène sociale comme une information visuospatiale
IPL
Map 3
SFG/MFG SFG/MFG
ASD < TD
ASD > TD SPL SPL SFG
Map 4
SFG
ACC
pNada Kojovic
2 à 4 ans: une période critique pour apprendre les interactions sociales
‣ En grandissant, les enfants
Typique Autisme avec un développement
typique développent une
exploration visuelle de plus en
2 ans
2 ans
plus ciblée
‣ Pendant la même période, les
enfants avec TSA se
3 ans
dispersent de plus en plus
3 ans
dans leur exploration des
interactions sociales
Autisme
4-5 ans
4×105 4×105 4×105 4×105
Typique
*
Median contour surface
Median contour surface
Median contour surface
Median contour surface
4-5 ans
*** ***
3×105 3×105 3×105 3×105
*** ***
2×105 *** 2×105 *** 2×105 2×105
*** ***
1×105 1×105 1×105 1×105
0 0 0 0
2 y.o. 3 y.o. 4-5 y.o. 2 y.o. 3 y.o. 4-5 y.o.
1
2
SD1
3
1
2
R 1
3
2
3
M
M
SD
SD
AD
SD
M
M
N RM
M
R
S
R
R
R
O
O
A
A
A
A
O
O
O
O
N
n=45 avec autisme & 47 développement
4×105
typique* 4×105 4×105
N
N
N
N
η2 = 0.15 η2 = 0.43 η2 = 0.48
surface
surface
tour surface ***
4×105 4×10 *** 5 4×105 η2 =***
0.43 η2 = 0.48
* η2 = 0.15
3×105 3×105 3×105
surface
surface
surface
***
4×105 *** Kojovic et al., in prep 4×105 ***
*
4×105 η2 = 0.15
*** η2 =***
0.43 η2 = 0.48
tour
tour
3×105 3×105 3×105
rface
rface
rface
*** ***
2×105 2×105 *** 2×105 *** ***Trajectoires atypiques de développement cérébral:
le “cerveau social” entre 2 et 4 ans
‣ Entre l’âge de 2 ans et de 4 ans, les enfants avec un TSA ont
des trajectoires atypiques de développement du plissement
cortical dans les régions qui traitent l’information sociale
Libero, Schaer et al., Cerebral Cortex 2018Figure S1
Le “cerveau social” entre 6 et 18 ans
Supratentorial Total gray matter
Supratentorial * Total grayVolume
matter de matièreTotal
grisewhite matter
‣ Si on mesure la structure
1150 p=0.885
1150
* 760 p=0.530 800 *
500 p=0.139
f =**
cérébrale, il y a peu de f = 0.005 f = 0.021 0.049
Volume (cm3)
Volume (cm3)
Volume (cm3)
Volume (cm3)
Volume (cm3)
1100 740 750 480
1100
différences consistantes 720 700 5 460
Figure
qui émergent malgré 1050
de 1050
700 650 440
nombreuses études 1000 1000 680 600 420
6 to 12 12 to 18 18 to 30 30+ 6 to 12 12 to 18 18 to 30 30+
ls
D
ls
ls
D
D
tro
AS
tro
tro
AS
AS
on
on
on
Cortical Subcortical
C
C
C
600 * Correlation entre
68 l’élargissement cortical
‣ En analysant les IRM de Cortical Subcortical
580
etp=0.391
la sévérité des
* symptômes
Volume (cm3)
Volume (cm3)
66
près de 1'000 p=0.277 550
Volume (cm )
Volume (cm3)
3
f = 0.036 66 f = 0.028
64
participants collectés 560 Significance (FDRLe “cerveau social” à l’adolescence et l’âge adulte
A l’adolescence et à l’âge adulte, toutes les études d’IRM fonctionnelles reportent
des différences d’activation du “cerveau social” chez les personnes avec un TSA
2 | Brain 2012: Page 2 of 15 Cortex frontal et pariétal inférieur (“système des neurones en miroir”)
S. J. Gotts et al.
(comportement de perception d’action et d’imitation)
Cortex préfrontal médial
(mentalisation, autoanalyse)
Cortex temporal antérieur
(connaissances des règles et préceptes
sociaux)
Amygdale
(processus de l’émotion)
Downloaded from http://brain.o
Sulcus temporal supérieur
(processus de mouvement biologique et
direction du regard de l’autre)
gyrus fusiforme
(reconnaissance des visages)
Figure 1 Areas of the ‘social brain’. A set of brain regions are commonly co-activated across a range of social tasks: the medial and
Figure adaptée de Gotts et al, Brain, 2012
ventromedial prefrontal cortex, the posterior cingulate/precuneus, the amygdala and anterior hippocampus, the anterior temporal lobes,Résumé intermédiaire
‣ Même si une réduction de l’orientation sociale
émerge déjà pendant la 1e année de vie, c’est
surtout entre 2 et 4 ans que l’écart commence à
se creuser en termes de compréhension des
interactions sociales et de développement cérébral
‣ La période de 2 à 4 ans représente donc une
fenêtre d’opportunité pendant laquelle une
intervention ciblant le développement des
compétences sociales est primordialeDirections futures (I)
in the analyses. Peaks (P1, N170, and Nc) were
mean 2.6, SD 1.3; CI, mean 3.6, SD 2.0), MSEL Verbal
identified for each electrode using automatic peak
IQ (ESDM, mean 45.3, SD 17.5; CI, mean 48.1, SD 21.2),
detection software and verified by inspection (E.J.H.J.).
and MSEL Nonverbal IQ (ESDM, mean 83.6, SD 13.3;
Components were measured within the following time
CI, mean 79.2, SD 11.3; F1,27 o 2.5, p 4.13, for all
windows (from stimulus onset): P1 was 50 to 200 ms,
comparisons). Children with ASD who provided
artifact-free data at the outcome compared with those
who did not provide data at baseline had lower ADOS FIGURE 1 Electrodes in the anterior and posterior left
L’intervention précoce change-t-elle le cerveau?
Social scores (F1,46 ¼ 5.2, p ¼ .03) and higher MSEL and right hemisphere regions (gray) and anterior and
Verbal IQ (F1,46 ¼ 9.9, p ¼ .003) but did not differ in posterior central regions (black). Note: EAR, COM, and
ADOS Restricted and Repetitive Behaviors (F1,46 ¼ 1.9, REF are anatomically marked locations for EEG sensor net
p ¼ .2) or MSEL Nonverbal IQ (F1,46 ¼ 0.06, p ¼ .8). placement.
EEG Protocol and Measurements
The EEG was recorded while 140 unique color
photographs of female faces (70) and toys (70) were
DAWSON
presented in random order on a monitor. Facial images
et al.
‣ Peu d’études à ce jour ont were chosen to reflect the ethnic and racial diversity of
the surrounding area. Objects were common toys
containing no facial features. Images were approxi-
mesuré l’impact de
mately 12 cm wide by 15 cm high and shown against a
standard gray background (28 cm wide by 23 cm high).
The EEG data were recorded from 128-channel
FIGURE 4 Differences in patterns of brain activation in
geodesic sensor nets (recorded online with reference Spe
l’intervention précoce intensive
to the vertex) at 250 Hz, with amplification set at
children with typical development, Early Start Denver
1,000", and bandpass filtering at 0.1 and 100 Hz. Cur
Model (ESDM) intervention, and community intervention.
Children were presented with trials consisting of 500-
SD
ms baseline, 500-ms stimulus presentation, and 1,000-
sur le développement cérébral
Note: Dependent variables are log EEG spectral power
ms post-stimulus recording periods followed by a (ESD
during viewing of the faces minus objects. Positive y and
random intertrial interval (0 to 500 ms). Testing was
terminated when the child had attended to 100 trials or F1,26
negative a scores indicate greater brain activation during
was no longer attending. Trials were rejected if the child
was not attending to the picture (recorded online by an in th
viewing of people’s faces than of objects.
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY
SD
VOLUME 51 NUMBER 11 NOVEMBER 2012 www.jaacap.org 1153 p¼
CI,
‣ Une des premières études
high
Vine
montre qu’après 2 ans
15;
Soci
SD
d’intervention précoce ESDM, (ESD
F1,27
on observe une normalisation (ESD
F1,27
de la réponse cérébrale grou
beh
lorsque l’enfant regarde des Com
65.4
photos de visage p¼
Soci
mea
Dawson et al., JACAAP 2012 F1,25
ESDEffet de l’intervention comportementale
‣ Même chez des bébés à risque de
TSA, une intervention de type
guidance parentale (10 sessions)
permet déjà de modifier
durablement l’activation cérébrale
en réponse à des stimuli sociaux
Figure 3. Electroencephalography (EEG) social and non
screenshot from the stimuli (middle); and topography
months in the normative cross-sectional control group (
(top) and nonsocial (bottom) video. PFR 5 promoting fir
sectional; Long. 5 longitudinal.
Jones et al., Autism Res 2017Objectifs futurs pour notre projet de recherche
‣ Mesurer l’effet de l’intervention précoce sur:
l’évolution des enfants à long terme
les trajectoires de développement cérébral
*
‣ Identifier des sous-groupes d’enfants à l’intérieur du
spectre (a)
de l’autisme, en particulier:
(d)
facteurs prédicteurs d’évolution
facteurs prédicteurs de réponse à certains types de traitement
(b)
bioRxiv preprint first posted online Aug. 30, 2017; doi: http://dx.doi.org/10.1101/180703. The copyright holder for this preprint (which was not
peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
(e)
(c)Directions futures (II)
Explorer des hypothèses alternatives
‣ L’hypothèse de la motivation sociale n’explique pas tous les symptômes de TSA
Processus X ?
?
? Difficultés sensorielles
Réduction de
l’orientation sociale
Intérêts restreints et
comportements répétitifs
Déprivation en
expériences sociales
Diminution de
Réduction des opportunités pour
“l’apprentissage social”
un apprentissage cognitif adéquat
Déficit de spécialisation des régions
Développement incomplet du cérébrales concernées par le traitement
potentiel cognitif de l’information sociale
(résumée par Chevallier et al., TICS 2012)F2,294 5 2.40, p 5 .09; group 3 age2: F2,274 5 1.87, p 5 .16),
1 RORB PCP4 indicating that the increase in EA-CSF in the HR-ASD group
1 1
relative to non-ASD groups was consistent over the interval
1
Des3 altérations cérébrales
2 2
3
non spécifiques
2
studied
3
du cerveau social
(covariates included age, age2, TCV, sex, and site).
4 4 Direct
4 group comparisons and inspection of the model
5
5 5
parameter estimates indicated that, on average across the
‣ Il semble ywm avoir déjà pendant lathe
vieHR-ASD
in utero et had
la première
6 6 6
wm study
wm period, group 12.20 cm3 more EA-CSF
année de vie des modifications
than hors des
the HR-negative régions
group cérébrales
(β 5 12.20, SE 5 3.96, t397 5
1 1 1
2 2 2
3.08,3 p 5 .002) and 12.14 cm3 more EA-CSF than the LR-
qui traitent4 l’information sociale
3 3
4 negative
4 group (β 5 12.14, SE 5 4.10, t397 5 2.96, p 5 .003)
5
5 5 2
6 6
after6
controlling for age, age , TCV, sex, and site. There were
wm wm no wmdifferences between the HR-negative and LR-negative
Anomalies de migration neuronale Augmentation du volume du liquide céphalo-rachidien
e-Color Composite of Multiple Markers
A
Low-Risk Infant with Normal MRI; ASD-negative at 24M
5.6 mm
h Autism
11.0 mm
B
6M 12M 24M
Layer 2/3 B
iled View of Panel E Inset Layer 3/4/5 High-Risk Infant with Increased Extra-Axial CSF; Diagnosed with ASD at 24M
Layer 4/5
Layer
1 6/6b
2
3
4
5
5.8 mm 6
Layer 2/3 CALB1 wm 6M 12M 24M
Layer 3/4/5 RORB
Overlay
Layer 5 PCP4 Stoner et al., NEJM 2014 Shen et al., Bio Psych 2017
Layer 6/6b CTGFL’hypothèse d’un déficit de prédiction
‣ Nous comprenons le monde “I can’t emphasize enough how critical it is to understand that staying
on a script is the sole means of keeping anxiety at a minimum. Even
qui nous entoure en faisant the smallest breach becomes a crisis because all we register at that
moment is unpredictability. We fear unpredictability above all else
continuellement des because we are out of control of our environment.”
prédictions sur ce qui va Completing the linkage to ritualistic behavior, Dora Raymaker,
director of the Academic Autistic Spectrum Partnership in Re-
suivre search and Education, writes:
“The experience of many of us is not that ‘insistence on sameness’
jumps out unbidden and unwanted and makes our lives hard, but that
“insistence on sameness” is actually a way of adapting to a confusing
and chaotic environment. . .”
‣ L’expérience préalable sert The same argument applies to stimming, a term used to refer
de filtre qui facilite la to self-stimulating behaviors. The seemingly compulsive need to
stim and their oftentimes social inappropriateness raises the
prédiction
Fig. 1. (A) et évite
A simple la system
Markov surprise
comprising probabilistically
possibility that these behaviors might be elaborate involuntary
linked depiction of the PIA hypothesis. Relationships between two events can be characterized by their streng
Fig. 2. (A) A schematic
states. The domains that serve as diagnostic criteriaseparation
for autism (language
(Δt).
Sinha et al, PNAS 2014
motor ticks. However, parental reports indicate that stimming
In this space, the interface between undetectable and detectable relationships marks the ASF, denoted by the
processing, social interactions, and behavioral repertoire) can all posits
hypothesis be modeled behaviors are most evident in situations of heightened external
that autism is accompanied by a shift of the ASF toward the upper left (red arrows) corresponding to a reduct
as temporally evolving Markov systems. The computation relationshipsof that
transition stimulation
are weak and/or (27),
have large suggesting
temporal that
spans. This shiftstimming
renders some may be an relationships,
interevent anxiolytic which are evident to
probabilities is a key requirement for estimating a Markov
invisible system.
to those(B) The
with response
autism. tobands
The vertical a chaotic world:
indicate an attempt
that different to on
tasks rely drown out theofinflux
the detection interevent relationships ove
‣ Un déficit de capacités prédictive chez les personnes avec
task of transition probability estimation: from an observed temporal
instance, whereashistory of unpredictable
motor-control environmental
and language learning operate in the information by social
millisecond regime, self-generated
interactions and planning involve
of multiple state-to-state transitions, estimate P(BjA, conditional ofperiodic
Δt); themanifestations
Behavioral and, hence, more predictable information. Consider
PIA may differ depending on which temporal regimes experience the thisASF shifts. As depicted
greatest
TSA pourrait représenter une hypothèse intéressante pour different
probability of one state (“B”) given the other (“A”) and autism
temporal subtypes may arise in part from ASF shifts of different kinds.
duration, first-person account from Temple Grandin:
Δt, beyond A’s occurrence. The PIA hypothesis states that autism may be
expliquer divers symptômes
associated with inaccuracies in estimating this conditional probability and,
impairment causes
“When I did stims such as dribbling sand through my fingers, it
environmental
hence, in one’s ability to discern predictive relationships between entities. calmedstimuli to appear
me down. When Imore chaotic,
stimmed, sounds that Given
hurt mytheears
prediction-reliant
stopped. nature of
leading to reduced habituation Mostand hence
kids with greater these repetitive actions
stress.
autism do behaviorswith dynamic
because objects, the PIA h
it feels
good in some way. It may counteract an plausible accountsensory
overwhelming of the difficulties that
its predictions regarding other traits one3. might expect
Difficulties to
in Interacting environment.
with Dynamic. .” Objects. The dynamic tism encounter in such settings.
find in ASD (Section 3), and open questionsworld
and presents challenges to those with autism. The Autism
implications
‣ La difficulté à prévenir les suites d’évènements s’apparente
(Section 4). Wandering and Elopement Initiative
Temple Grandin, Autism Asperger’s Digest, 2011
collaboration states that 4. Difficulties with Theory of Mind. Theory
two in three “elopers” (autistic children who attempt to run ability toofascribe invisible causes to observ
à vivre dans un monde gouverné par la magie, où les To summarize, a parsimonious interpretation the reliance
NEUROSCIENCE
2. The PIA Hypothesis as a Partial Account away)
of thehave a close call on
Autism withrituals
a traffic
andinjury (39).behaviors
stimming Accordingobserved
to by in
connecting
autism ispast
that history
they with current beh
relations entre les évènements sont obscures et qui peut
Phenotype the Center for Advanced
Rutgers
Infrastructure
emerge from, and and represent
Transportation at to
attempts a person actedthe
minimize,
likely
a certain
con- way, or anticipa
to act, requires the estimation of a co
Besides the aforementioned diagnostic domains, theUniversity,
hypothesisthe vast majority
sequences of(more than 75%) They
unpredictability. of people
allow for a proactive imposition
devenir anxiogène. on the autism spectrum
of impaired prediction can potentially account for a few other
cannot drive
of “sameness” on (40). In first-person
an otherwise
accounts, individuals with autism describe the difficulties they
overwhelmingGiven a certain observation about a per
environment.
stances, what are the likely precursors leadi
significant correlates of autism. had as children engaging2. in dynamic
Sensory It is estimateda that
games on the playground
Hypersensitivities. similar vein,90%
nearly whatofareallthe next stages in thL’hypothèse d’un déficit de prédiction
Ritualisation
Un moyen de faire face à l’anxiété générée
par l’imprévisibilité
Surcharge sensorielle
Par manque d’habituation
Altérations des Déficit de théorie de l’esprit
capacités Les interactions sociales sont complexes, et donc
prédictives particulièrement vulnérable à un déficit de
capacités prédictives
Difficultés à généraliser
Généraliser requière de s’appuyer sur les prédictions
et associations, plutôt que sur les informations
sensorielles uniquement
Compétences isolées
Dans des domaines qui sont le plus souvent
statiques (mathématiques, recherche visuelle, dessin)
et fortement basés sur des règlesUn effort conjugué entre clinique, intervention & recherche:
www.pole-autisme.ch
Aurélie Irène
Sara François
Nada Marie
Holger
Sondes Sonia
Lylia
Les équipes du CIPA dirigées par Hilary Wood: La Fondation Pôle Autisme dirigée par Stephan Eliez
Astrid Costes Mylène Richard Collaborations internationales:
Evelyne Antonietti Celine Muffat Christine Nordahl (UC Davis)
Patrizia Castellano & many others Vinod Menon (Stanford)
L’équipe de la Boussole dirigée par Martina Franchini
National Center of Competence in ResearchMerci pour votre attention!
Contact: marie.schaer@unige.ch
ou projet-autisme@unige.ch
Crédits photo: www.vincentcalmel.chVous pouvez aussi lire
