A fast structural development A slow ... - crm.umontreal.ca
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G. DehaeneG. DehaeneG. DehaeneG. Dehaene----LambertzLambertzLambertzLambertzINSERM/CEA/CNRSINSERM/CEA/CNRSINSERM/CEA/CNRSINSERM/CEA/CNRS
Cognitive Cognitive Cognitive Cognitive NeuroImagingNeuroImagingNeuroImagingNeuroImaging UnitUnitUnitUnit
FranceFranceFranceFrance
A fast structural development
A slow functional development
of the human brain
Questions on connectivity and dynamics
from a developmental perspective
Humans
Chimpanzees
cm3 Brain growth
Humandevelopmentis slow and not comparable to that of other animals
1 5 10 16 years
Synaptic densityBirth Puberty
Acoustic radiations
Cortico-corticalAssociative fibers
from Yakovlev & Lecours, 1967
1 year
Myelogenesis
Visual Cortex
Optic radiations
Gogtay & al, 2004
Cortical thicknessdecreases with age
Humans
Chimpanzees
cm3
Brain growth
Human development is fast
1 5 10 16 years
22 wGA Term 3 months 6 months 1 year
3rd trimester of gestation 2 years31 wGA 2 years
Specific human capacities developduring this period
(verbal communication and social cognition, Metacognition ??)
27w 29w
31w
36w
Preterm newborns (27 – 36w)
Newborns at term and infants
30w 30w 30w 31w
32w 32w 33w
34w 34w 35w
40w 44w 48w
28w 30w
Sulcation development during the last trimester of pregnancy
The third trimester of gestation: Neuronal migration and Sulcation development
J. Dubois (Neurospin) and P. Hüppi (Hôpitaux de Geneve)
Dubois , et al, Cerebral Cortex 2008
The first neurons make the preplate.Then, the migrating neurons will
split the preplate in two: - the marginal zone (layer I)- the subplate (layer VII)
Inside-out placement of the migrating neurons
between the MZ and the SPguided by the Cajal-Retzius cells
(Reelin)in the marginal zone (Layer I)
Marin-Padilla, TINS, 1998
Organization of the Cortical Plate
11 weeks of gestation
Marginal zone
Cortical Plate
Subplate
All pyramidal neurons of the neocortex are anchored to layer I by their original connections and grow by elongating their apical dendrites
creating an horizontal and vertical network
Organization of the Cortical Plate
30 wGA
40 wGA Marin-Padilla, 1982, 1998
1) Progressive organization in 6 layers from the depth to the surface2) Functional connections are first established in the subplate
MZ Marginal zoneCP cortical plateSP SubplateIZ intermediate zone (zone de migration)VZ Ventricular zone
The 6 layers organization and the differentiation between cortical areas is visible after 31 weeks of
gestation
A particular circuitry
� 2 thalamo-cortical networks during the last weeks of gestation: - transient circuits within the subplate- permanent circuit in the cortical plate
� connections with layer 1 ??
� Interneurons are migrating tangentielly and arrive in their location after the pyramidal neurons are in place
CP
35-50mm 50-65mm 65-80mm 80-95mm 95-110mm 110-130mm20-35mm
150-175mm 175-200 mm
Adults (Guevara & al, Neuroimg 2012)
Connectomist, Duclapet Poupon, 2012
Atlas of cortical fibersin full-term newborns (J. Dubois & al, in preparation)
Resting stateNetworks
Doria et al, PNAS, 2010lateral visual
medialvisual
Auditory
Somato-sensory
motor
cerebellum
BrainstemThalami
Default Mode
Left DorsalVisualStream
Executive Control
Right DorsalVisualStream
29-32 SA 33-37 SA 39-43 SA
(n=17) (n=21) (n=24) (n=8)
Full-term
Cortical plate
Subplate
30 wGA
Dark staining of the thalamo-cortical fibers
28 wGA
40 wGA
35 wGA
400 to < 20μv
Resting stateNetworks
Doria et al, PNAS, 2010lateral visual
medialvisual
Auditory
Somato-sensory
motor
cerebellum
BrainstemThalami
Default Mode
Left DorsalVisualStream
Executive Control
Right DorsalVisualStream
29-32 SA 33-37 SA 39-43 SA
(n=17) (n=21) (n=24) (n=8)
Full-term
Cortical plate
Subplate
30 wGA
Dark staining of the thalamo-cortical fibers
•Activity in the subplate in relation with thalamicrelays•Layer I activity•Astrocytes, •Vascular factors related to metabolic demand due to brain construction•etc…
HbO signal: One frame every 110 ms
Standard:the same syllable
is repeated
(ba or ga)
Voice MismatchThe gender of the voice
changed from time to
time
Block design: 20 sec of stimulation followed by 40 s of silence
in 12 preterms at 31 wGA, 3 days after birth
Phoneme MismatchThe identity of the syllable
changed from time to time
(e.g. ba to ga)
NIRS: hemodynamic responses to syllables:
Mahmoudzadeh et al, PNAS, 2013
Permutation testsPcor< .05
ST vs PmmST vs Vmm
0.5
-1
-0.5
0
1
StandardVoice MismatchPhoneme Mismatch
Left Right
Standard
Voice Mismatch
Phoneme Mismatch
0.3
0.6
-0.3
0
CH1
0 2010
0.3
0.6
-0.3
0
CH12
0 2010
0.3
0.6
-0.3
0
CH18
0 2010
0.3
0.6
-0.3
0
CH7
0 2010
Mahmoudzadeh et al, PNAS, 2013
Responseto a change of phoneme
Responseto novelty
e.g. baf baf baf
Male voice
600 ms
t-test
340 ms
t-test: Deviant -Standard
Change of phoneme
gam
Change of voice
baf
L R
L R
L R
L R
ERP to syllables at 30.4 wGA
(19 preterms)
32-64 channels
� The classical resting networks are observed in fMRI from the
first neural connections
� Linguistic and non linguistic information are processed
differently suggesting functional segregation
BUT
the micro neural circuitry is different (layers organisation and
subplate connexions, long-distance and interhemispheric
connexions)
� What are
� the relation between hemodynamique and neural
activity?
� the relation between evoked and spontaneous activity
Post-mortem
Myelin stain
Flechsig, 1920
Full-term birth One month-old 4 month-old
32 sem 40 sem 1 mois 3 mois 6 mois
15 mois 2 ans 4 ans 6 ans
Arborisation dendritique dans le cortex moteur (LeRoy Conel1939-5
Post-term: Myelination of the tracts
Synaptogenesis and pruning
Maturation affects DTI indices:
Transverse diffusivity decreases and FA increases
Neil et al, NMR in Biomed 2002Dubois et al, NeuroImage 2006
McCulloch et al, 1999
Maturation decreases the latency of the visual P1
7 weeks
ERP to face recorded from an occipital electrode
N1
P1
14 weeks
γβα +⋅+⋅= ageindexspeed DTIvP 1
Dubois et al, J Neuroscience 2008
Correlation between anatomical
and functional development
P1
6 weeks
mean
17 weeks
10 weeks
LGN CortexFA
Front
Synaptic densityBirth Puberty
Acoustic radiations
Cortico-corticalAssociative fibers
from Yakovlev & Lecours, 1967
1 year
Myelogenesis
Visual Cortex
Optic radiations
Maturation is not homogeneous across the brain
Frontal Cortex
Auditory Cortex
Birth Puberty1 year 3 years
from Huttenlocher & Dabholkar, 1997
Maturation
+
Maturation index computed on each voxel of a T2 image in a 2-month-oldLeroy & al, J of NS, 2012
Although immature, all regions, notablyfrontal regions, are participating to infant
cognition
Dehaene-Lambertz & al, Brain and Language, 2010
Stranger
Mother
-0.4
-0.2
0
0.2
0.4 Amygdala
1 2 3 4 5 6 7 8-0.8
-0.4
0
0.4
0.8 Orbitofrontal
Prefrontal
Dorsolateral Prefrontal
% signal change % signal change
forward speech
backward speech
Dehaene-Lambertz et al, Science, 2002
AsleepAwake
Three-month-olds
Voices
Photo from Anne Guedes
But the infant brainis slowwwwwwwwww
A systematic organization of phase delays
in response to sentences
Mean phase of the
BOLD response
1 9 s5 73
x=-60
L
x=-44
L
x=-52
L
Dehaene-Lambertz, Dehaene et al. (2006). Functional segregation of cortical language areas by
sentence repetition. Hum Brain Mapp, 27(5), 360-371.
fMRI responses to a sentence are fastest around primary auditory cortex.
They become increasingly slower in STS, temporal pole and temporo-parietal junction,
and slowest in inferior frontal cortex.
also observed in 3-month-old infants
L R
0 7.2 14.4 sTime after sentence onset
Heschl gyrus
Posterior STG
Middle STSAnterior STS
Temporal pole
% s
igna
l cha
nge
0.2
0.2
0
0.2
0
0.2
Heschl gyrus
Posterior STG
Middle STSAnterior STS
Temporal pole
0
0
0
0.2
00.2
0
0.2
0
0.2
0
0.2
0 14.4 s5 10
Mean phase of the BOLD response
Dehaene-Lambertz & al, PNAS, 2006
3-month-old infants
Comparing the phases in infants and adultssame gradient but time-range larger in infants
z= 41z= 17z = 4z = -8
0 14.4 s105
L R L R L R L R
L R L R L R L R
Mean phase of BOLD response
Adults
Infants
16 33 50 66 83 1000
1
2
3
4
P3 amplitude Visibility report
16 33 50 66 83 1000
0.2
0.4
0.6
0.8
1
ERPs to thresholded
visualstimuli in
adultsDel Cul, Baillet & Dehaene, Plos Biology, 2007
� Two types of regions in adults
� Regions in line with the stimulus
� Regions supporting second-order processes (attention, memory,
consciousness)
Visibilityrating
Critical stimulus(17-300 ms)
Backward mask 1 (33 ms)
Backward mask 2(1500 ms minus
stimulus duration)
Forward mask(1500 ms)
or
Face trial Control trial
Repeat 12-14 cycles
Face
ControlP400
Late Slow Wave
µv
Kouider & al, Science, 2013
In infants: Response to masked faces
30 5-month-olds
29 12-month-olds
21 15-month-olds
300 ms
50 ms
100 ms
150 ms
200 ms
250 ms
33 ms
17 ms
12 - 15 months
µv
Time (sec)
Late Slow Wave
P400
N290
Early Posterior Negativity
12-15 month-olds
5 month-olds
Non-linear effect on the diff (Face-Control)
800-1000 ms
A) A simple rule: AAAI AAAI AAAI AAAA
4
-4
μv
Response to a rule violation (900-1200 ms)vs a P300 in adults
Violation - CorrectViolation Correct
Violation
Correct-2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2
0
10
20
30
40
Time (s)-2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2
0
10
20
Am
plitu
de (p
A.m
)
Time (s)
MMR LSW Basirat et al, submitted
150 ms 350 ms 1000 ms1890 ms
12 3 4
1 2 3 4Rd nb of barepetition
Ga
B) (very) Late response to a predicted deviant stimulus
babies with the same macro architecture and
similar functions
� But dynamics are different due to the
heterogenous maturation of the brain
� Relatively fast maturation of the sensory systems
� Slow (very slow) second order processes, which can be
3 or 4 times slower than in adults
� How these properties can explain
sucessful learning ?
� Synchronisation between
regions with different speed
� Stability of the coupling when
long delays
� Hierarchy between regions
� Etc..
Frequency of occurrence of activity patterns in V1 under Spontaneous activity (S, y axis) versus movie (M, x axis)
Young Ferret P29 Ad Ferret P129
Berkes et alScience 2011
EEG in infants ?
-Hensch, Neuron 2013: Opening of critical windowrelated to inhibition of the endogeneous activity
- Berkes et al, Science 2011: progressive adaptation of internal models to the statistics of natural stimuli at the neural level
� Relation between spontaneous and evoked activity ?
- Infant in the matrix ?
Some questions
to conclude
� Can analyses of the spontaneous activity give indications
about the micro-structural organization of the brain (e.g.
interneurons activity, layer I involvement, thalamic relays) ?
� Can we reconcile the differences between hemodynamic and
neural recordings, notably during preterm life?
� What computational properties to understand the world and
create cultural artefacts are given by this type of organization?
What does mean the relative fast maturation of low-level regions
and the slow maturation of high-level networks?
Are the slow responses crucial for infants’ cognition or just a by-
product of maturation?
Collaborators:
Jessica Dubois
François Leroy
Lucie Hertz-Pannier
Stanislas Dehaene
Jean François Mangin
NIRS (Amiens)
Fabrice Wallois
Madhi Mahmouzadeh
Funding agencies:
� INSERM-CNRS-CEA
� McDonnell Foundation
� Agence Nationale pour
la Recherche
� Fondation Motrice
� Fondation de France