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Where macroscopy fails: going to microscopic architecture
Nicola Palomero-Gallagher
Institute of Neuroscience and Medicine (INM-1)
Research Centre Jülich
and
Department of Psychiatry, Psychotherapy and Psychosomatics
Medical Faculty, RWTH Aachen
Does macroscopy fail to provide the anatomical
ground truth of borders of cortical areas?
• No: E.g., delineation of higher visual areas on the fusiform
gyrus and prediction of cytoarchitecture by cortical folding
patterns
• Yes: E.g., cortical folding patterns are highly variable at
many sites and areal boundaries vary considerably in
relation to macroanatomical landmarks
Delineation of higher visual
areas on the fusiform gyrus
Prediction of cytoarchitecture
by cortical folding patterns
Weiner et al. (2014) The mid-fusiform sulcus: A landmark identifying both cytoarchitectonic and functional divisions of the human fusiform gyrus. Neuroimage 84: 453-465 Weiner et al. (2016) The cytoarchitecture of domain-specific regions in human high-level visual cortex. Cerebral Cortex, doi: 10.1093/cercor/bhw361
FG1
FG2
FG2 FG1
MFS MFS
Fischl B., Rajendran, N., Busa, E., Augustinack, J., Hinds, O., Mohlberg, H., Amunts, K., Zilles, K. (2008) Cortical folding patterns and predicting cytoarchitecture. Cerebral Cortex 18: 1973-1980 Hinds et al. (2009) Locating the functional and anatomical boundaries of human primary visual cortex. NeuroImage 46: 915-922
Ave
rage
dis
tan
ce (m
m)
bet
wee
n b
ou
nd
arie
s
V1 44 45 6 V2 2 4p 4a
Predictability of cytoarchitectonic borders
Agreement between cytoarchitectonically and landmark-based localization of boundaries of V1
Agreement between functionally and landmark-based localization of boundaries of V1
Distance (mm)
Co
rtic
al s
urf
ace
vert
ex c
ou
nt
Co
rtic
al s
urf
ace
vert
ex c
ou
nt
Lack of macroanatomical
landmarks
Cytoarchitectonic boundaries
vary independently from sulcal
patterns
R
L
Amunts, K., Schleicher, A., Bürgel, U., Mohlberg, H., Uylings, H.B.M., Zilles, K. (1999) Broca’s region revisited: Cytoarchitecture and intersubject variability. J. Comp. Neurol. 412: 319-341
33
25a
25p
orbito-frontal cortex
Palomero-Gallagher, N., Mohlberg, H., Zilles, K., Vogt, B. (2008) Cytology and receptor architecture of human anterior cingulate cortex. J. Comp. Neurol. 508: 906-926
• Boundaries of the primary visual cortex V1
• Boundaries of the primary motor cortex area 4
• Boundaries of the primary somatosensory cortex area 3a
• Boundaries of the primary somatosensory cortex area 3b
• Boundaries of the primary somatosensory cortex area 1
Further examples for the lack of landmarks
V1
V2
6
calcs
?
?
ips p-os
p-os ips
lins
p-os
2 cm
Meynert cells in layer IIIc
V1
V2
I II
II
IIIab
IIIc
IV
V
VIa VIb
III
IVa
IVb
IVca IVcb
V
VIa VIb
I
cs
3b
1
4
Betz giant cells
4
cs
7
3a
3b
4
cs
prcg
posg
Microscopical segregation
8
I
II
III
IVa
IVb
IVca
IVcb
V
VIa
VIb
I
II
IIIa
IIIb
IIIc
Va
Vb
VIa
VIb
Primary visual cortex V1 Primary motor cortex area 4
9
The cytoarchitectonic map of Brodmann (1909)
Brodmann, K., 1909. Vergleichende Lokalisationslehre der Großhirnrinde in ihren Prinzipien dargestellt auf Grund des Zellbaues. Barth, Leipzig
Talairach J & Tournoux P (1988). Co-planar stereotaxic atlas of the human brain. Stuttgart, New York, Thieme
• Based on visual inspection of a single hemisphere
• Underestimates the number of cortical areas
• Contains areas which do not exist (e.g. BA19)
• Does not provide information on intersubject variability
• 2D schematic drawing
• Talairach & Tournoux do not provide borders between cortical areas
10
BA18 BA17
I
II
III
IV
V
VIa
VIb
I
II
III
IVa
V
VIa
VIb
IVb
IVc
Identification of cytoarchitectonic borders
Boundaries between hierarchically higher associative cortical areas are difficult to define by simple visual inspection
Bludau, S., Eickhoff, S.B., Mohlberg, H., Caspers, S., Laird, A.R., Fox, P.T., Schleicher, A., Zilles, K., Amunts, K. (2014) Cytoarchitecture, probability maps and functions of the human frontal pole. Neuroimage 93: 260-275
Are more areas better than less? Discrepancies between
published maps of the anterior cingulate cortex
Sarkissov et al. (1955) Vogt et al. (1995)
17 areas 11 areas
von Economo & Koskinas (1925) Vogt & Vogt (1919)
23 areas 12 areas
Strasburger (1937)
24 areas
Brodmann (1910)
4 areas
What are the criteria for cytoarchitectonic mapping?
13 Brodmann (1914). Physiologie des Gehirns. In: von Bruns (ed.) Neue Deutsche Chirurgie. Stutgart, Verlag von Ferdinand Enke. pp 85-426
II. outer granular
IV. inner granular
III. outer pyramidal
V. inner pyramidal
VI. polymorphic
I. molecular
sup
ragr
anu
lar
infr
agra
nu
lar
IIIb
Va
VIa
VIb
IIIa
IIIc
Vb
• Laminar distribution of the packing density of neuronal cell bodies
• Absolute thickness of cortical layers
• Proportionate thickness of a layer relative to the other layers and to the total cortical depth
• Presence of clearly recognizable laminar borders and vertical columns
• Distribution of cell bodies throughout the layers: homogeneous or clustered
• Presence of special cell types such as Betz cells
IV
II
I
Quantification of cytoarchitectonic characteristics
GLI (Grey Level Index)
0% GLI 100%
Schleicher, Zilles, Kretschmann (1978) Verhandlungen der Anatomischen Gesellschaft 72,S: 413-415
Schleicher, Zilles, Wree (1986) Journal of Neuroscience Methods 18: 221-235
Schleicher & Zilles (1990) Journal of Microscopy 157: 367–381
volume fraction of cell bodies in total brain volume
14
Statististical testing of cytoarchitectonic borders
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0D
2
Profil #
* * *
*
Zilles, Schleicher, Palomero-Gallagher, Amunts (2002) In: Brain Mapping: The Methods, Elsevier, pp. 573-602.
Palomero-Gallagher, Mohlberg, Zilles, Vogt (2008) Journal of Comparative Neurology 508: 906-926.
a
b
0
5
10
15
20
25
GLI
(%
)
Cortical depth 0
5
10
15
20
25
GLI
(%
)
Cortical depth
a b
Mahalanobis distance (D2) = 3.8721
28
101
191
221 s32
s24b
s24a
33
15
Rostral
Caudal
16
Observer-independent and statistically
testable mapping of the anterior
cingulate cortex 33
25a
25p
s24a
s24b
s32
p24a
p24b
pv24c
pd24cd
pd24cv
p32
32‘
a24‘a
a24‘b
24‘cv
24‘cd
p24‘a
p24‘b
24‘dv
24‘dd
Palomero-Gallagher, Mohlberg, Zilles, Vogt (2008) J Comp Neurol 508: 906-926.
Palomero-Gallagher & Zilles (2009) In: Cingulate Neurobiology & Disease.
Oxford University Press, pp. 31-63.
Palomero-Gallagher, Hoffstaedter, Mohlberg, Eickhoff, Amunts, Zilles (in
preparation)
pd24cv
pd24cd
p32
25 s32
pv24c s24b
p24b
32‘
a24b‘
24c‘v
24c‘d
pACC
sACC
aMCC pMCC
a24a‘
p24a
s24a
33 p24a‘ p24b‘
24dv
24dd
Palomero-Gallagher, Mohlberg, Zilles, Vogt (2008) J Comp Neurol 508: 906-926.
Palomero-Gallagher & Zilles (2009) In: Cingulate Neurobiology & Disease. Oxford University Press, pp. 31-63.
The revised map of the anterior cingulate cortex
17
…
N=1
N=2
N=10
0% 100%
Interindividual variability in location and size
Area 32‘
18 Palomero-Gallagher, et al. (in preparation)
Maximum probabilistic maps
pd24c
pv24c
p32
25
s32 s24b
p24ab
32‘
24c‘v 24c‘d
a24ab‘
s24a
33
p24ab‘
24dv 24dd
19 Palomero-Gallagher, et al. (in preparation)
Tasks
e.g.:
Attention
Imagination of movements
Names
Reward task
Semantic discrimination
Wisconsin Test
etc.
Functional domains
e.g.:
Attention
Empathy
Sadness, fear, anger
Language
Episodic memory
Autonomic control
etc.
Functional characterization of ACC areas by means of a meta-
analysis of published data based on fMRI and own
multimodal data
Database:
• 25: Autonomic control
pACC: positive emotions
p32
25 s32
p24
pACC
sACC
s24
Functional characterization of ACC areas
Palomero-Gallagher, Eickhoff, Hoffstaedter, Schleicher, Mohlberg, Vogt, Amunts, Zilles (2015). NeuroImage 115: 177-190
Episodic memory
• s24: Sadness
Episodic memory
emotion induction
• p32: Sadness, fear, anxiety
• s32: Fear
Reward tasks
Empathy
Reward tasks
• p24: Conflict monitoring
Gustatory evaluation
sACC: negative emotions, autonomic
control
22
Maximum probability maps and fMRI
moving dots
stationary dots
V5 Wilms et al., Anat & Embryol, 2005 and NeuroImage, 2010
Summary
• Macroscopical landmarks are useful in certain brain regions, but not in all
• Cytoarchitecture provides anatomical ground truth
• Observer independent mapping is required to decide on reproducible areal boundaries and the true number of cytoarchitectonic areas
• Cytoarchitectonic probability maps are a useful anatomical basis for the analysis of neuroimaging data
Thanks to:
Institute of Neuroscience and Medicine, Research Centre Jülich Katrin Amunts Sebastian Bludau Julian Caspers Simon Eickhoff Felix Hoffstaedter Aleksandar Malikovic Hartmut Mohlberg Axel Schleicher Marcus Wilms Karl Zilles
Boston University Brent Vogt
Martinos Center for Biomedical Imaging Harvard Medical School Bruce Fischl
Stanford University Kalanit Grill-Spector Kevin Weiner
Thank you for your attention!