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!