Changes in network architecture in temporal lobe epilepsies

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UCL INSTITUTE OF NEUROLOGY DCEE

Changes in network architecture in temporal lobe epilepsies

66^th Annual Meeting of the American Epilepsy Society Tuesday, 4^th of November 2012

helmut@laufs.com

Department of Neurology and Brain Imaging Centre

Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

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Special thanks to:

Enzo Tagliazucchi (BIC, Frankfurt)

Roman Rodionov (UCL, London)

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Outline:

1. background: example (connectivity) studies TLE 2. brief methodological excursion: graph analysis 3. Results

4. Implications

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Two main clinical features of temporal lobe epilepsies:

interictally: cognitive impairment (memory)

ictally: dyscognitive seizures with

reduced consciousness

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interictal epileptic discharge-correlated BOLD-fMRI

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Fp2-F8

F8-T8

T8-P8

P8-O2

Fp1-F7 F7-T7

T7-P7

P7-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Fp1-F3 F3-C3

C3-P3

P3-Ref

FC6-Ref CP6-Ref

FC5-CP5

T7 b T7 b T7 b

Scan Start Scan Start Scan Start

100 µV

interictal epileptic discharge-correlated BOLD-fMRI

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Fp2-F8

F8-T8

T8-P8

P8-O2

Fp1-F7 F7-T7

T7-P7

P7-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Fp1-F3 F3-C3

C3-P3

P3-Ref

FC5-CP5

T7 b T7 b T7 b

100 µV

interictal epileptic discharge-correlated BOLD-fMRI

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Fp2-F8

F8-T8

T8-P8

P8-O2

Fp1-F7 F7-T7

T7-P7

P7-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Fp1-F3 F3-C3

C3-P3

P3-Ref

FC5-CP5

T7 b T7 b T7 b

100 µV

spikes: l I l I

interictal epileptic discharge-correlated BOLD-fMRI

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Fp2-F8

F8-T8

T8-P8

P8-O2

Fp1-F7 F7-T7

T7-P7

P7-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Fp1-F3 F3-C3

C3-P3

P3-Ref

FC5-CP5

T7 b T7 b T7 b

100 µV

convolution with hrf

interictal epileptic discharge-correlated BOLD-fMRI

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Fp2-F8

F8-T8

T8-P8

P8-O2

Fp1-F7 F7-T7

T7-P7

P7-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Fp1-F3 F3-C3

C3-P3

P3-Ref

FC5-CP5

T7 b T7 b T7 b

100 µV

convolution with hrf

L L

interictal epileptic discharge-correlated BOLD-fMRI

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0 6

3

Z score left

left

coronal sagittal axial

BOLD signal increases to interictal epileptic discharges (slice planes [x,y,z]=[-26,-35,1]).

0 6

3

Z score

Laufs et al. 2007

group analysis of patients with (left) TLE

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group analysis of patients with (left) TLE

0 6

3

Z score left

left

coronal sagittal axial 0

6

3

Z score

BOLD signal decreases in response to interictal epileptic discharges. Laufs et al. 2007 BOLD signal increases to interictal epileptic discharges (slice planes [x,y,z]=[-26,-35,1]).

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sleep

general anaesthesia

tasks

vegetative state

Gusnard and Raichle 2001 Laureys et al. 2004

perception and action

rest

(default mode) states of reduced

consciousness

Laufs et al. 2007

TLE

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Fp2-FC2 FC2-CP2 CP2-O2 Fp1-FC1 FC1-CP1 CP1-O1 F4-C4 C4-P4 P4-O2 F3-C3 C3-P3 P3-O1 F8-FC6 FC6-T8 T8-TP10 TP10-P8 F7-FC5 FC5-T7 T7-TP9 TP9-P7 Fz-Cz Cz-Pz Eog-Ref Ekg2-Ekg1

Scan Start Scan Start Scan Start Scan Start Scan Start

reduced activity in DMN

Laufs, Lengler et al. 2006 Hamandi et al. 2006 Gotman et al. 2005

…

increased activity in thalamus

fMRI correlates of generalised spike-wave activity

absence seizures: another example of impaired consciousness

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sleep

general anaesthesia

tasks

vegetative state

Gusnard and Raichle 2001 Laureys et al. 2004

perception and action

rest

(default mode) states of reduced

consciousness

Laufs et al. 2006, 2007

3/s GSW

TLE

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• networks are affected beyond the epileptogenic zone

• fMRI suitable to detect such networks

• we know pathology persists interictally

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• fMRI suitable to detect such networks

=> study networks with fMRI at rest (e.g. seed correlation)

Hum Brain Mapping 2012

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• fMRI suitable to detect activity changes in networks

=> link functional connectivity to (memory) function

Hum Brain Mapping 2012

*

* Calif. Verbal Learning Test

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from seed correlation to full brain

connectomics

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Functional brain network analysis

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Functional brain network analysis

pair-wise correlations

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Functional brain network analysis

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Functional brain network analysis

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Bringing functional connectivity to life

LS BD

JD

MK

RR AM

MW

VB

ET

A

HL AM

KJ

A graph is a group of nodes

(people, colleagues, actors, brain regions etc.) and a group of edges

representing relationships (love, hate, co-authorships, movie co- starrings, functional connectivity etc.)

Integrated (but segregated) social groups

Increased integration destroys the identitiy of

segregated modules

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Extracting functional modules by modularity (Q) optimization

Bringing functional connectivity to life

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Extracting functional modules by modularity (Q) optimization

Bringing functional connectivity to life

modularity ~ extent of segregation <-> integration

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centrality measure: node degree Bringing functional connectivity to life

node degree = number of ties a node has

“risk of a node for catching whatever is flowing through the network”

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data:

controls = 20 left TLE = 7 right TLE = 14

20 minutes resting state eyes closed

TR = 3 s

400 volumes

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modularity: TLE vs. controls

Link density = number of [possible] links between nodes

(the more links, the less reliable, i.e. small correlation value as threshold)

healthy controls TLE patients

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overall higher segregation in TLE

healthy controls TLE patients

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Tagliazucchi et al. 2012

higher segregation (modularity)

also in sleep vs. wakefulness

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node degree = number of ties a node has

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node degree = number of ties a node has

TLE < controls TLE > controls

fewer ties in TLE than in controls

more ties in TLE than in controls

R R

R

L R

R

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node degree = number of ties a node has

or: “potential of a node to influence what is going on in the network”

TLE < controls amygdala

TLE > controls posterior cingulate

fewer ties in TLE than in controls

more ties in TLE than in controls

R R

R

L R

R

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node degree = number of ties a node has

or: “potential of a node to influence what is going on in the network”

amygdala

=

modulation of memory encoding

R R

R

L R

R post. cingulate

=

awareness, episodic memory retrieval, DMN

TLE < controls amygdala

TLE > controls posterior cingulate

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Where might extra links

to posterior cingulate come from?

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Functional connectivity with seed in

“area tempestas”...

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Functional connectivity with seed in

“area tempestas”...

...in

^right

TLE patients reveals higher functional

connectivity to DMN regions than in controls.

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What is “area tempestas”?

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Clusters around the peak voxels for spike-correlated EEG-fMRI group analysis (yellow) and correlation between flumazenil binding and seizure frequency (blue) are superimposed on a T1 template. ce capsula externa; ci capsula interna; Cl claustrum; CN caudate nucleus; fPC frontal piriform cortex; GP globus pallidus; IC insular cortex; oc optic chiasm; Pu putamen; tPC temporal piriform cortex.

Laufs, Richardson et al. 2011

Group analysis of patients with focal epilepsies (non-TLE + TLE)

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Can we link back to the EEG?

(interictal epileptic discharges)

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correlation of node degree with # of IED (left TLE only)

right superior temporal gyrus (uncorrected) R L

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correlation of modularity with # of IED

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...are IED responsible after all?

-> BOLD surrogate of “aberrant neuronal activity ”

-> assuming IED cause high BOLD amplitude changes

-> look at BOLD signal variance

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BOLD signal variance

surrogate of aberrant neuronal activity

BOLD signal variance in TLE > controls (p<0.001 uncorrected)

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BOLD signal variance

Correlation of BOLD variance with # of IED

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BOLD signal variance

Correlation of BOLD variance with # of IED

No correlation with scalp IED!

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Conclusion

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Conclusion

• decreased integration (Q) in TLE

–> global network dysfunction?

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Conclusion

–> global network dysfunction?

• amygdala with fewer links (degree)

-> dysfunctional memory encoding

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Conclusion

• amygdala with fewer links (degree)

-> dysfunctional memory encoding

• posterior cingulate with more links (degree)

-> increased susceptibility for “shut down” (DMN)?

-> connections from crucial hubs like “area tempestas”

-> compensatory “over connection” (memory retrieval)?

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Conclusion

-> increased susceptibility for “shut down” (DMN)?

-> connections from crucial hubs like “area tempestas”

-> compensatory “over connection” (memory retrieval)?

• the more IED the fewer links in [contralateral] STG

-> IED “causal”? Why contralateral? Work to do!

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Conclusion

-> IED “causal”? Why contralateral? Work to do!

• trend for higher segregation (Q) with more IED -> IED “causal”:

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Conclusion

-> IED “causal”? Why contralateral? Work to do!

• trend for higher segregation (Q) with more IED -> IED “causal”:

• increased variance in TLE, no scalp IED-correlation -> spiking in TLE cause for segregation?

-> spiking not visible on scalp EEG but reflected in BOLD signal

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Thank you: Sandra Anti Florian Beißner

Sergey Borisov Ralf Deichmann Kolja Jahnke

Christine Preibisch Helmuth Steinmetz Annette Schavan Steffen Volz

Frederic von Wegner Andreas Kleinschmidt Karsten Krakow

David Carmichael John Duncan

Afraim Salek-Haddadi Khalid Hamandi

Louis Lemieux Roman Rodionov Rachel Thornton

Phil Boulby Matthias Koepp Mark Richardson Mark Symms NSE...

Matthew Walker Shelagh Smith

Ingmar Gutberlet Torben Lund Karl Friston FIL...

Bundesministerium für Bildung

und Forschung

LA 1452/3-1

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