Interaction between Pain and Fear: A functional MRI study A ...

Interaction between Pain and Fear: A functional MRI study A ...

Connectivity of a subgenual cingulate target for
treatment-resistant depression
Johansen-Berg H1, Behrens TEJ1, Matthews PM1, Katz E2, Metwalli N2, Lozano A3,
Mayberg H2
1
Centre for Functional MRI of the Brain, University of Oxford, UK; 2Emory
3
University School of Medicine, Atlanta, GA, USA; Toronto Western Hospital,
Division of Neurosurgery, Toronto, Ontario, Canada

Introduction

Results:
connectivity

Chronic deep-brain
stimulation (DBS) of
subgenual cingulate (BA25)
results in dramatic
remission of symptoms in
some previously treatmentresistant patients [1]
Effects of stimulation
may be mediated via
cortico-cortical
connections [2]

Distribution
regions.

From Mayberg et al, Neuron, 2004

Here, we use tractography to define the likely
connectivity of this region using diffusion data
acquired in healthy control subjects.

Characterising

subgenual

of connections
to pre-specified
target
Figure
4: Left: Distribution
of connections from
the
subgenual region to target areas. Group average results
showing probability of connection from subgenual seed
voxels to each target regions. Colour scale indicates
probability of connection from low (red, 50/5000 paths
reach target) to high (yellow, 500/5000)
Figure 5:
Above: Subgenual voxels colour coded
according to the target region with highest probability
of connection: red=DCG; yellow=VMF; blue=NAC; green=OFC.
(Note that this representation shows only the most
probable connections. There is a high degree of overlap
in connections to all eight target regions tested - see
Fig 4).

Blind Parcellation
detecting changes
clusters

of
in

subgenual cingulate based on
connectivity identifies two

Methods
Diffusion MR data: We acquired diffusion weighted images
(1.5T, max gradient strength 40mTm-1, 2x2x2mm voxels, 60
directions, b=1000smm-2) in 17 healthy subjects.
Locating electrode sites: We used routinely acquired
post-operative MR scans to locate electrodes in 13
patients (9 responders, 4 non-responders) treated with
DBS for depression [1]. Locations of contacts used for
stimulation were projected onto a standard brain with
reference to local landmarks by an experimenter blind to
clinical outcome.

Figure 1: Localising electrodes.
Left: example patient own scan with
location
of
stimulated
contact
indicated by cross hairs. Right:
Location on standard brain

Figure
6:
Reordered crosscorrelation
matrices for 16
healthy subjects.

Results:
locations

Figure
2:
Distribution
of
electrodes on standard brain.
Red=responders;
blue=nonresponders

Probabilistic tractography: Diffusion images were
processed using FDT [3,4]
(http://www.fmrib.ox.ac.uk/fsl). Using a multi-fibre
diffusion model [5], we generated probabilistic
connectivity distributions from the whole subgenual
cingulate and from individual masks of stimulated
electrode contacts.
To characterise the connectivity of the whole subgenual
region we first found the distribution of connections to
regions of interest chosen on the basis of changes in
PET activation following subgenual DBS [1].
Figure 3: Target ROIs. Pink=amygdala (Amy); Blue=Hypothalamus (Hth);
Green=Nucleus Accumbens (NA); Orange=Peri-acqueductal grey (PAG); Light
blue=dorsal
medial
frontal
(DMF);
Red=orbitofrontal
(OFC);
Yellow=ventral medial frontal (VMF); Brown=dorsal cingulate (DCG);
Black=subgenual seed mask.

a)

c)

d)

e)

Second,
we used blind connectivity-based parcellation
b)
[6] to detect whether we can define boundaries within
Figure
4:
Stepscortex
involved
in
blind
parcellation.
Probabilistic
the
cingulate
tractography is run from every voxel in a seed mask (a) and the
probability of connection to all other voxels in the brain (b) is
recorded in a connectivity matrix (c).
The cross-correlation matrix
(d) of the connectivity matrix is found and re-ordered (e) to bring
voxels with similar connection patterns close to each other. In this
way, clusters in the re-ordered matrix represent regions with distinct

Discussion

Figure
7:
Each
matrix was manually
divided
into
two
clusters, which are
mapped back onto the
brain

Connections

Figure
8:
Group
average
paths
from
posterior
cluster
(top,
blue)
and
anterior
cluster
(bottom, red)

from

electrode

Figure
9:
Location
of
electrodes
contact
points
(red=responders;
blue=non-responders) in relation to
population
probability
maps
of
anterior (red-yellow) and posterior
(blue-turquoise) clusters in subgenual
cingulate.
Figure
10:
Paths
from
effective
electrode contacts. Electrode contacts
are projected onto DTI data from
healthy
controls
and
pathways
generated. Paths consistently travel to
amygdala,
nucleus
accumbens,
hypothalamus, cingulum bundle, medial
frontal
cortex
and
orbitofrontal
cortex.
Paths
are
thresholded
to
include
those present
in of
>5/16
controls
Figure 11:
Quantitative
analysis
paths
from
each patient
forprobability
>2/8 patients.
effective for
electrodes.
The and
mean
of
connection to each target region is calculated
and normalised. Electrode locations in most
responders
generate
paths
to
all
target
regions. Connections to ventral medial frontal
cortex are variable and those to dorsal medial
frontal cortex are absent in two patients and
of low probability in others (see Figs 4 and
5).
Connections to PAG do not survive
thresholding.

The anterior and posterior portions of the subgenual
cingulate have distinct patterns of connectivity. Most
effective electrode locations were situtated in the
posterior cluster.
The effective action of DBS for depression may be
mediated via connections from both these regions to
hypothalamus, nucleus accumbens, amygdala, medial
prefrontal cortex, dorsal cingulate and orbitofrontal
cortex.
We cannot determine the relationship between response
to surgery and connectivity with such small patient
numbers, and by projecting contacts onto control DTI
data, but this preliminary result generates hypotheses
that could be further tested in larger follow-up studies.

Further
studies
should
demonstrate
whether
acquisition
Acknowledgements. Funded by the Wellcome Trust (HJB) and the UK MRC (HJB).
of
pre-operative
diffusion
data
aids
surgical
targeting
References: 1. Mayberg et al., Neuron (2005) 2.Katz et al., OHBM Meeting
(2005) 3.
by allowing
for individual
delineation
of Med
the
subgenual
Smith
et al., NeuroImage
(2004) 4. Behrens
et al., Magn Reson
(2003)
5. Behrens et
al., submitted. 6. Johansen-Berg et al., Proc.Natl.Acad.Sci.U.S.A (2004).
region with the effective connectivity fingerprint .

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