Wat is paniek?

U
M
Angst, Vrees, Paniek en
Serotonine
5HT, Gedrag en Functionele
Neuroanatomie
Dr. K.R.J. Schruers
Universiteit Maastricht
Academisch Angst Centrum
THE HIERARCHICAL DEFENSE SYSTEM
DEFENSIVE AVOIDANCE
DEFENSIVE APPROACH
ANTERIOR
CINGULATE
Discriminated
Avoidance
POSTERIOR
CINGULATE
AMYGDALA
Active
Avoidance
Passive
SEPTOHIPPOCAMPAL S. Avoidance
MEDIAL HYPOTHALAMUS
Directed
Escape
PERIAQUEDUCTAL Undirected
Escape
GRAY
Discriminated
Avoidance
DEFENSIVE
DISTANCE
Gray & McNaughton 2000
Anticipatory Anxiety in PD Patients (PET)
Boshuisen et al. 2002
Exploring fear – Results
Spider Phobics:
spiders > neutral
>
Amygdala, Insula
L
R P
Anterior Cingulate
A
Exploring fear – Results
Spider Phobics:
snakes > neutral
>
snake - neutral
L
spider - neutral
R
Ekman 1976
Goossens et al. 2005
THE HIERARCHICAL DEFENSE SYSTEM
DEFENSIVE AVOIDANCE
DEFENSIVE APPROACH
ANTERIOR
CINGULATE
Discriminated
Avoidance
POSTERIOR
CINGULATE
AMYGDALA
Active
Avoidance
Passive
SEPTOHIPPOCAMPAL S. Avoidance
MEDIAL HYPOTHALAMUS
Directed
Escape
PERIAQUEDUCTAL Undirected
Escape
GRAY
Discriminated
Avoidance
DEFENSIVE
DISTANCE
Gray & McNaughton 2000
100
%
90
80
70
60
50
40
30
20
10
0
Symptoms
Natural PA's
Experimental PA's
Schruers et al. 2003
What does CO2 do in the brain ?
CO2 + H2O
H+ + HCO3 -

ΔPH
Δ PH  0.1 μM
†
High Resolution MRI Mapping of Cerebrovascular Reactivity
A Feasibility Study
theme: vascular biology
F.H.R. van der Zande1, P.A.M. Hofman1, H.G.J. Boere2 and W.H. Backes1
Depts. of Radiology1 and Medical Instrumentation2, University Hospital Maastricht, Maastricht, The Netherlands
7%
CO2
Introduction
Cerebrovascular diseases are among the
leading causes of death in the western world.
The presence of a reduced perfusion pressure
has long been suspected as a risk factor for
ischemic stroke [1,2]. This is reflected by a
reduced cerebrovascular reactivity and an
increased oxygen consumption rate, and is
known as “misery perfusion” [3]. The
measurement of cerebral flow parameters
alone is not sufficient to assess the cerebral
haemodynamic
status.
The
initial
measurements have to be repeated after a
cerebrovascular vasodilatory stimulus, such
as hypercapnia. Doppler ultrasound, the only
widely available technique, provides data
with poor spatial resolution, only blood
velocity in the middle cerebral artery is
measured. PET, Xenon-CT and SPECT are
less available and also have major
drawbacks. We therefore implemented a
functional MRI technique
to assess the
e
cerebrovascular reserve capacity.
100%
O2
7%
CO2
100%
O2
7%
CO2
Results
100%
O2
1
0.5
0
-0.5
-1
-50
b
d
c
a
h
f
g
Fig. 1. Breathing circuit: (a) gas mixture inflow,
(b) breathing bag, (c, d) valves, (e) mouthpiece,
(f) peep valve, (g) rebreathing bag (7%CO2, 93%
O2), (h) outflow.
Materials & Methods
Healthy volunteers were studied with the
following protocol. The subjects inspired an
alternating gas mixture of 7% CO2 with 93%
O2 and 100% O2. To increase transition speed
between the high and low pCO2 state, a
special
0
50
100
150
200
250
|
|
0Fig. 2. Paradigm, capnometry and MR signal 12
intensity. Top: paradigm of alternating high andmin
low pCO2. Middle: capnometric data of one
subject with fitted curve of end tidal values (range
31–46 mmHg).
Bottom: mean signal intensity of grey matter in
one subject.
breathing apparatus was designed (Fig. 1) to
force rebreathing during the high pCO2 state.
Three cycles of alternating high and low
pCO2 were applied. During this time the
subjects were scanned using a fast BOLD
sensitive EPI sequence (voxel dimensions:
3.5 x 3.5 x 3.5 mm3, temporal resolution: 3
s.), with a total scanning time of 12 minutes.
Motion was restricted by fixating the head in
the head-coil. End tidal pCO2 was recorded
continuously. Data were post-processed using
linear modeling with the end tidal pCO2 as an
explanatory variable. A good fit between the
model and the data means that the change in
signal intensity of the voxel was caused by
the changing pCO2. The FMRIB-FSL
implementation of this statistical algorithm
was used [4].
Discussion & Conclusions
Thirteen healthy volunteers were scanned (7
female, mean age 29 y., range 20-47 y.). All
subjects tolerated the experiment with
minimal discomfort, the only complaint being
an increased breathing resistance during the
high pCO2 state. All experiments produced
adequate data. The curves of the end tidal
pCO2 had comparable shapes in all subjects
(Fig. 2), and the signal intensity of grey
matter voxels correlated with the end-tidal
pCO2. Statistical analysis showed a high
correlation of most grey matter voxels with
the vasodilatory stimulus. The Z statisticsmap shows a symmetrical image, as expected
in healthy subjects (Fig. 3a). The maximum
change in signal intensity between the high
and low pCO2 state is 15% with an average
of 2.9%.
a
program: vascular imaging
b
Fig. 3. Brain maps of Z statistics (a) and
standard deviation (b). Mean values of 13
subjects show a symmetrical image of high Z
values in grey matter and a homogeneous
distribution of low standard deviation.
The brain map of the SD (mean values of all
subjects) shows low values in a homogeneous
distribution (Fig. 3b). Therefore asymmetries
in
patients
with
compromised
cerebrovascular reactivity are expected to be
detectable.
Hypercapnia induced vasodilation causes an
increase of oxygenated blood in brain voxels
that contain small blood vessels. These
voxels will show an increased signal intensity
in BOLD imaging, however, the precise
mechanism and relation between signal
intensity of BOLD sequences and
haemodynamic parameters have not yet been
established.
We conclude that high resolution MRI
mapping of cerebrovascular reactivity is
technically feasible. In healthy subjects we
found a symmetrical distribution of the
cerebrovascular reactivity of mainly the grey
matter. This is in agreement with other PET
data [5]. Patient data are needed to validate
the clinical application of this technique.
Further studies are needed to establish the
exact relation between BOLD signal intensity
and
cerebrovascular reactivity.
References
1. Barnett, Stroke 1997; 28:1857-70.
2. Klijn et al., Stroke 1997; 28:2084-93.
3. Derdeyn et al., Neurology 1999; 53:251-9.
4. Woolrich et al., Neuroimage. 2001;
4:1370-86.
5. Rostrup E et al, Neuroimage 2000; 11:8797.
U
M
amygdala
Brainstem nuclei
Harper et al. 2004, J. Neurophysiol.
Air hunger PET
Brannan, Stephen et al. (2001) Proc. Natl. Acad. Sci. USA 98, 2029-2034
Copyright ©2001 by the National Academy of Sciences
Richerson 2004, Nature Reviews Neuroscience
Deakin & Graeff : 5HT and Mechanisms of Defense
Graeff 2004, Neuroscience & Biobehav. Rev.
Treatment
studies
The role of 5HT in
panic
Challenge
studies
3 Types of Challenges
2 Serotonergic challenges:
• TRP depletion
• 5-HTP administration
1 Panic challenge: 35% CO2 challenge as experimental
model for panic
TRP depletion and panic
TRP depl. PD patients:
panic 0
fear 0
(Goddard et al. ‘94)
TRP depl. + yohimbine in normals: fear  (Goddard et al. ‘95)
+ CCK in normals
: fear  (Koszycki et al. ‘96)
+ 35% CO2 in normals : fear 0 (Klaassen et al. ‘99)
phys. symptoms 
Tryptophan (TRP) depletion
L-TRP
5-HT
LNAA
Protein
L-Tryptophan
5-HT
TRP
X
BBB
Dietary tryptophan
5-HTP
TRP depletion and 35%CO2 provoked panic
in PD patients
Fear Scores
VAS-F
100
90
80
70
60
50
40
30
20
10
0
Pre
Post
Delta
TRP (+)
TRP(--)
TRP depletion and 35%CO2 provoked panic
in PD patients
Panic Symptoms
PSL
50
40
30
Pre
Post
Delta
20
10
0
TRP (+)
TRP(--)
5-Hydroxy Tryptophan
administration
5-HT
NH2
CH2--C--COOH
H
TRP
NH2
CH2--C--COOH
H
5-HTP
CH2--C--NH2
H2
5-HT
N
HO
N
HO
N
5-HTP administration and 35% CO2 induced panic
in panic disorder patients
Fear Scores
VAS-F
100
90
80
70
60
50
40
30
20
10
0
Pre
Post
Delta
PLAC
5-HTP
5-HTP administration and 35% CO2 induced panic
in panic disorder patients
Panic Symptoms
PSL
50
40
30
Pre
Post
Delta
20
10
0
PLAC
5-HTP
Tianeptine or Paroxetine and 35% CO2 induced panic
in panic disorder patients
Tianeptine
or
(6w)
Paroxetine
+
35% CO2 challenge
• Fear (VAS-F)
• Panic symptoms (PSL)
Schruers et al. 2004
VAAS paroxetine
Fear
Paroxetine
100
80
60
40
20
0
day 0
day 42
pre CO2
post CO2
VAAS tianeptine
Fear Tianeptine
100
80
60
40
20
0
day0
day 42
pre CO2
post CO2
PSL paroxetine
Symptoms
Paroxetine
50
40
30
20
10
0
day0
day 42
pre CO2
post CO2
PSL tianeptine
Symptoms Tianeptine
50
40
30
20
10
0
day0
day 42
pre CO2
post CO2
Conclusions
1) Tianeptine does have some anti-panic effect
2) How much ?
Not from present study
3) Mechanism ? Probably not via 5-HT reuptake
Hypersensitive 5HT receptors in PD?
Test via HPA Axis
Stress +
CRH
-
+
p ituitary
-
ACTH
+
a drenal
glands
Cortisol
Cortisol 
Hypersensitive receptors ?
Cortisol   
5-HT stimulates HPA Axis
5HT
+
CRH
-
+
p ituitary
-
ACTH
+
a drenal
glands
Cortisol
Hypersensitive 5HT receptors in PD?
Test via HPA Axis
5-HT enhancing drug: L-5HTP

CRH production  (hypothalamus)

ACTH production  (pituitary)

Cortisol production  (adrenal)
Cortisol Normals
ng/dl 1300
700
100
13.30
5-HTP
Placebo
14.30
15.00
15.30
time
Cortisol Patients
ng/dl 1300
700
100
13.30
5-HTP
Placebo
14.30
15.00
15.30
time
THE HIERARCHICAL DEFENSE SYSTEM
DEFENSIVE AVOIDANCE
DEFENSIVE APPROACH
ANTERIOR
CINGULATE
Discriminated
Avoidance
POSTERIOR
CINGULATE
AMYGDALA
Active
Avoidance
Passive
SEPTOHIPPOCAMPAL S. Avoidance
MEDIAL HYPOTHALAMUS
Directed
Escape
PERIAQUEDUCTAL Undirected
Escape
GRAY
Discriminated
Avoidance
DEFENSIVE
DISTANCE
Gray & McNaughton 2000
Fig. 1. The virtual predator and prey paradigm
D. Mobbs et al., Science 317, 1079 -1083 (2007)
Published by AAAS
Fig. 2. Statistical parametric maps illustrating BOLD responses to the aversive cues and activation for
the AIpredator conditions collapsed across blocks
D. Mobbs et al., Science 317, 1079 -1083 (2007)
Published by AAAS
Fig. 3. fMRI results illustrating the imminence effect in the predator condition
D. Mobbs et al., Science 317, 1079 -1083 (2007)
Published by AAAS