Angst, Vrees, Paniek en Serotonine

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 Discriminated Avoidance AMYGDALA Active Avoidance SEPTO- HIPPOCAMPAL S. Passive Avoidance MEDIAL HYPO- THALAMUS Directed Escape PERIAQUEDUCTAL GRAY Undirected Escape DEFENSIVE DISTANCE Gray & McNaughton 2000

Anticipatory Anxiety in PD Patients (PET) Boshuisen et al. 2002

Exploring fear Results Spider Phobics: spiders > neutral > Amygdala, Insula Anterior Cingulate L R P A

Exploring fear Results Spider Phobics: snakes > neutral > snake - neutral spider - neutral L R

Ekman 1976

Goossens et al. 2005

% 100 90 80 70 60 50 40 30 20 10 0 Symptoms Schruers et al. 2003 Natural PA's Experimental PA's

What does CO 2 do in the brain? CO 2 + H 2 O H + + HCO 3 ΔPH - Δ PH 0.1 μm

High Resolution MRI Mapping of Cerebrovascular Reactivity A Feasibility Study F.H.R. van der Zande 1, P.A.M. Hofman 1, H.G.J. Boere 2 and W.H. Backes 1 Depts. of Radiology 1 and Medical Instrumentation 2, University Hospital Maastricht, Maastricht, The Netherlands theme: vascular biology program: vascular imaging 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 1 alone is not sufficient to assess the cerebral 0.5 haemodynamic status. The initial 0 measurements have to be repeated after a -0.5 cerebrovascular vasodilatory stimulus, such -1 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 e to assess the cerebrovascular reserve capacity. b c d a h Materials & Methods f Fig. 1. Breathing circuit: (a) gas mixture inflow, (b) breathing bag, (c, d) valves, (e) mouthpiece, (f) peep valve, (g) rebreathing bag (7%CO 2, 93% O 2 ), (h) outflow. Healthy volunteers were studied with the following protocol. The subjects inspired an alternating gas mixture of 7% CO 2 with 93% O 2 and 100% O 2. To increase transition speed between the high and low pco 2 state, a special g 7% CO 2 100% O 2 100% 7% 7% CO 2 100% CO 2 O 2-50 0 50 100 150 200 250 O 2 0 Fig. 2. Paradigm, capnometry and MR signal 12 intensity. Top: paradigm of alternating high and min low pco 2. 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 pco 2 state. Three cycles of alternating high and low pco 2 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 mm 3, 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 pco 2 was recorded continuously. Data were post-processed using linear modeling with the end tidal pco 2 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 pco 2. The FMRIB-FSL implementation of this statistical algorithm was used [4]. Results 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 pco 2 state. All experiments produced adequate data. The curves of the end tidal pco 2 had comparable shapes in all subjects (Fig. 2), and the signal intensity of grey matter voxels correlated with the end-tidal pco 2. 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 pco 2 state is 15% with an average of 2.9%. a 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. b Discussion & Conclusions 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 References cerebrovascular reactivity. 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; 11:87-97.

U M amygdala Brainstem nuclei

Harper et al. 2004, J. Neurophysiol.

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 (Goddard et al. 94) fear 0 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 TRP 5-HT L-TRP 5-HTP Protein LNAA X 5-HT L-Tryptophan BBB Dietary tryptophan

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 TRP (+) TRP(--) Pre Post Delta

TRP depletion and 35%CO2 provoked panic in PD patients Panic Symptoms PSL 50 40 30 20 Pre Post Delta 10 0 TRP (+) TRP(--)

5-Hydroxy Tryptophan administration N NH2 CH2--C--COOH H 5-HT TRP HO N NH2 CH2--C--COOH H 5-HTP HO N CH2--C--NH2 H2 5-HT

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 PLAC 5-HTP Pre Post Delta

5-HTP administration and 35% CO2 induced panic in panic disorder patients Panic Symptoms PSL 50 40 30 20 Pre Post Delta 10 0 PLAC 5-HTP

Tianeptine or Paroxetine and 35% CO2 induced panic in panic disorder patients Tianeptine or (6w) + 35% CO2 challenge Paroxetine 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 + pituitary ACTH + adrenal glands Cortisol

Cortisol

Hypersensitive receptors? Cortisol

5-HT stimulates HPA Axis 5HT + - - CRH + pituitary ACTH + adrenal 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 14.30 15.00 15.30 5-HTP Placebo time

Cortisol Patients ng/dl 1300 700 100 13.30 14.30 15.00 15.30 5-HTP Placebo time

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