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Wat is paniek?
U M Angst, vrees, paniek en het Brein Over mensen en muizen Dr K.R.J. Schruers Psychiater, Hoofddocent School for Mental Health and Neuroscience Universiteit Maastricht Gasthoogleraar KU Leuven 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 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 Panic Disorder Panic Attacks: • Sudden fear or discomfort • Bodily symptoms • Sudden onset, peak in 10’ + Anticipatory Anxiety + Avoidance Behaviour Paniekaanval Intense fear or discomfort + 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. palpitations sweating trembling breathlessness choking chest discomfort nausea or abdominal distress feeling dizzy or faint derealization or depersonalization fear of losing control or going crazy fear of dying paresthesias chills PANIC Paniekstoornis 1 out of any 5: PA 1 out of any 25: PD PANIC Experimentele paniek: 35% CO2 100 % 90 80 70 60 50 40 30 20 10 0 Symptoms Natural PA's Experimental PA's Schruers et al. 2003 Griez et al 2007 What does CO2 do in the brain ? CO2 + H2O H+ + HCO3 - ΔPH Δ PH 0.1 μM † Feinstein et al 2013 (University of Iowa) Richerson 2004, Nature Reviews Neuroscience Serotonine Enteramine 5-Hydroxytryptamine Courtesy Sjacko Sobczak 1-2% Courtesy Sjacko Sobczak Essentiële aminozuren • • • • • • Valine Iso-leucine Tyrosine Leucine Phenylalanine Tryptofaan Courtesy Sjacko Sobczak PHE LEU TRP TYR ISO VAL ACTIVE TRANSPORT MECHANISM BLOOD BRAIN BARRIER Courtesy Sjacko Sobczak hydroxylase L-tryptofaan decarboxylase 5-OH-tryptofaan Serotonine (5-HT) Courtesy Sjacko Sobczak Acetylase (pineal) Serotonin (5-HT) N-acetyl 5-HT 5-hydroxy indole acetic acid (5-HIAA) O-methyl transferase Melatonin Courtesy Sjacko Sobczak 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 Up to now - Patients - CO2 provocation - 5HT manipulations What is the core of the panic system (regulation)? Need for - Healthy people - [Natural PA’s] - Natural variation of 5HT function Leibold et al 2013 Effect of 5HTLPR on 5HT Transporter: s/s 5HTT 5-HT Effect of 5HTLPR on 5HT Transporter: l/l 5HTT 5-HT 7% CO2 Goossens et al 2013 How do changes in CO2/PH trigger a neuron? Acid Sensing Ion Channels Ziemann et al, Cell, 2010 Doe je mee met onze studie? Eerst sluiten we je op in een kooi, en dan…. Informed consent procedure Rodent Model for Panic Rodent Study: Procedure Behavior: Open field test Wallace, 2007 Rodent Model for Panic: Behavior Distance moved air Open field Aversion Assay CO2 Rodent Model for Panic 5HT knock out mouse is less afraid Rodent Study: Procedure Immunohistochemistry Amygdala Hippocampus Raphe nucleus Applications? • Investigate the fundamental mechanisms of panic/fear: e.g. the role of 5HT • Model for testing new drugs • Biological basis for psychological therapy: interoceptive exposure (e.g. with CO2) What does CO2 do in the brain ? H+ + HCO3 - CO2 + H2O ΔPH Δ PH 0.1 μM † Acid Sensing Ion Channels Harper et al. 2004, J. Neurophysiol.
