Inflammation, aggression and personality

1. Inflammation, aggression and personality • Sara Bromander1,3,Rolf Anckarsäter2, Marianne Kristiansson3, Thomas Nilsson1 ,Kaj Blennow1, Henrik Zetterberg1, Henrik Anckarsäter1, Caroline Wass1,4 • 1 Institute of Neuroscience and Physiology, University of Gothenburg, Sweden, 2Dept of Anesthesiology and Intensive Care, Kungälv Hospital, Sweden 3Dept of Clinical Neuroscience, Division of Forensic Psychiatry, Karolinska Institutet, Huddinge, Sweden 4Schizophrenia and Addiction Program, Centre for Addiction and Mental Health, Toronto, ON, Canada

2. INFLAMMATION The reaction of the tissues to something that is not welcome and possibly dangerous

3. INFLAMMATION • Different markers may be measured • Both inflammatory and anti-inflammatory • A connection between inflammation and behaviour has long been suspected

4. Inflammation and behaviour • Background: • There is a relationship between stress, inflammation and different forms of psychiatric pathology (Dantzer 2004, Dean 2010) • The way the brain reacts to stress, especially in relationship to personality factors, is still insufficiently known • One way to look at the brain is to study cerebrospinal fluid (CSF) (Anckarsäter 2005, Söderström 2001), another to look at different markers in blood

5. Inflammation and psychiatric disorders • Classical sickness behavior after cytokine therapy (Dantzer et al 2004) • Increased risk of schizophrenia and autism after prenatal maternal infections (Freedman et al 2010) • Inflammatory dysbalance in several psychiatric disorders

6. Inflammation and aggression • Hostility is associated with increased levels of several inflammatory markers(Marsland et al 2008) • There seems to be a connection between variants of the CRP gene and impulsive personality traits(Suchankova et al 2009) • Measures of hostility/anger are increased in persons undergoing cytokine therapy (Kraus et al 2003)

7. Surgical Stress Study • General aim: to identify neurochemical and endocrine reactions to surgical stress • Specific aims: • To study the relationship between personality, inflammatory and neurochemical markers • To examine central and peripheral inflammatory markers before, directly after and in the morning after surgery

8. Surgical Stress Study • Methods and materials: • 35 neurologically healthy patients • Cerebrospinal fluid, Blood & Urine samples • Before (A-samples), 3 hours after (B-samples) and the morning after (C-samples) knee arthoplastic surgery • Subjects were asked to fill out personality questionnaires before arriving at the hospital • Exclusion criteria: • Psychotropic, anticoagulant, anti-parkinson or corticosteroid treatment

10. Results • Markers for dopamin and serotonin activity as well as for a ”leaky” blood-brain barrier, as well as for several cytokines, correlated with markers for impulsive and aggressive personality traits • Inflammation seems to be independently regulated centrally and peripherally, mirrored in levels of different cytokines.

11. Conclusion • There seems to be a connection between the levels of different inflammatory biomarkers and personality, including destructive personality traits • The brain´s immune system seems to be activated during surgery in a way that is different from in the periphery

12. Immunological Aspects of Aggression Study (IAGGS)hypotheses • Levels of inflammatory markers differ between violent offenders and normal controls • Levels of inflammatory markers correlate with violent/aggressive behavior • Levels of inflammatory markers correlate with aggressive personality traits

13. IAGGSmaterials and methods • 64 patients undergoing forensic psychiatric evaluation and 64 healthy controls • Blood samples at two separate occasions, 2 weeks in between • Personality and anxiety questionnaires

14. IAGGSmaterials and methods • Life History of Aggression scale: A 12 item scale assessing various aspects of aggressive behavior. • State Trait Anxiety Inventory: A short questionnaire assessing state-dependent level of anxiety. • Beck Depression Inventory: Assessment of depressive symptoms. • Temperament and Character Inventory (TCI) • Swedish University Scales of Personality (SSP), personality assessment scales • Cornell Coding guide for violent incidents: Instrumental versus hostile/reactive aggression

15. IAGGSmaterials and methods • C-Reactive Protein (CRP): a marker of general inflammation • Cytokines (IL- 1,2, 5, 6, 8, 10, 13, TNF)- immunological markers previously found to be affected by peripheral stress • Brain Derived Neurotrophic Factor (BDNF): an important growth factor known to be implicated in both brain plasticity and psychiatric disorders. The serum levels of this growth factor show a high correlation with CNS levels . • S-100B: An astrocyte-derived cytokine-like protein which is present in increased levels in serum in cases of brain damage, and also in several psychiatric disorders. • Beta-trace protein (TP): a marker of blood brain barrier integrity that may be assessed in serum. • Genetic markers

16. IAGGS • Inclusion criteria • Free from illegal drugs for at least four weeks • For the offender group: Convicted of a violent crime • Age between 18-65 years old. • For the control group: Not convicted of any violent crime • Both genders • Willingness to provide informed consent

17. IAGGS • Exclusion criteria • Current treatment with antipsychotic or antidepressant medication, as these have been shown to influence levels of inflammatory markers. • Ongoing infection or inflammatory disease. • Ongoing illicit substance abuse • In healthy controls: History of violent aggressive behavior • In healthy controls: History of psychiatric disorder

18. IAGGS • We hope to better be able to elucidate the correlations between violent behaviour and the inflammatory system, thus hopefully contributing to future treatment methods for forensic psychiatric patients

19. Contributions: • Swedish Board of Forensic Medicine • Gothenburg Medical Society • Bror Gadelius Memorial Fund • Knut and Alice Wallenberg Foundation • Rolf Anckarsäter, Marianne Kristiansson, Thomas Nilsson, Kaj Blennow, Henrik Zetterberg, Henrik Anckarsäter, Caroline Wass

20. Karolinska Scales of Personality (KSP) n=19 Comprises 135 items covering 4 factors grouped into 15 subscales. Four alternative answers on a Likert scale Well-known and validated

21. Temperament and Character Inventory (TCI) n=22 • Based on 238 statements consisting of four temperament and three character dimensions. • Well known and validated • Two alternatives: • ”true” • ”false”

23. Limitations • Small sample • Several possible confounders like diabetes, hypertension and different medications • Anaesthesia • Continuous sampling not possible

24. . Results: Serum IL-8 and IL-10 increased during and after surgery. SerumTNF-a decreased after surgery and CSF IL-2, IL-8, IL-10, IL-13 and TNF-a increased during and after surgery and CSF IL-5 increased after surgery. Correlations (p<0.01) were found between CSF IL-10, Inhibited aggression and Social anxiety and between CSF IL-10 and Verbal aggression. CSF IL-8 correlated negatively with Conscience. Serum IFN-g and IL-10 correlated positively with Guilt and negatively with Self-directedness, and IFN-g with Goal-orientation, serum TNF and Helpfulness correlated negatively. Conclusion: The present findings demonstrate that marked increases in brain cytokines differ from peripheral fluctuations. Furthermore, several cytokines were correlated with baseline destructive personality traits. These relationships indicate that peripheral stressors may induce central inflammatory changes, different from those in the periphery. Moreover, CNS inflammatory m processes may be related to destructive personality traits.