Health of mind captured: a brain trained to body talk

Transcription

1 Health of mind captured: a brain trained to body talk Szabolcs Kéri Budapest University of Technology and Economics, Department of Cognitive Science National Institute of Psychiatry and Addictions, Budapest, Hungary University of Szeged, Department of Physiology

2 The brain and its body: beyond the experience of the outside Holistic approach Homeostasis Interoception Disturbance in mental illness (i.e., stress- and trauma related disorders with depression and anxiety): SOCIAL ENVIRONMENT BRAIN - BODY

3 PTSD and MDD: disorders of the brain Posttraumatic stress disorder (PTSD): -Intense anxiety -Nightmares and flashbacks -Social isolation -Depression -Impaired learning and memory Comorbidity and overlap with Major depressive disorder (MDD) Modified after Koolhaas JM et al., 2011

4 Traditional Chinese Medicine (14-11 cent. BC, Shang dynasty) -Brain functions are distributed among the five zhang-organs -Brain diseases: systemic diseases Ayurveda (Hindu Medicine, 5000 BC) -Brain: sensation, movements, rational processes -Mind controls body: meditation as a treatment Western systematization and reductionism Eastern holism Modified after Sakatani, 2007

5 Plato (c BC): -Tripartite theory of soul: logical, spirited, and appetitive -Brain: separated from other mind-system by the neck Aristotle ( BC): -Soul is not a separate substance of which the body is made -Brain: to cool the blood (and sleep) Descartes, Kant, Huxley and others Enlightment s rationalism and empiricism THOUGHTS CAN CONTROL EMOTIONS AND YOU CAN LEARN HOW TO CHANGE IT The fundamental basis of Aaron Beck s (1976) concept: COGNITIVE-BEHAVIORAL THERAPY (CBT)

6 Thoughts cannot change everything: past memories of the unacceptable (the legacy of depressive and traumatic realism) MINDFULNESS-BASED APPROACH (Jon Kabat-Zin, 1978) - Based on Buddhist tradition Vipassanā - Remember (e.g., a trauma, major life events) - Non-judgmental and non-elaborative reflection - Focus on thoughts, feelings, and emotions from a mental distance in the present - Contemplate, be open, and accept CBT & Mindfulness is an evidence-based treatment of major depression and related conditions according to the NICE (National Institute for Health and Care Excellence) guidelines (CG90, 2009; updated: October 2012)

7 An unexpected moment in the meeting of East and West: The historical role of Transylvania (Romania and Hungary) Ram Mohan Roy ( ) Unitarian Church of Transylvania (since 1565) The Church of Székelyderzs (ca )

8 Fundamental questions What is the effect of environmental intervention (e.g., CBT & Mindfulness) on the brain and cognition? How is it related to changes in body? What is the specific role of inflammation and the microbiota gut - brain axis? Is there any translational potential in basic findings? Structural changes (e.g., hippocampal formation) Inflammation and gut-brain axis CBT & Mindfulness

9 The human microbiota gut brain axis trillion bacteria - Diversity and individual patterns - Viruses regulating bacteria - 4 million extra genes million neurons (the second brain ) Role: - Neuropsychiatric illness - Aging - Metabolic syndrome - Autoimmune processes/ allergy Modified after Lozupona et al., 2012 and Tillisch & Labus, 2014

10 CBT and Mindfulness Psychobiotics Modified after Bailey, 2014; Hariri and Holmes, 2006; Swidinski A et al., 2007

11 Measures of intestinal permeability, stress response, and low-grade inflammation 16s RNA: bacterial ribosome TLR-4 (Toll-Like Receptor-4): detecting bacterial lipopolysaccharide (LPS) IL-6 (Interleukin-6): most abundant circulating cytokine CRP (C-reactive protein): inflammatory protein produced by the liver FKBP5: regulator of cortisol receptor NF-κβ: transcription factor activated by cytokines BioM-10: a 10-item transcriptomics marker of stress and depression (activated glial cells and lymphocytes)

12 STRESS Toll-Like Receptor 4 (TLR-4) activity in microglia and astroglia LPS and its binding protein Mesenteric lymph nodes Garate I et al. J Neuroinflammtion 2011;8:151. Garate I et al. Biol Psychiatry 2013;73:32.

13 c o p i e s / m i c r o L Markers of bacterial translocation and TLR4 activation in individuals with major depression following major life events: the impact of therapeutic intervention Bacterial 16s rrna TLR-4 and TLR-2 activation in lymphocytes 4 0 * p < M D D t 1, 7 8 % M D D t 2, 5 6 % 0 M D D t 1 M D D t 2 t1 before CBT t2 - after CBT (16 weeks) MDD major depression HC healthy controls

14 Changes in gene expression in lymphocytes: before vs. after CBT 10-item transcriptomics marker scores NF-κβ * p < 0.05 Genes related to growth factor signaling, cytokines, and glial functions: MBP, EDG2, FZD3, ATXN1, EDNRB FGFR1, MAG, PMP22, UGT8, ERBB3 t1 before CBT t2 - after CBT (16 weeks) MDD major depression HC healthy controls

15 The relationship between symptom changes during CBT and TLR-4/NF-κβ HAM-D Hamilton Rating Scale for Depression

16 The relationship between symptom changes during CBT and BioM10 BUT: negative results for IL-6 and CRP (minor changes during CBT and no correlation with symptom improvement)

17 Interim summary: increased intestinal permeability, inflammation, and depression - Evidence of bacterial translocation (16s RNA) NF-κβ BioM10 CBT?? - Primary immune activation (TLR-4) TLR4 - Complex changes in leukocyte gene expression - Effect of psychological intervention (CBT) 16s RNA Kéri Sz et al. Brain Behav Immun 2014;40:235 Kéri Sz et al. J Affect Disord 2014;164:118. Figure modified after Tillisch & Labus, 2014

18 The HPA (hypothalamic pituitary - adrenal axis) and cortisol: new targets for stress- and trauma-related disorders Receptors for non-genomic actions, receptor modulators, and cortisol-inducible genes: FKBP5 GPR30 GLIZ SGK-1 [ ] Human hippocampus and leukocyte FKBP5 expression in mice amygdala and hippocampus glucocorticoid receptor (GR) Modified after Raabe & Spengler, 2013; Fani N et al., 2013; Scharf SH et al., 2012

19 V o l u m e ( m m 3 ) H i p p o c a m p a l v o l u m e ( m m 3 ) Changes in brain volume in patients with posttraumatic stress disorder (PTSD): before vs. after CBT FreeSurfer ROIs (Fischl B et al., 2002) Hippocampal formation Amygdala Medial orbitofrontal cortex (mofc) P T S D t 1 ( n = 3 9 ) p < 0.05 p < 0.05 T r a u m a C o n t o l t 1 ( n = 3 1 ) P T S D t 2 ( n = 3 9 ) T r a u m a C o n t r o l t 2 ( n = 3 1 ) L e f t R i g h t Levy E et al. Biol Psychiatry 2013;74:793. H i p p o c a m p u s A m y g d a l a m O F C P T S D b e f o r e C B T P T S D a f t e r C B T P T S D b e f o r e C B T P T S D a f t e r C B T

20 c o p i e s / m i c r o L R N A E x p r e s s i o n Indicators of intestinal permeability and cortisol receptor sensitivity in PTSD: before vs. after CBT Bacterial 16s rrna 2. 5 FKBP5 RPS6K p < p < P T S D t 1 ( n = 3 9 ) P T S D t 2 ( n = 3 9 ) 0. 0 P T S D t 1 ( n = 3 9 ) T r a u m a C o n t r o l t 1 ( n = 3 1 ) P T S D t 2 ( n = 3 9 ) T r a u m a C o n t r o l t 2 ( n = 3 1 ) Following CBT: -Decreased intestinal permeability (16s rrna ) -Decreased cortisol receptor sensitivity (FKBP5 ) -No changes in RPS6K, the peak significant marker of PTSD from Affymetrix array -Blood cortisol levels are not conclusive

21 Three-way correlation among improvements in posttraumatic symptoms, FKBP5, and hippocampal volume changes (post- vs. pre-cbt) CAPS Better improvement (reduced CAPS scores) - Increased hippocampal volume - Higher FKBP5 expression 1,2 0,9 FKBP5 0,6 0,3 0,0-0,3-0, Hippocampal Volume CAPS Clinician Administered PTSD Scale Levy E et al. Biol Psychiatry 2013;74:793.

22 N u m b e r o f e r r o r s Common impairment in stress- and trauma-related disorders: hippocampus-dependent memory Paired associates learning: object place associations Candy box task: - computer-based - with real persons (social influences on learning) 3 0 A u t is m ( n = 1 8 ) F r o n t o - t e m p o r a l ( n = 2 0 ) 2 0 A lz h e im e r ( n = 2 0 ) P T S D t 1 ( n = 3 9 ) P T S D t 2 ( n = 3 9 ) 1 0 C o n t r o l ( n = 2 5 ) 0 Kéri Sz. Cortex 2014;54:200. C o m p u t e r R e a l - l i f e

23 Interim summary Evidence for: - increased gut permeability - enhanced cortisol sensitivity (low FKBP5) - decreased hippocampal volume in PTSD CBT: some of these correlated deficits are ameliorated Paired-associates learning is boosted, especially in the social context

24 Is there impaired neuronal plasticity in people experiencing negative life events, showing pronounced low-grade inflammation but have no mental illness? A method for cognitive training: games (2 months, 30 min/day) Super Mario : spatial navigation, shifting allocentric and egocentric strategies Mahjong: clearing the board by removing all tiles in pairs that are identical, no other tile is lying above, left or right, or partially covering it

25 Structural changes in the human brain (after vs. before training) m m L H i p p o c a m p u s R H i p p o c a m p u s N. c a u d a t u s Kühn S et al. Mol Psychiatry 2014;19:265.; Szabó C et al. J Neurosci 2014;34:81.

26 The relationship between right hippocampal volume changes, negative life events, and NF-κβ Changes in Right Hippocampal Volume Changes in Right Hippocampal Volume NFkb Number of Negative Life Events

27 Interim summary Popular games induce structural changes in human brain Key regions: hippocampus and prefrontal cortex People experiencing negative life events show less plasticity NF-κβ is one of the key mediators

28 Limitations of the microbiota - gut brain - inflammation hypothesis Too general mechanism ( housekeeping ) Non-specificity of TLR and other pattern recognition receptor activation (damage-associated molecular patterns) Inflammation : part of normal (neuronal) homeostasis Causality Microbiota diversity and stability Methodological issues (e.g., clinically significant signals in big data studies, histological confirmation)

29 Debates, open questions, and future directions Key problem: response rate (CBT, antidepressants): 40 60% Psychobiotics, diet & exercise, n3-fatty acids, vitamin D [ ] New approach 1: genetically modified microbiota New approach 2: pharmacological augmentation of CBT Factors that affect BioM10, NF-κβ, and FKBP5: - Insulin-like growth factor-i (IGF-I) - IL-6, IL-10 (microrna146b) - [Oxytocin]

30 Acknowledgements The patients and their therapists The lab at National Psychiatric Center: Oguz Kelemen Csilla Szabó Rebeka Maróthi Support of University of Haifa s PTSD team and Emotion, Trauma, and Loss research group The National Excellence Program of Hungary supported by the European Union