Health of mind captured: a brain trained to body talk

Szabolcs Kéri

National Institute of Psychiatry and Addictions,

Budapest, Hungary

Budapest University of Technology and Economics, Department of Cognitive Science

University of Szeged, Department of Physiology

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

Posttraumatic stress disorder (PTSD): -Intense anxiety -Nightmares and flashbacks -Social isolation -Depression -Impaired learning and memory Comorbidity and overlap with Major depressive disorder (MDD)

PTSD and MDD: disorders of the brain

Modified after Koolhaas JM et al., 2011

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

Plato (c. 427-347 BC):

-Tripartite theory of soul: logical, spirited, and appetitive -Brain: separated from other ‘mind-system’ by the neck

Aristotle (384-322 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)

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)

An unexpected moment in the meeting of East and West: The historical role of Transylvania (Romania and Hungary)

Unitarian Church of Transylvania (since 1565)

The Church of Székelyderzs (ca. 1300-1340)

Ram Mohan Roy (1774-1833)

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?

CBT & „Mindfulness”

Structural changes (e.g., hippocampal formation)

Inflammation and gut-brain axis

The human microbiota – gut – brain axis

- 100 trillion bacteria

- Diversity and individual patterns

- Viruses regulating bacteria

- 4 million extra genes

- 100 million neurons (the „second brain”)

Modified after Lozupona et al., 2012 and Tillisch & Labus, 2014

Role: - Neuropsychiatric illness - Aging - Metabolic syndrome - Autoimmune processes/ allergy

CBT and „Mindfulness”

Psychobiotics

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

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)

LPS and its binding protein

Toll-Like Receptor 4 (TLR-4) activity in microglia and astroglia

STRESS

Mesenteric lymph nodes

Garate I et al. J Neuroinflammtion 2011;8:151. Garate I et al. Biol Psychiatry 2013;73:32.

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Bacterial 16s rRNA

TLR-4 and TLR-2 activation in lymphocytes

t1 – before CBT t2 - after CBT (16 weeks) MDD – major depression HC – healthy controls

Markers of bacterial translocation and TLR4 activation in individuals with major depression following major life events:

the impact of therapeutic intervention

* p < 0.05

Genes related to growth factor signaling, cytokines, and glial functions: MBP, EDG2, FZD3, ATXN1, EDNRB FGFR1, MAG, PMP22, UGT8, ERBB3

Changes in gene expression in lymphocytes: before vs. after CBT

t1 – before CBT t2 - after CBT (16 weeks) MDD – major depression HC – healthy controls

10-item transcriptomics marker scores NF-κβ

* p < 0.05

The relationship between symptom changes during CBT and TLR-4/NF-κβ

HAM-D – Hamilton Rating Scale for Depression

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)

Interim summary: increased intestinal permeability, inflammation, and depression

- Evidence of bacterial

translocation (16s RNA)

- Primary immune activation

(TLR-4)

- Complex changes in

leukocyte gene expression

- Effect of psychological

intervention (CBT)

16s RNA

CBT

NF-κβ BioM10

TLR4

?

?

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

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 […]

glucocorticoid receptor (GR)

FKBP5 expression in mice amygdala and hippocampus

Human hippocampus and leukocyte

Modified after Raabe & Spengler, 2013; Fani N et al., 2013; Scharf SH et al., 2012

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)

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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 )p < 0.05

p < 0.05

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Levy E et al. Biol Psychiatry 2013;74:793.

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Indicators of intestinal permeability and cortisol receptor sensitivity in PTSD: before vs. after CBT

p < 0.05

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p < 0.05

FKBP5 RPS6K

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

Bacterial 16s rRNA

Three-way correlation among improvements in posttraumatic symptoms, FKBP5, and hippocampal volume changes (post- vs. pre-CBT)

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- Better improvement (reduced CAPS scores) - Increased hippocampal volume - Higher FKBP5 expression

CAPS – Clinician Administered PTSD Scale Levy E et al. Biol Psychiatry 2013;74:793.

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)

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Kéri Sz. Cortex 2014;54:200.

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

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

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3Structural changes in the human brain (after vs. before training)

Kühn S et al. Mol Psychiatry 2014;19:265.; Szabó C et al. J Neurosci 2014;34:81.

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The relationship between right hippocampal volume changes, negative life events, and NF-κβ

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

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)

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]

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