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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
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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
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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
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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
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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)
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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)
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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)
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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
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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
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CBT and „Mindfulness”
Psychobiotics
Modified after Bailey, 2014; Hariri and Holmes, 2006; Swidinski A et al., 2007
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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)
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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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MD
D t
1
MD
D t
2
0
1 0
2 0
3 0
4 0
co
pie
s/m
icr
oL
M D D t 1 , 7 8 %
M D D t 2 , 5 6 %
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
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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
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The relationship between symptom changes during CBT and TLR-4/NF-κβ
HAM-D – Hamilton Rating Scale for Depression
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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)
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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
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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
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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)
Hi p
po
ca
mp
us
Am
yg
da
l a
mO
FC
5 0 0 0
1 0 0 0 0
1 5 0 0 0
Vo
lum
e (
mm
3)
P T S D t 1 ( n = 3 9 )
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
PT
SD
be
f or e
CB
T
PT
SD
af t
er C
BT
PT
SD
be
f or e
CB
T
PT
SD
af t
er C
BT
4 5 0 0
5 0 0 0
5 5 0 0
Hip
po
ca
mp
al
vo
lum
e (
mm
3)
R ig h t
L e f t
Levy E et al. Biol Psychiatry 2013;74:793.
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PT
SD
t1
(n
=3
9)
PT
SD
t2
(n
=3
9)
0
2 0
4 0
6 0
8 0
1 0 0
co
pie
s/m
icr
oL
Indicators of intestinal permeability and cortisol receptor sensitivity in PTSD: before vs. after CBT
p < 0.05
0 . 0
0 . 5
1 . 0
1 . 5
2 . 0
2 . 5
RN
A E
xp
re
ss
ion
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 )
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
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Three-way correlation among improvements in posttraumatic symptoms, FKBP5, and hippocampal volume changes (post- vs. pre-CBT)
-600
-300
0300
600
900
Hippocampal Volume
-0,6-0,3
0,00 ,3
0 ,60 ,9
1 ,2
FKBP5
-60
-40
-20
0
20
40
60
CA
PS
- 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.
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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)
Co
mp
ut e
r
Re
al -
l if e
0
1 0
2 0
3 0
Nu
mb
er
of e
rr
or
s
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 )
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 )
C o n t r o l ( n = 2 5 )
Kéri Sz. Cortex 2014;54:200.
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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
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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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L H
i pp
oc
am
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s
R H
i pp
oc
am
pu
s
N.
ca
ud
at u
s
- 1 0 0
0
1 0 0
2 0 0
3 0 0
mm
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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2 4 6 8 10 12 14
NFkb
-200
0
200
400
600
800
Ch
an
ges
in
Rig
ht
Hip
po
ca
mp
al
Vo
lum
e
0 1 2 3 4 5 6 7 8 9
Number of Negative Life Events
-200
0
200
400
600
800
Ch
an
ges
in
Rig
ht
Hip
po
ca
mp
al
Vo
lum
e
The relationship between right hippocampal volume changes, negative life events, and NF-κβ
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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
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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)
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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]
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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