Download Three Stage Theory Oct 2006

Neurological basis of anxiety
Seminar 2006-07
Matti Mintz
Psychobiology Research Unit
Department of Psychology
Tel Aviv University
http://freud.tau.ac.il/~mintz
[email protected]
29/10/06 netanya
In the future, neurology will provide satisfactory
explanation of anxiety (Freud).
Apprenticeship in the scientific process
 Acquire knowledge in a field: read, memorize.
 Recognize an important question: think, dream, be
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visionary.
Write a grant proposal: convince others to invest at your
project.
Recruit students: attract others.
Pose an operational hypothesis: be practical
Set a methodology to test the hypothesis: get familiar with
modern techniques and technology
Run the experiment: be dextral, meticulous, objective and
honest.
Write a scientific report: think, be relevant, be articulate.
Deal with the remarks of the reviewer: learn to
compromise with the unbelievers.
The questions
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Why after so many years of research the rate of
success in treating anxiety disorders is not
satisfactory?
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Should we screen the subjects for neurological
origins of anxiety disorders?
The plan:??????????????????????
 Anxiety explained by psychology.
 Anxiety explained by biological psychiatry.
 New neurobehavioral data.
 Theoretical implications.
 Clinical implications.
Emotion as an integrative response:
Psychological perspective
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Subjective feelings (introspection).
Internal body responses (sensations-emotions) including
autonomic & hormonal.
Cognitive associations (causality & simulation).
Facial expressions (genetic).
Action tendencies.
Mechanistic approach to emotional brain
Computation
Inputs:
 Genetically defined US’s
 Experience defined CS’s
 Thoughts & Memories
Outputs:
 Feelings
 Autonomic
 Facial
 Actions
 Cognitive
Emotion as an integrative response:
Biological perspective
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Limbic and cortical areas involved in emotion control.
All of the above control the hypothalamus.
The hypothalamus coordinates behavioral response by
acting on the ANS, endocrine system and motivation
system.
Motor ANS neurons exert a diffuse control over target
tissues; highly branched axons, multiple varicosities,
great transmitter diffusion.
Functions of the ANS (Squire et al., 2003)
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Visceral sensory and motor system. 24/10/06
Controls online the homeostasis of body’s physiology:
blood chemistry, respiration, circulation, digestion,
immune…
Innervates smooth muscles & many tissues.
Cannon (1939) referred to the “Wisdom of the body”
and the negative feedback as a key homeostatic
mechanism.
Autonomic: automatic, involuntary, visceral.
Sympathetic: sympathy, coordination between organs.
: subserves the “sympathies”, or emotions.
Parasympathetic: only recently discovered.
Example: Postural hypothension in dysautonomia.
Autonomic
ganglia
Spine
Preganglionic
Postganglionic
Para or pre-vertebral
ganglia
Target
SNS
1- preganglionic neuron
2- spinal nerve
4- para-vertebral ganglia
6- autonomic nerve
8- pre-vertebral ganglia
9- terminal ganglia
Brainstem (III, VII, IX, X-vagal)
Sacral spine
Autonomic ganglia
PSNS
29/10/06 netanya
SNS & PSNS pre- and postganglionic levels
Compared with skeletal motor system, the extra
synapse at peripheral ganglia allows:
 More divergence: from single spinal segment
to several ganglia; from single ganglia to
several organs (SNS > PSNS).
 Local integration: Sup. Cervical ganglion
innervates eyes, salivary & lacrimal glands,
blood vessels; ganglia receives sensory
afferents form the target organ; PSNS>SNS.
Autonomic reflex
arc
 ANS
responds to sensory
inputs, internal & external.
 Virtually all visceral reflexes
are mediated by circuits in
the brain stem or spinal cord.
 These reflexes are modulated
by central autonomic nuclei
in the brain stem,
hypothalamus & forebrain.
 This top-down control is
involuntary & does not reach
consciousness.
Biological-Psychiatry and Psychology
Normal fear/anxiety generated by limbic system
Aversive events:
Exo/Endogenous
CS/US
Normal processing by
brain-limbic structures
Normal anxiety:
Emotional-somatic state
Conscious feeling
Biological-Psychiatry and Psychology
Anxiety disorder generated by limbic system
Harmless & aversive
events
Limbic disorder:
Genetic/Acquired
Functional/Structural
GABA/Serotonin
Synaptic
Disordered processing by
brain-limbic structures
Excessive anxiety:
Emotional-somatic state
Conscious feeling
Alternative origins of anxiety disorder:
Non-limbic dysfunction?
Cortex:
 slow evaluation
 conscious feeling
Amygdala:
 rapid evaluation
 emotional state
Normal processing of a novel challenge
Encounter
with a novel
challenge
Adaptive
fear
response
Fast fear
processing
?
Slow motor
& cognitive
processing
Adaptive
motor/cognitive
response
When anxiety should become extinct ? 5/11/06
Encounter
with familiar
challenge
Extinction
of fear
processing
No fear
response
?
Activation of
motor plans
Adaptive motor
Response
Normal individual facing an
aversive challenge
The two stage theory of learning predicts:
1st stage: Fast acquisition of fear responses.
2nd stage: Slow acquisition of motor/cognitive responses.
Extension to three stage theory of learning:
3rd stage: Extinction of fear responses after acquisition of
motor/cognitive responses.
Individual with motor disorder facing
an aversive challenge
The three stage theory of learning predicts:
1st stage: Fast acquisition of fear responses.
2nd stage: Poor acquisition of motor responses.
3rd stage: No extinction of fear responses.
Possible implications for anxiety disorder
Theoretical: In contradiction to the present dogma,
disorders of anxiety may evolve from normal limbic
system that responds persistently due to interaction
with deficient sensory-motor system.
Clinical: In contradiction to the present dogma,
sensory-motor rehabilitation may ameliorate the
anxiety symptoms.
Comorbidity of balance and anxiety disorders
A special issue of the J. of Anxiety Disorders,
reviewed the experimental and clinical findings
related to comorbidity of balance disorders and
anxiety (Sklare et al., 2001).
Could the comorbidity be explained by the three
stage theory of learning?
Individual with balance disorder
facing balance-challenging conditions
The three stage theory of learning predicts:
1st stage: Fast acquisition of fear responses.
2nd stage: No acquisition of balance restoration motor
responses.
3rd stage: No extinction of fear responses, i.e., anxiety
disorder.
Origin of the comorbidity of balance-anxiety
disorders?
Theoretical hypothesis: Anxiety evolves from
normal limbic system that responds excessively and
persistently due to interaction with deficient balance
system.
Clinical implication: Balance rehabilitation may
ameliorate the anxiety symptoms.
The vestibulo-parabrachial network includes connections
between the vestibular nuclei and pathways mediating
anxiety responses (Balaban 2002).
Dominant Hdb mutation of C3HeB/Fej strain with
developmental vestibular stereocilia phenotype
A: SEM demonstrating elongated, abnormal stereocilia in utricle of 5
month old Hdb mouse.
B: Genotyping for presence of Myo7a missense mutation.
Avraham & Hertzano, 2004.
Hdb vs. wild-type in open-field test
Time in center (sec) - 1 month old
[Interaction: F(19,342)=2.6, p<0.001]
Time in HB (sec) - 1 month old
[Interaction: F(19,342)=2.5, p<0.001]
50
50
45
45
Hdb
Hdb
Wt
Wt
40
40
35
35
30
30
25
25
20
20
15
15
10
10
5
5
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Minutes
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Minutes
Fisher & Mintz
Hdb vs. wild-type in elevated Plus-Maze test
1 Month Old
Time in Closed Arms (sec)
2 Months Old
Time in Closed Arms (sec)
3 Months Old
Time in Closed Arms (sec)
40
40
40
30
30
30
20
20
20
10
10
10
0
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
10
*
§
35
30
25
no climbing
20
climbing
15
10
5
0
males
%Time spent in the open
arms (sec)
%entries into the open arms
C57/BL6 mice deprived of climbing activity
(P0-P50)
and tested on elevated Plus
Maze
ELEVATED PLUS MAZE
OPEN FIELD TEST
10
no climbing
8
climbing
6
4
2
0
males
females
females
§
1400
Distance moved (cm)
*
§
12
1200
no climbing
1000
climbing
800
600
400
200
0
males
• Climbing
females
effect
§ Gender effect
Pietropaolo, Yee, Mintz & Feldon
Comorbidity of balance and anxiety disorders
in childhood?
In children with anxiety as primary disorder.
In children with imbalance as primary disorder.
Children with anxiety as primary disorder
Group
Origin
Anxiety
(n=20)
Ambulatory
clinic
Control
(n=20)
Normal class
children
Diagnosis of
anxiety
Age
(yrsSEM)
Gender
(F/M)
Separation (n=11)
Generalized (n=7)
PTSD (n=1)
Phobias (n=1)
10.20.38
(7-14)
8/12
10.60.36
(7-13)
8/12
Erez et al., 2004
Children with anxiety disorders vs. controls:
 Reported more dizziness episodes (80 vs. 40%).
 Reported enhanced sensitivity to motion sickness
provoking situations.
 Were hypersensitive to the rotary chair test.
Children with anxiety disorders had more balance
mistakes relative to controls
Test
Manipulation effect
Group
effect
Interaction
G by M
Stand
heel-to-toe
Floor-bench
Eyes open-closed
ns
**
ns
ns
ns
Stand on
one-foot
Floor-bench-trampoline
Eyes open-closed
***
***
ns
*
ns
Stand on
cylinder
Head still-nodding
*
*
ns
Walk on
cubicles
Eyes open-closed
***
ns
ns
Walk on
rope
Normal-heel-to-toe
Eyes open-closed
***
***
*
ns
*
*p<0.05;
**p<0.01; ***p<0.001
Children with imbalance as primary disorder
N ♂/♀
Clinical Referred to OT
for balance
treatment
Control Normal class
children
Age
Age
(yrs±SE range
(yrs)
M
35 26/9 5.8±0.10 5.0-7.3
25 15/10 5.8±0.15 5.0-7.3
With Meidan, M., Sadeh, A., Brat, O.
Relation between parental report on balance and
self-reported emotionality
Vestibular Scale (Dunn)
60
Clinical
50
Control
r=-.32
40
30
20
r=-.52*
10
0
10
20
Anxiety - Depression (CBCL)
30
Relation between balance performance and
parental report on emotionality
Balance (Bruninks)
30
Clinical
25
Control
r=.03
20
15
10
r=-.72*
5
0
0
10
20
Anxiety - Depression (CBCL)
30
Balance rehabilitation in children with imbalance
as primary disorder
N ♂/♀
Age
Age
(yrs±SE range
(yrs)
M
25 22/3 5.4±0.08 5.0-6.1
Treated Referred to OT
for balance
treatment
24 21/3 5.4±0.09 5.0-6.1
Waiting list of
Nontreated similarly
referred children
With Weisman, E., Bar-Haim, Y., Brat, O.
Balance test (Bruninks-Oseretsky)
Treatment
15
15
14
14
13
13
12
12
11
11
10
10
9
9
8
8
7
7
6
6
5
5
4
Control
O
O
O
4
3
3
2
2
1
1
O
0
Before treatment
After treatment
Group by Time: p<.001
Anxiety level
Fear Survey: Child Report
O
O
O
15
0
150
100
100
50
50
0
0
Gr x Treatment: p<.001
O
CBCL: Parental reports
O
15.00
O
10.00
10.00
Gr x Treatment: p<.001
O
15.00
5.00
5.00
0.00
0.00
Before treatment
O
After treatment
Treatment
Control
Standard training
Training of balance skills through
a computerized game
It is the same kid
before - - - - - - - - - - - - - and - - - - - -- - - - - - - - - - after
2 months of training
Training of balance skills through
a computerized game
It is the same kid
before - - - - - - - - - - - - - and - - - - - -- - - - - - - - - - after
2 months of training
The computerized game:
how it is done
The computerized game:
visual interference
Conclusions concerning the origin of
anxiety disorders
The prevailing view in biological psychiatry is that
disorders of anxiety are the product of structural or
functional pathology of the limbic system.
The present hypothesis suggests that anxiety may be
precipitated by extralimbic sensory-motor
dysfunctions, in spite of normal limbic system.
Clinical implications: we consider the physical
treatment of anxiety as an alternative to the present
practice of pharmacological and psychological
approach.
End of presentation