Neurological%20basis%20of%20anxiety%20Seminar%202006-07

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Neurological basis of anxietySeminar 2006-07

• Matti Mintz
• Psychobiology Research Unit
• Department of Psychology
• Tel Aviv University
• http//freud.tau.ac.il/mintz
• mintz_at_freud.tau.ac.il
• 29/10/06 netanya

In the future, neurology will provide
satisfactory explanation of anxiety (Freud).
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Apprenticeship in the scientific process

• Acquire knowledge in a field read, memorize.
• Recognize an important question think, dream, be
  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.

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The questions

• Why after so many years of research the rate of
  success in treating anxiety disorders is not
  satisfactory?
• Should we screen the subjects for neurological
  origins of anxiety disorders?

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• The plan??????????????????????
• Anxiety explained by psychology.
• Anxiety explained by biological psychiatry.
• New neurobehavioral data.
• Theoretical implications.
• Clinical implications.

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Emotion as an integrative response
Psychological perspective

• Subjective feelings (introspection).
• Internal body responses (sensations-emotions)
  including autonomic hormonal.
• Cognitive associations (causality simulation).
• Facial expressions (genetic).
• Action tendencies.

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Mechanistic approach to emotional brain
Computation

• Outputs
• Feelings
• Autonomic
• Facial
• Actions
• Cognitive

• Inputs
• Genetically defined USs
• Experience defined CSs
• Thoughts Memories

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Emotion as an integrative response Biological
perspective

• 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.

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Functions of the ANS (Squire et al., 2003)

• Visceral sensory and motor system. 24/10/06
• Controls online the homeostasis of bodys
  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.

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Autonomic ganglia
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Spine Preganglionic
Postganglionic Target
Para or pre-vertebral ganglia
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SNS
1- preganglionic neuron 2- spinal nerve 4-
para-vertebral ganglia 6- autonomic nerve 8-
pre-vertebral ganglia 9- terminal ganglia
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Brainstem (III, VII, IX, X-vagal) Sacral
spine
Autonomic ganglia Near the target
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PSNS
29/10/06 netanya
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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 gt PSNS).
• Local integration Sup. Cervical ganglion
  innervates eyes, salivary lacrimal glands,
  blood vessels ganglia receives sensory afferents
  form the target organ PSNSgtSNS.

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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.

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Biological-Psychiatry and Psychology Normal
fear/anxiety generated by limbic system
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Biological-Psychiatry and PsychologyAnxiety
disorder generated by limbic system
Limbic disorder Genetic/Acquired Functional/Struc
tural GABA/Serotonin Synaptic
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Alternative origins of anxiety disorder Non-limbi
c dysfunction?

• Cortex
• slow evaluation
• conscious feeling

• Amygdala
• rapid evaluation
• emotional state

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Normal processing of a novel challenge
Adaptive fear response
Fast fear processing
Encounter with a novel challenge
?

Slow motor cognitive processing
Adaptive motor/cognitive response
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When anxiety should become extinct ? 5/11/06
Extinction of fear processing
No fear response
Encounter with familiar challenge
?
Activation of motor plans
Adaptive motor Response
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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.

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Individual with motor disorder facingan 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.

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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.

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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?

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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.

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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.

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The vestibulo-parabrachial network includes
connections between the vestibular nuclei and
pathways mediating anxiety responses (Balaban
2002).
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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.
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Hdb vs. wild-type in open-field test
Fisher Mintz
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Hdb vs. wild-type in elevated Plus-Maze test
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C57/BL6 mice deprived of climbing activity
(P0-P50) and tested on elevated Plus Maze
ELEVATED PLUS MAZE
OPEN FIELD TEST


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30
10
no climbing
no climbing
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8
climbing
climbing
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Time spent in the open arms (sec)
6
entries into the open arms
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4
10
2
5
0
0
males
females
females
males

1400
1200
no climbing
1000
climbing
800
Distance moved (cm)
600
400
200
0
females
males

• Climbing effect
• Gender effect

Pietropaolo, Yee, Mintz Feldon
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Comorbidity of balance and anxiety disorders in
childhood?

• In children with anxiety as primary disorder.
• In children with imbalance as primary disorder.

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Children with anxiety as primary disorder
Erez et al., 2004
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• 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.

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Children with anxiety disorders had more balance
mistakes relative to controls
Interaction G by M Group effect Manipulation effect Test
ns ns ns Floor-bench ns Eyes open-closed Stand heel-to-toe
ns ns Floor-bench-trampoline Eyes open-closed Stand on one-foot
ns Head still-nodding Stand on cylinder
ns ns Eyes open-closed Walk on cubicles
ns Normal-heel-to-toe Eyes open-closed Walk on rope
plt0.05 plt0.01 plt0.001
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Children with imbalance as primary disorder
With Meidan, M., Sadeh, A., Brat, O.
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Relation between parental report on balance and
self-reported emotionality
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Relation between balance performance and parental
report on emotionality
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Balance rehabilitation in children with imbalance
as primary disorder
With Weisman, E., Bar-Haim, Y., Brat, O.
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Balance test (Bruninks-Oseretsky)
Group by Time plt.001
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Anxiety level
Gr x Treatment plt.001
Gr x Treatment plt.001
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• Standard training

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Training of balance skills througha computerized
game
It is the
same kid before - - - - - -
- - - - - - - and - - - - - -- - - - - - - - -
- after 2
months of training
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Training of balance skills througha computerized
game
It is the
same kid before - - - - - -
- - - - - - - and - - - - - -- - - - - - - - -
- after 2
months of training
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The computerized gamehow it is done
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The computerized gamevisual interference
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Conclusions concerning the origin ofanxiety
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.

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End of presentation