1. Neurological basis of anxiety Seminar 2006-07
Matti Mintz
Psychobiology Research Unit
Department of Psychology
Tel Aviv University
In the future, neurology will provide satisfactory
explanation of anxiety (Freud).

2. 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.

3. 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?

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

5. 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.

6. Mechanistic approach to emotional brain
Computation
Outputs:
Feelings
Autonomic
Facial
Actions
Cognitive
Inputs:
Genetically defined US’s
Experience defined CS’s
Thoughts & Memories

7. 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.

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

9. Autonomic
ganglia

10. Spine Preganglionic Postganglionic Target
Para or pre-vertebral ganglia

11. SNS 1- preganglionic neuron 2- spinal nerve 4- para-vertebral ganglia
6- autonomic nerve
8- pre-vertebral ganglia
9- terminal ganglia

12. Brainstem (III, VII, IX, X-vagal)
Sacral spine
Autonomic ganglia
Near the target

13. PSNS

15. 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.

16. 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.

17. 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

18. Disordered processing by brain-limbic structures
Biological-Psychiatry and Psychology Anxiety disorder generated by limbic system
Harmless & aversive
events
Disordered processing by
brain-limbic structures
Excessive anxiety:
Emotional-somatic state
Conscious feeling
Limbic disorder:
Genetic/Acquired
Functional/Structural
GABA/Serotonin
Synaptic

19. Alternative origins of anxiety disorder: Non-limbic dysfunction?
Cortex:
slow evaluation
conscious feeling
Amygdala:
rapid evaluation
emotional state

20. Normal processing of a novel challenge
Adaptive
fear
response
Fast fear processing
Encounter
with a novel
challenge ?
Slow motor
processing

21. When anxiety should become extinct ?
Extinction
of fear
processing
No fear
response
Encounter
with familiar
challenge ?
Activation of motor plans
Adaptive motor
Response

22. 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.

23. 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.

24. 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.

25. 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?

26. 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.

27. 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.

28. The vestibulo-parabrachial network includes connections between the vestibular nuclei and pathways mediating anxiety responses (Balaban 2002).

29. 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.

30. Hdb vs. wild-type in open-field test
Fisher & Mintz

31. Hdb vs. wild-type in elevated Plus-Maze test

32. %Time spent in the open arms (sec)
C57/BL6 mice deprived of climbing activity (P0-P50) and tested on elevated Plus Maze
ELEVATED PLUS MAZE
OPEN FIELD TEST * * 35 12 30 10
no climbing
no climbing 25 8
climbing
climbing 20
%Time spent in the open arms (sec)
%entries into the open arms 6 15 4 10 5 2
males
females
males
females
1400
1200
no climbing
1000
climbing
800
Distance moved (cm)
600
400
200
males
females
Climbing effect
§ Gender effect
Pietropaolo, Yee, Mintz & Feldon

33. Comorbidity of balance and anxiety disorders in childhood?
In children with anxiety as primary disorder.
In children with imbalance as primary disorder.

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

35. 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.

36. Children with anxiety disorders had more balance mistakes relative to controls
Interaction
G by M
Group effect
Manipulation effect
Test ns
Floor-bench ns
Eyes open-closed **
Stand
heel-to-toe *
Floor-bench-trampoline ***
Eyes open-closed ***
Stand on one-foot
Head still-nodding *
Stand on cylinder
Walk on
cubicles
Normal-heel-to-toe ***
rope
*p<0.05; **p<0.01; ***p<0.001

37. Children with imbalance as primary disorder
With Meidan, M., Sadeh, A., Brat, O.

38. Relation between parental report on balance and self-reported emotionality

39. Relation between balance performance and parental report on emotionality

40. Balance rehabilitation in children with imbalance as primary disorder
With Weisman, E., Bar-Haim, Y., Brat, O.

41. Balance test (Bruninks-Oseretsky)1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 O
After treatment
Before treatment
Treatment
Control
Group by Time: p<.001

42. Anxiety level After treatment Before treatment
0.00
5.00
10.00
15.00 O
After treatment
Before treatment
Treatment
Control 50
100
150
CBCL: Parental reports
Fear Survey: Child Report
Gr x Treatment: p<.001
Gr x Treatment: p<.001

43. Standard training

44. Training of balance skills through a computerized game
It is the same kid
before and after
2 months of training

45. Training of balance skills through a computerized game
It is the same kid
before and after
2 months of training

46. The computerized game: how it is done

47. The computerized game: visual interference

48. 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.

50. End of presentation

51. Balance tests:
Balance sub-test of the Bruninks-Oseretsky Test of Motor Proficiency (Bruninks, 1978).
Vestibular scale of The Parental Sensory Profile Assessment (Dunn, 1999).
Anxiety tests:
Anxiety-Depression Parental Scale of the Child Behavior Checklist (CBCL; Achenbach, 1991).
Fear Survey Schedule for Children – self report (FSSC; Ollendick, 1983).

52. Conditioning procedures
EP: Conditioning of fear-CRs (freezing-CRs)
10 paired CS-US trials
CS – 2.8 kHz tone (0.4s, 73 dB)
US – white noise (0.1s, 100dB)
Conditioning of motor-CRs (eyeblink-CRs):
40 paired SC-US trials
US – periorbital train (0.1s, 50Hz)
(Neufeld & Mintz, 2001)

53. Amygdala-based fear-conditioning enhances the subsequent cerebellum-based motor conditioning

54. Lesions in the cerebellum and the amygdala

55. 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

56. Fast amygdala-based fear conditioning
CS-tone
US-airpuff
(Mintz & Wang-Ninio, 2001)

57. Poor motor conditioning in cerebellar rats

58. Extinction of fear after motor conditioning in controls but not in cerebellar rats