1. Anxiety: old data and new theory Jerusalem May 2004
Matti Mintz
Psychobiology Research Unit
Department of Psychology
Tel Aviv University
In the future, neurology will provide satisfactory
explanation of anxiety (Freud).

2. The plan:
Anxiety explained by psychology.
Anxiety explained by neuroscience.
Neurobehavioral data extending the present approach of biological psychiatry toward anxiety.
Clinical implications.

3. Normal fear/anxiety explained by Ψ
Aversive event:
Exo/Endogenous
CS/US
Parallel Limbic:
Neocortical/Subneocortical
Evaluation/Conditioning
Coherent response:
Emotional-somatic state
Conscious feeling

4. Normal fear/anxiety as explained by Φ
Cortex:
slow evaluation conscious feeling
Amygdala:
rapid evaluation emotional state

5. Does anxiety enhance motor conditioning ?
Adaptive
fear
response
Fast fear
conditioning
Encounter
with a novel
challenge ?
Slow motor
conditioning
Non-adaptive
motor
response

6. 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, M. & Mintz, M., 2001)

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

8. Is amygdala involved in the enhanced cerebellum-based motor conditioning

9. Amygdala mediates the acquisition of emotional responses, which subsequently enhance the conditioning of adaptive motor responses

10. Is anxiety extinguished after acquisition of adaptive motor responses?
Extinction
of fear
response
No fear
response
Encounter
with learned
challenge ?
Adaptive
motor plan of action
Adaptive
motor
response

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

12. Poor motor conditioning in cerebellar rats

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

14. 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 responses.
Extension to three stage theory of learning:
3rd stage: Extinction of fear responses after acquisition of motor responses.

15. Individual with motor disorder facing an aversive challenge
The three stage theory of learning predicts:
1st stage: Fast acquisition of fear responses.
2nd stage: No/poor acquisition of motor responses.
3rd stage: No extinction of fear responses (anxiety disorder?).

16. 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 motor system.
Clinical: In contradiction to the present dogma, motor rehabilitation may ameliorate the anxiety symptoms.

17. 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?

18. 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.

19. 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.

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

21. 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, K. & Hertzano, R.

22. Hdb vs. wild-type in open-field test
With Schahar Fisher

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

24. %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
With Susanna Pietropaolo
Benjamin K. Yee
Joram Feldon

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

26. Children with anxiety as primary disorder
Erez, O., Gordon, C.R., Sever, J., Sadeh, A. Mintz, M

27. 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.

28. 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

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

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

31. Relation between balance performance and parental report on emotionality

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

33. דוגמא של אימון בערסל:

34. 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

35. 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

36. 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.

37. (תגובה לכתבה 'כח המח' במוסף הארץ)
שלום
אני בן 29 שסובל מחרדת קהל (ומדי פעם מחרדה כללית). רציתי להגיד לכם שעליתם על משהו מהפכני !כאשר אני עומד לאבד את שיווי המשקל (נגיד להחליק) או כאשר אומרים לי לדבר בפני קהל ההרגשה זהה. ולכן אני חושב שזאת אותה מערכת משוב במח עבור חרדה כלשהי ואיבוד שיווי משקל.
הסבר : למצב של הרגשת איבוד שיווי משקל עם הקטנוע אני לא מוכן להגיע (מסוכן) ולכן מצבי החרדתי לא משתפר. חיפשתי משהו שיגרום לי להרגיש את תחושת איבוד שיווי המשקל החריפה אך לא יהיה מסוכן מדי והתחלתי ללכת על דופן האמבטיה .נוצר שיפור מסוים ברמת החרדה אך הרגשת איבוד שיווי המשקל למצב זה חלפה ועל מנת להמשיך בשיפור אני אצטרך למצוא משהו מסוכן יותר .לפי דעתי אם תפתחו שיטות בטוחות לאימון שיווי משקל עם רמת קושי עולה יהיה אפשר להתגבר על חרדות חזקות מכל הסוגים.
מקווה שהייתי מובן ולעזר
בהצלחה     אמיר

39. End of presentation

40. Auditory CS pathways

41. Bottom-up implementation of anatomy

42. 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).

43. Emotion and feeling
Emotion = bodily state mediated by subcortical & peripheral autonomic, endocrine & skeletomotor res.
Feeling = conscious sensation mediated by cingulate & frontal cortex.
Stimulus

44. Expansion of the limbic system
MacLean expanded the limbic system to include the septum, accumbens, amygdala, orbitofrontal cortex.
Amygdala and not the hippocampus coordinates the activity of the hypothalamus with the cortex.

45. Amygdala, rather than Papez’s hippocampus
Conscious feeling:
Cingulate cortex
Parahippocampal
Prefrontal
Amygdala
Somatic emotion:
Hypothalamus
Brainstem nuclei
Electrical stim of human amygdala → triggers feeling and somatic expression of fear.
Calcification of human amygdala (Urbach-Wiethe disease) → disrupts implicit processing of facial cues of fear but does not impair explicit recognition of faces/objects.

46. Amygdala mediates acquired emotional responses
Studied in context of classical conditioning: CS – US association and contingency (predictability).
Amygdala→ Rapid Res.
Tone CS→ Brainstem→ Thalamus
Cortex→ Amygdala→ Slow Res.
Somatosensory US→ Brainstem→ Thalamus→ Amygdala→ Rapid Res.

47. Output of the central n. through the stria terminalis & v
Output of the central n. through the stria terminalis & v. amygdalofugal pathway