1. Neurological basis of anxiety Seminar 2006-07 Matti Mintz Psychobiology Research Unit Department of Psychology Tel Aviv University http://freud.tau.ac.il/~mintz mintz@freud.tau.ac.il 29/10/06 netanya 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 Inputs:  Genetically defined US’s  Experience defined CS’s  Thoughts & Memories Outputs:  Feelings  Autonomic  Facial  Actions  Cognitive

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. Para or pre-vertebral ganglia Spine Preganglionic Postganglionic Target

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 29/10/06 netanya

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

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

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

22. Normal individual facing an aversive challenge The two stage theory of learning predicts: 1 st stage: Fast acquisition of fear responses. 2 nd stage: Slow acquisition of motor/cognitive responses. Extension to three stage theory of learning: 3 rd 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: 1 st stage: Fast acquisition of fear responses. 2 nd stage: Poor acquisition of motor responses. 3 rd stage: No extinction of fear responses.

24. 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. Possible implications for anxiety disorder

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: 1 st stage: Fast acquisition of fear responses. 2 nd stage: No acquisition of balance restoration motor responses. 3 rd 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. ELEVATED PLUS MAZE OPEN FIELD TEST 0 200 400 600 800 1000 1200 1400 males Distance moved (cm) no climbing climbing 0 5 10 15 20 25 30 35 %entries into the open arms no climbing climbing 0 2 4 6 8 10 12 %Time spent in the open arms (sec) no climbing climbing females males females males females * § * § § Climbing effect § Gender effect C57/BL6 mice deprived of climbing activity (P0-P50) and tested on elevated Plus Maze 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 G roup effect M anipulation effect Test ns Floor-bench ns Eyes open-closed ** Stand heel-to-toe * ns Floor-bench-trampoline *** Eyes open-closed *** Stand on one-foot ns*Head still-nodding * Stand on cylinder ns Eyes open-closed *** Walk on cubicles ns * *Normal-heel-to-toe *** Eyes open-closed *** Walk on 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 r=-.32 r=-.52*

39. Relation between balance performance and parental report on emotionality r=.03 r=-.72*

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 O After treatment 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 O O Before treatment Treatment Control Group by Time: p<.001

42. 0.00 5.00 10.00 15.00 O O After treatment 0.00 5.00 10.00 15.00 O O Before treatment Treatment Control 0 50 100 15 0 O O 0 50 100 150 O O CBCL: Parental reports Fear Survey: Child Report Gr x Treatment: p<.001 Anxiety level

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