Anxiety: old data and new theory Jerusalem May 2004 Matti Mintz Psychobiology Research Unit Department of Psychology Tel Aviv University http://freud.tau.ac.il/~mintz mintz@freud.tau.ac.il In the future, neurology will provide satisfactory explanation of anxiety (Freud).

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

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

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

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

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)

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

Is amygdala involved in the enhanced cerebellum-based motor conditioning

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

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

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

Poor motor conditioning in cerebellar rats

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

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.

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?).

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.

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, K. & Hertzano, R.

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

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

%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

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 Erez, O., Gordon, C.R., Sever, J., Sadeh, A. Mintz, M. 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 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

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

Relation between parental report on balance and self-reported emotionality

Relation between balance performance and parental report on emotionality

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

דוגמא של אימון בערסל:

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

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

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.

(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

End of presentation

Auditory CS pathways

Bottom-up implementation of anatomy

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).

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

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.

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.

Amygdala mediates acquired emotional responses 18.5.04 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.

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