Neurological basis of anxietySeminar 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).

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.

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?

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

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.

Mechanistic approach to emotional brain

ComputationInputs: Genetically defined US’s Experience defined CS’s Thoughts & Memories

Outputs: Feelings Autonomic Facial Actions Cognitive

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.

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.

Autonomicganglia

Para or pre-vertebral ganglia

Spine Preganglionic Postganglionic Target

SNS

1- preganglionic neuron2- spinal nerve4- para-vertebral ganglia6- autonomic nerve8- pre-vertebral ganglia9- terminal ganglia

Brainstem (III, VII, IX, X-vagal) Sacral spine

Autonomic gangliaNear the target

PSNS

29/10/06 netanya

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.

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.

Biological-Psychiatry and Psychology Normal fear/anxiety generated by limbic system

Aversive events:Exo/EndogenousCS/US

Normal processing by brain-limbic structures

Normal anxiety:Emotional-somatic stateConscious feeling

Biological-Psychiatry and PsychologyAnxiety disorder generated by limbic system

Harmless & aversiveevents

Disordered processing by brain-limbic structures

Excessive anxiety:Emotional-somatic stateConscious feeling

Limbic disorder:Genetic/AcquiredFunctional/StructuralGABA/SerotoninSynaptic

Amygdala: rapid evaluation emotional state

Cortex: slow evaluation conscious feeling

Alternative origins of anxiety disorder:Non-limbic dysfunction?

Normal processing of a novel challenge

Encounterwith a novelchallenge

Fast fear processing

Slow motor& cognitiveprocessing

Adaptivemotor/cognitiveresponse

?

Adaptivefearresponse

When anxiety should become extinct ? 5/11/06

Encounterwith familiarchallenge

Extinctionof fear processing

Activation of motor plans

Adaptive motorResponse

?

No fearresponse

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.

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.

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

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 & Hertzano, 2004.

Hdb vs. wild-type in open-field test

Time in HB (sec) - 1 month old [Interaction: F(19,342)=2.5, p<0.001]

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Minutes

Hdb Wt

Time in center (sec) - 1 month old[Interaction: F(19,342)=2.6, p<0.001]

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Minutes

Hdb Wt

Fisher & Mintz

1 Month OldTime in Closed Arms (sec)

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2 Months OldTime in Closed Arms (sec)

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3 Months Old T ime in Closed Arms (sec)

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

ELEVATED PLUS MAZE OPEN FIELD TEST

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males

Dis

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cm)

no climbing

climbing

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males femalesmales females

*

§*

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• Climbing effect

§ Gender effect

C57/BL6 mice deprived of climbing activity (P0-P50) and tested on elevated Plus Maze

Pietropaolo, Yee, Mintz & 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

Group Origin Diagnosis of anxiety

Age (yrsSEM)

Gender (F/M)

Anxiety (n=20)

Ambulatory clinic

Separation (n=11) Generalized (n=7) PTSD (n=1) Phobias (n=1)

10.20.38 (7-14)

8/12

Control (n=20)

Normal class children

10.60.36 (7-13)

8/12

Erez et al., 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

TestManipulation effectGroup effect

Interaction

G by M

Standheel-to-toe

Floor-bench ns Eyes open-closed **

nsnsns

Stand on one-foot

Floor-bench-trampoline *** Eyes open-closed ***

ns*ns

Stand on cylinder

Head still-nodding * *ns

Walk oncubicles

Eyes open-closed *** nsns

Walk onrope

Normal-heel-to-toe ***Eyes open-closed ***

*ns*

*p<0.05; **p<0.01; ***p<0.001

Children with imbalance as primary disorder

N ♂/♀ Age (yrs±SE

M

Age range (yrs)

Clinical Referred to OT for balance treatment

35 26/9 5.8±0.10 5.0-7.3

Control Normal class children

25 15/10 5.8±0.15 5.0-7.3

With Meidan, M., Sadeh, A., Brat, O.

Relation between parental report on balance and self-reported emotionality

10

20

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0 10 20 30

Anxiety - Depression (CBCL)

Ve

sti

bu

lar

Sc

ale

(D

un

n) Clinical

Control

r=-.32

r=-.52*

Relation between balance performance and parental report on emotionality

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0 10 20 30

Anxiety - Depression (CBCL)

Bal

ance

(B

run

inks

) Clinical

Control

r=.03

r=-.72*

Balance rehabilitation in children with imbalance as primary disorder

N ♂/♀ Age (yrs±SE

M

Age range (yrs)

Treated Referred to OT for balance treatment

25 22/3 5.4±0.08 5.0-6.1

Non-treated

Waiting list of similarly referred children

24 21/3 5.4±0.09 5.0-6.1

With Weisman, E., Bar-Haim, Y., Brat, O.

Balance test (Bruninks-Oseretsky)

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Before treatment

Treatment

Control

Group by Time: p<.001

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After treatment

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Before treatment

TreatmentControl

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100

150

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150

CBCL: Parental reports

Fear Survey: Child Report

Gr x Treatment: p<.001

Gr x Treatment: p<.001

Anxiety level

Standard training

Training of balance skills througha computerized game

It is the same kid before - - - - - - - - - - - - - and - - - - - -- - - - - - - - - - after 2 months of training

Training of balance skills througha computerized game

It is the same kid before - - - - - - - - - - - - - and - - - - - -- - - - - - - - - - after 2 months of training

The computerized game:how it is done

The computerized game:visual interference

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.

End of presentation