Post on 30-Dec-2015
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]
0
5
10
15
20
25
30
35
40
45
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Minutes
Hdb Wt
Time in center (sec) - 1 month old[Interaction: F(19,342)=2.6, p<0.001]
0
5
10
15
20
25
30
35
40
45
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Minutes
Hdb Wt
Fisher & Mintz
1 Month OldTime in Closed Arms (sec)
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10
2 Months OldTime in Closed Arms (sec)
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10
3 Months Old T ime in Closed Arms (sec)
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10
Hdb vs. wild-type in elevated Plus-Maze test
ELEVATED PLUS MAZE OPEN FIELD TEST
0
200
400
600
800
1000
1200
1400
males
Dis
tan
ce m
ove
d (
cm)
no climbing
climbing
0
5
10
15
20
25
30
35
%en
trie
s in
to t
he
op
en
arm
s
no climbing
climbing
0
2
4
6
8
10
12
%T
ime
sp
en
t in
th
e o
pe
n
arm
s (s
ec)
no climbing
climbing
females
males femalesmales females
*
§*
§
§
• 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
30
40
50
60
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
0
5
10
15
20
25
30
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)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
After treatment
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Before treatment
Treatment
Control
Group by Time: p<.001
0.00
5.00
10.00
15.00
After treatment
0.00
5.00
10.00
15.00
Before treatment
TreatmentControl
0
50
100
150
0
50
100
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