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SYMPTOMS AND SIGNS
CAUSED BY NEURAL
PLASTICITY
Signs and symptoms of disorders
• Not everything can be seen on MRI or
other imaging techniques
• Not everything has positive laboratory
tests
Neural plasticity play greater role
in generating symptoms and
signs than previously assumed
• Plastic changes are reversible
• Treatments without medicine and
surgery may alleviate pain and tinnitus
Neural plasticity
• The brain is far from being a fixed system
but it is continuously shaped and reshaped by what it receives from the
outside world.
• Sensory systems provide the input that
shapes the brain.
NEURAL PLASTICITY
• Adjust the nervous system to changing
demands (based on sensory input)
• Compensate for deficits through injury or
diseases
• Cause symptoms and signs of diseases
PROMOTERS OF NEURAL
PLASTICITY
• Deprivation of sensory input
• Overstimulation
DEPRIVATION
• “Use it or loose it”
NEURAL PLASTICITY
• NEURAL PLASTICITY IS AN ABILITY OF
THE NERVE CELLS TO CHANGE THEIR
FUNCTION OR STRUCTURE
• THE CHANGES OCCUR WITHOUT
DETECTABLE MORPHOLOGIC
CHANGES (USING STANDARD
CLINICAL METHODS)
FUNCTIONAL CHANGES ARE
CAUSED BY:
• CHANGE IN SYNAPTIC EFFICACY
• CHANGE IN NEURAL EXCITABILITY
• ELIMINATION OF NERVE CELLS
(APOPTOSIS)
• CREATION OR ELIMINATION OF
CONNECTIONS (AXONS AND
DENDRITES)
SYMPTOMS AND SIGNS
•
•
•
•
HYPERACTIVITY
HYPERSENSITIVITY
CHANGE IN NEURAL PROCESSING
CHANGE IN PERCEPTION OF
SENSORY INPUT
• CHANGE IN MOTOR FUNCTION
HYPERACTIVITY
•
•
•
•
MUSCLE SPASM
TINNITUS
PARESTHESIA (TINGLING)
PAIN
Success of treatment supports
hypotheses of neural plasticity
• Pain can be alleviated by electrical
stimulation
• Tinnitus can be alleviated by sound
stimulation
Hyperactivity of the vestibular
system
• Ménière's disease
– Air puffs applied to the inner ear can reverse
symptoms
HYPERSENSITIVITY
• LOWERED THRESHOLD FOR
SENSORY STIMULATION
• EXAGGERATED REACTION ON
SENSORY STIMULI
CHANGE IN NEURAL
PROCESSING
• ALLODYNIA
(PAIN FROM INNOCUOUS STIMULATION)
• HYPERPATHIA
(LOWERED TOLERANCE TO MODERATE
PAIN AND PROLONGED PAIN SENSATION)
CROSS MODAL INTERACTION
MECHANISMS OF NEURAL
PLASTICITY
• CHANGE IN SYNAPTIC EFFICACY
• NEW CONNECTIONS (SPROUTING)
UNMASKING OF DORMANT
SYNAPSES MAY CAUSE:
• INCREASE OF SENSORY RESPONSE
AREAS
• SPREAD OF MOTOR ACTIVATION
(SYNKINESIS)
• ACTIVATION OF NEW BRAIN REGIONS
MAY (“RE-WIRING”)
EXTENSION OF ACTIVATION OF
MOTOR AREAS
MAY CAUSE SYNKINESIS
• FACIAL SYNKINESIS AFTER INJURY TO
THE FACIAL NERVE
• LATERAL SPREAD OF BLINK REFLEX
IN HEMIFACIAL SPASM
ACTIVITY DEPENDENT
SYNAPTIC PLASTICITY
•
•
LONG TERM POTENTIATION (LTP)
LONG TERM DEPRESSION (LTD)
– HIGH-FREQUENCY TRAINS ARE
EFFECTIVE IN INDUCING LTP
(IS THE “NOVEL STIMULATION” OFTEN
REFEREED TO IN NEURAL PLASTICITY A
HIGH FREQUENCY TRAIN?)
ACTIVITY DEPENDENT
SYNAPTIC PLASTICITY
•
•
ACETYLCHOLINE IS IMPORTANT IN
DEVELOPMENT
NICOTINIC ACETYLCHOLINE
RECEPTORS MAY MODULATE
GLUTAMATE RECEPTORS
– MEDIATE LONG TERM CHANGES IN
SYNAPTIC EFFICACY
– AFFECT MATURATION OF THE NERVOUS
SYSTEM
ACTIVITY DEPENDENT
SYNAPTIC PLASTICITY
•
SYNCHRONOUS PRE AND POSTSYNAPTIC ACTIVATION PROMOTE
NEURAL PLASTICITY
– HEBB’S PRINCIPLE: “NEURONS THAT
FIRE TOGETHER WIRE TOGETHER”
ACTIVITY DEPENDENT
SYNAPTIC PLASTICITY
•
THE TEMPORAL PATTERN OF
NEURAL ACTIVITY IS IMPORTANT
NEW BRAIN REGIONS MAY
BECOME ACTIVATED
• DISORDERS OF THE VESTIBULAR
SYSTEM
– AWARENESS OF HEAD MOVEMENTS
– DIZZINESS
– NAUSEA AND VOMITING
NEW BRAIN REGIONS MAY
BECOME ACTIVATED
• CHRONIC PAIN
– ALLODYNIA
– INVOLVEMENT OF THE
SYMPATHETIC NERVOUS SYSTEM;
RSD*)
*) REFLEX SYMPATHETIC DYSTROPHY
NEW BRAIN REGIONS MAY
BECOME ACTIVATED
• ACTIVATION OF NON-SPECIFIC
PATHWAYS THROUGH SUBCORTICAL
ROUTES
• INVOLVEMENT OF THE LIMBIC
SYSTEM
Severe tinnitus is often associated
with affective (mood) disorders
• Depression
• Phonophobia
The amygdala is involved in fear
and other mood disorders
Symptoms and signs of
neuropathic pain
• Strong emotional components
• Depression
• High risk of suicide
The amygdala is involved in fear
and other mood disorders
• Subcortical connections to the amygdala
may induce emotional response
unconsiously
– uncontrollable fear and rage
INVOLVEMENT OF LIMBIC
SYSTEM STRUCTURES
• AFFECTIVE DISORDERS
– DEPRESSION IN PAIN AND TINNITUS
INVOLVEMENT OF LIMBIC
SYSTEM STRUCTURES
• EMOTIONAL REACTIONS TO STIMULI THAT
NORMALLY DO NOT CAUSE SUCH
REACTIONS
• EXAMPLES:
– CHRONIC PAIN (HYPERPATHIA)
– SEVERE TINNITUS (PHONOPHOBIA)
Connections from the auditory
system to the amygdala
• Cortical-cortical connections
(the “high route”)
• Subcortical connections
(the “low route”)
How can pain information reach
the amygdala?
• Through the thalamus
• Through routes that are enhanced by
expression of neural plasticity (re-routing
of information)
MAIN CONNECTIONS TO THE
AMYGDALA:
• THALAMUS (MEDIODORSAL)
• PREFRONTAL CORTEX
– (VIA MEDIODORSAL THALAMUS)
•
•
•
•
SEPTAL NUCLEI
PERIAQUEDUCTAL GRAY (PAG)
TEMPORAL ASSOCIATION CORTEX
MOST CONNECTIONS ARE
RECIPROCAL
The “high route” and the “low route” to the amygdala
Arousal
and
plasticity
Cortex
Auditory cortex
AAF
"High Route"
AI
Association
cortices
Polymodal
association
cortex
Other cortical
areas
AII
Nucleus
basalis
Amygdala
"Low Route"
AL
Thalamus
Dorsal
medial
MGB
ICX
ICC
DC
ABL
ACE
Thalamus
Endocrine
Ventral
MGB
Autonomic
Behavioral
Connections from the amygdala
Fig 3.7
From: Møller: Sensory Systems, 2002
Connections from a sensory system to the amygdala
“the high route”
From: Møller: Sensory Systems, 2003
HIGH ROUTE
• SLOW
• CARRIES HIGHLY PROCESSED
INFORMATION
– “SLOW AND ACCURATE”
Connections from a sensory system to the amygdala
“the low route”
From: Møller: Sensory Systems, 2003
LOW ROUTE
• IS FAST
• CARRIES UNPROCESSED
INFORMATION
– “FAST AND AND DIRTY”
Connections from the amygdala
From: Møller: Sensory Systems, 2003
CONCLUSION
• ACTIVATION OF NON-CLASSICAL
ASCENDING SENSORY PATHWAYS
CAN CAUSE SYMPTOMS AND SIGN OF
SEVERAL DISEASES
MANY REGIONS
OF THE BRAIN
ARE
CONNECTED
Which routes are
active?
Depends on
synaptic efficacy
SENSORY INPUT CAUSES
ABNORMAL EMOTIONAL
REACTIONS
•
•
•
•
•
•
TINNITUS
PHONOPHOBIA AND HYPERACUSIS
DIZZINESS
ALLODYNIA
CHRONIC PAIN
AUTISM
INVOLVEMENT OF THE LIMBIC
SYSTEM IN HEARING:
• UNMASKING OF CONNECTIONS FROM
THE CLASSICAL AUDITORY SYSTEM
TO COMPONENTS OF THE LIMBIC
SYSTEM INVOLVING:
– MEDIO-DORSAL MEDIAL GENICULATE
BODY
– ASSOCIATION CORTICES
– AMYGDALOID NUCLEI
Classical auditory
pathways
Non-classical
auditory pathways
From: Møller: Sensory Systems, 2003
ESCAPABLE AND
INESCAPABLE FEAR
AUTISM
• ABNORMAL PERCEPTION OF
SENSORY INPUT
• MAY BE CAUSED BY ABNORMAL
INVOLVEMENT OF THE AMYGDALA
AUTISM
• Kluver-Bucy wrote in 1939 regarding the effect of
bilateral amygdalectomy in monkeys:
• “Monkeys are no longer capable of functioning as
members of social groups. They cannot recognize the
social significance of the exteriorceptive (especially
visual, auditory and olfactory) signals that regulate social
behavior, or relate then to their own affective states
(moods), which regulate approach to or avoidance of
other members of the group and are thus the building
blocks of social interactions. They avoid other members
of the group and seem anxious and insecure”.
AUTISM
• Similarities with the Klüver-Bucy syndrome
AUTISM
• SPECULATION:
• Insufficient pruning or apoptosis is
involved in autism
– THE AMYGDALA IN AUTISTIC
CHILDREN SEEMS TO HAVE A
HIGHER DENSITY OF CELLS THAN
NORMAL.
AUTISM
• SPECULATION:
– NONSPECIFIC SENSORY PATHWAYS MAY
BE HYPERACTIVE CAUSING TOO MUCH
INPUT TO ASSOCIATION CORTICES AND
LIMBIC STRUCTURES.
– SPECIFIC SENSORY PATHWAYS MAY BE
HYPOACTIVE SO THAT LESS INPUT
REACHES PRIMARY CORTICES.
HOW CAN WE TEST IF
NONSPECIFIC PATHWAYS ARE
INVOLVED:
• NONSPECIFIC SENSORY PATHWAYS
ARE POLYMODAL
• EXAMPLE: STIMULATION OF THE
SOMATOSENSORY SYSTEM CHANGE
PERCEPTION OF TINNITUS
HOW CAN NONSPECIFIC
PATHWAYS
BECOME ACTIVATED?
• UNMASKING OF DORMANT SYNAPSES
• CREATION OR ELIMINATION OF NERVE
CELLS
HOW CAN NONSPECIFIC
PATHWAYS
BECOME ACTIVATED?
• CREATION OR ELIMINATION OF NERVE
CELLS
– REQUIRES TIME TO DEVELOP
– AGE RELATED
UNMASKING OF DORMANT
SYNAPSES
– ACTS INSTANTLY
– DEPENDS ON INPUT
– DEPENDS ON TEMPORAL INTEGRATION
– DEPENDS ON AVAILABILITY OF NEURAL
TRANSMITTERS
– CAN BE MANIPULATED BY DRUGS
HOW DO SYNAPSES BECOME
DORMANT?
• DURING (NORMAL) CHILDHOOD
DEVELOPMENT
• THROUGH STIMULATION (SENSORY
INPUT)
SYNAPTIC RECEPTORS
UNDERGO CHANGES
DURING MATURATION
•
•
•
GABA CAN BE EXCITATORY IN IMMATURE
TISSUE.
GABA SYNTHESIS DECREASES WITH AGE
ONLY NMDA RECEPTORS IN IMMATURE
TISSUE
CONCLUSION
• ACTIVATION OF NON-CLASSICAL
ASCENDING SENSORY PATHWAYS
CAN CAUSE SYMPTOMS AND SIGN OF
SEVERAL DISEASES
ONTOGENETIC DEVELOPMENT
DEPENDS ON:
• GENETICS (AND EPIGENETICS)
• STIMULATION (SENSORY INPUT)
“NEURONS THAT FIRE TOGETHER
WIRE TOGETHER” (HEBB, 1949).
• OTHER ENVIRONMENTAL FACTORS
• CHEMICAL FACTORS (DRUGS,
ALCOHOL ETC.)
• UNKNOWN FACTORS
ONTOGENETIC (CHILDHOOD)
DEVELOPMENT SHAPES THE
NERVOUS SYSTEM BY:
• APOPTOSIS
• PRUNING OF AXONS AND DENDRITES
• CHANGE IN SYNAPTIC EFFICACY
NORMAL DEVELOPMENT OF
THE CENTRAL
NERVOUS SYSTEM INVOLVES:
• APOPTOSIS
• ADJUSTMENT OF SYNAPTIC EFFICACY
ABNORMAL DEVELOPMENT OF
THE CENTRAL
NERVOUS SYSTEM MAY BE
CAUSED BY:
• FAILURE TO BLOCK SYNAPSES
• INADEQUATE PRUNING OF THE
NERVOUS SYSTEM
MAY PLAY A ROLE IN:
• DEVELOPMENTAL DISORDERS
• OCULAR DOMINANCE
• AUTISM
WHAT CAUSE PLASTIC
CHANGES
OF THE CNS?
•
•
•
•
DEPRIVATION OF INPUT
NOVEL INPUT
ACTIVITY GENERATED BY INJURY
UNKNOWN FACTORS
PLASTIC CHANGES OF THE
NERVOUS SYSTEM ARE
REVERSIBLE
• THE ASSOCIATED DISORDERS ARE
TREATABLE
– DEPENDING ON CORRECT DIAGNOSIS
DISORDERS CAUSED BY
NEURAL PLASTICITY ARE
TREATABLE
• EXAMPLES:
– ELECTRICAL STIMULATION (TENS) CAN
ALLEVIATE NATUROPATHIC PAIN
– TRAINING CAN REDUCE SYNKINESIS
– TRAINING CAN REDUCE TINNITUS
EXAMPLES OF REVERSAL OF
NEURAL PLASTICITY
• “TENS” (TRANSDERM ELECTRIC
NERVE STIMULATION) HAS BEEN
USED FOR MANY YEARS IN
TREATMENT OF CHRONIC PAIN
• RECENTLY SOUND STIMULATION IN
VARIOUS FORMS HAVE BEEN
INTRODUCED IN TREATMENT OF
SEVERE TINNITUS
Stimulation of somatosensory
system can relieve tinnitus
• Electrical stimulation of the ear or the
skin behind the ears have been used to
treat tinnitus
• Few systematic studies of efficacy have
been published
CONCLUSION
DISORDERS CAUSED BY
FUNCTIONAL CHANGES OF THE
CENTRAL NERVOUS SYSTEM:
• FEW AND OFTEN AMBIGUOUS
SYMPTOMS AND SIGNS
• OFTEN DIAGNOSED INCORRECTLY
• OFTEN TREATED INEFFECTIVELY IF AT
ALL