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 re-shaped 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 POST-SYNAPTIC 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

Connections from the amygdala

Auditory cortex

Thalamus

From: Møller: Sensory Systems, 2002Fig 3.7

DorsalmedialMGB

AII

VentralMGB

Thalamus

AAF

Endocrine

Behavioral

Autonomic

AI

ICXDC

ICC

Amygdala

Associationcortices

AL ABL ACE

Nucleusbasalis

Arousaland

plasticity

Cortex

"High Route"

"Low Route"

Polymodalassociation

cortex

Other corticalareas

From: Møller: Sensory Systems, 2003

Connections from a sensory system to the amygdala “the high route”

• SLOW

• CARRIES HIGHLY PROCESSED INFORMATION– “SLOW AND ACCURATE”

HIGH ROUTE

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”

From: Møller: Sensory Systems, 2003

Connections from the amygdala

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

From: Møller: Sensory Systems, 2003

Classical auditorypathways

Non-classical auditory pathways

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 SYSTEMMAY 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