SYMPTOMS AND SIGNS CAUSED BY NEURAL PLASTICITY
description
Transcript of SYMPTOMS AND SIGNS CAUSED BY NEURAL PLASTICITY
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