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Neural plasticity in otology
•
Chapter 132, Robert V Harrison
•
Ivan A Lopez PhD
Neural plasticity underlies many clinical events in otology:
• a) Adaptation to a vestibular insult, b) rehabilitation after hearing loss,
c) auditory learning after a cochlear implant all are mediated by neural
rewiring.
• Changes in the pattern of peripheral input in the auditory system have
effects on central neural organization. After a period of deafness,
functional and structural changes occur in the auditory brain.
• Neural plasticity is age-related. There is a maximum change in early
development.
• Early Cochlear implant or hearing aid benefit congenitally deaf child
(the earlier the better).
• Early detection and diagnosis of hearing cells (neonatal hearing
screening).
Definition of Plasticity
• Anatomical studies established that plasticity relates to
morpho-physiological (cellular and molecular) changes in the
brain.
• The auditory and vestibular system have the inherent ability
to modify or reorganize.
• Example Levi-Montalcini experiment (J Comp Neurol 1949,
91;209-242), where anatomical changes of the auditory
pathway after experimental lesions to the inner ear were
documented.
• Cell counts, axonal pathway changes and alteration to
neural structure were observed to follow partial or total
auditory deafferentation.
Methods to study plastic change
• Electrophysiological studies in animal model and
humans, functional neuro-imaging studies (PET,
functional MRI, magneto-encephalographic
studies.
• Behavioral studies monitored hearing
performance after manipulation of the auditory
input.
• Observation of improved sensory function over
time in patients with hearing or vestibular loss.
Time course of plastic change
•
Changes to the auditory system occur from minutes, to weeks or months and
years.
•
In acute plasticity auditory neuron receptive fields (excitatory and inhibitory
frequency tuning curves) change within 10 minutes after induction of cochlear
lesions or partial deafferentation.
•
Short term plastic changes may occurred but is not clear whether these changes
would be consolidated in longer term.
•
Extensive auditory system reorganization after trauma occur over longer time.
•
Studies have shown a modification of central tonotopic mapping as a result of
cochlear lesion.
•
The time course of plastic change occurs over many weeks. In some cases
extensive reorganization occurred, for example new axonal growth and
synaptogenesis have occurred.
Age related plasticity
• Reorganization of tonotopic maps after cochlear
lesions is significantly different when
experimental manipulation is done in the
neonate compared with the adult animal.
• Example: performance of a congenitally deaf
child provided with a cochlear implant at an early
age compared with a deaf child implanted a
much later age.
Reorganization of central tonotopic
maps after cochlear lesions
• Tonotopic maps can be considered the
mainline organizational feature of the
auditory system.
• These projections are called cochleo-topic
(or tonotopic), given the place coding of
sound frequency along the cochlear
length.
Tonotopic map in normal cat auditory cortex
as determined by microelectrode recordings
3 neurons
Isofrequency contours are imaginary planes that connect the positions of all the cells having similar frequencies
Aef: anterior ectosylvian fissure; pef, posterior ectosylvian fissure; sf: sylvian fissure
• What are the plastic changes in the
tonotopic map after ototoxic treatment?
• There is a reorganization of the tonotopic map.
• Age, time and dose dependent, degree of
cochlear damage.
Tonotopic map reorganization in a developmental model
after ototoxic treatment (cat)
• Amikacin was given
systemically, cochlear lesions
were bilaterally symmetric
• ABR shows hat the basal
region of the cochlea was
damaged, but apical areas
(6-8kHz region) were
preserved.
• The cortical tonotopic map is
characterized by a normal
representation of low
frequencies, but the cortical
region deprived of normal
input now contains neurons
tuned to 6-8 kHz
Cortical tonotopic maps in a cat with neonatal basal
cochlear lesion
The cochlear lesion was more extensive
With a severe basal region and hair cell
loss at the apical region
The ABR slopes down across al
frequencies
This animal developed a cortical
frequency map in which all neurons
have a common 6.6 kHz frequency
tuning
The low frequency region is severely
distorted
Cortical frequency map reorganization in adult chinchilla after ototoxic
treatment
A. Normal tonotopic map
B. Cochlear lesion. A typical finding overrepresentation of neurons with
frequency 2.5-3.5kHz
Conclusions
• Modification to cortical frequency maps
are the result of neural rewiring.
• The excitatory receptive fields of neurons
tuned to the common frequency are similar
in shape.
• They have similar minimum thresholds
and bandwidths
Adult versus developmental plasticity of sensory systems
• At the auditory cortex there seems to be a pattern of
reorganization of tonotopic maps after cochlear lesions
in the developing neonate similar to that of adult animal.
• Tonotopic maps in sub-cortical auditory nuclei show
significant differences in map reorganization after lesion
in a developmental model compared with mature
subjects.
• At sub-cortical levels there is evidence of age-related
plasticity.
Tonotopic map reorganization at
subcortical levels (IC)
• What are the changes in the subcortical levels
(inferior colliculus).
• In normal conditions the tonotopic maps shows
an orderly progression of the neuron
characteristics frequency .
• After cochlear lesion in the neonate there is
normal octave-spaced frequency up to 10 kHz,
at more ventral areas there is large region
containing identically tuned neurons.
Tonotopic map reorganization at
subcortical levels (IC)
• Normal
tonotopic map
of the chinchilla
inferior
colliculus.
Tonotopic maps of the chinchilla inferior
colliculus after ototoxic treatment
There is a normal octavespaced frequency
contours within the IC up to
10 KHz.
There is a large
region containing
identically tuned neurons
Amikacin 3 days
Maps derived from single neuron recordings in electrode tracks along the dorso-ventral axis of the IC
Conclusions
• These studies establish that tonotopic map
reorganization occurs at low levels in the
auditory pathway after basal cochlear
lesions induced in early postnatal period.
• In adults partial cochlear deaferentation
produces no reorganization at the level of
the cochlear nucleus.
Salient aspects of developmental and
adult plasticity experiments
Early development
Neural projections
between levels
have considerable
divergence throughout
the system
Dynamic cellular and
molecular changes occur
at this stage
Adult
Normally developed
projection system
Normal point to point
cochleotopic projection
System from the cochlea to
the auditory cortex
Developmental plasticity after
lesion
Cochlear lesion induced
Neonatally
At the level of the auditory
cortex and at the midbrain,
deaferented areas
contain neurons that seem
to be connected to
common points along the
cochlea
Adult plasticity
Cochlear lesions
induced in an adult
Very little evidence of
frequency maps
reorganization have been
seen.
Rewiring to produce
overrepresentation is
confined to the cortex
Tonotopic maps after long-term local
excitation of the cochlea
• What happen when there is
augmented cochlear afferent
activity?
Experiment
• Cats were reared in an environment where
an 8-kHz acoustic signal was constantly
present (55 to 60db). The 8kHZ tone was
frequency modulated to avoid adaptative
effects and hair cell damage.
• Six months after tonotopic maps were
created.
Tonotopic maps in the auditory cortex of a cat
Frequency map from
normal control
The 8 to 16 kHz
octave interval is
shaded to
Emphasize the
main difference
between subjects
Cat that spent
1 month postnatally
in an acoustic
environment with
a constant 8-KHz
signal.
Bottom (A) normal point to point normal organization
(B) Increase firing rate of a group of midcochlear neurons
Conditions for plasticity in the adult cortex
•
Plasticity of sensory cortex occurs after repeated chronic exposure to well
specified stimuli.
•
Plastic changes are evident only if the sensory stimulus as behavioral
significance to the animal.
•
Long term changes in the auditory neuron receptive field are induced in
tonal stimulation associated to various behavioral conditioning tasks.
•
A model was proposed that the nucleus basalis the source of cholinergic
projections to the sensory cortex has important role in plastic modifications
to cortical networks.
•
The developing system maybe significant different.
•
Passive overstimulation can result in the development of a modified map.
Animal models of deafness and effects of cochlear
implant electrical stimulation
• A wide range of structural and functional
changes have been observed in the auditory
system in association with experimental and
naturally occurring deafness.
• Important question relates whether stimulation
with a cochlear implant can serve to restore
critical features of auditory function such as
synaptic integrity.
Studies of cochlear electrical stimulation in
animal models of deafness
• Auditory terminal endings in deaf cats exhibit
morphological abnormalities that are partially reversible
with restored activity with cochlear implantation.
• There are positive effects of electrical stimulation on
auditory brain stem nuclei, midbrain and auditory cortex.
• Results suggest that there is a critical period or at least
age-related plasticity for the developing auditory cortex
Basic mechanism of plastic change
• Neural reorganization is the result of several
mechanism.
• The behavior of underused neurons depends on
the establishment of synaptic connections, the
pruning of underused synapses, and the
strength of individual connections.
• External neural and hormonal factors can
facilitate plastic change.
• Some mechanisms present during development
may not play important role in the mature brain.
• Initial connections involved chemotropic guidance
and myelination processes, are not present in the
mature brain.
• Drastic pruning of interneuronal connections do
not occur in the adult.
• Thus the mechanism of plasticity are different
during development and the adult brain.
Mechanisms of plasticity at a
systems physiology level
• As seen before during neonatal period the divergent
innervation pattern develops into the normal point to point
projection systems.
• Many mechanism are likely involved in this process.
• Growing neurons are making connections with target cells
and there is a physical space competition such that neurons
that are most proximal win out.
• Synaptic strengthening through long-term potentiation
strength the most directed connections and promote their
survival.
• Sound-driven neural activity likely is more influential in the
formation of the adult connectivity.
• This is the case if synaptic strength follow Hebbian rules,
• Robust strengthening of connections
between neurons is achieved under
conditions where patterns of pre-synaptic
and postsynaptic activity are highly
correlated.
• This is the case for an acoustic stimuli that
drives identical patterns in neighboring cell
groups.
Tonotopic map reorganization in
the developing subject
Auditory projection resulting from basal
cochlea lesion
during early developmental period,
At the AC and MB deaferented areas
contain neurons
connected to a common point along the
cochlea.
A mechanism to explain this is that
divergent neural projections are not
eliminated because in the adjacent
deafferented region there are not
neurons competing for target cells
There is always a small degree of
divergence associated with tonotopic
projections
Cortical map plasticity in adult subjects
This map represent changes after cochlear
lesion in a mature animal
Little evidence of frequency map
reorganization is found at the subcortical
levels
Rewiring to produce overrepresentation is
confined to the thalamocortex,
Two mechanisms
1) Alteration of preexisting neural
connections
2) Nerve growth processes such as
neurogenesis, axon sprouting and
synaptogenesis.
Conclusion
• In the auditory cortex and thalamus there is
some degree of divergent input.
There are laterally connecting local interneurons
and there are larger interneuronal connections
• They are normally inhibited.
• Local deaferentation release that inhibition
unmasking of existing lateral connections
Cellular level mechanism of plasticity
Post-tetanic potentiation: A presynaptic neuron
excites a second neuron, repeated presynaptic
modulation result in an increased effectiveness
of the synapse that is maintained for some time.
The theory behind short –term plasticity is that it is
caused by presynaptic Ca2+ accumulation that
enhances neurotransmitter release
Long term potentiation
• Long term modifications of synapses could be experimentally
induced.
• LTP can result from a repeated activation f the synapse.
• LTP exist ubiquitously in the brain.
• NMDA receptor is involved in LTP.
• NMDA receptor is a fast ionotropic ion channel activated by
glutamate.
• Synapses with NMDA receptor can develop LTP but not when the
receptor is blocked.
• The key aspect of the NMDA receptor is
that its ion channel has a voltage –
dependent Mg2+ block that can alter the
cell excitability, by controlling Ca2+
permeability .
• The metabotopic glutamate receptor can
also be involved in LTP.
Hebb’s Postulate
• Synaptic systems involving NMDA receptor frequently follow hebbian
rules.
• In 1949 Hebbs postulate that when an axon of cell A is near to excite
cell B and repeatedly or persistently takes part in firing it, some growth
process or metabolic change takes place in one or both cells such that
A efficiency as one of the cells firing B is increased.
• “Cells that fire together, wire together”
Acoustic stimulation results in groups of neurons in ascending arrays
with highly correlated activity.
Important condition for establishing and maintaining tonotopicity
When Neuron A talks to Neuron B,
glutamate binds to the NMDA channel and
opens it. No LTP occurs because the
magnesium ion blocks the channel!
If Neuron B is activated, magnesium
unblocks the channel but since Neuron A
is not active, no glutamate is bound and
the channel does not open.
Only when both Neuron A and Neuron B
are activated does the NMDA receptor
become activated: magnesium unblocks
the channel and glutamate opens the
channel.
In this way, the NMDA receptor acts as a
“coincidence detector” that detects the
simultaneous activation of both Neuron A
and Neuron B.
As Donald Hebb hypothesized, when both
neurons are activated at the same time,
their connections are strengthened
Pre and postsynaptic mechanism
for enhancing synaptic efficacy
1 More synaptic vesicles
2 Increase in the number of release
sites
3 Potentiation of a release by
increase vesicle available for release
4 Increase in the sensitivity of existing
postsynaptic receptors
5 Increase number of receptors
6 Synaptogenesis
Practical Issues relating to neural
plasticity in otology
• Hearing loss in infants: hearing loss during early
development may negatively affect central
development.
• There is a critical period during which cochlear
function needs to be particularly intact.
• Mild hearing loss, chronic conductive hearing
loss, and bilaterally asymmetric hearing loss
may alter normal central pathway development.
• Neonatal hearing disorders that might lead
to problems in language development
become evident 4 or 5 years later when
such development can be assessed.
• The best practical strategy is to have early
detection of hearing problems through
neonatal or infant hearing screening
programs and subsequent early
intervention with hearing aids, cochlea
implants and auditory habilitation training.
Experiments in deaf children with
cochlear implants
• Average post-implantation performance on
standard speech understanding test.
• All children were prelingually (congenitally)
deaf, the population was homogeneous in
terms of degree of residual hearing ,
school settings and access to
rehabilitation therapy.
• The data set has been divided into children
implanted at an early age compared with
children impaired later.
• On average children implanted at a young
age eventually outperform others.
• Similar conclusions are reached in other
interventions outcome studies in vision,
sensory motor training and education
The influence of age at implantation on speech hearing tests in
congenitally or prelingually deaf children
Test of auditory comprehension
Word intelligibility by picture identification
(WIPI)
Glendonal auditory screening procedure
(GASP)
Conclusions
• Compensation for any neural deficit is best
achieved by early intervention.
• Central auditory system development is guided
by cochlear activity patterns.
• A cochlear implant provided to a young infant
would aid hearing but also the augmented
stimulation of the system would have an
influence on central development.
Other hearing disorders
• Tinnitus could arise from auditory neurons that develop selfperpetuating activity.
• Synaptic efficacy can be increased by LTP and hebbian
mechanisms is easy to conceive of local circuits being reinforced to
the point of reverberation (positive feedback mode).
• Other mechanism: synchronous firing of extensive isofrequency
neural population results in all of them being connected together.
• Assuming that conscious perception has some basis in cortical
neural activity even low levels of resting activity could give rise to a
chronic sound sensation
Tinnitus
• There are different types of tinnitus i.e. central and
peripheral tinnitus.
• Studies on central auditory plasticity draw attention to
the fact that a cochlear lesion can cause central
reorganization.
• It is plausible that some traumatic event could set up
connection patterns that result in cortical
overrepresentation
• Although the central neurons are presumable the
immediate cause of the tinnitus sensation, the intimate
link to a causal peripheral lesion blurs any notion about
the real origin of the tinnitus.
Conclusions
• The brain is a constantly reorganizing
system.
• Plasticity is the rule, not the exception.
• Mechanism that stabilize the brain and
prevent plasticity need to be investigated.
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