Human Models of ExperienceDependent Brain Plasticity

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Human Models of Experience-Dependent Brain
Plasticity Animal studies have demonstrated
numerous examples of brain plasticity and have
revealed some of the underlying synaptic and
cellular mechanisms that allow continuous changes
and adaptations to occur in the CNS. With the
development of more sophisticated, non-invasive
methods to study the intact brain, plasticity
processes are now also being characterized in
the human brain. Methods 1. Functional
magnetic resonance imaging (fMRI) -detector
measures magnetic fields of atoms? -blood
flow increases to brain regions with greater
metabolic demands -oxygen absorbed from
hemoglobin -gt deoxygenated
hemoglobin has greater magnetic sensitivity -gt
increased fMRI signal 2. Structural
imaging 3. Electrophysiological measures
-EEG -event-related evoked potentials
(ERP) 4. Post-mortem anatomical studies
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In the mid 1980s, several researchers (e.g.,
Michael Merzenich, Jon Kaas) started to
study changes in sensory and motor maps of
animals in response to manipulations of
peripheral sensory receptors. The theoretical
basis for much of this work is provided by the
concept of cortical magnification factor a.
The area of cortex devoted to the analysis of
different sensory inputs is closely related to
the degree of sensitivity and resolution of
sensory processing. b. Similarly, the area of
motor cortex dedicated to control groups of
muscles is related to the complexity and skill
of movements to be executed. Examples a.
-fovea of retina highest spatial resolution,
greatest representation in V1 -fingers,
mouth, tongue in S1 highest sensitivity and
spatial resolution b. -fingers, tongue, lips in
M1
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Example of peripheral and central sensory
specialization Echolocation in Bats -emit 30
kHz sound plus harmonics CF constant frequency
component FM Frequency modulated
component -detect echo, about 61-61.5 kHz
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Two fundamental experimental approaches to
plasticity studies in humans 1. Plasticity
induced by loss of sensory input/motor output
e.g., blind, deaf, limb amputations 2.
Plasticity related to the acquisition of (or
predisposition for) special skills e.g.,
language, music, spatial skills Hypotheses
a. Loss of function (sensory, motor) should
decrease corresponding cortical
representation b. Compensation (i.e., increased
use of, and reliance on) in remaining sensory and
motor systems should increase their cortical
representation use-dependent shift in cortical
magnification factor c. Skill acquisition in
the absence of sensory- and motor deficits should
also result in a shift in cortical magnification
factor
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1. Plasticity induced by loss of peripheral
sensory input Cortical maps and their relative
size reflect highly specialized, functional
somatosensory and motor systems. Extensive
research in non-human animals has shown that
cortical maps are plastic and their relative
sizes can change in with experience (training -gt
increased size of trained portion of map, with
a corresponding shrinkage of other, non-trained
portions of map). Among the first to researchers
to extend this work to humans is Vilayanur
Ramachandran (1993) phantom limb sensations in
human amputation patients
(from Gazzaniga et al. Cognitive Neuroscience
Norton, 2002
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from hand
from face
gt sprouting of new axon collaterals to
re-innervate denervated target tissue
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Ramachandran (1993) there are some reports of
similar effects involving spread of
sexual feeling and orgasm to amputated foot and
legs, likely due to innervation of foot
representation in S1 by adjacent tissue that
responds to sensory input from genitals. These
are examples of intramodal plasticity, i.e.,
plasticity within the same sensory
modality. More larger-scale changes that cross
different sensory modalities are unlikely to
occur in the adult brain, even in situation of
drastic alterations in peripheral sensory
input. However, dramatic reorganization of the
CNS involving multiple sensory systems
(intermodal plasticity) appears to be elicited
with abnormal patterns of sensory input early in
life. In developmentally blind mammals (opossums
enucleated at postnatal day 4, prior to the
arrival of thalamic fibers in cortex), evidence
for massive intermodal plasticity is observed in
the neocortex of adults, suggesting that sensory
input plays a dominant role in the
determination of even very basic principles of
large-scale cortical organization such as
cortical sensory maps.
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Dark purple V1 Light purple extrastriate
cortex Red S1 Yellow A1 Dot electrode
penetration Red dot somatic Yellow dot
auditory Redyellow both Minus no sensory
response V1 in B and C -Architectonic V1 is
present -smaller in size -neurons respond to
tactile and auditory stimuli
(from Kahn Krubitzer, PNAS 99, 2002)
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• dramatic re-organization of cortical sensory
  fields following absence of visual stimulation
• even gross anatomical boundaries and functional
  fields of cortex respond to altered patterns
• of sensory input (major role of nurture over
  nature in cortical development)

(from Kahn Krubitzer, PNAS 99, 2002)
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Intermodal Plasticity in Humans Evidence from
Deaf Individuals Does early sensory deprivation
(e..g, deafness) lead to enhancement of
functioning in the remaining sensory
systems? Brain imaging studies show that the
pattern of brain activation in response to visual
stimuli is markedly different in congenitally
deaf individuals, with recruitment of areas that
normally do not show clear activation with visual
stimulation.
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The most consistent finding in the brains of
deaf individuals is enhanced activation of
multimodal association areas in the temporal and
parietal lobe to visual stimuli (see above). At
the same time, auditory areas also show enhanced
activation in response to visual and tactile
stimuli, as well as to signed language.
Surprisingly, however, enhanced responses to
such stimuli appears to occur only for secondary
and higher order auditory areas, with little
evidence available to suggest functional changes
in primary auditory cortex (A1) (see Bavelier et
al. TICS 10, 2006, also for figure above).
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Possible mechanisms mediating recruitment of
cortex in deaf individuals 1. Changes in
subcortical connectivity 2. Changes in
intracortical connectivity
Intact audition Deaf
Retina Cochlea
(images modified from Bavelier et al. TICS 10,
2006)
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What is the functional significance of intermodal
plasticity after sensory loss? -literature on
perceptual an cognitive skills in deaf
inconsistent (enhanced, unchanged,
impaired) -heterogeneous background and
etiology -Deaf native signers -5 of deaf
population -no clinical, neurological
diagnosis -deaf with deaf parents -born/raised
in signing community -no language
deprivation -no developmental delays -language
developmental milestones same as hearing
individuals -this sub-group of deaf individuals
represents the purest population to evaluate
the effects of auditory deprivation in the
absence of confounding factors such as language
deprivation, communication disruption, and
abnormal cognitive development
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For a number of visual perceptual abilities, deaf
individuals perform at the same level as subjects
with normal hearing, e.g., sensory thresholds
for -brightness discrimination -visual
flicker -contrast sensitivity -movement
direction and velocity -also, no differences
are apparent for foveal vision Differences do
emerge when visual functions in the periphery of
the visual field are examined e.g., detect
presence of moving light points at unpredicted,
peripheral locations also enhanced evoked
potentials, indicative of greater neuronal
excitation, for moving targets in the visual
periphery, but not the central visual
field differences are most pronounced when
distractor stimuli in the central visual
field are used, and subjects are asked to ignore
these and, thus, selectively attend to
the periphery gt greater attentional demand -gt
greater advantage of deaf individuals with
regard to peripheral vision
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Evidence for enhanced attention for visual
periphery in deaf subjects
Method -irrelevant distractor stimulus shown in
central or peripheral vision -subjects view
display with 6 target rings -have to identify
shape (square or diamond) Hypothesis peripheral
distractors are more effective in periphery for
deaf individuals Results hearing -gt central
stimulus more distracting deaf -gt
peripheral stimulus more distracting Conclusions
Deaf individuals enhanced processing of stimuli
in the periphery of their visual field Loss of
input from one sensory system enhances attention
and sensory processing in the spared sensory
domains. Such effects are notable for peripheral
vision, which normally receives less attentional
resources relative to central vision. Functions
enhanced visual detection of peripheral, moving
stimuli, which normally may be detected, at least
in part, by auditory signals (e.g.,
approaching vehicle, movement direction, time to
collision)
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Maladaptive consequences of intermodal
plasticity limits to functional restoration
Cochlear implants used to stimulate cochlear
nerve -gt increased metabolic activity of A1 in
deaf and significant functional
improvement/restoration of auditory functions
Intermodal plasticity in deaf -A1 and
association cortex becomes responsive to
non-auditory inputs, esp. sign language Does
intermodal plasticity limit the restoration
of auditory functions after cochlear
implants? (blue pre-operative hypometabolic
areas) CID score auditory test
battery) Results greater pre-operative
hypometabolism -gt better functional restoration
of hearing Conclusion Intermodal plasticity
mechanisms recruit auditory cortex, leaving it
non-responsive to subsequent auditory signals
gt little or no functional improvement of
hearing functions
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Caption for figure on previous slide
(from Lee et al, Nature 409, 2001)
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Intermodal plasticity in blindness Results
similar to those obtained with deaf individuals
have also been reported in the blind.
Again, simple measures of sensory threshold or
sound characteristics (intensity, pitch, timbre)
generally fail to show differences for sighted
and blind subjects. However, more complex aspects
of sound processing reveal enhanced auditory
perceptual abilities in the absence of visual
functions.
Binaural Sound Localization Monaural Sound
Localization
Sound to Closed Ear
Localized at Open Ear
(dashed line actual sound source from Lessard
et al. Nature 395, 1998)
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Binaural cues differences between ears
(intensity, timing) Monaural cues spectral
filtering of sound of pinna Methods sounds
presented in horizontal plane around
subjects Conclusions Blind subjects develop
excellent representation of 3-D space in the
absence of visual, spatial experience. Under
monaural conditions, control subjects show clear
deficits in sound localization. For about 50 of
blind subjects, sound localization under more
challenging, monaural conditions was highly
accurate, indicative of enhanced auditory spatial
skills in the absence of early visual input.
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Enhanced peripheral sound localization in blind
individuals Methods -four central and
peripheral speaks one in each location is target
(attended to) -subjects asked to respond to
occurrence rare, deviant sound only at target
speaker

• Results Same number of false alarms in
• central auditory field
• more false alarms for sighted subjects in
• periphery relative to blind subjects
• Enhanced, more accurate localization of sound in
  the peripheral auditory space in the absence
• of visual input consistent with work on
  enhancement of peripheral visual processing in
  deaf
• individuals.

(from Roeder et al, Nature 400, 1999)
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Similar to the results in deaf individuals,
enhanced sensory functions in blindness are
thought to be relate to recruitment of cortical
regions not directly involved in these sensory
abilities when vision is present. For example,
recent anatomical studies in primates have shown
hat there are direct projections from both S1
and A1 to primary and secondary visual cortex
areas, in addition to well-characterized
projections to parietal association areas. In the
absence of competition from visual inputs, all
these fiber systems likely are much more
developed, allowing the activation of
substantial portions of occipital and parietal
cortex for the processing of auditory and tactile
information in blind individuals.
S1
S1
A1
A1
Blind
Intact Vision
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Blindness also increases the use of tactile
information, in particular for Braille reading
conversion of simple, tactile information into
complex, semantic meaning. Imaging studies of
brain activity during Braille reading have shown
activation of somatosensory cortex language
areas (Wernickes) occipital cortex, including
V1 and VII
(from Sadato, The Neuroscientist 11, 2005)
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Functional role of occipital cortex in Braille
reading Does intermodal plasticity in occipital
cortex play a role in the ability to perform
Braille processing? Methods disrupt cortical
activity by transcranial magnetic stimulation
(TMS) while reading Braille
Areas for TMS application
(TMS triggered by disruption of laser beam)
(from Cohen et al, Nature 389 1997)
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• -EBB early blind reading Braille
• -EBR early blind reading embossed
• Roman letters
• -SVR sighted volunteers reading
• embossed Roman letters
• -UVB second group of early blind reading
• Brailel, studied by other
  investigators
• Results TMS over mid-occipital cortex
• disrupts Braille and Roman tactile reading in
• early blind subjects, but not in sighted
• volunteers
• Activity of occipital lobe is necessary for
• accurate processing of language-related
• somatosensory signals

(from Cohen et al, Nature 389 1997)
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Summary The absence of specific sensory inputs
to the human CNS results in widespread changes
of subcortical and cortical connectivity and
activation patterns. Generally, loss of a
sensory input in adult hood results in more
localized, intramodal re- organization, while
loss in early life or prior to birth results in
more widespread plasticity phenomena that cross
multiple cortical sensory and associational
domains. Related to these plasticity processes,
subtle changes in perceptual-cognitive functions
occur. However, these functional changes are
more modest than what would be predicted from
alterations observed in brain activation patterns
and consist mostly of small enhancements of
functions that normally play a smaller role
sensory and perceptual processes under
conditions of intact sensory inputs (e.g.,
peripheral visual and auditory space). A least
some of the intermodal recruitment of cortical
areas following early sensory loss appears to
assume important functional roles in processing
of the remaining sensory information, thus
participating in the special behavioral
strategies and skills carried out by individuals
with limited sensory inputs to the CNS (e.g.,
tactile reading in blindness).
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2. Plasticity related to skill acquisition/predisp
osition
Hypotheses The acquisition of highly
specialized skills should result in a shift in
cortical magnification factor. Alternatively
, the presence of a highly unusual
cortical magnification factor should serve as
a neurobiological basis for the predisposition
to develop specialized skills. E.g., musicians
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Performance for music involves -sensory and
perceptual processing of perhaps the most complex
sensory stimulus -very high degree of motoric
skill that is, high precise sequencing,
timing, coordination of digit (and even
additional) muscle group -continuous monitoring
of own (and also others) movement and sensory
feedback
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• Studies of the brains of musicians
• Anatomical differences
• -Auerbach (early 20th century) middle and
  posterior superior temporal gyrus enlarged
• in post mortem brains of musicians

Superior Temporal Gyrus Middle Temporal Gyrus
Inferior Temporal Gyrus
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Modern high resolution structural MRI imaging
techniques have revealed differences in -planum
temporale (A1) (esp. left/dominant
hemisphere) -hand representation in M1
(bilateral, but esp. in right/non-dominant
hemisphere) -anterior corpus callosum (larger
more axons, superior bimanual integration and
coordination) -cerebellum
(from Muente et al, Nat Rev Neurosci 3, 2002)
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• Increases size of hand representation in M1, esp.
  for right/non-dominant hemisphere
• reduced hemispheric laterality of cortical
  (hand) motor systems
• also reduced functional asymmetry for left and
  right hands
• Task line tracing, shape drawing, speed tapping
  for both hands
• Results musicians show smaller differences
  between dominant and non-dominant hand
• earlier onset of musical training
  relates to smaller hand asymmetry

(from Jaencke et al, Brain Cognition 34, 1997)
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2. Functional measures of plasticity e.g.,
Magnetoencephaloraphy -measures electromagnetic
fields across scalp, similar to more typical EEG
methodology -useful to measure spontaneous and
evoked activity of the neocortex
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Differences in the Somatosensory System
-compared evoked responses to digit stimulation
in musicians (string players) and
controls -greater cortical area responds thumb
(D1) and smaller finger (D5) of left (fingering)
hand for musicians -no differences for right
(bowing) hand (less skilled movements, no
independent digit movements) -greater effect
with earlier inception of musical practice,
suggestive of a role of experience (i.e.,
cumulative training), rather than predisposition
(from Elbert et al, Science 270, 1995)
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Differences in the Auditory Perceptual System
-music is composed of complex, temporal patterns
(sounds of different durations and speeds) Are
musicians more sensitive to small changes in the
temporal structure of sound sequences? -mismatch
negativity (MMN) evoked potentials in prefrontal
cortex elicited by irregularities and omitted
stimuli in a series of regular events e.g., tone
- tone - tone -tone - _____ - tone - tone - tone
EEG
MMN
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Play repeated, regular tones every 150 ms, with
some intermittent tones occurring 20 or 50 ms too
soon to musicians and non-musicians. TONE -
150 ms -gt TONE - 150 ms -gt TONE - 150 ms -gt TONE
- 100/130 ms -gt TONE

• Results
• -both groups show MMNs for larger
• deviations (50 ms)
• -only musicians show deviations to
• smaller (20 ms) deviations in temporal
• sequence of tones
• enhanced perceptual acuity in
• musicians

(from Rüsseler et al. Neurosci Lett 308. 2001)
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Differences in Large-Scale, Associative Brain
Activation With musical experience and
training, separate cortical areas appear to
become increasingly connected and functionally
integrated, e.g., musicians hearing music
(auditory activation) often automatically imagine
playing the music (association cortex
activation) or move hands/fingers to music (motor
activation) e.g., similarly, performing
music-like movements with hands/fingers leads
to imaginary reconstruction of musical sounds.
These observations suggest that different
cortical areas involved in music processing and
production become functional in a more
integrated manner. This hypothesis is supported
by brain imaging studies comparing whole brain
activation during passive listening to music with
activation during performance of music in the
absence of sound input (silent piano).
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Piano Music Mute Piano Playing
Brain activation in the two conditions becomes
progressively more similar with musical
training. The fact that one type of
modality-specific stimulus (either auditory or
movement) can elicit equivalent patterns of whole
brain activation suggests increased
functional coupling of different cortical regions
due to the musical learning experience. This
represent CNS plasticity at a very high level of
functional and cognitive processing. Summary
The studies of musicians and their brains has
provided compelling evidence for both
structural/anatomical and functional plasticity
in the human CNS, including modality specific
and intermodal changes in brain organization and
functioning.
(from Bangert et al. Ann NY Acad Sci, 930, 2001)
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Levels of Synaptic Plasticity