Transcript Neuroplasticity - University of Michigan–Flint

PTP 512
Neuroscience in Physical Therapy
Neuroplasticity
Reading Assignments
Lundy-Ekman: 72-74, 78-80
Shumway-Cook: 39-43, 83-89, 91-103
Min H. Huang, PT, PhD, NCS
RECOVERY OF FUNCTION
Recovery
• Restoration of damaged structures;
reactivation in brain areas surrounding
lesion
• Clinical improvement in the ability to
perform a movement or task in the same
way as premorbid, and regardless of the
mechanisms underlying changes
• e.g. constrain-induced movement therapy
to enhance motor recovery after stroke
Levin, Kleim, Wolf, 2008
Therapeutic Strategies Focusing on
Recovery
constraint-induced
movement therapy
after stroke
locomotor training after
spinal cord injury
Compensation
• Compensation refers to behavioral
substitution; activation in alternate brain
areas; appearance of new motor patterns
due to adaptation of remaining motor
patterns of substitution
• Performing an old movement in a new way
• e.g. use of adaptive device, equipment,
functional electrical stimulation, external
visual cues
Levin, Kleim, Wolf, 2008
Compensation
adaptive device for gait
Factors Affecting Recovery of Function
• Biological factors (endogenous)
– Age, gender, weight, genetic factors,
weight, premorbid condition
– Lesion size and progression speed
– Neurotrophic factors, e.g. brain-derived
neurotrophic factor (BDNF)
• Environmental factors (exogenous)
– Preinjury factors, e.g. dietary restriction,
exercise, environmental enrichment
– Postinjury factors, e.g. pharmacologic Rx
EARLY RESPONSES TO INJURY AND
RECOVERY OF FUNCTION
Mechanisms Underlying Recovery
of Function
• Direct mechanisms: resolution of
temporary changes and recovery of injured
neural tissue
• Indirect mechanisms: recovery completely
different neural circuits enable the recover
of lost or impaired function
Early Transient Events that Depress
Brain Function: Edema
• Common response following brain injury
• Edema can be local or remote from the site
of injury
• Edema may compress neuron’s cell body or
axon, causing focal ischemia, which
disrupts neural function, including synthesis
and transportation of neurotransmitter.
Eventually the synapse become inactive and
silent.
Edema
Early Transient Events that Depress
Brain Function: Diaschisis
• Loss of function in a structurally intact
brain area due to loss of input from an
anatomically connected area that is injured
• Neural shock due to diaschisis, such as
spinal cord shock (lasting 4-6 weeks postinjury), cerebral shock, is a short-term loss
of function near and far from lesion site.
Full recovery from neural shock is often
expected.
Metabolic Effect of Brain Injury:
Excitotoxicity
• After brain injury, neurons deprived of
oxygen die. These neurons also release
excessive glutamate from their axon
terminals, which causes surrounding
neurons to overexcite and triggers a
cascade of cell death, i.e. excitotoxicity.
• Damage after brain injury is not only limited
to direct neuronal death, but also the
indirect death from excitotoxicity.
Secondary injury after traumatic brain injury
Park E et al. CMAJ 2008;178:1163-1170
ischemia
Glutamate release
↑Glycolysis
↑Ca++ influx
Protein
enzyme
Lactic acid
↑Intracellular
H2 O
Oxygen free
radicals
Cell swelling
CELL DEATH
INTRACELLULAR RESPONSES TO
INJURY AND RECOVERY OF
FUNCTION
PNS and CNS Recovery:
Collateral Sprouting
• Axon of remaining neuron forms a collateral
sprout to reinnervate denervated target
With injury,
younger rats
develop more
collateral
sprouts than
older rats
Collateral sprouting
PNS and CNS Recovery:
Neural Regeneration
• Presynaptic axon
and its target cell
(postsynpatic )
are damaged
• Injured axon
sprouts to new
targets
• Regenerate the
axon at
1mm/month
Regenerative sprouting in CNS is
not functional and does not occur
• Neural regeneration occurs most frequently
in PNS because Schwann cells produce
nerve growth factor, which help recovery.
• Astrocytes and microglia form glial scars,
which physically block axonal regeneration
• Oligodendrocytes produce Nogo (neurite
outgrowth inhibitor), which inhibits axonal
regeneration
• Axons don’t naturally regenerate very large
distances
Synkinesis: aberrant regenerative
sprouting in PNS
• Axon sprouting can cause problems when
an inappropriate targets is innervated.
• After injury, motor axons innervate
different muscle than they previously did,
causing unwanted abnormal movements
when the neurons fire.
– e.g. Bell’s Palsy (CN VII): patients wink
when they intend to purse lips.
• Typically lasts no more than a few months
Woman with a history of Bell palsy 18 years
earlier and with synkinesis
(A–C)
before
treatment
(D–F)
After PT and
Chemodenervation
CNS Recovery:
Recovery of Synaptic Effectiveness
• Recovery from early transient events, such
as edema and diaschisis, neural shock
CNS Recovery:
Denervation Supersensitivity
• Occurs when neurons lose input from
another brain region, e.g. postsynaptic
neurons in the striatum become supersensitive to dopamine in patient with
Parkinson
CNS Recovery:
Synaptic Hypereffectiveness
• Occurs when only some branches of
presynaptic axons are damaged
• Remaining axons receive all
neurotransmitters that would normally be
distributed among
all branches
• Larger amount of
neurotransmitters
released to postsynaptic receptors
CNS Recovery: Unmasking of Silent
Synapses
• In normal CNS, many neurons are not used
due to competition of neural pathways
• Unused neurons become active
Functional Reorganization
(remapping) of Cerebral Cortex
Training can expand
cortical representation
areas (i.e. cortical map)
A1 = pre-training
A2 = post-training
Cortical area 3b
In adult monkey,
sensory training for 3
months on task
requiring repeated use
of tips of distal
phalanges of digits 2, 3,
and sometimes 4
Functional Reorganization
(remapping) of Cerebral Cortex
• Only patients with phantom limb pain (PLP)
showed an expansion of areas representing lip
into areas previously representing the hand on
fMRI
Lotze, et al., 2001
Functional Reorganization
(remapping) of Cerebral Cortex
• fMRI shows significant brain reorganization
in patients who develop hand paresis after
removal of brain tumor
After surgery,
multiple brain areas,
including the
ipsilateral side, are
activated during the
same task of finger
and thumb
movement.
Before
surgery
After
surgery
Structural Changes in Gray Matter and
White Matter after Reduced Sensory
and Motor Input
• Limb immobilization caused reduced nerve fiber
density and cortical thickness in the brain
48 hours later
16 days later
Langer, 2012
STRATEGIES AND PRINCIPLES TO
ENHANCE NEURAL PLASTICITY
Effect of Training on CNS
• Type of training
– Skill learning associated with cortical
reorganization
– Strength training is not associated with
cortical reorganization
• Early Intensive Training
– Early, high-dose, constrain-induced
movement therapy (CIMT) results in the
worse outcome compared to moderate
intensity CIMT or conventional therapy
Effect of Training on CNS
• Non-invasive cortical stimulation
– Stimulation applied during or shortly
before skill training enhances motor
learning. In contrast, stimulation after
skill training interferes with the skill
acquisition
– e.g. transcranial direct current
stimulation (ionto- phoresor), rTMS
Effect of Training on CNS
• Non-invasive cortical stimulation
Transcranial direct current
stimulation
(iontophoresor)
Transcranial magnetic
stimulation (TMS)
Effect of Training on CNS
• Somatosensory stimulation
– Using sensory-level electrical stimulation
combined with training
– e.g. TENS to hand muscles increase the
size of cortical hand map
– e.g. Cortical plasticity also occurs with
functional electrical stimulation applied
to lower extremities: ↑descending input
from corticospinal tract to activate TA
Effect of Training on CNS
• Somatosensory stimulation
Transcutaneous
electrical nerve
stimulation (TENS)
Functional electrical
stimulation (FES)
Effect of Training on CNS
• Constraint-Induced Movement Therapy
(CIMT)
– Restrain unaffected limb and work
other limb intensely (e.g. put intact arm
in a sling and use the
affected arm)
– Affected limb must
actively
engages in exercise,
functional activities
to benefit from CIMT
Principles of ExperienceDependent Plasticity
1. Use it or lose it
2. Use it and
improve it
3. Specificity
4. Repetition matters
5. Intensity matters
6. Time matters
7. Salience matters
(training
experience)
8. Age matters
9. Transference
10.Interference:
PLASTICITY AND LEARNING
Shift from short term to long term learning is
reflected in a move along the continuum of
neural modifiability.
Neurophysiologic Concepts of
Motor Learning
• Short-term learning occurs by altering
existing synapses
– ↑or ↓release of neurotransmitter
affecting the excitatory postsynaptic
potential (EPSP)
Neurophysiologic Concepts of
Motor Learning
• Long-term learning occurs by the
reduction or formation of new synapses or
structural changes on neurons, e.g.
– Habituation: decrease in synapses (C)
– Sensitization: increase in synapses (D)
Procedural Learning: Role of
Cerebellum
• Purkinje cells are output cells
• Climbing fibers signal error, critical for
correcting ongoing movements
• Mossy fibers bring sensory feedback
about ongoing movements, critical for
controls movements
• When climbing fiber increases its activity,
mossy fiber signals to Purkinje cells is
reduced, which change the synaptic
strength for the circuit
Procedural Learning: Role of
Cerebellum
Monkeys move arm
(1) Against an
expected load
(already learned)
(2) Against an
unexpectedly
increased load
(3) Against same
load as in (2) after Simple spikes from mossy fibers
Complex spikes from climbing
some practice
fibers
Declarative Forms of Learning:
Long-Term Potentiation
• LTP requires
simultaneous firing of
both presynaptic and
postsynaptic cells
• Postsynaptic neuron
must depolarize when
the Glutamate binds to
the NMDA receptor in
order to open the ion
channel
LTP conversion of silent synapses
to active synapses
Change
in presynaptic
cell to
produce
new
synapse
AMPA
receptors
inserted into
membrane
New dendritic spines formed
Lundy-Ekman Fig. 4-1
Complex Form of Motor Learning
• Sensory cortex of cats is
absolutely necessary to
learn a new skill, how
to supinate the forearm
to retrieve food.
• Once learned, ablation
of the sensory cortex
will not affect the
movement
Acquisition of Skills: Shift to
Automaticity
• Automaticity during skill acquisition is
associated with a reduction of brain
activation in several regions
• Older adults or individuals with
neurological diseases may activate more
brain areas or increase the activity levels in
order to perform the skills at the same level
as health individuals