1. Neuroplasticity
Lundy-Ekman, Chapter 4
Dr. Donald Allen

2. Outcomes Describe habituation and its role in therapy.
Explain what is happening during long-term potentiation.
Describe the anatomical and metabolic features of injury to the nervous system.
Describe the anatomical changes that can occur during the recovery from injury.
Describe the effects of forced use on recovery from an injury.

3. Plasticity
What makes something plastic?

4. Neuroplasticity Any change in the nervous system that is not periodic
Duration of more than a few seconds
Combination of both flexibility and stability

5. Types of Neuroplasticity
Habituation
Learning and Memory
Recovery from Injury

6. Habituation Considered by some to be the simplest form of learning
Decreased response to a repeated innocuous stimulus
Involves changes in neurotransmitter release (strength of synaptic connections)
Reversible
Stop repeating the stimulus
Change the stimulus
Sensitizing stimulus

8. How could you use habituation?
Use of techniques and exercises to decrease the neural response to a stimulus

9. Learning and Memory More long-lasting, persistent
Also involves changes in strength of synaptic connections
3 Main types of learning and memory

10. Motor Memory
AKA: Procedural memory
Learning a task
Riding a bike

11. Verbal Memory Declarative memory Items that can be spoken or written
Repetition?

12. Emotional Memory Not well understood
Memory for associations of emotions with specific places, people, etc.

13. Neurological mechanisms of Learning and Memory
Neuroimaging techniques
Initial stages of motor learning
Large and diffuse areas of the brain involved
With repetition
Decrease in number of brain regions which are active
Task learned
Only small, distinct regions of the brain show activity during performance of a task

14. Long-Term Memory
Long-term memory requires the synthesis of new proteins and growth of new synaptic connections
In animal studies, giving protein synthesis inhibitors blocks the formation of new memories

15. Long-term Potentiation
Proposed mechanism to explain long-term memory
Occurs in hippocampus (part of temporal lobe)
Hippocampus is important for processing verbal memory
Bilateral damage to hippocampus results in an inability to form new verbal memories

16. Studies on LTP Started with animal studies – slices of hippocampus
Repetitive stimulation will increase the responses to the stimulus
Started with animal studies – slices of hippocampus
Treatment
Single stimulus – measure response
Repeated stimuli
Single stimulus – measure response – now much larger response

18. Requirements for LTP
Cooperativity
Associativity
Specificity

19. Cooperativity
There must be multiple excitatory inputs into the hippocampal neuron that will exhibit LTP
The multiple inputs have an additive effect
The individual inputs do not have to be strong. Even weak inputs can show potentiation is they occur in association with strong inputs

20. Associativity
Both the presynaptic fibers and the postsynaptic cell must be activated together
An action potential in the presynaptic axon must produce an action potential in the postsynaptic neurons
I.e. The synapse must be effective

21. Specificity
Only synapses that are associated with an action potential in the postsynaptic neuron will be potentiated.

22. Effects of LTP Involves Increases in synaptic activity
Increased effectiveness of neuron firing

23. Role of non-neuronal cells in LTP
Astrocytes
Change shape rapidly in response to stimulation
Increase in astrocyte-neuron contacts in rats raised in challenging environment compared to standard conditions

24. Mechanism of LTP Conversion of ‘silent synapses’ into active synapses
Postsynaptic membrane is remodeled to form new dendritic spines and synapses

25. Recovery from Injury
What we see depends on what parts of the neuron are injured
Cell body
Axon

26. Injury to cell body If severe, will kill the cell
In general, dead neurons are not replaced
However, changes in the remaining neurons can promote recovery after the injury

27. Injury to Axon
Will cause degenerative changes, but will not necessarily kill the neuron
If axon severed, the two ends will seal
We now have a proximal section of the axon, which is attached to the cell body, and a distal section, which continues to the presynaptic terminal

28. Distal section of axon
This section is separated from the cell body and will degenerate
Wallerian degeneration

29. Glial cells will clean up the degenerating neurons
Glial cells will clean up the degenerating neurons. In the peripheral nervous system, what kind of glial cells will these be?
The postsynaptic cell will show some degenerative changes (it has lost inputs)
Trans-synaptic degeneration
Some may die. It depends on the importance of the lost inputs

30. Proximal section of axon
Still attached to soma, so has the potential to survive depending on what happens to the neuron
Central chromatolysis – dissolution of Nissl substance in the cell body
Cell body may die

31. Central Chromatolysis

32. Recovery After an Injury
Recovery is affected by age at time of injury
Recovery decreases with age
Children can have an entire cerebral hemisphere removed and show little permanent deficits

33. Regrowth of Axons after Injury
Sprouting (page 72, Fig 4-4)
Collateral sprouting
Denervated target is reinnervated by branches of intact axons
Regenerative sprouting
Target and axon both damaged
Target dies
Injured axon sends out collaterals to new targets

34. Functional Regeneration
More prevalent in peripheral nervous system
Schwann cells make growth factors that contribute to recovery of peripheral axons
NGF- Nerve growth factor
Recovery is better with a crush injury compared to a cutting injury
Growth is slow: 1 mm/day = 1 inch/month

35. CNS regeneration Little or no functional regeneration
No Schwann cells producing NGF
Oligodendrocytes inhibit growth of neurons
Incomplete cleanup of cellular debris by microglia

36. Potential problems during regeneration
Sprouting may innervate inappropriate targets
Motor neurons may innervate different muscles
May produce unintentional movements
Synkinesis
These movements are usually short-lived, and the individual relearns muscle control
Can also see confusion of sensory modalities

37. Changes in synapses after injury
Local edema and recovery of synaptic effectiveness
Denervation hypersensitivity
Synaptic hypereffectiveness
Unmasking of silent synapses

38. Effects of edema Local edema can occur after an injury
The edema can put pressure on axons or cell bodies
Some synapses may become inactive
Return of synaptic effectiveness
As the edema resolves, the effectiveness of the synapses can return

39. What does this mean for therapists?
Immediately after an injury, there can be a loss of function
Permanent or Temporary?
As edema resolves, the patient may exhibit a return of function

40. Denervation hypersensitivity
Occurs when there is damage to presynaptic terminals
The postsynaptic cells lose all or some of their synaptic inputs
Neurons like to maintain a moderate level of stimulation. Denervation removes this stimulation.

41. Postsynpatic neurons (and muscles) respond by producing more receptors
These new receptors will respond to neurotransmitters that are released by adjacent axons

42. Neuromuscular Junction and Denervation

43. Synaptic hypereffectiveness
Sometimes only some of the axon branches of a neuron are damaged
The presynaptic cell body still makes the usual amount of neurotransmitter, but now the neurotransmitter is distributed to less presynaptic terminals
Therefore, each terminal receives more neurotransmitter, and more neurotransmitter is released at each synapse

44. Unmasking of silent synapses
Disinhibition of silent synapses
Many synapses in the central nervous system appear to be non-functional (silent)
An injury to pathways in the brain can unmask these synapses and they can become functional

45. What chemicals are important for these changes in synapses?
NMDA receptors
Ca++ ions
Neurotrophins (growth factors)
Substance P
Nitric oxide
Changes in subtypes of sodium ion channels

46. Functional Reorganization of the Cerebral Cortex
When we look at somatosensory and motor areas of the cortex, we find that specific parts of the body can be mapped onto the surface of the cerebral cortex.
Determined by:
Studies like Broca’s and Wernicke’s
Recording which areas of the cortex show electrical activity after sensory stimulation or active muscle contraction

47. Further studies using MRI have confirmed the electrical studies
Large areas of cortex represent the hands and face (high number of sensory receptors and need for controlled movements)
For somatosensation, there are actually several different maps that are parallel to each other
General map for humans, but there will be differences between individuals

49. Changes in the Somatotopic map of the cerebral cortex
If we use a particular part of our body more, the area of cortex corresponding to the area will increase in size (Elbert et al., 1995)

50. This reorganization occurs through the unmasking of silent synapses
If a region of the body is lost, the area of cortex corresponding to the region will decrease in size.
In people with upper extremity amputations, much of the region of the cortex that use to correspond to the U/E becomes reorganized. The area can then provide a presentation of the face.
This reorganization occurs through the unmasking of silent synapses

51. Similar brain reorganization is thought to occur in people who are blind or deaf
People who are congenitally deaf often have enhanced peripheral vision to moving objects
People who are blind use visual areas of cortex when reading Braille writing

52. Complications of Reorganization
May see referred sensations after an amputation
Stimuli that are applied to one area of the body are felt to occur in a different part of the body
A touch to the chin may be felt as if it were applied to a missing fifth finger
Functional reorganization may also be a factor in some chronic pain syndromes, where pain persists after the injury heals.

53. Factors that can influence neuroplasticity
Neuronal activity
Overstimulation of somatosensory pathways causes the increased release of inhibitory neurotransmitters
If there is understimulation of sensory pathways, the cortex can become more sensitive to weak stimuli
Reduced activity can promote axonal growth to increase stimulation

54. Factors that can influence neuroplasticity – Growth Factors
Brain-derived neurotrophic factor (BDNF)
Supports survival of sensory neurons, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons
May be of use in local treatment of neurodegenerative disorders (Parkinson’s Disease)
May be of use in protecting motor neurons in patients with motor neuropathies and ALS

55. Growth Factors Continued
Nerve Growth Factor – NGF
May have a role in treating
Alzheimer’s Disease – protects cholinergic neurons in primates
Diabetic neuropathy
Chemotherapy-induced neuropathies
May promote neuroplasticity

56. Overview of Neuroplasticity
Defines how the nervous system responds to:
Injuries
Changes in neuronal activity

57. How does neuroplasticity affect the treatment of patients with CNS injuries
Forced-activity
Excito-toxicity

58. Forced Activity
Patient has an injury to the central nervous system. The studies in humans have mostly involved patients with strokes
Patient is made to use the affected body part
Studies have been done with people and animals

59. Kozlowski et al., 1996 Lesion to sensorimotor cortex
Forced use of limb immediately after lesion
Lesion increased in size: Excitotoxicity
Long-term behavioral deficits
Poor limb placement
Decreased response to sensory stimulation
Defective use of limb for postural support

60. Nudo et al., 1996 Also in animals
Small lesion in cortex associated with hand movements
See loss of function from lesion site
Also loss of function in adjacent, undamaged cerebral cortex
Initiated movement 5 days after lesion
Prevented loss of function in area adjacent to lesion
In some animals, neural reorganization: hand representation extended into regions which previously represented shoulder and elbow

61. Human Studies Most done by one research group and its students
Stroke patients
Restrain unaffected upper extremity
Practice tasks with affected extremity
Chronic stroke: > 1 year of dysfunction
Results: See motor improvements

62. Why could constraint therapy work?
Learned helplessness

63. Excitotoxicity Too Much Of A Good Thing Ischemia or TBI
Release and Spread of Glutamate
NMDA receptors – Ca++ influx
Too much Ca++ can kill neurons
Extension of region of neuron death