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Principles of Neuroplasticity:

Clinical Applications

How Does It Happen?

Synaptogenesis

Axon Growth & Regeneration

Hebb's Law (1949)

Proactive Interference: when an old memory disrupts the learning & remembering of a new memory

  • ie. trying to put dishes away at a new house; baseball player difficulty learning golf swing

“When an axon of cell A … excite[s] cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency, as one of the cells firing B, is increased.”

-The Organization of Behavior

Retroactive Interference: newly learned information disrupts or impedes the recall of previously learned information

  • ie. driving an automatic after driving a manual; switching a long-used password

Dendritic Modifications

Standard

Enriched

Neurons that fire together, wire together.

Neurons out of sync, fail to link.

Changes in dendritic:

  • length
  • branching
  • spine density
  • synapse number
  • size

Wohldmann et al, 2008

Interference in Memory

Johansson, Belichenko (2002)

Spinal plasticity is known to play a role in central neurogenic pain. Recent data suggest links between the learning deficit and the sensitization of pain circuits associated with inflammation or injury (central sensitization).

What is Neuroplasticity?

Ferguson et al, 2006

Interference in Motor Learning

changes in the functional organization of the brain as a result of learning & experience

  • As little as 6 min of uncontrollable shock to either the leg or the tail generates a learning deficit that lasts up to 48 h.
  • Deficits in functional locomotor recovery, sensory and autonomic recovery up to at least 6 weeks post-injury.
  • (comparable to ~3 human years)

The Problem...

Interference

  • Spinal cord has important role in processing nociceptive signals.
  • Spinal cord is vulnerable to nociceptive input after injury.
  • Acute nociceptive input is a common feature of polytraumatic automobile accidents (most common cause of SCI), and that pain affects 65-85% of human SCI population.
  • Co-morbid peripheral injuries may also play a role in dictating both functional recovery and nociceptive sensitization.

Use It or Lose It

Main Point: be careful, especially with acute SCI

-uncertain of implications to other neuro injuries

Ferguson et al, 2004

  • Occurs during development (and throughout lifespan)
  • Occurs during learning
  • Occurs during recovery after damage/disease to sensory, motor and cognitive areas of the brain and spinal cord.
  • Is an active area of research at many levels: molecular, cellular, system, clinical

Failure to drive specific brain functions can lead to functional degradation.

Plasticity in response to one experience can interfere with the acquisition of other behaviors.

Transference

  • Only rats receiving combination of chondroitinase and specific rehabilitation showed improved manual dexterity.
  • Rats that received general locomotor rehabilitation were better at ladder walking, but had worse skilled-reaching abilities than rats that received no treatment.
  • Chondroitinase treatment opens a window during which rehabilitation can promote recovery.
  • However, only the trained skills are improved and other functions may be negatively affected.

In brain injuries and cognitive impairments...

Plasticity in response to one experience can enhance acquisition of similar behaviors.

Why Is It Important?

How Does It Happen?

  • Attention and/or dual task ability is often impaired.
  • Varying levels:
  • alertness
  • sensory/focused attention (visual, auditory, tactile)
  • sustained attention
  • selective attention (distractibility)
  • alternating, divided attention (dual tasking)
  • Impairments on a given level should be approached by training on the same or a subordinate level.
  • On the other hand, training for a superordinate level may lead to overload of cognitive-attentive system and result in stagnation or even deterioration to subordinate levels of attention.

Sturm et al, 1997

Putting All the Pieces Together

Long-Term Potentiation (LTP)

  • increase in synaptic strength

Long-Term Depression (LTD)

  • Ability to constantly lay down new pathways for neural communication and to rearrange existing ones throughout life
  • necessary for learning, memory, and adaptation through experience.
  • important for functional recovery
  • Neurons (among other cells) alter their structure & function in response to variety of internal & external stimuli.

We use this principle every day having patients practice several different interventions, then measuring performance against standardized outcome measures and functional tasks/activities.

  • decrease in synaptic strength
  • It's our job!

1. Use therapy activities that are hierarchically organized (build upon success).

2. Minimize maladaptive behaviors, movement patterns, and pain.

3. Provide sufficient skilled repetition & intensity.

4. Instill patient motivation and attention to practice.

5. Ensure reinforcement of gains.

6. Make interventions functional, task-specific, and goal-oriented to each patient.

7. Actively facilitate generalization to functional activities from the start.

8. Build sense of cognitive self-efficacy.

9. Educate! Educate! Educate!

Use It and Improve It

Mechanisms for LTP/LTD

  • Increased/decreased release of neurotransmitter
  • Increased/decreased number of neurotransmitter receptors
  • Increased/decreased sensitivity of neurotransmitter receptors

Age Matters

Training that drives a specific brain function can lead to enhancement of a function.

Principles of Neuroplasticity

Training-induced plasticity occurs more readily in younger brains.

Merzenich, 1978

• Neuroplastic responses are altered in aged brains.

• Experience dependent synaptic potentiation (Barnes 2003) synaptogenesis (Greenough 1986) and

cortical map reorganization (Coq & Werri, 2001) are reduced in aging.

• Connection-Dependent: After deafferentiation (e.g. limb amputation), reorganization of cortex so muscles adjacent to amputated area have larger cortical representation.

• Use-Dependent: Motor learning alters body representation in the motor cortex. Areas used most have largest representation.

• After damage to brain, adjacent areas or contralesional areas can take over motor control.

Cortical somatotopic maps can be modified by sensory input, experience, and learning.

Merzenich, 1978

  • The brain of a child is resilient and extremely plastic.
  • ie. removal of child's left hemisphere: can still learn to speak if injury happened before age of 2

References

Future Directions

This doesn't mean you can't still create change in older patients!

Specificity

  • Animal studies not fully translatable to humans
  • younger relative age, more homogenous injury, less co-morbidities, 14% brain white matter volume vs. ~50% in humans
  • specific patient populations
  • optimal training/therapy parameters
  • "neuroprotective" effects
  • research on interventions in combination (ie. task-specific training + stem cell therapy)
  • Bliss, T.V., and Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthesized rabbit foowing stimulation of the perforant path. J. Physiol. 232, 331-356.
  • Cramer, et al (2011). Harnessing neuroplasticity for clinical applications. Brain. 134: 1591-1609.
  • Ferguson, A.R., Crown, E.D., and Grau, J. W. (2006). Nociceptive plasticity inhibits adaptive learning in the spinal cord. Neuroscience. 141, 421–431.
  • Ferguson, A.R., et al (2012). Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury. Frontiers in Physiology. 3:399, 1-17.
  • Hebb, D.O. (1949). The Organization of Behavior. New York: Wiley & Sons.
  • Johansson, B.B., and Belichenko, P.V. (2002). Neuronal plasticity and dendritic spines: effect of environmental enrichment on intact and postischemic rat brain. J. Cerebral Blood Flow & Metabolism. 22, 89-96.
  • Melton, A.W.; Lackum, W. J. von (1941). "Retroactive and proactive inhibition in retention: evidence for a two-factor theory of retroactive inhibition". American Journal of Psychology 54: 157–173.
  • Nudo, R. et al (2006). Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys. Experimental Brain Research, 169:1, 106-116.
  • Sturm, W., et al (1997). Do Specific Attention Deficits Need Specific Training?, Neuropsychological Rehabilitation: An International Journal, 7:2, 81-103
  • Wohldmann, E.L., Healy, A.F., Bourne Jr., L.E. (2008). A mental practice superiority effect: Less retroactive interference and more transfer than physical practice. Journal of Experimental Psychology: Learning, Memory, and Cognition, 34, 823-833.

Time Matters

Specific forms of neuronal plasticity and behavioral changes are dependent upon specific kind of experience.

The nature of the training experience dictates the nature of the plasticity.

Intensity Matters

  • Consolidation of memories requires time. (Silva 2004)
  • Critical period after brain damage. Delayed training resulted in less change in cortical remapping. (Nudo 2006)
  • There is a major cascade of events and neuronal reactions that occurs after injury.
  • Early intervention is critical!
  • Tough with delays in scheduling, referrals, high caseloads.

(Skilled) Repetition Matters

Induction of plasticity requires sufficient training intensity.

Induction of plasticity requires sufficient repetition

Salience

  • Low –intensity stimulation can induce weakening of synaptic response (LTD), whereas higher intensity stimulation will induce LTP.
  • Challenge patients, but make sure they are doing so safely and correctly.
  • Neural plasticity may be enhanced when the movement is purposeful & related to the behavior being trained.
  • Motivation, reward, and attention
  • Training fails to produce plasticity if the subject’s attention is drawn away from the activity or stimulus.
  • Simply engaging a neuronal circuit in task performance is not sufficient to drive plasticity.
  • Plasticity requires not only the acquisition of a specific skill, but also the continued performances of that skill over time.
  • So the role of repetition in driving plasticity and learning may be critical for rehabilitation.

Andrew Tran, SPT, CSCS

UCSF/SFSU - DPT Graduate Program

  • Non-skilled repetitive tasks do not result in map changes or synaptogenesis.
  • Merzenich and Jenkins concluded. “Plastic changes in brain representations are generated only when behaviors are specifically attended. When stimuli identical to those that induce plastic changes in an attending brain are instead delivered to a nonattending brain, there is no induction of cortical plasticity.
  • Attention must be paid.
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