Neural Injury and Repair

1. Neural Injury and Repair Noam Y. Harel, MD, PhD 12 November 2013 Brain and Behavior

2. Disclosures • I do not have any financial or other conflicts of interest to disclose for this learning session. • I do not affirm that all discussions of drug use will be consistent with either FDA or compendia-approved indications. Off-label and experimental drugs may be discussed.

3. Learning Objectives • Recognize differences between axonal injury and repair in the PNS versus CNS. • Understand levels of neural plasticity – from subcellular to network plasticity. • Recognize approaches and targets for improving neural repair. • Understand principles of neurorehabilitation – essential in conjunction with any other drug, cellular, or engineering-based treatments.

4. Injury:soma or nerve? Scenery: PNS or CNS? Machinery: intrinsic, extrinsic Strategery: Targets for repair and recovery

5. Injury: Soma Excitotoxicity (may be acute or chronic) Ischemia, trauma, etc Decreased ATP Inc intracellular Na+, Ca++ Membrane Depolarization Increased action potentials Glutamate release Decreased glutamate reuptake Increased extracellular glutamate Cell death SPREADING EXCITOTOXICITY Doble 1999 NECROSIS  INFLAMMATION APOPTOSISNO INFLAMMATION

6. Injury: Soma DP Agamanolis Chromatolysis

7. Injury: Nerve Prognosis Good (weeks) Fair (mo’s) Poor (surgery may help) . . . . Focal demyelination Axon disrupted Endo. disrupted Peri. disrupted Epi. disrupted Ray Jurewicz Deumenset al. NERVE CONDUCTION STUDIES/ELECTROMYOGRAPHY: Demyelination: Decreased conduction velocity Axonal loss: Decreased action potential amplitude

8. Injury: Nerve Wallerian Degeneration Intra-axonal organelle and microtubule breakdown (minutes-hours) Schwann cells begin axon breakdown and recruit more cells (hrs-days) Macrophages enter, accelerate process (1-2 weeks) Path cleared for axons to regrow proximal-->distal (weeks-months)

9. Scenery: Peripheral vs Central PNS CNS Ramon y Cajal

10. Scenery: Peripheral vs Central Wallerian Degeneration PNS yes Wallerian Degeneration CNS fail

11. Scenery: Peripheral vs Central PNS yes Schwanns help Oligodendrocyte debris, astrocytes, scarring hurt CNS fail

12. Machinery: Intrinsic vs Extrinsic CNS EXTRINSIC Inhibitors Akbik et al., 2012

13. Scenery: Peripheral vs Central Intrinsic growth potential (1-3 mm/d) PNS yes Sluggish growth potential (0.1 mm/d) CNS fail

14. Machinery: Intrinsic vs Extrinsic PNS INTRINSIC Advantages cAMP Seo & Kiyama, 2011 Regeneration-Associated Genes PNS neurons possess receptors and signal transduction machinery allowing themto grow in response to neurotrophins, retrograde injury signals

15. Machinery: Intrinsic vs Extrinsic What does regeneration look like? Growth Cones Letourneau

16. Machinery: Intrinsic vs Extrinsic What does regeneration look like? Growth Cones Ramesh 2004 Dickson 2002 Dynamic growth through regulation of actin and microtubule polymerization/depolymerization Hammarlund et al., 2009

17. Machinery: Intrinsic vs Extrinsic What does FAILED regeneration look like? Retraction Bulbs (of Cajal) Ramon y Cajal

18. Synapse regulation Receptor regulation Transmitter regulation Network adaptation Sprouting CNS PLASTICITY: A more realistic term than CNS regeneration Long-term Short-term, Long-term

19. Synapses, receptors, transmitters Glial cell Axonal bouton Dendritic spine Lesch, Waider 2012 Dendritic spines Xu et al., 2009

20. Network adaptation

21. Sprouting: Use What You Got Uninjured Direct regeneration Itinerant regeneration Sprouting from neighbor 6 Direct proximal sprouting 7 4 Sprouting to neighbor Indirect rerouting 2 1 Retargeting 3 5

22. Redundancy  Plasticity Recovery through Rerouting, not Regeneration Complexity  Redundancy VJ Wedeen

23. Recovery through Rerouting, not Regeneration

24. Strategery: Repair and Recovery Targets anyone? *class to fill-in*

25. Improve cleanup – macrophages instead of oligos? Reduce inflamm & scarring – steroids; chondroitinases; etc Add guidance scaffold – Schwanns; olfactory ensheathing glia; etc Replace growth factors – but can CNS neurons respond? gradients? Trigger RAGs – cAMP modulators (rolipram); direct ‘gene therapy’ Activate growth cones– calcium; microtubule stabilizers (eg taxol) Block extrinsic inhibitors – Mabs; receptor decoys; RhoA inhibitors Excite circuits– transmitter agonists; K+blockers; electrical stim; etc Replace neurons – Stem cells Remyelinate axons – Stem cells Rehabilitate!! Strategery: Repair and Recovery Targets anyone? • – ESSENTIAL IN CONJUNCTION WITH ALL THE ABOVE

26. Activity  Plasticity • ANY kind of activity/nerve stimulation: • exercise, electrical stim, magnetic stim, etc • Leads to increases in: • growth factors, especially BDNF • neurogenesis • glial cell support • angiogenesis • synaptogenesis Wu et al., 2008

27. Circuits need Pruning Plasticity isn’t just Growth birth injury regrowth 6yo consolidation 14 yo Shore, 1997

28. Education > Exertion Specificity > Sweaty • Learning (or re-learning) a variety of skilled, task-specific, repetitivetasks is more beneficial than general exercise alone. • Skilled: Better stimulates cortical networks • Task-specific: Real-life skills more motivating; prune unneeded circuits • Repetitive: to maintain gains/consolidate circuits, need to overlearn

29. Education > Exertion Specificity > Sweaty • Learning (or re-learning) a variety of skilled, task-specific, repetitivetasks is more beneficial than general exercise alone. • Rigorous, CONTROLLED clinical rehabilitation studies are woefully lacking, sorely needed

30. In both animals and humans, repetitive training in a specific task leads to improved performance in that task, without benefit in other tasks From the spinal cord injury field Cats trained to stand can stand but not walk better Cats trained to walk can walk but not stand better Rats trained to swim can swim but not walk better Rats trained to reach can reach but not climb better Humans trained on treadmill can walk better on treadmill but not over ground Practice Makes… Pigeonholed? De Leon et al, 1998; Smith et al, 2006; Dobkin et al, 2006; Garcia-Alias et al, 2009

31. Practice Makes… Pigeonholed?

32. The Dilemma: How to broaden the benefits of task-specific training? Practice variety of tasks within same broad category eg writing in print vs cursive letters, etc - Winstein and Wolf 2009 Random practice order rather than ordered blocks

33. Learning Objectives • Recognize differences between axonal injury and repair in the PNS versus CNS. • Understand levels of neural plasticity – from subcellular to network plasticity. • Recognize approaches and targets for improving neural repair. • Understand principles of neurorehabilitation – essential in conjunction with any other drug, cellular, or engineering-based treatments.

34. BAPTISTE, D. C. & FEHLINGS, M. G. (2006) Pharmacological approaches to repair the injured spinal cord. J Neurotrauma, 23, 318-34. BRADKE, F., FAWCETT, J. W. & SPIRA, M. E. (2012) Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci, 13, 183-93. CAFFERTY, W. B., MCGEE, A. W. & STRITTMATTER, S. M. (2008) Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci, 31, 215-20. HAREL, N. Y. & STRITTMATTER, S. M. (2006) Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat Rev Neurosci, 7, 603-16. KERSCHENSTEINER, M., SCHWAB, M. E., LICHTMAN, J. W. & MISGELD, T. (2005) In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat Med, 11, 572-7. KRAKAUER, J. W. (2006) Motor learning: its relevance to stroke recovery and neurorehabilitation. CurrOpinNeurol 1:84-90. PASCUAL-LEONE, A., AMEDI, A., FREGNI, F. & MERABET, L. B. (2005) The plastic human brain cortex. Annu Rev Neurosci, 28, 377-401. RAMON Y CAJAL, S., DEFELIPE, J. & JONES, E. G. (1991) Cajal's degeneration and regeneration of the nervous system, New York, Oxford University Press. Further Reading