1 International Neurorehabilitation Symposium February 12, 2009 Neural Plasticity and Locomotor Recovery: Robotics in Research Keith Tansey, MD, PhD Director, Spinal Cord Injury Research Crawford Research Institute, Shepherd Center Research Faculty, Departments of Neurology and Physiology Emory University School of Medicine Attending Physician, Spinal Cord Injury Clinic Veteran s Administration Medical Center Atlanta, USA
2 Trying to Recover Function after Neural Injury The Assumptions Molecules drive cellular functions. Nerve cells are connected in circuits. Those neural circuits are active. That activity drives behavior. Therefore, all one has to do is use molecules or cells to reconstruct circuits and you ll get behavioral recovery, correct?
3 Trying to Recover Function after Neural Injury The Problem from the Physiologist s Perspective To date, there have been only modest successes. Missing is the link between molecules or cells and behavior, the black box of physiology. What is the necessary and sufficient activity in which neural circuits to get recovery of what function? There are lots of interventions (molecules, cells, biomaterials, therapy) but limited outcome measures (behavior, although it is difficult to determine what is residual, compensatory, or recovered behavior, and, in animals, anatomy, but with axons studied more than synapses). Which of these interventions do we take to clinical trials and based on what criteria?
4 Trying to Recover Function after Neural Injury The Physiologist s Assertion To expect functional recovery from an intervention (and to justify moving from animal models to human studies) we need to know 1)What functional recovery are we trying to get? 2)Can we test the neural circuits involved in that function? 3)Does the intervention impact those neural circuits? 4)Is the story the same for animal models and humans? Today, we ll talk about 1) the recovery of locomotion after spinal cord injury, 2) some of the neural circuits responsible for locomotor function, and 3) how locomotor training may drive plasticity in those neural circuits in animal models and in patients.
5 What do we know about locomotor recovery in SCI? (at least the big picture) In Animal Models In Humans Complete Injury essentially no recovery essentially no recovery Complete Injury & recovery of some recovery of some Locomotor Training stepping balance/standing? Incomplete Injury much better recovery variable/limited recovery of stepping of stepping Incomplete Injury & little enhancement enhanced recovery Locomotor Training of stepping of stepping
6 BBB Rat Locomotor Score / Percent Spared Cord Uncoupling
7 Wiring Diagram of Sensory and Supraspinal Inputs to Spinal Central Pattern Generator (CPG) Circuits involved in Stepping after Incomplete Spinal Cord Injury So what is the circuitry for recovered stepping after spinal cord injury?
8 Supraspinal Circuits a Supraspinal Site for Stepping Hypothalamic Locomotor Region
9 Hypothalamic Locomotor Region Stimulation- Supraspinally Evoked Stepping without Limb Loading
10 Uncoupling of BBB and Supraspinally Evoked Stepping BBB
11 So is there any plasticity in these circuits with restorative neurological interventions?
12 Treadmill training in incomplete spinal injured rats changes gene expression at spinal and supraspinal levels but does not much improve stepping Cerebellum RMA dchip PM/MM all genes Motor Cortex RMA dchip PM/MM Lumbar Spinal Cord RMA 8743 all genes dchip PM/MM 4 rats trained 4 rats untrained all genes
13 Quadripedal Locomotor Training with Pelvic Body Weight Support Quadrapedal locomotor training does not improve BBB scores nor does it improve the ability of HLR stimulation to evoke stepping.
14 What do we know about locomotor recovery in SCI? (at least the big picture) In Animal Models In Humans Complete Injury essentially no recovery essentially no recovery Complete Injury & recovery of some some recovery of Locomotor Training stepping balance/standing? Incomplete Injury much better recovery variable/limited recovery of stepping of stepping Incomplete Injury & little enhancement enhanced recovery Locomotor Training of stepping of stepping
15 Where is there neural plasticity with locomotor training in human incomplete SCI?
16 Gait Recovery with Locomotor Training
17 Changes in Supraspinal Activation Patterns following Robotic Locomotor Therapy in Subjects with Motor Incomplete Spinal Cord Injury Study Patient characteristics: Level ASIA Time Patient Age of injury class since injury Medications 1 45 C5 C 14 weeks Gabapentin 2 20 C6 D 6 months Oral Baclofen 3 49 C5 C 1 year IT Baclofen 4 44 C6 C 4 years None
18 fmri changes (foot plantar flexion task) following locomotor training
19 So is there spinal plasticity with locomotor training in human incomplete SCI?
20 A Segmental Reflex - the Hoffman or H-Reflex The electrical equivalent of the muscle stretch reflex Measures: M max H max M hmax H/M max (M hmax )
21 Methods H-Reflex recording in the Lokomat Subjects were stepped with 40% body weight support at 1.8 and 2.5 km/hr and H-reflexes (n=50) were recorded at mid-stance and mid-swing of the gait cycle.
22 H-Reflexes are influenced by injury severity and context
23 Mid-stance H-Reflex responses in motor incomplete SCI subjects do not change following 3 months of robotic BWSTT Mid-stance H-Reflex parameters, mean +/- SD Motor Incomplete Motor Incomplete Pre-BWSTT Post-BWSTT Controls (n=8, 2/8 walking) (n=8, 7/8 walking) (n=4) H/M prone / / / H/M stand / / / H/M 1.8 km/hr / / / H/M 2.5 km/hr / / / Over-ground gait speed cm/s 7.8 +/ / * *Our experience is that the threshold speed to continue home walking is ~20 cm/s and for limited community ambulation is ~50 cm/s.
24 While mid-stance H-Reflex responses in motor incomplete SCI do not change overall following 3 months of robotic BWSTT, there is a relationship between final gait speed achieved and change in mid-stance H/M ratios post vs. pre-training. Change in H:M Ratio 1.8 km/h Post H:M Ratio - Pre H:M Ratio vs Recovered Gait Speed r 2 = 0.5 Change in H:M Ratio 2.5 km/h Post H:M Ratio - Pre H:M Ratio vs Recovered Gait Speed r 2 = Final Gait Speed cm/s Final Gait Speed cm/s
25 Hypothesis 1 After spinal cord injury, humans and animals differ in their spontaneous locomotor recovery because the relative contributions of the neural circuits for stepping, spinal and supraspinal, are different between humans and animals. That is to say, animal locomotion is spinal circuits>supraspinal circuits biased and human locomotion is supraspinal circuits>spinal circuits biased. Hypothesis 2 In complete SCI, locomotor training improves stepping in animals but not in humans because it works at the level of spinal circuits and those circuits are sufficient for stepping in animals but not in humans. In incomplete SCI, locomotor training improves stepping in humans because it also works at the level of supraspinal circuits and those circuits are important for stepping in humans. Any supraspinal effect of training provides no significant additional benefit to animals who count much more on their spinal circuitry for stepping.
26 Implications Differences between rat and human findings should be considered when translating ideas from the SCI lab to clinical interventions in patients. Specifically, some therapeutic interventions that improve locomotor scores in the rat after SCI may NOT cause locomotor recovery in humans after SCI because those interventions could be working at the level of infra-injury neural circuitry, circuitry which may be insufficient to support the recovery of stepping in patients. Since supraspinal centers appear to be important in gait recovery in humans following SCI, the ability of a therapeutic approach to improve supraspinally evoked locomotion in the rat SCI model (like with HLR stimulation) should be tested before the therapeutic approach is translated to a clinical trial.
27 In Conclusion...
29 Behavioral Outcomes in Rodent Models of SCI BASSO, BEATTIE & BRESNAHAN LOCOMOTOR RATING SCALE 0 No observable hindlimb (HL) movement 1 Slight movement of one or two joints, usually the hip &/or knee 2 Extensive movement of one joint or Extensive movement of one joint and slight movement of one other joint 3 Extensive movement of two joints 4 Slight movement of all three joints of the HL 5 Slight movement of two joints and extensive movement of the third 6 Extensive movement of two joints and slight movement of the third 7 Extensive movements of all three joints of the HL 8 Sweeping with no weight support or Plantar placement of the paw with no weight support 9 Plantar placement of the paw with weight support in stance only or Occasional, Frequent or Consistent weight supported dorsal stepping and no plantar stepping 10 Occasional weight supported plantar steps, no FL-HL coordination 11 Frequent to consistent weight supported plantar steps and no FL-HL coordination 12 Frequent to consistent weight supported plantar steps and occasional FL-HL coordination 13 Frequent to consistent weight supported plantar steps and frequent FL-HL coordination 14 Consistent weight supported plantar steps, consistent FL-HL coordination; and, predominant paw position during locomotion is rotated when it makes initial contact with the surface as well as just before it is lifted off at the end of stance or Frequent plantar stepping, consistent FL-HL coordination and occasional dorsal stepping 15 Consistent plantar stepping and Consistent FL-HL coordination; and, No toe clearance or occasional toe clearance during forward limb advancement Predominant paw position is parallel to the body at initial contact 16 Consistent plantar stepping and Consistent FL-HL coordination during gait; and Toe clearance occurs frequently during forward limb advancement Predominant paw position is parallel at initial contact and rotated at lift off 17 Consistent plantar stepping and Consistent FL-HL coordination during gait; and Toe clearance occurs frequently during forward limb advancement Predominant paw position is parallel at initial contact and lift off 18 Consistent plantar stepping and Consistent FL-HL coordination during gait; and Toe clearance occurs consistently during forward limb advancement Predominant paw position is parallel at initial contact and rotated at lift off 19 Consistent plantar stepping and Consistent FL-HL coordination during gait; and Toe clearance occurs consistently during forward limb advancement Predominant paw position is parallel at initial contact and lift off; and, Tail is down part or all of the time 20 Consistent plantar stepping and Consistent coordinated gait; consistent toe clearance; predominant paw position is parallel at initial contact and lift off; and, Trunk instability; Tail consistently up 21 Consistent plantar stepping and Coordinated gait; consistent toe clearance, predominant paw position is parallel throughout stance, consistent trunk stability; tail consistently up.