1. Pre-synaptic and Reciprocal Inhibition in the Hemiparetic UE: Mechanisms and Functional Implications Chetan Phadke

2. 2 Summary Types of spinal inhibition Underlying mechanisms Functional significance Special Case of the wrist muscles Effect of therapeutic interventions Future studies Need for inhibition

3. 3 Continuous Sensory Flow Periphery  Spinal cord Sensory fibers entering spinal cord have ascending and descending fibers (Cajal 1899) Exceeds the information processing ability of the CNS Sensory flow needs to be regulated Inhibition or dis-facilitation Inhibitory/Facilitatory interneurons Knikou (2008), Eccles (1960), Rudomin (1999), and For Review – Hultborn (2006)

4. 4 Sir John Carew Eccles Joint Nobel award (John C. Eccles, Alan Hodgkin, Andrew Huxley - 1963) ‘‘for discoveries concerning the ionic mechanism in the excitation and inhibition of the peripheral and central membranous sections of nerve cells’’ Willis (2006), Burke (2006) Where to inhibit?

5. 5 Site of Inhibition Three potential sites: sensory receptor, primary afferent terminal, and second-order cell Receptors: No sensory feedback Second-order cell: Afferents have already affected other systems Ia afferent terminal: Most economical Rudomin (1999), Knikou (2008)

6. 6 Types of inhibition Presnaptic Reciprocal Recurrent Post-synaptic Antagonist Ia Ia Post- synaptic Ia pre- synaptic Renshaw Descending Agonist

7. 7 Presynaptic Inhibition (PSI) Before the synapse Frank and Fuortes (1957) Decrease in EPSP (no change in membrane potential or excitability of post- synaptic cells) Frank & Fuortes (1957) ref. in Willis (2006)

8. 8 Presynaptic Inhibition Further evidence presynaptic nature of depression Strychnine did not change this depression Strychnine blocks postsynaptic depression Eccles (1963), Devanandan (1965), Rudomin (1999) How does it really work?

9. 9 PAD GABA

10. 10 PSI characteristics PSI accompanied by primary afferent depolarization Axo-axonal gamma-aminobutyric (GABA) synapses Reduction in the size of the presynaptic impulse Decrease in the monosynaptic transmission of the Ia excitatory effects Rudomin (1999)

11. 11 PSI testing methods Test reflex (e.g. soleus H-reflex) Conditioning impulse provided before test reflex stimulation Conditioning impulse could be either tendon vibration, cutaneous afferent stimulation, or muscle afferent stimulation of the synergist or antagonist muscle Upper and lower limb origin Rudomin (1999), Aimonetti (1999), Fujiwara (2008), Nakashima (1990), Zehr (2001)

12. 12 Inhibition Knikou 2008

13. 13 Knikou 2008 Dis-facilitation

14. 14 Sources of PSI Supraspinal Ia afferents from homonymous or heteronymous muscles Ia afferents from antagonists and agonists Ia afferents from synergistic muscles Ib afferents Cutaneous afferents (upper or lower limb) Rudomin (1999), Zehr (2007), Fujiwara (2008)

15. 15 Nakashima et al (1990) Cutaneous + median Cutaneous + radial +median Radial + median Release of inhibition So how does PSI help us?

16. 16 Task-specific PSI Upper limb and lower limb Onset of muscle contraction, PSI decreases in the target muscle Ia afferents Allows the Ia excitation on the motor neuron (stretch reflex) to contribute to muscle activity PSI is increased in the non-contracting muscle afferents This decrease in PSI in the target muscle has been attributed to supraspinal mechanisms Hultborn (1987), Collins (1998), Morita (1995)

17. 17 Aimonetti et al (1999)

18. 18 PSI: A Ubiquitous Phenomenon Posture, phase of walking, walking post- SCI, walking environment PSI increased during standing without a change in background EMG level Current intensity change did not affect PSI Goulart (2000), Koceja (1993), Capaday (1987), Yang (1993), Llewelleyn (1990), Phadke (2007), Stein (1995), Iles (1996), Jankowska (1976), Iles (1992), Nielsen (1993), Capaday (1995)

19. 19 Reciprocal Inhibition (RI) Inhibition of Ia afferents by antagonist large group I muscle afferents Disynaptic pathway (1 inhibitory interneuron) Pathway different than PSI Modulates alpha motor neuron activity Concomitant test and conditioning stimuli Day (1984)

20. 20 Knikou (2008)

21. 21 Aymard (1995)

22. 22 Two phases of RI 1) ISI = -1 to 3 ms and 2) +5 to +30 ms First is disynaptic reciprocal inhibition between radial Ia afferents and flexor alpha motoneurones Second is presynaptic inhibition of flexor Ia afferents Nakashima (1990), Huang (2006)

23. 23 Inhibition of H-reflex in arm Mechanical stimulation of finger tips decreased PSI and RI (ECR) Hand anesthesia increased PSI by 10% and decreased RI by 20% (ECR) Superficial radial nerve (wrist) stimulation decreased inhibition by 20% (FCR) Finger or superficial radial stimulation decreased PSI induced by radial nerve conditioning (up to 20% decrease; FCR) Cutaneous stimulation by itself produced no PSI RI did not change Aimonetti (1997 and 1999), Berardelli (1987), Nakashima (1990)

24. 24 Nakashima et al (1990) Effect of hand anesthesia BeforeDuringAfter anesthesia Cutaneous afferents exert a tonic influence on presynaptic pathways RIPSI

25. 25 Grip induced changes in PSI Similar levels of ECR reflex facilitation seen during hand clenching and cutaneous afferent stimulation without hand clenching ECR H-reflex was larger during hand clenching compared to isometric ECR contraction The cutaneous afferents may play a major role controlling reflex loops during hand motor activities Presynaptic inhibition might be depressed as the result of the large-scale activation of palm and finger cutaneous afferents liable to occur during hand clenching Aimonetti (1997 and 1999), Schmied (1997)

26. 26 Aimonetti et al (1999)

27. 27 Transcranial conditioning TES given 4.5 ms after test stimulus strongly facilitated FCR H-reflex TES decreased both RI and PSI Sub-threshold TMS given induced facilitation of FCR H-reflex TMS decreased both RI and PSI Mercuri (1997), Cowan (1986)

28. 28 Disynaptic inhibition in elbow muscles Disynaptic RI is seen between elbow flexors and extensors Conditioning stimulus of tendon tap activates Renshaw cells and RI induced by disynaptic inhibition is depressed Similar protocol used for wrist muscles, but RI level remained unchanged Katz (1991), Aymard (1995)

29. 29 Inhibition in the wrist muscles Ia afferents from antagonistic elbow muscles were found to facilitate actions of interneurons mediating inhibition between wrist flexors and extensors RI seen between flexors and extensors may not be disynaptic, but non-reciprocal group I inhibition 20 minutes of tendon vibration did not change RI between wrist flexors and extensors The dominant group I peripheral input to the interneurones mediating reciprocal inhibition between wrist muscles is not Ia, but Ib in origin Wargon (2006), Aymard (1995)

30. 30 Unique case of the wrist Wrist flexors and extensors are not truly antagonistic muscles because they work synergistically during hand clenching and work together to produce radial/ulnar deviation Wrist has movements in two planes and the complex movement of circumduction Wargon (2006), Aymard (1995) Does inhibition change post-stroke?

31. 31 Impaired inhibition post-stroke PSI and RI are impaired post-stroke (inhibition decreases) Inhibition replaced by facilitation Loss of normal facilitation Several pathways could be impaired leading to functional impairments Lamy (2008), Aymard (2000), Artieda (1991), Dietz (1992), Crone (1994, 2001, and 2003), Faist (1992), Morita (2001), Yanigasawa (1973), Kagamihara (2005), Nielsen (2007), Okuma (1996), Harburn (1995), Levin (1992)

32. 32 Pathways potentially related to impairment post-stroke Nielsen et al (2007)

33. 33 Spinal inhibition : Clinical manifestations No correlation between PSI/RI and spasticity post-stroke Acute stroke has more loss of inhibition compared to chronic stroke More affected side post-stroke shows more loss of inhibition compared to less- affected side Strong correlation between spasticity and paired-reflex depression Lamy (2008), Aymard (2000)

34. 34 Post-stroke: Lamy (2008)

35. 35 Lamy et al (2008)

36. 36 Lamy et al (2008)

37. 37 Similar trends in lower limbs Disynaptic Ia inhibition from peroneal nerve afferents to soleus motoneurones was tested RI increased in patients who showed good recovery of function with mild spasticity No change in patients who made a poor recovery and had more marked extensor spasticity In patients where serial recordings were obtained there was an increase in Ia inhibition during the recovery period following stroke Okuma (1996), Lamy (2008)

38. 38 Two-week TENS decreased clinical spasticity and increased vibratory inhibition of the soleus H reflex Substantial improvement in voluntary dorsiflexing force up to 820%, but not plantarflexing force Reduction in the magnitude of stretch reflexes in the spastic ankle plantarflexor Decrease in the EMG co-contraction ratios Levin MF (1992) TENS and lower limb trends

39. 39 Therapeutic Intervention and spinal excitability HANDS (hybrid, assistive neuromuscular dynamic system) EMG feedback based FES 3 week training, 40 minutes/day, 5 days/week, wearing the system 8 hours per day Decreased co-contraction (wrist flexor/extensor) H-reflex amplitude did not change, in 8/20 patients TMS could be evoked pre and post treatment (no change in MEPs, motor thresholds) increased intracortical inhibition post-treatment decreased MAS post-treatment improved hand function (drinking with glass and turn over a page) post-training increase in grip strength and increase in RI and PSI post-treatment Grip strength and drinking with glass increased 3 months f/u Fujiwara (2008)

40. 40 Figure 2 Reciprocal Inhibition Before and After the Hybrid Assistive Neuromuscular Dynamic Stimulation (HANDS) Therapy (Fujiwara 2008) Fujiwara (2008)

41. 41 Gap Analysis: Unknowns Is there a correlation between PSI/RI and hand function? Serial recovery post-stroke and change in PSI Can the spinal inhibition increase post- conditioning? Can it be used as an intervention? FES? Can r-TMS increase spinal inhibition? Wolpaw (2006)

42. 42 Unanswered Questions Can arm bicycling improve reflex inhibition and function post-stroke? Can the H-reflexes be down-trained by conditioning using Wolpaw’s protocol? Is practice/therapy for hand movements performed with cutaneous stimulation better than without? Does strengthening of muscles improve reflex inhibition?

43. 43 Future studies Establish correlation between spinal inhibition and dexterity of hand movements, grip strength, and muscle tightness Test single session effects of cutaneous stimulation during isokinetic movements of of the wrist joint in Biodex Serial testing of PSI/RI during 1 st year post-stroke

44. 44 Thank you

45. 45 Knikou 2008

46. 46 Basic Concepts in Neuroscience By Malcolm Slaughter, John Nyquist, Barbara E. Evans p.152

47. 47 Basic Concepts in Neuroscience By Malcolm Slaughter, John Nyquist, Barbara E. Evans p.150

48. 48 Knikou 2008

49. 49 Fig. 7. Homonymous recurrent inhibition in humans. (I) A stimulus S1 delivered to the posterior tibial nerve elicits anH1 reflex in the soleus muscle (A), while a supramaximal (SM) stimulus induces a maximal direct motor response (Mmax) (B) without an H-reflex to be present on the EMG because the antidromic motor volley collides with and eliminates the H-reflex evoked by the SM stimulus. When the stimulus S1 is delivered at an interval of 10ms before the SM stimulus, the H1 is no longer present but a new response called H (C) appears in the EMG. The diagrams II and III illustrate the different impulses, identified as arrows, propagating along the nerve fibres at C–T intervals of 5 and 12 ms. The Ia afferent volley induced by the SM test stimulus activates two motoneurons (E1 and E2). The white small arrow in diagram II represents the H1 reflex discharge in axon E1. White large arrows represent the Ia afferent test volley due to the test stimulus (II) and the following reflex discharge (III). Black arrows indicate the orthodromic motor volley evoking Mmax and the antidromic motor volley due to stimulation of motor axons by the SM test stimulus (II). Five milliseconds after the SM test stimulus, impulses travel both orthodromically in Ia fibres and antidromically inmotor axons. The H1 response, which runs along the E1 axon collideswith and eliminates the antidromic motor volley. Twelve milliseconds after the SM test stimulus, a reflex response develops in both motoneurons E1 and E2. This response is blocked in motoneuron E2 but not in motoneuron E1 because the antidromic impulse in motoneuron E1 was erased by the H1 response, as shown in diagram II. The diagram I was borrowed from Pierrot-Deseilligny et al. (1976), with permission, and diagrams II and III were adopted and modified from Hultborn and Pierrot- Deseilligny (1979a,b). Knikou 2008

50. 50 Fig. 6. Recurrent inhibition. Spinal circuit denotes the neuronal pathway ofRenshaw cells and their connections to - and -motoneurons, and Ia inhibitory interneurons between ankle flexors and extensors. Renshawcells depress the activity of – motoneurons, and Ia inhibitory interneurons. Broken lines indicate parallel control of-motoneurons, Ia inhibitory interneurons, andRenshawcells by the brain; closed circles: inhibition, closed triangles: facilitation. Knikou 2008

51. 51 Fig. 5. Non-reciprocal group I inhibition. Spinal circuit designates the neuronal pathway engaged on the soleus H-reflex depression following medialis gastrocnemius (MG) nerve stimulation at group I threshold. Dotted lines denote a neuronal network that is manifested only during the stance phase of locomotion in humans and animals, whereas Ib inhibition from MG to soleus reverses to excitation. Knikou 2008

52. 52 Fig. 4. Reciprocal Ia inhibition. (A) Spinal circuit designates the pathway of reciprocal inhibition exerted fromankle flexors following common peroneal (CP) nerve stimulation onto the soleus H-reflex. Reciprocal inhibition involves the Ia inhibitory interneuron and is exerted at a postsynaptic level and (B) waveform averages of 20 control and conditioned (by CP nerve stimulation) soleus H-reflexes evoked every 5 s at a conditioning test interval of 2ms are illustrated for a healthy subject while seated at rest. Conditioning stimulus intensity was delivered at the tibialis anterior motor threshold level (data adopted and modified from Knikou and Taglianetti, 2006). Knikou 2008

53. 53 Fig. 3. Presynaptic inhibition of Ia afferents reflected by changes of heteronymous Ia facilitation. (A) Sketch illustrates the spinal circuit during which femoral nerve (FN) stimulation at low intensities delivered after posterior tibial nerve stimulation induces monosynaptic excitation of soleus -motoneurons. Changes in the amount of heteronymous Ia facilitation reflect modulation of the on-going presynaptic inhibition acting on the Ia afferents of the conditioning afferent volley (quadriceps Ia afferents), (B) time course of soleus H-reflex facilitation by FN stimulation in one seated subject and (C) full-wave waveform rectified averages (n = 20) of the control and conditioned H-reflex following FN stimulation at −7.8ms are shown. Note that the heteronymous Ia reflex facilitation occurred without a significant change in the size of the M-wave (data adopted and modified from Knikou, 2006). Knikou 2008

54. 54 Fig. 2. Presynaptic inhibition of Ia afferents induced by a conditioning afferent volley. Common peroneal (CP) nerve stimulation at lowintensities is delivered before posterior tibial nerve stimulation to establish based on the amplitude of the conditioned soleus H-reflex the amount of presynaptic inhibition acting on soleus Ia afferent terminals (A) and average size of the soleus H-reflex conditioned by CP nerve stimulation at C–T intervals ranged from 60 to 120ms for 10 seated subjects (B) (data adopted and modified from Knikou and Taglianetti, 2006). Knikou 2008

55. 55 Aymard et al (1995)

56. 56 Fig. 1. The “simple” H-reflex pathway. Stimulation of the posterior tibial nerve at the popliteal fossa below motor threshold results in excitation of Ia afferents that largely induce monosynaptic excitation of homonymous _- motoneurons (A), which is evidenced on the EMG as an H-reflex. At maximal stimulus intensities the maximal M- wave (B) is observed without an H-reflex being present (C). The soleus H-reflex/current and M-wave/current recruitment curves constructed in one subject while standing are indicated in the left panel. In the right panel, the H-reflex/M-wave recruitment curve is indicated for the same recordings shown in the left panel. In both graphs, the H-reflex and M-wave are presented as a percentage of the Mmax. The reflex recruitment curve shown is not representative because differences across subjects are usually observed (From Knikou M, unpublished observations). Knikou 2008

57. 57 Huang, Y. -Z. et al. Neurology 2006;66:1088-1090 Figure 3. Reciprocal inhibition in subjects with dopa-responsive dystonia on and off medication and control subjects. (A) H reflex as a percentage of unconditioned size at all interstimulus intervals (ISIs). (B) Mean H-reflex size as a percentage of unconditioned size at the first (ISI 0 milliseconds), second (ISI 10, 20 milliseconds), and third (ISI 70, 100, 300 milliseconds) phases. Error bars indicate 1 SEM.