Pre-synaptic and Reciprocal Inhibition in the Hemiparetic UE:

Mechanisms and Functional Implications

Chetan Phadke

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

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

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

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

Types of inhibition

• Presnaptic

• Reciprocal

• Recurrent

• Post-synapticAntagonist

Ia

Ia Post-synaptic

Ia pre-synaptic

Renshaw

Descending

Agonist

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

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 doesit really work?

9

PADGABA

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

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

Inhibition

Knikou 2008

13Knikou 2008

Dis-facilitation

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)

15Nakashima et al (1990)

Cutaneous + median

Cutaneous + radial +median

Radial + median

Release of inhibition

So how does PSI help us?

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)

17Aimonetti et al (1999)

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

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)

20Knikou (2008)

21Aymard (1995)

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

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)

24Nakashima et al (1990)

Effect of hand anesthesia

Before During After anesthesia

Cutaneous afferents exert a tonic influence on presynaptic pathways

RI PSI

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)

26Aimonetti et al (1999)

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

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

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

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

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

Pathways potentially related to impairment post-stroke

Nielsen et al (2007)

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)

34Post-stroke: Lamy (2008)

35Lamy et al (2008)

36Lamy et al (2008)

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

• 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

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

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

Fujiwara (2008)

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

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

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 1st year post-stroke

44

Thank you

45Knikou 2008

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

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

48Knikou 2008

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

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

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 neuronalnetwork 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

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

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 heteronymousIa 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

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

55Aymard et al (1995)

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

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.