Previous activation of Ia fibres mediating the affer-ent volley of the H reflex produces a dramatic reflex depression at short ISIs (1–2 s), referred to as ‘post-activation depression’ or ‘homosynaptic depres-sion’ (Crone & Nielsen,1989). This raises particular methodological problems when using the H reflex (see Chapter1, pp.13–14). In addition, a reduction in post-activation depression at the synapse of the Ia afferent on the motoneurone seems to be one of the mechanisms underlying spasticity. The defini-tive work on this phenomenon was undertaken by Hultborn, Nielsen and colleagues and the following section is largely based on a comprehensive review by Hultborn & Nielsen (1998).
Background from animal experiments
It has long been known that the size of the mono-synaptic reflex in the cat decreases during repetitive stimulation (Eccles & Rall,1951), and a frequency-related depression of the reflex has been described at stimulus intervals as long as 10–20 s (Lloyd &
Wilson,1957). In a variety of preparations, inclu-ding the Ia-motoneurone synapse in the cat spinal cord, there is early facilitation of relatively short duration, superimposed on a depression of much longer duration (several seconds) when more than one impulse is conducted (see Curtis & Eccles,1960;
Mendell,1984; Hultborn et al.,1996). Statistical ana-lysis of the quantal release at the Ia-motoneurone synapse suggests that the early facilitation and the subsequent depression are both due to changes in the probability of transmitter release at the synapse (Kuno,1964; Hirst, Redman & Wong,1981). For the Ia-motoneurone synapse, it has been demonstrated that facilitation and depression dominate at dif-ferent frequencies (L ¨uscher, Ruenzel & Henneman, 1983), and depend on the particular Ia-motoneurone connection (facilitation being dominant for high-threshold ‘fast’ motoneurones and depression for low-threshold ‘slow’ ones, Honig, Collins & Mendell, 1983).
Post-activation depression 97
Functional significance
Ia afferents may have a background discharge and commonly discharge in relatively long bursts dur-ing natural movements. The overall synaptic efficacy at a given Ia-motoneurone synapse depends on the
‘adapted’ state of synaptic transmission created by the background Ia firing. If there is a pause in the dis-charge, the EPSP due to the first spike in a subsequent train of afferent impulses will be unaffected by these facilitation/depression processes. During the train, however, the post-activation depression would help hold the synaptic efficacy of the Ia fibre at a rela-tively low level during voluntary movements. This is likely to be important functionally (see Hultborn &
Nielsen,1998), because it would favour a low gain for the stretch reflex, and thus help prevent oscil-lations and clonus from developing (see Matthews, 1972). Differences in post-activation depression of the synaptic actions of the collaterals of the same group II afferents have been found in the cat in dorsal horn and intermediate zone interneurones, suggest-ing that post-activation depression could depend on the different target neurones of these collater-als (Hammar, Slawinska & Jankowska,2002). Differ-ences in the susceptibility of different terminals of the same Ia afferent could allow rapid adaptation of the monosynaptic Ia input to motoneurones but a constant input to other spinal targets (such as lum-bar propriospinal neurones, see Lamy et al.,2005) and to supraspinal centres.
Methodology
Under normal conditions synapses are activated by trains of impulses of varying frequency and pattern, but the rules of the activity dependency are best investigated under stereotyped conditions in which the response in the post-synaptic cell to stimula-tion of the presynaptic fibre covers a range of inter-vals following a conditioning stimulus. In practice, two methods may be used to assess post-activation depression at the Ia fibre-motoneurone synapse in humans. They are illustrated in Fig.2.12.
Post-activation depression following passive stretch of the test muscle
Passive dorsiflexion of the foot produces a consider-able reduction of the soleus H reflex at ISIs up to 2 s, and the reflex only returns to its control value at ISIs
>10 s (cf. Hultborn et al.,1996; Fig.2.12(b ),●). This depression is due to activity in large-diameter affer-ent fibres with receptors located in the leg muscles:
an ischaemic block just below the knee joint abol-ished the depression, but a similar block just proxi-mal to the ankle joint was ineffective. The same pas-sive dorsiflexion did not modify the amount of het-eronymous Ia facilitation of the soleus H reflex pro-duced by femoral nerve stimulation (Fig.2.12(b),❍).
This indicates that the depression: (i) is confined to the Ia pathway activated by the passive stretch, and (ii) is not due to presynaptic inhibition with primary afferent depolarisation (PAD) of Ia terminals directed to soleus motoneurones (because this should have reduced the femoral-induced heteronymous facili-tation of the H reflex by a similar extent; Chapter8, pp.345–6, see also Wood, Gregory & Proske,1996).
With passive wrist extension, there was similar depression of the FCR H reflex 2 s after the end of the stretch, (Fig.2.12(i ),(j )). However, passive wrist extension did not modify the FCR MEP (Fig.2.12(g ), (h )), indicating that the post-activation depression was not due to post-synaptic inhibition of the tested motoneurones. These results have been confirmed in experiments in the decerebrate cat in which there was depression of the EPSP originating from the pre-viously activated Ia afferents without depression of Ia EPSPs from other (heteronymous) nerves (Hultborn et al.,1996).
Post-activation depression occurring when the stimulus rate is increased
Depression at rest
It has long been known that stimulus rate has a depressive effect on the size of the test reflex (Magladery & McDougal,1950; Fig.2.12(c )).
This depression can be attributed to the previ-ous activation of Ia afferents because it is also observed after a conditioning stimulus that is
0 2 4 6 8
+ wrist ext.
H reflex
+ wrist ext MEP Passive
dorsiflexion
FCR MN
FCR
Passive wrist extension TMS
Median nerve
% of control
% of Mmax
(a)
(c)
(b)
(d ) 120°
110° 0 50 100 150
0 5 10 15
FN-induced facilitation H reflex
Time after dorsiflexion (s)
0 50 100
0 5 10 15
ISI (ms)
0 50 100
Contraction Rest
Control During ischaemia 1 2 15 1 2 15
(e) Angle of
ankle
(f )
(g) (h) (i)
(j)
% of control
Ia Q
Ia Soleus
Post-activation depression
H reflex MEP
PAD INs
Sol MN
Contraction Rest
Fig. 2.12. Evidence for post-activation depression in normal subjects. (a ) Sketch of the pathway for post-activation depression at the Ia-motoneurone (MN) synapse of soleus (Sol), and of heteronymous Ia facilitation from quadriceps (Q) to Sol. The pathway of presynaptic inhibition of Ia terminals is also represented (PAD INs). (b) The size of the Sol H reflex (●) and the amount of femoral-induced facilitation (1× MT, – 5.4 ms ISI, ❍) of the Sol H reflex, both expressed as a percentage of their control value, are plotted against the time after the end of a passive dorsiflexion (dotted line at the bottom of the panel, 10◦in 600 ms, too slow and too small to evoke any EMG activity). (c ) The size of the soleus H reflex (as a percentage of its value when elicited at an interstimulus interval [ISI] of 15 s) is plotted against the ISI between two consecutive stimuli at rest (●) and during Sol voluntary contraction (❍).
(d ), (e ) The size of the Sol H reflex at ISIs of 1, 2 and 15 s (as a percentage of its value at the 15-s ISI) at rest () and during voluntary contraction () before (d ) and 25 minutes after ischaemia by cuff around the upper part of the leg (e). (f) Sketch of the pathways explored in (g )–(j ). (g )–(j) The size of the MEP ((g ), (h )) and of the H reflex ((i ), (j )) of the flexor carpi radialis (FCR) are compared before (, (g ) and (i )) and 2 s after passive wrist extension (filled columns, (h ) and (j )). Modified from Hultborn & Nielsen (1998), with permission.
Post-activation depression 99
subthreshold for the H reflex or tendon jerk (T´abor´ıkov´a & Sax,1969; Katz et al.,1977; Crone &
Nielsen,1989).
Depression during voluntary contraction
During voluntary contraction of the tested muscle the depression is attenuated (Rothwell, Day & Mars-den,1986; Burke, Adams & Skuse,1989; Hultborn &
Nielsen,1998; Fig.2.12c). The most parsimonious explanation for this is that the enhanced Ia firing during voluntary contraction (see Chapter 3, pp.
133–5) causes a background level of post-activation depression, and this can only be enhanced slightly by the additional depression caused by a preced-ing H reflex. This interpretation is supported by the finding that the difference between the amount of post-activation depression observed at rest and during contraction (Fig.2.12(d ),, ) disappears when the activity of Ia afferents is blocked by ischaemia (Hultborn & Nielsen,1998; Fig.2.12(e )).
That the H reflex is still facilitated during con-traction indicates that other mechanisms outweigh the reduction caused by the background post-activation depression. These mechanisms include increased motoneurone excitability and, for the H reflex, decreased inhibitory mechanisms gating the test volley. Driving spindle afferents by vibration of the muscle tendon does not similarly abolish post-activation depression of the H reflex (Van Boxtel, 1986) but this could be due to the additional presy-naptic inhibition of Ia terminals produced by vibra-tion (see Chapter8, p.341).
Reflexes elicited in small motoneurones
Reflexes elicited in small motoneurones are more sensitive to post-activation depression, in agree-ment with animal data (see above). As a result, the decline of the reflex response when increasing the stimulus rate is greater for soleus H reflexes of small than of large size (Floeter & Kohn,1997).
This difference in susceptibility to homosynaptic depression may serve to concentrate the damping
effect upon those motoneurones that are the most likely to be activated by small stretches or pertur-bations, without disabling the stretch responses of higher-threshold motoneurones. The weaker sen-sitivity to post-activation depression of reflexes elicited in high-threshold motoneurones could also account for the lesser susceptibility of FCR H reflexes to high stimulus rates (Rossi-Durand et al., 1999).
Post-activation depression in spastic patients
Decreased post-activation depression in spastic patients
The depression produced by passive dorsiflex-ion is much less pronounced in spastic patients with spinal cord lesion(s), whether due to trauma or multiple sclerosis, than in healthy subjects (Fig. 2.13(a ); Nielsen & Hultborn, 1993; Nielsen, Petersen & Crone,1995; Hultborn & Nielsen,1998).
Similarly, the amount of post-activation depression of the FCR and soleus H reflexes, assessed as the size of the H reflex elicited every 2 s and expressed as a percentage of its value when elicited every 8 s, is significantly reduced on the affected side of hemi-plegic patients. In contrast, the depression is sim-ilar on their unaffected side and in normal subjects (Fig.2.13(b ),(c ); Aymard et al.,2000).
Post-activation depression and pathophysiology of spasticity
The reduction of post-activation depression would enhance the synaptic efficacy of trains of Ia impulses and could contribute to the stretch reflex exag-geration that characterises spasticity. As empha-sised by Hultborn and Nielsen (1998), the decreased depression seen in patients with a lesion of the central nervous system does not necessarily imply that post-activation depression is under direct control by descending pathways. Several lines of evidence suggest that adaptive changes in the
(a)
(b) (c)
Fig. 2.13. Reduction of post-activation depression in spastic patients. (a) The mean value (± SEM) of the soleus H reflex (expressed as a percentage of its control value) plotted against the time after the onset of passive dorsiflexion of the foot (illustrated by the dotted line at the bottom of the panel, 10◦in 600 ms, too slow and too small to evoke any EMG activity) in 30 healthy subjects (●) and 17 spastic patients with multiple sclerosis or spinal cord injury (❍). (b), (c) The mean value (+ SEM) of the FCR (b ) and soleus (c ) H reflex elicited every 2 s, and expressed as a percentage of its value when elicited every 8 s, is compared in 16 normal subjects () and on the affected () and unaffected (dashed columns) of hemiplegic patients (n = 16 in (b), and 10 in (c)). Modified from Hultborn & Nielsen (1998) (a ), and Aymard et al. (2000) ((b ), (c )), with permission.
efficacy of the Ia-motoneurone synapse develop following the changes in activity of motoneurones and Ia fibres resulting from the impairment of the motor command. (i) The fact that spastic-ity progresses during weeks or months after the causal lesion (whether a spinal lesion or stroke) fits this hypothesis, because such adaptive changes develop over time. (ii) In this respect, a longitu-dinal study of one patient with spinal cord injury found that the reduction of post-activation depres-sion developed with the transition from flaccid to spastic paralysis, even though reduced post-activation depression preceded clinically observ-able spasticity (Schindler-Ivens & Shield, 2000).
(iii) Contrary to several other electrophysiological changes explored (see Chapter12, pp.577–9), post-activation depression is unchanged on the unaf-fected side of patients with hemiplegia (Fig.2.12(b ), (c ), dashed columns). (iv) The synaptic efficacy of primary afferents can be up- or down-regulated by disuse or use of synapses, respectively (Gallago et al., 1979).