Annurev Neuro 070815 013913

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Human Spinal Motor Control
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Jens Bo Nielsen
Department of Neuroscience and Pharmacology and Department of Nutrition, Exercise
and Sports, University of Copenhagen, DK-2200 Copenhagen N, Denmark;
email: jbnielsen@sund.ku.dk
Annu. Rev. Neurosci. 2016.39:81-101. Downloaded from www.annualreviews.org
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Annu. Rev. Neurosci. 2016. 39:81–101 Keywords

First published online as a Review in Advance on human, spinal cord, reflex, voluntary movement
March 25, 2016
The Annual Review of Neuroscience is online at Abstract

neuro.annualreviews.org
Human studies in the past three decades have provided us with an emerg-
This article’s doi: ing understanding of how cortical and spinal networks collaborate to en-
10.1146/annurev-neuro-070815-013913
sure the vast repertoire of human behaviors. Humans have direct cortical
Copyright c 2016 by Annual Reviews. connections to spinal motoneurons, which bypass spinal interneurons and
All rights reserved
exert a direct (willful) muscle control with the aid of a context-dependent
integration of somatosensory and visual information at cortical level. How-
ever, spinal networks also play an important role. Sensory feedback through
spinal circuitries is integrated with central motor commands and contributes
importantly to the muscle activity underlying voluntary movements. Regu-
lation of spinal interneurons is used to switch between motor states such as
locomotion (reciprocal innervation) and stance (coactivation pattern). Cor-
tical regulation of presynaptic inhibition of sensory afferents may focus the
central motor command by opening or closing sensory feedback pathways.
In the future, human studies of spinal motor control, in close collaboration
with animal studies on the molecular biology of the spinal cord, will continue
to document the neural basis for human behavior.
81
Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
DIRECT CORTICAL CONTROL OF MUSCLE ACTIVITY . . . . . . . . . . . . . . . . . . . . 83
EVIDENCE THAT PART OF THE DESCENDING COMMAND
TO MOTONEURONS IS MEDIATED THROUGH SPINAL
PREMOTONEURONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
SENSORY FEEDBACK MECHANISMS CONTRIBUTE
DIRECTLY TO MUSCLE ACTIVATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
COORDINATION OF AGONISTS AND ANTAGONISTS . . . . . . . . . . . . . . . . . . . . . . 88
FROM SHAPING OF SENSORY FEEDBACK TO THE DISTINCTION
OF EXAFFERENCE AND REAFFERENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
CONCLUDING REMARKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
INTRODUCTION
The idea of reflexes and voluntary movements as two separate entities still shows up in contem-
porary textbooks of neuroscience, although several decades of animal and human research have
emphasized that descending motor pathways and sensory afferents converge on common neurons
in the spinal cord. Reflexes are therefore an integrated part of voluntary movements rather than
separate entities (Hultborn 2006, Nielsen 2004, Prochazka et al. 2000). Charles Scott Sherrington
(1857–1952) realized this already in 1906:
A simple reflex is probably a purely abstract conception, because all parts of the nervous system are
connected together and no part of it is probably ever capable of reaction without affecting and being
affected by various other parts, and it is a system certainly never absolutely at rest. But the simple reflex
is a convenient, if not a probable, fiction. Reflexes are of various degrees of complexity, and it is helpful
in analyzing complex reflexes to separate from them reflex components which we may consider apart
and therefore treat as though they were simple reflexes. (Sherrington 1906, p. 8)
As Sherrington pointed out, it may at times be useful to study a reflex as if it were separate from
the rest of the nervous system, but we need to constantly keep in mind that its function in the intact
organism may be understood only as a part of a much more complex system. Unfortunately, our
desire to break up the nervous system into smaller bits and pieces for research purposes has resulted
in some profound misunderstandings. Most importantly, a widespread misunderstanding persists
that reflexes are signs of primitive or immature spinal activity, which is suppressed by supraspinal
centers as part of normal maturation when voluntary movements develop. Reflex hyperexcitability
following lesion of the central motor pathways later in life is then seen as a pathological sign
of inefficient supraspinal inhibitory control of the spinal circuitries, which requires restoration
through antispastic medication. This would be a less obvious mistake if we realized that reflexes
are not separate entities, but are in fact closely integrated into all movements that we perform
and that reflex hyperexcitability is a plastic adaptation in the spinal cord circuitries to facilitate
voluntary movements.
The purpose of this review is to provide an overview of what we know today regarding the role
of the human spinal cord in the control of voluntary movements. I emphasize what we know about
how spinal neuronal circuitries are integrated into voluntary movements and are an integrated part
82 Nielsen
of the central motor command that reaches the muscles. It is not possible to mention all the terrific
work that has been done in this field with the limited space available. I should also mention that
I am strongly biased toward the interests that have driven my own research for the past 25 years.
For a more exhaustive account of the many contributions in the field, I would like to direct readers
to the brilliant book on the topic by David Burke and Emmanuel Pierrot-Deseilligny (2012).
DIRECT CORTICAL CONTROL OF MUSCLE ACTIVITY

In primates, including humans, corticospinal neurons with direct monosynaptic connections to the
spinal motoneurons are responsible for some of the descending control of muscle activity (Lemon
2008). In other vertebrates, the cortex has only indirect access to the motoneurons through the
spinal interneurons or brain stem nuclei. This is also true in rodents, despite some early claims of
the contrary (Alstermark & Ogawa 2004, Alstermark et al. 2004). In monkeys, these corticomo-
toneuronal (CM) cells exist mainly for the most distal finger and hand muscles, and convincing
evidence has been presented that these connections have evolved to facilitate fractionated finger
movements, which are important for manipulation of small objects (Lemon 2008). The CM cells
are located in a newly evolved part of the primary motor cortex (M1) caudal to the (old) M1, which
is the standard in other mammals and which contains corticospinal neurons with connections only
to spinal interneurons (Rathelot & Strick 2009).
In humans, we cannot determine the presence of CM cells directly, but two techniques pro-
vide reasonable indirect evidence of their existence. Transcranial magnetic stimulation elicits
short-latency responses in contralateral muscles in healthy awake subjects, which are consistent
with transmission in a fast-conducting direct monosynaptic pathway (Brouwer & Ashby 1990,
Rothwell 1997). Single motor unit measurements, H-reflex, and modeling studies have provided
good support for this (Figure 1; Brouwer & Ashby 1990, 1992; Nielsen et al. 1993; Palmer &
Ashby 1992; Petersen et al. 2003). However, it should be kept in mind that more indirect pathways
through excitatory neurons in the spinal cord would have latencies only slightly longer. Further-
more, the short latency of the responses is not sufficient evidence of direct CM connections given
the range of conduction velocities and the variability in the site of activation of corticospinal
neurons by cortical stimulation (Di Lazzaro et al. 2001, Nielsen et al. 1995, Petersen et al. 2003).
Independent evidence of the existence of CM connections comes from correlation and coher-
ence analysis of electroencephalogram (EEG) and electromyogram (EMG) recordings performed
during static voluntary contractions (Figure 1; Conway et al. 1995, Datta et al. 1991, Farmer
1998, Salenius et al. 1996). Modeling studies provide strong evidence that several features of the
coupling between EEG and EMG as well as between paired EMG recordings reflects the activity
of CM cells (Farmer 1998), although again, connections through more indirect pathways cannot
always be ruled out (Vaughan & Kirkwood 1997).
Taken together, these studies have provided good evidence that CM connections are quite
pronounced for all muscles that have so far been studied in human subjects, including muscles
of the back and large leg muscles (Figure 1; Petersen et al. 2003, Rothwell 1997). Obviously,
CM connections thus do not play a role in humans only for fractionated control of the finger
muscles, but must have a more general role for the control of movement. This is emphasized also
by findings showing that the CM pathway is active and contributes importantly to the control of
uncomplicated treadmill locomotion (Barthelemy & Nielsen 2010; Petersen et al. 1998b, 2001,
2012) and even hopping in human subjects (Zuur et al. 2010).
What advantage has evolution achieved by adding this direct control of muscle activity on top
of the more indirect control through spinal interneurons? One suggestion that probably springs
immediately to mind for most people is that the CM pathway may provide the means for conscious
www.annualreviews.org • Human Spinal Motor Control 83

EEG recording TMS Stimulation of Ia afferents
Single motor unit
Single motor unit

8 8
a b c
discharges
discharges
6 6
TMS 4 4
2 2
0 0
–2 –2
20 30 40 50 60 70 20 30 40 50 60 70
Latency following stimulation (ms) Latency following stimulation (ms)
0.5 0.015
d e
Probability
Coherence
0.4 0.010
0.3 0.005
0.2 0
0.1 –0.005
0 –0.010
0 20 40 60 –100 0 100
Frequency (Hz) Time (ms)
TA:TA
0.05
0.04 f
Probability
0.03
0.02
0.01
0.00
–300 –180 –60 0 60 180 300
EMG recording
Time (ms)
Figure 1
Evidence of corticomotoneuronal connections in human subjects. Indirect, noninvasive evidence of the existence of monosynaptic
connections between corticospinal neurons and spinal motoneurons may be obtained in awake human subjects by transcranial magnetic
stimulation (TMS) (b,c) and coherence analysis of either cortical [electroencephalogram (EEG)] and muscular activity [electromyogram
(EMG)] (d,e) or two separate recordings of muscular activity ( f ). (b,c) Corticospinal neurons can be excited by a brief magnetic pulse
applied by a magnetic coil placed over the appropriate part of the motor cortex in awake human subjects. If the intensity of the
magnetic pulse is adjusted appropriately, the evoked descending volley in the corticospinal tract may elicit a subthreshold excitatory
postsynaptic potential (EPSP) in the relevant spinal motoneurons. This EPSP may be demonstrated as a change in the discharge
probability of a single motor unit recorded from the muscle (b). In the illustrated example, the subject was asked to voluntarily activate
the tibialis anterior (TA) muscle, and the discharges of a single motor unit were recorded by a needle electrode inserted into the muscle.
TMS elicited a short-lasting (2-ms) increase of discharge probability at a latency of 45 ms (b). The short duration of this peak is
consistent with the short rise time of a monosynaptic EPSP. This interpretation is further supported by the observation that
stimulation of Ia afferents with known monosynaptic connections to the motoneurons elicits a peak with a similar short duration (c).
Data in panels b and c modified with permission from Nielsen & Petersen (1994). (d,e) EEG recorded from the motor cortex and EMG
recorded from a voluntarily activated muscle (TA in the illustrated example) show rhythmic modulation of the recorded activity at a
frequency of 15–35 Hz. As shown from a coherence analysis of the two signals in panel d, some of this activity is common for the two
sites, suggesting a close link between cortical and muscular activity. Panel e shows the EEG and EMG activities are not always
synchronous but may show a time lag, which is in the range expected for a fast-conducting direct pathway to the motoneurons. Data in
panels d and e modified with permission from Hansen et al. (2002). ( f ) A monosynaptic origin of corticomuscular coherence is further
supported by the observation of short-term synchrony between the discharges of pairs of TA motor units, which may be related to the
coherence in the 15–35-Hz frequency band. The subject was asked to voluntarily activate the TA muscle, and the discharges of two
different TA motor units were recorded with needle electrodes. The short duration of the central peak of synchronization suggests that
the motor unit activities are modulated by a common (monosynaptic) input from collaterals of last-order neurons, which are in all
likelihood identical to corticomotoneuronal cells. The secondary peaks at lags of approximately 50–60 ms on either side of the central
peak suggest that this last-order input modulates the discharge of the motor units at a frequency of about 20–30 Hz, i.e., corresponding
to the coherence observed in the paired EEG-EMG recordings in panels b and c. Data in panel f modified with permission from
Nielsen & Kagamihara (1994).
84 Nielsen
and deliberate—willful—control of the muscle activity by bringing it closer to the presumed

seat of deliberate (conscious) action in the cortex (Desmurget & Sirigu 2012, Haggard 2008,
Rappaport 2011). This is in line with the centuries-old idea that human movement is somehow
more conscious and deliberate than that of at least some animals, in whom movements to a higher
extent are assumed to be reflex-like and unconscious (Prochazka et al. 2000). It is difficult to
provide scientific proof of such ideas given the challenge of determining the level of conscious
involvement in other species (Edelman & Seth 2009, Weiskrantz 1995), and it should be noted
that research on human motor behavior has emphasized that voluntary and reflex movements are
so closely integrated that they are in practice impossible to distinguish (Prochazka & Ellaway
2012, Prochazka et al. 2000, Rothwell 2006). Even the most deliberate and consciously controlled
movements contain some degree of reflex involvement (Prochazka & Ellaway 2012, Prochazka
et al. 2000, Rothwell 2006).
In addition, sensory feedback may influence CM pathway activity at both the spinal motoneu-
ronal and cortical levels. The activity of the spinal motoneurons is influenced by the activity of
sensory afferents as well as other descending tracts, either directly or indirectly through interneu-
rons, and may in this way determine the access of the CM pathway to the muscles (Hultborn 2006;
Jankowska 1992, 2001). Sensory afferents (especially from proprioceptors) also have relatively di-
rect access to the CM neurons via ascending pathways, and the CM pathway thus is not only
activated as part of deliberate, voluntary movements, but may also take part as the efferent leg in
transcortical reflex loops (Cheney & Fetz 1984, Christensen et al. 2000, Lemon & Porter 1976).
These transcortical reflex loops have been shown to play a role in the control of finger and hand
muscles, but they also exist and play important roles in the control of other muscles, including
leg muscles (Macefield et al. 1996; Marsden et al. 1976, 1977b; Nielsen et al. 1997; Petersen et al.
1998a; Pruszynski 2014).
Recruitment of the CM pathway may coincide with situations in which we experience a need
to exert particular attention to the execution of our movements (Helm et al. 2015, Rosenkranz &
Rothwell 2004, Ruge et al. 2014, Weiss et al. 2014). This is the case when we have to perform
unfamiliar movements or tasks or when we feel compelled to pay particular attention to the
movement because we may otherwise hurt ourselves. Notably, electrophysiological experiments
have demonstrated that corticospinal excitability is greatly increased in such situations, making
it likely that recruitment of the CM pathway is closely associated to our subjective perception of
having to pay attention to the movement (Pascual-Leone et al. 2005, Weiss et al. 2014).
Somewhat in line with this, the CM pathway has likely also evolved to allow visual information
to be integrated more efficiently in the motor command that reaches the muscles (Georgopoulos &
Grillner 1989). Close integration of muscle activity with visual information may allow the activity
to be regulated in a context-dependent manner (Georgopoulos & Grillner 1989). The cortical in-
tegration of visual and somatosensory information may also make use of the different organization
of the motor cortex as compared to the spinal cord. Whereas the spinal cord is organized anatomi-
cally with motoneurons and interneurons controlling specific muscles and their synergists located
closely together, the motor cortex is organized in a mosaic where cortical neurons that regulate
very different muscles are located anatomically close together (Capaday et al. 2013, Lemon 1993,
Rathelot & Strick 2006, Schieber 2004). This allows for easier coordination of activity in a range
of different muscles throughout the limb and body, which is necessary to ensure the coordinated
muscle activity involved in most behaviors and in particular for the fundamental two states that hu-
mans encounter daily: stance and locomotion (Nielsen 2003). The higher functional significance
of transcortical reflexes as compared to segmental reflexes in primates and especially humans may
also be seen in this arrangement (Christensen et al. 2000; Macefield et al. 1996; Marsden et al.
1976, 1977b; Nielsen et al. 1997; Petersen et al. 1998a; Pruszynski 2014). Transcortical reflexes

may provide coordination of activation of muscles belonging to widely separate spinal segments
and may, through integration with visual information, ensure that this coordination is modulated
according to the specific circumstances in a context-dependent manner (Christensen et al. 2000;
Macefield et al. 1996; Marsden et al. 1976, 1977b; Nielsen et al. 1997; Petersen et al. 1998a;
Pruszynski 2014). It may thus even be speculated that the further evolution of the CM pathway
from primates to humans is somehow linked to our habitual bipedal gait and upright body pos-
ture, which require considerable coordination of muscles in most parts of the body integrated with
visual information to ensure a context-dependent adjustment of the control.
As is evident from these considerations, researchers still have no clear understanding of the role
of CM neurons in human motor control. Further carefully controlled experiments in humans that
may determine this role are greatly needed, similar to the work that has been performed in monkeys
to determine the significance of CM neurons in the control of fractionated finger movements
(Lemon 1993, 1999, 2008). Unfortunately, the field is trending away from carefully controlled
experiments using H-reflex testing and single motor unit recordings toward simple recording of
compound muscle potentials following transcranial magnetic stimulation, which does not allow
an adequate distinction between the CM pathway and other (indirect) descending pathways. This
needs to change if we are to understand the role of the CM pathway in humans. In monkeys,
reliable estimates of the percentage of corticospinal neurons with monosynaptic projections to
spinal motoneurons are difficult to obtain and depend on the species. In the macaque, estimates
ranging from 3% to 73% have been given (Lemon 1993, 1999, 2008; Firmin et al. 2014). We also
have no reliable estimates in human subjects. Clarification of this issue is of importance not only to
understand human motor control, but also to understand it in relation to the relevance of studies
on spinal interneurons in animals. We have a wealth of knowledge regarding spinal interneurons
in the cat, rat, and mouse, but to what extent are these relevant for humans, as none of these
species have any CM neurons (Alstermark & Ogawa 2004, Alstermark et al. 2004)? Although the
basic circuitry of the spinal cord is in all likelihood preserved across species, major differences
must exist in the descending control of these circuitries subsequent to the evolution of the CM
pathway. Understanding these differences in the future will be key to understanding both the CM
system and the spinal cord circuitries.
EVIDENCE THAT PART OF THE DESCENDING COMMAND

TO MOTONEURONS IS MEDIATED THROUGH SPINAL
PREMOTONEURONS
In the cat, the most direct corticospinal pathway to upper limb motoneurons is disynaptic through
propriospinal neurons located in the third and fourth cervical vertebrae (C3-C4) spinal segments
(Alstermark & Isa 2012, Illert et al. 1974). This pathway appears to be mainly of importance for
reaching movements in the cat (Alstermark et al. 1981). There has been some controversy in the
past as to whether a similar C3-C4 pathway exists and plays a similar functional role in primates,
including humans, given the evolution of the CM pathway in these species (Kirkwood et al. 2002,
Lemon 2008, Lemon et al. 2004, Maier et al. 1998). Part of this controversy has been explained by
a very significant feedforward inhibition of the C3-C4 pathway in monkeys, which has precluded
its demonstration under the restricted experimental conditions that are normally used (Alstermark
et al. 1999). Convincing data have now been presented, showing that when feedforward inhibition
is removed experimentally or under functional conditions, there is significant functional transmis-
sion through the C3-C4 pathway, and it appears to contribute to reaching in the monkey, similar
to what is seen in the cat (Alstermark & Isa 2012, Alstermark et al. 1999). In humans, Pierrot-
Deseilligny and his coworkers have provided evidence of excitation of cervical motoneurons from
86 Nielsen
sensory afferents at latencies that are consistent with transmission through C3-C4 propriospinal
neurons (Gracies et al. 1991; Malmgren & Pierrot-Deseilligny 1988; Mazevet et al. 1996; Pierrot-
Deseilligny 1996, 2002; Pierrot-Deseilligny & Marchand-Pauvert 2002). Significant convergence
between activation of sensory afferents and the corticospinal tract has been found, suggesting that
part of the corticospinal drive to cervical motoneurons is also mediated through these neurons in
humans (Burke et al. 1994, Gracies et al. 1994, Mazevet et al. 1996, Nicolas et al. 2001, Pauvert
et al. 1998). Most notably, cutaneous inhibition of transmission in the pathway has been shown to
suppress voluntary muscle activity, suggesting that the pathway contributes directly to the muscle
activity (Burke et al. 1994). In relation to movement, tonic feedforward inhibition of the pathway
appears to be removed, thereby allowing the pathway to contribute to the execution of upper-limb
goal-directed movements (Giboin et al. 2012, Iglesias et al. 2007). Some evidence has been pre-
sented that the pathway may be especially important in reach-to-grasp movements, but we still do
not have a clear understanding of how the propriospinal pathway supplements the direct CM path-
way, and opinions on the relative functional importance of the two pathways differ considerably
(Alstermark & Isa 2012, Lemon 2008). Critical studies that examine transmission in the
propriospinal pathway to cervical motoneurons in relation to functional motor tasks are needed
to resolve this.
Part of the corticospinal motor command to leg motoneurons may also be mediated through
excitatory premotoneurons in humans (Marchand-Pauvert et al. 1999, Simonetta-Moreau et al.
1999). These findings relate closely to findings in the cat spinal cord demonstrating the existence
of interneurons, which are characterized by activation from muscle spindle group II afferents,
but receive very significant input from the corticospinal tract and other descending pathways as
well as muscle spindle group I afferents ( Jankowska 1989). Human experiments have suggested
that spinal inhibition of transmission in this pathway is removed prior to the onset of and during
voluntary movements (Geertsen et al. 2011). Similar to what has been found in the cat, these and
related populations of group I and group II interneurons are likely also an integrated part of the
spinal circuitries involved in generation of the rhythmic muscle activity underlying locomotion
(Iglesias et al. 2008a,b; Marchand-Pauvert & Nielsen 2002a,b; Marchand-Pauvert et al. 2005).
Populations of interneurons such as these are likely helpful in switching between different states
of motor control, such as between stance and locomotion, and in this way play a fundamentally
important role in the selection of human motor behaviors.
SENSORY FEEDBACK MECHANISMS CONTRIBUTE

DIRECTLY TO MUSCLE ACTIVATION
The idea that muscles are activated indirectly through gamma motoneurons, which accelerate
spindle afferent discharge causing alpha motoneuronal activation and muscle activity, was pre-
dominant in the 1960s and early 1970s (Granit 1968, Granit et al. 1959, Matthews 1964). This
idea was effectively abandoned when measurement of spindle afferent discharge by microneurog-
raphy was introduced and demonstrated that spindles never increase their discharge until well
after muscle activity has started (Vallbo 1971). Alpha and gamma motoneurons thus appear to
be activated in parallel under most conditions in humans (for possible exceptions, see Hulliger
et al. 1989, Nielsen et al. 1994a, Prochazka et al. 1985), and the feedback activity through spindle
acceleration thus may only contribute to the muscle activity sometime after initiation of move-
ment (Vallbo 1971). There is indeed good evidence from experiments in both the upper and lower
limb and during various movements that sudden unloading (shortening) of the muscle results in
a significant drop in muscle activity (Angel et al. 1965, Sinkjaer et al. 2000). This demonstrates
that sensory feedback afferents contribute to the muscle activity through relatively direct reflex

pathways (Angel et al. 1965, Sinkjaer et al. 2000). Surprisingly, however, no convincing evidence
suggests that this feedback is mediated to any significant extent by the monosynaptic muscle spin-
dle group Ia reflex pathway (Macefield et al. 1996, Marsden et al. 1973, Sinkjaer et al. 2000).
Rather, in the distal upper limb, transcortical reflex pathways appear to mediate the main sensory
feedback contribution to movements, which is well in line with the weak monosynaptic Ia reflexes
and generally pronounced CM connections for these muscles (Macefield et al. 1996; Marsden
et al. 1973, 1976, 1977a, 1978).
In the leg, monosynaptic Ia reflexes are pronounced but nevertheless do not appear to contribute
significantly to the muscle activation—at least during locomotion (Sinkjaer et al. 2000). Dietz and
his coworkers were the first to notice that short-latency group I activation appeared to be strongly
reduced during locomotion and to suggest that transmission through spinal networks activated
by muscle spindle group II afferents could be of higher significance (Dietz et al. 1984a, 1985).
Studies of H-reflexes also indicated pronounced presynaptic inhibition during locomotion and
other movements, suggesting a functional suppression of Ia monosynaptic feedback (Capaday &
Stein 1986, 1987). Subsequent studies of the effect of unloading of the ankle plantarflexors during
the stance phase of gait demonstrated a very significant drop in EMG activity at a latency about
20 ms longer than that expected for transmission in the monosynaptic Ia pathway (af Klint et al.
2009, 2010; Grey et al. 2004, 2007; Sinkjaer et al. 2000). Block of Ia afferent transmission also
failed to influence the unloading effect, and the monosynaptic Ia afferent pathway thus does not
appear to contribute as a servo feedback mechanism to the muscle activity in the lower limb
either—at least during locomotion (af Klint et al. 2009, 2010; Grey et al. 2004, 2007; Sinkjaer
et al. 2000). Integration of sensory feedback with other commands at a premotoneuronal level
(i.e., spinal segmental interneurons, propriospinal neurons, or CM cells), rather than allowing the
sensory activity to influence the motoneurons themselves directly, appears to be of importance to
adjust the motor command optimally according to both internal and external influences.
Several spinal pathways probably mediate the sensory afferent contribution to muscle activity
during locomotion, but evidence from the cat provides strong support for an important role of load-
sensitive (Golgi tendon organ group Ib) pathways (Donelan et al. 2009; Pearson 2004, 2008). This
is supported by a line of studies in human subjects (af Klint et al. 2009, 2010; Grey et al. 2004, 2007;
Sinkjaer et al. 2000). It is unclear whether a separate population of load-sensitive interneurons is
involved or whether populations of interneurons mediating group I and group II sensory input
overlap (see above and Bannatyne et al. 2009, Dietz et al. 1984b, Jankowska 2001, Sinkjaer et al.
2000). It appears from cat experiments that these interneurons are an integrated part of the
rhythm-generating network in the spinal cord [central pattern generator (CPG)] (Gossard et al.
1994, McCrea et al. 1995). If so, further understanding of their contribution to human locomotion
may help clarify the role of the spinal CPG for human locomotion before and after central motor
lesions. Evidence of the behavioral effects of knocking out specific spinal interneuronal populations
in mouse models may be helpful in this regard (Akay et al. 2014, Dougherty et al. 2013, Zagoraiou
et al. 2009).
COORDINATION OF AGONISTS AND ANTAGONISTS

Charles Sherrington used his Nobel talk in 1932 to address how central inhibition contributes
to coordinate muscle activity and ensure the relaxation of antagonists when agonist muscles are
activated (Sherrington 1932). Sherrington was the first to demonstrate the central origin of recip-
rocal innervation of antagonist muscles, but the concept of reciprocal inhibition was mentioned
already by Galen of Pergamon (129–ca. 200 AD), and René Descartes (1596–1650) conceived of
a mechanical mechanism for coordination of eye muscles located peripherally in the muscles in
88 Nielsen
1636 (Descartes 1664). One of Sherrington’s pupils, John Eccles, demonstrated the disynaptic
nature of reciprocal inhibition in spinal motoneurons elicited by stimulation of antagonist nerves
and thus provided the crucial evidence that spinal interneurons activated by group Ia afferents
are responsible for mediating inhibition between antagonist motoneurons (Eccles et al. 1956).
Subsequent work in the cat spinal cord has revealed much of the physiology and anatomy of these
Ia inhibitory interneurons. In particular, it has been demonstrated that they are activated by de-
scending inputs in parallel with their corresponding alpha and gamma motoneurons, creating a
functional unit for the coordination of flexion-extension movements (Hultborn 1972; Hultborn
& Lundberg 1972; Hultborn & Udo 1972a,b; Hultborn et al. 1971b,c; Jankowska & Roberts
1971). Soon after this, Japanese and Russian scientists showed that reciprocal inhibition may be
demonstrated and evaluated in human subjects noninvasively by H-reflex testing of motoneuronal
excitability following conditioning stimulation of the antagonist nerve (Kots & Zhukov 1973,
Mizuno et al. 1971, Tanaka 1974). Subsequent studies have shown that transmission in the path-
way is modulated during voluntary movement, as would be expected from the organization of
descending and sensory inputs to the interneurons: Reciprocal inhibition of extensors is facilitated
in relation to flexion and reduced in relation to extension (Crone & Nielsen 1989; Crone et al.
1987; Day et al. 1983, 1984; Iles 1986; Kagamihara & Tanaka 1985). This occurs in relation to
both voluntary movements under controlled experimental settings in seated subjects (Crone &
Nielsen 1989; Crone et al. 1987; Day et al. 1983, 1984; Kagamihara & Tanaka 1985) as well as
during walking (Petersen et al. 1999) and bicycling (Pyndt et al. 2003) (Figure 2). Notably, this
is only the case in the very beginning and in the dynamic phase of the movement, whereas no
facilitation of transmission in the pathway is observed during static contraction (Crone et al. 1987,
Crone & Nielsen 1989, Iles 1986, Kagamihara & Tanaka 1985). This suggests that reciprocal in-
hibition acts mainly to prevent stretch reflex activation of the antagonist when the agonist muscle
is shortening. This is especially apparent at the onset of movement, when stretch of the antagonist
may be considerable. Patients with spasticity show little reciprocal inhibition, which may explain
why they are forced to move relatively slowly (Morita et al. 2001, Okuma & Lee 1996, Okuma
et al. 2002).
Reciprocal inhibition is also not desirable in some functional situations. Few of our joints
are strictly bidirectional, and few muscle pairs are only functional antagonists. Some degree of
coactivation of antagonists is therefore not surprising during functional motor tasks. When we are
unable to adequately predict external perturbations or are required to stabilize the position of a joint
for other reasons, we stiffen up, which is most effectively done by coactivating antagonist muscles
(Nielsen & Kagamihara 1992). The stiffness generated by coactivating the muscles around the joint
increases the stiffness of the joint manyfold and protects it against sudden external perturbations
(Nielsen et al. 1994b). This may also explain why many patients with damaged central motor
pathways show considerable coactivation during functional motor tasks. Rather than viewing this
as a pathological sign of the lesion, it should probably rather be seen as an adaptive strategy to
maintain balance and stability in light of muscle weakness.
Coactivation of antagonist muscle might theoretically be achieved by simply adjusting the level
of inhibition between the antagonists through their mutual inhibitory connections (Maier et al.
2005). There is indeed evidence that the muscles cannot be driven voluntarily during antagonist
coactivation to the same extent as during isolated flexion or extension, which could be consistent
with the preservation of reciprocal inhibition during coactivation (Tyler & Hutton 1986).
Nielsen & Kamamihara (1992), however, demonstrated that transmission in the Ia inhibitory
interneuronal pathway is greatly diminished during coactivation of antagonists, which naturally
facilitates their parallel activation. One contributing factor to this may be a functional uncoupling
of the usual parallel activation of Ia inhibitory interneurons and corresponding motoneurons.

a
la afferents
Motoneuron
Quadriceps
Tibialis
anterior
Soleus
b Plantarflexion c Dorsiflexion
Size of conditioned reflex

(% of control reflex)
100 CPN → SolH (% of control reflex) 100 CPN → SolH

80
80 Rest
60
Rest 40
60
20
40 0
Torque
TA
TA EMG
EMG
Sol Sol
EMG EMG
Torque
–100 0 100 200 300 400 –100 0 100 200 300 400
Time in relation to onset of Sol EMG (ms) Time in relation to onset of TA EMG (ms)
d e
120
120
110
110
100
100
90
90
80
80
70
70 60
60 50
0 200 400 600 800 1,000 0 100 200 300
Stance Swing Downstroke Upstroke
90 Nielsen
A considerable number of corticospinal neurons in monkeys indeed appear to activate spinal

motoneurons without collaterals to Ia inhibitory interneurons (Fetz & Cheney 1987), and some
indirect evidence suggests that this may also be the case in humans (Nielsen & Kagamihara
1994, Nielsen et al. 1993). In addition to this, evidence has been provided that Renshaw cells
are facilitated greatly during cocontraction of antagonists (Nielsen & Pierrot-Deseilligny 1996).
Renshaw cells provide recurrent inhibition of spinal motoneurons and inhibit their corresponding
Ia inhibitory interneurons (Hultborn et al. 1971a). Hultborn et al. (1971a) suggested that one role
of Renshaw cell inhibition could be to introduce flexibility in the control of the motoneuron–Ia
inhibitory interneuronal control; in accordance with this, Nielsen & Pierrot-Deseilligny (1996)
suggested that the increased Renshaw cell inhibition could play a pivotal role in switching from
a reciprocal activation pattern into an antagonist coactivation pattern.
Situations in which coactivation of antagonists is required usually also call upon effective and
precise control of joint position. This was originally suggested by Llewellyn et al. (1990) based
on cat experiments in which researchers observed that gamma motoneurons discharge vigorously
when cats are balancing on a narrow beam (Hulliger et al. 1989, Prochazka et al. 1985). This was in-
terpreted as a necessary increase in proprioceptive information to help the cat maintain balance on
the beam. Subsequent human experiments have demonstrated that a similar increase of Ia afferent
discharge is observed in human subjects performing coactivation of antagonist muscles (Nielsen
et al. 1994a). It might therefore be seen as somewhat surprising that monosynaptic Ia H-reflexes
and stretch reflexes are suppressed in both antagonistic muscles during cocontraction of antagonists
(Llewellyn et al. 1990, Nielsen & Kagamihara 1993, Nielsen et al. 1994b). Increased presynap-
tic inhibition of the terminals of the Ia afferents appears to cause this (Nielsen & Kagamihara
1993). Why increase Ia afferent activity only to suppress their central effects on the spinal mo-
toneurons? One reason may be that the increased Ia afferent activity is mainly for the benefit of
improved proprioception and that too-large reflexes in both antagonist muscles may endanger
the stability of the muscle activation (Llewellyn et al. 1990, Nielsen & Kagamihara 1993, Stein
& Oguztoreli 1976). High reflex gain has thus been shown to cause instability, possibly resulting
in clonus and tremor, and increased presynaptic inhibition may be one way of preventing this
(Llewellyn et al. 1990, Stein & Capaday 1988, Stein & Oguztoreli 1976).
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 2
Regulation of reciprocal inhibition in relation to voluntary movements in human subjects. Disynaptic reciprocal Ia inhibition may be
demonstrated in human subjects by conditioning the H-reflex by a low-intensity stimulation of the antagonist motor nerve. The
H-reflex reflects the excitability of the spinal motoneurons of the muscle in which it is elicited. When the antagonist nerve is stimulated
a few milliseconds prior to the H-reflex, the resulting disynaptic Ia inhibitory postsynaptic potential (IPSP) may therefore be visualized
as a depression of the size of the reflex. By measuring the size of this depression at different times during movement, it is possible to
obtain an estimate of how the nervous system regulates transmission in the reciprocal inhibitory pathway. In all cases, the size of the
reciprocal inhibition is expressed as the size of the conditioned reflex (with inhibition) in relation to the control reflex size (without
inhibition). Consequently, 100% signifies that it is not possible to elicit any inhibition, whereas values below 100% indicate
increasingly larger inhibition. Panels b and c show that reciprocal inhibition from ankle dorsiflexors to ankle plantarflexors [i.e., the
H-reflex was recorded in the soleus (Sol) muscle (SolH) and conditioned by stimulation of the common peroneal nerve (CPN)] is
reduced about 50 ms prior to plantarflexion (b) and increased at a similar time prior to ankle dorsiflexion (c). This is consistent with the
idea that increased reciprocal inhibition is necessary to reduce excitability of antagonist motoneurons (Sol in this case) when the agonist
is activated [tibialis anterior (TA) in this case]. Notice that in both cases, reciprocal inhibition does not change further during the actual
movement, which supports the hypothesis that reciprocal inhibition is functionally important mainly at the onset of movement.
Reciprocal inhibition is also regulated during walking (d ) and bicycling (e). Similar to what is observed in panels b and c, reciprocal
inhibition is reduced in the stance phase (d ) and during downstroke (e) where the Sol muscle is active but is increased during swing
phase (d ) and upstroke (e) when TA is active. Modified with permission from Petersen et al. (1999) and Pyndt et al. (2003).

FROM SHAPING OF SENSORY FEEDBACK TO THE DISTINCTION

OF EXAFFERENCE AND REAFFERENCE
Eccles was not the first to describe presynaptic inhibition of primary afferent synapses, but fol-
lowing initial work by Frank & Fuortes (1957), he and his coworkers were responsible for the
initial investigations of the physiology and pharmacology of presynaptic inhibition. They de-
scribed the distribution of presynaptic inhibition in the hind limb of the cat in detail and clarified
the GABAergic nature of the inhibition (Eccles et al. 1962, 1963). Major contributions have been
made since then, especially by Rudomin and his collaborators in Mexico (Rudomin & Schmidt
1999). In humans, presynaptic inhibition of sensory afferents has been evidenced from a depres-
sion of monosynaptic Ia reflexes without a corresponding depression of voluntary EMG activ-
ity or muscle responses to transcranial magnetic stimulation (Berardelli et al. 1987, Nielsen &
Petersen 1994). Hultborn et al. (1987a,b) introduced an elegant technique for assessing pre-
synaptic inhibition of Ia afferents. They demonstrated that the heteronymous monosynaptic Ia
facilitation of the soleus H-reflex produced by femoral nerve stimulation provides an efficient
means of evaluating the extent of presynaptic inhibition of the involved Ia afferents under differ-
ent conditions (Hultborn et al. 1987a,b; Morin et al. 1984). Using this and related techniques,
researchers have demonstrated that presynaptic inhibition is modulated strongly during voluntary
movement of the leg and apparently used to focus the sensory afferent feedback—more or less like
a spotlight—on the active motoneuronal pools (Crone & Nielsen 1989, Hultborn et al. 1987b,
Katz et al. 1988, Nielsen & Kagamihara 1993). This modulation takes place prior to onset and at
the very beginning of leg movements and must therefore be caused by descending regulation of
the interneurons, which mediate presynaptic inhibition of the Ia afferents projecting to distinct
motor nuclei (Hultborn et al. 1987b, Nielsen & Kagamihara 1993). This differential descending
control is only possible because several populations of presynaptic inhibitory interneurons with
projections to specific afferents exist (Rudomin et al. 2004). Interestingly, experiments using tran-
scranial magnetic stimulation have revealed that activation of the corticospinal tract appears to
increase presynaptic inhibition of Ia afferents in the upper limb, whereas it reduces presynaptic
inhibition in the lower limb (Meunier 1999, Meunier & Pierrot-Deseilligny 1998). Despite this
differential effect of corticospinal activation, presynaptic inhibition is also removed prior to and
at the onset of voluntary movement in the upper limb (Aymard et al. 2001).
Presynaptic inhibition thus appears to be a mechanism by which sensory input to specific
motoneurons and interneurons may be gated, allowing other inputs to have unrestricted access
to the involved neurons. As suggested above, this gating may be responsible for preventing the
monosynaptic Ia afferent pathway to the spinal motoneurons from contributing significantly to the
muscle activity during goal-directed movements (Crone & Nielsen 1989, Hultborn et al. 1987b,
Meunier & Pierrot-Deseilligny 1989), standing (Katz et al. 1988), and locomotion (Capaday &
Stein 1986, 1987; Faist et al. 1996). This may be to facilitate smooth movements and prevent
oscillations, similar to what has been observed during reaching in the mouse (Fink et al. 2014). In
these cases, Ia afferent activity may still contribute to the muscle activity through indirect spinal
and supraspinal pathways. Similarly, during cocontraction of antagonists, presynaptic inhibition
of Ia afferents may prevent oscillations, such as clonus and tremor, while allowing the same Ia
afferent activity to contribute to improved proprioception (Nielsen & Kagamihara 1993).
The observation that presynaptic inhibition of Ia afferent terminals on spinal motoneurons
is removed selectively at the onset of movement (Hultborn et al. 1987b, Meunier & Pierrot-
Deseilligny 1989, Nielsen & Kagamihara 1993) may suggest that the servo mechanism via the
muscle spindles and Ia afferent activity mainly plays a role in recruiting successive motoneurons
and facilitates the early acceleration of the movement, whereas it may be redundant later in the
movement. This specific hypothesis has not been addressed adequately so far.
92 Nielsen
Presynaptic inhibition may also play a role in selectively filtering predicted sensory feedback
while leaving unexpected, external sensory input intact. High-frequency bursts of Ia afferent activ-
ity thus are not influenced strongly by presynaptic inhibition, whereas (predicted) low-frequency
Ia afferent activity is filtered out (Enrı́quez-Denton et al. 2002). This is in line with the observation
that it is difficult to tickle ourselves because our nervous system predicts the sensory feedback pro-
duced by our movements and therefore specifically suppresses it while leaving unexpected sensory
input intact (Blakemore et al. 2000). Presynaptic inhibition may therefore also provide a way for
the nervous system to distinguish reafference (self ) from exafference (other), which is an important
component of current theories of motor control (Shadmehr et al. 2010, Wolpert et al. 2011). If
this idea is substantiated by experimental evidence, presynaptic inhibition would in many ways
bind together the lowest and the highest level of human motor control. Presynaptic inhibition is
thus a fitting epitome for this review.
CONCLUDING REMARKS
The success of studies of human spinal motor control has relied on the development of new,
noninvasive, electrophysiological techniques such as H-reflex testing, single motor unit analysis,
coherence and cross-correlation analysis, and transcranial magnetic stimulation (Farmer 1998,
Rothwell 1997, Schieppati 1987). With the continued exponential growth in computer power
and cheap electronic devices, there is every reason to assume that this success will continue well
into the future. The introduction of wireless, portable, and wearable electronic devices promises
to allow experiments to be taken out of the laboratory and performed during normal behavior
in everyday life. This may provide us with unprecedented information about neural control of
ordinary motor behavior.
Human motor studies have also relied heavily on the knowledge obtained from invasive studies
of neural circuitries and mechanisms in the cat spinal cord (Hultborn 2006). However, laboratories
performing experiments on the cat spinal cord have all but disappeared from the face of the
earth within the past 10 years, and the annual number of publications on cat spinal cord motor
mechanisms has dwindled from well over 100 in the early 1980s to 10–20 in recent years. There
are no doubt several explanations for why scientific interest has moved away from this animal
model, but the rise of molecular biology and the possibility of studying the behavioral role of
specific molecules and neuronal populations in the mouse spinal cord have no doubt been of
major importance (Akay et al. 2014, Azim et al. 2014, Butt & Kiehn 2003, Dougherty et al.
2013). In all probability, this is also where the future of human spinal cord motor studies is to
be found. Translating findings from genetically modified mouse models into studies of human
motor behavior will likely be key to our future understanding of the neuroscientific basis of motor
control in health and disease.
SUMMARY POINTS
1. Descending motor pathways and sensory afferents converge on common spinal interneu-
rons so that spinal neural circuits are closely integrated into the central motor command.
2. In humans, corticospinal neurons exert direct control of muscle activity through mono-
synaptic connections to spinal motoneurons, which bypass spinal interneurons. This en-
ables a direct, willful control of movements that may be integrated with visual information
and provide flexible and coordinated control of the whole body.

3. Sensory afferent feedback activity contributes directly to muscle activation through spinal
and supraspinal networks. This allows a task-dependent facilitation of muscle activation
through servo-like mechanisms.
4. Spinal networks contain sufficient flexibility to allow reciprocal activation as well as
coactivation of antagonist muscle pairs. This serves fundamentally different movement
strategies involving postural control and goal-directed movement.
5. Sensory afferent information to the nervous system may be filtered by presynaptic inhi-
bition of primary afferents. This may serve to diminish expected sensory feedback and
highlight unexpected (error) information.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
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NE39CH05-Nielsen ARI 26 May 2016 13:35

Annu. Rev. Neurosci. 2016. 39:81–101 Keywords

The Annual Review of Neuroscience is online at Abstract

DIRECT CORTICAL CONTROL OF MUSCLE ACTIVITY

www.annualreviews.org • Human Spinal Motor Control 83

EEG recording TMS Stimulation of Ia afferents

Single motor unit

Single motor unit

and deliberate—willful—control of the muscle activity by bringing it closer to the presumed

www.annualreviews.org • Human Spinal Motor Control 85

EVIDENCE THAT PART OF THE DESCENDING COMMAND

SENSORY FEEDBACK MECHANISMS CONTRIBUTE

www.annualreviews.org • Human Spinal Motor Control 87

COORDINATION OF AGONISTS AND ANTAGONISTS

www.annualreviews.org • Human Spinal Motor Control 89

Size of conditioned reflex

100 CPN → SolH (% of control reflex) 100 CPN → SolH

Stance Swing Downstroke Upstroke

A considerable number of corticospinal neurons in monkeys indeed appear to activate spinal

www.annualreviews.org • Human Spinal Motor Control 91

FROM SHAPING OF SENSORY FEEDBACK TO THE DISTINCTION

www.annualreviews.org • Human Spinal Motor Control 93

be perceived as affecting the objectivity of this review.

running. J. Physiol. 392:513–22

rhesus monkey. J. Physiol. 349:249–72

www.annualreviews.org • Human Spinal Motor Control 95

in the macaque pyramidal tract. J. Neurophysiol. 112:1229–40

Hultborn H, Jankowska E, Lindstrom S. 1971b. Recurrent inhibition of interneurones monosynaptically

Iglesias C, Nielsen JB, Marchand-Pauvert V. 2008a. Corticospinal inhibition of transmission in propriospinal-

www.annualreviews.org • Human Spinal Motor Control 97

co-contraction of antagonistic ankle muscles in man. Exp. Brain Res. 102:350–58

www.annualreviews.org • Human Spinal Motor Control 99

cortex. J. Neurosci. Methods 74:113–22

www.annualreviews.org • Human Spinal Motor Control 101

Volume 39, 2016

Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders

Ant Genetics: Reproductive Physiology, Worker Morphology,

Brain Disorders Due to Lysosomal Dysfunction

Maps of the Auditory Cortex

Alyssa A. Brewer and Brian Barton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385

Cumulative Index of Contributing Authors, Volumes 30–39 p p p p p p p p p p p p p p p p p p p p p p p p p p p 437

An online log of corrections to Annual Review of Neuroscience articles may be found at

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