Brain Stimulation (2008) 1, 60–66

www.brainstimjrnl.com

REVIEW ARTICLE

Modifying motor learning through gating and

homeostatic metaplasticity
Ulf Ziemann, MD, PhDa, Hartwig R. Siebner, MD, PhDb

a
Department of Neurology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
b
Department of Neurology, Christian-Albrechts-University, Kiel, Germany

Summary

Synaptic plasticity in the motor cortex is involved at least in some forms of motor learning. Recent
evidence showed that the extent of practice-dependent plasticity in the motor cortex can be purposefully
enhanced by experimental manipulation. One way of improving motor learning is to transiently increase
the excitability of the motor cortex during motor learning. This can be achieved by weakening the
excitability of intracortical inhibitory circuits concurrently with practice. This principle is being referred
to as ‘‘gating.’’ Another strategy to boost learning is to decrease the threshold for induction of synaptic
plasticity by lowering neuronal activity in the motor cortex before practice. This approach invokes home-
ostatic metaplasticity. Here we highlight how transcranial brain stimulation can exploit gating and home-
ostatic metaplasticity to enhance motor learning in healthy subjects and in patients after stroke.
Ó 2008 Elsevier Inc. All rights reserved.

Keywords motor learning; motor cortex; gating of plasticity; homeostatic metaplasticity; transcranial
brain stimulation

Synaptic plasticity in the form of long-term potentiation
(LTP) and long-term depression (LTD) is involved at least in
some forms of motor learning.1,2 Experiments in slices of rat
visual cortex established for the first time, that the same high-
frequency tetanic stimulation protocol resulted in LTP or
LTD, depending on the level of depolarization of the post-
synaptic cell.3 The level of postsynaptic depolarization was
manipulated either pharmacologically by injection of the
gamma-aminobutyric acid A (GABAA) receptor antagonist
bicuculline, or by current injection into the postsynaptic
Address reprint requests to: Prof. Ulf Ziemann, Department of Neurol-
ogy, Johann Wolfgang Goethe-University, Schleusenweg 2-16, D-60528
Frankfurt am Main, Germany.
E-mail address: u.ziemann@em.uni-frankfurt.de
Submitted August 3, 2007; revised August 22, 2007. Accepted for
publication August 22, 2007.
cell. LTD was induced by this tetanic stimulation protocol
whenever the postsynaptic depolarization exceeded a critical
level but was below the threshold for LTP induction. Depolar-
ization above this threshold resulted in induction of LTP.3
In motor cortex similar observations were made: LTP was
only induced if postsynaptic neurons were disinhibited
by local injection of bicuculline.4 The crucial point of
these experiments is that an identical induction protocol
can result in opposite expressions of synaptic plasticity
(LTD or LTP), depending on the excitability level of the
stimulated neurons at the time of conditioning. This thresh-
old dependence is referred to as gating (Figure 1A). Cortical
LTP and LTD are typically mediated by N-methyl-D-
aspartate (NMDA) receptor activation.4-6 The NMDA recep-
tor is characterized by a voltage-sensitive magnesium
block.7 One potentially important mechanism of gating

1935-861X/08/$ -see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.brs.2007.08.003
Modifying motor learning through gating and homeostatic metaplasticity 61

Figure 1 The curves show change in synaptic strength (1, potentiation; 2, depression; dashed horizontal line, no change) as a function of
the integrated postsynaptic response. (A) Gating. Upper diagram: A given stimulation or learning protocol (arrow) may not result in any overt
change in synaptic strength (indicated by open circle on the dashed line) if applied under ‘‘normal’’ postsynaptic excitability conditions (in-
dicated by the cyan rectangle). Lower diagram: In contrast, if applied at a time when the integrated postsynaptic response of the stimulated
cortex is enhanced (indicated by the rightward shift of the cyan rectangle) by disinhibiting or depolarizing experimental manipulation such as
temporary ischemic nerve block or excitability-enhancing transcranial brain stimulation then the same stimulation or learning protocol (arrow)
results in an increase in synaptic strength (indicated by green circle). One important mechanism of gating is the removal of a voltage-sensitive
magnesium block from NMDA receptors during depolarization,7 which results in enhancement of intracellular calcium entry and hence
enhancement of the postsynaptic response by the same stimulation or learning protocol. (B) Homeostatic metaplasticity. Upper diagram:
A given stimulation or learning protocol (arrow) may not result in any overt change of synaptic strength (indicated by open circle on the dashed
line) if applied in the context of ‘‘normal’’ previous postsynaptic neuronal activity (indicated by the cyan rectangle). Lower diagram: In con-
trast, if the preceding postsynaptic neuronal activity was low (indicated by the leftward shift of the cyan rectangle), for example, by means of
low-frequency rTMS or cathodal tDCS, the LTP induction threshold (crossing point of the curve with the dashed horizontal line) slides to the
left and the same stimulation or learning protocol (arrow) then leads to LTP (indicated by the green circle). One potentially important mech-
anism of homeostatic metaplasticity is a shift in the subunit expression of the NMDA receptor by low levels of postsynaptic activity from the
NMDA receptor 2A subunit (associated with fast kinetics of NMDA receptor mediated excitatory postsynaptic currents) to the NMDA recep-
tor 2B subunit (slow kinetics, resulting in stronger intracellular calcium entry and stronger postsynaptic activation).10 NMDA, N-methyl-
D-aspartate; rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation; LTP, long-term potentiation.

(enhancement of LTP) is the removal of this magnesium
block by disinhibition or depolarization, resulting in
stronger NMDA receptor-mediated postsynaptic responses
by virtue of increased intracellular calcium entry, and in
turn stronger LTP (Figure 1A).
Uncontrolled LTP and LTD tend to destabilize the activity
of neuronal networks. On the one hand, the induction of LTP
increases neuronal excitability which in turn would ‘‘gate’’
the induction of subsequent LTP. This runaway potentiation
would cause an excessive increase in neuronal firing rate. On
62
the other hand, an analogous problem would be caused by
uncontrolled LTD. The LTD-induced decrease in neuronal
excitability would favor the subsequent induction of LTD,
and so on. The result would be a reduction in postsynaptic
activity until the firing rate decreases to zero. Because of their
positive-feedback nature, LTP and LTD tend to destabilize
the activity of neuronal networks. Therefore, mechanisms
must exist, which stabilize synaptic excitability in a neuronal
network in the long run and keep neuronal firing rates within
a physiologic dynamic range. Recent work has identified
numerous mechanisms at the cellular and cell population
level that ensure the stability of neuronal firing rates.8-11
These mechanisms comprise the homeostatic regulation of
intrinsic neuronal excitability, scaling of synaptic strength,
and Hebbian plasticity itself. This stabilizing form of plastic-
ity is referred to as homeostatic metaplasticity.
One currently influential theory of homeostatic meta-
plasticity is the Bienenstock-Cooper-Munro (BCM) theory
of bidirectional synaptic plasticity.12 The crucial assumption
of the BCM theory is that the threshold for LTP induction is
not constant but varies as a function of previous activity of
the postsynaptic neuron. The BCM theory postulates the ex-
istence of a sliding modification threshold for synaptic plas-
ticity. According to the BCM model, the threshold for LTP
induction increases if the previous level of postsynaptic neu-
ronal activity was high, but decreases if it was low (Figure
1B). The opposite principle applies to the threshold for in-
duction of LTD. The threshold for LTD induction decreases
if the previous level of postsynaptic neuronal activity was
high, but increases if it was low.12 One potentially important
mechanism of homeostatic metaplasticity is a shift in the
subunit expression of the NMDA receptor: during low levels
of postsynaptic activity the NMDA receptor 2A subunit
(associated with fast kinetics of NMDA receptor-mediated
excitatory postsynaptic currents) is being replaced by the
NMDA receptor 2B subunit (slow kinetics, resulting in
stronger intracellular calcium entry, stronger postsynaptic
activation, and in turn stronger LTP, Figure 1B).10 Animal
experiments provided evidence that the BCM rule operates
in several models of plasticity to stabilize the level of activ-
ity in a neuronal network.13
In the following sections, we will summarize how gating
or homeostatic metaplasticity can be used to purposefully
enhance motor learning in healthy subjects and stroke
patients. The basic concept is that synaptic plasticity in
motor cortex is involved in these forms of motor learning,
and therefore motor learning should be subject to modifi-
cation by gating and homeostatic metaplasticity.
Gating of motor learning by disinhibition
in healthy subjects
In humans, cortical disinhibition cannot be achieved
by GABAA receptor antagonists because of their procon-
vulsive potential. Alternatively, an acute and transient
U. Ziemann, H.R. Siebner
disinhibition of the contralateral sensorimotor cortex can
be obtained by temporary ischemic nerve block of parts
of a limb.14 For instance, a cuff inflated over the proximal
forearm to a suprasystolic blood pressure leads to ischemic
nerve block with deafferentation and deefferentation of the
hand.15-19 If healthy subjects practiced a ballistic elbow
flexion movement (one movement every 10 seconds over
a period of 30 minutes) in the absence of this experimental
manipulation, then peak acceleration of the trained move-
ment did not improve. However, if these subjects performed
the same motor practice in the presence of disinhibition of
the training motor cortex induced by ischemic nerve block,
then peak acceleration of the trained movement increased
significantly.20 This suggests that disinhibition of the train-
ing motor cortex gated motor learning in healthy subjects
(increase of peak acceleration).
Gating of motor learning by disinhibition
in stroke patients
Similar observations were made in six chronic stroke
patients.21 The patients practiced repeatedly a pincer grip
movement with their affected hand. Motor learning (as
expressed by increases in peak acceleration of the trained
movement and a increase in maximum isometric force
between thumb and index finger) reached a plateau after
extensive practice but could be enhanced further if the
patients continued practice during selective anesthesia of
the upper cervical plexus,21 an experimental manipulation
that leads to hypesthesia and paresis of the upper arm but
leaves the training hand unaffected. This transient deaffer-
entation and deefferentation very likely resulted in disinhi-
bition of the training motor cortex and gated motor learning
in this group of stroke patients.21 This is a first proof-of-
principle study to demonstrate that motor relearning in
stroke is threshold dependent and can be gated by experi-
mental manipulation, in this case cortical disinhibition.
Gating of motor learning by transcranial
brain stimulation in healthy subjects
Transcranial brain stimulation can be used to modify the
excitability of the stimulated cortex.22-32 Certain stimulation
techniques typically increase motor cortical excitability
such as high-frequency (R5 Hz) repetitive transcranial
magnetic stimulation (high-frequency rTMS), intermittent
theta-burst stimulation (iTBS), anodal transcranial direct
current stimulation (anodal tDCS), and paired associative
stimulation (PAS) at an interstimulus interval of around 25
msec (PAS25msec).33 The increase in excitability emerges
during the period of stimulation and can last beyond the
time of stimulation itself. In the context of ‘‘gating,’’ these
transcranial stimulation techniques may provide an effective
means to induce a transient disinhibition or depolarization
Modifying motor learning through gating and homeostatic metaplasticity
of the stimulated motor cortex. The working hypothesis is
that the stimulation-induced disinhibition or depolarization
transiently increases motor cortical excitability, and thereby,
boosts motor learning.
The timing of transcranial stimulation relative to the
learning period may have an important impact on the
stimulation-induced ‘‘gating’’ of motor learning. Because
gating requires the acute increase of cortical excitability at
the time of the learning period, it is important that
excitability-enhancing transcranial stimulation is delivered
either during the period of learning (referred to as online
stimulation) or immediately before the learning period
(referred to as offline stimulation).
There is cumulating evidence to suggest that transcranial
brain stimulation can effectively gate learning-induced
plasticity in the human motor cortex. In healthy subjects,
online subthreshold (80% of resting motor threshold) high-
frequency (10 Hz) rTMS of the training motor cortex given
during the practice period improved the performance (ac-
curacy and speed) of sequential finger movements when
compared with a sham stimulation control session.34 Online
anodal tDCS of the primary motor cortex contralateral to
the performing hand enhanced implicit motor learning
when compared with tDCS of the contralateral premotor
or prefrontal cortex.35 Similarly, online anodal tDCS but
not cathodal tDCS of the training motor cortex or visual
area MT, which is involved in processing of visual motion
perception, facilitated learning of a visually guided tracking
task.36 In accordance with this work in the motor system,
spatial-discriminative tactile learning was boosted when
excitability-enhancing high-frequency rTMS (5 Hz) was
applied to the primary somatosensory cortex during the
learning phase.37
Single-pulse TMS given in strict synchronicity with
ballistic directionally specific thumb movements enhanced
the longevity of practice-dependent plasticity when com-
pared with training without TMS or with TMS applied in an
asynchronous manner.38 A similar strategy was applied in
the somatosensory system where a short burst of high-
frequency rTMS (15 Hz) was repeatedly given immediately
before each trial of a tactile spatial-discrimination task. In
this instance, the high-frequency rTMS bursts enhanced
cortical excitability for several seconds, and by this means
may have gated practice-dependent plasticity while the
subject performed the task.39
Finally, a short train of subthreshold 5-Hz rTMS (,600
stimuli) can attenuate intracortical inhibition for several
minutes without inducing a lasting change in the excitability
of corticospinal output neurons.40,41 Although not tested yet,
this rTMS induced regionally specific, transient disinhibition
of the stimulated motor cortex may be particularly suited to
gate learning-induced plasticity when learning is performed
within five to 10 minutes after rTMS conditioning.
When online or offline transcranial stimulation is used
to produce gating, it needs to be kept in mind that the
stimulation itself or its effects on neuronal excitability may
63
be potentially disruptive, resulting in interference with task-
related neuronal processing. It is conceivable that such a
detrimental effect may outbalance the positive effect of
stimulation-induced gating. However, there is so far rela-
tively little experimental evidence for this contention.
Anodal or cathodal tDCS applied to the training motor
cortex during a practice period of ballistic thumb move-
ments interfered with the development of practice-
dependent plasticity as measured by the magnitude of the
practice-induced change in the direction of TMS-induced
thumb movements toward the training direction.42 This
finding points to the notion that any stimulation during
task-related neuronal processing may potentially produce
interference because anodal and cathodal tDCS of motor
cortex have typically opposite effects on motor cortical
excitability: anodal tDCS enhances it and cathodal tDCS
decreases it.25,26 On the other hand, subthreshold low-
frequency rTMS (1 Hz) applied over the training motor
cortex to reduce its excitability23 during practice of finger
tracking movements did not interfere with learning perfor-
mance.43 Low-frequency rTMS applied over the training
motor cortex immediately before a practice session of
reaching movements in a force field also did not affect
the learning process per se, but degraded the formation of
a long-term memory.44 Furthermore, low-frequency rTMS
given over motor cortex after learning of a ballistic motor
task degraded the retention of this newly acquired skill,45,46
whereas retention of dynamic force-field learning was not
affected.46 These data suggest that a potentially detrimental
effect of transcranial brain stimulation on simultaneous or
subsequent motor learning is difficult to predict and likely
depends on the characteristics of the transcranial stimula-
tion protocol, the exact learning task, and when stimulation
is applied relative to learning.
Another potential, but as of yet not specifically tested,
concern is that a transcranial stimulation protocol resulting
in strong enhancement of excitability in the training motor
cortex may elicit a homeostatic response that raises the
threshold for subsequent learning-induced plasticity. This
concern was supported indirectly by one study that dem-
onstrated that online excitability-enhancing anodal tDCS of
the training motor cortex did not disrupt the simultaneously
ongoing formation of a motor memory of a movement
sequence but degraded its recall after the end of the
stimulation.47
Gating of motor learning by transcranial
brain stimulation in stroke patients
Several recent proof-of-principle studies suggest that it is
possible to gate motor relearning by transcranial stimulation
in stroke patients. In 15 chronic stroke patients, a two-
second train of subthreshold (80% of resting motor thresh-
old) high-frequency (10 Hz) rTMS was given to the affected
motor cortex immediately before patients performed a
64
practice block of sequential finger movements. This proce-
dure was repeated eight times. In concordance with a gating
effect, real but not sham rTMS of the affected motor cortex
enhanced learning of sequential finger movements of the
paretic hand.48 Another study showed that intermittent TBS
of the affected hemisphere resulted in a shortening of simple
reaction time of the paretic hand.49 However, because the
experimental design involved no learning task, this effect
was likely caused directly by TBS rather than reflecting a
gating effect. Furthermore, anodal tDCS of the affected mo-
tor cortex improved performance in the Jebsen-Taylor hand
function test (JTT) when compared with sham stimula-
tion.50,51 In these studies, anodal tDCS was given while pa-
tients performed subtests of the JTT that comprised tasks of
relevance in everyday life, such as turning over cards, pick-
ing up small objects and placing them in a can, picking up
beans with a teaspoon and placing them in a can (mimicking
a feeding function), stacking checkers, moving large light
cans, and moving heavy cans. Of note, repeated practice
of the JTT alone, or practice under sham stimulation, failed
to induce a measurable improvement. It is thus plausible to
assume that anodal tDCS of the affected motor cortex effec-
tively gated motor learning. In addition, it seems also possi-
ble to gate motor learning in chronic stroke patients by
decreasing the excitability of the unaffected motor cortex,
thereby decreasing inhibitory action from the unaffected
to affected motor cortex and in turn enhancing excitability
in the affected motor cortex. Cathodal tDCS50 and low-fre-
quency (1 Hz) rTMS of the motor cortex in the unaffected
hemisphere52 resulted in performance improvement in the
JTT in small groups of chronic stroke patients when com-
pared with a sham stimulation condition. Taken together,
these findings strongly suggest that gating of motor skill per-
formance and motor learning is possible in healthy subjects
and in chronic stroke patients by means of transcranial stim-
ulation techniques that transiently disinhibit or depolarize
the training cortex.53-64
Enhancement of motor learning by
homeostatic metaplasticity
Several recent studies provided converging evidence that
homeostatic metaplasticity occurs at the level of human
motor cortex. Ten minutes of subthreshold (90% of resting
motor threshold) preconditioning high-frequency (6 Hz)
rTMS enhanced the suppressive effect of subsequent supra-
threshold (115% of resting motor threshold) low-frequency
(1 Hz) rTMS on motor cortical excitability.65 Ten minutes of
low-frequency (1 Hz) rTMS, when given alone, had no
effect on the excitability of the stimulated motor cortex.
In contrast, when preceded by excitability-enhancing anodal
tDCS, the same 1 Hz rTMS protocol resulted in a depression
of motor cortex excitability, and vice versa, if preceded by
excitability-decreasing cathodal tDCS, it resulted in an in-
crease of motor cortex excitability.66 Similarly, a 20-second
U. Ziemann, H.R. Siebner
train of high-frequency (20 Hz) rTMS, when given alone,
had no overt effect on the excitability of the stimulated mo-
tor cortex. However, when preceded by anodal tDCS, the
same 20 Hz rTMS protocol resulted in a depression and if
preceded by cathodal tDCS in an increase of motor cortex
excitability,67 suggesting that it is possible to shape the
direction of rTMS-induced after-effects according to the
rules of homeostatic metaplasticity. Similarly, a paired-
associative stimulation protocol that under ‘‘normal’’
conditions induced LTP-like plasticity resulted no longer
in LTP-like plasticity or even LTD-like plasticity if preceded
by the same LTP-like plasticity inducing protocol.68 Alto-
gether, these findings are compatible with homeostatic
metaplasticity according to the BCM theory: high activity
(enhancement of motor cortical excitability by high-
frequency rTMS or anodal tDCS or LTP-like plasticity in-
ducing paired associative stimulation) favors the induction
of synaptic depression by a subsequent stimulation protocol
that by itself would induce no synaptic plasticity or even
LTP-like plasticity, whereas low activity (decrease of motor
cortical excitability by cathodal tDCS or LTD-like plasticity
inducing paired associative stimulation) favors the induction
of synaptic potentiation by a subsequent stimulation proto-
col. It shall be noted that one recent report put to question
the general validity of a homeostatic interaction between
two subsequent transcranial stimulation protocols.69 In
that study it was found that preconditioning anodal or
cathodal tDCS interacted with motor cortical excitability
enhancing PAS in a homeostatic manner, but only if the
two stimulation protocols were applied simultaneously. In
contrast, if PAS immediately followed tDCS, then a syner-
gistic rather than homeostatic interaction was observed, ie,
anodal tDCS led to an enhancement of the PAS induced
increase in motor cortical excitability, and cathodal tDCS
to a decrease.69 It is currently unclear how these findings can
be explained, but they show that interactions between two
transcranial stimulation protocols may be more complex
than hitherto thought, and whether homeostatic metaplastic-
ity occurs may depend on the exact nature and effects of the
stimulation protocols and when they are applied relative to
each other.
It is a currently intriguing question how homeostatic
metaplasticity affects motor learning. As motor learning
can be conceived as an at least partially LTP-dependent
process,1,2,70,71 it would be plausible to expect, according to
the rules of homeostatic metaplasticity, that a stimulation
protocol that induces depression will result in enhancement
of subsequent motor learning. Preliminary data in healthy
subjects are in agreement with this hypothesis: subjects
practiced a rapid thumb flexion movement. Motor learning
was measured by an increase in the peak acceleration of the
trained movement. Motor learning was significantly stron-
ger if subjects performed the practice subsequent to an
LTD-like plasticity inducing PAS protocol compared with
when they performed the same training subsequent to a
control stimulation protocol that did not induce synaptic
Modifying motor learning through gating and homeostatic metaplasticity
plasticity.72 Recently, homeostatic metaplasticity was also
observed in the somatosensory domain: perceptual learning
induced by peripheral high-frequency (20 Hz) stimulation
of the median nerve occurred if preceded by an LTD-like
plasticity inducing PAS protocol applied to the learning pri-
mary somatosensory cortex but was suppressed if preceded
by an LTP-like plasticity inducing PAS protocol (data
unpublished).
Enhancing motor learning by exploiting the principle of
homeostatic metaplasticity may constitute an interesting
possibility in future neurorehabilitation trials.60 However,
to use motor cortical excitability-depressing protocols to
enhance subsequent practice-dependent plasticity in pa-
tients, it needs to be demonstrated that the motor cortex still
expresses a normal pattern of homeostatic metaplasticity in
the patients. This is an important issue to be addressed in
future studies.
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