J Neurophysiol 111: 2516 –2524, 2014.
First published March 26, 2014; doi:10.1152/jn.00882.2013.
Combining D-cycloserine with motor training does not result in improved
general motor learning in neurologically intact people or in people with stroke
Kendra M. Cherry,1 Eric J. Lenze,2 and Catherine E. Lang1,3,4
1
Program in Physical Therapy, Washington University, St. Louis, Missouri; 2Department of Psychiatry, Washington
University, St. Louis, Missouri; 3Program in Occupational Therapy, Washington University, St. Louis, Missouri;
and 4Department of Neurology, Washington University, St. Louis, Missouri
Submitted 10 December 2013; accepted in final form 19 March 2014
stroke; D-cycloserine; motor learning; behavioral training
THE PREVALENCE OF STROKE AND the extensive costs associated
with persistent disability after stroke have generated an urgent
need for multidisciplinary neurorehabilitation research. It is
now understood that the nervous system has remarkable adaptive capacity. Specifically, the central nervous system retains
its ability to reorganize in structure and function in response to
behavioral experience following neurological injury. Stroke
rehabilitation involves cognitive learning and motor learning
that guide the adaptation of the central nervous system. Recent
stroke rehabilitation trials with intensive behavioral training
have resulted in statistically (Lo et al. 2010) and sometimes
Address for reprint requests and other correspondence: C. E. Lang, 4444
Forest Park Blvd, Washington Univ., St. Louis, MO 01120 (e-mail: langc
@wustl.edu).
2516
clinically meaningful improvements (Duncan et al. 2007; Wolf
et al. 2006), but improvements do not restore prestroke function. As it has become increasingly clear that behavioral
training alone will not be able to eliminate stroke-related
deficits and disability, there is a growing need to find an
effective pharmacological agent that will facilitate the neurobiological processes of learning, thus improving human stroke
outcomes.
In the fields of psychology and psychiatry, a novel strategy
is emerging in which exposure therapy, thought to be a kind of
emotional learning, is combined with a pharmacological enhancer of learning and memory. The agent used for many of
these recent studies is the learning and memory agonist D-cycloserine (DCS). DCS was originally approved by the U.S.
Food and Drug Administration in 1964 for use as an antibiotic
to treat tuberculosis. It is now known that DCS has a second
action: mediating memory formation. Specifically, DCS acts at
the glycine/serine regulatory site of the N-methyl-D-aspartate
(NMDA) receptor (NMDAR), boosting long-term potentiation
(LTP). When tested as an augmenting agent in exposure
therapy in patients with acrophobia, oral DCS given immediately before 30-min exposure sessions enhanced habituation
(Ressler et al. 2004). Similar pilot studies in social phobia,
post-traumatic stress disorder, and panic disorder have been
successful in improving exposure therapy response (Davis
2010; Guastella et al. 2008; Hofmann et al. 2006a,b; Norberg
et al. 2008).
So far, tests of DCS in humans have focused primarily on
facilitating emotional and extinction-based learning in the
context of cognitive behavioral therapy. The NMDARs
through which DCS promotes LTP, however, are also utilized
in motor learning pathways (Butefisch et al. 2000; Hess et al.
1996).
To our knowledge, there is no literature about the use of
DCS in combination with motor training to promote motor
learning in humans. It has been found, however, that DCS
successfully facilitated recovery of motor and memory function after closed head injury in a mouse model (Yaka et al.
2007). Moreover, studies investigating the impact of DCS
administered in combination with brain stimulation have found
increased cortical plasticity in humans (Kuo et al. 2008;
Nitsche et al. 2004). An important next step is to evaluate
whether DCS, given in combination with motor training, facilitates motor learning in humans. Such a combination, if
successful, could make rehabilitation training more efficient,
more effective, and more long-lasting.
0022-3077/14 Copyright © 2014 the American Physiological Society
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Cherry KM, Lenze EJ, Lang CE. Combining D-cycloserine
with motor training does not result in improved general motor
learning in neurologically intact people or in people with stroke. J
Neurophysiol 111: 2516 –2524, 2014. First published March 26,
2014; doi:10.1152/jn.00882.2013.—Neurological rehabilitation involving motor training has resulted in clinically meaningful improvements in function but is unable to eliminate many of the impairments
associated with neurological injury. Thus there is a growing need for
interventions that facilitate motor learning during rehabilitation therapy, to optimize recovery. D-Cycloserine (DCS), a partial N-methylD-aspartate (NMDA) receptor agonist that enhances neurotransmission throughout the central nervous system (Ressler KJ, Rothbaum
BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L,
Davis M. Arch Gen Psychiatry 61: 1136 –1144, 2004), has been
shown to facilitate declarative and emotional learning. We therefore
tested whether combining DCS with motor training facilitates motor
learning after stroke in a series of two experiments. Forty-one healthy
adults participated in experiment I, and twenty adults with stroke
participated in experiment II of this two-session, double-blind study.
Session one consisted of baseline assessment, subject randomization,
and oral administration of DCS or placebo (250 mg). Subjects then
participated in training on a balancing task, a simulated feeding task,
and a cognitive task. Subjects returned 1–3 days later for posttest
assessment. We found that all subjects had improved performance
from pretest to posttest on the balancing task, the simulated feeding
task, and the cognitive task. Subjects who were given DCS before
motor training, however, did not show enhanced learning on the
balancing task, the simulated feeding task, or the associative recognition task compared with subjects given placebo. Moreover, training
on the balancing task did not generalize to a similar, untrained balance
task. Our findings suggest that DCS does not enhance motor learning
or motor skill generalization in neurologically intact adults or in adults
with stroke.
EFFECTS OF
D-CYCLOSERINE
METHODS
General Experimental Design
This study used a repeated-measures design with two sessions
(Fig. 1). Experiment I examined the effects of DCS combined with
motor training on learning in neurologically intact participants while
experiment II examined the effects of DCS plus motor training on
learning in individuals with chronic stroke. Experiment I was completed before experiment II. This study was approved by the Washington University Human Research Protection Office and was conducted in compliance with the Helsinki Declaration. All participants
provided informed consent before beginning the study and were
compensated for their time.
Experiment I: Neurologically Intact Participants
Forty-one neurologically intact adults participated in experiment I.
Participants were included if they were 1) 18 years of age or older, and
2) had sufficient cognitive skills to actively participate. People were
excluded if they had 1) history of neurological condition or injury; 2)
balance impairment or vestibular disorder; 3) history of upper or
2517
lower extremity condition, injury, or surgery that could compromise
performance and safety on motor training tasks; 3) any cognitive,
sensory, or communication problem that would prevent completion of
the study; 4) current use of medications for, or diagnosis of, seizure
disorder, kidney disease, or liver disease; 5) current substance abuse
or dependence; or if they were 6) women who were pregnant, possibly
pregnant, or breastfeeding.
Experiment II: Stroke Participants
Twenty adults with stroke participated in experiment II. Additional
inclusion criteria for people with stroke were that they 1) had a
confirmed ischemic or hemorrhagic stroke, 2) were 6 or more months
poststroke, and 3) had unilateral upper extremity and lower extremity
weakness. People with stroke were excluded if they had 1) any other
neurological diagnosis, or 2) current participation in other stroke
treatment, or if they had any of the other exclusion criteria listed for
the control participants.
Medication
D-cycloserine is approved by the U.S. Food and Drug Administration for use as an antibiotic to treat tuberculosis. Peak blood levels
occur within 2– 8 h after dosing, the half-life is estimated to be 10 h,
and DCS is central nervous system penetrant. DCS was selected as the
pharmacological agent for this study because of its additional role in
mediating memory formation through its action as a partial NMDAR
agonist (Flood et al. 1992; Hood et al. 1989). The 250-mg dose was
selected because previous studies have shown that doses of 25–250
mg of DCS are associated with improved behavioral outcomes
(Kuriyama et al. 2011; Otto et al. 2010; Ressler et al. 2004), while a
dose of ⬎250 mg does not yield superior outcomes (Ressler et al.
2004) and doses greater than 500 mg DCS can lead to NMDA
antagonist effects (Heresco-Levy et al. 2013). In this study, DCS was
taken orally 1 h before motor training which is consistent with the
timing reported in current literature (Gottlieb et al. 2011; Hofmann et
al. 2006a; Otto et al. 2010).
Tasks
We deliberately selected three specific motor tasks that are similar
to the types of tasks used in traditional neurorehabilitation and that are
relevant to daily function.
Primary trained motor task. The primary trained motor task was a
stability platform balance task (Lafayette Instrument; model 16030L)
(Taubert et al. 2010). Successful performance of this task requires that
a subject anticipate changes in posture and coordinate muscle activation in response to self-induced perturbations. The stability platform
task was selected because of its ecological validity, as decreased
dynamic balance is a significant contributor to fall risk (Toraman and
Yildirim 2010) and maintaining stability during dynamic activities is
required for many daily activities including walking and reaching.
For each 30-s trial, participants were instructed to stand on the
movable platform with feet facing forward and to keep the platform
level for as much time as possible. The use of a supporting handrail
Fig. 1. General experimental design. DCS, Dcycloserine. *Associative recognition task only
included in experiment II.
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The purposes of this study were to 1) determine if DCS
facilitates learning in two types of motor tasks, and 2) determine if the learning that occurs through the practice of the two
motor tasks generalizes to another, related motor task. We
initially investigated this combination in a neurologically intact
population (experiment I) and then in a population of individuals with chronic stroke (experiment II). The design parameters
of this study were selected based on the parameters reported in
previous clinical studies that used DCS. A single 250-mg dose
was used for our assay because studies based on a single dose
have found improved outcomes (Hofmann et al. 2006a; Ressler
et al. 2004; Wilhelm et al. 2008), while chronic treatment with
DCS has not shown efficacy (Fakouhi et al. 1995; Quartermain
et al. 1994). The motor training tasks were a lower extremity
stability platform task (Taubert et al. 2010) and an upper
extremity simulated feeding task (Schaefer and Lang 2012). In
addition to these two motor tasks, a declarative learning task
that would be expected to be facilitated by NMDAR agonism
was added to experiment II to explicitly test the proposed
mechanisms of enhancing NMDAR function. The generalizability of motor learning was evaluated by having the participants perform an untrained balance task at pretest and posttest
only. Our hypotheses were 1) that both the neurologically
intact and stroke participants would demonstrate improved
performance with practice, 2) that training on the stability
platform task would result in improved performance on the
untrained balance task (generalization effect), and 3) that
participants given DCS would demonstrate greater improvements in performance than individuals given placebo (time ⫻
drug interaction).
ON MOTOR LEARNING
2518
EFFECTS OF
D-CYCLOSERINE
(single leg stance) of the Berg Balance Test (Berg 1995; Blum and
Korner-Bitensky 2008), a modification was made and the subject
performed single leg stance on the floor rather than on the narrow
balance beam. This modification reduced the level of difficulty of the
task by increasing the amount of area that the foot had in contact with
the support surface. Each participant performed five pretest trials and
five posttest trials of the single leg stance task. Performance for a
given trial was quantified as the amount of time (to the tenth of a
second) that a subject maintained balance.
Trained cognitive task. An associative recognition cognitive task
was added to the training paradigm for experiment II as an explicit test
of NMDAR function. Associative recognition tasks have been shown
to activate the hippocampus, striatum, frontal cortex, and anterior
cingulate and employ NMDAR-dependent LTP mechanisms (Bunge
et al. 2004; Duzel et al. 2003; Yonelinas et al. 2001). Associative
recognition requires the ability to form new associations between
unrelated items. The specific associative recognition task selected was
one in which participants were instructed to associate and remember
60 “target” nonword-image pairs. Before the pretest and each training
trial, participants participated in a study session during which they
were shown all 60 target pairs in a random order (stimulus presentation ⫽ 1.5 s; interstimulus interval ⫽ 1.0 s) and were instructed to
associate and remember the target pairs. Following a study session,
participants completed a test session in which they were shown 60
slides in a random order and had to indicate whether each pair was a
target or “foil” by pressing the 1 or 2 key, respectively, on a standard
keyboard (stimulus presentation ⫹ response time ⫽ 1.0 s; interstimulus interval ⫽ 1.0 s). Foil pairs consisted of pairs in which the
nonword, the image, or both were not target items or in which
the nonword and the image were incorrectly paired target items. The
number of target pairs included in a test session ranged from 15 to 30
pairs. Each participant performed one pretest, five training, and one
posttest trial(s) of the associative recognition task. No study session
was given before the posttest; participants had to recall target pairs
after a 24- to 48-h period between sessions.
Instructions, stimuli, and feedback were presented electronically on
a laptop computer screen using the E-Prime 2.0 software (Psychology
Software Tools, Pittsburgh, PA). Nonwords (e.g.,“blauds,” “woodcug”) were displayed in Calibri, size 72 font on the left side of the
screen while the image of a familiar object (e.g., comb, apple)
appeared on the right side of the screen. Nonwords were selected from
a database of nonwords provided by the English Lexicon Project
(Balota et al. 2007). All nonwords were pronounceable, five to seven
letters in length, and had no more than two syllables. Images were
selected from a bank of Microsoft Clip Art. All images were single
items, considered to be familiar to most American adults.
Performance on the associative recognition task was measured as
the percentage of correct responses (0 –100%) for the trial. Responses
were considered correct if a participant identified a target pair as a
target pair or identified a foil pair as a foil pair. Responses were
incorrect if a participant indicated that a target pair was a foil pair or
responded that a foil pair was a target pair, or if the participant did not
enter a response in the allotted timeframe following stimulus presentation. The response reaction time was gauged as the time interval
from stimulus presentation to the number one key or the number two
key being struck, indicating a response. If a participant did not enter
a response in the allotted time, reaction time was entered as 1,000 ms.
Participants received immediate feedback about the accuracy of each
response as the word(s) “correct,” “incorrect,” or “no response detected” appeared on the screen for 0.5 s after each stimulus.
Feedback. For all tasks, feedback regarding objective performance
was given at the end of each trial (e.g., number of beans transferred,
number of seconds in balance and correct or incorrect response). No
feedback was provided concerning the specific techniques implemented during task performance. This allowed participants to engage
in discovery learning in which they adapted their technique and
movement strategies based on trial and error. This form of learning
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was permitted for initial balance and positioning on the platform, but
no upper extremity support was permitted once the trial began. If
participants with stroke were unable to maintain the stability platform
level for 5 s during a 30-s pretrial, the task was modified by attaching
bungees from the midline of the undercarriage of stability platform to
each side of the support frame. This adjustment increased the resistance of the platform and reduced the difficulty of the task. Each
subject performed 5 pretest trials, 25 training trials, and 5 posttest
trials on the stability platform with a 2-min seated rest break after
every 5 trials to prevent fatigue. Performance was quantified as the
total amount of time (to the tenth of a second) that a subject was able
to maintain the platform ⫾ 3° of horizontal during each trial.
Secondary trained motor task. The secondary trained motor task
consisted of spooning beans from one bowl to another (Schaefer and
Lang 2012). Successful performance of this task requires coordination
of arm and hand muscle activation as well as fine control of the
magnitude of muscle force generation across the limb. This task was
selected because it simulates feeding, a task that is relevant to daily
function and self-care (Blennerhassett et al. 2008; Duncan et al. 2001).
For the simulated feeding task, participants were seated in a chair
without armrests at a table. For each 30-s trial, participants were
instructed to spoon as many beans as possible, transferring two beans
at a time, from one bowl to another bowl. The bowl nearest the
participant from which the beans were spooned contained 200 beans
at the beginning of each trial and was positioned 21 cm from the target
bowl. Neurologically intact participants were required to perform the
simulated feeding task with their nondominant hand so that the task
was novel and underpracticed. Participants with stroke performed the
simulated feeding task with the upper extremity most affected by their
stroke. The use of the dominant/unaffected hand was permitted for
initial positioning of the spoon in the nondominant/affected hand, but
no use of the s hand was permitted once the trial began. If participants
with stroke were unable to spoon six or more beans (three successful
repetitions) in a 30-s pretrial, the task was modified by sliding a piece
of cylindrical foam over the spoon’s handle to increase the diameter
of the handle to 2.5 mm and/or by repositioning the target bowl to a
position 10 cm away from the starting bowl. These modifications
reduced the difficulty of the task and allowed participants with limited
dexterity and grip strength to participate. Each participant performed
5 pretest trials, 30 training trials, and 5 posttest trials on the simulated
feeding task with a 2-min seated rest break after every 10 trials to
prevent fatigue. Performance for each trial was quantified as the
number of beans transferred from the starting bowl to the target bowl.
Untrained motor task. Experiments I and II also included an
untrained balance task to determine if training on the primary balance
task generalized to improved balance performance on a similar, but
untrained task. Single leg stance on a balance beam was selected as
the untrained task because it is a sensitive tool for assessing balance
capacity (Curtze et al. 2010) and it has the ability to be graded for
different abilities by changing the beam width. Additionally, the task
is clinically relevant because single leg balance is a significant
predictor of injurious falls in older persons (Vellas et al. 1997) and
reflects the single leg support phase of gait required for walking and
stair climbing.
For this task, participants were instructed to place their foot on the
balance beam (19 cm high, 60 cm long, and 1¾ cm wide), lift their
other leg off of the support surface, and try to maintain balance for as
long as possible without touching down with any part of their body.
Although the data indicate that there is no difference in unilateral
postural stability between the dominant and nondominant lower extremities (Hoffman et al. 1998) for consistency, neurologically intact
participants performed the single leg stance balance beam task on
their nondominant leg. Participants with stroke balanced on the lower
extremity most affected by their stroke. The use of upper extremity
support was permitted for initial balance and positioning on the
balance beam, but no upper extremity support was permitted once the
trial began. If a subject with stroke scored less than a 2 on item 14
ON MOTOR LEARNING
EFFECTS OF
D-CYCLOSERINE
was selected because it is associated with higher levels of engagement
in rehabilitation (Castronova 2002).
Order of Experiment
2519
Data Analysis
SPSS Statistics 21 (IBM, Armonk, NY) was used for all statistical
analyses, and criterion was set at ␣ ⫽ 0.05. To test whether DCS
augmented learning, we used a 2 ⫻ 2 mixed model ANOVA with a
within subject factor of time (pretest vs. posttest) and a between
subjects factor of drug (DCS vs. placebo). This mixed model analysis
was performed for the stability platform task, the simulated feeding
task, the single leg stance task, and the associative recognition task. A
significant interaction between time and group would support the
hypothesis that DCS facilitates learning. The same analyses were
performed in experiments I and II.
RESULTS
Participants
Participants were enrolled in experiment I from January
2013 through May 2013 and in experiment II from July 2013
through September 2013. All 41 neurologically intact participants and 20 participants with mild to moderate stroke, who
were enrolled, were randomized (Table 1). Half of the participants (19 neurologically intact and 10 with stroke) received
the study drug. There were no significant demographic differences between the groups that received DCS vs. those that
received the placebo in either experiment (P ⬍ 0.05), with the
exception of dominant side for experiments I and II and
affected side in experiment II (Table 1). Differences in these
factors are unlikely to influence the results, because neurologically intact participants all used their nondominant extremity
to perform the tasks and participants with stroke all used their
affected side to complete motor tasks. There was an average of
1.3 days between sessions for participants in experiment I and
Table 1. Demographic data
Neurologically Intact Participants: Experiment I
Characteristics
Age (means ⫾ SD)
Gender
Male
Female
Race
Caucasian
African American
Dominant side
Right
Left
Affected Side
Right
Left
Months since stroke (means ⫾ SD)
Stroke location
Cortical
Subcortical
Posterior circulation
Unknown
NIHSS score (median, IQR)
ARAT score (means ⫾ SD)
BBS score (means ⫾ SD)
SB test score (means ⫾ SD)
Participants with Stroke: Experiment II
DCS group
(n ⫽ 19)
Placebo group
(n ⫽ 22)
Group differences
(P value)
DCS group
(n ⫽ 10)
Placebo group
(n ⫽ 10)
Group differences
(P value)
44.6 ⫾ 13.7
43.7 ⫾ 13.7
P ⫽ 0.950
55.3 ⫾ 9.6
51.4 ⫾ 11.0
P ⫽ 0.429
10
9
15
7
P ⫽ 0.116
7
3
4
6
P ⫽ 0.398
4
15
4
18
P ⫽ 0.655
7
3
4
6
P ⫽ 0.398
15
4
20
2
P ⫽ 0.033
6
4
9
1
P ⫽ 0.003
9
1
25 ⫾ 11
3
7
21 ⫾ 13
P ⫽ 0.028
6
1
1
2
1,2
34 ⫾ 14
46 ⫾ 7
2.6 ⫾ 2.6
8
1
0
1
1,2
41 ⫾ 8
47 ⫾ 8
2.8 ⫾ 3.4
P ⫽ 0.520
P ⫽ 0.727
P ⫽ 0.582
P ⫽ 0.148
P ⫽ 0.561
P ⫽ 0.228
Values are counts except where indicated. DCS, D-cycloserine; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale: scores for the
motor subset range from 0 to 18, with lower scores indicating less impairment; ARAT, Action Research Arm Test: scores range from 0 to 57, with lower scores
indicating more impairment; BBS, Berg Balance Scale: scores range from 0 to 56, with lower scores indicating more impairment; SB, Short Blessed Test: scores
range from 0 to 28, with lower scores indicating less impairment.
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During the first session in experiment I, a trained clinical interviewer provided informed consent, gathered demographic data, and
gathered baseline measurements of performance on 2–5 trials of 1) a
stability platform balancing task, 2) a simulated feeding task, and 3)
a single leg stance task, in a randomized order. Experiment II included
stroke-specific descriptive measures in addition to the items listed for
experiment I. These consisted of the National Institutes of Health
Stroke Scale (Brott et al. 1989), Short Blessed Test (Katzman et al.
1983), Action Research Arm Test (Lang et al. 2006), and the Berg
Balance Test (Berg 1995; Blum and Korner-Bitensky 2008), which
served to describe stroke severity, cognition, upper extremity function, and balance, respectively.
After assessment of baseline measures and before behavioral training, participants were provided with either 250 mg DCS or placebo,
taken orally. Medication assignment was randomized, with concealed
allocation. DCS and placebo pills were manufactured to look identical
and were individually packaged in identical, opaque pill bottles
labeled with an ID number corresponding to the subject ID number.
Randomization was done by separate personnel located in another
building and pills were distributed to the participants by a blinded
experimenter. Following the administration of DCS or placebo, participants rested for 60 min.
Following the rest period, behavioral training commenced. This
training is described in detail above and consisted of repeated practice
of 1) a stability platform task, 2) a simulated feeding task, and 3) an
associative recognition task (experiment II only). The order of tasks
was randomized. During the second session, which took place 1–3
days after the first session, participants completed the posttest, consisting of five trials of each task. Participants did not receive DCS or
placebo during the second session.
ON MOTOR LEARNING
2520
EFFECTS OF
D-CYCLOSERINE
an average of 2.2 days between sessions in experiment II. All
participants completed both sessions of the experiment, and no
adverse effects of participation were reported.
Experimental Paradigm and Learning
A
days between sessions. These findings suggest that our assay
would have adequate sensitivity to detect facilitation effects.
Experiment I
Figure 3 shows group data for the trained stability platform
(A), trained simulated feeding (B), and untrained single leg
stance (C) tasks. Participants improved on both trained tasks,
as indicated by significant main effects of time [stability
platform: F ⫽ 128.3, degrees of freedom (df) ⫽ 1, P ⬍ 0.001;
simulated feeding: F ⫽ 108.6, df ⫽ 1, P ⬍ 0.001]. Training on
the stability platform did not, however, generalize to the
untrained single leg stance task, as indicated by a nonsignificant main effect of time (F ⫽ 0.06, df ⫽ 1, P ⫽ 0.802).
Moreover, participants who received DCS did not demonstrate
enhanced performance on any task compared with participants
who were given placebo, as indicated by nonsignificant inter-
Stability Platform
Day 1
Pill given
30
B
Day 2
Day 2
25
Seconds in balance
Seconds in balance
25
Stability Platform
Day 1
Pill given
30
20
15
10
5
20
15
10
5
0
0
0
10
20
30
40
0
10
20
Trial Number
Simulated Feeding
Day 1
Pill given
D
Day 2
Beans transferred
30
25
20
15
40
Simulated Feeding
Day 1
Pill given
25
Day 2
20
15
10
5
10
0
10
20
30
0
40
Trial Number
20
30
40
Day 1
Pill given
100
Day 2
80
60
40
20
0
0
J Neurophysiol • doi:10.1152/jn.00882.2013 • www.jn.org
10
Trial Number
Associative Recognition Accuracy
E
Percentage of correct responses
Fig. 2. Individual training data. Left: data
from experiment I, neurologically intact participants CT18 (A) and CT25 (C). Right: data
from experiment II, participants with stroke
CTS01 (B), CTS20 (D), and CTS18 (E).
Beans transferred
C
30
Trial Number
Pretest
1
2
3
Trial Number
4
5
Posttest
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All participants showed improved performance within a
session on stability platform, simulated feeding, and associative recognition (experiment II only) tasks. Example data from
single participants are provided in Fig. 2. With training, participants were able to maintain the platform within three
degrees of horizontal for more seconds per trial on the stability
platform (Fig. 2, A and B), to successfully transfer more beans
per trial during simulated feeding (Fig. 2, C and D), and to
correctly identify more nonword and image pairs as either
targets or foils on the associative recognition task (Fig. 2E).
Moreover, these performance changes were retained for 1–3
ON MOTOR LEARNING
EFFECTS OF
DCS
Placebo
Performance
C
10
5
es
t
t
t
st
es
Pr
Po
Pr
et
es
t
0
15
es
5
20
st
10
Single Leg Stance
Performance
8
Fig. 3. Mean pretest and posttest performance
for each group in experiment I. Error bars
represent SE. Subjects improved on both
trained tasks [stability platform: P ⬍ 0.001
(A); simulated feeding: P ⬍ 0.001 (B)] from
pretest to posttest but training did not generalize to the untrained single leg stance task [P ⫽
0.802 (C)]. Subjects who received DCS did
not demonstrate enhanced performance on any
task compared with participants who were
given placebo (stability platform: P ⫽ 0.555;
simulated feeding: P ⫽ 0.196; single leg
stance: P ⫽ 0.864).
6
4
2
es
st
Po
Pr
et
es
t
t
0
action effects (stability platform: F ⫽ 0.36, df ⫽ 1, P ⫽ 0.555;
simulated feeding: F ⫽ 1.73, df ⫽ 1, P ⫽ 0.196; single leg
stance: F ⫽ 0.03, df ⫽ 1, P ⫽ 0.864).
Experiment II
Figure 4 shows group data for the trained stability platform
(A), trained simulated feeding (B), trained associative recognition (C), and untrained single leg stance (D) tasks. Subjects
improved on all trained tasks, as indicated by significant main
effects of time (stability platform: F ⫽ 47.45, df ⫽ 1, P ⬍
0.001; simulated feeding: F ⫽ 22.97, df ⫽ 1, P ⬍ 0.001;
associative recognition: F ⫽ 28.30, df ⫽ 1, P ⬍ 0.001).
Training on the stability platform, again, did not generalize to
the untrained single leg stance task, as indicated by a nonsignificant main effect of time (F ⫽ 0.322, df ⫽ 1, P ⫽ 0.578). As
was the case in experiment I, participants with stroke who
received DCS did not exhibit enhanced performance compared
with participants who were given placebo, as indicated by
nonsignificant interaction effects (stability platform: F ⫽ 0.00,
df ⫽ 1, P ⫽ 0.993; simulated feeding: F ⫽ 0.429, df ⫽ 1, P ⫽
0.521; associative recognition: F ⫽ 0.159, df ⫽ 1, P ⫽ 0.695;
single leg stance: F ⫽ 0.067, df ⫽ 1, P ⫽ 0.798).
DISCUSSION
We found that administration of a single dose of DCS, 1 h
before a motor and cognitive training session, did not enhance
the effects of training. This was true for both neurologically
intact adults (experiment I) and adults with chronic stroke
(experiment II). We also found that DCS did not promote
generalization of motor training to an untrained motor task in
either participant group. To our knowledge, this study was the
first test of DCS in combination with motor training as an
enhancer of motor learning in humans. The protocol used to
test DCS was quick, easy to administer, and inexpensive. Thus,
if it can be shown that performance on these tasks can be
enhanced with some agent, the protocol could serve as an
economical assay for testing a range of pharmacological agents
or other interventions for their ability to facilitate motor learning, before moving to a full-scale, randomized, controlled trial.
There are several possible explanations for why DCS failed
to enhance the learning on these motor tasks. One option is that
NMDARs were saturated. If NMDARs were saturated and
already functioning optimally, the addition of DCS to the
system would not enhance performance. We reasoned that this
was a highly probable explanation for the negative results
found in neurologically intact participants, and we proceeded
with experiment II because NMDAR function is chronically
reduced following stroke (Dhawan et al. 2010, 2011; Friedman
et al. 2000). In spite of the likelihood that NMDAR function
was reduced in people with stroke, DCS did not enhance
learning.
A second possible explanation may be that the dose of DCS
administration or the dose of motor training was inappropriate
for enhancing motor learning. We selected a single dose rather
than repeated dosing because a single 250-mg dose is welltolerated (Rodebaugh and Lenze 2013) and avoids receptor
desensitization, and changes in NMDAR subunit composition
can occur with repeated dosing (Parnas et al. 2005). A number
of other studies have found that a wide range of dosing, from
25 to 500 mg, is effective in enhancing cognitive-behavioral
outcomes (Javitt 2013; Otto et al. 2010; Ressler et al. 2004). A
dose of 250 mg was selected to ensure that the substance would
be biologically active in the central nervous system but not so
high as to cause NMDAR antagonism that may occur with
doses ⬎500 mg (Simeon et al. 1970). Because DCS is a partial
NMDA agonist, and learning itself augments NMDAR activ-
J Neurophysiol • doi:10.1152/jn.00882.2013 • www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on July 28, 2017
10
(seconds in balance)
2521
Simulated Feeding
Po
15
ON MOTOR LEARNING
25
et
(seconds in balance)
20
Performance
B
Stability Platform
(number of beans transferred)
A
D-CYCLOSERINE
D
60
40
20
Po
8
6
4
2
st
Po
st
te
es
et
st
st
te
es
Pr
ity, it remains possible that DCS at the given dosage still
resulted in antagonism and receptor saturation. In support of
this possibility is the finding that DCS improved LTP-like
plasticity at a dosage of 100 mg, but combining the drug with
a plasticity induction procedure (transcranial direct current
stimulation) reduced motor learning (Kuo et al. 2008; Nitsche
et al. 2004). Thus future studies could be designed to test
different dosages to rule out the possibility that the missing
effect was caused by suboptimal dosing.
With regards to the dose of motor training, this protocol was
designed to serve as a simple assay to probe for the effects of
combining DCS with motor training. As such, only one dose of
DCS and 1 day of training was implemented. Moreover, a
single training session showed efficacy in studies that combined DCS with behavioral training in the psychiatric literature
(Davis 2010; Guastella et al. 2008) and in a plasticity-induction
procedure (Kuo et al. 2008; Nitsche et al. 2004). It is possible
that enhancement of motor learning, unlike extinction or emotional learning, requires repeated sessions to occur. Thus a
single dose of DCS may have enhanced motor learning if more
practice were provided. A study of amphetamine in a monkey
model showed that a single dose of the drug resulted in
improved motor performance when combined with 2 wk of
motor skill training (Barbay et al. 2006).
Another explanation for our results is that the timing of DCS
administration might not have been optimal to avoid antagonism. Data from other clinical studies indicate that administration of DCS should take place 1 h before treatment sessions
(Guastella et al. 2008; Hofmann et al. 2006b) and that DCS
does not improve performance during training but rather that
the memory effects of DCS are only detected when tested 24 h
or more after training (Kandel 2001). Specifically, it is thought
that DCS works to transfer learning from short-term NMDAindependent to longer term NMDA-dependent forms of mem-
t
0
t
0
Single Leg Stance
10
Performance
Associative Recognition Accuracy
st
t
es
Po
Pr
st
et
te
es
et
Pr
80
et
Performance
(percentage of correct responses)
C
5
st
t
0
10
te
5
15
st
10
20
Pr
Performance
(seconds in balance)
DCS
Placebo
15
Simulated Feeding
25
ory, a phenomenon termed consolidation (Kandel 2001; Norberg et al. 2008). Peak brain levels of DCS are reached 4 – 8 h
after administration, so dosing 1 h before training has the
maximal effect after training has ended, as desired (Javitt
2013). Given its role in consolidation, the option of delaying
DCS administration until after the training session may be
considered in future studies. While DCS would still be circulating during the posttraining “consolidation window,” this
would allow researchers to administer DCS only after sessions
in which significant improvements are made (Norberg et al.
2008). Other studies, however, indicate that DCS does have a
direct effect on neuroplasticity (Nitsche et al. 2004; Teo et al.
2007). If this is the case, timing of DCS administration should
occur no later than 2 h before behavioral training to guarantee
that peak plasma concentrations occur during motor training.
Future studies could be designed to elucidate the optimal
timing of DCS administration and clarify whether the effects of
the agent are primarily that of direct neuroplasticity or learning
consolidation.
It is also possible that the tasks selected for motor training
were not challenging enough and that participants experienced
a ceiling effect. Even though many participants with stroke had
worse performance than healthy subjects, the possibility of a
ceiling effect cannot be ruled out because individuals with
stroke may have lower maximal performance capacity. The
explanation that our results occurred due to a ceiling effect is
unlikely, however, because all participants in experiments I and
II demonstrated a steady increase in performance during motor
training and did not reach performance plateaus. Moreover,
other reports using similar tasks have demonstrated continued
increases in performance over multiple days of training (McNevin et al. 2003; Schaefer and Lang 2012; Wulf et al. 2003). It
should be acknowledged that while we found a null effect of
DCS on the two trained motor tasks that were employed in our
J Neurophysiol • doi:10.1152/jn.00882.2013 • www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on July 28, 2017
Fig. 4. Mean pretest and posttest performance
for each group in experiment II. Error bars
represent SE. Subjects improved on all trained
tasks [stability platform: P ⬍ 0.001 (A); simulated feeding: P ⬍ 0.001 (B); associative
recognition: P ⬍ 0.001 (C)] from pretest to
posttest but training did not generalize to the
untrained single leg stance task [P ⫽ 0.578
(D)]. Subjects who received DCS did not
demonstrate enhanced performance on any
task compared with participants who were
given placebo (stability platform: P ⫽ 0.993;
simulated feeding: P ⫽ 0.521; associative
recognition: P ⫽ 0.695; single leg stance: P ⫽
0.798).
B
Stability Platform
20
Performance
A
ON MOTOR LEARNING
(number of beans transferred)
D-CYCLOSERINE
(seconds in balance)
EFFECTS OF
Po
2522
EFFECTS OF
D-CYCLOSERINE
GRANTS
This work is supported by National Institute of Child Health and Human
Development Grants R01-HD-068290 and T32-HD-007434, the Foundation
for Physical Therapy, and the Washington University Spencer T. Olin Fellowship.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: K.M.C., E.J.L., and C.E.L. conception and design of
research; K.M.C. performed experiments; K.M.C., E.J.L., and C.E.L. analyzed
2523
data; K.M.C., E.J.L., and C.E.L. interpreted results of experiments; K.M.C.,
E.J.L., and C.E.L. prepared figures; K.M.C., E.J.L., and C.E.L. drafted manuscript; K.M.C., E.J.L., and C.E.L. edited and revised manuscript; K.M.C.,
E.J.L., and C.E.L. approved final version of manuscript.
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