Maturation of inhibitory and excitatory motor cortex pathways in children.
ABSTRACT To study intracortical inhibition and facilitation with paired-pulse transcranial magnetic stimulation in children, adolescents and adults.
Paired-pulse transcranial magnetic stimulation (interstimulus intervals (ISI): 1, 3, 5, 10 and 20 ms) was applied over the primary motor cortex (M1) in 30 healthy subjects (range 6-30 years, median age 15 years and 8 months, SD 7,9) divided in three groups: adults (>or=18 years), adolescents (> 10 and < 18 years) and children (<or=10 years).
We observed significantly less intracortical inhibition (SICI) in children's M1 compared to that of adults. Adolescents showed significantly less SICI at the 5 ms interval than did adults. No significant differences were apparent in intracortical facilitation (ICF).
We postulate that, as in adults, the maturing M1 possesses horizontal glutamatergic cross-links that represent the neuronal substrate of excitatory intracortical pathways. GABAergic interneurons, the neuronal substrate of inhibitory intracortical pathways, mature between childhood and adulthood. Reduced GABAergic inhibition may facilitate neuronal plasticity and motor learning in children.
- SourceAvailable from: Sagari Sarkar[Show abstract] [Hide abstract]
ABSTRACT: Little is known about how sex influences functional brain maturation. The current study investigated sex differences in the maturation of event-related potential (ERP) amplitudes during an auditory oddball task (N = 170; age = 6-17 years). Performance improved with age. N200 amplitude declined with age: parietal sites showed earlier development than temporal and frontal locations. Girls showed greater bilateral frontal P300 amplitude development, approaching the higher values observed in boys during childhood. After controlling for age, right frontal P300 amplitude was associated with reaction time in girls. The findings demonstrate sex differences in ERP maturation in line with behavioral and neuroimaging studies.Developmental Neuropsychology 07/2012; 37(5):415-33. · 2.67 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Since GABAA-mediated intracortical inhibition has been shown to underlie plastic changes throughout the lifespan from development to aging, here, the aging motor system was used as a model to analyze the interdependence of plastic alterations within the inhibitory motorcortical network and level of behavioral performance. Double-pulse transcranial magnetic stimulation (dpTMS) was used to examine inhibition by means of short-interval intracortical inhibition (SICI) of the contralateral primary motor cortex in a sample of 64 healthy right-handed human subjects covering a wide range of the adult lifespan (age range 20-88 years, mean 47.6 ± 20.7, 34 female). SICI was evaluated during resting state and in an event-related condition during movement preparation in a visually triggered simple reaction time task. In a subgroup (N = 23), manual motor performance was tested with tasks of graded dexterous demand. Weak resting-state inhibition was associated with an overall lower manual motor performance. Better event-related modulation of inhibition correlated with better performance in more demanding tasks, in which fast alternating activation of cortical representations are necessary. Declining resting-state inhibition was associated with weakened event-related modulation of inhibition. Therefore, reduced resting-state inhibition might lead to a subsequent loss of modulatory capacity, possibly reflecting malfunctioning precision in GABAAergic neurotransmission; the consequence is an inevitable decline in motor function.Journal of Neuroscience 05/2013; 33(21):9039-9049. · 6.75 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The developmental pathophysiology of autism spectrum disorders (ASD) is currently not fully understood. However, multiple lines of evidence suggest that the behavioral phenotype may result from dysfunctional inhibitory control over excitatory synaptic plasticity. Consistent with this claim, previous studies indicate that adults with Asperger's Syndrome show an abnormally extended modulation of corticospinal excitability following a train of repetitive transcranial magnetic stimulation (rTMS). As ASD is a developmental disorder, the current study aimed to explore the effect of development on the duration of modulation of corticospinal excitability in children and adolescents with ASD. Additionally, as the application of rTMS to the understanding and treatment of pediatric neurological and psychiatric disorders is an emerging field, this study further sought to provide evidence for the safety and tolerability of rTMS in children and adolescents with ASD. Corticospinal excitability was measured by applying single pulses of TMS to the primary motor cortex both before and following a 40 s train of continuous theta burst stimulation. 19 high-functioning males ages 9-18 with ASD participated in this study. Results from this study reveal a positive linear relationship between age and duration of modulation of rTMS after-effects. Specifically we found that the older participants had a longer lasting response. Furthermore, though the specific protocol employed typically suppresses corticospinal excitability in adults, more than one third of our sample had a paradoxical facilitatory response to the stimulation. Results support the safety and tolerability of rTMS in pediatric clinical populations. Data also support published theories implicating aberrant plasticity and GABAergic dysfunction in this population.Frontiers in Human Neuroscience 08/2014; 8:627. · 2.90 Impact Factor
Maturation of inhibitory and excitatory motor cortex
pathways in children
Michael Walthera,1, Steffen Berweckb,2, Joachim Schessld, Michaela Linder-Luchta,1,
Urban M. Fietzekb,2, Franz X. Glockerc,3, Florian Heinenb,2, Volker Malla,*
aDivision of Neuropediatrics and Muscular Disorders, Department of Pediatrics and Adolescent Medicine,
University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany
bPaediatric Neurology and Developmental Medicine, University of Munich, Lindwurmstr. 4, 80337 Munich, Germany
cDept. of Neurology, University of Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany
dFriedrich-Baur-Institute, Clinic of Neurology, Ludwig-Maximilians-University, Ziemssenstr. 1, 80336 Munich, Germany
Received 23 December 2008; received in revised form 3 February 2009; accepted 16 February 2009
Objective: To study intracortical inhibition and facilitation with paired-pulse transcranial magnetic stimulation in children, ado-
lescents and adults. Methods: Paired-pulse transcranial magnetic stimulation (interstimulus intervals (ISI): 1, 3, 5, 10 and 20 ms) was
applied over the primary motor cortex (M1) in 30 healthy subjects (range 6–30 years, median age 15 years and 8 months, SD 7,9)
divided in three groups: adults (P 18 years), adolescents (> 10 and < 18 years) and children (6 10 years). Results: We observed
significantly less intracortical inhibition (SICI) in children’s M1 compared to that of adults. Adolescents showed significantly less
SICI at the 5 ms interval than did adults. No significant differences were apparent in intracortical facilitation (ICF). Conclusion:
We postulate that, as in adults, the maturing M1 possesses horizontal glutamatergic cross-links that represent the neuronal substrate
of excitatory intracortical pathways. GABAergic interneurons, the neuronal substrate of inhibitory intracortical pathways, mature
between childhood and adulthood. Reduced GABAergic inhibition may facilitate neuronal plasticity and motor learning in children.
? 2009 Elsevier B.V. All rights reserved.
Keywords: Children; Neuronal plasticity; Cortical excitability; Intracortical inhibition; Intracortical facilitation; Motor cortex maturation; Trans-
cranial magnetic stimulation
Intracortical inhibition and facilitation are two inter-
acting phenomena representing a homeostatic regulatory
concept in synaptic plasticity. Animal experiments and
animal motor cortex slice preparation studies revealed
excitatory horizontal pathways in the cortical layer II/
III that span the M1 and are blocked by inhibitory
0387-7604/$ - see front matter ? 2009 Elsevier B.V. All rights reserved.
Abbreviations: AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; cMEP, conditioned MEP; EMG, electromyography; GABA, ga-
mma aminobutyric acid; ICF, intracortical facilitation; ISI, interstimulus interval; LTD, long-term depression; LTP, long-term potentiation; M1,
primary motor cortex; MEP, motor-evoked potential; MT, motor threshold; NMDA, N-methyl-D-aspartic acid; PP, paired-pulse; SEM, standard
error of mean; SICI,short interval intracortical inhibition; TMS, transcranial magnetic stimulation; TS, test stimulus; ucMEP, unconditioned MEP.
*Corresponding author. Tel.: +49 (761) 270 4310; fax: +49 (761) 270 4344.
1Tel.: +49 761 270 4315.
2Tel.: +49 89 5160 7851.
3Tel.: +49 761 270 5001.
Brain & Development 31 (2009) 562–567
mechanisms [1–3]. The motor cortex ´s moment-to-
moment plasticity is induced by a change in the intracor-
pathways, thus mediating the intensity of intracortical
facilitation . In cat M1 slice preparation studies, the
level of GABAergic intracortical inhibition correlates
inversely to activity-dependent and long-term plasticity
effects . The GABergic system A’s maturation process
during brain development has been well documented in
mature mice M1 in in-vitro rodent experiments with cor-
tical cultures [6–8]. During nascent synaptogenesis,
GABA was initially revealed as an excitatory neurotrans-
mitter, shifting to inhibitory characteristics during the
development of the K+/Cl?Transporter . GABA´s
inhibitory intensity is thus developmentally determined.
This, and an additional increase in glutamatergic trans-
mission, lead to a matured, narrowed GABA/glutamate
enabled us to better understand the cortical circuits in
human adult M1, namely, that they are responsible for
activity-dependent neuronal plasticity. Kujirai et al.
demonstrated intracortical inhibition (SICI) at the inter-
stimulus intervals (ISI) of 1–6 ms in their TMS-investi-
gation using a paired-pulse paradigm, while ISI of 10
and 20 ms induce intracortical facilitation (ICF) .
Further studies demonstrate this inhibition as GABAer-
gic, showing the reinforcement of glutamate-mediated
excitatory pathways after blocking the GABA uptake
These results provide evidence of an activity-depen-
dent dynamic interaction in adult human M1 similar
to the moment-to-moment synaptic plasticity in animal
experiments. This interaction ´s function seems to behave
in an almost linear and reciprocal manner [11,13] – thus
a high GABAergic inhibition level leads to less, and a
low GABAergic level to greater synaptic plasticity. It
remains unclear whether GABAergic intracortical inhi-
bition involves a maturation process in human M1 as
This study evaluates the hypothesis of a maturation
process in intracortical inhibition and facilitation evalu-
ated using the short interval paired-pulse paradigm in
children, adolescents and adults.
Our study was approved by the Ethics Committee of
the University of Freiburg, Germany (Number 181/07).
All participants gave informed consent; parents pro-
vided informed consent for participants under 18 years.
Thirty healthy subjects were included (19 male, 11
female), 10 children (6 10 years, n = 10, mean age = 8 -
years and 3 months, range 6–10 years), 10 adolescents
(>10 and < 18 years, n = 10, mean age = 12 years and
10 months, range 11–17 years) and 10 adults (P
18 years, n = 10, mean age = 25 years and 8 months,
range 21–30 years).
The lower age limit of 10 years in the intermediate
‘‘adolescents” group was set following a study con-
ducted in our department that revealed relatively great
individual variation in how the brain matures at that
age . Corticospinal pathway values above that age
have also been shown to be adult-like .
2.2. Transcranial magnetic stimulation
Subjects sat in upright position on a chair. A 70 mm
figure-eight-shaped stimulation coil was centered tan-
gentially on the scalp over the contralateral motor cor-
interosseus dorsalis muscle (MDI) and adjusted to the
position whence the maximum MEP amplitude was
obtained. The coil’s handle was pointed in a posterior
direction. Orientation was achieved using the preauricu-
lar and parasagittal line, and the coil position was kept
recorded from the first interosseous dorsalis muscle
using the belly-tendon recording technique with surface
Ag-AgCl electrodes (diameter 8 mm). Responses were
recorded using a Multi-Liner electromyograph (Jaeger
Toennies, Ho ¨chberg, Germany). The corner frequencies
of the bandpass-filter were set at 2 Hz and 10 kHz,
respectively. Sampling rate was 5 kHz. Two monophasic
magnetic stimulators (Magstim 200, Magstim Com-
pany, Whitland, UK) were connected with a bistim
device and discharged into the figure-eight-shaped coil.
All TMS procedures, including the evaluation of the
motor threshold (MT), were performed using the bistim
device; MT determination therefore included the change
in stimulus intensity by the bistim set-up.
2.3. Motor threshold (MT)
Relaxed MT was determined by raising the stimulus
intensity in 1% step-wise increments according to inter-
national standards (minimal EMG-response (P 50 lV)
in at least 5 of 10 successive stimulations) .
2.4. SICI/ ICF
Stimuli were applied while the subjects were relaxing.
The intensity of the conditioning stimulus was 20%
below the motor threshold. At this low intensity, the
TMS-impulse does not produce significant corticospinal
activation . The test stimulus (TS) magnitude was set
to produce an MEP at a range of 200–600 lV when
given alone. An interstimulus interval (ISI) of 1, 3,
5 ms (revealing SICI and) 10 and 20 ms (revealing
ICF) between conditioning and test stimulus was used
M. Walther et al./Brain & Development 31 (2009) 562–567
throughout the experiments. Conditioned and uncondi-
tioned stimuli were applied in a randomized order. 10
stimuli were applied for every ISI 10 stimuli applied
and documented for off-line analysis. We analyzed the
EMG baseline (pre-stimulus period, 100 ms in each sin-
gle-trial) by square root means of single-trial EMG data
in order to document relaxation in children similar to
that in to adults.
2.5. Statistic analysis
The SICI/ICF ratio was calculated as the quotient of
unconditioned motor-evoked potential (ucMEP). Statis-
tic analysis was performed for the group-mean of every
single SICI/ICF-ratio. Due to abnormally-distributed
data, we used nonparametric tests. In a first step, we
employed a one-way analysis of variance by ranks
(Kruskal–Wallis test) to test the influence of age on
SICI/ICF ratios. In case of significance, a nonparamet-
ric test for two unrelated samples (Mann–Whitney test)
was used to test differences between two age groups.
3.1. Single pulse analysis
Relaxation control based on analysis of the square
root mean of single-trial rectified EMG data revealed
no significant difference between children and adults
(p = 0.326). We obtained reproducible MEPs from all
participants. The resting MT mean fluctuated between
72.30% of maximum stimulator output (MSO) (range
40–95%) in children, and 53.9% of MSO (range 45–
65%) in adults (p = 0.07). The mean TS magnitude to
produce an MEP between 200 and 600 lV ranged
between 85% of MSO (range 55–100%) in children,
77% in adolescents (range 45–90%), and 59% of MSO
(range 40–70%) in adults.
3.2. Cortical excitability
The Kruskal–Wallis test depicts a significant influ-
ence of age on the inhibitory ISIs (1, 3 and 5 ms), but
no significant influence on the facilitating ISIs (10 and
20 ms). The Mann–Whitney-Test shows significantly
lower intracortical inhibition for the ISIs 1, 3 and 5 ms
between children and adults, whereas we noted no sig-
nificant differences, except for the 5 ms ISI, between
adults and adolescents. Among the adolescents, the
5 ms ISI likewise showed lower intracortical inhibition
compared to the 1 ms and 3 ms ISI. There were no sig-
nificant differences between the inhibitory ISIs in chil-
dren and adolescents (Table 1, Figs. 1 and 2).
Our study revealed a significant influence of age on
intracortical inhibition, but no influence on intracortical
facilitation. We observed significantly lower SICI in
children compared to adults in all the inhibitory ISI
tested (1, 3 and 5 ms). We found significantly lower SICI
The table depicts the mean, range and standard error of the mean (SEM) of the SICI/ICF-ratio for each ISI in the different age groups. The influence
of age groups was tested by means of the Kruskal–Wallis test for each ISI. Differences between two age groups were tested by means of the Mann-
Whitney test. The footnotes illustrate significant results from the statistical analyses.
ISI (ms) MEP in mV (child) MEP in mV (adolescents) MEP in mV (adults)
Kruskal–Wallis Test:*p 6 0.01;**p 6 0.001.
ap 6 0.05
bp 6 0.001
1(child against adult)
2(child against adolescent)
3(adolescents against adult)
M. Walther et al./Brain & Development 31 (2009) 562–567
in adolescents than in adults in the 5 ms ISI. No other
significant age-effect in intracortical facilitation was
apparent. This confirms our hypothesis that GABAergic
The application of TMS paired-pulse technique in
children requires thorough evaluation of methodical
aspects. SICI and ICF correlate closely with the ucMEP
amplitude. It is well known that MEP amplitudes are
smaller in children than adults, even when using the
same stimulus output. This is due to their higher motor
threshold [14,18]. We therefore standardized the MEP
amplitude at a range of 200–600 lV. Furthermore, SICI
and ICF must be evaluated under relaxed conditions, as
muscle facilitation is known to eradicate intracortical
Fig. 1. Boxes in Fig. 1 and 2 show minimum, first quartile, median,
third quartile and maximum. If a significant influence was proven in
the Kruskal–Wallis test, differences between age groups were evaluated
by the Mann–Whitney test. Significant differences compared to adults
(p < 0.05) are marked (?). (a) Trace I and II show sample EMG
discharges of an adult participant. Lower MEP amplitude after paired-
pulse stimulation at the 3 ms ISI (II) compared to EMG-amplitude
after single-pulse TMS stimulation (I) reveals intracortical inhibition.
Traces III and IV show sample EMG discharges of a child. Stimulation
in paired-pulse TMS mode at 3 ms ISI (IV) depicts slightly higher
EMG-amplitude than in single-pulse stimulation, showing that facil-
itation in this ICI is even possible in the maturing M1 (III). (b) The
SICI ratios of the short ISIs (1, 3, 5 ms) are depicted in boxplots for the
three groups. Compared to adults. Significant lower inhibition in
children was evident in all ISIs. Compared with adults and children,
the group of adolescents revealed no significant differences in the group
of the inhibitory ISIs, except for the 5 ms ISI, which showed a
significantly higher ICI in adolescents than in adults.
Fig. 2. (a) Sample EMG Traces of an adult (I and II) and child (III
and IV) revealed higher EMG-amplitude (II and IV) in the paired-
pulse TMS mode (ISI 20 ms) than in single-pulse TMS mode (I and
III). (b) ICF ratios of the longer ISIs (10, 20 ms) are depicted in
boxplots for the three groups. No significant influence of age groups on
the facilitating ISIs was apparent.
M. Walther et al./Brain & Development 31 (2009) 562–567
inhibition at the 2 ms interval . This effect could also
apply to other ISIs. We analyzed the EMG baseline to
verify relaxation in children and adults. The square root
mean of rectified EMG data revealed no significant dif-
ference in relaxation between the groups. Taking this
data into account, we conclude that the differences
found in SICI are contingent upon maturation and are
not due to methodology.
Since GABA seems to be the responsible procurer of
intracortical inhibition in animal studies [5,3,20], TMS
studies demonstrated GABAergic origin of SICI in
humans as well [10,12] There is little knowledge about
intracortical inhibition in the maturing human cortex,
but some evidence of lower SICI in juvenile M1, as dem-
onstrated in the 2 ms ISI . Their finding is consistent
with our results.
There are data from postmortem human slice prepa-
ration studies that likewise support the idea of a matu-
ration process of the GABAergic system in the human
cortex. As in rodents, GABA conduct in the prenatal
human cortex as excitatory neurotransmitters, however,
during the first days after birth, GABA’s function
switches from an excitatory to an inhibitory role .
Brooks–Kayal and Pritchett demonstrated a multiplica-
tion of GABAAreceptors during human brain matura-
tion, linkedwith the
benzodiazepine-sensitive subtypes to just one in adult-
hood . Those studies ´ results were analogous to
GABAergic maturation in animal studies, and they con-
cur with our results as well. A multiplication of GABAA
receptors may explain our in vivo evidence of increasing
intracortical inhibition from childhood to adulthood.
If the structural maturation of the GABAergic system
in animals resembles that of humans, we should be jus-
tified in presuming similarities in the functional role of
GABAergic intracortical inhibition maturation for syn-
aptic plasticity in animals and humans as well. Recent
data from rodents showed a developmental shift in the
effectiveness of an LTP-inducing protocol during corti-
cal maturation. In that study, the efficiency of synaptic
plasticity is in inverse correlation to the developing
age. This effect could be eradicated by blocking GAB-
Aergic inhibition . Taking their data into account,
our results support the idea of a synaptic-plasticity mat-
uration process, mediated by GABAergic intracortical
inhibition in humans.
In contrast to SICI, intracortical facilitation is a func-
tion of the strength of excitatory neuronal circuits med-
iated by glutamatergic synapses [24,25]. As with to the
GABAergic system, animal studies support the concept
of an maturation process of the glutamatergic system.
The more excitation input the glutamatergic circuits
receive after birth, the more they begin to replace GABA
as crucial excitatory neurotransmitters . Our results
depicted a strong ICF in children for both ISI (10 ms
and 20 ms). This presupposes preexisting glutamatergic
circuits mediated by inhibition-modulated synaptic plas-
ticity in that age group.
Our results provide evidence that the inhibitory
GABAergic system undergoes a maturation process.
Because the GABAergic system is believed to be a key
regulator of synaptic plasticity, our findings seem to
indicate an enhanced plasticity capacity in the first dec-
ade of primary motor cortex maturation, which would
facilitate motor learning during that period. Additional
studies are necessary to determine whether motor learn-
ing is the only aspect possibly influenced by this matura-
tion process of inhibition, or if there are other potential
effects, for example on the recovery from brain insults in
juvenile brains. This may have an impact on motor
learning and recovery after brain injury which has to
be assessed in further studies.
This paper was presented at the 3rd German-Japa-
nese Symposium of Pediatric Neurology on September
2008, Munich, Germany.
 Keller A. Intrinsic connections between representation zones in
the cat motor cortex. Neuroreport 1993;4:515–8.
 Aroniadou VA, Keller A. The patterns and synaptic properties of
horizontal intracortical connections in the rat motor cortex. J
 Hess G, Jacobs KM, Donoghue JP. N-methyl-D-aspartate recep-
tor mediated component of field potentials evoked in horizontal
pathways of rat motor cortex. Neuroscience 1994;61:225–35.
 Jacobs KM, Donoghue JP. Reshaping the cortical motor map by
 Keller A. Intrinsic synaptic organization of the motor cortex.
Cereb Cortex 1993;3:430–41.
 Swanwick CC, Murthy NR, Mtchedlishvili Z, Sieghart W, Kapur
J. Development of gamma-aminobutyric acidergic synapses in
cultured hippocampal neurons.
 Jensen K, Jensen MS, Bonefeld BE, Lambert JD. Developmental
increase in asynchronous GABA release in cultured hippocampal
neurons. Neuroscience 2000;101(3):581–8.
 Klueva J, Meis S, deLima AD, Voigt T, Munsch T. Develop-
mental downregulation of GABAergic drive parallels formation
of functional synapses in cultured mouse neocortical networks.
Dev Neurobiol 2008;68(7):934–49.
 Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD,
Ferbert A, et al. Corticocortical inhibition in human motor
cortex. J Physiol (Lond) 1993;471:501–19.
 Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J.
Differential effects on motorcortical inhibition induced by block-
ade of GABA uptake in humans. J Physiol 1999;517(Pt 2):591–7.
 Ziemann U, Rothwell JC, Ridding MC. Interaction between
intracortical inhibition and facilitation in human motor cortex. J
Physiol (Lond) 1996;496(Pt 3):873–81.
J Comp Neurol
M. Walther et al./Brain & Development 31 (2009) 562–567
 Ziemann U, Lo ¨nnecker S, Paulus BJ, Steinhoff W. The effect of
lorazepam on the motor cortical excitability in man. Exp Brain
 ZiemannU. TMSand
 Mall V, Berweck S, Fietzek UM, Glocker FX, Oberhuber U,
Walther M, Schessl J, et al. Low level of intracortical inhibition in
children shown by transcranial magnetic stimulation. Neuropedi-
 Mu ¨ller K, Ebner B, Ho ¨mberg V. Maturation of fastest afferent
and efferent central and peripheral pathways: no evidence for a
constancyof central conduction
 Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G,
Cracco RQ, et al. Non-invasive electrical and magnetic stimula-
tion of the brain, spinal cord and roots: basic principles and
procedures for routine clinical application. Report of an IFCN
committee. Electroencephalogr clin Neurophysiol 1994;91:79–92.
 Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L,
Insola A, et al. Effects of voluntary contraction on descending
volleys evoked by transcranial stimulation in conscious humans. J
Physiol (Lond) 1998;508:625–34.
 Garvey MA, Ziemann U, Bartko JJ, Denckla MB, Barker CA,
Wassermann EM. Cortical correlates of neuromotor development
in healthy children. Clin Neurophysiol 2003;114:1662–70.
 Hanajima R, Furubayashi T, Iwata NK, Shiio Y, Okabe S,
Kanazawa I, et al. Further evidence to support different mech-
anisms underlying intracortical inhibition of the motor cortex.
Exp Brain Res 2003;151:427–34.
 Hess G, Aizenman CD, Donoghue JP. Conditions for the
induction of long-term potentiation in layer II/III horizontal
connectionsofthe rat motor
 Ben-Ari Y, Tseeb V, Raggozzino D, Khazipov R, Gaiarsa JL. c-
Aminobutyric acid (GABA): a fast excitatory transmitter which
may regulate the development of hippocampal neurones in early
postnatal life. Prog Brain Res 1994;102:261–73.
 Brooks-Kayal AR, Pritchett DB. Developmental changes in
human c-aminobutyric acidA receptor subunit composition.
Ann Neurol 1993;34:687–93.
 Meredith RM, Floyer-Lea AM, Paulsen O. Maturation of long-
term potentiation induction rules in rodent hippocampus: role of
GABAergic inhibition. J Neurosci 2003;3(23(35)):11142–6.
 Ziemann U, Chen R, Cohen LG, Hallett M. Dextromethorphan
decreases the excitability of the human motor cortex. Neurology
 Schwenkreis P, Witscher K, Janssen F, Addo A, Dertwinkel R,
Zenz M, et al. Influence of the N-methyl-D-aspartate antagonist
memantine on human motor cortex excitability. Neurosci Lett
M. Walther et al./Brain & Development 31 (2009) 562–567