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Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Submitted 4 April 2005; accepted in final form 6 September 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Karni et al. 1995; Nudo et al. 1996) or by chronic changes in afferent input (Weiss et al. 2000). This is associated with local changes in the balance of neuronal excitation or inhibition. Repetitive practice of a specific movement or of a movement sequence is associated with an increase in the excitability of the sensorimotor cortex, which can be measured using transcranial magnetic stimulation (TMS) over periods as short as 10 min (Classen et al. 1998). The increase in excitability is greater during motor learning than with similar simple movements alone (Pascual-Leone et al. 1995). Several studies have provided evidence for local cortical functional reorganization within a similar short motor skill training period (Butefisch et al. 2000; Floyer-Lea and Matthews 2004; Muellbacher et al. 2001; Sanes et al. 1992).
Modulation of inhibitory activity may play a critical role in motor learning. Long-term cortical plasticity with axonal sprouting and development of new synaptic connections (Darian-Smith and Gilbert 1994) is associated with changes in the number or type of postsynaptic GABA receptors (Skangiel-Kramska et al. 1994). "Unmasking" of existing horizontal connections within the cortex allows rapid changes in sensory or motor representations (Huntley 1997). Unmasking of these connections can be produced experimentally by reducing local cortical inhibition through blockade of GABA receptors in animal models (Jacobs and Donoghue 1991). Reduction in GABA inhibition facilitates long-term potentiation (LTP)-like activity in motor cortex (Castro-Alamancos and Connors 1996; Castro-Alamancos et al. 1995). Pharmacological evidence suggesting that plasticity of human sensorimotor cortex is modulated by changes in local GABA concentration comes from observations such as the suppression of use-dependent functional adaptations of motor and somatosensory cortex by the GABAA receptor agonist lorazepam (Butefisch et al. 2000; Pleger et al. 2003).
Previous work has established the potential for rapid changes in brain GABA concentrations that appear to be functionally relevant. In a pioneering study, (Petroff et al. 1999) showed acute increases in cortical GABA with the anticonvulsant inhibitor of GABA breakdown by GABA transaminase, vigabatrin, with a mean rate of increase approaching 20% of the estimated rate of tricarboxylic acid cycle turnover. Similar increases later were seen in both GABA and its metabolites homocarnosine and pyrilidinone after treatment with topiramate (Petroff et al. 1999). Decreases in GABA concentration were found over the course of 30–40 min in the primary sensorimotor cortex after ischemic forearm nerve block, a context expected to be associated with sensory cortical plasticity in response to the altered afferent input (Levy et al. 2002).
Here we test directly the hypothesis that decreases in local GABA concentration accompany human neocortical functional reorganization with motor learning. We report measurements of GABA levels in the left primary sensorimotor cortex using magnetic resonance spectroscopy (MRS) during 30 min of training in a motor learning task demanding accurate tracking of a short (8 cycle), repeated sinusoidal pattern by varying isometric pressure generation with the (dominant) right hand (Floyer-Lea and Matthews 2004). We also tested for changes during performance of a similar task without a specific learning component and during rest. We show that motor task learning is associated with rapid, reversible decreases in GABA concentration in the region of the sensorimotor cortex contralateral to the hand moved.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Thirty-six healthy right-hand dominant subjects participated in this study (mean age, 25 yr; range, 20–31 yr). All gave informed consent according to a protocol approved by the local research ethics committee.
Motor learning task
The motor learning task has been described in detail previously (Floyer-Lea and Matthews 2004). In brief, two vertical bars were shown on a screen: the right (red) bar indicated the target force, and the left (blue) bar gave a continuous measure of the subject's response. Subjects were required to track the target force by maintaining the two bars at equal height at all times. Root mean square (RMS) tracking error was measured throughout the experiment. Thirteen subjects tracked a repeating 8-s sequence of force changes. Ten other subjects tracked a nonrepeating, pseudorandom sequence of force changes. A further seven subjects performed no task, but lay relaxed and in the scanner throughout the data collection period. All subjects performed the task (or remained at rest) for 30 min while GABA spectra were acquired continuously.
MRS
GABA-edited spectra (3T Varian Innova MRI) using a MEGA-PRESS sequence for simultaneous three-dimensional (3D) voxel localization, water suppression, and editing (Mescher et al. 1998) were acquired from a 2 x 2 x 2-cm3 voxel centered on the hand region of the left primary motor cortex (Yousry et al. 1997), identified on sagittal and axial T1-weighted axial scout scans. A selective double-banded 180° pulse was created from 20-ms Gaussian pulses. The frequency of the first band of this pulse was set to 4.7 ppm to suppress water. The second band was alternated between 1.9 ppm, the resonance frequency of C3 protons (strongly coupled to the observed C4 GABA protons and 3.0 ppm; condition A), and 7.5 ppm, which is symmetrically disposed about the water resonance to equalize off-resonance effects (condition B). The resonance at 1.9 ppm was inverted 180° during condition A but not during condition B. In condition A, the GABA C4 (triplet) resonance (at 3.0 ppm) therefore was fully refocused, whereas in condition B, this peak was not refocused, but phase modulated so that the outer triplet signals were inverted at echo time TE = 68 ms. The difference spectra from conditions A and B (at TE = 68 ms) revealed the edited GABA spectrum without the larger overlapping creatine resonance. One hundred ninety-two acquisition GABA spectra were acquired at rest at the start and end of the experiment, and 10 64-acquisition GABA spectra were acquired serially (and subsequently averaged in consecutive 192-acquisition blocks for purposes of analysis) throughout the task period.
To test for the regional specificity of GABA changes with motor learning, six subjects were studied while performing the learning task with alternating GABA acquisitions from 8 ml volume of interest (VOI) placed over the contra- (VOI 1) and ipsilateral (VOI 2) sensorimotor cortices. Before the experiment began, separate shim settings were optimized for each of the two voxels, and values were changed dynamically as acquisitions from the two voxels alternated between the baseline and the last acquisition block.
Analysis
The spectra were analyzed using the linear combination model (LCM) (Provencher 1993), adapted to incorporate the analysis with GABA editing as has been described previously (Wylezinska et al. 2003). Nonspecific effects limiting signal stability (e.g., head movement) can be associated with resonance frequency shifts. The N-acetyl aspartic acid (NAA) resonance frequency was measured in each of the serial spectra, and spectra in which the resonance shifted by >10 Hz (a threshold defined on the basis of preliminary metabolite phantom studies) were not used for measurements. GABA levels were determined from area under the model-fitted GABA resonance peak at 3.0 ppm (Fig. 1). To correct for the expected contribution from mobile brain macromolecules (MM; which include cytosolic proteins) (Behar et al. 1994) to this resonance, a parameterized MM spectrum was included in the basis set of modeled spectra. The parameterized components of the MM spectrum were derived from metabolite-nulled spectra [acquired using condition A of the MEGA-PRESS editing sequence (in which the Cr resonance normally is present) with inversion recovery using a preinversion pulse and recovery time (TI) adjusted to minimize the creatine peak (TI = 0.720s)], which were measured independently in six subjects.
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Statistics
Statistical analyses were performed using SPSS for Windows (version 12). Observations on changes in relative GABA concentration were tested with a general linear model, with repeated measures analysis applied with a significance threshold of P < 0.05. To test for changes in relative glutamate concentration during the learning task, a paired t-test was used to compare baseline and 30-min learning time-point values.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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We first measured GABA levels in the left primary sensorimotor cortex using MRS throughout 30 min of performance of a motor learning task demanding accurate tracking of a short (8 cycle), repeated sinusoidal pattern by varying isometric pressure generation with the (dominant) right hand, and matched tracking of a continuously pseudorandomly varying sinusoidal pattern or rest. There was a significant time-dependent effect on performance during the learning task (F = 13.046, P = 0.002) and a strong interaction between time and task (repeated sinusoid vs. pseudorandomly varying sinusoid; F = 7.844, P = 0.011). As expected, task performance for subjects repeating a fixed sinusoidal pattern (n = 13) improved over the 30-min training period: the tracking error decreased between the first and last 10-min task periods by >20% (paired t-test; t = 9.6; P < 0.001). In contrast, subjects (n = 10) tracking the nonrepetitively varying tracking target did not show a significant reduction of tracking error over a 30-min period (Fig. 1).
GABA concentration decreases in the contralateral primary sensorimotor cortex with motor learning
Spectra averaging signal over 3.2 min were generated from data acquired from a voxel localized to the hand area of the primary sensorimotor contralateral to the hand performing the learning before, during, and after the task period (Fig. 2). The baseline, resting GABA concentration estimate (1.49 ± 0.28 mM) was similar to those found in other MRS studies (McLean et al. 2002). Significant time-dependent effects were found for GABA concentration overall (F = 13.046, P = 0.002), and there was a strong interaction between time and task (repeated sinusoid vs. pseudorandomly varying sinusoid; F = 7.844, P = 0.011). The GABA concentration measured by MRS decreased (18%) during sequence learning (1.21 ± 0.32 mM; ANOVA, F = 10.8; P < 0.01; Fig. 3). However, the GABA concentration did not change with similar force generation tracking with unlearnable, nonrepetitive movements (F = 0.90; not significant) or with simply rest (F = 1.12; not significant) over the same period of time (Fig. 3). Additional data acquired 20 min after cessation of any short-term motor learning showed a partial recovery of the GABA concentration (1.33 ± 0.21 mM) by 
40% of the maximum decrease.
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Significant changes in the relative concentration of glutamate, the metabolic precursor to GABA, were not found (P = 0.9).
Lack of nonspecific changes in NAA with motor learning
To test the possibility that the decrease in the observed GABA concentration was caused by nonspecific changes in the sensitivity or noise of the acquired spectra, MRS resonance intensities of NAA were evaluated during the motor sequence learning period. In contrast to the decrease observed in the GABA signal during motor learning, the NAA signal intensity (which is greater and therefore potentially allows more sensitive assessment of relative changes) did not change significantly (F = 0.23; not significant; Fig. 4).
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A separate experiment was performed to test for the specificity of cortical GABA concentration changes from measurements in spectroscopic voxels of identical sizes placed over the left (contralateral) and right (ipsilateral) primary sensorimotor cortices. Interleaved measurements of relative GABA concentrations were conducted at baseline, before start of the learning paradigm, and after 25–35 min of training. There was a significant difference in the changes associated with learning for the two hemispheres (F = 7.24, P = 0.04; n = 6). Relative GABA concentration in the left primary sensorimotor cortex voxel decreases by a mean 27% (P < 0.05), whereas GABA in the homologous right hemisphere did not show significant change.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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). The observation that the GABA concentration in the sensorimotor cortex decreased while performing the repetitive tracking but not while tracking an unlearnable, nonrepetitive varying force sequence shows that short-term cortical GABA modulation was specific for learning and not a consequence simply of performance of tracking itself. The rapid partial recovery of GABA concentration after completion of the repetitive tracking task suggests that the GABA modulation may be associated primarily with encoding of the task (which during the period of task performance), rather than its longer-term consolidation (which occurs after training) (Shadmehr and Holcomb 1997). The changes were not found in the ipsilateral motor cortex voxel, suggesting at least some regional specificity to the effects. However, a striking feature is that substantial decreases (almost 20%) were observed using a relatively large voxel, implying that they involve a cortical region at least of similar extent to the tracking-associated activation changes observed by functional MRI (fMRI) in the primary sensorimotor cortex (Floyer-Lea and Matthews 2004; Karni et al. 1995).
The demonstration of a stable relative NAA concentration confirmed that changes were specific for GABA, ruling out trivial measurement confounds as a cause of apparent concentration decrease, such as head movement leading to a decrease in coupling between the head and radiofrequency coil. A decrease in GABA concentration could result from a decrease in GABA production or through an increase in GABA reuptake and catabolism. GABA is produced in the presynaptic terminals of GABAergic neurons from glutamic acid (Glu) by the action of glutamic acid decarboxylase (GAD). We did not find evidence for decreases in Glu concentrations during learning; a previous study showing reductions in cortical GABA concentrations in primary somatosensory cortex during ischemic nerve block also did not report corresponding reductions in Glu (Levy et al. 2002). Together, these findings suggest that any reduction in GABA production likely is related to a down-regulation of GAD rather than at an earlier stage in the GABA synthesis. GAD activity and GABA concentrations are modulated during a variety of physiological conditions (Garraghty et al. 1991; Grattan et al. 1996). Previous studies in both animals (Manor et al. 1996) and humans (Shen et al. 1999) have shown that there is active turnover of GABA. Estimates based on these studies suggest that the rate of GABA synthesis is sufficiently rapid for its inhibition alone to account for the rate of decrease in total GABA observed here.
A theoretical alternative to concentration changes for explaining a decrease in GABA signal independent of any change in glutamate or NAA is that selective relaxation time changes might make the GABA less visible to MRS (e.g., by shortening the spin-spin relaxation time and broadening of the resonance) during the learning period. The GABA signal includes contributions from different pools of GABA. GABA is stored in vesicles in the presynaptic terminal and present as free GABA in the synaptic cleft, as well as in the presynaptic neurons and glial cells after reuptake. Pools of GABA in which GABA is relatively immobilized, e.g., by association with macromolecules, could be less visible using our MRS sequence. Thus it also is possible that a mechanism such as a reduction in GABA release, causing a relative reduction of the proportion of GABA in the synaptic cleft and an increase in (MM rich) vesicular GABA, could therefore contribute to the decrease in the observed GABA signal. However, the magnitude of the changes makes this unlikely; such large relaxation time changes with short-term changes in functional state would be unprecedented as far as we are aware. We have direct evidence that nonspecific relaxation effects (e.g., from changes in local magnetic susceptibility), affecting all metabolites, also did not occur, because changes in line-width (reflecting spin-spin relaxation time changes) were not observed for either GABA or NAA (M. Wylezinska and P. M. Matthews, unpublished observations). The BOLD contrast effect associated with motor learning, which arises from a decrease in local relative deoxyhemoglobin concentration (increasing T2*), would be expected to be associated with a relative increase in neurotransmitter resonance intensity if any change was observed, because the magnitude and extent of an fMRI BOLD effect in the sensorimotor cortex decreases over time with this paradigm (Floyer-Lea and Matthews 2004).
Cortical GABA concentration was reduced during tracking of a learnable, repeated sequence, but no significant changes were seen during force tracking identical except for a nonrepetitive variation. The experimental design allowed subjects to be aware of the distinction between the tracking sequences, which led to different cognitive contexts for the two types of tracking contrasted. A limitation of the study is that the cognitive context for the tasks could be controlled only to a limited extent: the two tasks were not fully matched for difficulty or attentional demands. Nonetheless, the most striking distinction between behavior with the two sequences was that there was significant learning (improvement in tracking) with the repeated sequence. Neurons within the basal forebrain are particularly active during learning (Wilson and Rolls 1990), and lesions of the basal forebrain have been shown to abolish the cortical plasticity associated with motor skill learning (Conner et al. 2003). The basal forebrain sends cholinergic and GABAergic projections to wide regions of the cortex including the primary sensorimotor cortex (Semba 2000). The GABAergic basal forebrain neurons preferentially synapse with cortical GABAergic interneurons (Freund and Meskenaite 1992), suggesting that activation of the basal forebrain during directed learning could reduce GABA levels in the cortex through inhibition of the cortical GABAergic interneurons. A mechanism involving such a relatively diffuse projection system could explain the apparently widespread nature (inferred from the magnitude of changes seen in the large voxel used) of the GABA concentration decreases seen.
Decreases in cortical GABA concentration would be expected to lower relative inhibition in the sensorimotor cortex during motor sequence learning. A recent rodent study using pharmacological modulation of cortical GABA showed a strong negative correlation between the forepaw sensory stimulation-evoked BOLD fMRI response and GABA concentration measured by MRS, consistent with a reduction of inhibition with a decrease in GABA concentration (Chen et al. 2005). LTP-type changes in synaptic strength have been shown to occur in the rodent primary motor cortex only when GABAergic inhibition is lifted (Castro-Alamancos et al. 1995). "Unmasking" latent horizontal connections by disinhibition allows new muscle synergies to be generated rapidly (Schneider et al. 2002). Short-term modulation of cortical inhibition may therefore be an important facilitatory mechanism for the neocortical LTP-like activity critical to motor cortex plasticity with motor skill learning, extending the roles suggested previously in establishing new hippocampal circuits or columnar architecture in the developing visual cortex (Engel et al. 2001; Hensch and Stryker 2004).
Our studies have focused on a single neurotransmitter system and do not address wider issues of changes that may occur with use or adaptive plasticity. Here we are proposing GABA as one element (although potentially an important, facilitatory one) contributing to local cortical changes during fast motor learning. Future work needs to better characterize primary effector neurotransmitter changes, to relate the GABA concentration changes observed here to mechanisms of consolidation and long-term, slow learning, to modulation by other neurotransmitter systems, and to any shifts in use-dependent patterns of energy metabolism (e.g., with altered neuronal–glial interactions).
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GRANTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. M. Matthews, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK (E-mail: paul{at}fmrib.ox.ac.uk)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Butefisch CM, Davis BC, Wise SP, Sawaki L, Kopylev L, Classen J, and Cohen LG. Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci USA 97: 3661–3665, 2000.
Castro-Alamancos MA and Connors BW. Short-term synaptic enhancement and long-term potentiation in neocortex. Proc Natl Acad Sci USA 93: 1335–1339, 1996.
Castro-Alamancos MA, Donoghue JP, and Connors BW. Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex. J Neurosci 15: 5324–5333, 1995.[Abstract]
Chen Z, Silva AC, Yang J, and Shen J. Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminase. J Neurosci Res 79: 383–391, 2005.[CrossRef][ISI][Medline]
Classen J, Liepert J, Wise SP, Hallett M, and Cohen LG. Rapid plasticity of human cortical movement representation induced by practice. J Neurophysiol 79: 1117–1123, 1998.
Conner JM, Culberson A, Packowski C, Chiba AA, and Tuszynski MH. Lesions of the basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron 38: 819–829, 2003.[CrossRef][ISI][Medline]
Darian-Smith C and Gilbert CD. Axonal sprouting accompanies functional reorganization in adult cat striate cortex. Nature 368: 737–740, 1994.[CrossRef][Medline]
Engel D, Pahner I, Schulze K, Frahm C, Jarry H, Ahnert-Hilger G, and Draguhn A. Plasticity of rat central inhibitory synapses through GABA metabolism. J Physiol 535: 473–482, 2001.
Floyer-Lea A and Matthews PM. Changing brain networks for visuomotor control with increased movement automaticity. J Neurophysiol 92: 2405–2412, 2004.
Freund TF and Meskenaite V. Gamma-aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex. Proc Natl Acad Sci USA 89: 738–742, 1992.
Garraghty PE, LaChica EA, and Kaas JH. Injury-induced reorganization of somatosensory cortex is accompanied by reductions in GABA staining. Somatosens Mot Res 8: 347–354, 1991.[ISI][Medline]
Grattan DR, Rocca MS, Strauss KI, Sagrillo CA, Selmanoff M, and McCarthy MM. GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase (GAD65 and GAD67) are reduced in the diagonal band of Broca during the afternoon of proestrus. Brain Res 733: 46–55, 1996.[CrossRef][ISI][Medline]
Hensch TK and Stryker MP. Columnar architecture sculpted by GABA circuits in developing cat visual cortex. Science 303: 1678–1681, 2004.
Huntley GW. Correlation between patterns of horizontal connectivity and the extend of short-term representational plasticity in rat motor cortex. Cereb Cortex 7: 143–156, 1997.
Jacobs KM and Donoghue JP. Reshaping the cortical motor map by unmasking latent intracortical connections. Science 251: 944–947, 1991.
Karni A, Meyer G, Jezzard P, Adams MM, Turner R, and Ungerleider LG. Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 377: 155–158, 1995.[CrossRef][Medline]
Levy LM, Ziemann U, Chen R, and Cohen LG. Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation. Ann Neurol 52: 755–761, 2002.[CrossRef][ISI][Medline]
Manor D, Rothman DL, Mason GF, Hyder F, Petroff OA, and Behar KL. The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA). Neurochem Res 21: 1031–1041, 1996.[ISI][Medline]
McLean MA, Busza AL, Wald LL, Simister RJ, Barker GJ, and Williams SR. In vivo GABA+ measurement at 1.5T using a PRESS-localized double quantum filter. Magn Reson Med 48: 233–241, 2002.[CrossRef][ISI][Medline]
Mescher M, Merkle H, Kirsch J, Garwood M, and Gruetter R. Simultaneous in vivo spectral editing and water suppression. NMR Biomed 11: 266–272, 1998.[CrossRef][ISI][Medline]
Muellbacher W, Ziemann U, Boroojerdi B, Cohen L, and Hallett M. Role of the human motor cortex in rapid motor learning. Exp Brain Res 136: 431–438, 2001.[CrossRef][ISI][Medline]
Nudo RJ, Milliken GW, Jenkins WM, and Merzenich MM. Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J Neurosci 16: 785–807, 1996.
Pascual-Leone A, Nguyet D, Cohen LG, Brasil-Neto JP, Cammarota A, and Hallett M. Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J Neurophysiol 74: 1037–1045, 1995.
Petroff OA, Hyder F, Mattson RH, and Rothman DL. Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy. Neurology 52: 473–478, 1999.
Petroff OA and Rothman DL. Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin. Mol Neurobiol 16: 97–121, 1998.[ISI][Medline]
Pleger B, Schwenkreis P, Dinse HR, Ragert P, Hoffken O, Malin JP, and Tegenthoff M. Pharmacological suppression of plastic changes in human primary somatosensory cortex after motor learning. Exp Brain Res 148: 525–532, 2003.[ISI][Medline]
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30: 672–679, 1993.[ISI][Medline]
Sanes JN, Wang J, and Donoghue JP. Immediate and delayed changes of rat motor cortical output representation with new forelimb configurations. Cereb Cortex 2: 141–152, 1992.
Schneider C, Devanne H, Lavoie BA, and Capaday C. Neural mechanisms involved in the functional linking of motor cortical points. Exp Brain Res 146: 86–94, 2002.[CrossRef][ISI][Medline]
Semba K. Multiple output pathways of the basal forebrain: organization, chemical heterogeneity, and roles in vigilance. Behav Brain Res 115: 117–141, 2000.[CrossRef][ISI][Medline]
Shadmehr R and Holcomb HH. Neural correlates of motor memory consolidation. Science 277: 821–825, 1997.
Sheikh SN, Martin SB, and Martin DL. Regional distribution and relative amounts of glutamate decarboxylase isoforms in rat and mouse brain. Neurochem Int 35: 73–80, 1999.[CrossRef][ISI][Medline]
Shen J, Petersen KF, Behar KL, Brown P, Nixon TW, Mason GF, Petroff OA, Shulman GI, Shulman RG, and Rothman DL. Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. Proc Natl Acad Sci USA 96: 8235–8240, 1999.
Skangiel-Kramska J, Glazewski S, Jablonska B, Siucinska E, and Kossut M. Reduction of GABAA receptor binding of [3H]muscimol in the barrel field of mice after peripheral denervation: transient and long-lasting effects. Exp Brain Res 100: 39–46, 1994.[ISI][Medline]
Weiss T, Miltner WH, Huonker R, Friedel R, Schmidt I, and Taub E. Rapid functional plasticity of the somatosensory cortex after finger amputation. Exp Brain Res 134: 199–203, 2000.[CrossRef][ISI][Medline]
Wilson FA and Rolls ET. Learning and memory is reflected in the responses of reinforcement-related neurons in the primate basal forebrain. J Neurosci 10: 1254–1267, 1990.[Abstract]
Wylezinska M, Matthews PM, and Jezzard P. Quantitation of GABA in human brain using MEGA-PRESS editing and LCM analysis. Proc Inter Soc Mag Res Med 11: 1997, 2003.
Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, and Winkler P. Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 120: 141–157, 1997.
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, P < 0.01), indicating that learning was taking place. Subjects did not show improvement during the random tracking task (
). Error bars represent SE.
). Bar indicates period during which subjects performed the sequence or random tracking tasks. Variance is shown as SE.