Baclofen, a GABABreceptor agonist, impairs motor learning in healthy people and changes inhibitory dynamics in motor areas

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Levenstein , View ORCID Profile Liliana Capitao , View ORCID Profile Charlotte J Stagg doi: https://doi.org/10.1101/2025.03.27.645701 Ioana-Florentina Grigoras 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 2 MRC Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 3 Oxford Health NHS Foundation Trust , Oxford, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ioana-Florentina Grigoras For correspondence: ioana.grigoras{at}ndcn.ox.ac.uk Elias Geist 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elias Geist Ainslie Johnstone 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 2 MRC Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford , UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site William T Clarke 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 3 Oxford Health NHS Foundation Trust , Oxford, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for William T Clarke Uzay Emir 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 4 Department of Radiology, The University of North Carolina at Chapel Hill 5 Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Uzay Emir Caroline Nettekoven 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 2 MRC Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 6 Western Institute for Neuroscience, Western University , London, ON, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Caroline Nettekoven Jacob M. Levenstein 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 7 Thompson Institute, University of the Sunshine Coast , Birtinya, QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jacob M. Levenstein Liliana Capitao 8 Psychology Researcher Centre (CIPsi), School of Psychology, University of Minho , Campus de Gualtar, 4710-057 Braga, Portugal Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Liliana Capitao Charlotte J Stagg 1 Wellcome Centre for Integrative Neuroimaging , FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 2 MRC Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford , UK 3 Oxford Health NHS Foundation Trust , Oxford, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Charlotte J Stagg Abstract Full Text Info/History Metrics Preview PDF Abstract Inhibition mediated by γ-aminobutyric acid (GABA) is implicated in motor plasticity and learning, with [GABA] in the motor cortex decreasing during motor learning. However, the causal relationship between [GABA] and learning has yet to be determined. Here, we conducted a within-subject, double-blind, placebo-controlled, crossover study to investigate the effect of increased GABAergic inhibition via GABA B -receptor agonist baclofen on motor learning and Magnetic Resonance Spectroscopic Imaging (MRSI) metrics. Increasing GABA-mediated inhibition with baclofen did not change response times, but significantly impaired motor sequence learning. In parallel, we demonstrated a blunting of the expected decrease in [GABA] during motor learning. These results highlight a causal role for GABAergic inhibition in motor learning and may have clinical implications: baclofen is commonly used to treat post brain-injury spasticity, but may impair motor learning during rehabilitation. Introduction Motor learning is essential in everyday life: from learning how to reach and grab objects to learning complex movements, our daily activities rely on previously acquired motor skills. Increasing evidence indicates that inhibition mediated by γ-aminobutyric acid (GABA), the most common inhibitory neurotransmitter, plays a key role in motor plasticity and learning 1 , 2 . Early mechanistic studies in rodents showed that GABA antagonists in the primary motor cortex (M1) induced long-term potentiation (LTP)-like plasticity 3 , while TMS studies in humans indicate that administration of GABA agonists leads to the suppression of LTP-like processes in M1 4 . Further, the concentration of GABA ([GABA]) in M1 decreases during motor learning 5 and decreases in M1 [GABA] induced by non-invasive brain stimulation correlate with better motor learning 6 . However, it is not clear whether this observed decrease in GABA is necessary for motor learning. Baclofen is a specific GABA B -receptor agonist commonly used in clinical practice as a muscle relaxant 7 . When administered orally, it crosses the blood-brain barrier and reaches a peak plasma concentration in approximately 1-2 hours, with a half-life of 3-6 hours 8 . Its GABA B -receptor specificity makes it a good pharmacological intervention for motor learning studies, as GABA B receptors show high expression in areas related to motor control, such as the frontal cortex, thalamic nuclei and cerebellum 9 . Indeed, impairments in visuomotor adaptation after a single dose of 10-20mg baclofen have previously been reported 10 , 11 . However, the neural mechanisms underlying this behavioural change remain unclear. Eighteen young healthy participants participated in a within-subject, double-blind, placebo-controlled pharmaco-MRI study. Each participant had an MRI brain scan 45 minutes after administration of a single dose of 20mg of baclofen or placebo, during which Magnetic Resonance Spectroscopic Imaging (MRSI) data was acquired from the primary motor cortex (M1) and premotor cortex (PMC) before and after learning of a serial reaction time task (SRTT). We hypothesised that baclofen would reduce motor learning compared with placebo, and that behavioural decrement would be accompanied by a blunting of the expected learning-related [GABA] decrease in the motor cortices contralateral to the hand performing the task. Results Baclofen significantly impairs motor sequence learning, but not motor performance To quantify motor learning, participants performed a serial reaction time task (SRTT) with their right hand whilst in the MRI. Response times (RTs) in the first block (R1), where stimuli were presented in a non-predictable order, were not significantly different between baclofen and placebo sessions (paired t-test: t(13) = 0.161, p = 0.875, Figure 1A ), suggesting that baclofen did not modulate motor performance per se . We therefore normalised the median RT for each sequence block (S1 to S11) to the median RT in block R1 to directly compare learning between the two sessions. Download figure Open in new tab Fig. 1. The effect of baclofen on the serial reaction time task (SRTT) (A) No significant differences between baclofen and placebo sessions for response times on the first random block (B) Motor sequence learning was significantly impaired after baclofen administration compared to placebo (R1 and R2 – random blocks 1 and 2; S1 to S11 – sequence blocks 1 to 11) Consistent with learning, participants significantly reduced their RTs during the task blocks where visual stimuli were presented in a learnable sequence [Repeated-Measures ANOVA with within-subject factors of Drug (baclofen, placebo) and Block (S1 to S11), Main Effect of Block (F(3.179, 41.330) = 9.261, p < 0.001)]. As previously reported, baclofen significantly reduced learning compared with placebo [Main Effect of Drug (F(1,13) = 6.070, p = 0.029), Figure 1B ), but there was no significant Block by Drug interaction (Block x Drug Interaction (F(4.568, 59.380) = 1.089, p = 0.373)). Baclofen blunts learning-related [GABA] decrease during motor learning To investigate the neurochemical effects of Baclofen, we quantified mean [GABA] in M1 and PMC before and after participants performed the SRTT ( Figure 2A-B ). The predicted [GABA] decrease during motor learning was significantly different between the baclofen and placebo sessions, such that baclofen led to a blunting of the expected learning-related decrease in GABA [Repeated-measured ANOVA with factors of Drug (baclofen, placebo), Time (pre-task, post-task) and Region of Interest (ROI; left M1, left PMC), Drug x Time interaction (F(1, 13) = 5.908; p = 0.030; Figure 2C )]. Download figure Open in new tab Fig. 2. (A-B) Examples of GABA/tCr concentrations in voxels in the left primary motor cortex (A) and left premotor cortex (B). The anatomical mask for each brain region is shown in blue. (C) [GABA] before and after motor learning task. Baclofen significantly affected the pattern of [GABA] change during motor learning across both ROIs (D-E) Pre-task [GABA] did not significantly change in the left primary motor cortex (D) and left premotor cortex (E) after baclofen administration. (F) [Glu] before and after motor learning task. Baclofen did not significantly affect the pattern of [Glu] change during motor learning, but there was a significant increase in [Glu] between the pre- and post-task timepoints. To determine whether this effect of baclofen on learning-related [GABA] was driven by differences in pre-task [GABA] between baclofen and placebo in left M1 and premotor cortex, we compared [GABA] prior to learning. There was no significant difference in [GABA] between the baclofen and placebo sessions in either region prior to learning (M1: t(14) = 1.915, p = 0.076; PMC: t(14) = 0.946, p = 0.360, Figure 2D-E ). ). To determine the anatomical specificity of this baclofen-induced blunting of learning-related [GABA] decrease, we performed identical analyses for the right, ipsilateral, M1 and PMC (Repeated-measured ANOVA with factors of Drug (baclofen, placebo), Time (pre-task, post-task) and ROI (right M1, right PMC)). Unlike the left, contralateral, cortical areas, there was no significant Drug x Time interaction for the homologous right hemisphere regions (F(1, 13) = 0.026; p = 0.874). To determine the neurochemical specificity of our [GABA] results, we performed identical analyses for glutamate in the left M1 and PMC ( Figure 2F ). Unlike for [GABA], there was no significant Drug x Time interaction for glutamate (F(1,13) = 0.579; p = 0.461). There was a significant main effect of Time (F(0.840, 10.920) = 8.174; p = 0.019), suggesting, as might be expected, that glutamate increased in both brain regions after learning, but this increase did not differ between drug conditions. MRSI-derived [GABA] measurements were significantly correlated with behavioural metrics Finally, we investigated whether [GABA] related to behavioural metrics. Mean RT during the random blocks of the SRTT was significantly correlated with pre-task [GABA] in the left PMC in the placebo session, such that greater left PMC [GABA] correlated with slower RTs (r(13) = 0.539, p = 0.038; figure 3A ). This relationship was not demonstrated in the baclofen session (r(13) = -0.230, p = 0.409; r-to-z (placebo v baclofen) z = 2.050, p = 0.040). There were no significant correlations between pre-task M1 [GABA] and RTs in either session (placebo: r(13) = 0.274, p = 0.324; baclofen: r(13) = -0.089, p = 0.752, Figure 3B ). This relationship was neurotransmitter-specific: we found no significant correlations between RTs and glutamate levels in either the left M1 (placebo: r(13) = 0.253, p = 0.363; baclofen: r(13) = -0.312, p = 0.258) or the left PMC (placebo: r(13) = 0.019, p = 0.946; baclofen: r(13) = -0.188, p = 0.502). Download figure Open in new tab Fig. 3. Relationship between pre-task [GABA] and response times during random button presses. (A) Significant correlation between pre-task [GABA] in the left premotor cortex (A) and response times during the placebo session. (B) No significant correlation between pre-task [GABA] in the left M1 and response times (C-D) Relationship between Δ[GABA] and a learning metric calculated based on performance during the SRTT We then went on to investigate the relationships between neurotransmitters and motor learning. There was a significant correlation between the learning-related change in [GABA] in left PMC and the learning-related decrease in RT in the baclofen session, but not in the placebo session, such that greater decreases in PMC [GABA] correlated with greater learning (baclofen: r(12) = 0.576, p = 0.031; placebo: r(12) = -0.245, p = 0.399; r-to-z (baclofen v placebo) z = 2.140, two-tailed p = 0.032, Figure 3C ). There was no such relationship between learning and change in left M1 [GABA] (baclofen: r(12) = -0.348, p = 0.223; placebo: r(12) = 0.288, p = 0.318, Figure 3D ). There was a significant difference between the [GABA] change and behavioural change correlations in the left PMC and M1 on the baclofen sessions (r-to-z z = 2.390, two-tailed p = 0.017). When looking at glutamate, we found a significant correlation between learning-related change in [Glu] in the left M1 and the learning-related decrease in RT in the baclofen session, but not in the placebo session. Specifically, smaller increases in M1 [Glu] correlated with greater learning (baclofen: r(12) = 0.571, p = 0.033; placebo: r(12) = -0.076, p = 0.797). There was no such relationship between learning and change in PMC [Glu] (baclofen: r(12) = -0.047, p = 0.873; placebo: r(12) = 0.285, p = 0.323). Baclofen increased contentedness, but did not significantly alter working memory To ensure that the demonstrated baclofen-induced decrease in motor learning was not driven by changes in mood, working memory or attention, participants performed a series of tests. The 16 Bond-Lader Visual Analogue scales (BLVAS) were loaded onto three mood components: alertness, contentedness, and calmness. Each mood component was quantified before (baseline), and 1h and 2.5 hours after drug administration. There was a significant main effect of drug on contentedness, but not on alertness or calmness (Main Effect of Drug; Contentedness: F(1, 14) = 5.142, p = 0.038; Alertness: F(1, 14) = 4.164, p = 0.061; Calmness: F(1, 14) = 0.653, p = 0.433), such that participants felt more content in the baclofen than placebo session. The possible effects of baclofen on cognition were assessed via the CANTAB battery. There was no significant drug-related difference in task performance on the spatial working memory task (Main effect of Drug (F(1, 17) = 0.335, p = 0.570)), the pattern recognition memory task (Main effect of Drug (Accuracy: F(1, 17) = 1.294, p = 0.271; RT: F(1, 17) = 1.792, p = 0.198)), Rapid visual processing (paired t-test RT: t(15) = 1.759, p = 0.099) or Spatial Span (Main effect of Drug (Length: F(1, 17) = 2.227, p = 0.154; Errors: (F(1, 17) = 0.221, p = 0.644)). Discussion Understanding the physiological changes underpinning motor learning is essential if we are to develop novel approaches to enhance plasticity, and hence optimise behaviour. Here, we used the GABA B receptor-specific agonist baclofen to address the hypothesis that decreasing GABA is necessary for optimal motor learning. We found that increasing GABA-mediated inhibition via baclofen led to significantly impaired learning, in the absence of changes in response times generally. Baclofen blunted the expected learning-related decrease in [GABA], and the decrease in PMC [GABA] during learning correlated with decreased RTs in the baclofen session, but not during placebo. There were no drug-induced changes in working memory that would explain these drug-related effects. Baclofen impairs motor sequence learning Since [GABA] decreases in M1 are associated with motor learning 5 , 6 , 12 and baclofen is known to suppress neuroplastic processes in the motor cortex 4 , we tested whether increasing GABAergic inhibition using a pharmacological intervention would impair motor learning in healthy volunteers. Baclofen led to a significant decrease in motor learning, supporting the hypothesis that decreases in [GABA] are necessary for motor learning to occur. To the best of our knowledge, this is the first report of impairments in motor sequence learning following baclofen administration: our previous paper 11 , using 10mg of baclofen demonstrated a significant baclofen-induced decrement in visuomotor adaptation, but only a trend towards impaired sequence learning. Differences in drug dose and task design might account for this discrepancy, in particular, our previous paper used 10mg baclofen rather than the 20mg used here. Baclofen modulates learning-related changes, but not baseline, [GABA] Intuitively, we might have expected that resting MRS(I)-derived metrics of GABA might be modulated by baclofen. However, previous studies of GABA-modulating drugs have not shown consistent modulation of MRS-quantified GABA in cortical areas in humans, most reporting null results 13 – 18 . This is likely explained by MRS metrics not directly measuring the synaptic activity of GABA receptors 19 – 22 . Instead, MRSI provides measurements of the total amount of MR-visible GABA within each of the 96 MRSI voxels (375 mm 3 ), acquired over minutes. This MRSI-derived GABA measurement has been hypothesised to reflect extrasynaptic, tonic inhibition 19 , although this is yet to be confirmed. Baclofen has non-subtype-specificity for any GABA B receptor subtype, activating both pre- and post-synaptic GABA B receptors 23 . Presynaptically, baclofen binds to the GABA B receptor and decreases the quantity of neurotransmitter released into the synaptic cleft. Postsynaptically, baclofen binds to the GABA B receptor and leads to hyperpolarisation of the cell, but its binding to the receptors instead of the endogenous neurotransmitter could mean that the endogenous GABA remains longer in the synaptic cleft until feedback mechanisms increase its reuptake into glial cells and neurons. Therefore, depending on the proportion of pre-and post-synaptic receptors bound by baclofen, total [GABA] might be expected to either decrease or increase 24 – 27 . Only one study has so far looked at the effect of baclofen on MRS- derived metrics and reported no significant changes in the right parietal lobe [GABA] between baclofen and placebo 17 . However, this study used a between-subject design in individuals with alcohol-dependence who received a 2-week treatment with baclofen at a high dose (30-75mg), which makes it difficult to predict what the effect of a single-dose of baclofen would be in a healthy population. Baclofen-induced changes in PMC [GABA] significantly correlate with changes in motor sequence learning Baclofen blunts the physiological M1 [GABA] decrease during motor learning, which was associated with impairments in performance on a motor sequence learning task. We found a significant relationship between learning-related changes in the premotor cortex [GABA] and learning-related changes during SRTT during the baclofen session, but not placebo such that, better learning was associated with a larger decrease in the premotor cortex [GABA] during motor learning. Since the premotor cortex is involved in motor planning and movement preparation, it is not surprising that it has an important contribution towards motor learning 28 , being linked to associative learning (sensory cues become associated with appropriate motor commands) in both healthy individuals and patients 29 – 31 , as well as implicit motor sequence learning and imitation learning 32 , 33 . Moreover, reorganisation of the premotor cortex was associated with improvements in motor function after stroke 34 . Higher task fMRI-derived activation of the dorsal PMC during motor learning has also been associated with higher cognitive demands of the task 35 and better behavioural outcomes on a motor learning task 36 . Therefore, it is possible that during the baclofen session, when GABAergic inhibition is higher in M1, the premotor cortex contributes more to the process of motor learning than in the placebo session, but that hypothesis remains to be tested. In the placebo sessions, there were no significant correlations between learning-related [GABA] changes in either M1 or PMC [GABA] and learning-related behavioural changes, which is consistent with previous findings 37 . One possible explanation is that [GABA] dynamics and behavioural improvements do not follow a linear relationship. Alternatively, by collecting the MRSI data in the 10 minutes following the motor sequence learning task, [GABA] levels might be returning to baseline and thus, our [GABA] metrics might be affected by homeostatic processes not related to motor learning. Relationship between response times and [GABA] in left PMC in placebo sessions We found a significant correlation between RTs and [GABA] in the left premotor cortex during the placebo sessions, but not after baclofen administration. The premotor cortex is known to be involved in motor planning and sensorimotor integration and has strong connections to the ipsilateral M1 28 , 38 – 41 . fMRI studies investigating the brain areas active during simple response time tasks show a cortical network linked to the identification of the visual stimuli and movement execution, which includes the bilateral premotor cortices 42 . In non-human primates, micro-stimulation of the premotor cortex, but not motor cortex, during the preparatory activity, led to slower response time in monkeys, likely because the cortical area needs time to restore preparatory activity 43 . In humans, delivering single TMS pulses to the premotor cortex at less than 25ms after the visual stimulus leads to faster RTs, suggesting that preconditioning the premotor cortex decreases the time needed for motor execution 44 . Our results are in line with these studies, showing that lower inhibition in the premotor cortex is associated with faster response times; individual variability in [GABA] may be the neural substrate for individual variability in response times. Previously, our group has demonstrated a correlation between baseline RTs and M1 [GABA] 19 , which was not demonstrated here. However, previous studies have used a much larger voxel volume (i.e., 8 cm 3 as opposed to the 0.375 cm 3 used here). Therefore, although previous studies used an MRS voxel focused on M1, that voxel included regions of the premotor cortex, which might have been driving the correlations previously observed. [Glu] in motor areas increases after motor learning Finally, we found a significant increase in glutamate after the motor learning task across the two study sessions, which likely reflects the increased activity in the motor areas during motor task performance. The possible mechanisms underlying this process have been previously discussed in detail, although definitive evidence confirming these ideas is still lacking 45 . Generally, intermediate to long echo times (>20ms), as used here (TE=32ms), have been proposed as more sensitive to compartmental shift 46 , 47 than shorter echo times, so the increase in glutamate after the task could potentially be a result of glutamate moving from the vesicular compartment, largely invisible to MRS, to the extracellular and cytosolic compartment, visible to MRS. Other studies have also reported increases in glutamate after motor activation (finger tapping, hand clenching) and motor learning, using sequences with TE ranging from 12ms to 80ms 48 – 50 and a meta-analysis investigating changes in glutamate after motor and visual task performance is consistent with our findings 46 . Thus, the changes we found here might not be specific to motor learning, but motor activation in general. We also found a significant relationship between learning-related changes in the left M1 glutamate and learning-related changes in behavioural metrics in the baclofen session, such that greater increases in glutamate are associated with lower learning. It is possible that, with increased inhibition via baclofen, the proposed “excitation:inhibition balance” changes and higher increases in glutamate become maladaptive. Some previous studies report no significant correlation between glutamate changes and learning improvements 50 , 51 , which is consistent with our results in the placebo session. However, there is also a report of resting [Glu] levels predicting learning, although there are no reports of correlations between change in [Glu] and learning improvements 52 . Conclusion We conducted a within-subject, double-blind, placebo-controlled study to investigate how increasing GABAergic inhibition via the pharmacological agent baclofen affected motor learning and brain chemistry. We found that baclofen significantly impaired performance on a motor sequence learning task, but did not impair simple response times. These behavioural impairments were associated with significant learning-related changes in [GABA] in the left M1 and left premotor cortex. In previous studies in older healthy individuals, motor learning was not associated with decreases in [GABA], but learning-related changes in GABA significantly correlated with motor learning improvements, age, and baseline GABA 53 . Stroke survivors with a previous history of receiving GABA agonists had a significantly worse motor function on admission to a rehabilitation program, though the administration of GABA agonists had no significant effect on subsequent motor rehabilitation outcomes 54 . Taken together, these results may inform a potential change in clinical guidance towards baclofen use: if baclofen administration impairs motor learning in healthy people, further studies should investigate whether it also impairs motor rehabilitation in patients who receive it as a muscle relaxant. Methods Participants We recruited 18 healthy participants who provided their written informed consent to all experimental procedures, as approved by the Central University Research Ethics Committee (Ethics reference: R55534/RE004). All participants met the inclusion criteria: aged 18-35 years (mean age +/- SEM 24.3 +/- 4.1 years, 8 males), right-handed as per the Edinburgh Inventory 55 , no self-reported history of any psychiatric or neurological illness, not taking any medication, not musically trained (not more than Grade 6 on the Associated Board of the Royal Schools of Music) and 3T MRI safety criteria. Experimental design This was a within-subject, double-blind, placebo-controlled study. Participants attended two sessions at least one week apart, starting at the same time of day, with the order of the sessions randomised across the group ( Figure 4A ). Download figure Open in new tab Fig. 4. (A) Timeline of each testing session. (B) a. Map of GABA/tCr in one of the sessions. Voxels that pass quality checks are shown in red and excluded ones in blue. b. Group level map of the spatial coverage of the MRSI volume on interest across all sessions (15 participants x 2 session); (C) Representative spectrum On arrival, participants completed a Bond-Lader Visual Analogue Scale (BLVAS) mood questionnaire and were familiarised with the serial reaction time task (SRTT). Participants were then given the drug (baclofen or placebo) and had a 45-minute break. Participants then filled in a second BLVAS questionnaire before having an MRI scan. We first acquired a T1- weighted structural image before pre-task MRSI (sequence details below), which started approximately 75 minutes after drug administration, to allow for baclofen to be absorbed and reach peak plasma concentration 8 , 56 . Participants then completed the SRTT, followed by a post-task MRSI acquisition. The scan timings were chosen so that the MRSI scans and motor learning tasks fell within the peak plasma concentration time for baclofen, which is 1-2 hours after drug administration 8 . After the MRI scan, participants filled in a third BLVAS questionnaire 2 hours after treatment administration and performed a battery of Cambridge Cognition (CANTAB) memory tests. Serial Reaction Time Task (SRTT) Participants were instructed to use their right index, middle, ring, and little fingers to press buttons 1-4 on an MRI-compatible 4-button box in response to a visual cue, as quickly and accurately as possible. Participants were also instructed to not press a button before the visual cue appeared on the screen. At the beginning of each block, participants would see a screen with four dashes. One of the dashes would then be replaced by an asterisk, which represented the visual stimulus for the participant to press the corresponding button. The SRTT was composed of two types of blocks: sequence blocks and random blocks, each with 60 trials repeated at a frequency of 1.5Hz. During random blocks, the visual cues were presented in a random order. During each sequence block, the same 12-button sequence was repeated five times. A different sequence was used for each session (sequence 1: 3-1-2-4-2-3-2-1-4-1-3-4; sequence 2: 3-4-2-1-3-1-2-4-1-4-3-2). We calculated response times (RTs) for each block as the time between stimulus presentation and the button press. We excluded incorrect button presses, pre-emptive button presses (RT < 50ms) and outliers (± 2.7 SD from the mean of each block). We then calculated the median RT for each block and normalised it by dividing it by the median RT of the first random block (R1). To correlate behaviour with MRS measures of [GABA], we also calculated the slope of RT change as a learning measure for each session by fitting a linear regression model to the data in sequence blocks 1 to 11. One participant was excluded from further analysis because their learning measure on one session being an outlier on the Grubbs test. To investigate how changes in neurochemicals relate to changes in behaviour on the motor sequence task, we first calculated the change of a neurochemical during motor learning as the difference between the pre- and post-task [GABA] and [Glu] respectively, so higher values of this metric would represent larger decreases in that neurochemical during motor learning. To assess changes in motor learning, we calculated the motor learning metric as the difference in median response times between the first and last sequence blocks normalised by the median response time to the first random block [(S1-S11)/R1], so that higher values of this metric would represent larger decreases in response time during motor sequence learning and therefore, better learning. MR Data Acquisition and Analysis Participants had an MRI brain scan in a 3T MAGNETOM Prisma system (Siemens Healthineers, Elangen, Germany) equipped with a 32-channel receive head coil (Siemens Healthineers). Three participants did not complete the MRI scan and were therefore not included in the neuroimaging analysis. First, we acquired a T1-weighted structural image (MPRAGE, 1 mm isotropic, TR = 1.9 s, TE = 3.96 ms, TI = 912 ms, TA = 7.3 min, field of view 232 x 256 x 192mm 3 , flip angle 8°). MRSI was acquired pre- and post-task using a semi-LASER prepared MRSI sequence, with density- weighted concentric ring trajectories (CRTs) k-space sampling 57 , TR = 1.4 s, TE = 32 ms, TA = 2 x 4.5min, voxel size = 5 x 5 x 15 mm 3 , field of view = 85 x 35 mm 2 , slice thickness = 15 mm). The semi-LASER selected volume (“MRSI slab”) was manually placed to cover both the left- and right-hand knobs at the posterior margin of the precentral gyrus 58 , excluding tissue outside the brain to minimise contamination due to mobile lipids 57 . Reconstruction of MRSI data and neurochemical quantification was performed using in-house scripts and LCModel, as described in previous studies 57 , 59 – 61 . Briefly, after metabolite cycling reconstruction 62 and coil-combination 63 , we corrected for frequency and phase shifts, removed residual water using HLSVD 64 , and corrected for eddy currents 65 . Neurochemicals were quantified using LCModel with a basis set containing 26 metabolites, default LCModel macromolecules, no soft constraints on metabolites, a baseline stiffness setting (DKMTMN) of 0.25 and a chemical shift of 0.5 to 4.2ppm. Metabolite concentrations are reported as a ratio to total creatine (creatine + phosphocreatine; tCr). We then excluded voxels with Cramer-Rao lower bands (CRLB) > 50%, signal-to-noise ratio (SNR) 1 ( Fig.4B -a). To confirm the accurate placement of the MRSI slab in all participants, metabolite maps were registered to MNI space using linear and then non-linear registration (FLINT and FNIRT, 66 , 67 ). All MRSI slabs included the left-hand knob ( Fig.4B -b). A representative spectrum is included in Figure 4C . To quantify GABA in the brain regions responsible for motor control, we registered anatomical MNI maps of left and right M1 and premotor cortex to each participant’s structural scan using FLIRT and FNIRT 66 . For each participant, we calculated the mean [GABA] from the voxels that passed quality control in each region of interest. Working memory tests To investigate the effect of baclofen on cognitive functions, participants completed four working memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) on a tablet (Apple iPad Air 2) at approximately 3 hours after treatment administration 68 . These four tests were: Spatial Working Memory (SWM), Pattern Recognition Memory (PRM), Spatial Span (SSP), and Rapid Visual Processing (RVP). Due to technical difficulties, 3 participants could not complete the SWM, PRM and RVP tests on one of the sessions. Spatial working memory A number of boxes appeared on the screen and participants were instructed to tap one box to find out whether there was a token in it. Only one token appeared in each of the boxes, so participants had to remember which boxes they had already found tokens in and which boxes they still needed to check. Participants committed errors whenever they tapped a box in which they had already looked for a second time. The number of total errors was reported for increasing task difficulties (4, 6, 8 and 12 blocks). A strategy metric was also recorded, quantifying how many times the participants had started searching from the same block, indicating a strategy for task performance. Pattern Recognition Memory Participants were presented with a set of shapes, which they were instructed to remember. Pattern recognition memory was evaluated at two time points: immediately after the presentation of the set of shapes and at approximately 20 minutes. Participants were asked to recall the shapes they remembered from two possible options. The percentage of correct choices and the response times for pattern recognition were recorded for both the immediate and delayed time points. Rapid Visual Processing Digits between 2 and 9 were briefly displayed in the centre of the screen in a pseudorandom order. Participants were instructed to tap a red button on the screen if the following target sequences appeared: 3-5-7, 2-4-6 and 4-6-8. We recorded three metrics: the accuracy of sequence detection, median response times and the probability of false alarm. Spatial Span For each trial, a set of 9 boxes appeared on the screen, out of which a subset would change colour one at a time, forming a sequence. In the forward version of this task, participants were asked to tap the boxes in the order they had lit up previously; in the reverse version, participants were asked to tap the boxes in the reserve order. The sequence gradually increased from 2 to 9 boxes, making the task more difficult to perform. The length of the most difficult correctly-recalled sequence was recorded, as well as the number of errors made, for both the forward and the reverse spatial span. Mood questionnaires Participants completed the Bond-Lader Visual Analogue scale (BLVAS) three times during each session. The BLVAS has 16 scales, each 100mm long with the 2 opposite sides of the spectrum at each end, e.g. alert – drowsy, calm – excited 69 . At each time point, participants were asked to mark how they felt at that specific moment on each scale. Similar to previous studies, the 16 scales were grouped into 3 categories: alertness (alert, strong, clear-headed, well-coordinated, energetic, quick-witted, attentive, proficient, interested), contentedness (contented, tranquil, happy, social, friendly) and calmness (calm, relaxed) 69 . The mean value for each category was calculated at each time point, with lower values indicating stronger feelings on that respective scale. Statistical Analyses All behavioural data were analysed using MATLAB (v. R2020b, MathWorks) and Prism (v.9.3.0, GraphPad Software). MRSI data were analysed using in-house Bash scripts, R (RCoreTeam 2013) and Prism. Analysis was performed using repeated-measures ANOVAs with Geisser-Greenhouse’s correction or paired t-tests with significance levels of 𝛼 = 0.05 to investigate the within-subject effects of baclofen compared to placebo. Relationships between MRSI and behavioural metrics were investigated by calculating Pearson’s correlation coefficients. All graphs show mean ± SD or individual data points unless otherwise indicated. Authorship contributions Conceptualisation: IFG, AJ, CJS Experimental design and data collection: IFG, EG, AJ, WTC, UE, LC, CJS Data analysis: IFG, EG, WTC, UE, CN, JML, CJS Writing – original draft: IFG and CJS Writing – review & editing: IFG, EG, AJ, WTC, UE, CN, JML, LC, CJS Funding acquisition: CJS Acknowledgements CJS was supported by a Wellcome Trust Senior Research Fellowship (224430/Z/21/Z). WTC was supported by a Wellcome Trust Career Development Award (225924/Z/22/Z). The Wellcome Centre for Integrative Neuroimaging is supported by core funding from the Wellcome Trust (203139/Z/16/Z and 203139/A/16/Z). WTC was supported by a Wellcome Trust Career Development Award (225924/Z/22/Z). LC currently works at the Psychology Research Centre (PSI/01662), School of Psychology, University of Minho, supported by the Foundation for Science and Technology (FCT) through the Portuguese State Budget (Ref.: UID/PSI/ 01662/2020). LC is individually funded by a Research Fellowship also from the Foundation for Science and Technology (FCT) (Ref: 2021.00415.CEECIND). This study was supported by the NIHR Oxford Health Biomedical Research Centre (OH BRC, NIHR203316). The views expressed are those of the authors and not necessarily those of the NHS, NIHR or the Department of Health. References 1. ↵ Dayan , E. & Cohen , L. G . Neuroplasticity subserving motor skill learning . Neuron 72 , 443 – 454 ( 2011 ). OpenUrl CrossRef PubMed Web of Science 2. ↵ Bachtiar , V. & Stagg , C. J . The role of inhibition in human motor cortical plasticity . Neuroscience 278 , 93 – 104 ( 2014 ). OpenUrl CrossRef PubMed 3. ↵ Castro-Alamancos , M. A. , Donoghue , J. P. & Connors , B. W . Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex . J Neurosci 15 , 5324 – 5333 ( 1995 ). OpenUrl Abstract / FREE Full Text 4. ↵ McDonnell , M. N. , Orekhov , Y. & Ziemann , U . Suppression of LTP-like plasticity in human motor cortex by the GABAB receptor agonist baclofen . Exp Brain Res 180 , 181 – 186 ( 2007 ). OpenUrl CrossRef PubMed Web of Science 5. ↵ Kolasinski , J. et al. The dynamics of cortical GABA in human motor learning . J. Physiol. (Lond .) 597 , 271 – 282 ( 2019 ). OpenUrl CrossRef PubMed 6. ↵ Stagg , C. J. , Bachtiar , V. & Johansen-Berg , H . The role of GABA in human motor learning . Curr Biol 21 , 480 – 484 ( 2011 ). OpenUrl CrossRef PubMed 7. ↵ Simon , O. & Yelnik , A. P . Managing spasticity with drugs . Eur J Phys Rehabil Med 46 , 401 – 410 ( 2010 ). OpenUrl PubMed 8. ↵ Ziemann , U. , Lönnecker , S. , Steinhoff , B. J. & Paulus , W . Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study . Ann. Neurol . 40 , 367 – 378 ( 1996 ). OpenUrl CrossRef PubMed Web of Science 9. ↵ Bowery , N. G. , Hudson , A. L. & Price , G. W . GABAA and GABAB receptor site distribution in the rat central nervous system . Neuroscience 20 , 365 – 383 ( 1987 ). OpenUrl CrossRef PubMed Web of Science 10. ↵ Willerslev-Olsen , M. , Lundbye-Jensen , J. , Petersen , T. H. & Nielsen , J. B . The effect of baclofen and diazepam on motor skill acquisition in healthy subjects . Exp Brain Res 213 , 465 ( 2011 ). 11. ↵ Johnstone , A. , Grigoras , I. , Petitet , P. , Capitão , L. P. & Stagg , C. J . A single, clinically relevant dose of the GABAB agonist baclofen impairs visuomotor learning . The Journal of Physiology 599 , 307 – 322 ( 2021 ). OpenUrl CrossRef PubMed 12. ↵ Floyer-Lea , A. , Wylezinska , M. , Kincses , T. & Matthews , P. M . Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning . J. Neurophysiol . 95 , 1639 – 1644 ( 2006 ). OpenUrl CrossRef PubMed Web of Science 13. ↵ Licata , S. C. et al. A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: a proton MRS study at 4 T . Psychopharmacology (Berl ) 203 , 819 – 829 ( 2009 ). OpenUrl CrossRef 14. Licata , S. C. , Jensen , J. E. , Conn , N. A. , Winer , J. P. & Lukas , S. E . Zolpidem increases GABA in depressed volunteers maintained on SSRIs . Psychiatry Res 224 , 28 – 33 ( 2014 ). OpenUrl CrossRef PubMed 15. Henry , M. E. et al. The acute and late CNS glutamine response to benzodiazepine challenge: A pilot pharmacokinetic study using proton magnetic resonance spectroscopy . Psychiatry Research: Neuroimaging 184 , 171 – 176 ( 2010 ). OpenUrl CrossRef 16. Li , Q. , Chen , C. & Gong , T . High-field MRS study of GABA+ in patients with migraine: response to levetiracetam treatment . Neuroreport 29 , 1007 – 1010 ( 2018 ). OpenUrl CrossRef PubMed 17. ↵ Morley , K. C. et al. Neurometabolite Levels in Alcohol Use Disorder Patients During Baclofen Treatment and Prediction of Relapse to Heavy Drinking . Front Psychiatry 9 , 412 ( 2018 ). 18. ↵ Ferland , M. C. et al. Transcranial Magnetic Stimulation and H1-Magnetic Resonance Spectroscopy Measures of Excitation and Inhibition Following Lorazepam Administration . Neuroscience 452 , 235 – 246 ( 2021 ). OpenUrl CrossRef PubMed 19. ↵ Stagg , C. J. et al. Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex . J. Physiol. (Lond .) 589 , 5845 – 5855 ( 2011 ). OpenUrl CrossRef PubMed 20. Tremblay , S. et al. Relationship between transcranial magnetic stimulation measures of intracortical inhibition and spectroscopy measures of GABA and glutamate+glutamine . J. Neurophysiol . 109 , 1343 – 1349 ( 2013 ). OpenUrl CrossRef PubMed Web of Science 21. Mooney , R. A. , Cirillo , J. & Byblow , W. D . GABA and primary motor cortex inhibition in young and older adults: a multimodal reliability study . J. Neurophysiol . 118 , 425 – 433 ( 2017 ). OpenUrl CrossRef PubMed 22. ↵ Dyke , K. et al. Comparing GABA-dependent physiological measures of inhibition with proton magnetic resonance spectroscopy measurement of GABA using ultra-high-field MRI . NeuroImage 152 , 360 – 370 ( 2017 ). OpenUrl CrossRef PubMed 23. ↵ Benarroch , E. E . GABAB receptors: structure, functions, and clinical implications . Neurology 78 , 578 – 584 ( 2012 ). OpenUrl CrossRef PubMed 24. ↵ Mott , D. D. , Lewis , D. V. , Ferrari , C. M. , Wilson , W. A. & Swartzwelder , H. S . Baclofen facilitates the development of long-term potentiation in the rat dentate gyrus . Neurosci Lett 113 , 222 – 226 ( 1990 ). OpenUrl CrossRef PubMed Web of Science 25. Olpe , H. R. & Karlsson , G . The effects of baclofen and two GABAB-receptor antagonists on long-term potentiation . Naunyn Schmiedebergs Arch Pharmacol 342 , 194 – 197 ( 1990 ). OpenUrl CrossRef PubMed Web of Science 26. Ohliger-Frerking , P. , Wiebe , S. P. , Stäubli , U. & Frerking , M . GABA(B) receptor-mediated presynaptic inhibition has history-dependent effects on synaptic transmission during physiologically relevant spike trains . J Neurosci 23 , 4809 – 4814 ( 2003 ). OpenUrl Abstract / FREE Full Text 27. ↵ McDonnell , M. N. , Orekhov , Y. & Ziemann , U . The role of GABA(B) receptors in intracortical inhibition in the human motor cortex . Exp Brain Res 173 , 86 – 93 ( 2006 ). OpenUrl CrossRef PubMed Web of Science 28. ↵ Kantak , S. S. , Stinear , J. W. , Buch , E. R. & Cohen , L. G . Rewiring the brain: potential role of the premotor cortex in motor control, learning, and recovery of function following brain injury . Neurorehabil Neural Repair 26 , 282 – 292 ( 2012 ). OpenUrl CrossRef PubMed Web of Science 29. ↵ Halsband , U. & Freund , H. J . Premotor cortex and conditional motor learning in man . Brain 113 ( Pt 1 ) , 207 – 222 ( 1990 ). OpenUrl CrossRef PubMed Web of Science 30. Nowak , D. A. et al. Continuous theta-burst stimulation over the dorsal premotor cortex interferes with associative learning during object lifting . Cortex 45 , 473 – 482 ( 2009 ). OpenUrl CrossRef PubMed Web of Science 31. ↵ Steele , C. J. & Penhune , V. B . Specific increases within global decreases: a functional magnetic resonance imaging investigation of five days of motor sequence learning . J Neurosci 30 , 8332 – 8341 ( 2010 ). OpenUrl Abstract / FREE Full Text 32. ↵ Bischoff-Grethe , A. , Goedert , K. M. , Willingham , D. T. & Grafton , S. T . Neural substrates of response-based sequence learning using fMRI . J Cogn Neurosci 16 , 127 – 138 ( 2004 ). OpenUrl CrossRef PubMed Web of Science 33. ↵ Vogt , S. et al. Prefrontal involvement in imitation learning of hand actions: effects of practice and expertise . Neuroimage 37 , 1371 – 1383 ( 2007 ). OpenUrl CrossRef PubMed Web of Science 34. ↵ Fridman , E. A. et al. Reorganization of the human ipsilesional premotor cortex after stroke . Brain 127 , 747 – 758 ( 2004 ). OpenUrl CrossRef PubMed Web of Science 35. ↵ Cross , E. S. , Schmitt , P. J. & Grafton , S. T . Neural substrates of contextual interference during motor learning support a model of active preparation . J Cogn Neurosci 19 , 1854 – 1871 ( 2007 ). OpenUrl CrossRef PubMed Web of Science 36. ↵ Tomassini , V. et al. Structural and functional bases for individual differences in motor learning . Hum Brain Mapp 32 , 494 – 508 ( 2011 ). OpenUrl CrossRef PubMed Web of Science 37. ↵ Kolasinski , J. et al. The dynamics of cortical GABA in human motor learning . J Physiol 597 , 271 – 282 ( 2019 ). OpenUrl CrossRef PubMed 38. ↵ Muakkassa , K. F. & Strick , P. L . Frontal lobe inputs to primate motor cortex: evidence for four somatotopically organized ‘premotor’ areas . Brain Res 177 , 176 – 182 ( 1979 ). OpenUrl CrossRef PubMed Web of Science 39. Riehle , A. & Requin , J . Monkey primary motor and premotor cortex: single-cell activity related to prior information about direction and extent of an intended movement . J Neurophysiol 61 , 534 – 549 ( 1989 ). OpenUrl CrossRef PubMed Web of Science 40. Churchland , M. M. , Yu , B. M. , Ryu , S. I. , Santhanam , G. & Shenoy , K. V . Neural variability in premotor cortex provides a signature of motor preparation . J Neurosci 26 , 3697 – 3712 ( 2006 ). OpenUrl Abstract / FREE Full Text 41. ↵ Shenoy , K. V. , Sahani , M. & Churchland , M. M . Cortical control of arm movements: a dynamical systems perspective . Annu Rev Neurosci 36 , 337 – 359 ( 2013 ). OpenUrl CrossRef PubMed Web of Science 42. ↵ Kansaku , K. , Hanakawa , T. , Wu , T. & Hallett , M . A shared neural network for simple reaction time . Neuroimage 22 , 904 – 911 ( 2004 ). OpenUrl CrossRef PubMed 43. ↵ Churchland , M. M. & Shenoy , K. V . Delay of movement caused by disruption of cortical preparatory activity . J Neurophysiol 97 , 348 – 359 ( 2007 ). OpenUrl CrossRef PubMed Web of Science 44. ↵ Zangrandi , A. et al. Conditioning transcranial magnetic stimulation of ventral premotor cortex shortens simple reaction time . Cortex 121 , 322 – 331 ( 2019 ). OpenUrl CrossRef PubMed 45. ↵ Mangia , S. et al. Metabolic and hemodynamic events after changes in neuronal activity: current hypotheses, theoretical predictions and in vivo NMR experimental findings . J Cereb Blood Flow Metab 29 , 441 – 463 ( 2009 ). OpenUrl CrossRef PubMed Web of Science 46. ↵ Mullins , P. G . Towards a theory of functional magnetic resonance spectroscopy (fMRS): A meta-analysis and discussion of using MRS to measure changes in neurotransmitters in real time . Scand J Psychol 59 , 91 – 103 ( 2018 ). OpenUrl CrossRef PubMed 47. ↵ Lea-Carnall , C. A. , El-Deredy , W. , Stagg , C. J. , Williams , S. R. & Trujillo-Barreto , N. J . A mean-field model of glutamate and GABA synaptic dynamics for functional MRS . Neuroimage 266 , 119813 ( 2023 ). 48. ↵ Schaller , B. , Xin , L. , O’Brien , K. , Magill , A. W. & Gruetter , R . Are glutamate and lactate increases ubiquitous to physiological activation? A (1)H functional MR spectroscopy study during motor activation in human brain at 7Tesla . Neuroimage 93 Pt 1 , 138 – 145 ( 2014 ). 49. Volovyk , O. & Tal , A . Increased Glutamate concentrations during prolonged motor activation as measured using functional Magnetic Resonance Spectroscopy at 3T . Neuroimage 223 , 117338 ( 2020 ). 50. ↵ Eisenstein , T. , Furman-Haran , E. & Tal , A . Increased cortical inhibition following brief motor memory reactivation supports reconsolidation and overnight offline learning gains . Proc Natl Acad Sci U S A 120 , e2303985120 ( 2023 ). OpenUrl CrossRef PubMed 51. ↵ Kim , S. , Stephenson , M. C. , Morris , P. G. & Jackson , S. R . tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: A 7 T magnetic resonance spectroscopy study . Neuroimage 99 , 237 – 243 ( 2014 ). OpenUrl CrossRef PubMed 52. ↵ Bell , T. K. , Craven , A. R. , Hugdahl , K. , Noeske , R. & Harris , A. D . Functional Changes in GABA and Glutamate during Motor Learning . eNeuro 10 , ENEURO.0356-20.2023 ( 2023 ). 53. ↵ King , B. R. et al. Baseline sensorimotor GABA levels shape neuroplastic processes induced by motor learning in older adults . Hum Brain Mapp 41 , 3680 – 3695 ( 2020 ). OpenUrl CrossRef PubMed 54. ↵ Johnstone , A. , Brander , F. , Kelly , K. , Bestmann , S. & Ward , N . Differences in outcomes following an intensive upper-limb rehabilitation program for patients with common central nervous system-acting drug prescriptions . Int J Stroke 17474930211006287 ( 2021 ) doi: 10.1177/17474930211006287 . OpenUrl CrossRef 55. ↵ Oldfield , R. C . The assessment and analysis of handedness: the Edinburgh inventory . Neuropsychologia 9 , 97 – 113 ( 1971 ). OpenUrl CrossRef PubMed Web of Science 56. ↵ Agarwal , S. K. et al. A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers . J Child Neurol 30 , 37 – 41 ( 2015 ). OpenUrl CrossRef PubMed 57. ↵ Steel , A. et al. Metabolite-cycled density-weighted concentric rings k-space trajectory (DW-CRT) enables high-resolution 1 H magnetic resonance spectroscopic imaging at 3-Tesla . Sci Rep 8 , 7792 ( 2018 ). 58. ↵ Kolasinski , J. et al. A Mechanistic Link from GABA to Cortical Architecture and Perception . Curr Biol 27 , 1685 – 1691 .e3 ( 2017 ). OpenUrl CrossRef PubMed 59. ↵ Provencher , S. W . Automatic quantitation of localized in vivo 1H spectra with LCModel . NMR Biomed 14 , 260 – 264 ( 2001 ). OpenUrl CrossRef PubMed Web of Science 60. Nettekoven , C. R. et al. Cerebellar GABA change during visuomotor adaptation relates to adaptation performance and cerebellar network connectivity: A Magnetic Resonance Spectroscopic Imaging study . 2021.12.19.473367 Preprint at doi: 10.1101/2021.12.19.473367 ( 2022 ). OpenUrl Abstract / FREE Full Text 61. ↵ Andrushko , J. W. et al. Repeated unilateral handgrip contractions alter functional connectivity and improve contralateral limb response times . Sci Rep 13 , 6437 ( 2023 ). 62. ↵ Emir , U. E. , Burns , B. , Chiew , M. , Jezzard , P. & Thomas , M. A . Non-water-suppressed short-echo-time magnetic resonance spectroscopic imaging using a concentric ring k-space trajectory . NMR Biomed 30 , ( 2017 ). 63. ↵ Walsh , D. O. , Gmitro , A. F. & Marcellin , M. W . Adaptive reconstruction of phased array MR imagery . Magn Reson Med 43 , 682 – 690 ( 2000 ). OpenUrl CrossRef PubMed 64. ↵ Cabanes , E. , Confort-Gouny , S. , Le Fur , Y. , Simond , G. & Cozzone , P. J . Optimization of residual water signal removal by HLSVD on simulated short echo time proton MR spectra of the human brain . J Magn Reson 150 , 116 – 125 ( 2001 ). OpenUrl CrossRef PubMed Web of Science 65. ↵ Klose , U . In vivo proton spectroscopy in presence of eddy currents . Magn Reson Med 14 , 26 – 30 ( 1990 ). OpenUrl CrossRef PubMed Web of Science 66. ↵ Jenkinson , M. & Smith , S . A global optimisation method for robust affine registration of brain images . Med Image Anal 5 , 143 – 156 ( 2001 ). OpenUrl CrossRef PubMed Web of Science 67. ↵ Jenkinson , M. , Bannister , P. , Brady , M. & Smith , S . Improved optimization for the robust and accurate linear registration and motion correction of brain images . Neuroimage 17 , 825 – 841 ( 2002 ). OpenUrl CrossRef PubMed Web of Science 68. ↵ Falconer , D. W. , Cleland , J. , Fielding , S. & Reid , I. C . Using the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess the cognitive impact of electroconvulsive therapy on visual and visuospatial memory . Psychol Med 40 , 1017 – 1025 ( 2010 ). OpenUrl CrossRef PubMed 69. ↵ Bond , A. & Lader , M . The use of analogue scales in rating subjective feelings . British Journal of Medical Psychology 47 , 211 – 218 ( 1974 ). OpenUrl CrossRef Web of Science View the discussion thread. Back to top Previous Next Posted April 01, 2025. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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