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Recent studies suggest an important role of the principal inhibitory neurotransmitter GABA for motor performance in the context of aging. Nonetheless, as previous magnetic resonance spectroscopy (MRS) studies primarily reported resting-state GABA levels, much less is known about transient changes in GABA levels during motor task performance and how these relate to behavior and brain activity patterns. Therefore, we investigated GABA+ levels of left primary sensorimotor cortex (SM1) acquired before, during, and after execution of a unimanual/bimanual action selection task in 30 (human) young adults (YA; age 24.5 ± 4.1, 15 male) and 30 older adults (OA; age 67.8 ± 4.9, 14 male). In addition to task-related MRS data, task-related functional magnetic resonance imaging (fMRI) data were acquired. Behavioral results indicated lower motor performance in OA as opposed to YA, particularly in complex task conditions. MRS results demonstrated lower GABA+ levels in OA as compared with YA. Furthermore, a transient task-related decrease of GABA+ levels was observed, regardless of age. Notably, this task-induced modulation of GABA+ levels was linked to task-related brain activity patterns in SM1 such that a more profound task-induced instantaneous lowering of GABA+ was related to higher SM1 activity. Additionally, higher brain activity was related to better performance in the bimanual conditions, despite some age-related differences. Finally, the modulatory capacity of GABA+ was positively related to motor performance in OA but not YA. Together, these results underscore the importance of transient dynamical changes in neurochemical content for brain function and behavior, particularly in the context of aging.SIGNIFICANCE STATEMENT Emerging evidence designates an important role to regional GABA levels in motor control, especially in the context of aging. However, it remains unclear whether changes in GABA levels emerge when executing a motor task and how these changes relate to brain activity patterns and performance. Here, we identified a transient decrease of sensorimotor GABA+ levels during performance of an action selection task across young adults (YA) and older adults (OA). Interestingly, whereas a more profound GABA+ modulation related to higher brain activity across age groups, its association with motor performance differed across age groups. Within OA, our results highlighted a functional merit of a task-related release from inhibitory tone, i.e. lowering regional GABA+ levels was associated with task-relevant brain activity. ispartof: JOURNAL OF NEUROSCIENCE vol:42 issue:6 pages:1119-1130 ispartof: location:United States status: published

Few studies have identified the intrahemispheric functional connectivity between the ipsilateral dorsal premotor cortex (PMd) and the primary motor hand area (M1hand) due to technical limitations. In this proof-of-concept study, a novel neuronavigated dsTMS set-up was employed, combining stimulation over left PMd and left M1hand using the edge of a butterfly coil and a small cooled-coil. This arrangement was warranted because coil (over)heating and inter coil distance are limiting factors when investigating connectivity between stimulation targets in close proximity and over a longer duration. The proposed set-up was designed to deal with these limitations. Specifically, the effect of four dual-site transcranial magnetic stimulation (dsTMS) protocols on twenty-eight right-handed participants (12 males) was evaluated. These protocols differed in stimulus order, interstimulus interval and current direction induced in PMd. A structural scan with electric (E-)field modeling was obtained from seven participants prior to dsTMS, demonstrating that PMd and M1hand were effectively stimulated. Results indicate that one protocol, in which a latero-medial current was induced in PMd 2.8 ms prior to stimulation over M1hand, induced a sex-mediated effect. In males, significant inhibition of motor-evoked potentials was identified, whereas females demonstrated a facilitatory effect that did not survive correction for multiple comparisons. E-field simulations revealed that the E-field induced by the coil targeting PMd was maximal in PMd, with weaker E-field strengths extending to regions beyond PMd. Summarizing, the current dsTMS set-up enabled stimulating at an inter-target distance of 35 mm without any indications of coil-overheating.

Using a cross-sectional design, we aimed to identify the effect of aging on sensorimotor function and cortical motor representations of two intrinsic hand muscles, as well as the course and timing of those changes. Furthermore, the link between cortical motor representations, sensorimotor function, and intracortical inhibition and facilitation was investigated. Seventy-seven participants over the full adult lifespan were enrolled. For the first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscle, cortical motor representations, GABAA-mediated short-interval intracortical inhibition (SICI), and glutamate-mediated intracortical facilitation (ICF) were assessed using transcranial magnetic stimulation over the dominant primary motor cortex. Additionally, participants' dexterity and force were measured. Linear, polynomial, and piecewise linear regression analyses were conducted to identify the course and timing of age-related differences. Our results demonstrated variation in sensorimotor function over the lifespan, with a marked decline starting around the mid-thirties. Furthermore, an age-related reduction in cortical motor representation volume and maximal MEP of the FDI, but not for ADM, was observed, occurring mainly until the mid-forties. Area of the cortical motor representation did not change with advancing age. Furthermore, cortical motor representations, sensorimotor function, and measures of intracortical inhibition and facilitation were not interrelated. This work was supported by the Research Fund KU Leuven (C16/15/070), the Research Foundation Flanders grant (G089818N), the Excellence of Science grant (EOS 30446199, MEMODYN) and the Hercules fund AUHL/11/01 (R-3987) and I005018N. The authors declare no competing financial interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Cuypers, K (reprint author), Katholieke Univ Leuven, Dept Movement Sci, Grp Biomed Sci, Movement Control & Neuroplastic Res Grp, Leuven, Belgium; Hasselt Univ, REVAL Res Inst, Agoralaan, Diepenbeek, Belgium. koen.cuypers@kuleuven.be

Although gamma aminobutyric acid (GABA) is of particular importance for efficient motor functioning, very little is known about the relationship between regional GABA levels and motor performance. Some studies sug- gest this relation to be subject to age-related differences even though literature is scarce. To clarify this matter, we employed a comprehensive approach and investigated GABA levels within young and older adults across multiple motor tasks as well as multiple brain regions. Specifically, 30 young and 30 older adults completed a task battery of three different bimanual tasks. Furthermore, GABA levels were obtained within bilateral primary sensorimotor cortex (SM1), bilateral dorsal premotor cortex, the supplementary motor area and bilateral dorso- lateral prefrontal cortex (DLPFC) using magnetic resonance spectroscopy. Results indicated that older adults, as compared to their younger counterparts, performed worse on all bimanual tasks and exhibited lower GABA levels in bilateral SM1 only. Moreover, GABA levels across the motor network and DLPFC were differentially associated with performance in young as opposed to older adults on a manual dexterity and bimanual coordination task but not a finger tapping task. Specifically, whereas higher GABA levels related to better manual dexterity within older adults, higher GABA levels predicted poorer bimanual coordination performance in young adults. By de- termining a task-specific and age-dependent association between GABA levels across the cortical motor network and performance on distinct bimanual tasks, the current study advances insights in the role of GABA for motor performance in the context of aging. ispartof: Neuroimage vol:231 issue:May 2021 ispartof: location:United States status: published

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels. ispartof: NEUROIMAGE vol:191 pages:537-548 ispartof: location:United States status: published

OBJECTIVE: Force decline during strong contractions is dominated by changes in the periphery whereas during weaker contraction changes in voluntary activation become more important. We compared force decline and contributing factors in persons with multiple sclerosis (PwMS) during low and high intensity contractions.METHODS: Index finger abduction force, force evoked by electrical stimulation of the ulnar nerve at rest (RTw), and during MVCs were investigated in 19 PwMS and 19 controls. Participants performed contractions in sets of six contractions (7 s-on, 3 s-off) at 25% or 80% MVC. After each set, a 5 s-MVC was performed with superimposed nerve stimulation followed by RTw. Contractions were repeated until MVC dropped below 80% of initial MVC.RESULTS: Low compared to high intensity contractions caused a greater decline in voluntary activation and a smaller decline in RTw. Compared to controls, PwMS accomplished equal sets of contractions but showed a smaller decline in RTw. Female PwMS showed poorer voluntary activation. The number of low intensity contractions was associated with sense of fatigue in PwMS.CONCLUSION: Although, no difference in fatigability was observed, the mechanism contributing to force decline differed between PwMS and controls during submaximal contractions.SIGNIFICANCE: During weak contractions, fatigue and fatigability are associated in PwMS.

We investigated the effect of age on the ability to modulate GABAA-ergic and GABAB-ergic inhibitory activity during stopping of action (reactive inhibition) and preparation to stop (proactive inhibition). Twenty-five young and twenty-nine older adults performed an anticipated response version of the stop-signal task with varying levels of stop-signal probability. Paired-pulse transcranial magnetic stimulation was applied to left primary motor cortex to assess the modulation of GABAA-mediated short-interval intracortical inhibition (SICI) during stopping and GABAB-mediated long-interval intracortical inhibition (LICI) during the anticipation of a stop-signal. At the behavioral level, reactive inhibition was affected by aging as indicated by longer stop-signal reaction times in older compared to young adults. In contrast, proactive inhibition was preserved at older age as both groups slowed down their go response to a similar degree with increasing stop-signal probability. At the neural level, the amount of SICI was higher in successful stop relative to go trials in young but not in older adults. LICI at the start of the trial was modulated as a function of stop-signal probability in both young and older adults. Our results suggest that specifically the recruitment of GABAA-mediated intracortical inhibition during stopping of action is affected by aging. ispartof: Aging-US vol:11 issue:2 pages:371-385 ispartof: location:United States status: published

Over the last decade, there has been an increasing number of studies combining transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). MRS provides a manner to non-invasively investigate molecular concentrations in the living brain and thus identify metabolites involved in physiological and pathological processes. Particularly the MRS-detectable metabolites glutamate, the major excitatory neurotransmitter, and gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, are of interest when combining TMS and MRS. TMS is a non-invasive brain stimulation technique that can be applied either as a neuromodulation or neurostimulation tool, specifically targeting glutamatergic and GABAergic mechanisms. The combination of TMS and MRS can be used to evaluate alterations in brain metabolite levels following an interventional TMS protocol such as repetitive TMS (rTMS) or paired associative stimulation (PAS). MRS can also be combined with a variety of non-interventional TMS protocols to identify the interplay between brain metabolite levels and measures of excitability or receptor-mediated inhibition and facilitation. In this review, we provide an overview of studies performed in healthy and patient populations combining MRS and TMS, both as a measurement tool and as an intervention. TMS and MRS may reveal complementary and comprehensive information on glutamatergic and GABAergic neurotransmission. Potentially, connectivity changes and dedicated network interactions can be probed using the combined TMS-MRS approach. Considering the ongoing technical developments in both fields, combined studies hold future promise for investigations of brain network interactions and neurotransmission. ispartof: NEUROIMAGE vol:224 ispartof: location:United States status: published

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article. ispartof: RADIOLOGY vol:295 issue:1 pages:171-180 ispartof: location:United States status: published

Aging is accompanied by marked changes in motor behavior and its neural correlates. At the behavioral level, age-related declines in motor performance manifest, for example, as a reduced capacity to inhibit interference between hands during bimanual movements, particularly when task complexity increases. At the neural level, aging is associated with reduced differentiation between distinct functional systems. Functional connectivity (FC) dedifferentiation is characterized by more homogeneous connectivity patterns across various tasks or task conditions, reflecting a reduced ability of the aging adult to modulate brain activity according to changing task demands. It is currently unknown, however, how whole-brain dedifferentiation interacts with increasing task complexity. In the present study, we investigated age- and task-related FC in a group of 96 human adults across a wide age range (19.9-74.5 years of age) during the performance of a bimanual coordination task of varying complexity. Our findings indicated stronger task complexity-related differentiation between visuomotor- and nonvisuomotor-related networks, though modulation capability decreased with increasing age. Decreased FC modulation mediated larger complexity-related increases in between-hand interference, reflective of worse bimanual coordination. Thus, the ability to maintain high motor performance levels in older adults is related to the capability to properly segregate and modulate functional networks. Research Foundation Flanders (G089818 N); Excellence of Science grant (EOS, 30446199, MEMODYN); KU Leuven Research Fund (C16/15/070). Monteiro, TS (corresponding author), Res Ctr Movement Control & Neuroplast, Grp Biomed Sci, Tervuursevest 101 Box 1501, B-3001 Leuven, Belgium. thiago.santosmonteiro@kuleuven.be

Imitation problems are commonly reported in children with an autism spectrum disorder. However, it has not yet been determined whether imitation problems persist into young adulthood. In this study, we investigated imitation skills of 20 intellectually able young adults with autism spectrum disorder relative to 19 age-matched neurotypical adults. For this purpose, we used a bar-transport task, which evokes the application of the end-state comfort principle. Specifically, we examined whether young adults with autism spectrum disorder imitated the means-end structure of a demonstrator’s bar-transport action with and without application of the end-state comfort principle (imitation task). In addition, we examined whether participants spontaneously applied the end-state comfort principle during a similar bar-transport task (free execution task). Results revealed that young adults with autism spectrum disorder imitated the means-end structure of observed actions to the same degree as neurotypical adults ( p = 0.428). In contrast, they applied the end-state comfort principle less often during free executed actions ( p = 0.035). Moreover, during these actions, they were slower to place the bar into the penholder ( p = 0.023), which contributed to the reduced efficiency of their performance. Findings suggest that imitation abilities of young adults with autism spectrum disorder are preserved and that observing others’ actions might promote more efficient action planning in this population.

Background. Learning processes of writing skills involve the re-engagement of previously established motor programs affected by Parkinson disease (PD). To counteract the known problems with consolidation in PD, transcranial direct current stimulation (tDCS) could be imperative to achieve a lasting regeneration of habitual motor skills. Objective. To examine tDCS-enhanced learning of writing and explore alterations in cortical excitability after stimulation in PD compared with healthy controls (HCs). Methods. Ten patients and 10 HCs received 2 training sessions combined with 20 minutes of 1-mA anodal tDCS or sham on the left primary motor cortex in a randomized crossover design. Writing skills on a tablet and paper were assessed at baseline, after training, and after 1 week of follow-up. Before and immediately after the intervention, cortical excitability and inhibition were measured during rest and activity. Results. Writing amplitude and velocity improved when practice was tDCS supplemented compared with sham in PD. Benefits were sustained at retention for trained and untrained tasks on the tablet as well as for writing on paper. No improvements were found for HCs. Reduced resting motor thresholds after tDCS indicated tDCS-enhanced cortical excitability. Additionally, increments in motor-evoked potential amplitudes correlated with improved writing in PD, whereas HCs showed the opposite pattern. Conclusion. Our results endorse the usefulness of tDCS-boosted learning in PD, at least when applied to improving writing capacity. Although further confirmatory studies are needed, these novel findings are striking because tDCS-mediated consolidation was found for learning a motor task directly affected by PD. ispartof: NEUROREHABILITATION AND NEURAL REPAIR vol:33 issue:12 pages:1050-1060 ispartof: location:United States status: published

Levels of GABA, the main inhibitory neurotransmitter in the brain, can be regionally quantified using magnetic resonance spectroscopy (MRS). Although GABA is crucial for efficient neuronal functioning, little is known about age‐related differences in GABA levels and their relationship with age‐related changes in brain structure. Here, we investigated the effect of age on GABA levels within the left sensorimotor cortex and the occipital cortex in a sample of 85 young and 85 older adults using the MEGA‐PRESS sequence. Because the distribution of GABA varies across different brain tissues, various correction methods are available to account for this variation. Considering that these correction methods are highly dependent on the tissue composition of the voxel of interest, we examined differences in voxel composition between age groups and the impact of these various correction methods on the identification of age‐related differences in GABA levels. Results indicated that, within both voxels of interest, older (as compared to young adults) exhibited smaller gray matter fraction accompanied by larger fraction of cerebrospinal fluid. Whereas uncorrected GABA levels were significantly lower in older as compared to young adults, this age effect was absent when GABA levels were corrected for voxel composition. These results suggest that age‐related differences in GABA levels are at least partly driven by the age‐related gray matter loss. However, as alterations in GABA levels might be region‐specific, further research should clarify to what extent gray matter changes may account for age‐related differences in GABA levels within other brain regions.

It has been argued that age-related changes in the neurochemical and neurophysiological properties of the GABAergic system may underlie increases in reaction time (RT) in older adults. However, the role of GABA levels within the sensorimotor cortices (SMC) in mediating interhemispheric interactions (IHi) during the processing stage of a fast motor response, as well as how both properties explain interindividual differences in RT, are not yet fully understood. In this study, edited magnetic resonance spectroscopy (MRS) was combined with dual-site transcranial magnetic stimulation (dsTMS) for probing GABA+ levels in bilateral SMC and task-related neurophysiological modulations in corticospinal excitability (CSE), and primary motor cortex (M1)-M1 and dorsal premotor cortex (PMd)-M1 IHi, respectively. Both CSE and IHi were assessed during the preparatory and premotor period of a delayed choice RT task. Data were collected from 25 young (aged 18-33 years) and 28 older (aged 60-74 years) healthy adults. Our results demonstrated that older as compared to younger adults exhibited a reduced bilateral CSE suppression, as well as a reduced magnitude of long latency M1-M1 and PMd-M1 disinhibition during the preparatory period, irrespective of the direction of the IHi. Importantly, in older adults, the GABA+ levels in bilateral SMC partially accounted for task-related neurophysiological modulations as well as individual differences in RT. In contrast, in young adults, neither task-related neurophysiological modulations, nor individual differences in RT were associated with SMC GABA+ levels. In conclusion, this study contributes to a comprehensive initial understanding of how age-related differences in neurochemical properties and neurophysiological processes are related to increases in RT. ispartof: NEUROIMAGE vol:243 ispartof: location:United States status: published

Aging is associated with gradual alterations in the neurochemical characteristics of the brain, which can be assessed in-vivo with proton-magnetic resonance spectroscopy (

Aging is typically associated with substantial declines in motor functioning as well as robust changes in the functional organization of brain networks. Previous research has investigated the link between these 2 age-varying factors but examinations were predominantly limited to the functional organization within motor-related brain networks. Little is known about the relationship between age-related behavioral impairments and changes in functional organization at the whole brain (i.e., multiple network) level. This knowledge gap is surprising given that the decreased segregation of brain networks (i.e., increased internetwork connectivity) can be considered a hallmark of the aging process. Accordingly, we investigated the association between declines in motor performance across the adult lifespan (20-75 years) and age-related modulations of functional connectivity within and between resting state networks. Results indicated that stronger internetwork resting state connectivity observed as a function of age was significantly related to worse motor performance. Moreover, performance had a significantly stronger association with the strength of internetwork as compared with intranetwork connectivity, including connectivity within motor networks. These findings suggest that age-related declines in motor performance may be attributed to a breakdown in the functional organization of large-scale brain networks rather than simply age-related connectivity changes within motor-related networks.

Healthy aging is associated with mechanistic changes in gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter in the human brain. While previous work mainly focused on magnetic resonance spectroscopy (MRS)-based GABA+ levels and transcranial magnetic stimulation (TMS)-based GABAA receptor (GABAAR) activity in the primary sensorimotor (SM1) cortex, the aim of the current study was to identify age-related differences in positron emission tomography (PET)-based GABAAR availability and its relationship with GABA+ levels (i.e. GABA with the contribution of macromolecules) and GABAAR activity. For this purpose, fifteen young (aged 20-28 years) and fifteen older (aged 65-80 years) participants were recruited. PET and MRS images were acquired using simultaneous time-of-flight PET/MR to evaluate age-related differences in GABAAR availability (distribution volume ratio with pons as reference region) and GABA+ levels. TMS was applied to identify age-related differences in GABAAR activity by measuring short-interval intracortical inhibition (SICI). Whereas GABAAR availability was significantly higher in the SM cortex of older as compared to young adults (18.5%), there were neither age-related differences in GABA+ levels nor SICI. A correlation analysis revealed no significant associations between GABAAR availability, GABAAR activity and GABA+ levels. Although the exact mechanisms need to be further elucidated, it is possible that a higher GABAAR availability in older adults is a compensatory mechanism to ensure optimal inhibitory functionality during the aging process. ispartof: NEUROIMAGE vol:226 ispartof: location:United States status: published

The cerebellum appears to undergo late maturation in children and early decline at older age. Whether these age-related changes affect bimanual coordination performance remains unclear at best. Here, we identified the ages at which bimanual coordination performance stops improving and starts declining. In an independent cohort, we defined brain regions of interest involved in bimanual coordination using functional magnetic resonance imaging. We used these regions of interest to investigate the extent to which the gray matter of cerebellar and other brain regions explains bimanual coordination performance from 10- to 80-year-olds. Results showed that bimanual coordination performance starts declining from the age of 40 years. In participants aged 10-20 years, cerebellar lobule VI was the only significant brain predictor of bimanual coordination performance. In participants aged 60-80 years, this cerebellar region, together with the primary sensorimotor cortex, formed a group of strongest predictors. These results from 2 independent samples (10-20 and 60-80 years) suggest that cerebellar lobule VI is critical for the development and preservation of bimanual coordination skills in children and older adults, respectively. In addition, post hoc analyses suggested that the primary motor cortex mediated the adverse effect of age on bimanual coordination performance in older adults. ispartof: NEUROBIOLOGY OF AGING vol:65 pages:109-120 ispartof: location:United States status: published

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community. This work was supported by NIH grants R01 EB016089, R01 EB023963 and P41 EB015909. Data collection was supported by the Shandong Provincial Key Research and Development Plan of China (2016ZDJS07A16) and the National Natural Science Foundation of China for Young Scholars (no. 81601479). IDW thanks Mrs. J. Bigley of the University of Sheffield MRI Unit for her assistance with data acquisition. JJP was supported by NIAAA grant K23 AA020842. MPS was supported by NIH grant F32 EY025121. NAJP receives salary support from NIH grant K99 MH107719. The authors acknowledge implementation contributions from a number of employees of Siemens Medical Solutions, including Dr. Keith Heberlein and Dr. Sinyeob Ahn, to the Siemens WIP sequences, which are shared with several research sites under sequencespecific agreements.

Direct eye contact is a powerful social cue to regulate interpersonal interactions. Previous behavioral studies showed a link between eye contact and motor mimicry, indicating that the automatic mimicry of observed hand movements is significantly enhanced when direct eye contact exists between the observer and the observed model. In the present study, we aim to investigate the neurophysiological basis of the previously reported behavioral enhancements. Here, transcranial magnetic stimulation (TMS) was applied to assess changes in cortico-motor excitability at the level of the primary motor cortex (M1) to explore whether and how the motor system is facilitated from observing others’ hand movements and, in particular, how this process is modulated by eye contact. To do so, motor evoked potentials (MEPs) were collected from two hand muscles while participants received single-pulse TMS and naturally observed video clips of an actor showing hand opening movements or static hands. During the bservation, either direct or averted eye gaze was established between the subject and the observed actor. Our findings show a clear effect of eye gaze on observation-induced motor facilitation. This indicates that the mapping or mirroring’ of others' movements is significantly enhanced when movement observation is accompanied by direct eye gaze compared to averted eye gaze. Our results support the notion that eye contact is a powerful social signal with the ability to direct human non-verbal social behavior. Furthermore, our findings are important for understanding the role of the mirror motor system in the mapping of socially relevant actions. publisher: Elsevier articletitle: Direct eye contact enhances mirroring of others’ movements: A transcranial magnetic stimulation study journaltitle: Neuropsychologia articlelink: http://dx.doi.org/10.1016/j.neuropsychologia.2016.12.011 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved. ispartof: Neuropsychologia vol:95 pages:111-118 ispartof: location:England status: published

Declines in both cortical grey matter and bimanual coordination performance are evident in healthy ageing. However, the relationship between ageing, bimanual performance, and grey matter loss remains unclear, particularly across the whole adult lifespan. Therefore, participants (N = 93, range 20-80 years) performed a complex Bimanual Tracking Task, and structural brain images were obtained using magnetic resonance imaging. Analyses revealed that age correlated negatively with task performance. Voxel-based morphometry analysis revealed that age was associated with grey matter declines in task-relevant cortical areas and that grey matter in these areas was negatively associated with task performance. However, no evidence for a mediating effect of grey matter in age-related bimanual performance decline was observed. We propose a new hypothesis that functional compensation may account for the observed absence of mediation, which is in line with the observed pattern of increased inter-individual variance in performance with age.

Objective To evaluate a modified electrode montage with respect to its effect on tACS-dependent modulation of corticospinal excitability and discomfort caused by neurosensory side effects accompanying stimulation. Methods In a double-blind cross-over design, the classical electrode montage for primary motor cortex (M1) stimulation (two patch electrodes over M1 and contralateral supraorbital area) was compared with an M1 centre-ring montage. Corticospinal excitability was evaluated before, during, immediately after and 15 minutes after tACS (10 min., 20 Hz vs. 30 s low-frequency transcranial random noise stimulation). Results Corticospinal excitability increased significantly during and immediately after tACS with the centre-ring montage. This was not the case with the classical montage or tRNS stimulation. Level of discomfort was rated on average lower with the centre-ring montage. Conclusions In comparison to the classic montage, the M1 centre-ring montage enables a more focal stimulation of the target area and, at the same time, significantly reduces neurosensory side effects, essential for placebo-controlled study designs. This research is funded by the Interuniversity Attraction Poles Programme initiated by the Belgian Science Policy (P7/11). Additional support is provided by the Research Fund KU Leuven (C16/15/070), Flanders Fund for Scientific Research (G.0721.12, G0708.14). K.F.H. is supported by the Internal Funding of the KU Leuven [OT/11/71 F+ fellowship, PDM/15/182]. H.F. is supported by a postdoctoral fellowship from the Flanders Fund for Scientific Research. A.T. and G.B. are supported by Lundbeckfonden (Grant Nr. R118-A11308) and an Interdisciplinary Synergy Grant "Basics" sponsored by NovoNordisk fonden (recipients: Hartwig Siebner, Axel Thielscher and Lars K Hansen, Grant Nr. 11413).

Successfully switching between tasks is critical in many daily activities. Age‐related slowing of this switching behavior has been documented extensively, but the underlying neural mechanisms remain unclear. Here, we investigated the contribution of brain white matter changes associated with myelin alterations to age‐related slowing of switching performance. Diffusion tensor imaging derived radial diffusivity (RD) and magnetization transfer imaging derived magnetization transfer ratio (MTR) were selected as myelin sensitive measures. These metrics were studied in relation to mixing cost (i.e., the increase in reaction time during task blocks that require task switching) on a local‐global switching task in young (n = 24) and older (n = 22) adults. Results showed that higher age was associated with widespread increases in RD and decreases in MTR, indicative of white matter deterioration, possibly due to demyelination. Older adults also showed a higher mixing cost, implying slowing of switching performance. Finally, mediation analyses demonstrated that decreases in MTR of the bilateral superior corona radiata contributed to the observed slowing of switching performance with increasing age. These findings provide evidence for a role of cortico‐subcortical white matter changes in task switching performance deterioration with healthy aging. Hum Brain Mapp 37:4084–4098, 2016. © 2016 Wiley Periodicals, Inc.

Even though it has been suggested that the dorsolateral prefrontal cortex (DLPFC) and dorsal premotor cortex (PMd) are highly involved in the planning of bimanual movements, the exact nature (facilitatory or inhibitory) of their role is not well understood. Using a dual-site transcranial magnetic stimulation (TMS) paradigm, we examined the functional influence from DLPFC and PMd to the contralateral primary cortex (M1) during the preparation of a complex bimanual coordination task in which inter-hand movement frequency was manipulated. Only the left PMd showed inter-hand frequency-specific modulations in the interaction with the contralateral M1. Left PMd-right M1 interaction became facilitatory during the preparation phase when the left hand had to move faster than the right hand, while inhibitory modulation was observed when the movement frequency arrangement was reversed. Interestingly, bilateral DLPFC showed a facilitatory interaction with the contralateral M1s during the preparation period only in difficult conditions, irrespective of the inter-hand frequency ratio, suggesting a less task-specific role in the organization of complex bimanual actions. Observed task-related modulations in DLPFC-M1 and left PMd-right M1 interactions during preparation were significantly correlated with up-coming performance, predicting successful bimanual movements. These observations highlight the distinct roles of DLPFC and left PMd in the preparation of bimanual movements that require a differential contribution of each limb.

Even though declines in sensorimotor performance during healthy aging have been documented extensively, its underlying neural mechanisms remain unclear. Here, we explored whether age-related subcortical atrophy plays a role in sensorimotor performance declines, and particularly during bimanual manipulative performance (Purdue Pegboard Test). The thalamus, putamen, caudate and pallidum of 91 participants across the adult lifespan (ages 20-79 years) were automatically segmented. In addition to studying age-related changes in the global volume of each subcortical structure, local deformations within these structures, indicative of subregional volume changes, were assessed by means of recently developed shape analyses. Results showed widespread age-related global and subregional atrophy, as well as some notable subregional expansion. Even though global atrophy failed to explain the observed performance declines with aging, shape analyses indicated that atrophy in left and right thalamic subregions, specifically subserving connectivity with the premotor, primary motor and somatosensory cortical areas, mediated the relation between aging and performance decline. It is concluded that subregional volume assessment by means of shape analyses offers a sensitive tool with high anatomical resolution in the search for specific age-related associations between brain structure and behavior. publisher: Elsevier articletitle: Subcortical volumetric changes across the adult lifespan: Subregional thalamic atrophy accounts for age-related sensorimotor performance declines journaltitle: Cortex articlelink: http://dx.doi.org/10.1016/j.cortex.2015.01.003 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved. ispartof: Cortex vol:65 pages:128-138 ispartof: location:Italy status: published

Motor coordination is the combination of body movements performed in a well-planned and controlled manner based upon motor commands from the brain. Several interventions have been in practice to improve motor control. Transcranial direct current stimulation (tDCS) is getting a lot of attention these days for its effect in improving motor functions. Studies focusing on the ability of tDCS to improve motor control, inhibition and coordination are sparse. Therefore, the influence of tDCS stimulation at the right dorsolateral prefrontal cortex (DLPFC) on motor control and coordination was investigated, in a sham-controlled double-blinded pseudo-randomized design, with a multi-limb coordination task in healthy young subjects. Number of errors and reaction time were used as outcome parameters. Our findings showed that, anodal tDCS reduced the number of errors only in the heterolateral coordination condition, however there was no change in reaction time. No changes were found for the homolateral and three-limb coordination condition. This work is supported by the Flanders Fund for Scientific Research (G075810) and the Special Research Fund UHasselt. The authors like to thank I-BioStat (Interuniversity Institute for Biostatistics and statistical Bioinformatics, Hasselt University) for their contribution in the statistical analysis.

The goal of this study was to optimize the transcranial magnetic stimulation (TMS) protocol for acquiring a reliable estimate of corticospinal excitability (CSE) using single-pulse TMS. Moreover, the minimal number of stimuli required to obtain a reliable estimate of CSE was investigated. In addition, the effect of two frequently used stimulation intensities [110% relative to the resting motor threshold (rMT) and 120% rMT] and gender was evaluated. Thirty-six healthy young subjects (18 males and 18 females) participated in a double-blind crossover procedure. They received 2 blocks of 40 consecutive TMS stimuli at either 110% rMT or 120% rMT in a randomized order. Based upon our data, we advise that at least 30 consecutive stimuli are required to obtain the most reliable estimate for CSE. Stimulation intensity and gender had no significant influence on CSE estimation. In addition, our results revealed that for subjects with a higher rMT, fewer consecutive stimuli were required to reach a stable estimate of CSE. The current findings can be used to optimize the design of similar TMS experiments. This work is supported by the Flanders Fund for Scientific Research (G075810). Koen Cuypers is supported by the Special Research Fund UHasselt. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Purpose: To assess the effects of atDCS on motor performance in patients with multiple sclerosis (MS). Previously, anodal transcranial direct current stimulation (atDCS) has been shown to improve motor performance in healthy subjects and neurodegenerative populations. However, the effect of atDCS on motor performance is not examined in MS. Methods: In the current study, a sham controlled double-blind crossover design was used to evaluate the effect of 20 minutes of 1mA atDCS or sham tDCS (stDCS) on a unimanual motor sequence-training task, consisting of sequential finger presses on a computer keyboard with the most impaired hand. Patients received stimulation (atDCS or stDCS) during motor training. tDCS was applied over the primary motor cortex contralateral to the most impaired hand. Motor performance was assessed immediately before, during and 30 minutes after stimulation. Results: Although we need to be careful with the interpretation of the data due to lack of power, our results showed no significant effect of atDCS on motor performance. Conclusions: Our findings indicate that atDCS-supported motor training was not able to improve motor performance more than sham-supported motor training. Possibly, the effects of atDCS are mediated by specific MS-related characteristics. Furthermore, increasing atDCS intensity and offering multiple stimulation sessions might be necessary to optimize motor performance resulting from atDCS-supported motor training. We would like to thank the Rehabilitation and MS Centre of Overpelt and especially Prof. Dr. Bart Van Wijmeersch and Mr. Jan Kuppens for helping us with patient recruitment. This work is supported by the Flanders Fund for Scientific Research (G075810). Koen Cuypers is supported by the Special Research Fund UHasselt.

The application of anodal transcranial direct current stimulation (atDCS) to the human brain has been shown to elicit corticospinal (CS) excitability changes. This study evaluated the effect of a single session of atDCS on CS excitability in patients with multiple sclerosis (MS). atDCS and sham tDCS (stDCS) were applied to the primary motor cortex (M1) contralateral to the more severely impaired hand for 20min in a double-blinded crossover design. Changes in CS excitability were assessed using transcranial magnetic stimulation (TMS). The area under the recruitment curves increased significantly after application of atDCS (+56.58%, p=0.023) but not after stDCS. A sigmoidal curve-analysis revealed a higher plateau of the curve after atDCS (+22.2%, p0.001). Our results showed that atDCS over M1 has the ability to increase CS output and projection strength in MS-patients, suggesting that atDCS can be considered during neural rehabilitation to facilitate motor recovery in MS.

Age-related declines in central processing may affect corticospinal (CS) excitability that underlies the emergence of voluntary responses to external stimuli. We used single-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex to explore the evolution of CS excitability in 14 young and ten elderly healthy right-handed participants. Motor-evoked potentials (MEPs) were elicited in the right or left first dorsal interosseus (FDI) during the preparatory and premotor periods of a choice reaction time (CRT) task, which required selection of left or right index finger responses. Both age groups showed significant suppression of CS excitability in the preparatory period. However, suppression was generally less pronounced in older than in young adults. Moreover, our data indicated that a reduced suppression in the right FDI during the preparatory period was associated with longer reaction times (RTs) in older adults only. In the premotor period, both age groups demonstrated comparable facilitation levels towards movement onset. Our findings indicate that increased RTs among older individuals could be directly associated with declines in preparatory processes. ispartof: Age vol:35 issue:5 pages:1705-19 ispartof: location:Netherlands status: published

Perceptual processes play an important role in motor learning. While it is evident that visual information greatly contributes to learning new movements, much less is known about provision of prescriptive proprioceptive information. Here, we investigated whether passive (proprioceptively-based) movement training was comparable to active training for learning a new bimanual task. Three groups practiced a bimanual coordination pattern with a 1∶2 frequency ratio and a 90° phase offset between both wrists with Lissajous feedback over the course of four days: 1) passive training; 2) active training; 3) no training (control). Retention findings revealed that passive as compared to active training resulted in equally successful acquisition of the frequency ratio but active training was more effective for acquisition of the new relative phasing between the limbs in the presence of augmented visual feedback. However, when this feedback was removed, performance of the new relative phase deteriorated in both groups whereas the frequency ratio was better preserved. The superiority of active over passive training in the presence of augmented feedback is hypothesized to result from active involvement in processes of error detection/correction and planning. ispartof: PLoS One vol:7 issue:5 ispartof: location:United States status: published

The long‐term effect of daily somatosensory stimulation with transcutaneous electrical nerve stimulation (TENS) on reorganization of the motor cortex was investigated in a group of neurologically intact humans. The scalp representation of the corticospinal projection to the finger (APB, ADM) and forearm (FCR, ECR) muscles was mapped by means of transcranial magnetic stimulation (TMS) before and after a 3‐week intervention period, using map area and volume, and topographical overlaps between the cortical motor representations of these muscles as primary dependent measures. Findings revealed a significant increase in cortical motor representation of all four muscles for the TENS group from pre to posttest (all, P ≤ 0.026). No significant changes in cortical motor representations were observed in the control group. The present observations highlight the potential benefit of sensory training by means of TENS as a useful complementary therapy in neurorehabilitation. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.

Background. Transcutaneous electrical nerve stimulation (TENS) is commonly used in neurorehabilitation for the treatment of pain and spasticity. Objective. The long-term effects of sensory stimulation by means of TENS on hand sensitivity were investigated in patients with multiple sclerosis (MS). Methods. TENS was applied for 3 weeks (1 hour per day) on the median nerve region of the dominant hand. Sensitivity was assessed by the Semmes—Weinstein monofilaments before and 12 hours following the last intervention as well as 3 weeks later. Results. Long-lasting increases in tactile sensitivity were achieved by repetitive stimulation of sensory afferents with TENS in MS patients but not in healthy subjects. This increased sensitivity was not only restricted to the median nerve area but also expanded to the ulnar nerve area. Remarkably, MS patients reached the same level of sensitivity as healthy subjects immediately after the intervention, and long-term effects were reported 3 weeks later. Conclusions. The findings of this study demonstrated lasting improvements in tactile sensitivity of the fingers as a result of a long-term TENS intervention in MS patients, who ultimately reached a level comparable with that of healthy subjects.