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Interlimb coordination deteriorates as a result of aging. Due to its ubiquity in daily life, a greater understanding of the underlying neurophysiological changes is required. Here, we combined electroencephalography time-frequency spectral power and functional connectivity analyses to provide a comprehensive overview of the neural dynamics underlying the age-related deterioration of interlimb coordination involving all four limbs. Theta, alpha and beta oscillations in the frontal, central and parietal regions were analyzed in twenty younger (18-30 years) and nineteen older adults (65-78 years) during a complex interlimb reaction time task. Reaction time was significantly higher in older adults across all conditions, and the discrepancy between both age groups was largest in the most complex movement condition. Older adults demonstrated enhanced beta event-related desynchronization (i.e., the attenuation of beta power), which further increased along with task complexity and was positively linked to behavioral performance. Theta functional connectivity between frontal, central and parietal regions generally increased with movement complexity, irrespective of age group. In general, frontoparietal alpha band functional connectivity tended to be reduced in older versus younger adults, although these contrasts did not survive multiple comparison corrections. Overall, spectral results suggest that enhanced beta desynchronization in older adults reflects a successful compensatory mechanism to cope with increased difficulty during complex interlimb coordination. Functional connectivity results suggest that theta and alpha band connectivity are prone to respectively task- and age-related modulations. Future work could target these spectral and functional connectivity dynamics through noninvasive brain stimulation to potentially improve interlimb coordination in older adults.

Although, at first sight, one might assume that the human brain is constructed in a roughly symmetric fashion, at closer investigation it becomes apparent that it is inherently asymmetric, i.e., that homotopic brain regions show structural and functional differences [1]. This applies on a structural/anatomical level with, e.g., the right frontal lobe and left occipital lobe tending to protrude over the centerline in a counterclockwise manner called the Yakovlevian torque, but also on the level of brain activity, with certain functions being linked to asymmetric areas of brain activity, such as language which is mainly (but not exclusively) located in the left hemisphere. However, it has been demonstrated that with advancing age, this functional asymmetry of the brain undergoes plastic changes [1]. Over the years, several models have been developed to explain age-related changes in brain asymmetry, such as the Hemispheric Asymmetry Reduction in Older Adults (HAROLD), the right-hemisphere aging, and the Scaffolding Theory of Aging and Cognition (STAC) model ([2] for review). Even though each model succeeds in explaining a subset of brain changes, none accomplishes to serve as an all-encompassing explanation. Therefore, another more recent attempt categorizes the existing evidence on brain aging into three main lines of interpretation, also applicable to brain lateralization: dedifferentiation, neural inefficiency, and compensatory plasticity [3, 4]. In brief, the dedifferentiation model assumes an age-related reduction in the signal-to-noise ratio and specialization of brain regions, resulting in an over-recruitment of task-specific and-unspecific brain regions in older versus younger adults; the neural inefficiency model hypothesizes a diminished signal processing efficiency of the aging brain, leading to a compensatory over-recruitment of task-specific brain regions; and the compensatory neural plasticity model describes (like the dedifferentiation model) an increased task-specific and-unspecific over-recruitment of brain regions with advancing age, however not as the result of malfunctioning but rather of compensatory functional reorganization [4]. As previously stated, advancing age simultaneously impacts lateralization structurally and functionally and a multitude of techniques are employed to study these changes. Structural changes in brain lateralization can be examined using neuroimaging. For example, alterations in the ratio between the two hemispheres' local cortical thickness, gray matter volume (e.g., using voxel-based morphometry analysis) or white matter connectivity (e.g., as assessed with diffusion-weighted imaging) of homologous brain regions can yield information about the brain's structural aging process [4]. At the intersection of brain structure and function, non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) are powerful tools to examine the cortex's lateralization. For example, single-pulse (sp)TMS can be used for investigating cortico-spinal excitability (CSE) and the spatial extent and localization of a muscle's cortical motor representation (i.e., motor map) at the primary motor cortex (M1). In addition, dual-site (ds)TMS can be applied to study the interaction of a motor-related brain region and M1 [5]. This can be done at rest or during a task for investigating the chronometry of CSE or an interaction on a temporal scale of milliseconds. While evidence on the lateralization of the brain's motor function using TMS is scarce, our recent work indicated no evidence for age-related differences in lateralization, i.e., in the ratio of the two hemispheres' CSE, motor map size and volume [6]. Lastly, repetitive (r)TMS can temporarily interfere with a brain region's function, resulting in a measurable change of behavior. For example, repetitive stimulation of Broca's area on the left hemisphere interferes with speech, while stimulating the anatomical homologue has no language-related effect. This allows us to study the laterality of a broader set of brain functions such as cognitive tasks [1]. When focusing on brain activation, functional magnetic resonance imaging (fMRI) is a prominent tool to capture the fluctuations in the blood-oxygen-level-dependent (BOLD) signal over time during a task or at rest. Studying task-induced hemodynamic changes in specific brain regions helps to infer their function. More specifically, brain regions engaging synchronously in response to stimuli suggest shared functionality and, altogether, form a connection or network. In the absence of stimuli, i.e., at rest, brain activity is translated into Editorial www.aging-us.com

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

Objective To systematically review how patient characteristics and/or transcranial direct current stimulation (tDCS) parameters influence tDCS effectiveness in respect to upper limb function post-stroke. Methods Three electronic databases were searched for sham-controlled randomised trials using the Fugl-Meyer Assessment for upper extremity as outcome measure. A meta-analysis and nine subgroup-analyses were performed to identify which tDCS parameters yielded the greatest impact on upper limb function recovery in stroke patients. Results Eighteen high-quality studies (507 patients) were included. tDCS applied in a chronic stage yields greater results than tDCS applied in a (sub)acute stage. Additionally, patients with low baseline upper limb impairments seem to benefit more from tDCS than those with high baseline impairments. Regarding tDCS configuration, all stimulation types led to a significant improvement, but only tDCS applied during therapy, and not before therapy, yielded significant results. A positive dose–response relationship was identified for current/charge density and stimulation duration, but not for number of sessions. Conclusion Our results demonstrate that tDCS improves upper limb function post-stroke. However, its effectiveness depends on numerous factors. Especially chronic stroke patients improved, which is promising as they are typically least amenable to recovery. Significance The current work highlights the importance of several patient-related and protocol-related factors regarding tDCS effectiveness.

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.

Aging is associated with alterations in the brain including structural and metabolic changes. Previous research has focused on neurometabolite level differences associated to age in a variety of brain regions, but the relationship among metabolites across the brain has been much less studied. Investigating these relationships can reveal underlying neurometabolic processes, their interdependency, and their progress throughout the lifespan. Using

BACKGROUND: The dorsal premotor cortex (PMd) is a key region in bimanual coordination. However, causal evidence linking PMd functionality during motor planning and execution to movement quality is lacking. OBJECTIVE: We investigated how left (PMdL) and right PMd (PMdR) are causally involved in planning and executing bimanual movements, using short-train repetitive transcranial magnetic stimulation (rTMS). Additionally, we explored to what extent the observed rTMS-induced modulation of performance could be explained by rTMS-induced modulation of PMd-M1 interhemispheric interactions (IHI). METHODS: Twenty healthy adults (mean age ± SD = 22.85 ± 3.73 years) participated in two sessions, in which either PMdL or PMdR was targeted with rTMS (10 Hz) in a pseudo-randomized design. PMd functionality was transiently modulated during the planning or execution of a complex bimanual task, whereby the participant was asked to track a moving dot by controlling two dials. The effect of rTMS on several performance measures was investigated. Concurrently, rTMS-induced modulation of PMd-M1 IHI was measured using a dual-coil paradigm, and associated with the rTMS-induced performance modulation. RESULTS: rTMS over PMdL during planning increased bilateral hand movement speed (p = 0.03), thereby improving movement accuracy (p = 0.02). In contrast, rTMS over PMdR during both planning and execution induced deterioration of movement stability (p = 0.04). rTMS-induced modulation of PMd-M1 IHI during planning did not predict rTMS-induced performance modulation. CONCLUSION: The current findings support the growing evidence on PMdL dominance during motor planning, as PMdL was crucially involved in planning the speed of each hand, subserving bimanual coordination accuracy. Moreover, the current results suggest that PMdR fulfills a role in continuous adjustment processes of movement. ispartof: BRAIN STIMULATION vol:14 issue:2 pages:423-434 ispartof: location:United States status: published

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

Dual-site transcranial magnetic stimulation (ds-TMS) is well suited to investigate the causal effect of distant brain regions on the primary motor cortex, both at rest and during motor performance and learning. However, given the broad set of stimulation parameters, clarity about which parameters are most effective for identifying particular interactions is lacking. Here, evidence describing inter-and intra-hemispheric interactions during rest and in the context of motor tasks is reviewed. Our aims are threefold: (1) provide a detailed overview of ds-TMS literature regarding inter-and intra-hemispheric connectivity; (2) describe the applicability and contributions of these interactions to motor control, and; (3) discuss the practical implications and future directions. Of the 3659 studies screened, 109 were included and discussed. Overall, there is remarkable variability in the experimental context for assessing ds-TMS interactions, as well as in the use and reporting of stimulation parameters, hindering a quantitative comparison of results across studies. Further studies examining ds-TMS interactions in a systematic manner, and in which all critical parameters are carefully reported, are needed. This work was supported by the KULeuven Special Research Fund grant (C16/15/070), Research Foundation Flanders grant (G089818N and G039821N), and the Excellence of Science grant (EOS 30446199, MEMODYN). SVM (11L9322N) and MH (11F6921N) are funded by a grant from the Research Foundation Flanders. SVM is supported by the UHasselt Special Research Fund grant (BOF21INCENT15).

Multiple Sclerosis (MS) has been shown to significantly impair brain connectivity, as alterations in functional and structural networks have been identified and associated with clinical status, particularly cognitive deficits. We aimed to identify structural connectivity changes in grey matter networks following cognitive rehabilitation (CR) in persons with MS (PwMS). Fifteen long-standing PwMS underwent a 5-week CR-program and five healthy controls (HC) were also investigated. T1-weighted MRI scans and neuropsychological tests were obtained before and after CR. T1-weighted scans were used to examine grey matter networks with graph analytic parameters [betweenness centrality (BC), degree (D), clustering (Cl), path length (PL) and small world properties: connectedness, gamma and lambda values]. Results were analysed at the whole brain level and for each brain lobe. Before CR, PwMS displayed lower values for D in the left parietal lobe (p = 0.009) compared to HC. After CR, significant increases in Cl located in frontal (p = 0.024) and temporal (p = 0.026) regions in PwMS were accompanied by significant decreases in PL located in the right parietal lobe (p = 0.025) and BC globally (p = 0.010). Overall, CR may prevent a network worsening in long-standing PwMS by increasing local efficiency of the brain and therefore facilitating compensation mechanisms.

Purpose Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

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

in the brain from MR-measurements of the current-induced magnetic field B z. Aim: We test the performance of a standard reconstruction algorithm ("projected current density algorithm", PCD, Jeong et al. 2014) for human brain data. We compare it with current flow simulations using personal-ized head models. Methods: 1. We generated ground-truth data for the TES current flow and Bz-field using a detailed head model and SimNIBS (www.simnibs.org). We applied the PCD algorithm to the B z-field and quantified the reconstruction performance by comparison with the ground-truth current flow. We additionally compared the PCD results with simulations using a simple head model ("3c" with scalp, bone and a homogeneous intracranial compartment). 2. We reconstructed the current flow from in-vivo MRCDI data (G€ oksu et al, 2018) with the PCD algorithm. We also used head models of different complexities ("3c" and "4c": scalp, skull, CSF & brain) and optimized their conductivities to minimize the root-mean-square difference between the measured and simulated B z. Results: 1. For simulated B z data, the PCD algorithm only coarsely reconstructed the true current flow. Even the simple head model performed better. 2. For measured B z data, current flows obtained with personalized head models and fitted conductivities explained the measurements better than the current flow reconstructed with the PCD algorithm. This was already the case for the simple head model (3c). The more detailed model (4c) resulted in further statistically significant improvements. However, for all models, the unexplained variance stayed above the noise floor, indicating remaining differences to unknown true current flow. Conclusions: The PCD algorithm has low accuracy for MRCDI data of the brain. However, MRCDI is useful for evaluations and improvements of current flow simulations with anatomically detailed personalized head models.

The net output of the primary motor cortex (M1) is shaped by several (non-)motor brain regions including the dorsal premotor cortex (PMd) which is playing an important role in sensorimotor integration, response selection, bimanual motor control, and motor learning. Previous dual-site transcranial magnetic stimulation (dsTMS) setups mainly investigated the interhemispheric PMd – M1 interactions, as testing the intrahemispheric PMd – M1 interactions yield technical difficulties due to the vicinity of both regions. A novel dsTMS setup was used in a sample of 23 young healthy right-handed adults to probe intrahemispheric left PMd – M1 interactions at rest. Biphasic stimuli were applied to M1 to elicit an MEP of at least 1 mV peak-to-peak amplitude (testing stimulus, TS) in the resting first dorsal interosseus (FDI). The conditioning stimulus (CS) was applied ∼2 cm anterior to M1 at an interstimulus interval (ISI) of 6 ms and an intensity of 75% of the resting motor threshold (rMT). To physiologically test this setup, short-interval intra-cortical inhibition (SICI) was measured with the same coil arrangement, using two coils targeted at M1 (ISI = 3 ms, CS intensity = 75% rMT, TS intensity = 1 mV). First, SICI could robustly be elicited using the novel coil setup. Second, conditioning left PMd lead to a robust modulation of left M1 output when using a CS intensity of 75% rMT. This interaction was mostly found to be inhibitory. However, in some subjects (∼15%) a facilitatory PMd – M1 interaction was seen. This novel coil setup opens new opportunities to measure intrahemispheric PMd – M1 interactions at rest and in different task-related contexts without facing technical difficulties such as large stimulation distances due to coil size or coil heating (particularly in small coils).

Suboptimal inhibitory control is a major factor contributing to motor/cognitive deficits in older age and pathology. Here, we provide novel insights into the neurochemical biomarkers of inhibitory control in healthy young and older adults and highlight putative neurometabolic correlates of deficient inhibitory functions in normal aging. Age-related alterations in levels of glutamate–glutamine complex (Glx), N-acetylaspartate (NAA), choline (Cho), and myo-inositol (mIns) were assessed in the right inferior frontal gyrus (RIFG), pre-supplementary motor area (preSMA), bilateral sensorimotor cortex (SM1), bilateral striatum (STR), and occipital cortex (OCC) with proton magnetic resonance spectroscopy (1H-MRS). Data were collected from 30 young (age range 18–34 years) and 29 older (age range 60–74 years) adults. Associations between age-related changes in the levels of these metabolites and performance measures or reactive/proactive inhibition were examined for each age group. Glx levels in the right striatum and preSMA were associated with more efficient proactive inhibition in young adults but were not predictive for reactive inhibition performance. Higher NAA/mIns ratios in the preSMA and RIFG and lower mIns levels in the OCC were associated with better deployment of proactive and reactive inhibition in older adults. Overall, these findings suggest that altered regional concentrations of NAA and mIns constitute potential biomarkers of suboptimal inhibitory control in aging.

Recent transcranial magnetic stimulation (TMS) research indicated that the ability of the dorsolateral prefrontal cortex (DLPFC) to disinhibit the contralateral primary motor cortex (M1) during motor preparation is an important predictor for bimanual motor performance in both young and older healthy adults. However, this DLPFC-M1 disinhibition is reduced in older adults. Here, we transiently suppressed left DLPFC using repetitive TMS (rTMS) during a cyclical bimanual task and investigated the effect of left DLPFC suppression: (1) on the projection from left DLPFC to the contralateral M1; and (2) on motor performance in 21 young (mean age ± SD = 21.57 ± 1.83) and 20 older (mean age ± SD = 69.05 ± 4.48) healthy adults. As predicted, without rTMS, older adults showed compromised DLPFC-M1 disinhibition as compared to younger adults and less preparatory DLPFC-M1 disinhibition was related to less accurate performance, irrespective of age. Notably, rTMS-induced DLPFC suppression restored DLPFC-M1 disinhibition in older adults and improved performance accuracy right after the local suppression in both age groups. However, the rTMS-induced gain in disinhibition was not correlated with the gain in performance. In sum, this novel rTMS approach advanced our mechanistic understanding of how left DLPFC regulates right M1 and allowed us to establish the causal role of left DLPFC in bimanual coordination. FUNDING This work was supported by the Hercules fund AUHL/11/01 (R-3987) awarded to RM, the Internal Research Fund KU Leuven (C16/15/070), the Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek; FWO) grant (G089818N) and Excellence of Science grant (EOS 30446199, MEMODYN) awarded to SS and colleagues. ACKNOWLEDGMENTS We are thankful to R. Clerckx for his support in programming the bimanual tracking task and for his help in preprocessing the acquired task data. We additionally thank E. Ghasemian Shivran and several master students of KU Leuven and UHasselt who assisted with data collection. Helpful comments on the latest version of the manuscript were given by S. Depestele.

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 (

The role of the dorsolateral prefrontal cortex (DLPFC) in the regulation of bimanual coordination appears to become crucial with aging. Age-related changes in the involvement of the DLPFC in bimanual coordination were studied by using disruptive repetitive TMS (rTMS), inducing a transient lesion in this brain structure. Neurophysiological as well as behavioral effects of suppressing DLPFC during the preparation and execution of a bimanual task were studied in 41 healthy adults (young and old). Specifically, we combined short-train rTMS with single pulse TMS to examine the effect of DLPFC suppression on the interhemispheric projection to the contralateral primary motor cortex (M1) during motor preparation. Findings revealed that compromised interhemispheric DLPFC-M1 disinhibition during motor preparation in older adults resulted in less accurate bimanual performance. The altered DLPFC-M1 interaction in older adults appeared to result from a decline in local inhibitory mechanisms in the DLPFC. In addition, the induction of DLPFC suppression affected task accuracy, but not movement stability in both age groups. Taken together, these results suggest that DLPFC acts as a key regulator in the control of bimanual movement coordination.

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.

Contract grant sponsor: Research Fund of KU Leuven, Belgium; Contract grant number: OT/11/071; Contract grant sponsor: Flanders Fund for Scientific Research; Contract grant numbers: G0721.12 and G0708.14; Contract grant sponsor: Inter-university Attraction Poles Program of the Belgian Federal Government; Contract grant number: Grant P7/11; Contract grant sponsor: Research Foundation-Flanders (FWO); Contract grant sponsor: VIDI Grant from the Netherlands Organization for Scientific Research (NWO); Contract grant number: 639.072.411.