Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection.

Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.

Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair.

Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.

Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance.

Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. VIDEO ABSTRACT.

Association between Inhibitory-Excitatory Balance and Brain Activity Response during Cognitive Flexibility in Young and Older Individuals.

Cognitive flexibility represents the capacity to switch among different mental schemes, providing an adaptive advantage to a changing environment. The neural underpinnings of this executive function have been deeply studied in humans through fMRI, showing that the left inferior frontal cortex (IFC) and the left inferior parietal lobule (IPL) are crucial. Here, we investigated the inhibitory-excitatory balance in these regions by means of γ-aminobutyric acid (GABA+) and glutamate + glutamine (Glx), measured with magnetic resonance spectroscopy, during a cognitive flexibility task and its relationship with the performance level and the local task-induced blood oxygenation level-dependent (BOLD) response in 40 young (18-35 years; 26 female) and 40 older (18-35 years; 21 female) human adults. As the IFC and the IPL are richly connected regions, we also examined whole-brain effects associated with their local metabolic activity. Results did not show absolute metabolic modulations associated with flexibility performance, but the performance level was related to the direction of metabolic modulation in the IPL with opposite patterns in young and older individuals. The individual inhibitory-excitatory balance modulation showed an inverse relationship with the local BOLD response in the IPL. Finally, the modulation of inhibitory-excitatory balance in IPL was related to whole-brain effects only in older individuals. These findings show disparities in the metabolic mechanisms underlying cognitive flexibility in young and older adults and their association with the performance level and BOLD response. Such metabolic differences are likely to play a role in executive functioning during aging and specifically in cognitive flexibility.

Combining muscle-computer interface guided training with bihemispheric tDCS improves upper limb function in patients with chronic stroke.

Transcranial direct current stimulation (tDCS) may facilitate neuroplasticity but with a limited effect when administered while patients with stroke are at rest. Muscle-computer interface (MCI) training is a promising approach for training patients with stroke even if they cannot produce overt movements. However, using tDCS to enhance MCI training has not been investigated. We combined bihemispheric tDCS with MCI training of the paretic wrist and examined the effect of this intervention in patients with chronic stroke. A crossover, double-blind, randomized trial was conducted. Twenty-six patients with chronic stroke performed MCI wrist training for three consecutive days at home while receiving either real tDCS or sham tDCS in counterbalanced order and separated by at least 8 mo. The primary outcome measure was the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE) that was measured 1 wk before training, on the first training day, on the last training day, and 1 wk after training. There was neither a significant difference in the baseline FMA-UE score between groups nor between intervention periods. Patients improved 3.9 ± 0.6 points in FMA-UE score when receiving real tDCS, and 1.0 ± 0.7 points when receiving sham tDCS (P = 0.003). In addition, patients also showed continuous improvement in their motor control of the MCI tasks over the training days. Our study showed that the training paradigm could lead to functional improvement in patients with chronic stroke. We argue that appropriate MCI training in combination with bihemispheric tDCS could be a useful adjuvant for neurorehabilitation in patients with stroke.NEW & NOTEWORTHY Bihemispheric tDCS combined with a novel MCI training for motor control of wrist extensor can improve upper limb function especially a training-specific effect on the wrist movement in patients with chronic stroke. The training regimen can be personalized with adjustments made daily to accommodate the functional change throughout the intervention. This demonstrates that bihemispheric tDCS with MCI training could complement conventional poststroke neurorehabilitation.

Frequency-dependent connectivity in large-scale resting-state brain networks during sleep.

Functional connectivity (FC) during sleep has been shown to break down as non-rapid eye movement (NREM) sleep deepens before returning to a state closer to wakefulness during rapid eye movement (REM) sleep. However, the specific spatial and temporal signatures of these fluctuations in connectivity patterns remain poorly understood. This study aimed to investigate how frequency-dependent network-level FC fluctuates during nocturnal sleep in healthy young adults using high-density electroencephalography (hdEEG). Specifically, we examined source-localized FC in resting-state networks during NREM2, NREM3 and REM sleep (sleep stages scored using a semi-automatic procedure) in the first three sleep cycles of 29 participants. Our results showed that FC within and between all resting-state networks decreased from NREM2 to NREM3 sleep in multiple frequency bands and all sleep cycles. The data also highlighted a complex modulation of connectivity patterns during the transition to REM sleep whereby delta and sigma bands hosted a persistence of the connectivity breakdown in all networks. In contrast, a reconnection occurred in the default mode and the attentional networks in frequency bands characterizing their organization during wake (i.e., alpha and beta bands, respectively). Finally, all network pairs (except the visual network) showed higher gamma-band FC during REM sleep in cycle three compared to earlier sleep cycles. Altogether, our results unravel the spatial and temporal characteristics of the well-known breakdown in connectivity observed as NREM sleep deepens. They also illustrate a complex pattern of connectivity during REM sleep that is consistent with network- and frequency-specific breakdown and reconnection processes.

Baseline GABA+ levels in areas associated with sensorimotor control predict initial and long-term motor learning progress.

Synaptic plasticity relies on the balance between excitation and inhibition in the brain. As the primary inhibitory and excitatory neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu), play critical roles in synaptic plasticity and learning. However, the role of these neurometabolites in motor learning is still unclear. Furthermore, it remains to be investigated which neurometabolite levels from the regions composing the sensorimotor network predict future learning outcome. Here, we studied the role of baseline neurometabolite levels in four task-related brain areas during different stages of motor skill learning under two different feedback (FB) conditions. Fifty-one healthy participants were trained on a bimanual motor task over 5 days while receiving either concurrent augmented visual FB (CA-VFB group, N = 25) or terminal intrinsic visual FB (TA-VFB group, N = 26) of their performance. Additionally, MRS-measured baseline GABA+ (GABA + macromolecules) and Glx (Glu + glutamine) levels were measured in the primary motor cortex (M1), primary somatosensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and medial temporal cortex (MT/V5). Behaviorally, our results revealed that the CA-VFB group outperformed the TA-VFB group during task performance in the presence of augmented VFB, while the TA-VFB group outperformed the CA-VFB group in the absence of augmented FB. Moreover, baseline M1 GABA+ levels positively predicted and DLPFC GABA+ levels negatively predicted both initial and long-term motor learning progress in the TA-VFB group. In contrast, baseline S1 GABA+ levels positively predicted initial and long-term motor learning progress in the CA-VFB group. Glx levels did not predict learning progress. Together, these findings suggest that baseline GABA+ levels predict motor learning capability, yet depending on the FB training conditions afforded to the participants.

Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism.

Preliminary data and clinical experience have suggested an increased risk of abnormal uterine bleeding (AUB) in women of reproductive age treated with anticoagulants, but solid data are lacking. The TEAM-VTE study was an international multicenter prospective cohort study in women aged 18 to 50 years diagnosed with acute venous thromboembolism (VTE). Menstrual blood loss was measured by pictorial blood loss assessment charts at baseline for the last menstrual cycle before VTE diagnosis and prospectively for each cycle during 3 to 6 months of follow-up. AUB was defined as an increased score on the pictorial blood loss assessment chart (>100 or >150) or self-reported AUB. AUB-related quality of life (QoL) was assessed at baseline and the end of follow-up using the Menstrual Bleeding Questionnaire. The study was terminated early because of slow recruitment attributable to the COVID-19 pandemic. Of the 98 women, 65 (66%) met at least one of the 3 definitions of AUB during follow-up (95% confidence interval [CI], 57%-75%). AUB occurred in 60% of women (36 of 60) without AUB before VTE diagnosis (new-onset AUB; 95% CI, 47%-71%). Overall, QoL decreased over time, with a mean Menstrual Bleeding Questionnaire score increase of 5.1 points (95% CI, 2.2-7.9), but this decrease in QoL was observed only among women with new-onset AUB. To conclude, 2 of every 3 women who start anticoagulation for acute VTE experience AUB, with a considerable negative impact on QoL. These findings should be a call to action to increase awareness and provide evidence-based strategies to prevent and treat AUB in this setting. This was an academic study registered at www.clinicaltrials.gov as #NCT04748393; no funding was received.

MRS-assessed brain GABA modulation in response to task performance and learning.

Gamma-aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the human brain, has long been considered essential in human behavior in general and learning in particular. GABA concentration can be quantified using magnetic resonance spectroscopy (MRS). Using this technique, numerous studies have reported associations between baseline GABA levels and various human behaviors. However, regional GABA concentration is not fixed and may exhibit rapid modulation as a function of environmental factors. Hence, quantification of GABA levels at several time points during the performance of tasks can provide insights into the dynamics of GABA levels in distinct brain regions. This review reports on findings from studies using repeated measures (n = 41) examining the dynamic modulation of GABA levels in humans in response to various interventions in the perceptual, motor, and cognitive domains to explore associations between GABA modulation and human behavior. GABA levels in a specific brain area may increase or decrease during task performance or as a function of learning, depending on its precise involvement in the process under investigation. Here, we summarize the available evidence and derive two overarching hypotheses regarding the role of GABA modulation in performance and learning. Firstly, training-induced increases in GABA levels appear to be associated with an improved ability to differentiate minor perceptual differences during perceptual learning. This observation gives rise to the 'GABA increase for better neural distinctiveness hypothesis'. Secondly, converging evidence suggests that reducing GABA levels may play a beneficial role in effectively filtering perceptual noise, enhancing motor learning, and improving performance in visuomotor tasks. Additionally, some studies suggest that the reduction of GABA levels is related to better working memory and successful reinforcement learning. These observations inspire the 'GABA decrease to boost learning hypothesis', which states that decreasing neural inhibition through a reduction of GABA in dedicated brain areas facilitates human learning. Additionally, modulation of GABA levels is also observed after short-term physical exercise. Future work should elucidate which specific circumstances induce robust GABA modulation to enhance neuroplasticity and boost performance.

Targeted memory reactivation during post-learning sleep does not enhance motor memory consolidation in older adults.

Targeted memory reactivation (TMR) during sleep enhances memory consolidation in young adults by modulating electrophysiological markers of neuroplasticity. Interestingly, older adults exhibit deficits in motor memory consolidation, an impairment that has been linked to age-related degradations in the same sleep features sensitive to TMR. We hypothesised that TMR would enhance consolidation in older adults via the modulation of these markers. A total of 17 older participants were trained on a motor task involving two auditory-cued sequences. During a post-learning nap, two auditory cues were played: one associated to a learned (i.e., reactivated) sequence and one control. Performance during two delayed re-tests did not differ between reactivated and non-reactivated sequences. Moreover, both associated and control sounds modulated brain responses, yet there were no consistent differences between the auditory cue types. Our results collectively demonstrate that older adults do not benefit from specific reactivation of a motor memory trace by an associated auditory cue during post-learning sleep. Based on previous research, it is possible that auditory stimulation during post-learning sleep could have boosted motor memory consolidation in a non-specific manner.

Capturing Mercury-197m/g for Auger Electron Therapy and Cancer Theranostic with Sulfur-Containing Cyclen-Based Macrocycles.

The interest in mercury radioisotopes, 197mHg (t1/2 = 23.8 h) and 197gHg (t1/2 = 64.14 h), has recently been reignited by the dual diagnostic and therapeutic nature of their nuclear decays. These isotopes emit γ-rays suitable for single photon emission computed tomography imaging and Auger electrons which can be exploited for treating small and metastatic tumors. However, the clinical utilization of 197m/gHg radionuclides is obstructed by the lack of chelators capable of securely binding them to tumor-seeking vectors. This work aims to address this challenge by investigating a series of chemically tailored macrocyclic platforms with sulfur-containing side arms, namely, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), and 1,7-bis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,10-diacetic acid (DO2A2S). 1,4,7,10-Tetrazacyclododecane-1,4,7,10-tetracetic acid (DOTA), the widest explored chelator in nuclear medicine, and the nonfunctionalized backbone 1,4,7,10-tetrazacyclododecane (cyclen) were considered as well to shed light on the role of the sulfanyl arms in the metal coordination. To this purpose, a comprehensive experimental and theoretical study encompassing aqueous coordination chemistry investigations through potentiometry, nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, and density functional theory (DFT) calculations, as well as concentration- and temperature-dependent [197m/gHg]Hg2+ radiolabeling and in vitro stability assays in human serum was conducted. The obtained results reveal that the investigated chelators rapidly complex Hg2+ in aqueous media, forming extremely thermodynamically stable 1:1 metal-to-ligand complexes with superior stabilities compared to those of DOTA or cyclen. These complexes exhibited 6- to 8-fold coordination environments, with donors statically bound to the metal center, as evidenced by the presence of 1H-199Hg spin-spin coupling via NMR. A similar octacoordinated environment was also found for DOTA in both solution and solid state, but in this case, multiple slowly exchanging conformers were detected at ambient temperature. The sulfur-rich ligands quantitatively incorporate cyclotron-produced [197m/gHg]Hg2+ under relatively mild reaction conditions (pH = 7 and T = 50 °C), with the resulting radioactive complexes exhibiting decent stability in human serum (up to 75% after 24 h). By developing viable chelators and understanding the impact of structural modifications, our research addresses the scarcity of suitable chelating agents for 197m/gHg, offering promise for its future in vivo application as a theranostic Auger-emitter radiometal.

Electric Field Gradient Calculations for Ice VIII and IX Using Polarizable Embedding: A Comparative Study on Classical Computers and Quantum Simulators.

We test the performance of the polarizable embedding variational quantum eigensolver self-consistent field (PE-VQE-SCF) model for computing electric field gradients with comparisons to conventional complete active space self-consistent-field (CASSCF) calculations and experimental results. We compute quadrupole coupling constants for ice VIII and ice IX. We find close agreement of the quantum-computing PE-VQE-SCF results with the results from the classical PE-CASSCF calculations and with experiment. Furthermore, we observe that the inclusion of the environment is crucial for obtaining results that match the experimental data. The calculations for ice VIII are within the experimental uncertainty for both CASSCF and VQE-SCF for oxygen and lie close to the experimental value for ice IX as well. With the VQE-SCF, which is based on an adaptive derivative-assembled problem-tailored (ADAPT) ansatz, we find that the inclusion of the environment and the size of the different basis sets do not directly affect the gate counts. However, by including an explicit environment, the wavefunction and therefore the optimization problem become more complicated, which usually results in the need to include more operators from the operator pool, thereby increasing the depth of the circuit.

Neurological soft signs in adolescents are associated with brain structure.

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

On the performance of HRPA(D) for NMR spin-spin coupling constants: Smaller molecules, aromatic and fluoroaromatic compounds.

In this study, the performance of the doubles-corrected higher random-phase approximation [HRPA(D)] has been investigated in calculations of nuclear magnetic resonance spin-spin coupling constants (SSCCs) for 58 molecules with the experimental values used as the reference values. HRPA(D) is an approximation to the second-order polarization propagator approximation (SOPPA) and is, therefore, computationally less expensive than SOPPA. HRPA(D) performs comparable and sometimes even better than SOPPA, and therefore, when calculating SSCCs, it should be considered as an alternative to SOPPA. Furthermore, it was investigated whether a coupled-cluster singles, doubles and perturbative triples [CCSD(T)] or Møller-Plesset second order (MP2) geometry optimization was optimal for a SOPPA and a HRPA(D) SSCC calculation for eight smaller molecules. CCSD(T) is the optimal geometry optimization for the SOPPA calculation, and MP2 was optimal for HRPA(D) SSCC calculations.

Performance of range-separated long-range SOPPA short-range density functional theory method for vertical excitation energies.

In this paper, benchmark results are presented on the calculation of vertical electronic excitation energies using a long-range second-order polarization propagator approximation (SOPPA) description with a short-range density functional theory description based on the Perdew-Burke-Ernzerhof (PBE) functional. The excitation energies are investigated for 132 singlet states and 71 triplet states across 28 medium-sized organic molecules. The results show that overall SOPPA-srPBE always performs better than PBE and that SOPPA-srPBE performs better than SOPPA for singlet states, but slightly worse than SOPPA for triplet states when CC3 results are the reference values.

Divergences in classical and quantum linear response and equation of motion formulations.

Calculating molecular properties using quantum devices can be performed through the quantum linear response (qLR) or, equivalently, the quantum equation of motion (qEOM) formulations. Different parameterizations of qLR and qEOM are available, namely naïve, projected, self-consistent, and state-transfer. In the naïve and projected parameterizations, the metric is not the identity, and we show that it depends on redundant orbital rotations. This dependency may lead to divergences in the excitation energies for certain choices of the redundant orbital rotation parameters in an idealized noiseless setting. Furthermore, this leads to a significant variance when calculations include statistical noise from finite quantum sampling.

The variational quantum eigensolver self-consistent field method within a polarizable embedded framework.

We formulate and implement the Variational Quantum Eigensolver Self Consistent Field (VQE-SCF) algorithm in combination with polarizable embedding (PE), thereby extending PE to the regime of quantum computing. We test the resulting algorithm, PE-VQE-SCF, on quantum simulators and demonstrate that the computational stress on the quantum device is only slightly increased in terms of gate counts compared to regular VQE-SCF. On the other hand, no increase in shot noise was observed. We illustrate how PE-VQE-SCF may lead to the modeling of real chemical systems using a simulation of the reaction barrier of the Diels-Alder reaction between furan and ethene as an example.

On the geometry dependence of the nuclear magnetic resonance chemical shift of mercury in thiolate complexes: A relativistic density functional theory study.

Thiolate containing mercury(II) complexes of the general formula [Hg(SR) n ] 2 - n have been of great interest since the toxicity of mercury was recognized. 199Hg nuclear magnetic resonance spectroscopy (NMR) is a powerful tool for characterization of mercury complexes. In this work, the Hg shielding constants in a series of [Hg(SR) n ] 2 - n complexes are therefore investigated computationally with particular emphasis on their geometry dependence. Geometry optimizations and NMR chemical shift calculations are performed at the density functional theory (DFT) level with both the zeroth-order regular approximation (ZORA) and four-component relativistic methods. The four exchange-correlation (XC) functionals PBE0, PBE, B3LYP, and BLYP are used in combination with either Dyall's Gaussian-type (GTO) or Slater-type orbitals (STOs) basis sets. Comparing ZORA and four-component calculations, one observes that the calculated shielding constants for a given molecular geometry have a constant difference of ∼ 1070 ppm. This confirms that ZORA is an acceptable relativistic method to compute NMR chemical shifts. The combinations of four-component/PBE0/v3z and ZORA/PBE0/QZ4P are applied to explore the geometry dependence of the isotropic shielding. For a given coordination number, the distance between mercury and sulfur is the key factor affecting the shielding constant, while changes in bond and dihedral angles and even different side groups have relatively little impact.

The Importance of Anharmonicity and Solvent Effects on the OH Radical Attack on Nucleobases.

Previous theoretical investigations of the reactions between an OH radical and a nucleobase have stated the most important pathways to be the C5-C6 addition for pyrimidines and the C8 addition for purines. Furthermore, the abstraction of a methyl hydrogen from thymine has also been proven an important pathway. The conclusions were based solely on gas-phase calculations and harmonic vibrational frequencies. In this paper, we supplement the calculations by applying solvent corrections through the polarizable continuum model (PCM) solvent model and applying anharmonicity in order to determine the importance of anharmonicity and solvent effects. Density functional theory (DFT) at the ωB97-D/6-311++G(2df,2pd) level with the Eckart tunneling correction is used. The total reaction rate constants are found to be 1.48 ×10-13 cm3 molecules-1s-1 for adenine, 1.02 ×10-11 cm3 molecules-1s-1 for guanine, 5.52 ×10-13 cm3 molecules-1s-1 for thymine, 1.47 ×10-13 cm3 molecules-1s-1 for cytosine and 7.59 ×10-14 cm3 molecules-1s-1 for uracil. These rates are found to be approximately two orders of magnitude larger than experimental values. We find that the tendencies observed for preferred pathways for reactions calculated in a solvent are comparable to the preferred pathways for reactions calculated in gas phase. We conclude that applying a solvent has a larger impact on more parameters compared to the inclusion of anharmonicity. For some reactions the inclusion of anharmonicity has no effect, whereas for others it does impact the energetics.

Task-Related Modulation of Sensorimotor GABA+ Levels in Association with Brain Activity and Motor Performance: A Multimodal MRS-fMRI Study in Young and Older Adults.

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.