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•TMS and MRS reveal complementary and comprehensive information on neurotransmission.•TMS-MRS combinations can uncover healthy and pathological brain functionality.•Repetitive TMS can modulate metabolite levels.•TMS-MRS combinations may probe connectivity and dedicated network interactions. 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.

•Randomized, sham-controlled, within-subject study of β-tACS in younger adults.•Fixed 20 Hz-, individualized β-, and sham EEG-tACS during a bimanual motor task.•Individualized β-tACS improved bimanual motor control versus fixed- and sham tACS.•Individualized β-tACS enhanced N β desynchronization during planning.•β desynchronization was only related to motor control improvements during planning. To unveil if 3 mA peak-to-peak high-definition β transcranial alternating current stimulation (tACS) applied over C4 –the area overlaying the right sensorimotor cortex–enhances bimanual motor control and affects movement-related β desynchronization (MRβD), thereby providing causal evidence for the polymorphic role of MRβD in motor control. In this sham-controlled, crossover study, 36 participants underwent 20 min of fixed 20 Hz tACS; tACS individualized to peak β activity during motor planning at baseline; and sham tACS randomized over three consecutive days. Each participant underwent all three conditions for a total of 108 sessions, ensuring within-subject comparisons. Before, during, and after tACS, participants performed a bimanual tracking task (BTT) and 64-channel electroencephalography (EEG) data was measured. Spatiotemporal and temporal clustering statistics with underlying linear mixed effect models were used to test our hypotheses. Individualized tACS significantly improved bimanual motor control, both online and offline, and increased online MRβD during motor planning compared to fixed tACS. No offline effects of fixed and individualized tACS on MRβD were found compared to sham, although tACS effects did trend towards the hypothesized MRβD increase. Throughout the course of the study, MRβD and bimanual motor performance increased. Exclusively during motor planning, MRβD was positively associated to bimanual motor performance improvements, emphasizing the functionally polymorphic role of MRβD. tACS was well tolerated and no side-effects occurred. Individualized β-tACS improves bimanual motor control and enhances motor planning MRβD online. These findings provide causal evidence for the importance of MRβD when planning complex motor behavior. [Display omitted]

•GABAAR availability was higher in older as compared to young adults.•GABAAR activity and GABA+ levels were similar across age groups.•GABAAR availability, GABAAR activity and GABA+ levels were not correlated. 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.

•Metabolites levels were measured from seven brain regions in young and older people.•Graph theory was used to investigate metabolites relationships within and across regions.•The resulting metabolic networks strongly suggest common underlying properties.•Choline showed a rich interregional network, indicating a global homogeneous distribution.•Creatine related consistently to N-acetylaspartate and choline across the brain areas in both age groups. 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 1H-MRS, we investigated the relationship among metabolite concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-Inositol (mIns) and glutamate-glutamine complex (Glx) in seven voxel locations, i.e., bilateral sensorimotor cortex, bilateral striatum, pre-supplementary motor area, right inferior frontal gyrus and occipital cortex. These measurements were performed on 59 human participants divided in two age groups: young adults (YA: 23.2 ± 4.3; 18–34 years) and older adults (OA: 67.5 ± 3.9; 61–74 years). Our results showed age-related differences in NAA, Cho, and mIns across brain regions, suggesting the presence of neurodegeneration and altered gliosis. Moreover, associative patterns among NAA, Cho and Cr were observed across the selected brain regions, which differed between young and older adults. Whereas most of metabolite concentrations were inhomogeneous across different brain regions, Cho levels were shown to be strongly related across brain regions in both age groups. Finally, we found metabolic associations between homologous brain regions (SM1 and striatum) in the OA group, with NAA showing a significant correlation between bilateral sensorimotor cortices (SM1) and mIns levels being correlated between the bilateral striata. We posit that a network perspective provides important insights regarding the potential interactions among neurochemicals underlying metabolic processes at a local and global level and their relationship with aging.

Background Type 2 diabetes (T2DM) affects brain structure and function, and is associated with an increased risk of dementia and mild cognitive impairment. It is known that exercise training has a beneficial effect on cognition and brain structure and function, at least in healthy people, but the impact of exercise training on these aspects remains to be fully elucidated in patients with T2DM. Objective To determine the impact of exercise training on cognition and brain structure and function in T2DM, and identify the involved physiological mediators. Methods This paper systematically reviews studies that evaluate the effect of exercise training on cognition in T2DM, and aims to indicate the most beneficial exercise modality for improving or preserving cognition in this patient group. In addition, the possible physiological mediators and targets involved in these improvements are narratively described in the second part of this review. Papers published up until the 14th of January 2025 were searched by means of the electronic databases PubMed, Embase, and Web of Science. Studies directly investigating the effect of any kind of exercise training on the brain or cognition in patients with T2DM, or animal models thereof, were included, with the exception of human studies assessing cognition only at one time point, and studies combining exercise training with other interventions (e.g. dietary changes, cognitive training, etc.). Study quality was assessed by means of the TESTEX tool for human studies, and the CAMARADES tool for animal studies. Results For the systematic part of the review, 22 papers were found to be eligible. 18 out of 22 papers (81.8%) showed a significant positive effect of exercise training on cognition in T2DM, of which two studies only showed significant improvements in the minority of the cognitive tests. Four papers (18.2%) could not find a significant effect of exercise on cognition in T2DM. Resistance and endurance exercise were found to be equally effective for achieving cognitive improvement. Machine-based power training is seemingly more effective than resistance training with body weight and elastic bands to reach cognitive improvement. In addition, BDNF, lactate, leptin, adiponectin, GSK3β, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as plausible mediators directly from studies investigating the effect of exercise training on brain structure and function in T2DM. Via these mediators, exercise training induces multiple beneficial brain changes, such as increased neuroplasticity, increased insulin sensitivity, and decreased inflammation. Conclusion Overall, exercise training beneficially affects cognition and brain structure and function in T2DM, with resistance and endurance exercise having similar effects. However, there is a need for additional studies, and more methodological consistency between different studies in order to define an exercise program optimal for improving cognition in T2DM. Furthermore, we were able to define several mediators involved in the effect of exercise training on cognition in T2DM, but further research is necessary to unravel the entire process. Key points The current body of literature demonstrates a positive effect of exercise training on the brain in T2DM, but simultaneously emphasizes the need for additional studies on this topic. BDNF, lactate, leptin, adiponectin, GSK3β, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway have been identified as factors mediating the effect of exercise on the brain in T2DM. There is a need for a standardised cognitive test battery to investigate the effect of exercise on cognition in T2DM.

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.

•GABA levels were lower in older as compared to young adults for the SM1 voxel only.•The association between GABA levels and motor performance was task-dependent.•Age affected the association between GABA levels and motor performance. 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 suggest 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 dorsolateral 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 determining 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.

•The interplay between premotor-motor network dynamics, GABA+ levels, and reaction time was explored in young and older adults.•Bilateral SMC GABA+ levels are reduced in older adults.•Older adults show deficiencies in task-related GABAB receptor-mediated neurotransmission in the (pre)motor-motor network.•Altered (pre)motor-motor network dynamics and slower reaction times in older adults are at least in part explained by lower SMC GABA+ levels. 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.

The cerebellum is essential for motor control and learning, relying on structural and functional integrity. Age-related atrophy leads to Purkinje cell loss, but subtle neurochemical changes in GABA, Glx (glutamate + glutamine), and glutathione (GSH) may precede degeneration and contribute to motor decline. 25 younger (YA) and 25 older adults (OA) were included in this study. Magnetic resonance spectroscopy (MRS), using the MEGA-PRESS sequence, was used to investigate how age affects GABA, Glx and GSH levels in the right cerebellar hemisphere, and their relationship with motor performance, measured using a visuomotor bimanual tracking task (BTT). In line with previous work YA outperformed OA on both the simple and complex task variants of the BTT. Furthermore, YA demonstrated faster short-term motor learning as compared to OA. On the metabolic level, no significant age group differences in cerebellar GABA, Glx or GSH levels, nor any task-related modulation of GABA or Glx were observed. Additionally, neither baseline neurometabolite levels nor their modulation predicted motor performance or learning. These results align with previous research suggesting that neurometabolic aging is region-specific, with the cerebellum potentially being more resilient due to its slower aging process. Since neither baseline nor task-related modulation of GABA, Glx, or GSH predicted motor performance or learning, cerebellar neurometabolite concentrations may not directly underlie age-related behavioral changes. Instead, volumetric decline and changes in structural and functional connectivity in the aging cerebellum may play a more significant role in motor decline as compared to neurochemical alterations. Nonetheless, it is important to consider that motor performance and learning rely on distributed brain networks-including cortical and subcortical structures-which also undergo age-related changes and may contribute to observed behavioral declines. While our findings do not support a direct role of cerebellar neurometabolite levels in age-related motor performance differences, they underscore the complexity of neurochemical aging.

Although tDCS has been shown to improve motor learning, previous studies reported rather small effects. Since physiological effects of tDCS depend on intensity, the present study evaluated this parameter in order to enhance the effect of tDCS on skill acquisition. The effect of different stimulation intensities of anodal tDCS (atDCS) was investigated in a double blind, sham controlled crossover design. In each condition, thirteen healthy subjects were instructed to perform a unimanual motor (sequence) learning task. Our results showed (1) a significant increase in the slope of the learning curve and (2) a significant improvement in motor performance at retention for 1.5 mA atDCS as compared to sham tDCS. No significant differences were reported between 1 mA atDCS and sham tDCS; and between 1.5 mA atDCS and 1 mA atDCS.