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Verbal Working memory (vWM) capacity measures the ability to maintain and manipulate verbal information for a short period of time. The specific neural correlates of this construct are still a matter of debate. The aim of this study was to conduct a coordinate-based meta-analysis of 42 fMRI studies on visual vWM in healthy subjects ( = 795, males = 459, females = 325, unknown = 11; age range: 18-75). The studies were obtained after an exhaustive literature search on PubMed, Scopus, Web of Science, and Brainmap database. We analyzed regional activation differences during fMRI tasks with the anisotropic effect-size version of seed-based d mapping software (ES-SDM). The results were further validated by performing jackknife sensitivity analyses and heterogeneity analyses. We investigated the effect of numerous relevant influencing factors by fitting corresponding linear regression models. We isolated consistent activation in a network containing fronto-parietal areas, right cerebellum, and basal ganglia structures. Regarding lateralization, the results pointed toward a bilateral frontal activation, a left-lateralization of parietal regions and a right-lateralization of the cerebellum, indicating that the left-hemisphere concept of vWM should be reconsidered. We also isolated activation in regions important for response inhibition, emphasizing the role of attentional control in vWM. Moreover, we found a significant influence of mean reaction time, load, and age on activation associated with vWM. Activation in left medial frontal gyrus, left precentral gyrus, and left precentral gyrus turned out to be positively associated with mean reaction time whereas load was associated with activation across the PFC, fusiform gyrus, parietal cortex, and parts of the cerebellum. In the latter case activation was mainly detectable in both hemispheres whereas the influence of age became manifest predominantly in the left hemisphere. This led us to conclude that future vWM studies should take these factors into consideration.

Recent functional magnetic resonance imaging (fMRI) studies revealed lower neural activation during processing of an n-back task following working memory training, indicating a training-related increase in neural efficiency. In the present study, we asked if the training induced regional neural activation is accompanied by changes in glucose consumption. An active control and an experimental group of healthy middle-aged volunteers conducted 32 sessions of visual and verbal n-back trainings over 8 weeks. We analyzed data of 52 subjects (25 experimental and 27 control group) for practice effects underlying verbal working memory task and 50 subjects (24 experimental and 26 control group) for practice effects underlying visual WM task. The samples of these two tasks were nearly identical (data of 47 subjects were available for both verbal and visual tasks). Both groups completed neuroimaging sessions at a hybrid PET/MR system before and after training. Each session included criterion task fMRI and resting state positron emission tomography with FDG (FDG-PET). As reported previously, lower neural activation following n-back training was found in regions of the fronto-parieto-cerebellar circuitry during a verbal n-back task. Notably, these changes co-occurred spatially with a higher relative FDG-uptake. Decreased neural activation within regions of the fronto-parietal network during visual n-back task did not show co-occurring changes in relative FDG-uptake. There was no direct association between neuroimaging and behavioral measures, which could be due to the inter-subjects’ variability in reaching capacity limits. Our findings provide new details for working memory training induced neural efficiency on a molecular level by integrating FDG-PET and fMRI measures.

Cerebral palsy (CP) is an umbrella term encompassing motor and often additional disabilities, resulting from insult to the developing brain and remaining throughout life. Imaging-detected alterations in white matter microstructure affect not only motor but also sensorimotor pathways. In this context, piano training is believed to promote sensorimotor rehabilitation for the multiplicity of skills and neuronal processes it involves and integrates. However, it remains unknown how this contribution may occur. Here, effects of 1.5 years of piano training in an adolescent with unilateral CP were investigated through tests of manual function and by comparing fractional anisotropy, mean diffusivity, radial and axial diffusivity in neuronal pathways pre- vs. post-training. In the absence of a control condition and of data from a larger cohort, both probabilistic neighborhood and deterministic tractography were employed to reduce bias associated with a single-case analysis and/or with user-input. No changes in manual function were detected with the tests performed. In turn, the two tractography methods yielded similar values for all studied metrics. Furthermore, post-hoc analyses yielded increased fractional anisotropy accompanied by decreases in mean diffusivity in the bilateral dorsal cingulate that were at least as large as and more consistent than in the bilateral corticospinal tract. This suggests contributions of training to the development of non-motor processes. Reduced anisotropy and correspondingly high mean diffusivity were observed for the bilateral corticospinal tract as well as for the right arcuate and the inferior longitudinal fasciculus, two sensory processing-related pathways, confirming the importance of sensorimotor rehabilitation in CP.

Neural correlates of working memory training remain a matter of debate, especially in older adults. We used functional magnetic resonance imaging (fMRI) together with an n-back task to measure brain plasticity in healthy middle-aged adults following an 8-week adaptive online verbal working memory training. Participants performed 32 sessions of this training on their personal computers. In addition, we assessed direct effects of the training by applying a verbal working memory task before and after the training. Participants (mean age 55.85 ± 4.24 years) were pseudo-randomly assigned to the experimental group (n=30) or an active control group (n=27). Training resulted in an activity decrease in regions known to be involved in verbal working memory (i.e., fronto-parieto-cerebellar circuitry and subcortical regions), indicating that the brain became potentially more efficient after the training. These activation decreases were associated with a significant performance improvement in the n-back task inside the scanner reflecting considerable practice effects. In addition, there were training-associated direct effects in the additional, external verbal working memory task (i.e., HAWIE-R digit span forward task), indicating that the training generally improved performance in this cognitive domain. These results led us to conclude that even at advanced age cognitive training can improve working memory capacity and increase neural efficiency in specific regions or networks.

Aging is known to affect nociceptive processing, e.g., the ability to inhibit pain. This study aims to investigate whether pain responses in older individuals are associated with prefrontal characteristics, namely (i) executive functioning performance and (ii) structural brain variations in the prefrontal cortex. Heat and pressure stimuli were applied to assess pressure pain sensitivity and endogenous pain inhibition in 46 healthy older individuals. Executive functioning performance was assessed in three domains (i.e., cognitive inhibition, shifting, and updating) and structural brain variations were assessed in both gray and white matter. Overall pain responses were significantly associated with the executive functioning domains cognitive inhibition and shifting. However, no specific type of pain response showed an especially strong association. Endogenous pain inhibition specifically showed a significant association with gray matter volume in the prefrontal cortex and with variations in white matter structure of tracts connecting the prefrontal cortex with the periaqueductal gray. Hierarchical regression analyses showed that these variations in the prefrontal cortex can explain variance in pain inhibition beyond what can be explained by executive functioning. This might indicate that known deficits in pain inhibition in older individuals are associated with structural variations in prefrontal areas.

Despite growing interest in cognitive interventions from academia and industry, it remains unclear if working memory (WM) training, one of the most popular cognitive interventions, produces transfer effects. Transfer effects are training-induced gains in performance in untrained cognitive tasks, while practice effects are improvements in trained task. The goal of this study was to evaluate potential transfer effects by comprehensive cognitive testing and neuroimaging. In this prospective, randomized-controlled, and single-blind study, we administered an 8-week n -back training to 55 healthy middle-aged (50–64 years) participants. State-of-the-art multimodal neuroimaging was used to examine potential anatomic and functional changes. Relative to control subjects, who performed non-adaptive WM training, no near or far transfer effects were detected in experimental subjects, who performed adaptive WM training. Equivalently, no training-related changes were observed in white matter integrity, amplitude of low frequency fluctuations, glucose metabolism, functional and metabolic connectivity. Exploratory within-group comparisons revealed some gains in transfer tasks, which, however, cannot be attributed to an increased WM capacity. In conclusion, WM training produces transfer effects neither at the cognitive level nor in terms of neural structure or function. These results speak against a common view that training-related gains reflect an increase in underlying WM capacity. Instead, the presently observed practice effects may be a result of optimized task processing strategies, which do not necessarily engage neural plasticity.

Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) is a powerful method for mapping cerebral glucose metabolism as a proxy of neural activity, assuming a steady-state during the recording interval. We asked if a clinical FDG-PET imaging protocol might also capture changes in neural activity associated with performance of a working memory (WM) task. To test this concept, we examined hybrid PET/MR data for FDG-PET and simultaneous functional magnetic resonance imaging (fMRI) in a sample of healthy volunteers. The PET image acquisition started 30 min after a bolus injection of approximately 100 MBq FDG, and the WM task was undertaken starting at approximately 60 min post-injection. We reconstructed FDG-PET sum images corresponding to baseline (44–60 min p.i.) and WM tasks (63- 71 min p.i.), each with intensity scaling to the corresponding global mean. Compared to the baseline resting condition, relative FDG uptake increased during WM task performance in brain regions previously associated with WM. Furthermore, these metabolically active regions partly overlapped with the regions showing task-dependent increases in BOLD signal in simultaneous fMRI. We find evidence for WM task-induced neural activation using a clinical FDG-PET imaging protocol. These findings encourage the development of dedicated protocols for tracking neural correlates of cognitive function.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients die from the disease within 2–5 years. The molecular pathogenesis underlying the immunologic changes that occur in IPF is poorly understood. We characterize noncanonical aryl-hydrocarbon receptor (ncAHR) signaling in DCs as playing a role in the production of IL-6 and increased IL-17 + cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2, which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing mice harboring a floxed AHR exon 2 deletion (AHR Δex2 ) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c + cells and primary fibroblasts were treated ex vivo with relevant TLR agonists and AHR-modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis; however, AHR Δex2 mice treated with blm developed more fibrosis, and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2, and fibrotic fibroblasts activated IL-6 production in CD103 + DCs. Study of human samples corroborated the relevance of these findings in patients with IPF. We also show, for the first time to our knowledge, that AHR exon 2 floxed mice retain the capacity for ncAHR signaling.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and IL-17, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHR ) with mice harboring a CD11c-Cre. Bleomycin was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHR mice treated with bleomycin developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2. Study of human samples corroborate the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.