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© The Author(s) 2021. Motor sequence learning (MSL) is supported by dynamical interactions between hippocampal and striatal networks that are thought to be orchestrated by the prefrontal cortex. In the present study, we tested whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex (DLPFC) prior to MSL can modulate multivoxel response patterns in the stimulated cortical area, the hippocampus and the striatum. Response patterns were assessed with multivoxel correlation structure analyses of functional magnetic resonance imaging data acquired during task practice and during resting-state scans before and after learning/stimulation. Results revealed that, across stimulation conditions, MSL induced greater modulation of task-related DLPFC multivoxel patterns than random practice. A similar learning-related modulatory effect was observed on sensorimotor putamen patterns under inhibitory stimulation. Furthermore, MSL as well as inhibitory stimulation affected (posterior) hippocampal multivoxel patterns at post-intervention rest. Exploratory analyses showed that MSL-related brain patterns in the posterior hippocampus persisted into post-learning rest preferentially after inhibitory stimulation. These results collectively show that prefrontal stimulation can alter multivoxel brain patterns in deep brain regions that are critical for the MSL process. They also suggest that stimulation influenced early offline consolidation processes as evidenced by a stimulation-induced modulation of the reinstatement of task pattern into post-learning wakeful rest. Belgian Research Foundation Flanders (FWO; G099516N); KU Leuven; FWO (G0D7918N, G0B1419N, 1524218N); Excellence of Science (EOS, 30446199, MEMODYN); European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (703490); FWO (132635) postdoctoral fellowship; Air Force Office of Scientific Research (AFOSR, Virginia, USA; FA9550-16-1-0191).

While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and the basal ganglia during motor learning. Our results indicate that while stimulation did not modulate motor performance nor task-related brain activity, it influenced connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence, to the best of our knowledge, that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus. This work was supported by the Belgian Research Foundation Flanders (FWO; G099516N) and internal funds from KU Leuven. GA also received support from FWO (G0D7918N, G0B1419N, 1524218N) and Excellence of Science (EOS, 30446199, MEMODYN, with SPS and DM). MAG, ND and MPV received salary support from these grants. MAG is funded by a predoctoral fellowship from FWO (1141320N). Financial support for author BRK was provided by the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (703490) and a postdoctoral fellowship from FWO (132635). This study applies tools developed under National Institutes of Health (NIH) Grants R01- EB-016089, R01-023963, and P41-EB015909; RAEE also receives salary support from these grants. NAJP receives salary support from NIH Grant R00-MH-107719. EMR received salary support from the Air Force Office of Scientific Research (AFOSR, Virginia, USA; FA9550-16-1-0191).

Previous research has shown that targeted memory reactivation (TMR) protocols using acoustic or olfactory stimuli can boost motor memory consolidation. While somatosensory information is crucial for motor control and learning, the effects of somatosensory TMR on motor memory consolidation remain elusive. Here, healthy young adults (n = 28) were trained on a sequential serial reaction time task and received, during the offline consolidation period that followed, sequential electrical stimulation of the fingers involved in the task. This somatosensory TMR procedure was applied during either a 90-minute diurnal sleep (NAP) or wake (NONAP) interval that was monitored with electroencephalography. Consolidation was assessed with a retest following the NAP/NONAP episode. Behavioral results revealed no effect of TMR on motor performance in either of the groups. At the brain level, somatosensory stimulation elicited changes in oscillatory activity in both groups. Specifically, TMR induced an increase in power in the mu band in the NONAP group and in the beta band in both the NAP and NONAP groups. Additionally, TMR elicited an increase in sigma power and a decrease in delta oscillations in the NAP group. None of these TMR-induced modulations of oscillatory activity, however, were correlated with measures of motor memory consolidation. The present results collectively suggest that while somatosensory TMR modulates oscillatory brain activity during post-learning sleep and wakefulness, it does not influence motor performance in an immediate retest.

Previous research in young adults has demonstrated that both motor learning and transcranial direct current stimulation (tDCS) trigger decreases in the levels of gamma‐aminobutyric acid (GABA) in the sensorimotor cortex, and these decreases are linked to greater learning. Less is known about the role of GABA in motor learning in healthy older adults, a knowledge gap that is surprising given the established aging‐related reductions in sensorimotor GABA. Here, we examined the effects of motor learning and subsequent tDCS on sensorimotor GABA levels and resting‐state functional connectivity in the brains of healthy older participants. Thirty‐six older men and women completed a motor sequence learning task before receiving anodal or sham tDCS to the sensorimotor cortex. GABA‐edited magnetic resonance spectroscopy of the sensorimotor cortex and resting‐state (RS) functional magnetic resonance imaging data were acquired before and after learning/stimulation. At the group level, neither learning nor anodal tDCS significantly modulated GABA levels or RS connectivity among task‐relevant regions. However, changes in GABA levels from the baseline to post‐learning session were significantly related to motor learning magnitude, age, and baseline GABA. Moreover, the change in functional connectivity between task‐relevant regions, including bilateral motor cortices, was correlated with baseline GABA levels. These data collectively indicate that motor learning‐related decreases in sensorimotor GABA levels and increases in functional connectivity are limited to those older adults with higher baseline GABA levels and who learn the most. Post‐learning tDCS exerted no influence on GABA levels, functional connectivity or the relationships among these variables in older adults., Gamma‐aminobutyric acid (GABA)‐edited magnetic resonance spectroscopy of the sensorimotor cortex and resting‐state (RS) functional magnetic resonance imaging data were acquired before and after a motor learning task and either anodal or sham transcranial direct current stimulation (tDCS). Results demonstrated that neither motor sequence learning nor subsequent tDCS significantly modulated GABA+ levels or RS functional connectivity at the group level in older adults. However, individual differences in the learning‐related modulations in GABA+ levels were associated with the participants' age, baseline GABA+ levels, and the magnitude of learning. Higher baseline GABA was also linked to a learning‐related increase in RS functional connectivity between motor task‐relevant regions, including bilateral motor cortices.

We aimed at comparing the effects of intravenous (i.v.) and inhaled (inh.) levosimendan (LEVO) on survival, inflammatory cytokines and the apoptotic mediator caspase-3 in a rat model of severe sepsis induced by cecal ligation and incision (CLI).Twenty-eight anesthetized/ventilated male Sprague-Dawley rats (body weight 528 +/- 20 g) underwent laparotomy. Cecal mobilisation served as control (SHAM, n = 7). In all other groups, severe sepsis was induced by CLI. No further intervention occurred in the CLI-group (n = 7). 180 min after CLI, 24 microg/kg i.v. LEVO was administered in the CLI + LEVO-IV-group (n = 7), and 24 microg/kg inh. LEVO was administered via jet nebulizer in the CLI + LEVO-INH-group (n = 7).CLI induced arterial hypotension, with i.v. and inh. LEVO attenuating blood pressure decrease over 390 min [CLI 34(31/50), CLI + LEVO-IV 82(69/131)*, CLI + LEVO-INH 78(62/85)* mmHg; median(25/75% quartile), *P0.05]. CLI induced metabolic acidosis. I.v. and inh. LEVO avoided arterial pH [CLI 7.18(7.16/7.2), CLI + LEVO-IV 7.27(7.24/7.31)*, CLI + LEVO-INH 7.26(7.24/7.28)*] and base excess deterioration [CLI -19(-21.8/-17.9), CLI + LEVO-IV -13(-14.8/-12)*, CLI + LEVO-INH -12.7(-14/-12.2)* mmol/l]. Overall mortality in the CLI-group was 57% compared to 0%* in both LEVO-treated groups after 390 min. LEVO administration significantly attenuated the increase in proinflammatory interleukin (IL)-1beta [CLI 896(739/911), CLI + LEVO-IV 302(230/385)*, CLI + LEVO-INH 346(271/548) pg/ml] and IL-6 [CLI 35651(31413/35816), CLI + LEVO-IV 21156(18397/28026), CLI + LEVO-INH 13674(10105/24843) pg/ml] in the plasma and reduced cleaved caspase-3 expression in the spleen.In a rat model of severe sepsis induced by CLI, i.v. and inh. LEVO equally attenuated arterial hypotension, metabolic acidosis and prolonged survival. Moreover, i.v. and inh. LEVO inhibited proinflammatory mediator release and reduced splenic caspase-3 expression.

Summary Background High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). By limiting the pulmonal inflammation cascade the anti-inflammatory cytokine interleukin (IL)-10 may have protective effects. Via inhalation, IL-10 reaches the pulmonary system directly and in high concentrations. Methods Thirty six male, anesthetized and mechanically ventilated Sprague–Dawley rats were randomly assigned to the following groups (n = 9, each): SHAM: pressure controlled ventilation with pmax = 20 cmH2O, PEEP = 4; VILI: ventilator settings were changed for 20 min to pmax = 45 cmH2O, PEEP = 0; IL-10high: inhalation of 10 μg/kg IL-10 prior to induction of VILI; and IL-10low: inhalation of 1 μg/kg IL-10 prior to induction of VILI. All groups were ventilated and observed for 4 h. Results High-pressure ventilation increased the concentrations of macrophage inflammatory protein (MIP)-2 and IL-1β in bronchoalveolar lavage fluid (BALF) and plasma. This effect was reduced by the inhalation of IL-10 (10 μg/kg). Additionally, IL-10 increased the animal survival time (78% vs. 22% 4-h mortality rate) and reduced NO-release from ex vivo cultured alveolar macrophages. Moreover, VILI-induced pulmonary heat shock protein-70 expression was reduced by IL-10 aerosol in a dose-dependent manner. Similarly, the activation of matrix metalloproteinase (MMP)-9 in BALF was reduced dose-dependently by IL-10. IL-10-treated animals showed a lower macroscopic lung injury score and less impairment of lung integrity and gas exchange. Conclusions Prophylactic inhalation of IL-10 improved survival and reduced lung injury in experimental VILI. Results indicate that this effect may be mediated by the inhibition of stress-induced inflammation and pulmonary biotrauma.

OBJECTIVES Mechanical ventilation during critical care can cause structural and functional disturbances in the lung with subsequent release of proinflammatory mediators, termed ventilator-induced lung injury (VILI). VILI progressively provokes decreased efficiency of gas exchange with subsequent hypoxic pulmonary vasoconstriction leading to cardiopulmonary alterations, such as pulmonary hypertension and right heart failure. We therefore aimed to evaluate whether inhalation therapy with levosimendan, a calcium-sensitizer with pulmonary vasodilating properties, could attenuate VILI and improve short-term survival in a rat experimental model. DESIGN Experimental animal model. SETTING University hospital. SUBJECTS Forty male Sprague-Dawley rats. INTERVENTIONS Rats were randomly treated as follows (n = 8, each group): 1) inhalation of the solvent only before induction of VILI, no further intervention; 2) inhalation of 240 microg of levosimendan before VILI induction; 3) inhalation of 24 microg of levosimendan before VILI induction; 4) intravenous administration of 24 microg/kg levosimendan before VILI induction; 5) control group with surgical preparation only. All groups were observed for 4 hrs. MEASUREMENTS AND MAIN RESULTS After 4 hrs following induction of VILI, levels of interleukin-1beta and macrophage inflammatory protein-2 in plasma and bronchoalveolar lavage fluid were analyzed by enzyme-linked immunosorbent assay. Nitric oxide release from alveolar macrophages was measured by Griess assay. Content of matrix metalloproteinase-2 and matrix metalloproteinase-9 in bronchoalveolar lavage fluid was analyzed by gelatin zymography. Inhalation of 240 microg of levosimendan significantly improved survival after 4 hrs and mean arterial blood pressure compared with VILI only. Additionally, inhalation of 240 microg and infusion of 24 microg/kg levosimendan significantly reduced the release of interleukin-1beta, the nitric oxide release from alveolar macrophages, macrophage inflammatory protein-2 in plasma, and the macrophage inflammatory protein-2 and matrix metalloproteinase-9 content in bronchoalveolar lavage fluid compared with VILI only. CONCLUSIONS Our study demonstrates that prophylactic inhalation of 240 microg of levosimendan improves survival and reduces release of inflammatory mediators in our experimental model of VILI. This might affect the clinical prophylaxis and treatment of VILI.

Background: Due to demographic changes the number of patients increases. Hence the number of hospitalizations as well as the number of prescribed drugs increases, too. Outpatient drug prescription is affected by several rules as the social security code (SGB V). However these rules only have small influence[for full text, please go to the a.m. URL], 21. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie, 9. Deutscher Pharmakovigilanztag

In order to evaluate possible health effects of environmental exposure of humans towards methyl mercury species, relevant exposure experiments using methyl mercury chloride in aqueous solution and Chinese hamster ovary (CHO) cells were performed. The solution was monitored for the presence of monomethyl, dimethyl and elemental mercury by several analytical techniques including chromatographic as well as atomic absorption and mass spectrometric methods. Methyl mercury induces structural chromosomal aberrations (CA) and sister chromatid exchanges (SCE) in CHO cells. At a concentration of methyl mercury in the culture medium of 1.0 x 10(-6) M where the frequencies of CA and SCE are significantly elevated, the intracellular concentration was 1.99 x 10(-16) mol/cell. Possible biochemical processes leading to the cytogenetic effects are discussed together with toxicological consequences, when humans (e.g. workers at waste deposits) are exposed to environmental concentrations of methyl mercury.

In the present study platelet size distribution was investigated after induction of immunothrombocytopenia by rabbit-anti-mouse-platelet-serum (RAMPS) and after vincristine-induced thrombocytopenia. The platelet size distribution after a single dose of RAMPS showed a shift to larger volumes at day 1 and 2, and a decrease to slightly smaller volumes than normal at day 8. These differences, however, were not statistically significant. After vincristine administration, a dose-dependent increase of the platelet size distribution was demonstrated, which lasted from day 1-7. It is suggested that in immune-induced thrombocytopenia the young platelets released from bone marrow megakaryocytes are not exclusively large platelets. On the other hand the early appearance of large platelets after vincristine administration points to a toxic or segregating effect of vincristine on circulating platelets. Therefore, in our experiments, the platelet size is not suitable for the differentiation of young and old platelets.