Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs).

A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.

Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2.

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2-3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

RATIONALE: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. AIMS: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. METHODS AND DESIGN: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. STUDY OUTCOMES: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. DISCUSSION: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

The Hare and the Hedgehog: Empirical evidence on the relationship between the individual Pace of Life and the speed-accuracy continuum.

Against the background of the speed-accuracy trade-off, we explored whether the Pace of Life can be used to identify heterogeneity in the strategy to place more weight on either fast or accurate accomplishments. The Pace of Life approaches an individual's exposure to time and is an intensively studied concept in the evolutionary biology research. Albeit overall rarely, it is increasingly used to understand human behavior and may fulfill many criteria of a personal trait. In a controlled laboratory environment, we measured the participants' Pace of Life, as well as their performance on a real-effort task. In the real-effort task, the participants had to encode words, whereby each word encoded correctly was associated with a monetary reward. We found that individuals with a faster Pace of Life accomplished more tasks in total. At the same time, they were less accurate and made more mistakes (in absolute terms) than those with a slower Pace of Life. Thus, the Pace of Life seems to be useful to identify an individual's stance on the speed-accuracy continuum. In our specific task, placing more weight on speed instead of accuracy paid off: Individuals with a faster Pace of Life were ultimately more successful (with regard to their monetary revenue).

The fast and the furious-An experimental investigation of the pace of life and risky speed choice in traffic.

Despite discernible improvements in the last decades, speeding is still a pertinent problem for road safety, fuel efficiency, and greenhouse gas mitigation. In order to understand individual speeding decisions, we need a better understanding of who speeds. In our paper, we test whether individuals' general pace of life is associated with speeding decisions. We use a novel speed-choice experiment that confronts participants with a scenario in which they repeatedly decide between driving fast or slow. This decision is associated with different accident risks. Before the experiment, each participant's pace of life was measured. Our results show that individuals with a slower pace of life are more likely to choose slow in the experiment and are also more likely to switch to slow, even when they had success by driving fast in the preliminary round. Therefore, individuals' pace of life may contribute to our understanding of speeding.

Cognitive performance of 20 healthy humans supplemented with L-homoarginine for 4 weeks.

l-homoarginine (l-hArg) is an endogenous non-proteinogenic amino acid. Low l-hArg concentrations are associated with increased all-cause mortality, fatal strokes, and worse outcome after stroke. On the other hand, oral supplementation with l-hArg in mice improved neurological deficits and preserved cardiac function in experimental models of stroke and heart failure, respectively. Recently, oral supplementation with 125 mg daily l-hArg capsules in healthy volunteers demonstrated increased l-hArg plasma levels. Therefore, oral l-hArg supplementation could represent a potential treatment for patients with cerebrovascular disease. In addition to vascular physiology, animal studies have suggested that l-hArg might play a role in synapse function, neurotransmitter metabolism and cognitive training. However the direct influence of l-hArg on cognitive function has not been studied so far. In this study, cognitive performance in healthy humans was analyzed concerning memory, learning, and attention following supplementation with placebo or l-hArg for 4 weeks. Our results did not reveal any effects on cognition, neither impairment nor improvement, upon l-hArg supplementation. Therefore, potential l-hArg treatment is not expected to cause any acute neurocognitive or behavioral side effects.

tDCS over the motor cortex improves lexical retrieval of action words in poststroke aphasia.

One-third of stroke survivors worldwide suffer from aphasia. Speech and language therapy (SLT) is considered effective in treating aphasia, but because of time constraints, improvements are often limited. Noninvasive brain stimulation is a promising adjuvant strategy to facilitate SLT. However, stroke might render "classical" language regions ineffective as stimulation sites. Recent work showed the effectiveness of motor cortex stimulation together with intensive naming therapy to improve outcomes in aphasia (Meinzer et al. 2016). Although that study highlights the involvement of the motor cortex, the functional aspects by which it influences language remain unclear. In the present study, we focus on the role of motor cortex in language, investigating its functional involvement in access to specific lexico-semantic (object vs. action relatedness) information in poststroke aphasia. To this end, we tested effects of anodal transcranial direct current stimulation (tDCS) to the left motor cortex on lexical retrieval in 16 patients with poststroke aphasia in a sham-controlled, double-blind study design. Critical stimuli were action and object words, and pseudowords. Participants performed a lexical decision task, deciding whether stimuli were words or pseudowords. Anodal tDCS improved accuracy in lexical decision, especially for words with action-related content and for pseudowords with an "action-like" ending ( t15 = 2.65, P = 0.036), but not for words with object-related content and pseudowords with "object-like" characteristics. We show as a proof-of-principle that the motor cortex may play a specific role in access to lexico-semantic content. Thus motor-cortex stimulation may strengthen content-specific word-to-semantic concept associations during language treatment in poststroke aphasia. NEW & NOTEWORTHY The role of motor cortex (MC) in language processing has been debated in both health and disease. Recent work has suggested that MC stimulation together with speech and language therapy enhances outcomes in aphasia. We show that MC stimulation has a differential effect on object- and action-word processing in poststroke aphasia. We propose that MC stimulation may specifically strengthen word-to-semantic concept association in aphasia. Our results potentially provide a way to tailor therapies for language rehabilitation.

tDCS Over the Motor Cortex Shows Differential Effects on Action and Object Words in Associative Word Learning in Healthy Aging.

Healthy aging is accompanied by a continuous decline in cognitive functions. For example, the ability to learn languages decreases with age, while the neurobiological underpinnings for the decline in learning abilities are not known exactly. Transcranial direct current stimulation (tDCS), in combination with appropriate experimental paradigms, is a well-established technique to investigate the mechanisms of learning. Based on previous results in young adults, we tested the suitability of an associative learning paradigm for the acquisition of action- and object-related words in a cohort of older participants. We applied tDCS to the motor cortex (MC) and hypothesized an involvement of the MC in learning action-related words. To test this, a cohort of 18 healthy, older participants (mean age 71) engaged in a computer-assisted associative word-learning paradigm, while tDCS stimulation (anodal, cathodal, sham) was applied to the left MC. Participants' task performance was quantified in a randomized, cross-over experimental design. Participants successfully learned novel words, correctly translating 39.22% of the words after 1 h of training under sham stimulation. Task performance correlated with scores for declarative verbal learning and logical reasoning. Overall, tDCS did not influence associative word learning, but a specific influence was observed of cathodal tDCS on learning of action-related words during the NMDA-dependent stimulation period. Successful learning of a novel lexicon with associative learning in older participants can only be achieved when the learning procedure is changed in several aspects, relative to young subjects. Learning success showed large inter-individual variance which was dependent on non-linguistic as well as linguistic cognitive functions. Intriguingly, cathodal tDCS influenced the acquisition of action-related words in the NMDA-dependent stimulation period. However, the effect was not specific for the associative learning principle, suggesting more neurobiological fragility of learning in healthy aging compared with young persons.

PilY1 Promotes Legionella pneumophila Infection of Human Lung Tissue Explants and Contributes to Bacterial Adhesion, Host Cell Invasion, and Twitching Motility.

Legionnaires' disease is an acute fibrinopurulent pneumonia. During infection Legionella pneumophila adheres to the alveolar lining and replicates intracellularly within recruited macrophages. Here we provide a sequence and domain composition analysis of the L. pneumophila PilY1 protein, which has a high homology to PilY1 of Pseudomonas aeruginosa. PilY1 proteins of both pathogens contain a von Willebrand factor A (vWFa) and a C-terminal PilY domain. Using cellular fractionation, we assigned the L. pneumophila PilY1 as an outer membrane protein that is only expressed during the transmissive stationary growth phase. PilY1 contributes to infection of human lung tissue explants (HLTEs). A detailed analysis using THP-1 macrophages and A549 lung epithelial cells revealed that this contribution is due to multiple effects depending on host cell type. Deletion of PilY1 resulted in a lower replication rate in THP-1 macrophages but not in A549 cells. Further on, adhesion to THP-1 macrophages and A549 epithelial cells was decreased. Additionally, the invasion into non-phagocytic A549 epithelial cells was drastically reduced when PilY1 was absent. Complementation variants of a PilY1-negative mutant revealed that the C-terminal PilY domain is essential for restoring the wild type phenotype in adhesion, while the putatively mechanosensitive vWFa domain facilitates invasion into non-phagocytic cells. Since PilY1 also promotes twitching motility of L. pneumophila, we discuss the putative contribution of this newly described virulence factor for bacterial dissemination within infected lung tissue.

Oral supplementation with L-homoarginine in young volunteers.

AIMS: Low blood concentrations of the naturally occurring amino acid L-homoarginine (L-hArg) are related to impaired cardiovascular outcome and mortality in humans and animals. L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro. The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation. METHODS: In a double-blind, randomized, placebo-controlled crossover study, 20 young volunteers received 125 mg L-hArg once daily for 4 weeks. Kinetic parameters (Cmax , Tmax and AUC0-24h ) were calculated after ingestion of single and multiple doses of oral supplementation as primary endpoint. Secondary endpoints that were evaluated were routine laboratory, L-arginine, asymmetric dimethylarginine (ADMA), pulse wave velocity (PWV), augmentation index (AIx), flow-mediated vasodilatation (FMD), corticospinal excitability, i.e. motor threshold (MT), and cortical excitability, i.e. intracortical inhibition (ICI) and facilitation (ICF). RESULTS: One hour after ingestion (Tmax ), L-hArg increased the baseline L-hArg plasma concentration (2.87 ± 0.91 µmol l-1 , mean ± SD) by 8.74 ± 4.46 [95% confidence intervals 6.65; 10.9] and 17.3 ± 4.97 [14.9; 19.6] µmol l-1 (Cmax ), after single and multiple doses, respectively. Once-only and 4 weeks of supplementation resulted in AUCs0-24h of 63.5 ± 28.8 [50.0; 76.9] and 225 ± 78.5 [188; 2624] µmol l-1 *h, for single and multiple doses, respectively. Routine laboratory parameters, L-arginine, ADMA, PWV, AIx, FMD, MT, ICI and ICF did not change by L-hArg supplementation compared to baseline. CONCLUSION: Once daily orally applied 125 mg L-hArg raises plasma L-hArg four- and sevenfold after single dose and 4 weeks of supplementation, respectively, and is safe and well tolerated in young volunteers.

Polyketide synthase (PKS) reduces fusion of Legionella pneumophila-containing vacuoles with lysosomes and contributes to bacterial competitiveness during infection.

L. pneumophila-containing vacuoles (LCVs) exclude endocytic and lysosomal markers in human macrophages and protozoa. We screened a L. pneumophila mini-Tn10 transposon library for mutants, which fail to inhibit the fusion of LCVs with lysosomes by loading of the lysosomal compartment with colloidal iron dextran, mechanical lysis of infected host cells, and magnetic isolation of LCVs that have fused with lysosomes. In silico analysis of the mutated genes, D. discoideum plaque assays and infection assays in protozoa and U937 macrophage-like cells identified well established as well as novel putative L. pneumophila virulence factors. Promising candidates were further analyzed for their co-localization with lysosomes in host cells using fluorescence microscopy. This approach corroborated that the O-methyltransferase, PilY1, TPR-containing protein and polyketide synthase (PKS) of L. pneumophila interfere with lysosomal degradation. Competitive infections in protozoa and macrophages revealed that the identified PKS contributes to the biological fitness of pneumophila strains and may explain their prevalence in the epidemiology of Legionnaires' disease.

Characterization of phenolic compounds in Brazilian pepper (Schinus terebinthifolius Raddi) exocarp.

The objective of this study was to characterize the phenolic composition of Brazilian pepper (Schinus terebinthifolius Raddi) exocarp extract. Using UHPLC-DAD-MS/MS analysis, four anthocyanins, three biflavonoids, gallic acid, and two types of hydrolyzable tannins (galloyl glucoses, galloyl shikimic acids) were tentatively identified. The structure of the so far unknown 7-O-methylpelargonidin 3-O-ß-D-galactopyranoside was elucidated by 2D NMR. Within the group of gallotannins, galloyl shikimic acids with uncommon degrees of galloylation (tetra- to hexagalloyl shikimic acids) were detected. Among the biflavonoids, I3',II8-biapigenin (amentoflavone), I6,II8-biapigenin (agathisflavone), and II-2,3-dihydro-I3',II8-biapigenin were identified, which have already been described for Anacardiaceae. From the results of the present study together with previous findings on the phenolic profile of other Anacardiaceae plants, it is concluded that 7-methoxylated flavonoids are a chemotaxonomic trait frequently found in this family.

Development of movement-related intracortical inhibition in acute to chronic subcortical stroke.

OBJECTIVE: A prospective longitudinal cohort study in stroke patients was performed to better understand the role of γ-aminobutyric acid-dependent intracortical inhibition (ICI) for recovery after stroke. METHODS: Patients with acute first-ever subcortical stroke and hand paresis were recruited, and motor function as well as ICI were measured up to 1 year after stroke. Motor recovery was defined as the change in hand motor function from the acute to the chronic stage (Δ = recovery over 1 year). Primary outcome measures for hand motor function were the recovery of grip strength (ΔGS) and finger-tapping speed (ΔFT). Using double-pulse transcranial magnetic stimulation, we studied ICI in the ipsilesional primary motor cortex during the preparation of a movement with the paretic hand at different time points during recovery (first week, 7 weeks, 3 months, and 1 year after stroke). RESULTS: Eleven patients were enrolled (mean age 62.9 ± 3.8 years). The results of a multiple regression analysis showed a significant association of movement-related ICI in the acute stage only (first week) with motor recovery over 1 year (ΔGS: R(2) = 0.75, F = 17.6, p = 0.006; ΔFT: R(2) = 0.55, F = 7.3, p = 0.035). More disinhibition of ICI in the acute phase of stroke predicted more improvement in ΔGS (ß = -0.86, p = 0.006) and ΔFT (ß = -0.74, p = 0.035), independent of the initial motor deficit. CONCLUSIONS: Movement-related ICI one week after a subcortical stroke is associated with better outcome of hand motor function. Disinhibition in the ipsilesional primary motor cortex could be a mechanism of how the brain attempts to promote motor recovery after stroke.

The aging motor system as a model for plastic changes of GABA-mediated intracortical inhibition and their behavioral relevance.

Since GABAA-mediated intracortical inhibition has been shown to underlie plastic changes throughout the lifespan from development to aging, here, the aging motor system was used as a model to analyze the interdependence of plastic alterations within the inhibitory motorcortical network and level of behavioral performance. Double-pulse transcranial magnetic stimulation (dpTMS) was used to examine inhibition by means of short-interval intracortical inhibition (SICI) of the contralateral primary motor cortex in a sample of 64 healthy right-handed human subjects covering a wide range of the adult lifespan (age range 20-88 years, mean 47.6 ± 20.7, 34 female). SICI was evaluated during resting state and in an event-related condition during movement preparation in a visually triggered simple reaction time task. In a subgroup (N = 23), manual motor performance was tested with tasks of graded dexterous demand. Weak resting-state inhibition was associated with an overall lower manual motor performance. Better event-related modulation of inhibition correlated with better performance in more demanding tasks, in which fast alternating activation of cortical representations are necessary. Declining resting-state inhibition was associated with weakened event-related modulation of inhibition. Therefore, reduced resting-state inhibition might lead to a subsequent loss of modulatory capacity, possibly reflecting malfunctioning precision in GABAAergic neurotransmission; the consequence is an inevitable decline in motor function.

Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand.

BACKGROUND AND PURPOSE: Mechanisms of skill learning are paramount components for stroke recovery. Recent noninvasive brain stimulation studies demonstrated that decreasing activity in the contralesional motor cortex might be beneficial, providing transient functional improvements after stroke. The more crucial question, however, is whether this intervention can also enhance the acquisition of complex motor tasks, yielding longer-lasting functional improvements. In the present study, we tested the capacity of cathodal transcranial direct current stimulation (tDCS) applied over the contralesional motor cortex during training to enhance the acquisition and retention of complex sequential finger movements of the paretic hand. METHOD: Twelve well-recovered chronic patients with subcortical stroke attended 2 training sessions during which either cathodal tDCS or a sham intervention were applied to the contralesional motor cortex in a double-blind, crossover design. Two different motor sequences, matched for their degree of complexity, were tested in a counterbalanced order during as well as 90 minutes and 24 hours after the intervention. Potential underlying mechanisms were evaluated with transcranial magnetic stimulation. RESULTS: tDCS facilitated the acquisition of a new motor skill compared with sham stimulation (P=0.04) yielding better task retention results. A significant correlation was observed between the tDCS-induced improvement during training and the tDCS-induced changes of intracortical inhibition (R(2)=0.63). CONCLUSIONS: These results indicate that tDCS is a promising tool to improve not only motor behavior, but also procedural learning. They further underline the potential of noninvasive brain stimulation as an adjuvant treatment for long-term recovery, at least in patients with mild functional impairment after stroke.

Subthalamic nucleus stimulation restores the efferent cortical drive to muscle in parallel to functional motor improvement.

Pathological synchronization in large-scale motor networks constitutes a pathophysiological hallmark of Parkinson's disease (PD). Corticomuscular synchronization in PD is pronounced in lower frequency bands (< 10 Hz), whereas efficient cortical motor integration in healthy persons is driven in the beta frequency range. Electroencephalogram and electromyogram recordings at rest and during an isometric precision grip task were performed in four perioperative sessions in 10 patients with PD undergoing subthalamic nucleus deep-brain stimulation: (i) 1 day before (D0); (ii) 1 day after (D1); (iii) 8 days after implantation of macroelectrodes with stimulation off (D8StimOff); and (iv) on (D8StimOn). Analyses of coherence and phase delays were performed in order to challenge the effects of microlesion and stimulation on corticomuscular coherence (CMC). Additionally, local field potentials recorded from the subthalamic nucleus on D1 allowed comprehensive mapping of motor-related synchronization in subthalamocortical and cerebromuscular networks. Motor performance improved at D8StimOn compared with D0 and D8StimOff paralleled by a reduction of muscular activity and CMC in the theta band (3.9-7.8 Hz) and by an increase of CMC in the low-beta band (13.7-19.5 Hz). Efferent motor cortical drives to muscle presented mainly below 10 Hz on D8StimOff that were suppressed on D8StimOn and occurred on higher frequencies from 13 to 45 Hz. On D1, coherence of the high-beta band (20.5-30.2 Hz) increased during movement compared with rest in subthalamomuscular and corticomuscular projections, whereas it was attenuated in subcorticocortical projections. The present findings lend further support to the concept of pathological network synchronization in PD that is beneficially modulated by stimulation.

The involvement of the left motor cortex in learning of a novel action word lexicon.

Current theoretical positions assume that action-related word meanings are established by functional connections between perisylvian language areas and the motor cortex (MC) according to Hebb's associative learning principle. To test this assumption, we probed the functional relevance of the left MC for learning of a novel action word vocabulary by disturbing neural plasticity in the MC with transcranial direct current stimulation (tDCS). In combination with tDCS, subjects learned a novel vocabulary of 76 concrete, body-related actions by means of an associative learning paradigm. Compared with a control condition with "sham" stimulation, cathodal tDCS reduced success rates in vocabulary acquisition, as shown by tests of novel action word translation into the native language. The analysis of learning behavior revealed a specific effect of cathodal tDCS on the ability to associatively couple actions with novel words. In contrast, we did not find these effects in control experiments, when tDCS was applied to the prefrontal cortex or when subjects learned object-related words. The present study lends direct evidence to the proposition that the left MC is causally involved in the acquisition of novel action-related words.

Distinct temporospatial interhemispheric interactions in the human primary and premotor cortex during movement preparation.

The preparation of a voluntary unimanual action requires sequential processing in bihemispheric motor areas. In both animals and humans, activity in the dorsal premotor cortex (PMd) ipsilateral to the moving hand has been demonstrated to precede ipsilateral primary motor cortex (M1) activity. We investigated with double-pulse transcranial magnetic stimulation how right-hemispheric motor areas (rM1, rPMd) modulate left M1 (lM1) during the preparatory period of a finger movement with the dominant right hand. We tested the hypothesis that the influence of higher order motor areas such as rPMd on lM1 (rPMd-lM1) precedes interhemispheric interactions between homologue primary motor areas (rM1-lM1). rPMd-lM1 showed modulation in the early and late phase of movement preparation, whereas the intrinsic state of inhibition between rM1-lM1 was only modulated in the late phase. The present results complement existing hierarchical models of cortical movement control by demonstrating temporospatially distinct involvement of interhemispheric interactions from PMd and M1 during movement preparation.

No effects of enhanced central norepinephrine on finger-sequence learning and attention.

RATIONALE: When paired with training, substances that increase monoaminergic transmission in the brain support motor and language learning in healthy subjects and in rehabilitation after brain lesions. OBJECTIVES: To test the hypotheses that enhancement of central norepinephrine by the selective norepinephrine reuptake inhibitor reboxetine (1) improves skilled motor performance, (2) promotes skilled motor learning, and (3) does not exert these effects by modulation of attention. METHODS: In a double blind, placebo-controlled, crossover study in healthy, adult subjects (n=16), finger-sequence performance and learning was measured after the stimulation of the central noradrenergic system with a single dose (8 mg) of reboxetine and placebo. Effects on attention were assessed by the standardized continuous performance test "CPT-M". RESULTS: No differential effects of reboxetine or placebo on finger-sequence performance, learning and parameters of attention were found. CONCLUSION: Selective stimulation of the central noradrenergic system did not promote skilled motor learning or performance as assessed by finger-sequences. The plasticity-enhancing effect of reboxetine, documented in other studies, appears to be dependent on specific neurophysiological and neuropsychological characteristics of the task, and cannot be generalized to other behavioral paradigms.