Investigating Different Levels of Bimanual Interaction With a Novel Motor Learning Task: A Behavioural and Transcranial Alternating Current Stimulation Study

Many tasks require the skilled interaction of both hands, such as eating with knife and fork or keyboard typing. However, our understanding of the behavioural and neurophysiological mechanisms underpinning bimanual motor learning is still sparse. Here, we aimed to address this by first characterising learning-related changes of different levels of bimanual interaction and second investigating how beta tACS modulates these learning-related changes. To explore early bimanual motor learning, we designed a novel bimanual motor learning task. In the task, a force grip device held in each hand (controlling x- and y-axis separately) was used to move a cursor along a path of streets at different angles (0°, 22.5°, 45°, 67.5°, and 90°). Each street corresponded to specific force ratios between hands, which resulted in different levels of hand interaction, i.e., unimanual (Uni, i.e., 0°, 90°), bimanual with equal force (Bieq, 45°), and bimanual with unequal force (Biuneq 22.5°, 67.5°). In experiment 1, 40 healthy participants performed the task for 45 min with a minimum of 100 trials. We found that the novel task induced improvements in movement time and error, with no trade-off between movement time and error, and with distinct patterns for the three levels of bimanual interaction. In experiment 2, we performed a between-subjects, double-blind study in 54 healthy participants to explore the effect of phase synchrony between both sensorimotor cortices using tACS at the individual’s beta peak frequency. The individual’s beta peak frequency was quantified using electroencephalography. 20 min of 2 mA peak-to-peak amplitude tACS was applied during task performance (40 min). Participants either received in-phase (0° phase shift), out-of-phase (90° phase shift), or sham (3 s of stimulation) tACS. We replicated the behavioural results of experiment 1, however, beta tACS did not modulate motor learning. Overall, the novel bimanual motor task allows to characterise bimanual motor learning with different levels of bimanual interaction. This should pave the way for future neuroimaging studies to further investigate the underlying mechanism of bimanual motor learning

Investigating the role of inhibition in human motor learning

Motor learning is extremely important in everyday life: from learning how to reach and grab objects to learning complex movements, like driving a car or playing the piano, most daily activities and hobbies rely on previously acquired motor skills. Increasing evidence indicates that inhibition mediated by GABA, the most common inhibitory neurotransmitter, plays a key role in learning new motor skills. Modulating GABAergic inhibition may therefore influence motor learning. In this thesis, I investigated the role of inhibition in human motor learning by conducting two within-subject, randomised, placebo-controlled pharmacological studies, targeting distinct GABA-receptors, in young, healthy volunteers. In each study, I used a GABA receptor agonist, hypothesising that increasing GABAergic inhibition would lead to impairments in motor learning. Firstly, I used baclofen, a GABAB-receptor agonist, in a pharmaco-neuroimaging study. I evaluated the participants’ motor learning behaviour and their patterns of brain activity during task performance and at rest. Using a novel technique, Magnetic Resonance Spectroscopic Imaging (MRSI), I measured [GABA] in motor areas before and after task performance. I found that baclofen significantly impaired motor sequence learning and changed the pattern of learning-related [GABA] dynamics during learning. Baclofen was associated with the recruitment of additional brain areas during task performance, likely as a compensatory mechanism, and with decreased functional connectivity in resting-state networks. In the second study, I used zolpidem, a GABAA-receptor agonist. I measured participants’ motor learning behaviour and their cortical excitability using transcranial magnetic stimulation (TMS). Zolpidem significantly slowed down response times and impaired the retention of visuomotor adaptation skills. I found no significant effects of zolpidem on TMS metrics. Taken together, these results enhance our understanding of the neurophysiological mechanisms underlying human motor learning. They are also clinically relevant: both baclofen and zolpidem are commonly administered medications and they might be detrimental to the motor rehabilitation of clinical populations

Recent advances in the role of excitation–inhibition balance in motor recovery post-stroke

Stroke affects millions of people worldwide each year, and stroke survivors are often left with motor deficits. Current therapies to improve these functional deficits are limited, making it a priority to better understand the pathophysiology of stroke recovery and find novel adjuvant options. The excitation–inhibition balance undergoes significant changes post-stroke, and the inhibitory neurotransmitter γ-aminobutyric acid (GABA) appears to play an important role in stroke recovery. In this review, we summarise the most recent studies investigating GABAergic inhibition at different stages of stroke. We discuss the proposed role of GABA in counteracting glutamate-mediated excitotoxicity in hyperacute stroke as well as the evidence linking decreased GABAergic inhibition to increased neuronal plasticity in early stroke. Then, we discuss two types of interventions that aim to modulate the excitation–inhibition balance to improve functional outcomes in stroke survivors: non-invasive brain stimulation (NIBS) and pharmacological interventions. Finding the optimal NIBS administration or adjuvant pharmacological therapies would represent an important contribution to the currently scarce therapy options

Oxytocin Exhibits Neuroprotective Effects on Hippocampal Cultures under Severe Oxygen–Glucose Deprivation Conditions

Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen–glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT’s potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT’s precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection

Oxytocin Exhibits Neuroprotective Effects on Hippocampal Cultures under Severe Oxygen-Glucose Deprivation Conditions.

Peer reviewed: TruePublication status: PublishedFunder: Carol Davila University of Medicine and Pharmacy, Bucharest, RomaniaFunder: Interdisziplinäres Zentrum für Klinische Forschung (IZKF) JenaFunder: Foundation “Else Kröner-Fresenius-Stiftung” within the Else Kröner Research School for Physicians “AntiAge”Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen-glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT's potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT's precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection

Neuronal Transmembrane Chloride Transport Has a Time-Dependent Influence on Survival of Hippocampal Cultures to Oxygen-Glucose Deprivation

Neuronal ischemia results in chloride gradient alterations which impact the excitatory–inhibitory balance, volume regulation, and neuronal survival. Thus, the Na+/K+/Cl− co-transporter (NKCC1), the K+/ Cl− co-transporter (KCC2), and the gamma-aminobutyric acid A (GABAA) receptor may represent therapeutic targets in stroke, but a time-dependent effect on neuronal viability could influence the outcome. We, therefore, successively blocked NKCC1, KCC2, and GABAA (with bumetanide, DIOA, and gabazine, respectively) or activated GABAA (with isoguvacine) either during or after oxygen-glucose deprivation (OGD). Primary hippocampal cultures were exposed to a 2-h OGD or sham normoxia treatment, and viability was determined using the resazurin assay. Neuronal viability was significantly reduced after OGD, and was further decreased by DIOA treatment applied during OGD (p < 0.01) and by gabazine applied after OGD (p < 0.05). Bumetanide treatment during OGD increased viability (p < 0.05), while isoguvacine applied either during or after OGD did not influence viability. Our data suggests that NKCC1 and KCC2 function has an important impact on neuronal viability during the acute ischemic episode, while the GABAA receptor plays a role during the subsequent recovery period. These findings suggest that pharmacological modulation of transmembrane chloride transport could be a promising approach during stroke and highlight the importance of the timing of treatment application in relation to ischemia-reoxygenation

Magnetic resonance spectroscopic imaging markers of inhibitory and excitatory motor cortical function in healthy individuals and those with amyotrophic lateral sclerosis

A balance of excitatory and inhibitory signalling within key cortical regions in the motor network regulates overall network activity and connectivity in humans. This balance can be non-invasively assessed by quantifying glutamate and GABA across cortical regions using magnetic resonance spectroscopic imaging (MRSI). We present planned analyses of a large dataset comprising healthy adults across a range of ages, and patients with amyotrophic lateral sclerosis (ALS) - a neurodegenerative disorder of the motor system in which altered cortical excitability is consistently observed. Using a novel MRSI protocol, GABA and glutamate are mapped in high spatial resolution across a region of interest encompassing both primary motor cortices. We will use the free software FSL-MRS toolkit to pre-process the MRSI data, fit spectra and quantify metabolite concentration. This dataset will allow the spatial distribution of neurochemical concentrations to be characterised in healthy individuals and disease, and the effect of age to be addressed. Furthermore, by combining MRS and functional MRI data, the role of neurochemicals in determining motor network function can be investigated and biomarkers of future therapeutic response to be developed. Identifying physiological processes underlying motor function and plasticity may yield targets for modulation to improve function or treat disease

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London