IGFBPL1 Regulates Axon Growth through IGF-1-mediated Signaling Cascades

Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF-1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Variation in postoperative outcomes of patients with intracranial tumors: insights from a prospective international cohort study during the COVID-19 pandemic

Background: This study assessed the international variation in surgical neuro-oncology practice and 30-day outcomes of patients who had surgery for an intracranial tumor during the COVID-19 pandemic. Methods: We prospectively included adults aged ≥18 years who underwent surgery for a malignant or benign intracranial tumor across 55 international hospitals from 26 countries. Each participating hospital recorded cases for 3 consecutive months from the start of the pandemic. We categorized patients’ location by World Bank income groups (high [HIC], upper-middle [UMIC], and low- and lower-middle [LLMIC]). Main outcomes were a change from routine management, SARS-CoV-2 infection, and 30-day mortality. We used a Bayesian multilevel logistic regression stratified by hospitals and adjusted for key confounders to estimate the association between income groups and mortality. Results: Among 1016 patients, the number of patients in each income group was 765 (75.3%) in HIC, 142 (14.0%) in UMIC, and 109 (10.7%) in LLMIC. The management of 200 (19.8%) patients changed from usual care, most commonly delayed surgery. Within 30 days after surgery, 14 (1.4%) patients had a COVID-19 diagnosis and 39 (3.8%) patients died. In the multivariable model, LLMIC was associated with increased mortality (odds ratio 2.83, 95% credible interval 1.37–5.74) compared to HIC. Conclusions: The first wave of the pandemic had a significant impact on surgical decision-making. While the incidence of SARS-CoV-2 infection within 30 days after surgery was low, there was a disparity in mortality between countries and this warrants further examination to identify any modifiable factors

Insights into the neural basis of paradoxical kinesia in Parkinson’s disease

Enhancements in peak motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of ‘paradoxical kinesis’ in patients with Parkinson’s disease. Might the latter phenomenon thus reflect a physiological process? The first study outlined in this thesis suggests this may be the case, as maximal effort grips in healthy subjects undergo dramatic enhancements when the imperative visual cue is accompanied by an intense auditory tone. Analogous enhancements in motor performance are demonstrated in a second study of patients with Parkinson’s disease and age-matched healthy controls. Remarkably, the facilitating effect of loud auditory tones is similar whether patients are off or on dopaminergic medication, suggesting a potentially non-dopaminergic basis for the phenomenon. A role of sub-cortical systems in the performance enhancements engendered by intense stimuli is next considered. Local field potentials recorded from the subthalamic nuclei of patients with Parkinson’s disease, whilst they undertake the above established paradigm, identify both theta/alpha (5-12 Hz) and high gamma/high frequency (55-375 Hz) activity as exhibiting remarkable scaling with maximal motor responses to the visual cue alone, but having little explanatory influence on performance enhancements beyond this. In the final study, a short-latency evoked potential in subthalamic nucleus local field potential recordings, which scales in amplitude with both stimulus intensity and corresponding enhancements in biomechanical measures of maximal handgrips, is identified. Interference with this potential through high frequency deep brain stimulation of the same nucleus, leads to a diminished behavioural effect of stimulus intensity. Recordings of a similar evoked potential in the related pedunculopontine nucleus – a key component of the reticular activating system – provide support for this neural signature as a physiological correlate of ascending arousal, propagated from the reticular activating system to exert an ‘energizing’ influence on motor circuitry through the subthalamic nucleus

Doing better than your best: loud auditory stimulation yields improvements in maximal voluntary force.

Could task performance be constrained by our ability to fully engage necessary neural processing through effort of will? The StartReact phenomenon suggests that this might be the case, as voluntary reaction times are substantially reduced by loud sounds. Here, we show that loud auditory stimulation can also be associated with an improvement in the force and speed of force development when 18 healthy subjects are repeatedly asked to make a maximal grip as fast and as strongly as possible. Peak grip force was increased by 7.2 ± 1.4% (SEM) (P < 0.0001), and the rate of force development was increased by 17.6 ± 2.0% (P < 0.00001), when imperative visual cues were accompanied by a loud auditory stimulus rather than delivered alone. This implies that loud auditory stimuli may allow motor pathways to be optimised beyond what can be achieved by effort of will alone

Bilateral functional connectivity of the basal ganglia in patients with Parkinson's disease and its modulation by dopaminergic treatment

Parkinson’s disease is characterised by excessive subcortical beta oscillations. However, little is known about the functional connectivity of the two basal ganglia across hemispheres and specifically the role beta plays in this. We recorded local field potentials from the subthalamic nucleus bilaterally in 23 subjects with Parkinson’s disease at rest, on and off medication. We found suppression of low beta power in response to levodopa (t22 = −4.4, p<0.001). There was significant coherence between the two sides in the beta range in 19 of the subjects. Coherence was selectively attenuated in the low beta range following levodopa (t22 = −2.7; p = 0.01). We also separately analysed amplitude co-modulation and phase synchronisation in the beta band and found significant amplitude co-modulation and phase locking values in 17 and 16 subjects respectively, off medication. There was a dissociable effect of levodopa on these measures, with a significant suppression only in low beta phase locking value (t22 = −2.8, p = 0.01) and not amplitude co-modulation. The absolute mean values of amplitude co-modulation (0.40±0.03) and phase synchronisation (0.29±0.02) off medication were, however, relatively low, suggesting that the two basal ganglia networks may have to be approached separately with independent sensing and stimulation during adaptive deep brain stimulation. In addition, our findings highlight the functional distinction between the lower and upper beta frequency ranges and between amplitude co-modulation and phase synchronization across subthalamic nuclei

Bilateral functional connectivity of the basal ganglia in patients with Parkinson's disease and its modulation by dopaminergic treatment

Parkinson’s disease is characterised by excessive subcortical beta oscillations. However, little is known about the functional connectivity of the two basal ganglia across hemispheres and specifically the role beta plays in this. We recorded local field potentials from the subthalamic nucleus bilaterally in 23 subjects with Parkinson’s disease at rest, on and off medication. We found suppression of low beta power in response to levodopa (t22 = −4.4, p&lt;0.001). There was significant coherence between the two sides in the beta range in 19 of the subjects. Coherence was selectively attenuated in the low beta range following levodopa (t22 = −2.7; p = 0.01). We also separately analysed amplitude co-modulation and phase synchronisation in the beta band and found significant amplitude co-modulation and phase locking values in 17 and 16 subjects respectively, off medication. There was a dissociable effect of levodopa on these measures, with a significant suppression only in low beta phase locking value (t22 = −2.8, p = 0.01) and not amplitude co-modulation. The absolute mean values of amplitude co-modulation (0.40±0.03) and phase synchronisation (0.29±0.02) off medication were, however, relatively low, suggesting that the two basal ganglia networks may have to be approached separately with independent sensing and stimulation during adaptive deep brain stimulation. In addition, our findings highlight the functional distinction between the lower and upper beta frequency ranges and between amplitude co-modulation and phase synchronization across subthalamic nuclei

Improvements in rate of development and magnitude of force with intense auditory stimuli in patients with Parkinson's disease

Patients with Parkinson's disease can show brief but dramatic normalization of motor activity in highly arousing situations, a phenomenon often termed paradoxical kinesis. We sought to mimic this in a controlled experimental environment. Nine patients with Parkinson's disease and nine age-matched healthy controls were asked to grip a force dynamometer as quickly and strongly as possible in response to a visual cue. A loud (96dB) auditory stimulus was delivered at the same time as the visual cue in ∼50% of randomly selected trials. In patients with Parkinson's disease, the experiment was conducted after overnight withdrawal of antiparkinsonian drugs and again 1h after patients had taken their usual morning medication. Patients showed improvements in the peak rate of force development and the magnitude of force developed when loud auditory stimuli accompanied visual cues. Equally, they showed improvements in the times taken to reach the peak rate of force development and their maximal force. The paradoxical facilitatory effect of sound was similar whether patients were off or on their usual antiparkinsonian medication, and could be reproduced in age-matched healthy controls. We conclude that motor improvement induced by loud auditory stimuli in Parkinson's disease is related to a physiological phenomenon which survives both with and after withdrawal of antiparkinsonian medication. The potential independence of the mediating pathways from the dopaminergic system provides impetus for further investigation as it may yield a novel nondopaminergic target for therapeutic manipulation in Parkinson's disease. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd

Subthalamic nucleus gamma oscillations mediate a switch from automatic to controlled processing: a study of random number generation in Parkinson's disease.

In paced random number generation (RNG) participants are asked to generate numbers between 1 and 9 in a random fashion, in synchrony with a pacing stimulus. Successful task performance can be achieved through control of the main biases known to exist in human RNG compared to a computer generated series: seriation, cycling through a set of available numbers, and repetition avoidance. A role in response inhibition and switching from automatic to controlled processing has previously been ascribed to the subthalamic nucleus (STN). We sought evidence of frequency-specific changes in STN oscillatory activity which could be directly related to use of such strategies during RNG. Local field potentials (LFPs) were recorded from depth electrodes implanted in the STN of 7 patients (14 sides) with Parkinson's disease (PD), when patients were on dopaminergic medication. Patients were instructed to (1) generate a series of 100 numbers between 1 and 9 in a random fashion, and (2) undertake a control serial counting task, both in synchrony with a 0.5 Hz pacing stimulus. Significant increases in LFP power (p ≤ 0.05) across a narrow gamma frequency band (45-60 Hz) during RNG, compared to the control counting task, were observed. Further, the number of 'repeated pairs' (a decline in which reflects repetition avoidance bias in human RNG) was positively correlated with these gamma increases. We therefore suggest that STN gamma activity is relevant for controlled processing, in particular the active selection and repetition of the same number on successive trials. These results are consistent with a frequency-specific role of the STN in executive processes such as suppression of habitual responses and 'switching-on' of more controlled processing strategies