A model for studying the energetics of sustained high frequency firing

Regulating membrane potential and synaptic function contributes significantly to the energetic costs of brain signaling, but the relative costs of action potentials (APs) and synaptic transmission during high-frequency firing are unknown. The continuous high-frequency (200-600Hz) electric organ discharge (EOD) of Eigenmannia, a weakly electric fish, underlies its electrosensing and communication. EODs reflect APs fired by the muscle-derived electrocytes of the electric organ (EO). Cholinergic synapses at the excitable posterior membranes of the elongated electrocytes control AP frequency. Based on whole-fish O2 consumption, ATP demand per EOD-linked AP increases exponentially with AP frequency. Continual EOD-AP generation implies first, that ion homeostatic processes reliably counteract any dissipation of posterior membrane ENa and EK and second that high frequency synaptic activation is reliably supported. Both of these processes require energy. To facilitate an exploration of the expected energy demands of each, we modify a previous excitability model and include synaptic currents able to drive APs at frequencies as high as 600 Hz. Synaptic stimuli are modeled as pulsatile cation conductance changes, with or without a small (sustained) background conductance. Over the full species range of EOD frequencies (200–600 Hz) we calculate frequency-dependent “Na+-entry budgets” for an electrocyte AP as a surrogate for required 3Na+/2K+-ATPase activity. We find that the cost per AP of maintaining constant-amplitude APs increases nonlinearly with frequency, whereas the cost per AP for synaptic input current is essentially constant. This predicts that Na+ channel density should correlate positively with EOD frequency, whereas AChR density should be the same across fish. Importantly, calculated costs (inferred from Na+-entry through Nav and ACh channels) for electrocyte APs as frequencies rise are much less than expected from published whole-fish EOD-linked O2 consumption. For APs at increasingly high frequencies, we suggest that EOD-related costs external to electrocytes (including packaging of synaptic transmitter) substantially exceed the direct cost of electrocyte ion homeostasis.BJ and JEL thank the Natural Sciences and Engineering Research Council of Canada (http://www.nserc-crsng.gc.ca) for funding. MRM acknowledges support from the National Science Foundation (https://www.nsf.gov/) (grants IOS1257580 and IOS1350753). CEM acknowledges support from the Ottawa Hospital Research Institute (www.ohri.ca). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. APC funded, in part, by University of Oklahoma Libraries Open Access Fund.Ye

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Background information.

<p><b>A.</b> (modified from Ref. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196508#pone.0196508.ref005" target="_blank">5</a>]) <i>Eigenmannia</i>, showing the electric organ (EO) location and the anterior(a)/posterior(p) disposition of its constituent electrocytes, each innervated posteriorly by a (central pacemaker driven) cholinergic electromotor neuron synapse (i.e., electroplaque). Due to the rapidly alternating head-positive/head-negative polarization from the continual EO discharge (EOD), the fish in its aqueous medium approximates an oscillating dipole [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196508#pone.0196508.ref006" target="_blank">6</a>]. <b>B.</b> Plot from Ref. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196508#pone.0196508.ref006" target="_blank">6</a>], summarizing the unexpected observation (calculated from whole fish O₂ consumption data linked to <i>Eigenmannia</i> EOD frequencies) that APs cost more as AP frequency increases. <b>C</b>. Left, an MKZ-simulated AP train (gNa_max = 700 μS) driven by pulsatile I_clamp as labeled, and right, one AP with the time scale expanded to make evident the apparent threshold region (~-17 mV) (inset: V_peak as a function of I_stim).</p

Validation of low-cost wireless EEG system for measuring event-related potentials

This study used the traditional P300 speller paradigm to compare a medical grade Electroencephalography (EEG) system, the G.Tec, with a consumer grade EEG system, the Emotiv, in the detection of P300 components within Event Related Potential (ERP) signals. The experiment focused on four electrodes known to produce optically induced visual evoked potential. A successful comparison of the two approaches was made. It was shown that both systems could measure an ERP. The paper concludes with discussion comparing the low-cost wireless EEG system with the medical grade EEG system

Na⁺ entry for various synaptic stimulus regimes^∆.

<p>Na⁺ entry for various synaptic stimulus regimes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196508#t002fn003" target="_blank">^∆</a>.</p

Simulation of a JAR.

<p>For APs at frequencies ± 10 Hz near 400 Hz, with gNa_max at 783 μS, V_peak differs minimally. This suggests that typical ± 10 Hz JARs in <i>Eigenmannia</i> might require no increased expression of Nav channels.</p

Epm-simulated APs stimulated by pulsatile synaptic current.

<p><b>A.</b> One AP from a 200 Hz AP train (stimulus: syn_clamp1.0_200Hz) with gNa_max = 700 μS. <b>B.</b> For gNa_max values as labeled, APs from trains with stimulus syn_clamp1.0_200Hz or syn_clamp1.0_600Hz. First column, gNa_max = 700 μS; second column, for syn_clamp1.0_600Hz, gNa_max is raised to 1126 μS to bring V_peak to 13 mV. See text for further explanation.</p

Sustained step and ramp I_clamp stimulation of Epm.

<p>Standard gNa_max (700 μS) is used unless otherwise specified, I_stim as labeled, other parameters as in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196508#pone.0196508.t001" target="_blank">Table 1</a></b>. See text for further explanation.</p