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Purpose: To evaluate the outcome of orbital floor injection of betamethasone and methylprednisolone in the management of uveitis, with particular reference to its efficacy in avoiding increase in systemic immunosuppressive drugs. Methods: A sample of all patients attending the Uveitis Service at Moorfields Eye Hospital was carried out over a three-month period. All patients who had received one or more orbital floor injections of betamethasone (4 mg) and methylprednisolone (Depo-Medrone; 40 mg) in the management of their uveitis were identified and the case notes reviewed. Results: A total of 48 patients who had received 75 orbital floor injections were identified during the sample period. Most patients had either panuveitis (n = 24) or pars planitis (n = 14). One-month post-injection visual acuity (VA) had improved by at least one Snellen line after 33/75 injections (44%) and at least two lines after 11/75 (15%), was unchanged after 25 (33%), but had deteriorated in 14 (19%). VA was not recorded after 3/75 injections. The only complications recorded were periorbital haemorrhage (n = 1) and complaints of persistent pain after an injection (n = 1). Symptoms (pain and subjective vision) improved after 36/75 injections (47%), were unchanged after 24 (32%), and were reported as worse after five (7%). Additionally, three patients reported an improvement in symptoms which lasted less than one month. Signs other than VA were improved after 28/75 (37%), were unchanged after 38 (51%), and deteriorated after only one injection. Of the 31 patients given orbital floor injections to avoid systemic therapy, seven (23%) subsequently went on to require it, and the clinical course then improved in 45%. Conclusions: Combined orbital floor injection of betamethasone and methylprednisolone can result in improved visual acuity, symptoms, and signs of inflammation in uveitis, and may therefore avoid the necessity for increased systemic medication. [ABSTRACT FROM AUTHOR]

Biofilms of Staphylococcus epidermidis were cultured at various specific growth rates, and susceptibilities to tobramycin were compared with those of equivalent plank-tonic populations. In all instances, susceptibility increased significantly with increasing specific growth rate. However, resuspension of the biofilms increased susceptibility, suggesting some involvement of the glycocalyx in reducing antibiotic permeation of the biofilm. Cells that dispersed spontaneously from the biofilms at steady state were particularly susceptible to this agent. Since such cells correspond to newly-divided daughter cells, the relationship between tobramycin susceptibility and the phase in the division cycle was investigated. Susceptibility was enhanced in cultures dividing synchronously shortly before, during and shortly after cell separation. Perfusion of actively-growing S. epidermidis biofilms with tobramycin also demonstrated increased susceptibility with increasing growth rate, but also showed rapid recovery following removal of the agent. [ABSTRACT FROM AUTHOR]

Head-fixation of mice enables high-resolution monitoring of neuronal activity coupled with precise control of environmental stimuli. Virtual reality can be used to emulate the visual experience of movement during head fixation, but a low inertia floating real-world environment (mobile homecage, MHC) has the potential to engage more sensory modalities and provide a richer experimental environment for complex behavioral tasks. However, it is not known whether mice react to this adapted environment in a similar manner to real environments, or whether the MHC can be used to implement validated, maze-based behavioral tasks. Here, we show that hippocampal place cell representations are intact in the MHC and that the system allows relatively long (20 min) whole-cell patch clamp recordings from dorsal CA1 pyramidal neurons, revealing sub-threshold membrane potential dynamics. Furthermore, mice learn the location of a liquid reward within an adapted T-maze guided by 2-dimensional spatial navigation cues and relearn the location when spatial contingencies are reversed. Bilateral infusions of scopolamine show that this learning is hippocampus-dependent and requires intact cholinergic signalling. Therefore, we characterize the MHC system as an experimental tool to study sub-threshold membrane potential dynamics that underpin complex navigation behaviors., (© 2024. The Author(s).)

Background: At-risk alcohol use is associated with increased adverse health consequences, yet is undertreated in healthcare settings. People residing in rural areas need improved access to services; however, few interventions are designed to meet the needs of rural populations. Mobile interventions can provide feasible, low-cost, and scalable means for reaching this population and improving health, and behavioral economic approaches are promising., Methods: We conducted a pilot randomized controlled trial focused on acceptability and feasibility of a mobile behavioral economic intervention for 75 rural-residing adults with at-risk alcohol use. We recruited participants from a large healthcare system and randomized them to one of four virtually-delivered conditions reflecting behavioral economic approaches: episodic future thinking (EFT), volitional choice (VC), both EFT and VC, or enhanced usual care control (EUC). The intervention included a telephone-delivered induction session followed by two weeks of condition-consistent ecological momentary interventions (EMIs; 2x/day) and ecological momentary assessments (EMAs; 1x/day). Participants completed assessments at baseline, post-intervention, and two-month follow-up, and provided intervention feedback., Results: All participants completed the telephone-delivered session and elected to receive EMI messages. Average completion rate of EMAs across conditions was 92.9%. Among participants in active intervention conditions, 89.3% reported the induction session was helpful and 80.0% reported it influenced their future drinking. We also report initial alcohol use outcomes., Discussion: The behavioral economic intervention components and trial procedures evaluated here appear to be feasible and acceptable. Next steps include determination of their efficacy to reduce alcohol use and public health harms., Competing Interests: The authors of this paper have no conflicts of interest to declare., (© 2024 The Author(s).)

Understanding cortical function requires studying multiple scales: molecular, cellular, circuit, and behavioral. We develop a multiscale, biophysically detailed model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. Neuron types, densities, spatial distributions, morphologies, biophysics, connectivity, and dendritic synapse locations are constrained by experimental data. The model includes long-range inputs from seven thalamic and cortical regions and noradrenergic inputs. Connectivity depends on cell class and cortical depth at sublaminar resolution. The model accurately predicts in vivo layer- and cell-type-specific responses (firing rates and LFP) associated with behavioral states (quiet wakefulness and movement) and experimental manipulations (noradrenaline receptor blockade and thalamus inactivation). We generate mechanistic hypotheses underlying the observed activity and analyzed low-dimensional population latent dynamics. This quantitative theoretical framework can be used to integrate and interpret M1 experimental data and sheds light on the cell-type-specific multiscale dynamics associated with several experimental conditions and behaviors., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: In vivo patch-clamp recording techniques provide access to the sub- and suprathreshold membrane potential dynamics of individual neurons during behavior. However, maintaining recording stability throughout behavior is a significant challenge, and while methods for head restraint are commonly used to enhance stability, behaviorally related brain movement relative to the skull can severely impact the success rate and duration of whole-cell patch-clamp recordings., New Method: We developed a low-cost, biocompatible, and 3D-printable cranial implant capable of locally stabilizing brain movement, while permitting equivalent access to the brain when compared to a conventional craniotomy., Results: Experiments in head-restrained behaving mice demonstrate that the cranial implant can reliably reduce the amplitude and speed of brain displacements, significantly improving the success rate of recordings across repeated bouts of motor behavior., Comparison With Existing Method(s): Our solution offers an improvement on currently available strategies for brain stabilization. Due to its small size, the implant can be retrofitted to most in vivo electrophysiology recording setups, providing a low cost, easily implementable solution for increasing intracellular recording stability in vivo., Conclusions: By facilitating stable whole-cell patch-clamp recordings in vivo, biocompatible 3D printed implants should accelerate the investigation of single neuron computations underlying behavior., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Touchscreen-based behavioral assays provide a robust method for assessing cognitive behavior in rodents, offering great flexibility and translational potential. The development of touchscreen assays presents a significant programming and mechanical engineering challenge, where commercial solutions can be prohibitively expensive and open-source solutions are underdeveloped, with limited adaptability., New Method: Here, we present Visiomode (www.visiomode.org), an open-source platform for building rodent touchscreen-based behavioral tasks. Visiomode leverages the inherent flexibility of touchscreens to offer a simple yet adaptable software and hardware platform. The platform is built on the Raspberry Pi computer combining a web-based interface and powerful plug-in system with an operant chamber that can be adapted to generate a wide range of behavioral tasks., Results: As a proof of concept, we use Visiomode to build both simple stimulus-response and more complex visual discrimination tasks, showing that mice display rapid sensorimotor learning including switching between different motor responses (i.e., nose poke versus reaching)., Comparison With Existing Methods: Commercial solutions are the 'go to' for rodent touchscreen behaviors, but the associated costs can be prohibitive, limiting their uptake by the wider neuroscience community. While several open-source solutions have been developed, efforts so far have focused on reducing the cost, rather than promoting ease of use and adaptability. Visiomode addresses these unmet needs providing a low-cost, extensible platform for creating touchscreen tasks., Conclusions: Developing an open-source, rapidly scalable and low-cost platform for building touchscreen-based behavioral assays should increase uptake across the science community and accelerate the investigation of cognition, decision-making and sensorimotor behaviors both in health and disease., Competing Interests: Declaration of Competing Interest The authors declare no declarations of competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Motor cortex generates descending output necessary for executing a wide range of limb movements. Although movement-related activity has been described throughout motor cortex, the spatiotemporal organization of movement-specific signaling in deep layers remains largely unknown. Here we record layer 5B population dynamics in the caudal forelimb area of motor cortex while mice perform a forelimb push/pull task and find that most neurons show movement-invariant responses, with a minority displaying movement specificity. Using cell-type-specific imaging, we identify that invariant responses dominate pyramidal tract (PT) neuron activity, with a small subpopulation representing movement type, whereas a larger proportion of intratelencephalic (IT) neurons display movement-type-specific signaling. The proportion of IT neurons decoding movement-type peaks prior to movement initiation, whereas for PT neurons, this occurs during movement execution. Our data suggest that layer 5B population dynamics largely reflect movement-invariant signaling, with information related to movement-type being routed through relatively small, distributed subpopulations of projection neurons., Competing Interests: Declaration of interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Motivational incentive interventions are highly effective for smoking cessation. Yet, these interventions are not widely available to people who want to quit smoking, in part, due to barriers such as administrative burden, concern about the use of extrinsic reinforcement (i.e., incentives) to improve cessation outcomes, suboptimal intervention engagement, individual burden, and up-front costs., Purpose: Technological advancements can mitigate some of these barriers. For example, mobile abstinence monitoring and digital, automated incentive delivery have the potential to lower the clinic burden associated with monitoring abstinence and administering incentives while also reducing the frequency of clinic visits. However, to fully realize the potential of digital technologies to deliver motivational incentives it is critical to develop strategies to mitigate longstanding concerns that reliance on extrinsic monetary reinforcement may hamper internal motivation for cessation, improve individual engagement with the intervention, and address scalability limitations due to the up-front cost of monetary incentives. Herein, we describe the state of digitally-delivered motivational incentives. We then build on existing principles for creating just-in-time adaptive interventions to highlight new directions in leveraging digital technology to improve the effectiveness and scalability of motivational incentive interventions., Conclusions: Technological advancement in abstinence monitoring coupled with digital delivery of reinforcers has made the use of motivational incentives for smoking cessation increasingly feasible. We propose future directions for a new era of motivational incentive interventions that leverage technology to integrate monetary and non-monetary incentives in a way that addresses the changing needs of individuals as they unfold in real-time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Coughlin, Bonar, Walton, Fernandez, Duguid and Nahum-Shani.)

Executing learned motor behaviors often requires the transformation of sensory cues into patterns of motor commands that generate appropriately timed actions. The cerebellum and thalamus are two key areas involved in shaping cortical output and movement, but the contribution of a cerebellar-thalamocortical pathway to voluntary movement initiation remains poorly understood. Here, we investigated how an auditory "go cue" transforms thalamocortical activity patterns and how these changes relate to movement initiation. Population responses in dentate/interpositus-recipient regions of motor thalamus reflect a time-locked increase in activity immediately prior to movement initiation that is temporally uncoupled from the go cue, indicative of a fixed-latency feedforward motor timing signal. Blocking cerebellar or motor thalamic output suppresses movement initiation, while stimulation triggers movements in a behavioral context-dependent manner. Our findings show how cerebellar output, via the thalamus, shapes cortical activity patterns necessary for learned context-dependent movement initiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cerebellar climbing-fiber-mediated complex spikes originate from neurons in the inferior olive (IO), are critical for motor coordination, and are central to theories of cerebellar learning. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels expressed by IO neurons have been considered as pacemaker currents important for oscillatory and resonant dynamics. Here, we demonstrate that in vitro, network actions of HCN1 channels enable bidirectional glutamatergic synaptic responses, while local actions of HCN1 channels determine the timing and waveform of synaptically driven action potentials. These roles are distinct from, and may complement, proposed pacemaker functions of HCN channels. We find that in behaving animals HCN1 channels reduce variability in the timing of cerebellar complex spikes, which serve as a readout of IO spiking. Our results suggest that spatially distributed actions of HCN1 channels enable the IO to implement network-wide rules for synaptic integration that modulate the timing of cerebellar climbing fiber signals., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

From patch-clamp techniques to recombinant DNA technologies, three-dimensional protein modeling, and optogenetics, diverse and sophisticated methods have been used to study ion channels and how they determine the electrical properties of cells., (© 2017 Cold Spring Harbor Laboratory Press.)