A Physiological Marker for Deep Brain Ultrasonic Neuromodulation.

OBJECTIVES: Transcranial ultrasound neuromodulation (TUSN) is a noninvasive and spatially specific therapy that promises to deliver treatments tailored to the specific needs of individuals. To fulfill this promise, each treatment must be modified to adequately correct for variation across individual skulls and neural anatomy. This study examines the use of ultrasound-induced voltage potentials (measured with electroencephalography [EEG]) to guide TUSN therapies. MATERIALS AND METHODS: We measured EEG responses in two awake nonhuman primates during sonication of 12 targets surrounding two deep brain nuclei, the left and right lateral geniculate nucleus. RESULTS: We report reliable ultrasound evoked potentials measured with EEG after the deep brain ultrasonic modulation in nonhuman primates. Robust responses are observed after just ten repetitions of the ultrasonic stimuli. Moreover, these potentials are only evoked for specific deep brain targets. Furthermore, a behavioral study in one subject shows a direct correspondence between the target with maximal EEG response and ultrasound-based modulation of visual choice behavior. Thus, this study provides evidence for the feasibility of EEG-based guidance for ultrasound neuromodulation therapies.

Integrated rapid-cycle comparative effectiveness trials using flexible point of care randomisation in electronic health record systems.

Whilst the Randomised Controlled Trial remains the gold standard for deriving robust causal estimates of treatment efficacy, too often a traditional design proves prohibitively expensive or cumbersome when it comes to assessing questions regarding the comparative effectiveness of routinely used treatments. As a result, patients experience variation in practice as clinicians lack the evidence needed to personalise treatments effectively. This variation may be classified as unwarranted, where existing evidence is ignored, or legitimate where in the absence of evidence, clinicians rely on experience, expert opinion, and inferred principles from basic science to make decisions. We argue that within the right ethical and technological framework, legitimate variation can be transformed into a mechanism for evidence generation and learning. Learning Health Systems which harness existing variation in practice, represent a novel approach for generating evidence from everyday clinical practice. The development of these systems has gained traction due to the increased availability of modern Electronic Health Record Systems. However, despite their promise, overcoming hurdles to successfully integrating clinical trials within Learning Health Systems has proven challenging. This article describes the origins of integrated clinical trials and explores two main barriers to their further implementation - how best to obtain informed consent from patients to participate in routine comparative effectiveness research, and how to automate and integrate randomisation into a clinical workflow. Having described these barriers, we present a potential solution in the form of a research pipeline using a novel form of flexible point-of-care randomisation to allow clinicians and patients to participate in studies where there is clinical equipoise.

Controlled ultrasonic interventions through the human skull.

Transcranial focused ultrasound enables precise and non-invasive manipulations of deep brain circuits in humans, promising to provide safe and effective treatments of various neurological and mental health conditions. Ultrasound focused to deep brain targets can be used to modulate neural activity directly or localize the release of psychoactive drugs. However, these applications have been impeded by a key barrier-the human skull, which attenuates ultrasound strongly and unpredictably. To address this issue, we have developed an ultrasound-based approach that directly measures and compensates for the ultrasound attenuation by the skull. No additional skull imaging, simulations, assumptions, or free parameters are necessary; the method measures the attenuation directly by emitting a pulse of ultrasound from an array on one side of the head and measuring with an array on the opposite side. Here, we apply this emerging method to two primary future uses-neuromodulation and local drug release. Specifically, we show that the correction enables effective stimulation of peripheral nerves and effective release of propofol from nanoparticle carriers through an ex vivo human skull. Neither application was effective without the correction. Moreover, the effects show the expected dose-response relationship and targeting specificity. This article highlights the need for precise control of ultrasound intensity within the skull and provides a direct and practical approach for addressing this lingering barrier.

Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions of interest. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MRI imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Targeted drug release from stable and safe ultrasound-sensitive nanocarriers.

Targeted delivery of medication has the promise of increasing the effectiveness and safety of current systemic drug treatments. Focused ultrasound is emerging as noninvasive and practical energy for targeted drug release. However, it has yet to be determined which nanocarriers and ultrasound parameters can provide both effective and safe release. Perfluorocarbon nanodroplets have the potential to achieve these goals, but current approaches have either been effective or safe, but not both. We found that nanocarriers with highly stable perfluorocarbon cores mediate effective drug release so long as they are activated by ultrasound of sufficiently low frequency. We demonstrate a favorable safety profile of this formulation in a non-human primate. To facilitate translation of this approach into humans, we provide an optimized method for manufacturing the nanocarriers. This study provides a recipe and release parameters for effective and safe drug release from nanoparticle carriers in the body part specified by focused ultrasonic waves.

Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Sustained modulation of primate deep brain circuits with focused ultrasonic waves.

BACKGROUND: Transcranial focused ultrasound has the potential to noninvasively modulate deep brain circuits and impart sustained, neuroplastic effects. OBJECTIVE: Bring the approach closer to translations by demonstrating sustained modulation of deep brain circuits and choice behavior in task-performing non-human primates. METHODS: Low-intensity transcranial ultrasound of 30 s in duration was delivered in a controlled manner into deep brain targets (left or right lateral geniculate nucleus; LGN) of non-human primates while the subjects decided whether a left or a right visual target appeared first. While the animals performed the task, we recorded intracranial EEG from occipital screws. The ultrasound was delivered into the deep brain targets daily for a period of more than 6 months. RESULTS: The brief stimulation induced effects on choice behavior that persisted up to 15 minutes and were specific to the sonicated target. Stimulation of the left/right LGN increased the proportion of rightward/leftward choices. These effects were accompanied by an increase in gamma activity over visual cortex. The contralateral effect on choice behavior and the increase in gamma, compared to sham stimulation, suggest that the stimulation excited the target neural circuits. There were no detrimental effects on the animals' discrimination performance over the months-long course of the stimulation. CONCLUSION: This study demonstrates that brief, 30-s ultrasonic stimulation induces neuroplastic effects specifically in the target deep brain circuits, and that the stimulation can be applied daily without detrimental effects. These findings encourage repeated applications of transcranial ultrasound to malfunctioning deep brain circuits in humans with the goal of providing a durable therapeutic reset.

Remus: System for remote deep brain interventions.

Transcranial-focused ultrasound brings personalized medicine to the human brain. Ultrasound can modulate neural activity or release drugs in specific neural circuits but this personalized approach requires a system that delivers ultrasound into specified targets flexibly and on command. We developed a remote ultrasound system (Remus) that programmatically targets deep brain regions with high spatiotemporal precision and in a multi-focal manner. We validated these functions by modulating two deep brain nuclei-the left and right lateral geniculate nucleus-in a task-performing nonhuman primate. This flexible system will enable researchers and clinicians to diagnose and treat specific deep brain circuits in a noninvasive yet targeted manner, thus embodying the promise of personalized treatments of brain disorders.

Stochastic Resonance Governs Memory Consolidation Accuracy in a Neural Network Model.

The formation and recollection of memories is a multi-step neural process subject to errors. We propose a computational model of memory nodes receiving input from a colored tic-tac-toe board. We report memory errors during consolidation and reconsolidation when different noise levels are introduced into the model. The model is based on Hebbian plasticity and attempts to store the color and position of an X or O from the board. Memory nodes simulating neurons use an integrate-and-fire model to represent the correct or incorrect storage of the board information by scaling synaptic weights. We explored how baseline firing rate, which we considered analogous to noise in storing memory, impacted the creation of correct and incorrect memories. We found that a higher firing rate was associated with fewer accurate memories. Interestingly, the ideal amount of noise for correct memory storage was nonzero. This phenomenon is known as stochastic resonance, wherein random noise enhances processing. We also examined how many times our model could reactivate a memory before making an error. We found an exponentially decaying response, with a low firing rate yielding more stable memories. Even though our model incorporates only two memory nodes, it provides a basis for examining the consolidation and retrieval of memory storage based on the unique visual input of a tic-tac-toe board. Further work may incorporate different inputs, more nodes, and increased network complexity. Clinical Relevance- This model enables investigation of how the human cortex may utilize and exploit noise during information processing.

Embedded point of care randomisation for evaluating comparative effectiveness questions: PROSPECTOR-critical care feasibility study protocol.

INTRODUCTION: Many routinely administered treatments lack evidence as to their effectiveness. When treatments lack evidence, patients receive varying care based on the preferences of clinicians. Standard randomised controlled trials are unsuited to comparisons of different routine treatment strategies, and there remains little economic incentive for change.Integrating clinical trial infrastructure into electronic health record systems offers the potential for routine treatment comparisons at scale, through reduced trial costs. To date, embedded trials have automated data collection, participant identification and eligibility screening, but randomisation and consent remain manual and therefore costly tasks.This study will investigate the feasibility of using computer prompts to allow flexible randomisation at the point of clinical decision making. It will compare the effectiveness of two prompt designs through the lens of a candidate research question-comparing liberal or restrictive magnesium supplementation practices for critical care patients. It will also explore the acceptability of two consent models for conducting comparative effectiveness research. METHODS AND ANALYSIS: We will conduct a single centre, mixed-methods feasibility study, aiming to recruit 50 patients undergoing elective surgery requiring postoperative critical care admission. Participants will be randomised to either 'Nudge' or 'Preference' designs of electronic point-of-care randomisation prompt, and liberal or restrictive magnesium supplementation.We will judge feasibility through a combination of study outcomes. The primary outcome will be the proportion of prompts displayed resulting in successful randomisation events (compliance with the allocated magnesium strategy). Secondary outcomes will evaluate the acceptability of both prompt designs to clinicians and ascertain the acceptability of pre-emptive and opt-out consent models to patients. ETHICS AND DISSEMINATION: This study was approved by Riverside Research Ethics Committee (Ref: 21/LO/0785) and will be published on completion. TRIAL REGISTRATION NUMBER: NCT05149820.

Clinician preference instrumental variable analysis of the effectiveness of magnesium supplementation for atrial fibrillation prophylaxis in critical care.

Atrial fibrillation is a frequently encountered condition in critical illness and causes adverse effects including haemodynamic decompensation, stroke and prolonged hospital stay. It is a common practice in critical care to supplement serum magnesium for the purpose of preventing episodes of atrial fibrillation. However, no randomised studies support this practice in the non-cardiac surgery critical care population, and the effectiveness of magnesium supplementation is unclear. We sought to investigate the effectiveness of magnesium supplementation in preventing the onset of atrial fibrillation in a mixed critical care population. We conducted a single centre retrospective observational study of adult critical care patients. We utilised a natural experiment design, using the supplementation preference of the bedside critical care nurse as an instrumental variable. Using routinely collected electronic patient data, magnesium supplementation opportunities were defined and linked to the bedside nurse. Nurse preference for administering magnesium was obtained using multilevel modelling. The results were used to define "liberal" and "restrictive" supplementation groups, which were inputted into an instrumental variable regression to obtain an estimate of the effect of magnesium supplementation. 9114 magnesium supplementation opportunities were analysed, representing 2137 critical care admissions for 1914 patients. There was significant variation in magnesium supplementation practices attributable to the individual nurse, after accounting for covariates. The instrumental variable analysis showed magnesium supplementation was associated with a 3% decreased relative risk of experiencing an atrial fibrillation event (95% CI - 0.06 to - 0.004, p = 0.03). This study supports the strategy of routine supplementation, but further work is required to identify optimal serum magnesium targets for atrial fibrillation prophylaxis.

Micro-/Nanoscale Approach for Studying Scale Formation and Developing Scale-Resistant Surfaces.

Blockage of pipelines due to accretion of salt particles is detrimental in desalination and water-harvesting industries as they compromise productivity, while increasing maintenance costs. We present a micro-/nanoscale approach to study fundamentals of scale formation, deposition, and adhesion to engineered surfaces with a wide range of surface energies fabricated using the initiated chemical vapor deposition method. Silicon wafers and steel substrates are coated with poly(1 H,1 H,2 H,2 H-perfluorodecylacrylate) or pPFDA, poly(tetravinyl-tetramethylcyclotetrasilohexane) or pV4D4, poly(divinylbenzene) or pDVB, poly(1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasilohexane) or pV3D3, and cross-linked copolymers of poly(2-hydroxyethylmethacrylate) and poly(ethylene glycol) diacrylate or p(PHEMA- co-EGDA). Particles of salt (CaSO4·2H2O) are formed and shaped with a focused ion beam and adhered to a tipless cantilever beam using a micromanipulator setup to study their adhesion strength with a molecular force probe (MFP). Adhesion forces were measured on the substrates in wet and dry conditions to evaluate the effects of interfacial fluid layers and capillary bridges on net adhesion strength. The adhesion between salt particles and the pPFDA coatings decreased by 5.1 ± 1.15 nN in wet states, indicating the influence of capillary bridging between the particle and the liquid layer. In addition, scale nucleation and growth on various surfaces is examined using a quartz crystal microbalance (QCM), where supersaturated solution of CaSO4·2H2O is passed over bare and polymer-coated quartz substrates while mass gain is measured in real time. The salt accretion decreased by 2 folds on pPFDA-coated substrates when compared to that on p(HEMA- co-EGDA) coatings. Both MFP and QCM studies are essential in studying the impact of surface energy and roughness on the extent of scale formation and adhesion strength. This study can pave way for the design of scale-resistant surfaces with potential applications in water treatment, energy harvesting, and purification industries.