The processing of threat- and fear-related responses is known to involve the amygdala and the bed nucleus of the stria terminalis. Malignant activity in these nuclei is associated with several important disorders, including generalized anxiety disorder and post-traumatic stress disorder. A noninvasive approach to modulate these deep brain circuits could provide novel treatment options for these disorders, but current noninvasive approaches cannot access these targets directly. This study modulates these nuclei using transcranial low-intensity focused ultrasound in nonhuman primates. The ultrasound was delivered into these circuits prior to an emotional stimulus (neutral, submissive, or threatening monkey faces or snake images) while measuring the system's autonomic response using pupil size. We found that the neuromodulation substantially reduced the pupillary responses to threat images. The effect was specific to threat face images and specific to focused ultrasound; it was not observed for other types of images or for unfocused or no-ultrasound. Thus, focused ultrasound targeting fear circuits can suppress responses to threat images. This approach could be developed into noninvasive treatments of disorders that affect these circuits.

The monitoring of vital signs in patients undergoing anesthesia began with the very first case of anesthesia and has evolved alongside the development of anesthesiology ever since. Patient monitoring started out as a manually performed, intermittent, and qualitative assessment of the patient's general well-being in the operating room. In its evolution, patient monitoring development has responded to the clinical need, for example, when critical incident studies in the 1980s found that many anesthesia adverse events could be prevented by improved monitoring, especially respiratory monitoring. It also facilitated and perhaps even enabled increasingly complex surgeries in increasingly higher-risk patients. For example, it would be very challenging to perform and provide anesthesia care during some of the very complex cardiovascular surgeries that are almost routine today without being able to simultaneously and reliably monitor multiple pressures in a variety of places in the circulatory system. Of course, anesthesia patient monitoring itself is enabled by technological developments in the world outside of the operating room. Throughout its history, anesthesia patient monitoring has taken advantage of advancements in material science (when nonthrombogenic polymers allowed the design of intravascular catheters, for example), in electronics and transducers, in computers, in displays, in information technology, and so forth. Slower product life cycles in medical devices mean that by carefully observing technologies such as consumer electronics, including user interfaces, it is possible to peek ahead and estimate with confidence the foundational technologies that will be used by patient monitors in the near future. Just as the discipline of anesthesiology has, the patient monitoring that accompanies it has come a long way from its beginnings in the mid-19th century. Extrapolating from careful observations of the prevailing trends that have shaped anesthesia patient monitoring historically, patient monitoring in the future will use noncontact technologies, will predict the trajectory of a patient's vital signs, will add regional vital signs to the current systemic ones, and will facilitate directed and supervised anesthesia care over the broader scope that anesthesia will be responsible for.

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.

Rationale The intravenous anesthetic propofol is known to induce positive mood effects during routine clinical use, suggesting it might be repurposed as an antidepressant, but also raising concerns about abuse potential. How propofol's acute effects vary by dose and with repeated infusions is unknown. Objectives This exploratory analysis aimed to (1) compare the immediate mood effects of propofol administered at two different doses, (2) describe how those mood effects change with repeated infusions, and (3) evaluate whether acute mood improvement predicts later antidepressant response. Methods Twenty-four adults with moderate-to-severe treatment-resistant depression were randomized into two dosing groups. Six low- or high-dose propofol infusions were administered under blinded conditions over a two-week period. Self-reported mood states were recorded before and after each infusion using the Positive and Negative Affect Schedule (PANAS-X). Abuse potential was evaluated with the Drug Effects Questionnaire (DEQ-5). Results At the first infusion, propofol induced acute improvements in PANAS-X Sadness, Fear, Joviality, and Serenity scales (p < 0.002), independent of dose. Over the series of six infusions, acute changes in Sadness, Fear, and Joviality, but not Serenity, diminished with infusion number (p < 0.002). The DEQ-5 "want more" rating decreased across infusions (p = 0.002). Changes in PANAS-X scales with the first infusion did not predict later improvement in depression severity (p > 0.05). Conclusion Cumulative changes in mood states observed with repeated infusions suggest that propofol engages adaptive mechanisms in mood circuitry. Subjective responses with repeated infusions do not indicate increasing potential for abuse in this patient population.

IntroductionThe combination of magnetic and focused ultrasonic fields generates focused electric fields at depth entirely noninvasively. This noninvasive method may find particularly important applications in targeted treatments of the deep brain circuits involved in mental and neurological disorders. Due to the novelty of this method, it is nonetheless unknown which parameters modulate neural activity effectively.MethodsWe have investigated this issue by applying the combination of magnetic and focused ultrasonic fields to deep brain visual circuits in two non-human primates, quantifying the electroencephalographic gamma activity evoked in the visual cortex. We hypothesized that the pulse repetition frequency of the ultrasonic stimulation should be a key factor in modulating the responses, predicting that lower frequencies should elicit inhibitory effects and higher frequencies excitatory effects.ResultsWe replicated the results of a previous study, finding an inhibition of the evoked gamma responses by a strong magnetic field. This inhibition was only observed for the lowest frequency tested (5 Hz), and not for the higher frequencies (10 kHz and 50 kHz). These neuromodulatory effects were transient and no safety issues were noted.DiscussionWe conclude that this new method can be used to transiently inhibit evoked neural activity in deep brain regions of primates, and that delivering the ultrasonic pulses at low pulse repetition frequencies maximizes the effect.

The anesthetic propofol is proposed to have antidepressant effects. Although propofol has been observed to induce short-term positive mood effects during routine clinical use, the dose-dependent effects of repeated infusions with depressed subjects remains unknown. We hypothesized that immediate drug-induced mood improvements would change with repeated infusions and that immediate improvement would predict later antidepressant response.

Glutamatergic and GABAergic systems have emerged as pharmacological targets that, when appropriately modulated, can trigger therapeutic neuroplasticity. The anesthetic drug propofol modulates the function of GABA-A and NMDA receptors and can elicit transient positive mood states. To test the hypothesis that propofol has antidepressant and neuroplastic effects, we conducted a blinded randomized controlled trial (NCT03684447) to compare two doses of propofol.

Burst suppression is a brain state consisting of high-amplitude electrical activity alternating with periods of quieter suppression that can be brought about by disease or by certain anesthetics. Although burst suppression has been studied for decades, few studies have investigated the diverse manifestations of this state within and between human subjects. As part of a clinical trial examining the antidepressant effects of propofol, we gathered burst suppression electroencephalographic (EEG) data from 114 propofol infusions across 21 human subjects with treatment-resistant depression. This data was examined with the objective of describing and quantifying electrical signal diversity. We observed three types of EEG burst activity: canonical broadband bursts (as frequently described in the literature), spindles (narrow-band oscillations reminiscent of sleep spindles), and a new feature that we call low-frequency bursts (LFBs), which are brief deflections of mainly sub-3-Hz power. These three features were distinct in both the time and frequency domains and their occurrence differed significantly across subjects, with some subjects showing many LFBs or spindles and others showing very few. Spectral-power makeup of each feature was also significantly different across subjects. In a subset of nine participants with high-density EEG recordings, we noted that each feature had a unique spatial pattern of amplitude and polarity when measured across the scalp. Finally, we observed that the Bispectral Index Monitor, a commonly used clinical EEG monitor, does not account for the diversity of EEG features when processing the burst suppression state. Overall, this study describes and quantifies variation in the burst suppression EEG state across subjects and repeated infusions of propofol. These findings have implications for the understanding of brain activity under anesthesia and for individualized dosing of anesthetic drugs.

Background:Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not.Methods:Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life.Results:Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05).Conclusions:The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Foot placement can be selected to anticipate upcoming perturbations, but it is unclear how this anticipatory strategy is influenced by available response time or precise knowledge of the perturbation's characteristics. This study investigates anticipatory and reactive locomotor strategies for repeated underfoot perturbations with varying levels of temporal certainty, physical certainty, and available response time. Thirteen healthy adults walked with random underfoot perturbations from a mechanized shoe. Temporal certainty was challenged by presenting the perturbations with or without warning. Available response time was challenged by adjusting the timing of the warning before the perturbation. Physical certainty was challenged by making perturbation direction (inversion or eversion) unpredictable for certain conditions. Linear-mixed effects models assessed the effect of each condition on the percentage change ofmargin of stability and step width. For perturbations with one stride or less of response time, we observed few changes to step width or margin of stability. As response time increased to two strides, participants adopted wider steps in anticipation of the perturbation (P=0.001). Physical certainty had little effect on gait for the step of the perturbation, but participants recovered normal gait sooner when the physical nature of the perturbation was predictable (P<0.001). Despite having information about the timing and direction of upcoming perturbations, individuals do not develop perturbation-specific feedforward strategies. Instead, they use feedback control to recover normal gait after a perturbation. However, physical certainty appears to make the feedback controller more efficient and allows individuals to recover normal gait sooner.

AbstractBackgroundAmbulation over complex terrain requires active control of foot placement to maintain a normal kinematic relationship between the center of mass and base of support. Recent investigations have suggested that foot placement location may be selected to anticipate shifts to the underfoot center of pressure. However, it is unclear whether temporal affordance and physical certainty contribute to the selection of a perturbation-specific anticipatory strategy. This study investigates anticipatory and reactive locomotor strategies for repeated underfoot perturbations with varying levels of temporal certainty, temporal affordance, and physical certainty.MethodsThirteen healthy adults walked with random underfoot perturbations from a mechanized shoe. Temporal certainty was challenged by presenting the perturbations with or without warning. Temporal affordance was challenged by adjusting the timing of a warning tone before the perturbation. Physical certainty was challenged with conditions that included only eversion perturbations, only inversion perturbations, or both eversion and inversion perturbations. Linear-mixed effects models assessed the effect of each condition on the percent change of margin of stability and step width, respectively.ResultsFor temporally uncertain perturbations and perturbations with one stride or less of affordance, we observed few changes to step width or margin of stability. As affordance increased to two strides, participants adopted a wider step width in anticipation of the perturbation (p = 0.001). Physical certainty had little effect on gait for the step of the perturbation, but participants recovered normal gait sooner when the physical nature of the perturbation was predictable (p < 0.001).DiscussionDespite having information about the timing and magnitude of upcoming perturbations, individuals do not develop perturbation specific feedforward strategies but instead rely on feedback control to recover normal gait after a perturbation. However, physical certainty appears to improve the efficiency of the feedback controller and allows individuals to recover normal gait sooner.

Introduction: Recent evidence suggests that high doses of anesthetics produce significant and durable antidepressant effects in those with drug-resistant depression, comparable to the positive effects of electroconvulsive therapy (ECT) [1][2]. Maintaining a 70-90% EEG burst suppression ratio (BSR) for ~15 minutes seems to yield the strongest antidepressant effects [2]. To date, no dosing guidelines or algorithms have been published by any group to aid anesthesiologists in achieving 15 minutes of 70-90% burst suppression with the administration of these drugs in human subjects.

Background Acute kidney injury (AKI) is a common complication of cardiac surgery. An intraoperative monitor of kidney perfusion is needed to identify patients at risk for AKI. The authors created a noninvasive urinary oximeter that provides continuous measurements of urinary oxygen partial pressure and instantaneous urine flow. They hypothesized that intraoperative urinary oxygen partial pressure measurements are feasible with this prototype device and that low urinary oxygen partial pressure during cardiac surgery is associated with the subsequent development of AKI. Methods This was a prospective observational pilot study. Continuous urinary oxygen partial pressure and instantaneous urine flow were measured in 91 patients undergoing cardiac surgery using a novel device placed between the urinary catheter and collecting bag. Data were collected throughout the surgery and for 24 h postoperatively. Clinicians were blinded to the intraoperative urinary oxygen partial pressure and instantaneous flow data. Patients were then followed postoperatively, and the incidence of AKI was compared to urinary oxygen partial pressure measurements. Results Intraoperative urinary oxygen partial pressure measurements were feasible in 86/91 (95%) of patients. When urinary oxygen partial pressure data were filtered for valid urine flows greater than 0.5 ml · kg–1 · h–1, then 70/86 (81%) and 77/86 (90%) of patients in the cardiopulmonary bypass (CPB) and post-CPB periods, respectively, were included in the analysis. Mean urinary oxygen partial pressure in the post-CPB period was significantly lower in patients who subsequently developed AKI than in those who did not (mean difference, 6 mmHg; 95% CI, 0 to 11; P = 0.038). In a multivariable analysis, mean urinary oxygen partial pressure during the post-CPB period remained an independent risk factor for AKI (relative risk, 0.82; 95% CI, 0.71 to 0.95; P = 0.009 for every 10-mmHg increase in mean urinary oxygen partial pressure). Conclusions Low urinary oxygen partial pressures after CPB may be associated with the subsequent development of AKI after cardiac surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New