Decoding and perturbing decision states in real time.

In dynamic environments, subjects often integrate multiple samples of a signal and combine them to reach a categorical judgment1. The process of deliberation can be described by a time-varying decision variable (DV), decoded from neural population activity, that predicts a subject's upcoming decision2. Within single trials, however, there are large moment-to-moment fluctuations in the DV, the behavioural significance of which is unclear. Here, using real-time, neural feedback control of stimulus duration, we show that within-trial DV fluctuations, decoded from motor cortex, are tightly linked to decision state in macaques, predicting behavioural choices substantially better than the condition-averaged DV or the visual stimulus alone. Furthermore, robust changes in DV sign have the statistical regularities expected from behavioural studies of changes of mind3. Probing the decision process on single trials with weak stimulus pulses, we find evidence for time-varying absorbing decision bounds, enabling us to distinguish between specific models of decision making.

Polymer Modification of Lipases, Substrate Interactions, and Potential Inhibition.

An industrially important enzyme, Candida antarctica lipase B (CalB), was modified with a range of functional polymers including hydrophilic, hydrophobic, anionic, and cationic character using a "grafting to" approach. We determined the impact of polymer chain length on CalB activity by synthesizing biohybrids of CalB with each polymer at three different chain lengths, using reversible addition-fragmentation chain transfer (RAFT) polymerization. The activity of CalB in both aqueous and aqueous-organic media mixtures was significantly enhanced for acrylamide (Am) and N,N-dimethyl acrylamide (DMAm) conjugates, with activity remaining approximately constant in 25 and 50% ethanol solvent systems. Interestingly, the activity of N,N-dimethylaminopropyl-acrylamide (DMAPA) conjugates increased gradually with increasing organic solvent content in the system. Contrary to other literature reports, our study showed significantly diminished activity for hydrophobic polymer-protein conjugates. Functional thermal stability assays also displayed a considerable enhancement of retained activity of Am, DMAm, and DMAPA conjugates compared to the native CalB enzyme. Thus, this study provides an insight into possible advances in lipase production, which can lead to new improved lipase bioconjugates with increased activity and stability.

Global-scale drivers of crop visitor diversity and the historical development of agriculture.

Understanding diversity in flower-visitor assemblages helps us improve pollination of crops and support better biodiversity conservation outcomes. Much recent research has focused on drivers of crop-visitor diversity operating over spatial scales from fields to landscapes, such as pesticide and habitat management, while drivers operating over larger scales of continents and biogeographic realms are virtually unknown. Flower and visitor traits influence attraction of pollinators to flowers, and evolve in the context of associations that can be ancient or recent. Plants that have been adopted into agriculture have been moved widely around the world and thereby exposed to new flower visitors. Remarkably little is known of the consequence of these historical patterns for present-day crop-visiting bee diversity. We analyse data from 317 studies of 27 crops worldwide and find that crops are visited by fewer bee genera outside their region of origin and outside their family's region of origin. Thus, recent human history and the deeper evolutionary history of crops and bees appear to be important determinants of flower-visitor diversity at large scales that constrain the levels of visitor diversity that can be influenced by field- and landscape-scale interventions.

Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders.

Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.

Activation of persons living with HIV for treatment, the great study.

BACKGROUND: Patient empowerment represents a potent tool for addressing racial, ethnic and socioeconomic disparities in health care, particularly for chronic conditions such as HIV infection that require active patient engagement. This multimodal intervention, developed in concert with HIV patients and clinicians, aims to provide HIV patients with the knowledge, skills, attitudes and tools to become more activated patients. METHODS/DESIGN: Randomized controlled trial of a multimodal intervention designed to activate persons living with HIV. The intervention includes four components: 1) use of a web-enabled hand-held device (Apple iPod Touch) loaded with a Personal Health Record (ePHR) customized for HIV patients; 2) six 90-minute group-based training sessions in use of the device, internet and the ePHR; 3) a pre-visit coaching session; and 4) clinician education regarding how they can support activated patients. Outcome measures include pre- post changes in patient activation measure score (primary outcome), eHealth literacy, patient involvement in decision-making and care, medication adherence, preventive care, and HIV Viral Load. DISCUSSION: We hypothesize that participants receiving the intervention will show greater improvement in empowerment and the intervention will reduce disparities in study outcomes. Disparities in these measures will be smaller than those in the usual care group. Findings have implications for activating persons living with HIV and for other marginalized groups living with chronic illness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02165735, 6/13/2014.

Evaporative deposition in receding drops.

We present a framework for calculating the surface density profile of a stain deposited by a drop with a receding contact line. Unlike a pinned drop, a receding drop pushes fluid towards its interior, continuously deposits mass across its substrate as it evaporates, and does not produce the usual "coffee ring." For a thin, circular drop with a uniform evaporation rate, we find the surface density of the stain goes as η(r) ∝ ((r/a0)(-1/2)-r/a0), where r is the radius from the drop center and a0 is the initial outer radius. Under these conditions, the deposited stain has a mountain-like morphology. Our framework can easily be extended to investigate new stain morphologies left by drying drops.

Real-world evidence that among atrial fibrillation patients warfarin is associated with reduced nonelective admissions compared with those on DOACs.

BACKGROUND: Randomized trials show inconsistent estimates on risks of direct-acting oral anticoagulants (DOACs) versus warfarin in bleeding and mortality for atrial fibrillation (AF) patients. Trials are confounded by additional DOAC adherence support, while warfarin has a low time in therapeutic range. Few real-world studies compared emergency hospitalization risk between DOAC and warfarin users in AF. This study aimed to determine emergency hospitalization risk for AF patients on DOACs or warfarin in real-world settings. METHODS: A tapered-matched real-world cohort extracted data from 412 English general practices' primary care records linked with emergency department (ED) and hospitalization data from the ECLIPSE database. AF patients with new DOAC or warfarin prescriptions were included. The primary outcome was all-cause ED attendance; the secondary outcomes were ED re-attendance, nonelective hospitalization, and rehospitalization within 12 months. Weighted Cox regression estimated relative risk difference. RESULTS: 39 201 DOAC patients were matched with 13 145 warfarin patients. DOAC patients had a 25% higher likelihood of attending ED (odds ratio 1.25; 95% confidence interval [CI] 1.01-1.55). DOAC use also associated with higher ED re-attendance, nonelective hospitalization, and rehospitalization within 12 months: 1.41 (95% CI 1.00-1.98), 1.26 (1.00-1.57), and 1.54 (1.01-2.34), respectively, with p-values < .05. CONCLUSIONS: DOACs for AF thromboprophylaxis are associated with the increased risk of ED attendance, recurrent hospitalization, and numerical rise in ED re-attendance and first nonelective hospitalization compared to warfarin. However, these real-world data cannot establish if this difference results from medication adherence, lack of regular DOAC clinic monitoring, unmeasured confounders, or fundamental agent efficacy disparities.

Rates of Incidental Findings in Brain Magnetic Resonance Imaging in Children.

Importance: Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives: To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, Setting, and Participants: This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main Outcomes and Measures: Percentage of children with IFs in each category and prevalence of specific IFs. Results: A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387). Conclusions and Relevance: Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Remote, brain region-specific control of choice behavior with ultrasonic waves.

The ability to modulate neural activity in specific brain circuits remotely and systematically could revolutionize studies of brain function and treatments of brain disorders. Sound waves of high frequencies (ultrasound) have shown promise in this respect, combining the ability to modulate neuronal activity with sharp spatial focus. Here, we show that the approach can have potent effects on choice behavior. Brief, low-intensity ultrasound pulses delivered noninvasively into specific brain regions of macaque monkeys influenced their decisions regarding which target to choose. The effects were substantial, leading to around a 2:1 bias in choices compared to the default balanced proportion. The effect presence and polarity was controlled by the specific target region. These results represent a critical step towards the ability to influence choice behavior noninvasively, enabling systematic investigations and treatments of brain circuits underlying disorders of choice.

Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation.

BACKGROUND: Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for non-invasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. OBJECTIVE: In this study, we sought to examine the involvement of peripheral auditory system activation from tFUS stimulation applied to elicit motor responses. The purpose was to determine to what extent ultrasound induced auditory artifact could be a factor in ultrasound motor neuromodulation. METHODS: In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. RESULTS: We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. CONCLUSION: These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.

Frequency Dependence of Ultrasound Neurostimulation in the Mouse Brain.

Ultrasound neuromodulation holds promise as a non-invasive technique for neuromodulation of the central nervous system. However, much remains to be determined about how the technique can be transformed into a useful technology, including the effect of ultrasound frequency. Previous studies have demonstrated neuromodulation in vivo using frequencies <1 MHz, with a trend toward improved efficacy with lower frequency. However, using higher frequencies could offer improved ultrasound spatial resolution. We investigate the ultrasound neuromodulation effects in mice at various frequencies both below and above 1 MHz. We find that frequencies up to 2.9 MHz can still be effective for generating motor responses, but we also confirm that as frequency increases, sonications require significantly more intensity to achieve equivalent efficacy. We argue that our results provide evidence that favors either a particle displacement or a cavitation-based mechanism for the phenomenon of ultrasound neuromodulation.

Localization of ultrasound-induced in vivo neurostimulation in the mouse model.

Developments in the use of ultrasound to stimulate and modulate neural activity have raised the possibility of using ultrasound as a new investigative and therapeutic tool in brain research. Although the phenomenon of ultrasound-induced neurostimulation has a long history dating back many decades, until now there has been little evidence of a clearly localized effect in the brain, a necessary requirement for the technique to become genuinely useful. Here we report clearly distinguishable effects in sonicating rostral and caudal regions of the mouse motor cortex. Motor responses measured by normalized electromyography in the neck and tail regions changed significantly when sonicating the two different areas of motor cortex. Response latencies varied significantly according to sonication location, suggesting that different neural circuits are activated depending on the precise focus of the ultrasound beam. Taken together, our findings present good evidence of the ability to target selective parts of the motor cortex with ultrasound neurostimulation in the mouse, an advance that should help to set the stage for developing new applications in larger animal models, including humans.

Effective parameters for ultrasound-induced in vivo neurostimulation.

Ultrasound-induced neurostimulation has recently gained increasing attention, but little is known about the mechanisms by which it affects neural activity or about the range of acoustic parameters and stimulation protocols that elicit responses. We have established conditions for transcranial stimulation of the nervous system in vivo, using the mouse somatomotor response. We report that (1) continuous-wave stimuli are as effective as or more effective than pulsed stimuli in eliciting responses, and responses are elicited with stimulus onset rather than stimulus offset; (2) stimulation success increases as a function of both acoustic intensity and acoustic duration; (3) interactions of intensity and duration suggest that successful stimulation results from the integration of stimulus amplitude over a time interval of 50 to 150 ms; and (4) the motor response elicited appears to be an all-or-nothing phenomenon, meaning stronger stimulus intensities and durations increase the probability of a motor response without affecting the duration or strength of the response.

Genetic dissection reveals two separate retinal substrates for polarization vision in Drosophila.

BACKGROUND: Linearly polarized light originates from atmospheric scattering or surface reflections and is perceived by insects, spiders, cephalopods, crustaceans, and some vertebrates. Thus, the neural basis underlying how this fundamental quality of light is detected is of broad interest. Morphologically unique, polarization-sensitive ommatidia exist in the dorsal periphery of many insect retinas, forming the dorsal rim area (DRA). However, much less is known about the retinal substrates of behavioral responses to polarized reflections. SUMMARY: Drosophila exhibits polarotactic behavior, spontaneously aligning with the e-vector of linearly polarized light, when stimuli are presented either dorsally or ventrally. By combining behavioral experiments with genetic dissection and ultrastructural analyses, we show that distinct photoreceptors mediate the two behaviors: inner photoreceptors R7+R8 of DRA ommatidia are necessary and sufficient for dorsal polarotaxis, whereas ventral responses are mediated by combinations of outer and inner photoreceptors, both of which manifest previously unknown features that render them polarization sensitive. CONCLUSIONS: Drosophila uses separate retinal pathways for the detection of linearly polarized light emanating from the sky or from shiny surfaces. This work establishes a behavioral paradigm that will enable genetic dissection of the circuits underlying polarization vision.

Use of echocardiography for hemodynamic monitoring.

OBJECTIVE: To assess the accuracy of echocardiography for hemodynamic monitoring. DATA SOURCES: A computerized MEDLINE search was used with the following search headings: monitoring (physiologic and intra-operative) and both echocardiography and transesophageal echocardiography. A number of studies were obtained from the reference lists of cardiology reviews and textbooks. STUDY SELECTION: Studies that were designed to assess the accuracy of hemodynamic monitoring. DATA EXTRACTION: From the selected studies, the accuracy of different techniques for measuring preload and cardiac output was compared. DATA SYNTHESIS: Hypovolemia can be detected accurately by measuring left ventricular end-diastolic area. At high preload, Doppler-based methods are more accurate, although further studies in critical care patients are needed. Cardiac output is best measured by measuring Doppler flow, preferably across the aortic valve. CONCLUSIONS: Echocardiography can be used to make accurate hemodynamic measurements; however, training is required. Further studies are needed to validate these methods in the management of critically ill patients.