Study of the K_{L}→π

The rare decay K_{L}→π^{0}νν[over ¯] was studied with the dataset taken at the J-PARC KOTO experiment in 2016, 2017, and 2018. With a single event sensitivity of (7.20±0.05_{stat}±0.66_{syst})×10^{-10}, three candidate events were observed in the signal region. After unveiling them, contaminations from K^{±} and scattered K_{L} decays were studied, and the total number of background events was estimated to be 1.22±0.26. We conclude that the number of observed events is statistically consistent with the background expectation. For this dataset, we set an upper limit of 4.9×10^{-9} on the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level.

Search for K_{L}→π

A search for the rare decay K_{L}→π^{0}νν[over ¯] was performed. With the data collected in 2015, corresponding to 2.2×10^{19} protons on target, a single event sensitivity of (1.30±0.01_{stat}±0.14_{syst})×10^{-9} was achieved and no candidate events were observed. We set an upper limit of 3.0×10^{-9} for the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level (C.L.), which improved the previous limit by almost an order of magnitude. An upper limit for K_{L}→π^{0}X^{0} was also set as 2.4×10^{-9} at the 90% C.L., where X^{0} is an invisible boson with a mass of 135 MeV/c^{2}.

Health resource utilization among US veterans with psychogenic nonepileptic seizures: A comparison before and after video-EEG monitoring.

OBJECTIVE: Prior to establishing the correct diagnosis, patients with psychogenic nonepileptic seizures (PNES) frequently endure significant costs and morbidities associated with utilization of health care resources. In this study of the US veterans population, we aimed to investigate for potential changes in health resource utilization before versus after video-EEG (VEEG) confirmation and disclosure of the PNES diagnosis. METHODS: We prospectively studied 65 veterans with VEEG confirmed diagnosis of PNES, and followed their health care utilization during the subsequent 3 years after the diagnosis. Primary outcomes entailed comparing the quantities of post-VEEG outpatient visits and diagnostic procedures versus those during the 3-year span prior to the diagnosis. Secondary outcome involved specifically the measures of seizure-related antiepileptic drug (AED) use from time points before and after VEEG. RESULTS: Within the category of non-psychiatric outpatient visits, we observed significant post-diagnostic decrease in the utilization of PNES-related outpatient visits (p < 0.001). Contrastingly, we found significant post-diagnostic increase in the utilization of non-PNES-related outpatient visits (p = 0.004). When examining exclusively for psychiatric outpatient visits, we further observed a trend toward increased attendance of outpatient visits (p = 0.056) after VEEG. Utilization of diagnostic procedures was not significantly different before versus after VEEG (p = 0.293). 52.3% of the patients were prescribed AEDs for seizure-related purpose during the one-year period leading up to VEEG. By comparison, only 7.7%, 12.3%, and 10.8% of the patients were still on AEDs for seizure-related purpose at the one-year, two-year, and three-year time points after VEEG, respectively. CONCLUSION: We demonstrate new evidence that VEEG confirmation of the PNES diagnosis among US veterans can significantly reduce key measures of non-psychiatric/PNES-related resource utilization, while also potentially associating with appropriate enhancement of psychiatric outpatient visits. However, our results suggest that within this patient population, further efforts are necessary to address heightened demands for non-PNES-related outpatient visits after VEEG.

Dissecting inhibitory brain circuits with genetically-targeted technologies.

The evolution of genetically targeted tools has begun to allow us to dissect anatomically and functionally heterogeneous interneurons, and to probe circuit function from synapses to behavior. Over the last decade, these tools have been used widely to visualize neurons in a cell type-specific manner, and engage them to activate and inactivate with exquisite precision. In this process, we have expanded our understanding of interneuron diversity, their functional connectivity, and how selective inhibitory circuits contribute to behavior. Here we discuss the relative assets of genetically encoded fluorescent proteins (FPs), viral tracing methods, optogenetics, chemical genetics, and biosensors in the study of inhibitory interneurons and their respective circuits.

Cell type-specific and time-dependent light exposure contribute to silencing in neurons expressing Channelrhodopsin-2.

Channelrhodopsin-2 (ChR2) has quickly gained popularity as a powerful tool for eliciting genetically targeted neuronal activation. However, little has been reported on the response kinetics of optogenetic stimulation across different neuronal subtypes. With excess stimulation, neurons can be driven into depolarization block, a state where they cease to fire action potentials. Herein, we demonstrate that light-induced depolarization block in neurons expressing ChR2 poses experimental challenges for stable activation of specific cell types and may confound interpretation of experiments when 'activated' neurons are in fact being functionally silenced. We show both ex vivo and in vivo that certain neuronal subtypes targeted for ChR2 expression become increasingly susceptible to depolarization block as the duration of light pulses are increased. We find that interneuron populations have a greater susceptibility to this effect than principal excitatory neurons, which are more resistant to light-induced depolarization block. Our results highlight the need to empirically determine the photo-response properties of targeted neurons when using ChR2, particularly in studies designed to elicit complex circuit responses in vivo where neuronal activity will not be recorded simultaneous to light stimulation. DOI: http://dx.doi.org/10.7554/eLife.01481.001.

Perceiving electrical stimulation of identified human visual areas.

We studied whether detectable percepts could be produced by electrical stimulation of intracranial electrodes placed over human visual areas identified with fMRI. Identification of areas was confirmed by recording local-field potentials from the electrode, such as face-selective electrical responses from electrodes over the fusiform face area (FFA). The probability of detecting electrical stimulation of a visual area varied with the position of the area in the visual cortical hierarchy. Stimulation of early visual areas including V1, V2, and V3 was almost always detected, whereas stimulation of late visual areas such as FFA was rarely detected. When percepts were elicited from late areas, subjects reported that they were simple shapes and colors, similar to the descriptions of percepts from early areas. There were no reports of elaborate percepts, such as faces, even in areas like FFA, where neurons have complex response properties. For sites eliciting percepts, the detection threshold was determined by varying the stimulation current as subjects performed a forced-choice detection task. Current thresholds were similar for late and early areas. The similarity between both percept quality and threshold across early and late areas suggests the presence of functional microcircuits that link electrical stimulation with perception.

Computer-controlled electrical stimulation for quantitative mapping of human cortical function.

Cortical mapping with electrical stimulation (ES) in neurosurgical patients typically involves the manually controlled delivery of suprathreshold electrical current to a discrete area of the brain. Limited numbers of trials and imprecise current delivery methods increase the variability of the behavioral response and make it difficult to collect quantitative mapping data, which is especially important in research studies of human cortical function. To overcome these limitations, the authors developed a method for computer-controlled delivery of defined electrical current to implanted intracranial electrodes. They demonstrate that stimulation can be time locked to a behavioral task to rapidly and systematically measure the detection threshold for ES in human visual cortex over many trials. Computer-controlled ES is well suited for the systematic and quantitative study of the function of virtually any region of cerebral cortex. It may be especially useful for studying human cortical regions that are not well characterized and for verifying the presence of stimulation-evoked percepts that are difficult to objectively confirm.

Electrical microstimulation thresholds for behavioral detection and saccades in monkey frontal eye fields.

The frontal eye field (FEF) is involved in the transformation of visual signals into saccadic eye movements. Although it is often considered an oculomotor structure, several lines of evidence suggest that the FEF also contributes to visual perception and attention. To better understand the range of behaviors to which the FEF can contribute, we tested whether monkeys could detect activation of their FEF by electrical microstimulation with currents below those that cause eye movements. We found that stimulation of FEF neurons could almost always be detected at levels below those needed to generate saccades and that the electrical current needed for detection was highly correlated with that needed to generate a saccade. This relationship between detection and saccade thresholds can be explained if FEF neurons represent preparation to make particular saccades and subjects can be aware of such preparations without acting on them when the representation is not strong.

Perception matches selectivity in the human anterior color center.

Human ventral cortex contains at least two visual areas selective for color [1]: a posterior center in the lingual gyrus labeled V4 [2-4], V8 [5], or VO-1 [6] and an anterior center in the medial fusiform that has been labeled V4alpha[3, 4]. We examined the properties of the anterior color center using electrical recording and electrical stimulation in a subject with an electrode implanted over the anterior color center, as determined with BOLD fMRI in the same subject. Presentation of visual stimuli evoked local field potentials from the electrode. Consistent with fMRI, the potentials were larger for chromatic than achromatic stimuli. The potentials differed depending on stimulus color, with blue-purple colors evoking the largest response. The spatial receptive field of the electrode was central/parafoveal with a contralateral bias. In the absence of a visual stimulus, electrical stimulation of the electrode produced an artificial visual percept of a blue-purple color near the center of gaze. These results provide direct evidence of a tight link between selectivity and perception in ventral temporal cortex. Electrical stimulation of the anterior color center is sufficient to produce the conscious percept of a color whose identity is determined by the selectivity of the stimulated neurons.

Behavioral detection of electrical microstimulation in different cortical visual areas.

The extent to which areas in the visual cerebral cortex differ in their ability to support perceptions has been the subject of considerable speculation. Experiments examining the activity of individual neurons have suggested that activity in later stages of the visual cortex is more closely linked to perception than that in earlier stages [1-9]. In contrast, results from functional imaging, transcranial magnetic stimulation, and lesion studies have been interpreted as showing that earlier stages are more closely coupled to perception [10-15]. We examined whether neuronal activity in early and later stages differs in its ability to support detectable signals by measuring behavioral thresholds for detecting electrical microstimulation in different cortical areas in two monkeys. By training the animals to perform a two-alternative temporal forced-choice task, we obtained criterion-free thresholds from five visual areas--V1, V2, V3A, MT, and the inferotemporal cortex. Every site tested yielded a reliable threshold. Thresholds varied little within and between visual areas, rising gradually from early to later stages. We similarly found no systematic differences in the slopes of the psychometric detection functions from different areas. These results suggest that neuronal signals of similar magnitude evoked in any part of visual cortex can generate percepts.