[Hierarchical Decision-Making Mechanism of the Frontal Lobe].

Actions performed by humans require various levels of volitional control, ranging from highly practiced, automatic actions to those done in unfamiliar environments which necessitate deliberate controls. The multiple cortical motor areas in the frontal lobe regulate actions that vary in the levels of automaticity vs. intentionality. Further more, a part of the medial prefrontal cortex was found to contribute to the selection of the behavioral tactics, an internal protocol of how to decide what to do, which is a more abstract level of decision making than the selection of action per se. The frontal lobe as a whole functions as a hierarchically organized neural network that regulate both automatic and intentional actions.

Non-overlapping sets of neurons encode behavioral response determinants across different tasks in the posterior medial prefrontal cortex.

Higher mammals are able to simultaneously learn and perform a wide array of complex behaviors, which raises questions about how the neural representations of multiple tasks coexist within the same neural network. Do neurons play invariant roles across different tasks? Alternatively, do the same neurons play different roles in different tasks? To address these questions, we examined neuronal activity in the posterior medial prefrontal cortex of primates while they were performing two versions of arm-reaching tasks that required the selection of multiple behavioral tactics (i.e., the internal protocol of action selection), a critical requirement for the activation of this area. During the performance of these tasks, neurons in the pmPFC exhibited selective activity for the tactics, visuospatial information, action, or their combination. Surprisingly, in 82% of the tactics-selective neurons, the selective activity appeared in a particular task but not in both. Such task-specific neuronal representation appeared in 72% of the action-selective neurons. In addition, 95% of the neurons representing visuospatial information showed such activity exclusively in one task but not in both. Our findings indicate that the same neurons can play different roles across different tasks even though the tasks require common information, supporting the latter hypothesis.

Non-additive activity modulation during a decision making task involving tactic selection.

Human brain imaging has revealed that stimulus-induced activity does generally not simply add to the pre-stimulus activity, but rather builds in a non-additive way on this activity. Here we investigate this subject at the single neuron level and address the question whether and to what extent a strong form of non-additivity where activity drops post-cue is present in different areas of monkey cortex, including prefrontal and agranular frontal areas, during a perceptual decision making task involving action and tactic selection. Specifically we analyze spike train data recorded in vivo from the posterior dorsomedial prefrontal cortex (pmPFC), the supplementary motor area (SMA) and the presupplementary motor area (pre-SMA). For each neuron, we compute the ratio of the trial-averaged pre-stimulus spike count to the trial-averaged post-stimulus count. We also perform the ratio and averaging procedures in reverse order. We find that the statistics of these quantities behave differently across areas. pmPFC involved in tactic selection shows stronger non-additivity compared to the two other areas which more generically just increase their firing rate pos-stimulus. pmPFC behaved more similarly to pre-SMA, a likely consequence of the reciprocal connections between these areas. The trial-averaged ratio statistic was reproduced by a surrogate inhomogeneous Poisson process in which the measured trial-averaged firing rate for a given neuron is used as its time-dependent rate. Principal component analysis (PCA) of the trial-averaged firing rates of neuronal ensembles further reveals area-specific time courses of response to the stimulus, including latency to peak neural response, for the typical population activity. Our work demonstrates subtle forms of area-specific non-additivity based on the fine variability structure of pre- and post-stimulus spiking activity on the single neuron level. It also reveals significant differences between areas for PCA and surrogate analysis, complementing previous observations of regional differences based solely on post-stimulus responses. Moreover, we observe regional differences in non-additivity which are related to the monkey's successful tactic selection and decision making. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-021-09702-0.

Neuronal Representations of Tactic-Based Sensorimotor Transformations in the Primate Medial Prefrontal, Presupplementary, and Supplementary Motor Areas: A Comparative Study.

Adaptive context-dependent behaviors necessitate the flexible selection of multiple behavioral tactics, i.e., internal protocols for selecting an action. Previous primate studies have shown that the posterior medial prefrontal cortex (pmPFC) contributes to the selection, retention, and use of tactics, but the manner in which this area employs selected tactics to convert sensory information into action and how that manner differs from downstream cortical motor areas have yet to be fully elucidated. To address this issue, the present study recorded neuronal activity in two monkeys as they performed a two-choice arm reaching task that required the selection of multiple tactics when converting spatial cue information into the direction of arm reaching. Neuronal populations in both pmPFC and presupplementary motor area (pre-SMA) represented tactics during their selection, maintenance in memory, and their use in determining an action. Additionally, they represented the monkeys' action in the behavioral epoch in which the direction of reaching was determined. A striking contrast between the pmPFC and the pre-SMA was the representation of the spatial cue location in the former and its absence in the latter area. In individual neurons, neurons in pmPFC and pre-SMA had either single or mixed representation of tactics and action. Some of the pmPFC neurons additionally encoded cue location. Finally, neurons in the supplementary motor area mainly represented the action. Taken together, the present results indicate that, of these three areas, the pmPFC plays a cardinal role during the integration of behavioral tactics and visuospatial information when selecting an action.

Non-centralized and functionally localized nervous system of ophiuroids: evidence from topical anesthetic experiments.

Ophiuroids locomote along the seafloor by coordinated rhythmic movements of multi-segmented arms. The mechanisms by which such coordinated movements are achieved are a focus of interest from the standpoints of neurobiology and robotics, because ophiuroids appear to lack a central nervous system that could exert centralized control over five arms. To explore the underlying mechanism of arm coordination, we examined the effects of selective anesthesia to various parts of the body of ophiuroids on locomotion. We observed the following: (1) anesthesia of the circumoral nerve ring completely blocked the initiation of locomotion; however, initiation of single arm movement, such as occurs during the retrieval of food, was unaffected, indicating that the inability to initiate locomotion was not due to the spread of the anesthetic agent. (2) During locomotion, the midsegments of the arms periodically made contact with the floor to elevate the disc. In contrast, the distal segments of the arms were pointed aborally and did not make contact with the floor. (3) When the midsegments of all arms were anesthetized, arm movements were rendered completely uncoordinated. In contrast, even when only one arm was left intact, inter-arm coordination was preserved. (4) Locomotion was unaffected by anesthesia of the distal arms. (5) A radial nerve block to the proximal region of an arm abolished coordination among the segments of that arm, rendering it motionless. These findings indicate that the circumoral nerve ring and radial nerves play different roles in intra- and inter-arm coordination in ophiuroids.

A brittle star-like robot capable of immediately adapting to unexpected physical damage.

A major challenge in robotic design is enabling robots to immediately adapt to unexpected physical damage. However, conventional robots require considerable time (more than several tens of seconds) for adaptation because the process entails high computational costs. To overcome this problem, we focus on a brittle star-a primitive creature with expendable body parts. Brittle stars, most of which have five flexible arms, occasionally lose some of them and promptly coordinate the remaining arms to escape from predators. We adopted a synthetic approach to elucidate the essential mechanism underlying this resilient locomotion. Specifically, based on behavioural experiments involving brittle stars whose arms were amputated in various ways, we inferred the decentralized control mechanism that self-coordinates the arm motions by constructing a simple mathematical model. We implemented this mechanism in a brittle star-like robot and demonstrated that it adapts to unexpected physical damage within a few seconds by automatically coordinating its undamaged arms similar to brittle stars. Through the above-mentioned process, we found that physical interaction between arms plays an essential role for the resilient inter-arm coordination of brittle stars. This finding will help develop resilient robots that can work in inhospitable environments. Further, it provides insights into the essential mechanism of resilient coordinated motions characteristic of animal locomotion.

Detecting Causality by Combined Use of Multiple Methods: Climate and Brain Examples.

Identifying causal relations from time series is the first step to understanding the behavior of complex systems. Although many methods have been proposed, few papers have applied multiple methods together to detect causal relations based on time series generated from coupled nonlinear systems with some unobserved parts. Here we propose the combined use of three methods and a majority vote to infer causality under such circumstances. Two of these methods are proposed here for the first time, and all of the three methods can be applied even if the underlying dynamics is nonlinear and there are hidden common causes. We test our methods with coupled logistic maps, coupled Rössler models, and coupled Lorenz models. In addition, we show from ice core data how the causal relations among the temperature, the CH4 level, and the CO2 level in the atmosphere changed in the last 800,000 years, a conclusion also supported by irregularly sampled data analysis. Moreover, these methods show how three regions of the brain interact with each other during the visually cued, two-choice arm reaching task. Especially, we demonstrate that this is due to bottom up influences at the beginning of the task, while there exist mutual influences between the posterior medial prefrontal cortex and the presupplementary motor area. Based on our results, we conclude that identifying causality with an appropriate ensemble of multiple methods ensures the validity of the obtained results more firmly.

Representation of Behavioral Tactics and Tactics-Action Transformation in the Primate Medial Prefrontal Cortex.

UNLABELLED: To expedite the selection of action under a structured behavioral context, we develop an expedient to promote its efficiency: tactics for action selection. Setting up a behavioral condition for subhuman primates (Macaca fuscata) that induced the development of a behavioral tactics, we explored neuronal representation of tactics in the medial frontal cortex. Here we show that neurons in the posterior medial prefrontal cortex, but not much in the medial premotor cortex, exhibit activity representing the behavioral tactics, in advance of action-selective activity. Such activity appeared during behavioral epochs of its retrieval from instruction cues, maintenance in short-term memory, and its implementation for the achievement of action selection. At a population level, posterior medial prefrontal cortex neurons take part in transforming the tactics information into the information representing action selection. The tactics representation revealed an aspect of neural mechanisms for an adaptive behavioral control, taking place in the medial prefrontal cortex. SIGNIFICANCE STATEMENT: We studied behavioral significance of neuronal activity in the posterior medial prefrontal cortex (pmPFC) and found the representation of behavioral tactics defined as specific and efficient ways to achieve objectives of actions. Neuronal activity appeared during behavioral epochs of its retrieval from instruction cues, maintenance in short-term memory, and its use preceding the achievement of action selection. We found further that pmPFC neurons take part in transforming the tactics information into the information representing action selection. A majority of individual neurons was recruited during a limited period in each behavioral epoch, constituting, as a whole, a temporal cascade of activity. Such dynamics found in behavioral-tactics specific activity characterize the participation of pmPFC neurons in executive control of purposeful behavior.

Transplantation of Unique Subpopulation of Fibroblasts, Muse Cells, Ameliorates Experimental Stroke Possibly via Robust Neuronal Differentiation.

OBJECTIVE: Muse cells reside as pre-existing pluripotent-like stem cells within the fibroblasts, are nontumorigenic, exhibit differentiation capacity into triploblastic-lineage cells, and replenish lost cells when transplanted in injury models. Cell fate and function of human skin fibroblast-derived Muse cells were evaluated in a rat stroke model. METHODS: Muse cells (30,000), collected by pluripotent surface marker stage-specific embryonic antigen-3, were injected stereotaxically into three deposits within the rat ischemic cortex at 2 days after transient middle cerebral artery occlusion, and the cells' biological effects were examined for more than 84 days. RESULTS: Muse cells spontaneously and promptly committed to neural/neuronal-lineage cells when cocultured with stroke brain slices. Muse-transplanted stroke rats exhibited significant improvements in neurological and motor functions compared to control groups at chronic days 70 and 84, without a reduction in the infarct size. Muse cells survived in the host brain for up to 84 days and differentiated into NeuN (∼ 65%), MAP-2 (∼ 32%), calbindin (∼ 28%), and GST-π (∼ 25%)-positive cells in the cortex, but glial fibrillary acidic protein-positive cells were rare. Tumor formation was not observed. Muse cells integrated into the sensory-motor cortex, extended their neurites into cervical spinal cord, and displayed normalized hind limb somatosensory evoked potentials. INTERPRETATION: Muse cells are unique from other stem cells in that they differentiate with high ratio into neuronal cells after integration with host brain microenvironment, possibly reconstructing the neuronal circuit to mitigate stroke symptoms. Human fibroblast-derived Muse cells pose as a novel source of transplantable stem cells, circumventing the need for gene manipulations, especially when contemplating autologous cell therapy for stroke.

Optogenetic patterning of whisker-barrel cortical system in transgenic rat expressing channelrhodopsin-2.

The rodent whisker-barrel system has been an ideal model for studying somatosensory representations in the cortex. However, it remains a challenge to experimentally stimulate whiskers with a given pattern under spatiotemporal precision. Recently the optogenetic manipulation of neuronal activity has made possible the analysis of the neuronal network with precise spatiotemporal resolution. Here we identified the selective expression of channelrhodopsin-2 (ChR2), an algal light-driven cation channel, in the large mechanoreceptive neurons in the trigeminal ganglion (TG) as well as their peripheral nerve endings innervating the whisker follicles of a transgenic rat. The spatiotemporal pattern of whisker irradiation thus produced a barrel-cortical response with a specific spatiotemporal pattern as evidenced by electrophysiological and functional MRI (fMRI) studies. Our methods of generating an optogenetic tactile pattern (OTP) can be expected to facilitate studies on how the spatiotemporal pattern of touch is represented in the somatosensory cortex, as Hubel and Wiesel did in the visual cortex.

Extended practice of a motor skill is associated with reduced metabolic activity in M1.

How does long-term training and the development of motor skills modify the activity of the primary motor cortex (M1)? To address this issue, we trained monkeys for ~1-6 years to perform visually guided and internally generated sequences of reaching movements. Then, we used [(14)C]2-deoxyglucose (2DG) uptake and single-neuron recording to measure metabolic and neuron activity in M1. After extended practice, we observed a profound reduction of metabolic activity in M1 for the performance of internally generated compared to visually guided tasks. In contrast, measures of neuron firing displayed little difference during the two tasks. These findings suggest that the development of skill through extended practice results in a reduction in the synaptic activity required to produce internally generated, but not visually guided, sequences of movements. Thus, practice leading to skilled performance results in more efficient generation of neuronal activity in M1.

Optogenetically induced seizure and the longitudinal hippocampal network dynamics.

Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons. However, our current understanding of seizure dynamics is still limited. Here we propose a novel in vivo model of seizure-like afterdischarges using optogenetics, and report on investigation of directional network dynamics during seizure along the septo-temporal (ST) axis of hippocampus. Repetitive pulse photostimulation was applied to the rodent hippocampus, in which channelrhodopsin-2 (ChR2) was expressed, under simultaneous recording of local field potentials (LFPs). Seizure-like afterdischarges were successfully induced after the stimulation in both W-TChR2V4 transgenic (ChR2V-TG) rats and in wild type rats transfected with adeno-associated virus (AAV) vectors carrying ChR2. Pulse frequency at 10 and 20 Hz, and a 0.05 duty ratio were optimal for afterdischarge induction. Immunohistochemical c-Fos staining after a single induced afterdischarge confirmed neuronal activation of the entire hippocampus. LFPs were recorded during seizure-like afterdischarges with a multi-contact array electrode inserted along the ST axis of hippocampus. Granger causality analysis of the LFPs showed a bidirectional but asymmetric increase in signal flow along the ST direction. State space presentation of the causality and coherence revealed three discrete states of the seizure-like afterdischarge phenomenon: 1) resting state; 2) afterdischarge initiation with moderate coherence and dominant septal-to-temporal causality; and 3) afterdischarge termination with increased coherence and dominant temporal-to-septal causality. A novel in vivo model of seizure-like afterdischarge was developed using optogenetics, which was advantageous in its reproducibility and artifact-free electrophysiological observations. Our results provide additional evidence for the potential role of hippocampal septo-temporal interactions in seizure dynamics in vivo. Bidirectional networks work hierarchically along the ST hippocampus in the genesis and termination of epileptic seizures.

Neuronal representation of task performance in the medial frontal cortex undergoes dynamic alterations dependent upon the demand for volitional control of action.

Neural network contributing to forelimb task performance in the frontal cortex is dynamically reorganized by the necessity for volitional control of action. Neurons in the posterior medial prefrontal cortex (pmPFC) exhibit clear activity modulation when monkeys volitionally select the correct response tactic from multiple choices, but such activity disappears if selection of a tactic is unnecessary. Prompted by these results, we studied how the requirement to select an appropriate tactic affects the neural representation of action in downstream cortical areas. Two monkeys performed a spatial arm-reaching task with either left or right targets. The task required the monkeys to reach either toward (concordant trials) or away from (discordant trials) an illuminated target. Under the dual-tactic condition, concordant and discordant trials were randomly intermixed, requiring the selection of a response tactic. Under the single-tactic condition, only concordant trials were presented, allowing the monkeys to use the same tactic. Neurons in the pmPFC exhibited clear activity related to task performance under the former condition, but such activity disappeared under the latter condition. In contrast, neurons related to task performance were present under both conditions in supplementary motor area (SMA) and presupplementary motor area (pre-SMA). However, the efficacy of action representation by SMA but not pre-SMA neurons dramatically improved under the single-tactic condition. These results suggest that selection of the appropriate response tactic reorganizes neural circuits in specific motor areas in the medial frontal cortex, in addition to the pmPFC.

Frequency-dependent entrainment of neocortical slow oscillation to repeated optogenetic stimulation in the anesthetized rat.

Local field potential (LFP) slow oscillation (<1Hz) is typically observed in the cortex during sleep or while under anesthesia and reflects synchronous activation/inactivation of the cortical neuron population. The oscillation can be entrained to repeated external sensory stimuli. To better understand the neural mechanism underlying slow-oscillation generation and its entrainment to external stimuli, we delivered optical stimulation to the cortex of anesthetized rats that exogenously expressed the light-sensitive cation channel channelrhodopsin-2 (ChR2) and simultaneously monitored LFPs across cortical layers. We found that the LFPs could be effectively entrained to repeated optical stimulation at 1Hz in deep layers. A stimulus-triggered current-source density (CSD) analysis showed that the evoked oscillation had the same depth and temporal profile as the slow oscillations, indicating that both oscillations have the same neural mechanism. Optical stimulation primarily induced the transition from the cortical up to down state. These results suggest that the anesthetized rat cortex has an intrinsic mechanism that leads to oscillation near 1Hz; effective entrainment to the 1Hz stimulation reflects the resonated state of the cortex to that stimulus. Our study is the first to demonstrate optogenetic manipulation of cortical slow oscillation and provides a mechanistic explanation for slow-oscillation entrainment.

Neuronal activity in the primate dorsomedial prefrontal cortex contributes to strategic selection of response tactics.

The functional roles of the primate posterior medial prefrontal cortex have remained largely unknown. Here, we show that this region participates in the regulation of actions in the presence of multiple response tactics. Monkeys performed a forelimb task in which a visual cue required prompt decision of reaching to a left or a right target. The location of the cue was either ipsilateral (concordant) or contralateral (discordant) to the target. As a result of extensive training, the reaction times for the concordant and discordant trials were indistinguishable, indicating that the monkeys developed tactics to overcome the cue-response conflict. Prefrontal neurons exhibited prominent activity when the concordant and discordant trials were randomly presented, requiring rapid selection of a response tactic (reach toward or away from the cue). The following findings indicate that these neurons are involved in the selection of tactics, rather than the selection of action or monitoring of response conflict: (i) The response period activity of neurons in this region disappeared when the monkeys performed the task under the behavioral condition that required a single tactic alone, whereas the action varied across trials. (ii) The neuronal activity was found in the dorsomedial prefrontal cortex but not in the anterior cingulate cortex that has been implicated for the response conflict monitoring. These results suggest that the medial prefrontal cortex participates in the selection of a response tactic that determines an appropriate action. Furthermore, the observation of dynamic, task-dependent neuronal activity necessitates reconsideration of the conventional concept of cortical motor representation.

Bio-amplifier with Driven Shield Inputs to Reduce Electrical Noise and its Application to Laboratory Teaching of Electrophysiology.

We describe a custom-designed bio-amplifier and its use in teaching neurophysiology to undergraduate students. The amplifier has the following features: 1) differential amplification with driven shield inputs, which makes it workable even in electrically unshielded environments, 2) high input impedance to allow recordings of small signals through high signal source impedance, 3) dual fixed frequency bandpass filters (1-340Hz for surface EMG, EEG, local field potential etc and 320Hz - 3.4kHz for neuronal action potential recording) and independent gain controllers (up to x107,000) to allow the recording of different signals from the same source (e.g., local field potential and spiking activity of neurons), and 4) printed circuit board technology for easy replication with consistent quality. We compared its performance with a commercial amplifier in an electrically noisy environment. Even without any electrostatic shield, it recorded clear electromyographic activity with little interference from other electric appliances. In contrast, the commercial amplifier's performance severely deteriorated under the same condition. We used this amplifier to build a computer-controlled stimulation and measurement system for electroencephalographic recordings by undergraduate students. The students successfully recorded various sensory evoked potentials with clarity that otherwise would have required costly instruments. This amplifier is a low-cost yet reliable instrument for electro-physiological recording both in education and research.

Deciphering elapsed time and predicting action timing from neuronal population signals.

The proper timing of actions is necessary for the survival of animals, whether in hunting prey or escaping predators. Researchers in the field of neuroscience have begun to explore neuronal signals correlated to behavioral interval timing. Here, we attempt to decode the lapse of time from neuronal population signals recorded from the frontal cortex of monkeys performing a multiple-interval timing task. We designed a Bayesian algorithm that deciphers temporal information hidden in noisy signals dispersed within the activity of individual neurons recorded from monkeys trained to determine the passage of time before initiating an action. With this decoder, we succeeded in estimating the elapsed time with a precision of approximately 1 s throughout the relevant behavioral period from firing rates of 25 neurons in the pre-supplementary motor area. Further, an extended algorithm makes it possible to determine the total length of the time-interval required to wait in each trial. This enables observers to predict the moment at which the subject will take action from the neuronal activity in the brain. A separate population analysis reveals that the neuronal ensemble represents the lapse of time in a manner scaled relative to the scheduled interval, rather than representing it as the real physical time.

Opto-current-clamp actuation of cortical neurons using a strategically designed channelrhodopsin.

BACKGROUND: Optogenetic manipulation of a neuronal network enables one to reveal how high-order functions emerge in the central nervous system. One of the Chlamydomonas rhodopsins, channelrhodopsin-1 (ChR1), has several advantages over channelrhodopsin-2 (ChR2) in terms of the photocurrent kinetics. Improved temporal resolution would be expected by the optogenetics using the ChR1 variants with enhanced photocurrents. METHODOLOGY/PRINCIPAL FINDINGS: The photocurrent retardation of ChR1 was overcome by exchanging the sixth helix domain with its counterpart in ChR2 producing Channelrhodopsin-green receiver (ChRGR) with further reform of the molecule. When the ChRGR photocurrent was measured from the expressing HEK293 cells under whole-cell patch clamp, it was preferentially activated by green light and has fast kinetics with minimal desensitization. With its kinetic advantages the use of ChRGR would enable one to inject a current into a neuron by the time course as predicted by the intensity of the shedding light (opto-current clamp). The ChRGR was also expressed in the motor cortical neurons of a mouse using Sindbis pseudovirion vectors. When an oscillatory LED light signal was applied sweeping through frequencies, it robustly evoked action potentials synchronized to the oscillatory light at 5-10 Hz in layer 5 pyramidal cells in the cortical slice. The ChRGR-expressing neurons were also driven in vivo with monitoring local field potentials (LFPs) and the time-frequency energy distribution of the light-evoked response was investigated using wavelet analysis. The oscillatory light enhanced both the in-phase and out-phase responses of LFP at the preferential frequencies of 5-10 Hz. The spread of activity was evidenced by the fact that there were many c-Fos-immunoreactive neurons that were negative for ChRGR in a region of the motor cortex. CONCLUSIONS/SIGNIFICANCE: The opto-current-clamp study suggests that the depolarization of a small number of neurons wakes up the motor cortical network over some critical point to the activated state.

Cannula-aided penetration: a simple method to insert structurally weak electrodes into brain through the dura mater.

We developed a simple and inexpensive method to insert structurally weak electrodes into the brain through the thickened dura mater in chronic animal experiments. It uses a commonly available intravenous (IV) needle and a cannula to secure a small puncture in the dura mater, through which an electrode is advanced into the underlying cerebral cortex. In addition to its simplicity and cost-effectiveness, this method provides greater degree of freedom regarding the shape and the placement of electrodes compared to the conventional guide tube systems.

Interval time coding by neurons in the presupplementary and supplementary motor areas.

Interval timing is an essential guiding force of behavior. Previous reports have implicated the prefrontal and parietal cortex as being involved in time perception and in temporal decision making. We found that neurons in the medial motor areas, in particular the presupplementary motor area, participate in interval timing in the range of seconds. Monkeys were trained to perform an interval-generation task that required them to determine waiting periods of three different durations. Neuronal activity contributed to the process of retrieving time instructions from visual cues, signaled the initiation of action in a time-selective manner, and developed activity to represent the passage of time. These results specify how medial motor areas take part in initiating actions on the basis of self-generated time estimates.