A Second Introduction to the Neurobiology of Interval Timing.

Time is a critical variable that organisms must be able to measure in order to survive in a constantly changing environment. Initially, this paper describes the myriad of contexts where time is estimated or predicted and suggests that timing is not a single process and probably depends on a set of different neural mechanisms. Consistent with this hypothesis, the explosion of neurophysiological and imaging studies in the last 10 years suggests that different brain circuits and neural mechanisms are involved in the ability to tell and use time to control behavior across contexts. Then, we develop a conceptual framework that defines time as a family of different phenomena and propose a taxonomy with sensory, perceptual, motor, and sensorimotor timing as the pillars of temporal processing in the range of hundreds of milliseconds.

An abstract categorical decision code in dorsal premotor cortex.

The dorsal premotor cortex (DPC) has classically been associated with a role in preparing and executing the physical motor variables during cognitive tasks. While recent work has provided nuanced insights into this role, here we propose that DPC also participates more actively in decision-making. We recorded neuronal activity in DPC while two trained monkeys performed a vibrotactile categorization task, utilizing two partially overlapping ranges of stimulus values that varied on two physical attributes: vibrotactile frequency and amplitude. We observed a broad heterogeneity across DPC neurons, the majority of which maintained the same response patterns across attributes and ranges, coding in the same periods, mixing temporal and categorical dynamics. The predominant categorical signal was maintained throughout the delay, movement periods and notably during the intertrial period. Putting the entire population's data through two dimensionality reduction techniques, we found strong temporal and categorical representations without remnants of the stimuli's physical parameters. Furthermore, projecting the activity of one population over the population axes of the other yielded identical categorical and temporal responses. Finally, we sought to identify functional subpopulations based on the combined activity of all stimuli, neurons, and time points; however, we found that single-unit responses mixed temporal and categorical dynamics and couldn't be clustered. All these point to DPC playing a more decision-related role than previously anticipated.

Different subtypes of motor cortex pyramidal tract neurons projects to red and pontine nuclei.

Introduction: Pyramidal tract neurons (PTNs) are fundamental elements for motor control. However, it is largely unknown if PTNs are segregated into different subtypes with distinct characteristics. Methods: Using anatomical and electrophysiological tools, we analyzed in mice motor cortex PTNs projecting to red and pontine midbrain nuclei, which are important hubs connecting cerebral cortex and cerebellum playing a critical role in the regulation of movement. Results: We reveal that the vast majority of M1 neurons projecting to the red and pontine nuclei constitutes different populations. Corticopontine neurons have higher conduction velocities and morphologically, a most homogeneous dendritic and spine distributions along cortical layers. Discussion: The results indicate that cortical neurons projecting to the red and pontine nuclei constitute distinct anatomical and functional pathways which may contribute differently to sensorimotor integration.

Discrimination of Regular and Irregular Rhythms Explained by a Time Difference Accumulation Model.

Perceiving the temporal regularity in a sequence of repetitive sensory events facilitates the preparation and execution of relevant behaviors with tight temporal constraints. How we estimate temporal regularity from repeating patterns of sensory stimuli is not completely understood. We developed a decision-making task in which participants had to decide whether a train of visual, auditory, or tactile pulses, had a regular or an irregular temporal pattern. We tested the hypothesis that subjects categorize stimuli as irregular by accumulating the time differences between the predicted and observed times of sensory pulses defining a temporal rhythm. Results suggest that instead of waiting for a single large temporal deviation, participants accumulate timing-error signals and judge a pattern as irregular when the amount of evidence reaches a decision threshold. Model fits of bounded integration showed that this accumulation occurs with negligible leak of evidence. Consistent with previous findings, we show that participants perform better when evaluating the regularity of auditory pulses, as compared with visual or tactile stimuli. Our results suggest that temporal regularity is estimated by comparing expected and measured pulse onset times, and that each prediction error is accumulated towards a threshold to generate a behavioral choice.

Integrating Somatosensory Information Over Time.

Our choices are often informed by temporally integrating streams of sensory information. This has been well demonstrated in the visual and auditory domains, but the integration of tactile information over time has been less studied. We designed an active touch task in which participants explored a spheroid-shaped object to determine its inclination with respect to the horizontal plane (inclined to the left or the right). In agreement with previous findings, our results show that more errors, and longer decision times, accompany difficult decisions (small inclination angles). To gain insight into the decision-making process, we used a time-controlled task in which the experimenter manipulated the time available for tactile exploration on a trial-by-trial basis. The behavioral results were fit with a bounded accumulation model and an independent sampling model that assumes no sensory accumulation. The results of model fits favor an accumulation-to-bound mechanism and suggest that participants integrate the first 600 ms of 1800 ms-long stimuli. This means that the somatosensory system benefits from longer streams of information, although it does not make use of all available evidence.

Sucrose intensity coding and decision-making in rat gustatory cortices.

Sucrose's sweet intensity is one attribute contributing to the overconsumption of high-energy palatable foods. However, it is not known how sucrose intensity is encoded and used to make perceptual decisions by neurons in taste-sensitive cortices. We trained rats in a sucrose intensity discrimination task and found that sucrose evoked a widespread response in neurons recorded in posterior-Insula (pIC), anterior-Insula (aIC), and Orbitofrontal cortex (OFC). Remarkably, only a few Intensity-selective neurons conveyed the most information about sucrose's intensity, indicating that for sweetness the gustatory system uses a compact and distributed code. Sucrose intensity was encoded in both firing-rates and spike-timing. The pIC, aIC, and OFC neurons tracked movement direction, with OFC neurons yielding the most robust response. aIC and OFC neurons encoded the subject's choices, whereas all three regions tracked reward omission. Overall, these multimodal areas provide a neural representation of perceived sucrose intensity, and of task-related information underlying perceptual decision-making.

Monkeys Share the Human Ability to Internally Maintain a Temporal Rhythm.

Timing is a fundamental variable for behavior. However, the mechanisms allowing human and non-human primates to synchronize their actions with periodic events are not yet completely understood. Here we characterize the ability of rhesus monkeys and humans to perceive and maintain rhythms of different paces in the absence of sensory cues or motor actions. In our rhythm task subjects had to observe and then internally follow a visual stimulus that periodically changed its location along a circular perimeter. Crucially, they had to maintain this visuospatial tempo in the absence of movements. Our results show that the probability of remaining in synchrony with the rhythm decreased, and the variability in the timing estimates increased, as a function of elapsed time, and these trends were well described by the generalized law of Weber. Additionally, the pattern of errors shows that human subjects tended to lag behind fast rhythms and to get ahead of slow ones, suggesting that a mean tempo might be incorporated as prior information. Overall, our results demonstrate that rhythm perception and maintenance are cognitive abilities that we share with rhesus monkeys, and these abilities do not depend on overt motor commands.

The parietal cortices participate in encoding, short-term memory, and decision-making related to tactile shape.

We routinely identify objects with our hands, and the physical attributes of touched objects are often held in short-term memory to aid future decisions. However, the brain structures that selectively process tactile information to encode object shape are not fully identified. In this article we describe the areas within the human cerebral cortex that specialize in encoding, short-term memory, and decision-making related to the shape of objects explored with the hand. We performed event-related functional magnetic resonance imaging in subjects performing a shape discrimination task in which two sequentially presented objects had to be explored to determine whether they had the same shape or not. To control for low-level and nonspecific brain activations, subjects performed a temperature discrimination task in which they compared the temperature of two spheres. Our results show that although a large network of brain structures is engaged in somatosensory processing, it is the areas lining the intraparietal sulcus that selectively participate in encoding, maintaining, and deciding on tactile information related to the shape of objects.

Conversion of sensory signals into perceptual decisions.

A fundamental problem in neurobiology is to understand how brain circuits represent sensory information and how such representations give rise to perception, memory and decision-making. We demonstrate that a sensory stimulus engages multiple areas of the cerebral cortex, including primary sensory, prefrontal, premotor and motor cortices. As information transverses the cortical circuits it shows progressively more relation to perception, memory and decision reports. In particular, we show how somatosensory areas on the parietal lobe generate a parameterized representation of a tactile stimulus. This representation is maintained in working memory by prefrontal and premotor areas of the frontal lobe. The presentation of a second stimulus, that monkeys are trained to compare with the first, generates decision-related activity reflecting which stimulus had the higher frequency. Importantly, decision-related activity is observed across several cortical circuits including prefrontal, premotor and parietal cortices. Sensory information is encoded by neuronal populations with opposite tuning, and suggests that a simple subtraction operation could be the underlying mechanism by which past and present sensory information is compared to generate perceptual decisions.

Sense, memory, and decision-making in the somatosensory cortical network.

The brain constructs representations of objects and concepts based in sensory information combined with experience. This mental process, that we call perception, is the result of a chain of events consisting of phenomena such as detection, memory, discrimination, categorization and decision-making. Although the phenomenon of perception is not necessarily dependent on a given sensory modality (e.g. visual perception, auditory, tactile), single sensory models are indispensable for studying the neural mechanisms that generate it. The somatosensory system is a suitable model for studying the manner in which presentation of a single physical variable (e.g. vibration) triggers a perceptual process. Here, we discuss some recent studies in the somatosensory system that in our view, constitute a breakthrough to understanding decision making.

Functional impact of interneuronal inhibition in the cerebral cortex of behaving animals.

This paper reviews recent progress in understanding the functional roles of inhibitory interneurons in behaving animals and how they affect information processing in cortical microcircuits. Multiple studies have shown that the morphological subtypes of inhibitory cells show distinct electrophysiological properties, as well as different molecular and neurochemical identities, providing a large mosaic of inhibitory mechanisms for the dynamic processing of information in the cortex. However, it is only recently that some specific functions of different interneuronal subtypes have been described in behaving animals. In this regard, influential results have been obtained using the known differences of interneurons and pyramidal cells recorded extracellularly to dissociate the functional roles that these two classes of neurons may play in the cortical microcircuits during various behaviors. Neurons can be segregated into fast-spiking (FS) cells that show short action potentials, high discharge rates, and correspond to putative interneurons; and regular-spiking (RS) cells that show larger action potentials and correspond to pyramidal neurons. Using this classification strategy, it has been found that cortical inhibition is involved in sculpting the tuning to different stimulus or behavioral features across a wide variety of sensory, association, and motor areas. Recent studies have suggested that the increase in high-frequency synchronization during information processing and spatial attention may be mediated by FS activation. Finally, FS are active during motor planning and movement execution in different motor areas, supporting the notion that inhibitory interneurons are involved in shaping the motor command but not in gating the cortical output.

Dopamine neurons code subjective sensory experience and uncertainty of perceptual decisions.

Midbrain dopamine (DA) neurons respond to sensory stimuli associated with future rewards. When reward is delivered probabilistically, DA neurons reflect this uncertainty by increasing their firing rates in a period between the sensory cue and reward delivery time. Probability of reward, however, has been externally conveyed by visual cues, and it is not known whether DA neurons would signal uncertainty arising internally. Here we show that DA neurons code the uncertainty associated with a perceptual judgment about the presence or absence of a vibrotactile stimulus. We observed that uncertainty modulates the activity elicited by a go cue instructing monkey subjects to communicate their decisions. That is, the same go cue generates different DA responses depending on the uncertainty level of a judgment made a few seconds before the go instruction. Easily detected suprathreshold stimuli elicit small DA responses, indicating that future reward will not be a surprising event. In contrast, the absence of a sensory stimulus generates large DA responses associated with uncertainty: was the stimulus truly absent, or did a low-amplitude vibration go undetected? In addition, the responses of DA neurons to the stimulus itself increase with vibration amplitude, but only when monkeys correctly detect its presence. This finding suggests that DA activity is not related to actual intensity but rather to perceived intensity. Therefore, in addition to their well-known role in reward prediction, DA neurons code subjective sensory experience and uncertainty arising internally from perceptual decisions.

The orientation dependence of the Hermann grid illusion.

The Hermann grid illusion (HGI), elicited by a grid displayed as either horizontal-vertical (HV) or oblique (45 degrees ) configuration, was measured as the luminance necessary to cancel the illusory spots at the grid intersections. Overall, the HGI produced by the oblique grid was about one-third of that produced by the HV grid. The observers exhibited different sensitivities to the HGI orientation, and seemed to perceive the illusion in two manners: with moderate anisotropy (reduction of about 20%, three subjects) or large anisotropy (90% reduction, four subjects). The quantitative reduction of the HGI elicited by the oblique pattern tested and its reduction to almost zero in some subjects, constitute a benchmark for any model aimed at explaining the HGI on psychophysical grounds.

A hidden sensory function for motor cortex.

Sensory perception has traditionally been attributed to the activation of sensory cortices. However, by inducing an illusory perception of movement, Naito and colleagues show in this issue of Neuron that the illusory perception of movement is related to activation of primary motor cortex.

From sensation to action.

Key to understanding somatosensation is the form of how the mechanical stimuli are represented in the evoked neuronal activity of the brain. Here, we focus on studies that address the question of which components of the evoked neuronal activity in the somatosensory system represent the stimulus features. We review experiments that probe whether these neuronal representations are essential to somatosensation. We also discuss recent results that suggest how the somatosensory stimuli are represented in the brain during short-term memory. Finally, we review data that show the neuronal correlates of a decision during somatosensory perception.