Insular and prelimbic cortices control behavioral accuracy and precision in a temporal decision-making task in rats.

The anterior insular cortex (AIC) comprises a region of sensory integration. It appears to detect salient events in order to guide goal-directed behavior, code tracking errors, and estimate the passage of time. Temporal processing in the AIC may be instantiated by the integration of representations of interoception. Projections between the AIC and the medial prefrontal cortex (mPFC) - found both in rats and humans - also suggest a possible role for these structures in the integration of autonomic responses during ongoing behavior. Few studies, however, have investigated the role of AIC and mPFC in decision-making and time estimation tasks. Moreover, their findings are not consistent, so the relationship between temporal decision-making and those areas remains unclear. The present study employed bilateral inactivations to explore the role of AIC and prelimbic cortex (PL) in rats during a temporal decision-making task. In this task, two levers are available simultaneously (but only one is active), one predicting reinforcement after a short, and the other after a long-fixed interval. Optimal performance requires a switch from the short to the long lever after the short-fixed interval elapsed and no reinforcement was delivered. Switch behavior from the short to the long lever was dependent on AIC and PL. During AIC inactivation, switch latencies became more variable, while during PL inactivation switch latencies became both more variable and less accurate. These findings point to a dissociation between AIC and PL in temporal decision-making, suggesting that the AIC is important for temporal precision, and PL is important for both temporal accuracy and precision.

Time perception and pain: Can a temporal illusion reduce the intensity of pain?

It is commonly known-and previous studies have indicated-that time appears to last longer during unpleasant situations. This study examined whether a reciprocal statement can be made-that is, whether changes in the perception of time can influence our judgment (or rating) of a negative event. We used a temporal illusion method (Pomares et al. Pain 152, 230-234, 2011) to induce distortions in the perception of time. Two stimuli were presented for a constant time: a full clock, which stayed on the screen until its clock hand completed a full rotation (360°); and a short clock, in which the clock hand moved just three-quarters of the way (270°), thus suggesting a reduced interval duration. However, both stimuli were shown for the same amount of time. We specifically investigated (a) whether we could induce a temporal illusion with this simple visual manipulation, and (b) whether this illusion could change participants' ratings of a painful stimulus. In Experiment I (n = 22), to answer (a) above, participants were asked to reproduce the duration in which the different clocks were presented. In Experiment II (n = 30), a painful thermal stimulation was applied on participants' hands while the clocks were shown. Participants were asked to rate the perceived intensity of their pain, and to reproduce its duration. Results showed that, for both experiments, participants reproduced a longer interval after watching the full clock compared with the short clock, confirming that the clock manipulation was able to induce a temporal illusion. Furthermore, the second experiment showed that participants rated the thermal stimuli as less painful when delivered with the short clock than with the full clock. These findings suggest that temporal distortions can modulate the experience of pain.

Time encoding migrates from prefrontal cortex to dorsal striatum during learning of a self-timed response duration task.

Although time is a fundamental dimension of life, we do not know how brain areas cooperate to keep track and process time intervals. Notably, analyses of neural activity during learning are rare, mainly because timing tasks usually require training over many days. We investigated how the time encoding evolves when animals learn to time a 1.5 s interval. We designed a novel training protocol where rats go from naive- to proficient-level timing performance within a single session, allowing us to investigate neuronal activity from very early learning stages. We used pharmacological experiments and machine-learning algorithms to evaluate the level of time encoding in the medial prefrontal cortex and the dorsal striatum. Our results show a double dissociation between the medial prefrontal cortex and the dorsal striatum during temporal learning, where the former commits to early learning stages while the latter engages as animals become proficient in the task.

Correction to: Rules of Conduct for Behavior Analysts in the Presence of Hypothetical Constructs: A Commentary on Eckard and Lattal (2020).

[This corrects the article DOI: 10.1007/s40614-020-00272-w.].

Reward signaling by the rodent medial frontal cortex.

The anatomical relevance and functional significance of medial parts of the rodent frontal cortex have been intensely debated over the modern history of neuroscience. Early studies emphasized common functions among medial frontal regions in rodents and the dorsolateral prefrontal cortex of primates. Behavioral tasks emphasized memory-guided performance and persistent neural activity as a marker of working memory. Over time, it became clear that long-standing concerns about cross-species homology were justified and the view emerged that rodents are useful for understanding medial parts of the frontal cortex in primates, and not the dorsolateral prefrontal cortex. Here, we summarize a series of studies on the rodent medial frontal cortex that began with an interest in studying working memory in the perigenual prelimbic area and ended up studying reward processing in the medial orbital region. Our experiments revealed a role for a 4-8Hz "theta" rhythm in tracking engagement in the consumption of rewarding fluids and denoting the value of a given reward. Evidence for a functional differentiation between the rostral and caudal medial frontal cortex and its relationship to other frontal cortical areas is also discussed with the hope of motivating future work on this part of the cerebral cortex.

Equivalence relations do exist before they are tested: Confirmatory evidence revealed by EEG measurements.

We examined equivalence-based N400 effects by comparing EEG data from participants with different experiences with equivalence testing. Before a priming task used in EEG measurement, Group 1 was given only matching-to-sample training trials whereas Group 2 was exposed to matching-to-sample training and equivalence probe trials. We asked whether exposure to the reinforcement contingency was sufficient to bring about an N400 outcome that might indicate potentially emergent equivalence relations or if such a response depended on experience with equivalence tests. Results showed robust N400 in both groups. Experience with equivalence tests did not further increase the N400 effects. Our findings add confirmatory evidence that equivalence relations may originate via the reinforcement contingency alone. Furthermore, complementary EEG data collected from priming tasks involving words from natural language showed functional overlap between laboratory-defined equivalence and natural word-based N400 effects.

Rules of Conduct for Behavior Analysts in the Presence of Hypothetical Constructs: A Commentary on Eckard and Lattal (2020).

Eckard and Lattal (2020) summarized the behavioristic view of hypothetical constructs and theories, and then, in a novel and timely manner, applied this view to a critique of internal clock models of temporal control. In our three-part commentary, we aim to contribute to the authors' discussion by first expanding upon their view of the positive contributions afforded by constructs and theories. We then refine and question their view of the perils of reifying constructs and assigning them causal properties. Finally, we suggest to behavior analysts four rules of conduct for dealing with mediational theories: tolerate constructs proposed with sufficient reason; consider them seriously, both empirically and conceptually; develop alternative, behavior-analytic models with overlapping empirical domains; and contrast the various models. Through variation and selection, behavioral science will evolve.

Temporal regularity and stimulus control in multiple fixed interval schedules.

In multiple fixed interval schedules of reinforcement, different time intervals are signaled by different environmental stimuli which acquire control over behavior. Previous work has shown that temporal performance is controlled not only by external stimuli but also by temporal aspects of the task, depending on the order in which the different intervals are trained - intermixed across trials or in blocks of several trials. The aim of this study was to further describe the training conditions under which the stimuli acquire control over temporal performance. We manipulated the number of consecutive trials of each fixed interval (FI) per training block (Experiment I) and the number of FIs trained (Experiment II). The results suggest that when trained in blocks of several consecutive trials of the same FI, temporal performance is controlled by temporal regularities across trials and not by the visual stimuli that signal the FIs. One possible account for those data is that the temporal cues overshadow the visual stimuli for the control of temporal performance. Similar results have also been observed with humans, which suggest that temporal regularity overcomes the stimuli in the control of behavior in temporal tasks across species.

A model for the peak-interval task based on neural oscillation-delimited states.

Specific mechanisms underlying how the brain keeps track of time are largely unknown. Several existing computational models of timing reproduce behavioral results obtained with experimental psychophysical tasks, but only a few tackle the underlying biological mechanisms, such as the synchronized neural activity that occurs throughout brain areas. In this paper, we introduce a model for the peak-interval task based on neuronal network properties. We consider that Local Field Potential (LFP) oscillation cycles specify a sequence of states, represented as neuronal ensembles. Repeated presentation of time intervals during training reinforces the connections of specific ensembles to downstream networks - sets of neurons connected to the sequence of states. Later, during the peak-interval procedure, these downstream networks are reactivated by previously experienced neuronal ensembles, triggering behavioral responses at the learned time intervals. The model reproduces experimental response patterns from individual rats in the peak-interval procedure, satisfying relevant properties such as the Weber law. Finally, we provide a biological interpretation of the parameters of the model.

A common representation of time across visual and auditory modalities.

Humans' and non-human animals' ability to process time on the scale of milliseconds and seconds is essential for adaptive behaviour. A central question of how brains keep track of time is how specific temporal information across different sensory modalities is. In the present study, we show that encoding of temporal intervals in auditory and visual modalities are qualitatively similar. Human participants were instructed to reproduce intervals in the range from 750 ms to 1500 ms marked by auditory or visual stimuli. Our behavioural results suggest that, although participants were more accurate in reproducing intervals marked by auditory stimuli, there was a strong correlation in performance between modalities. Using multivariate pattern analysis in scalp EEG, we show that activity during late periods of the intervals was similar within and between modalities. Critically, we show that a multivariate pattern classifier was able to accurately predict the elapsed interval, even when trained on an interval marked by a stimulus of a different sensory modality. Taken together, our results suggest that, while there are differences in the processing of intervals marked by auditory and visual stimuli, they also share a common neural representation.

Medial Frontal Theta Is Entrained to Rewarded Actions.

Rodents lick to consume fluids. The reward value of ingested fluids is likely to be encoded by neuronal activity entrained to the lick cycle. Here, we investigated relationships between licking and reward signaling by the medial frontal cortex (MFC), a key cortical region for reward-guided learning and decision-making. Multielectrode recordings of spike activity and field potentials were made in male rats as they performed an incentive contrast licking task. Rats received access to higher- and lower-value sucrose rewards over alternating 30 s periods. They learned to lick persistently when higher-value rewards were available and to suppress licking when lower-value rewards were available. Spectral analysis of spikes and fields revealed evidence for reward value being encoded by the strength of phase-locking of a 6-12 Hz theta rhythm to the rats' lick cycle. Recordings during the initial acquisition of the task found that the strength of phase-locking to the lick cycle was strengthened with experience. A modification of the task, with a temporal gap of 2 s added between reward deliveries, found that the rhythmic signals persisted during periods of dry licking, a finding that suggests the MFC encodes either the value of the currently available reward or the vigor with which rats act to consume it. Finally, we found that reversible inactivations of the MFC in the opposite hemisphere eliminated the encoding of reward information. Together, our findings establish that a 6-12 Hz theta rhythm, generated by the rodent MFC, is synchronized to rewarded actions.SIGNIFICANCE STATEMENT The cellular and behavioral mechanisms of reward signaling by the medial frontal cortex (MFC) have not been resolved. We report evidence for a 6-12 Hz theta rhythm that is generated by the MFC and synchronized with ongoing consummatory actions. Previous studies of MFC reward signaling have inferred value coding upon temporally sustained activity during the period of reward consumption. Our findings suggest that MFC activity is temporally sustained due to the consumption of the rewarding fluids, and not necessarily the abstract properties of the rewarding fluid. Two other major findings were that the MFC reward signals persist beyond the period of fluid delivery and are generated by neurons within the MFC.

Dynamic representation of time in brain states.

The ability to process time on the scale of milliseconds and seconds is essential for behaviour. A growing number of studies have started to focus on brain dynamics as a mechanism for temporal encoding. Although there is growing evidence in favour of this view from computational and in vitro studies, there is still a lack of results from experiments in humans. We show that high-dimensional brain states revealed by multivariate pattern analysis of human EEG are correlated to temporal judgements. First, we show that, as participants estimate temporal intervals, the spatiotemporal dynamics of their brain activity are consistent across trials. Second, we present evidence that these dynamics exhibit properties of temporal perception, such as scale invariance. Lastly, we show that it is possible to predict temporal judgements based on brain states. These results show how scalp recordings can reveal the spatiotemporal dynamics of human brain activity related to temporal processing.

Individual differences in long-range time representation.

On the basis of experimental data, long-range time representation has been proposed to follow a highly compressed power function, which has been hypothesized to explain the time inconsistency found in financial discount rate preferences. The aim of this study was to evaluate how well linear and power function models explain empirical data from individual participants tested in different procedural settings. The line paradigm was used in five different procedural variations with 35 adult participants. Data aggregated over the participants showed that fitted linear functions explained more than 98% of the variance in all procedures. A linear regression fit also outperformed a power model fit for the aggregated data. An individual-participant-based analysis showed better fits of a linear model to the data of 14 participants; better fits of a power function with an exponent ß > 1 to the data of 12 participants; and better fits of a power function with ß < 1 to the data of the remaining nine participants. Of the 35 volunteers, the null hypothesis ß = 1 was rejected for 20. The dispersion of the individual ß values was approximated well by a normal distribution. These results suggest that, on average, humans perceive long-range time intervals not in a highly compressed, biased manner, but rather in a linear pattern. However, individuals differ considerably in their subjective time scales. This contribution sheds new light on the average and individual psychophysical functions of long-range time representation, and suggests that any attribution of deviation from exponential discount rates in intertemporal choice to the compressed nature of subjective time must entail the characterization of subjective time on an individual-participant basis.

Mistakes were made: neural mechanisms for the adaptive control of action initiation by the medial prefrontal cortex.

Studies in rats, monkeys and humans have established that the medial prefrontal cortex is crucial for the ability to exert adaptive control over behavior. Here, we review studies on the role of the rat medial prefrontal cortex in adaptive control, with a focus on simple reaction time tasks that can be easily used across species and have clinical relevance. The performance of these tasks is associated with neural activity in the medial prefrontal cortex that reflects stimulus detection, action timing, and outcome monitoring. We describe rhythmic neural activity that occurs when animals initiate a temporally extended action. Such rhythmic activity is coterminous with major changes in population spike activity. Testing animals over a series of sessions with varying pre-stimulus intervals showed that the signals adapt to the current temporal demands of the task. Disruptions of rhythmic neural activity occur on error trials (premature responding) and lead to a persistent encoding of the error and a subsequent change in behavioral performance (i.e. post-error slowing). Analysis of simultaneously recorded spike activity suggests that the presence of strong theta rhythms is coterminous with altered network dynamics, and might serve as a mechanism for adaptive control. Computational modeling suggests that these signals may enable learning from errors. Together, our findings contribute to an emerging literature and provide a new perspective on the neuronal mechanisms for the adaptive control of action.

Executive dysfunction in Parkinson's disease and timing deficits.

Patients with Parkinson's disease (PD) have deficits in perceptual timing, or the perception and estimation of time. PD patients can also have cognitive symptoms, including deficits in executive functions such as working memory, planning, and visuospatial attention. Here, we discuss how PD-related cognitive symptoms contribute to timing deficits. Timing is influenced by signaling of the neurotransmitter dopamine in the striatum. Timing also involves the frontal cortex, which is dysfunctional in PD. Frontal cortex impairments in PD may influence memory subsystems as well as decision processes during timing tasks. These data suggest that timing may be a type of executive function. As such, timing can be used to study the neural circuitry of cognitive symptoms of PD as they can be studied in animal models. Performance of timing tasks also maybe a useful clinical biomarker of frontal as well as striatal dysfunction in PD.

Stimulus control in multiple temporal discriminations.

In multiple fixed interval (FI) schedules, rats are trained to discriminate different FIs that are signaled by different stimuli. After extensive training, the different stimuli often acquire control over performance, observed by an earlier increase in responding for stimuli that signal shorter FIs, as compared with stimuli that signal longer FIs. The order in which the different FIs are trained, either intermixed across cycles or in blocks of several cycles, may seem irrelevant given that average performance at asymptote may be similar. In this study, rats were trained in two procedures with multiple FIs presented intermixed within sessions or in blocks of one interval per session. Similar performance was observed at asymptote, but an inspection of early cycles in each session revealed that different stimuli acquired control over performance only when trained intermixed within each session. Although the stimuli reliably signaled the upcoming FI, when trained in successive blocks of 60 cycles, rats rapidly adjusted performance early in the sessions on the basis of the temporal aspects of the task, and not on the basis of the stimulus presented in the current cycle. These results are discussed in terms of overshadowing of the stimuli by temporal cues and in terms of conditions under which a stimulus acquires control over performance.

Lost in transition: aging-related changes in executive control by the medial prefrontal cortex.

Neural correlates of aging in the medial prefrontal cortex (mPFC) were studied using an operant delayed response task. The task used blocks of trials with memory-guided (delayed alternation) and visually-guided (stimulus-response) responding. Older rats (24 months) performed at a slow pace compared with younger rats (6 months). They wasted time engaged in nonessential behaviors (e.g., licking on spouts beyond the period of reward delivery) and were slow to respond at the end of the delay period. Aged mPFC neurons showed normal spatial processing. They differed from neurons in younger rats by having reduced modulations by imperative stimuli indicating reward availability and reduced activity associated with response latencies for reward collection. Older rats showed reduced sensitivity to imperative stimuli at three levels of neural activity: reduced fractions of neurons with changes in firing rate around the stimulus, reduced correlation over neurons at the time of the stimulus as measured with analysis of population activity, and reduced amplitudes of event-related fluctuations in intracortical field potentials at the time of the imperative stimulus. Our findings suggest that aging alters the encoding of time-sensitive information and impairs the ability of prefrontal networks to keep subjects "on task."

Noradrenergic control of error perseveration in medial prefrontal cortex.

The medial prefrontal cortex (mPFC) plays a key role in behavioral variability, action monitoring, and inhibitory control. The functional role of mPFC may change over the lifespan due to a number of aging-related issues, including dendritic regression, increased cAMP signaling, and reductions in the efficacy of neuromodulators to influence mPFC processing. A key neurotransmitter in mPFC is norepinephrine. Previous studies have reported aging-related changes in the sensitivity of mPFC-dependent tasks to noradrenergic agonist drugs, such as guanfacine. Here, we assessed the effects of yohimbine, an alpha-2 noradrenergic antagonist, in cohorts of younger and older rats in a classic test of spatial working memory (using a T-maze). Older rats (23-29 mo.) were impaired by a lower dose of yohimbine compared to younger animals (5-10 mo.). To determine if the drug acts on alpha-2 noradrenergic receptors in mPFC and if its effects are specific to memory-guided performance, we made infusions of yohimbine into mPFC of a cohort of young rats (6 mo.) using an operant delayed response task. The task involved testing rats in blocks of trials with memory- and stimulus-guided performance. Yohimbine selectively impaired memory-guided performance and was associated with error perseveration. Infusions of muscimol (a GABA-A agonist) at the same sites also selectively impaired memory-guided performance, but did not lead to error perseveration. Based on these results, we propose several potential interpretations for the role for the noradrenergic system in the performance of delayed response tasks, including the encoding of previous response locations, task rules (i.e., using a win-stay strategy instead of a win-shift strategy), and performance monitoring (e.g., prospective encoding of outcomes).

Reversible Inactivation of Rat Premotor Cortex Impairs Temporal Preparation, but not Inhibitory Control, During Simple Reaction-Time Performance.

Previous studies by our lab and others have established a role for medial areas of the prefrontal cortex (mPFC) in the top-down control of action during simple reaction-time (RT) tasks. However, the neural circuits that allow mPFC to influence activity in the motor system have remained unclear. In the present study, we used a combination of tract-tracing and reversible inactivation methods to examine the role of a motor-related area in the rat frontal cortex, called the rostral forelimb area (RFA), in the top-down control of action. Neural tracing studies involved used electrical microstimulation to identify RFA and injections of biotinylated dextran amines (BDA) to map out connections of RFA with other parts of the frontal cortex. Connections were found between RFA and mPFC, the agranular insular cortex, and the primary motor cortex. Reversible inactivations using muscimol infusions into RFA increased response times and eliminated delay-dependent speeding, but did not increase premature responding. These results are markedly different from what is obtained when muscimol is infused into mPFC, which leads to excessive premature responding and a reduction of RTs to stimuli at short delays (Narayanan et al., 2006). We also tested animals during the RT task after inactivating the agranular insular cortex, which contains neurons that projects to and receives from RFA and mPFC, and found no effects on RT performance. Together, these studies suggest that RFA is a premotor region in the rat frontal cortex that competes with mPFC to control action selection. We suggest that RFA controls the threshold that is used to initiate responding and generates prepotent excitation over responding that is crucial for temporal preparation.

The effect of stimulus discriminability on strategies for learning multiple temporal discriminations.

The goal was to identify training conditions under which temporal intervals that are signaled by different stimuli are memorized (i.e., the temporal behavior is readily shown to be under stimulus control). Undergraduate students were trained on three signaled temporal discriminations using a peak procedure. The intervals were trained in either blocks of trials or with trials intermixed within the session, and then they were given a transfer test with intermixed trials. There were two levels of stimulus discriminability, defined by the similarity of the stimuli. Most participants memorized the intervals when the discriminations were intermixed within the session, or were easy, but not when the discriminations occurred in blocks and were difficult. In the transfer tests, those participants trained in the difficult discrimination that occurred in blocks of trials typically continued to perform as they did during the last-trained interval, regardless of the stimulus presented. These results are better explained by a memory retrieval than a memory storage account.