Catalin V. Buhusi

What makes us tick? Functional and neural mechanisms of interval timing.

Time is a fundamental dimension of life. It is crucial for decisions about quantity, speed of movement and rate of return, as well as for motor control in walking, speech, playing or appreciating music, and participating in sports. Traditionally, the way in which time is perceived, represented and estimated has been explained using a pacemaker–accumulator model that is not only straightforward, but also surprisingly powerful in explaining behavioural and biological data. However, recent advances have challenged this traditional view. It is now proposed that the brain represents time in a distributed manner and tells the time by detecting the coincidental activation of different neural populations.

Differential effects of methamphetamine and haloperidol on the control of an internal clock.

Humans and animals process temporal information as if they were using an internal stopwatch that can be stopped and reset, and whose speed is adjustable. Previous data suggest that dopaminergic drugs affect the speed of this internal stopwatch. Using a paradigm in which rats have to filter out the gaps that (sometimes) interrupted timing, the authors found that methamphetamine and haloperidol also affect the stop and reset mechanism of the internal clock, possibly by modulating attentional components that are dependent on the content and salience of the timed events. This is the first report of both clock and attentional effects of dopaminergic drugs on interval timing in the same experimental setting.

Relative time sharing: new findings and an extension of the resource allocation model of temporal processing

Individuals time as if using a stopwatch that can be stopped or reset on command. Here, we review behavioural and neurobiological data supporting the time-sharing hypothesis that perceived time depends on the attentional and memory resources allocated to the timing process. Neuroimaging studies in humans suggest that timekeeping tasks engage brain circuits typically involved in attention and working memory. Behavioural, pharmacological, lesion and electrophysiological studies in lower animals support this time-sharing hypothesis. When subjects attend to a second task, or when intruder events are presented, estimated durations are shorter, presumably due to resources being taken away from timing. Here, we extend the time-sharing hypothesis by proposing that resource reallocation is proportional to the perceived contrast, both in temporal and non-temporal features, between intruders and the timed events. New findings support this extension by showing that the effect of an intruder event is dependent on the relative duration of the intruder to the intertrial interval. The conclusion is that the brain circuits engaged by timekeeping comprise not only those primarily involved in time accumulation, but also those involved in the maintenance of attentional and memory resources for timing, and in the monitoring and reallocation of those resources among tasks.

Relativity Theory and Time Perception: Single or Multiple Clocks?

Background Current theories of interval timing assume that humans and other animals time as if using a single, absolute stopwatch that can be stopped or reset on command. Here we evaluate the alternative view that psychological time is represented by multiple clocks, and that these clocks create separate temporal contexts by which duration is judged in a relative manner. Two predictions of the multiple-clock hypothesis were tested. First, that the multiple clocks can be manipulated (stopped and/or reset) independently. Second, that an event of a given physical duration would be perceived as having different durations in different temporal contexts, i.e., would be judged differently by each clock. Methodology/Principal Findings Rats were trained to time three durations (e.g., 10, 30, and 90 s). When timing was interrupted by an unexpected gap in the signal, rats reset the clock used to time the “short” duration, stopped the “medium” duration clock, and continued to run the “long” duration clock. When the duration of the gap was manipulated, the rats reset these clocks in a hierarchical order, first the “short”, then the “medium”, and finally the “long” clock. Quantitative modeling assuming re-allocation of cognitive resources in proportion to the relative duration of the gap to the multiple, simultaneously timed event durations was used to account for the results. Conclusions/Significance These results indicate that the three event durations were effectively timed by separate clocks operated independently, and that the same gap duration was judged relative to these three temporal contexts. Results suggest that the brain processes the duration of an event in a manner similar to Einsteins special relativity theory: A given time interval is registered differently by independent clocks dependent upon the context.

Perplexing effects of hippocampal lesions on latent inhibition : A neural network solution

Experimental data indicate that hippocampal lesions might impair, spare, or even facilitate latent inhibition (LI). Furthermore, when LI is impaired by the lesions, it might be reinstated by haloperidol administration. The present article applies a neural network model of classical conditioning (N. A. Schmajuk, Y. W. Lam, & J. A. Gray, 1996) to investigate the possible causes of these puzzling results. According to the model, LI is manifested because preexposure of the conditioned stimulus (CS) reduces Novelty, defined as proportional to the sum of the mismatches between predicted and observed events, thereby reducing attention to the CS and retarding conditioning. It is assumed that hippocampal lesions affect the prediction of events. Computer simulations reveal that, depending on the behavioral protocol (i.e., procedure and total time of CS preexposure), Novelty in hippocampal lesioned animals might be larger, equal, or smaller (corresponding to smaller, equal, or larger LI) than in normal controls. Reinstatement of LI by haloperidol administration is explained by assuming that dopaminergic antagonists decrease the value of Novelty, when Novelty increases following hippocampal lesions.

Modeling Pharmacological Clock and Memory Patterns of Interval Timing in a Striatal Beat-Frequency Model with Realistic, Noisy Neurons

In most species, the capability of perceiving and using the passage of time in the seconds-to-minutes range (interval timing) is not only accurate but also scalar: errors in time estimation are linearly related to the estimated duration. The ubiquity of scalar timing extends over behavioral, lesion, and pharmacological manipulations. For example, in mammals, dopaminergic drugs induce an immediate, scalar change in the perceived time (clock pattern), whereas cholinergic drugs induce a gradual, scalar change in perceived time (memory pattern). How do these properties emerge from unreliable, noisy neurons firing in the milliseconds range? Neurobiological information relative to the brain circuits involved in interval timing provide support for an striatal beat frequency (SBF) model, in which time is coded by the coincidental activation of striatal spiny neurons by cortical neural oscillators. While biologically plausible, the impracticality of perfect oscillators, or their lack thereof, questions this mechanism in a brain with noisy neurons. We explored the computational mechanisms required for the clock and memory patterns in an SBF model with biophysically realistic and noisy Morris–Lecar neurons (SBF–ML). Under the assumption that dopaminergic drugs modulate the firing frequency of cortical oscillators, and that cholinergic drugs modulate the memory representation of the criterion time, we show that our SBF–ML model can reproduce the pharmacological clock and memory patterns observed in the literature. Numerical results also indicate that parameter variability (noise) – which is ubiquitous in the form of small fluctuations in the intrinsic frequencies of neural oscillators within and between trials, and in the errors in recording/retrieving stored information related to criterion time – seems to be critical for the time-scale invariance of the clock and memory patterns.

Memory for timing visual and auditory signals in albino and pigmented rats

The authors hypothesized that during a gap in a timed signal, the time accumulated during the pregap interval decays at a rate proportional to the perceived salience of the gap, influenced by sensory acuity and signal intensity. When timing visual signals, albino (Sprague-Dawley) rats, which have poor visual acuity, stopped timing irrespective of gap duration, whereas pigmented (Long-Evans) rats, which have good visual acuity, stopped timing for short gaps but reset timing for long gaps. Pigmented rats stopped timing during a gap in a low-intensity visual signal and reset after a gap in a high-intensity visual signal, suggesting that memory for time in the gap procedure varies with the perceived salience of the gap, possibly through an attentional mechanism.

Time sharing in rats: A peak-interval procedure with gaps and distracters.

Four hypotheses (switch, instructional-ambiguity, memory decay, and time sharing) were evaluated in a reversed peak-interval procedure with gaps by presenting distracter stimuli during the uninterrupted timed signal. The switch, instructional-ambiguity, and memory-decay hypotheses predict that subjects should time through the distracter and delay responding during gaps. The time-sharing hypothesis assumes that the internal clock shares attentional and working-memory resources with other processes, so that both gaps and distracters delay timing by causing working memory to decay. We found that response functions were displaced both by gaps and by distracters. Computer simulations show that when combined, the memory-decay and time-sharing hypotheses can mechanistically address present data, suggesting that these two hypotheses may reflect different levels of analysis of the same phenomenon.

Temporal Integration as a Function of Signal and Gap Intensity in Rats (Rattus norvegicus) and Pigeons (Columba livia)

Previous data suggest that rats (Rattus norvegicus) and pigeons (Columba livia) use different interval-timing strategies when a gap interrupts a to-be-timed signal: Rats stop timing during the gap, and pigeons reset their timing mechanism after the gap. To examine whether the response rule is controlled by an attentional mechanism dependent on the characteristics of the stimuli, the authors manipulated the intensity of the signal and gap when rats and pigeons timed in the gap procedure. Results suggest that both rats and pigeons stop timing during a nonsalient gap and reset timing after a salient gap. These results also suggest that both species use similar interval-timing mechanisms, influenced by nontemporal characteristics of the signal and gap.

Time-scale invariance as an emergent property in a perceptron with realistic, noisy neurons

In most species, interval timing is time-scale invariant: errors in time estimation scale up linearly with the estimated duration. In mammals, time-scale invariance is ubiquitous over behavioral, lesion, and pharmacological manipulations. For example, dopaminergic drugs induce an immediate, whereas cholinergic drugs induce a gradual, scalar change in timing. Behavioral theories posit that time-scale invariance derives from particular computations, rules, or coding schemes. In contrast, we discuss a simple neural circuit, the perceptron, whose output neurons fire in a clockwise fashion based on the pattern of coincidental activation of its input neurons. We show numerically that time-scale invariance emerges spontaneously in a perceptron with realistic neurons, in the presence of noise. Under the assumption that dopaminergic drugs modulate the firing of input neurons, and that cholinergic drugs modulate the memory representation of the criterion time, we show that a perceptron with realistic neurons reproduces the pharmacological clock and memory patterns, and their time-scale invariance, in the presence of noise. These results suggest that rather than being a signature of higher order cognitive processes or specific computations related to timing, time-scale invariance may spontaneously emerge in a massively connected brain from the intrinsic noise of neurons and circuits, thus providing the simplest explanation for the ubiquity of scale invariance of interval timing.