Matthew S. Matell

Neuropsychological mechanisms of interval timing behavior

Interval timing in the seconds-to-minutes range is believed to underlie a variety of complex behaviors in humans and other animals. One of the more interesting problems in interval timing is trying to understand how the brain times events lasting for minutes with millisecond-based neural processes. Timing models proposing the use of coincidence-detection mechanisms (e.g., the detection of simultaneous activity across multiple neural inputs) appear to be the most compatible with known neural mechanisms. From an evolutionary perspective, coincidence detection of neuronal activity may be a fundamental mechanism of timing that is expressed across a wide variety of species. BioEssays 22:94-103, 2000.

Interval Timing and the Encoding of Signal Duration by Ensembles of Cortical and Striatal Neurons

This study investigated the firing patterns of striatal and cortical neurons in rats in a temporal generalization task. Striatal and cortical ensembles were recorded in rats trained to lever press at 2 possible criterion durations (10 s or 40 s from tone onset). Twenty-two percent of striatal and 15% of cortical cells had temporally specific modulations in their firing rate, firing at a significantly different rate around 10 s compared with 40 s. On 80% of trials, a post hoc analysis of the trial-by-trial consistency of the firing rates of an ensemble of neurons predicted whether a spike train came from a time window around 10 s versus around 40 s. Results suggest that striatal and cortical neurons encode specific durations in their firing rate and thereby serve as components of a neural circuit used to represent duration.

Behavioral Properties of the Trigeminal Somatosensory System in Rats Performing Whisker-Dependent Tactile Discriminations

To address several fundamental questions regarding how multiwhisker tactile stimuli are integrated and processed by the trigeminal somatosensory system, a novel behavioral task was developed that required rats to discriminate the width of either a wide or narrow aperture using only their large mystacial vibrissae. Rats quickly acquired this task and could accurately discriminate between apertures of very similar width. Accurate discriminations required a large number of intact facial whiskers. Systematic removal of individual whiskers caused a decrease in performance that was directly proportional to the number of whiskers removed, indicating that tactile information from multiple whiskers is integrated as rats gauge aperture width. In different groups of rats, different sets of whiskers were removed in patterns that preferentially left whisker rows or whisker arcs intact. These different whisker removals caused similar decreases in performance, indicating that individual whiskers within the vibrissal array are functionally equivalent during performance of this task. Lesions of the barrel cortex abolished the ability of rats to discriminate, demonstrating that this region is critically involved in this tactile behavior. Interestingly, sectioning the facial nerve, which abolished whisker movements, did not affect the ability to perform accurate discriminations, indicating that active whisker movements are not necessary for accurate performance of the task. Collectively, these results indicate that the trigeminal somatosensory system forms internal representations of external stimuli (in this case, aperture width) by integrating tactile input from many functionally equivalent facial whiskers and that the vibrissal array can function as a fine-grained distance detector without active whisker movements.

Differential modulation of clock speed by the administration of intermittent versus continuous cocaine

The roles that psychostimulant sensitization and tolerance play in temporal perception in the seconds-to-minutes range were assessed in rats. Cocaine (20 mg/kg/day) was administered for 2 weeks either intermittently via daily injections (induces sensitization) or continuously via an osmotic minipump (induces tolerance). Interval timing was evaluated throughout administration and withdrawal. Injections of cocaine caused immediate, proportional, leftward shifts in peak times, indicating an increase in the speed of an internal clock. These shifts grew progressively larger with repeated administration, indicating that stimulant-induced increases in clock speed can be sensitized. Continuous cocaine administration produced no reliable effects. These results suggest that the mechanisms of sensitization may play a considerable role in drug-induced alterations of the perception of time.

Not “just” a coincidence: Frontal‐striatal interactions in working memory and interval timing

The frontal cortex and basal ganglia play central roles in working memory and in the ability to time brief intervals. We outline recent theoretical and empirical work to suggest that working memory and interval timing rely not only on the same anatomic structures, but also on the same neural representation of a specific stimulus. Specifically, cortical neurons may fire in an oscillatory fashion to form representations of stimuli, and the striatum (a basal ganglia structure) may detect those patterns of cortical firing that occur co‐incident to important events. Information about stimulus identity can be extracted from which cortical neurons are involved in the representation, and information about duration can be extracted from their relative phase. The principles derived from these biologically based models also fit well with a family of behaviourally based models that emphasise the importance of time in many working memory phenomena.

Reinforcement-induced within-trial resetting of an internal clock.

Rats were trained on a modified peak-interval timing procedure in which three response levers were individually associated with different criterion durations (10, 30 and 90 s) following the onset of a tone stimulus. Delivery of response-dependent reinforcement for each duration was independent of both the responding and the delivery of reinforcement for the other durations, such that the tone stimulus stayed on during food delivery, and no change in the primed reinforcement times occurred. We report here that the delivery of reinforcement at an earlier criterion duration produces a rightward shift in the temporal response functions for later durations by the amount of time that has already elapsed in the trial. This reset in temporal accumulation produces large discrepancies between the programmed and expected (peak) times of reinforcement and suggests that rats are unable to make conditional reinforcement-based discriminations of interval duration.

Multiple mechanisms for temporal processing

Many models suggest that time perception is mediated by a unitary mechanism. For example, scalar expectancy theory (SET), the dominant model of timing for the past 30 years, suggests that temporal processing is mediated by a centralized clock-counter module in which elapsed time is measured by the summation of pacemaker pulses (Gibbon et al., 1984). A number of alternative, neurally plausible models have been proposed with clock processes that incorporate either the pacemaker-counter elements of SET, or other neural dynamics such as decay processes or state-dependent network activity (Staddon and Higa, 1999; Karmarkar and Buonomano, 2007; Simen et al., 2011a,b). While these models differ in the mechanisms utilized for the temporal control of behavior, they all suggest that timing is accomplished by a single, amodal process. Support for the hypothesis that timing is mediated by a single mechanism comes from several sources. A number of studies demonstrate that performance is independent of whether the task utilizes motor or “perceptual” temporal representations (Ivry and Hazeltine, 1995; Meegan et al., 2000). Additionally, although an effect of interval duration has been postulated for over a hundred years, such an effect has not been consistently identified; Lewis and Miall (2009), for example, failed to identify a fundamental change in timing performance or “break-point” using stimuli ranging from 68 ms to 16.7 min. We suggest the alternative hypothesis that timing functions are mediated by multiple, overlapping neural systems, which may be flexibly engaged depending on the task requirements. These systems may function independently of one another and may be adaptively engaged pro re nata, such that single or multiple systems may be active during any one timing task, depending on environmental conditions and behavioral requirements. One line of support for this hypothesis comes from a quantitative meta-analysis of 41 neuroimaging studies of time perception in which we found that different neural structures were engaged depending on stimulus duration and the “motor” or “perceptual” nature of the task (Wiener et al., 2010a). Of particular interest in this context, however, is the fact that the meta-analysis also demonstrated two areas engaged across all tasks: supplementary motor area (SMA) and right inferior frontal gyrus (rIFG). In subsequent analyses of this dataset, however, we found that even in regions active across several conditions there is evidence of multiple timing mechanisms at work. Consider the SMA for example. Recent observations suggest that the SMA is a heterogeneous structure that may be functionally divided into the SMA “proper” and pre-SMA (Nachev et al., 2008). A rostro-caudal gradient in the SMA has been proposed according to which SMA and pre-SMA subserve motor and cognitive processes, respectively. Consistent with this finding, we found evidence for a functional gradient in the SMA, wherein perceptual timing tasks are more likely to activate voxels within the pre-SMA while motor timing tasks are associated with SMA proper activation-likelihood (Figure ​(Figure11A). Figure 1 A subset of the results from our previous meta-analysis of neuroimaging timing studies. (A) Sagittal section of a rendered brain including SMA voxels from perceptual or motor timing tasks (regardless of duration length) and their overlap. Crosshairs are ... Fractionation of temporal processing may also be evident in the basal ganglia, a brain region often implicated in studies of time perception and with high connectivity to the SMA. Figure ​Figure1B1B depicts voxels from SMA and basal ganglia regions with significant activation-likelihood. Once again, different patterns of activation-likelihood were noted as a function of the duration of the stimulus and nature of the task. For example, there was a greater propensity for the basal ganglia to be activated during sub-second timing tasks. However, it is crucial to note that the basal ganglia interact with numerous other regions, and so these activation patterns must be considered in the larger context of interactive networks. Additional work beyond neuroimaging also argues for multiple timing systems. For example, we recently adopted a behavioral genetics paradigm to look at single-nucleotide polymorphisms in genes associated with different aspects of the dopamine system (Wiener et al., 2011). We found that a polymorphism affecting the expression of striatal D2 receptors was associated with poorer performance on a perceptual timing task, but only when the intervals tested were below 1 s. In contrast, subjects with a polymorphism affecting the expression of the enzyme catechol-O-methyltransferase (COMT), which is known to regulate prefrontal dopamine tone, were impaired during supra-second, but not sub-second timing. This work suggests that different dopaminergic systems may underlie distinct timing procedures. Another line of data supporting the claim that multiple mechanisms mediate timing comes from the fact that at least under some circumstances timing mechanisms appear to be both modality-specific and mediated by local neural structures. For example, adaptation to focal regions of the visual field produces duration distortions that are localized to that spatial region (Burr et al., 2007). Interestingly, modality-specific regions appear to be invoked for temporal expectations even in the absence of the stimuli themselves (Bueti and Macaluso, 2010), suggesting that the process may be mediated by simulation. The fact that subject strategies influence the neural circuits recruited for timing is also consistent with the hypothesis that multiple distinct procedures underlie timing. For example, a recent study demonstrated that subjects recruited different neural networks depending on whether they implicitly used a beat-based or duration-based strategy (Grahn and McAuley, 2009). Similarly, recordings from rodent striatum demonstrate that patterns of temporally varying neural activity may reflect an integration of the passage of time with its associated action (Portugal et al., 2011), further suggesting that the computations contributing to temporal control may critically depend on both environmental and behavioral context. The hypothesis that timing may be mediated by multiple distinct procedures also accounts for the puzzling lack of neurologic disorders characterized by a profound and selective impairment in temporal processing. Although syndromes characterized by selective deficits in vision, audition, language, attention, and multiple other faculties have been identified, we are unaware of a similar disorder involving temporal processing. Additionally, studies of patients and animals with brain lesions often demonstrate relatively mild deficits in temporal processing. The above discussion is not intended to be exhaustive. Differences in performance on tasks assessing timing for synchronized or syncopated beat timing (Jantzen et al., 2004), as well as explicit or implicit timing to temporal intervals (Coull and Nobre, 2008; Wiener et al., 2010b) have also been identified. A challenge for future research will be to identify these different timing networks and to clarify the functional relationship between them.

Fast forward: Supramarginal gyrus stimulation alters time measurement

The neural basis of temporal processing is unclear. We addressed this important issue by performing two experiments in which repetitive transcranial magnetic stimulation (rTMS) was administered in different sessions to the left or right supramarginal gyrus (SMG) or vertex; in both tasks, two visual stimuli were presented serially and subjects were asked to judge if the second stimulus was longer than the first (standard) stimulus. rTMS was presented on 50% of trials. Consistent with a previous literature demonstrating the effect of auditory clicks on temporal judgment, rTMS was associated with a tendency to perceive the paired visual stimulus as longer in all conditions. Crucially, rTMS to the right SMG was associated with a significantly greater subjective prolongation of the associated visual stimulus in both experiments. These findings demonstrate that the right SMG is an important element of the neural system underlying temporal processing and, as discussed, have implications for neural and cognitive models of temporal perception and attention.

Impulsive responding on the peak-interval procedure.

The pattern of responding on a peak-interval timing task allows one to make inferences regarding the sources of variation that contribute to interval timing behavior. Non-temporal factors such as impulsivity may impact the validity of these inferences. Rats were trained on a 15s peak-interval procedure (PI) or a mixed 15s behaviorally dependent variable-interval, 15s peak-interval procedure (bdVIPI) for an extended number of sessions. Extended training on the PI revealed a bi-modal distribution in the times at which subjects started responding for temporally predictable reinforcement, suggesting that multiple processes contribute to the behavioral pattern obtained in this procedure. Training on the bdVIPI eliminated the early mode of this bi-modal distribution, thereby decreasing the variation in start times. These results suggest that alternative response options can modulate the influence of impulsivity in timing tasks.

Averaging of temporal memories by rats.

Rats were trained on a mixed fixed-interval schedule in which stimulus A (tone or light) indicated food availability after 10 s and stimulus B (the other stimulus) indicated food availability after 20 s. Testing consisted of nonreinforced probe trials in which the stimulus was A, B, or the compound AB. On single-stimulus trials, rats responded with a peak of activity around the programmed reinforced time. On compound-stimulus trials, rats showed a single scalar peak of responding at a time midway between those for stimulus A and B. These results suggest that when provided with discrepant information regarding the temporal predictability of reinforcement, rats compute an average of the scheduled reinforcement times for the A and B stimuli and use this average to generate an expectation of reward for the compound stimuli.