Dopamine And Interval Timing

Over the last two decades, advances have been made in specifying brain systems involved in temporal processing, and links have been established between cognitive processes underlying timing and particular pharmacological and physiological manipulations (Gibbon et al., 1997; Ivry, 1996; Rao et al., 2001). Extensive animal work has described the role of dopaminergic brain systems and the striato-frontal circuitry in timing behavior. Specifically, the output dopaminergic neurons originating in the substantia nigra pars compacta (SNc) and projecting to the striatum, as well as the striatum itself, are thought to implement the pacemaker-accumulator system in interval timing (Meck, 1986; Matell et al., this volume). The striatum is thought to serve as the accumulator by integrating the action potentials of the dopaminergic pacemaker cells. Data consistent to this hypothesis showed that striatal lesions eliminated timing in rats, and that timing did not recover after administration of L-Dopa to the lesioned striata. In contrast, timing in rats is restored when L-Dopa is applied to damage in the SNc, suggesting that those dopaminergic cells that survive the lesion act effectively again under L-Dopa supplementation (Hinton and Meck, 1997).

The method used to assess interval timing in the previously described animal studies was the peak-interval procedure (Catania, 1970). A human analog of the PI procedure was developed and used to test interval timing competence in both normal and brain-diseased human subjects (Malapani et al., 1998a, 1998b; Rakitin et al., 1998). This task first demonstrates a standard time interval a number of times, and then requires the subjects to reproduce that interval from memory throughout a block of trials. Reproduction of the interval consists of pressing a response key just before the expected end of the interval and releasing the key just afterward. Feedback is delivered after some of these trials either in the form of a histogram indicating whether the response was too short or too long (that is, within 15% of target time) or in the form of reminder trials (fixed-interval (FI) trials).

In animals tested with the PI procedure, the integrity of the striato-nigral dopam-inergic system determines the pacemaker's speed in emitting pulses. In contrast, timing distortions in PD patients tested with the human analog of the PI task primarily involve temporal memory processes (Gibbon et al., 1997; Malapani et al., 1998b). Moreover, the memory-based distorted time production of PD patients is DA dependent in that it is alleviated with DA replacement therapy (Gibbon et al., 1997; Malapani et al., 2002a).

DA-dependent timing errors were evident in an experiment that asked PD patients to reproduce time intervals both on and off levodopa medication. When asked to produce two different intervals in separate blocks within a single experimental session, patients off medication reproduced the short value (8 sec) long and the long value (21 sec) short. We described this deficit as migration. It is as though there was a mutual attraction, or "coupling," in memory for these two target times. However, when the same patients, while unmedicated, reproduced only one interval (e.g., 21 sec) in a session, they reproduced that interval as too long, indicating a lengthening or "slowing" of temporal processing. In contrast, production on medication was accurate for both one and two intervals in a session. It was the dependence of the direction of DA-dependent timing errors on the number of intervals produced in a session, together with the fact that the observed shifts persisted despite abundant corrective feedback, that led us to attribute these PD timing inaccuracies to a memory failure. This hypothesis was also consistent with the pattern of gradual and rather persistent drifts in accuracy, which is suggested by extensive animal work to reflect deficits related to memory functions of the interval timing system (Meck, 1996).

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