Paced finger-tapping abnormalities in bipolar disorder indicate timing dysfunction

Alterations in time perception and neural circuitry associated with internal timing have been found in several neuropsychiatric disorders that share phenomenological and genetic overlap with bipolar disorder, including schizophrenia (1, 2) and attention-deficit hyperactivity disorder (ADHD) (3). Precise knowledge of how time is encoded by the brain remains elusive, yet it has become apparent that a number of structures (e.g., the cerebellum, basal ganglia, orbitofrontal cortex, insula, parietal cortex, prefrontal cortex) and neurotransmitter systems (e.g., dopamine and glutamate) contribute in various ways to time perception. Many of these very same regions and systems have also been implicated in the pathophysiology of bipolar disorder (4). However, investigations of time perception in bipolar disorder for short durations, i.e., those in the second or millisecond range, are scarce. Only two reports, both from the same group (5, 6), have, to our knowledge, included bipolar disorder patients and compared them with a control group on time perception in the suprasecond range. However, in both cases, the sample was not restricted to bipolar disorder participants only, making results difficult to interpret. Bschor et al. (5) reported that depressed (meeting criteria for DSM-IV major depressive episode) and manic (DSM-IV manic) patients did not differ from controls on either a 7-second time production or an 8-second time-estimation task. In a subsequent study by the same group using the same criteria (6), depressed patients over-reproduced a 6-second interval, and no differences between patients and controls were observed in a 1-second time reproduction task. To our knowledge, no studies have examined explicit timing in bipolar disorder in the subsecond time domain, although bipolar disorder participants showed significant timing abnormalities on an implicit motor timing task, namely eyeblink conditioning (7). It is generally accepted that the frontal cortex, basal ganglia, and cerebellum are integrally involved in time perception, with a consensus emerging that different timescales utilize different neural circuits (8–10). A recent meta-analysis of 41 functional neuroimaging studies of perceptual and motor timing by Weiner et al. (11) used a robust activation likelihood estimation algorithm and found strong support for the theory that subsecond and suprasecond durations depend on somewhat distinct neural networks, with the former more likely to recruit subcortical structures such as the basal ganglia and cerebellum and the latter more likely to activate cortical structures such as the supplementary motor area and prefrontal cortex. The finding that the cerebellum is activated predominantly during subsecond tasks is consistent with other suggestions that this structure may be critical for the encoding of subsecond time intervals (9, 12). Moreover, the Weiner et al. study found that activation of the cerebellum was consistent across motor and perceptual timing tasks, supporting the proposal that this structure serves as a timekeeper for brief durations (13). In the present study, we examined explicit subsecond timing in bipolar disorder using a paced finger-tapping task with a 500-ms intertap interval using the synchronization–continuation paradigm. In this task, participants first tapped in time with a tone (synchronization). They then attempted to continue tapping in its absence while maintaining that pace (continuation). The 500-ms interval was chosen because it is short enough to minimize the engagement of brain regions involved in higher-order cognitive processes, including working memory. Subsecond intervals also prompt anticipatory taps; that is, taps are not in response to hearing the paced tone, but instead occur when participants expect it to occur (14). Therefore, at this interval duration, tapping pace can be expected to rely on an internal clock even during the synchronization portion of the task when external pacing tones are occurring (3). The synchronization–continuation paradigm benefits from the existence of a widely known model of human timing developed by Wing and Kristofferson (15) that partitions the production of a sequence of finger taps during the continuation portion of the task into its fundamental components: (i) a central ‘clock’ timekeeper, and (ii) the delay between the neural command and the execution of the movement. This mathematical model uses the variance and autocovariance properties of the series of taps to determine whether the source of timing variability is due to the central timekeeper or the motor delay. In controls, Wing and Kristofferson (15) demonstrated that the central timekeeper variance increases as a function of the time interval being kept, while the variance in motor delay remains virtually constant across all intervals. By decomposing variability into clock and motor components, this model allows insight into the origins of any group differences in intrasubject timing variability. We hypothesized that bipolar disorder patients would show greater intrasubject variability and shorter intertap intervals in comparison to controls, as well as higher central timekeeper variance as estimated by the clock component of the Wing–Kristofferson mathematical model. An additional goal of this study was to investigate whether deficits in finger-tapping performance could differentiate between acutely ill and clinically stable groups of bipolar disorder participants. We predicted that the manic bipolar disorder group would display increased temporal variability of finger tapping relative to control participants, and that euthymic bipolar disorder participants would fall between these groups. Moreover, we hypothesized that this variability would be most pronounced in the continuation condition because variability is generally expected to increase in the absence of a pacing stimulus, an effect that should be amplified in the manic group.