Search

Behavioral and electrophysiology studies have shown that humans possess a certain self-awareness of their individual timing ability. However, conflicting reports raise concerns about whether humans can discern the direction of their timing error, calling into question the extent of this timing awareness. To understand the depth of this ability, the impact of nondirectional feedback and reinforcement learning on time perception were examined in a unique temporal reproduction paradigm that involved a mixed set of interval durations and the opportunity to repeat every trial immediately after receiving feedback, essentially allowing a “redo.” Within this task, we tested two groups of participants on versions where nondirectional feedback was provided after every response, or not provided at all. Participants in both groups demonstrated reduced central tendency and exhibited significantly greater accuracy in the redo trial temporal estimates, showcasing metacognitive ability, and an inherent capacity to adjust temporal responses despite the lack of directional information or any feedback at all. Additionally, the feedback group also exhibited an increase in the precision of responses on the redo trials, an effect not observed in the no-feedback group, suggesting that feedback may specifically reduce noise when making a temporal estimate. These findings enhance our understanding of timing self-awareness and can provide insight into what may transpire when this is disrupted.

Temporal processing is an integral aspect of human cognition and perception. Recent studies have suggested that patients suffering from concussion exhibit a deficit in temporal processing, characterized by poor performance on a variety of timing tasks. However, the majority of studies focusing on temporal processing deficits in concussion have focused on visual timing mechanisms. As temporal processing may be dominant for auditory-based processing, and so less susceptible to noise, we investigated patients with TBI and compared them to normal healthy controls on a battery of temporal processing tasks, including paced finger tapping and temporal bisection with sub-second intervals. The results of our investigation found that traumatic brain patients were unimpaired on the paced finger tapping task, suggesting that temporal processing deficits do not extend into motor timing and rhythmicity domain. In the temporal bisection task, TBI patients maintained precision but had a significantly higher bisection point, characterized by a greater propensity to judge stimuli as "short" and were significantly slower than controls. Analysis with a drift-diffusion model of perceptual decision-making revealed that TBI patients were specifically impaired in evidence accumulation, suggesting a smaller signal to noise ratio. Specifically, it demonstrated that patients had higher decision threshold and slower drift rates for accumulating evidence in order to arrive at a decision. Patients had to surmount higher evidence thresholds to reach a decision and were slower than controls in their rate of evidence accumulation. These results suggest specific deficits in temporal perceptual decision-making may predict the neural temporal pathways that may be compromised or unaffected, paving the way for designing targeted therapies to address these impairments.

Interval timing is a fundamental component action, and is susceptible to motor-related temporal distortions. Previous studies have shown that movement biases temporal estimates, but have primarily considered self-modulated movement only. However, real-world encounters often include situations in which movement is restricted or perturbed by environmental factors. In the following experiments, we introduced viscous movement environments to externally modulate movement and investigated the resulting effects on temporal perception. In two separate tasks, participants timed auditory intervals while moving a robotic arm that randomly applied four levels of viscosity. Results demonstrated that higher viscosity led to shorter perceived durations. Using a drift-diffusion model and a Bayesian observer model, we confirmed these biasing effects arose from perceptual mechanisms, instead of biases in decision making. These findings suggest that environmental perturbations are an important factor in movement-related temporal distortions, and enhance the current understanding of the interactions of motor activity and cognitive processes.

The perception and measurement of spatial and temporal dimensions have been widely studied. Yet, whether these two dimensions are processed independently is still being debated. Additionally, whether EEG components are uniquely associated with time or space, or whether they reflect a more general measure of magnitude quantity remains unknown. While undergoing EEG, subjects performed a virtual distance reproduction task, in which they were required to first walk forward for an unknown distance or time, and then reproduce that distance or time. Walking speed was varied between estimation and reproduction phases, to prevent interference between distance or time in each estimate. Behaviorally, subject performance was more variable when reproducing time than when reproducing distance, but with similar patterns of accuracy. During estimation, EEG data revealed the contingent negative variation (CNV), a measure previously associated with timing and expectation, tracked the probability of the upcoming interval, for both time and distance. However, during reproduction, the CNV exclusively oriented to the upcoming temporal interval at the start of reproduction, with no change across spatial distances. Our findings indicate that time and space are neurally separable dimensions, with the CNV both serving a supramodal role in temporal and spatial expectation, yet an exclusive role in preparing duration reproduction.

Objective Hospitals report cards (HRC) are publicly available Internet websites that provide patients with quality-related information on hospitals and enable hospital comparisons. We aim to identify factors that explain the (intended) use of HRC, including differences between current users and non-users. Methods Drawing on UTAUT (Unified Theory of Acceptance and Use of Technology), a cross-sectional study was conducted. Data were derived from an online survey with 1350 respondents and analyzed using structural equation modeling. Results 42% of the survey participants had already used HRC to search for a hospital. Performance expectancy, facilitating conditions, and attitude were found to be significantly related to HRC use intention, with notable differences between users and non-users. Effort expectancy and social influence did not show any significant effects in both subsamples. Conclusion Patients consider HRC to be a useful instrument and are willing to make the efforts it takes to use HRC. The greater effect of performance expectancy in the non-user sample (compared to the user sample) indicates a certain disillusion among users. Practice implications Health policy makers should focus on reviewing and restructuring the information content of HRC. In addition, coordinated efforts are still required to facilitate HRC access, especially for the ‘less fortunate’.

A critical aspect of behavior is that mobile organisms must be able to precisely determine where and when to move. A better understanding of the mechanisms underlying precise movement timing and action planning is therefore crucial to understanding how we interact with the world around us. Recent evidence suggests that our experience of time is directly and intrinsically computed within the motor system, consistent with the theory of embodied cognition. To investigate the role of the motor system, we tested human subjects (n= 40) on a novel task combining reaching and time estimation. In this task, subjects were required to move a robotic manipulandum to one of two physical locations to categorize a concurrently timed suprasecond. Critically, subjects were divided into two groups: one in which movement during the interval was unrestricted and one in which they were restricted from moving until the stimulus interval had elapsed. Our results revealed a higher degree of precision for subjects in the free-moving group. A further experiment (n= 14) verified that these findings were not due to proximity to the target, counting strategies, bias, or movement length. A final experiment (n= 10) replicated these findings using a within-subjects design, performing a time reproduction task, in which movement during encoding of the interval led to more precise performance. Our findings suggest that time estimation may be instantiated within the motor system as an ongoing readout of timing judgment and confidence.

The paramedian forehead flap is commonly used in nasal reconstruction, and survival of the distal part of the flap is usually essential for a good cosmetic outcome. Venous congestion leading to tissue necrosis is a recognized complication with this flap. The standard paramedian forehead flap is designed with a number of aims. These are to include the supratrochlear artery, to maximize mobility of the flap pedicle, to maximize the reach of the flap, and to minimize cosmetic implications at the donor site. The supratrochlear artery does not possess sizable venae comitantes; thus, the main pathway for venous drainage of the paramedian forehead flap is through superficial veins. The pattern and location of the superficial veins varies and therefore a standard skin pedicle design cannot be expected to always include sufficient veins to prevent venous congestion and subsequent flap necrosis. This article demonstrates the superficial venous anatomy of the forehead using computed tomographic venography, clinical demonstration, and cadaveric dissection, and describes a technique that can be carried out to augment flap venous drainage by performing careful dissection to identify additional superficial veins at the margins of the flap skin pedicle. One or more veins can then be mobilized and included with the flap pedicle to augment its venous drainage. Use of this technique should lead to a lower incidence of flap necrosis secondary to venous congestion.

The neural mechanisms underlying time perception are of vital importance to a comprehensive understanding of behavior and cognition. Recent work has suggested a supramodal role for beta oscillations in measuring temporal intervals. However, the precise function of beta oscillations and whether their manipulation alters timing has yet to be determined. To accomplish this, we first re-analyzed two, separate EEG datasets and demonstrate that beta oscillations are associated with the retention and comparison of a memory standard for duration. We next conducted a study of 20 human participants using transcranial alternating current stimulation (tACS), over frontocentral cortex, at alpha and beta frequencies, during a visual temporal bisection task, finding that beta stimulation exclusively shifts the perception of time such that stimuli are reported as longer in duration. Finally, we decomposed trialwise choice data with a drift diffusion model of timing, revealing that the shift in timing is caused by a change in the starting point of accumulation, rather than the drift rate or threshold. Our results provide evidence for the intrinsic involvement of beta oscillations in the perception of time, and point to a specific role for beta oscillations in the encoding and retention of memory for temporal intervals.

A remarkable aspect of conscious perception is that moments carryover from one to the next, also known as temporal continuity. This ability is thus crucial for detecting regularities, such as in speech and music, and may rely on an accurate perception of time. Investigations of human time perception have detailed two electroencephalographic (EEG) components associated with timing, the contingent negative variation (CNV) and late positive component of timing (LPCt); however, the precise roles of these components in timing remain elusive. Recently, we demonstrated that the perception of duration is influenced by durations presented on prior trials, which we explained by the creation of an implicit memory standard that adapts to local changes in sequence presentation. Here, we turn to the neural basis of this effect. Human participants performed a temporal bisection task in which they were required to classify the duration of auditory stimuli into short and long duration categories; crucially, the presentation order was first-order counterbalanced, allowing us to measure the effect of each presented duration on the next. EEG recordings revealed that the CNV and LPCt signals both covaried with the duration presented on the current trial, with CNV predicting reaction time and LPCt predicting choice. Additionally, both signals covaried with the duration presented in the prior trial but in different ways, with the CNV amplitude reflecting the change in the memory standard and the LPCt reflecting decision uncertainty. Furthermore, we observed a repetition enhancement effect of duration only for the CNV, suggesting that this signal additionally indexes the similarity of successive durations. These findings demonstrate dissociable roles for the CNV and LPCt, and demonstrate that both signals are continuously updated on a trial-by-trial basis that reflects shifts in temporal decisions.

Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that, in a majority of studies, the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener et al., 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feedforward mechanism from parietal to prefrontal regions mediates temporal encoding and demonstrate a dissociation between early and late phases of encoding processes.

A number of lines of evidence implicate dopamine in timing [Rammsayer, T. H. Neuropharmacological approaches to human timing. In S. Grondin (Ed.), Psychology of time (pp. 295–320). Bingley, UK: Emerald, 2008; Meck, W. H. Neuropharmacology of timing and time perception. Brain Research, Cognitive Brain Research, 3, 227–242, 1996]. Two human genetic polymorphisms are known to modulate dopaminergic activity. DRD2/ANKK1-Taq1a is a D2 receptor polymorphism associated with decreased D2 density in the striatum [Jönsson, E. G., Nothen, M. M., Grunhage, F., Farde, L., Nakashima, Y., Propping, P., et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry, 4, 290–296, 1999]; COMT Val158Met is a functional polymorphism associated with increased activity of the COMT enzyme such that catabolism of synaptic dopamine is greater in pFC [Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., et al. Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nature Neuroscience, 8, 594–596, 2005]. To investigate the role of dopamine in timing, we genotyped 65 individuals for DRD2/ANKK1-Taq1a, COMT Val158Met, and a third polymorphism, BDNF Val66Met, a functional polymorphism affecting the expression of brain-derived neurotrophic factor [Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269, 2003]. Subjects were tested on a temporal discrimination task with sub- and supra-second intervals (500- and 2000-msec standards) as well as a spontaneous motor tempo task. We found a double dissociation for temporal discrimination: the DRD2/ANKK1-Taq1a polymorphism (A1+ allele) was associated with significantly greater variability for the 500-msec duration only, whereas the COMT Val158Met polymorphism (Val/Val homozygotes) was associated with significantly greater variability for the 2000-msec duration only. No differences were detected for the BDNF Vall66Met variant. Additionally, the DRD2/ANKK1-Taq1a polymorphism was associated with a significantly slower preferred motor tempo. These data provide a potential biological basis for the distinctions between sub- and supra-second timing and suggest that BG are integral for the former whereas pFC is implicated in the latter.

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.

Background Existing follow-up guidelines after treatment for melanoma are based largely on dated literature and historical precedent. This study aimed to calculate recurrence rates and establish prognostic factors for recurrence to help redesign a follow-up schedule. Methods Data were retrieved from the Sydney Melanoma Unit database for all patients with a single primary melanoma and American Joint Committee on Cancer (AJCC) stage I–II disease, who had received their first treatment between 1959 and 2002. Recurrence rates, timing and survival were recorded by substage, and predictive factors were analysed. Results Recurrence occurred in 18·9 per cent (895 of 4748) of patients overall, 5·2 per cent (95 of 1822) of those with stage IA disease, 18·4 per cent (264 of 1436) with IB, 28·7 per cent (215 of 750) with IIA, 40·6 per cent (213 of 524) with IIB and 44·3 per cent (86 of 194) with IIC disease. Overall, the median disease-free survival time was 2·6 years, but there were marked differences between AJCC subgroups. Primary tumour thickness, ulceration and tumour mitotic rate were important predictors of recurrence. Conclusion A new follow-up schedule was proposed: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB–IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.

Objective: Information on prognosis for patients with cutaneous melanoma after locoregional or distant recurrence is sparse and controversial. The aim of this study was to analyze factors influencing outcome after the development of a first relapse.Methods: Information was extracted from the Sydney Melanoma Unit database for 873 melanoma patients with American Joint Committee on Cancer (AJCC) Stage I and II disease treated between 1960 and 2002 who relapsed following treatment of their primary melanoma. Clinical and pathologic factors predicting survival were analyzed using the Cox proportional hazards regression model.Results: Initial presentation of recurrence was local: 95 patients (10.9%), in transit: 86 patients (9.9%), regional lymph node: 300 patients (34.4%), and distant: 392 patients (44.9%). Independent prognostic factors for survival of the 481 patients with only locoregional recurrence were type of recurrence, primary tumor ulceration, and patient age. Predictors for longer survival in the 392 patients with distant metastasis at the time of first presentation with recurrence were lung vs other sites and diagnosis of relapse after 1990 compared with diagnosis before 1980.Conclusions: The type of recurrence is the most important prognostic factor in melanoma patients who relapse. Primary tumor ulceration is the most important pathologic predictor. The results of this study suggest that management of distant metastases may have improved over the last 25 years, but many confounders and improved staging techniques make assessment of this unreliable.

Summary Background Recommended selective neck dissections for primary cutaneous tumours on the head and neck are based largely on clinical recurrence data acquired prior to the era of lymphatic mapping and sentinel lymph node (SLN) biopsy. This study aimed to examine lymphatic drainage patterns from the forehead in order to provide evidence upon which to base recommendations regarding the extent of neck dissection. Methods Data were collected prospectively from all patients undergoing lymphoscintigraphy following diagnosis of a primary cutaneous tumour on the forehead. The site of injection of radioisotope was documented using a co-ordinate-based mapping system. The forehead was divided into glabellar, supra-orbital and anterior temple zones. The location of all SLNs was recorded and drainage patterns were analysed. Results Between 1994 and 2006, 152 patients underwent lymphoscintigraphy for primary cutaneous tumours on the forehead. Drainage was to 3.0 SLNs in 2.1 lymph node fields (mean values). Drainage was to ipsilateral SLNs in 85% of cases. Between zones there were significant differences in drainage patterns and the frequency of bilateral drainage. From the glabellar zone, drainage was more frequently to a higher number of SLNs and SLN fields, and to level I nodes. Conclusions The forehead can be divided into zones with patterns of lymphatic drainage that vary significantly in terms of number of SLNs, number of SLN sites, likelihood of drainage to contralateral SLNs and predictability of drainage pattern. Drainage to level 1 nodes from the anterior temple is rare, suggesting that it may be safe to exclude this level when performing a selective neck dissection for tumours in this zone.

Individual participants vary greatly in their ability to estimate and discriminate intervals of time. This heterogeneity of performance may be caused by reliance on different time perception networks as well as individual differences in the activation of brain structures utilized for timing within those networks. To address these possibilities we utilized event-related functional magnetic resonance imaging (fMRI) while human participants (n = 25) performed a temporal or color discrimination task. Additionally, based on our previous research, we genotyped participants for DRD2/ANKK1-Taq1a, a single-nucleotide polymorphism associated with a 30–40% reduction in striatal D2 density and associated with poorer timing performance. Similar to previous reports, a wide range of performance was found across our sample; crucially, better performance on the timing versus color task was associated with greater activation in prefrontal and sub-cortical regions previously associated with timing. Furthermore, better timing performance also correlated with increased volume of the right lateral cerebellum, as demonstrated by voxel-based morphometry. Our analysis also revealed that A1 carriers of the Taq1a polymorphism exhibited relatively worse performance on temporal, but not color discrimination, but greater activation in the striatum and right dorsolateral prefrontal cortex, as well as reduced volume in the cerebellar cluster. These results point to the neural bases for heterogeneous timing performance in humans, and suggest that differences in performance on a temporal discrimination task are, in part, attributable to the DRD2/ANKK1 genotype.

We tested human participants on a modified peak procedure in order to investigate the relation between interval timing and reward processing, and examine the interaction of this relation with three different dopamine-related gene polymorphisms. These gene polymorphisms affected the expression of catechol-o-methyltransferase, which catabolizes synaptic dopamine primarily in the prefrontal cortex (COMT Val158Met polymorphism), D2 dopamine receptors primarily in the striatum (DRD2/ANKK1-Taq1a polymorphism), and dopamine transporters, which clear synaptic dopamine in the striatum (DAT 3' VNTR variant). The inclusion of these polymorphisms allowed us to investigate dissociable aspects of the dopamine system and their interaction with reward magnitude manipulations in shaping timed behavior. These genes were chosen for their roles in reward processing and cortico-striatal information processing that have been implicated for interval timing. Consistent with recent animal studies, human participants initiated their timed anticipatory responding earlier when expecting a larger reward in the absence of any changes in the timing of response termination or perceived time. This effect however was specific to two out of four evaluated COMT and DRD2 polymorphism combinations that lead to high prefrontal dopamine coupled with high D2 density and low prefrontal dopamine coupled with low D2 density. Larger rewards also decreased timing precision indices, some of which interacted with the COMT polymorphism. Furthermore, the COMT polymorphism that leads to higher prefrontal dopamine resulted in weaker manifestation of memory variability (relative to threshold variability) in timed behavior. There was no effect of DAT polymorphisms on any of the core behavioral measures. These results suggest that the reward modulates decision thresholds rather than clock speed, and that these effects are specific to COMT and DRD2 epistasis effects that presumably constitute a balanced prefrontal and striatal dopamine transmission.

The cerebellum has long been implicated in time perception, particularly in the subsecond range. The current set of studies examines the role of the cerebellum in suprasecond timing, using analysis of behavioral data in subjects with cerebellar lesions. Eleven cerebellar lesion subjects and 17 controls were tested on temporal estimation, reproduction and production, for times ranging from 2 to 12 s. Cerebellar patients overproduced times on both the reproduction and production tasks; the effect was greatest at the shortest duration. A subset of patients also underestimated intervals. Cerebellar patients were significantly more variable on the estimation and reproduction tasks. No significant differences between normal and cerebellar patients were found on temporal discrimination tasks with either sub- or suprasecond times. Patients with damage to the lateral superior hemispheres or the dentate nuclei showed more significant impairments than those with damage elsewhere in the cerebellum, and patients with damage to the left cerebellum had more significant differences from controls than those with damage to the right. These data suggest that damage to the middle-to-superior lobules or the left hemisphere is especially detrimental to timing suprasecond intervals. We suggest that this region be considered part of a network of brain structures including the DLPFC that is crucial for interval timing.

Completion lymph node dissection (CLND) following positive sentinel node biopsy (SNB) for melanoma detects additional nonsentinel node (NSN) metastases in approximately 20% of cases. This study aimed to establish whether NSN status can be predicted, to determine its effect on survival, and to develop survival tree models for the sentinel node (SN) positive population. Sydney Melanoma Unit (SMU) patients with at least 1 positive SN, meeting inclusion criteria and treated between October 1992 and June 2005, were identified from the Unit database. Survival characteristics, potential predictors of survival, and NSN status were assessed using the Kaplan–Meier method, Cox regression model, and logistic regression analyses, respectively. Classification tree analysis was performed to identify groups with distinctly different survival characteristics. A total of 323 SN-positive melanoma patients met the inclusion criteria. On multivariate analysis, age, gender, primary tumor thickness, mitotic rate, number of positive NSNs, or total number of positive nodes were statistically significant predictors of survival. NSN metastasis, found at CLND in 19% of patients, was only predicted to a statistically significant degree by ulceration. Multivariate analyses demonstrated that survival was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis revealed 4 prognostically distinct survival groups. Patients with NSN metastases could not be reliably identified prior to CLND. Prognosis following CLND was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis defined distinctly different survival groups more accurately than use of single-factor analysis.

Several lines of evidence have implicated the subthalamic nucleus (STN) in behaviors that require precise temporal control. In order to investigate this possibility further, we trained rats to perform a peak-interval (PI) timing task [S. Roberts, Isolation of an internal clock, J. Exp. Psychol. Anim. B 7 (1981) 242-268] with two durations (10 s and 40 s), and then lesioned the STN by microinjection of ibotenic acid. Lesioned animals were able to maintain precise temporal control, yet were unable to inhibit operant responses late in the trial, at times that were unlikely to yield reinforcement. These results indicate the involvement of the STN in impulsive or perseverative response inhibition, but not in temporal processing.

We report data from 31 subjects with focal hemisphere lesions (15 left hemisphere) as well as 16 normal controls on a battery of tasks assessing the estimation, production and reproduction of time intervals ranging from 2–12 seconds. Both visual and auditory stimuli were employed for the estimation and production tasks. First, ANOVAs were performed to assess the effect of stimulus modality on estimation and production tasks; a significant effect of stimulus modality was observed for the production but not the estimation task. Second, accuracy was significantly different for the 2 second interval as compared to longer intervals. Subsequent analyses of the data from 4–12 second stimuli demonstrated that patients with brain lesions were more variable than controls on the estimation and reproduction tasks. Additionally, patients with brain lesions but not controls exhibited significant differences in performance on the different tasks; patients with brain lesions under-produced but over-estimated time intervals of 4–12 seconds but performed relatively well on the reproduction task, a pattern of performance consistent with a “fast clock”. There was a significant correlation between impaired performance and lesions of the parietal lobe but there was no effect of laterality of lesion or correlation between lateral frontal lobe lesions and impairment on any task.

Methamphetamine (MAP), an indirect dopamine agonist, has been shown to produce a leftward shift in the time of responding under operant response protocols that encourage repetitive responding (e.g., lever pressing). Given the involvement of striatal dopamine activity in the control of discrete motor behavior, as well as in the timing of these responses, an important question arises as to whether a dissociation is possible between changes in the timing of discrete responding and timing of other behaviors. Rats were trained on a modified peak-interval (PI) procedure such that reward was contingent upon the presence of the animal's snout in a nosepoke apparatus at the target time, as an alternative to the typical requirement of a discrete head entry response. Thus spatial selection, but not necessarily motor behavior, at the appropriate time was required to receive a reward. Rats were given MAP in one of 3 doses (0.5, 1.0, or 1.5 mg/kg), or a saline control injection before PI sessions to determine whether the drug elicits a dose-dependent effect on timing of spatial position, as it has been shown to do for discrete behaviors. Following administration of MAP, the peak time of the proportion of time spent in the nosepoke did not change, while the peak time of the rate of response shifted to the left. Single-trial analysis revealed a similar pattern: Position of response step functions defined by being in the nosepoke did not shift, but step functions based on response rate changed with increasing doses of MAP. These data support a model of multiple timing processes controlling different behaviors, at least one of which is specific to discrete motor behavior and is modifiable by dopamine.

Complex cognitive tasks such as visual working memory (WM) involve networks of interacting brain regions. Several neurotransmitters, including an appropriate dopamine concentration, are important for WM performance. A number of gene polymorphisms are associated with individual differences in cognitive task performance. COMT, for example, encodes catechol-o-methyl transferase the enzyme primarily responsible for catabolizing dopamine in the prefrontal cortex. Striatal dopamine function, linked with cognitive tasks as well as habit learning, is influenced by the Taq-Ia polymorphism of the DRD2/ANKK1 gene complex; this gene influences the density of dopamine receptors in the striatum. Here, we investigated the effects of these polymorphisms on a WM task requiring the maintenance of 4 or 6 items over delay durations of 1 or 5 seconds. We explored main effects and interactions between the COMT and DRD2/ANKK1-Taq-Ia polymorphisms on WM performance. Participants were genotyped for COMT (Val(158)Met) and DRD2/ANKK1-Taq-Ia (A1+, A1-) polymorphisms. There was a significant main effect of both polymorphisms. Participants' WM reaction times slowed with increased Val loading such that the Val/Val homozygotes made the slowest responses and the Met/Met homozygotes were the fastest. Similarly, WM reaction times were slower and more variable for the DRD2/ANKK1-Taq-Ia A1+ group than the A1- group. The main effect of COMT was only apparent in the DRD2/ANKK1-Taq-Ia A1- group. These findings link WM performance with slower dopaminergic metabolism in the prefrontal cortex as well as a greater density of dopamine receptors in the striatum.

BackgroundThe neural basis of timing remains poorly understood. Although controversy persists, many lines of evidence, including studies in animals, functional imaging studies in humans and lesion studies in humans and animals suggest that the basal ganglia are important for temporal processing [1].Methodology/principal findingsWe report data from a wide range of timing tasks from two subjects with disabling neurologic deficits caused by bilateral lesions of the basal ganglia. Both subjects perform well on tasks assessing time estimation, reproduction and production tasks. Additionally, one subject performed normally on psychophysical tasks requiring the comparison of time intervals ranging from milliseconds to seconds; the second subject performed abnormally on the psychophysical task with a 300ms standard but did well with 600ms, 2000ms and 8000ms standards. Both subjects performed poorly on an isochronous rhythm production task on which they are required to maintain rhythmic tapping.Conclusions/significanceAs studies of subjects with brain lesions permit strong inferences regarding the necessity of brain structures, these data demonstrate that the basal ganglia are not crucial for many sub- or supra-second timing operations in humans but are needed for the timing procedures that underlie the production of movements. This dissociation suggests that distinct and dissociable processes may be employed to measure time intervals. Inconsistencies in findings regarding the neural basis of timing may reflect the availability of multiple temporal processing routines that are flexibly implemented in response to task demands.