Variability in interval production is due to timing-dependent deficits in Huntington's disease.

In Huntington's disease (HD), increased variability is seen in performance of motor tasks that require implicit control of timing. We examined whether timing variability was also evident in an explicit interval-timing task. Sixty subjects (21 controls, 19 manifest HD, and 20 pre-manifest HD) performed a single-interval production task with three target intervals (1.1 s, 2.2 s, 3.3 s). We analyzed accuracy (proportional error) and precision (standard deviation) across groups and intervals. No differences were seen in accuracy across groups or intervals. Precision was significantly lower in manifest (P = 0.0001) and pre-manifest HD (P = 0.04) compared with controls. This was particularly true for pre-manifest subjects close to diagnosis (based on probability of diagnosis in 5 years). Precision was correlated with proximity to diagnosis (r2 = 0.3, P < 0.01). To examine the source of reduced precision, we conducted linear regression of standard deviation with interval duration. Slope of the regression was significantly higher in manifest HD (P = 0.02) and in pre-manifest HD close to diagnosis (P = 0.04) compared with controls and pre-manifest participants far from diagnosis. Timing precision is impaired before clinical diagnosis in Huntington's disease. Slope analysis suggests that timing variability (decreased precision) was attributable to deficits in timing-dependent processes. Our results provide additional support for the proposal that the basal ganglia are implicated in central timekeeping functions. Because the single interval production task was sensitive to deficits in pre-manifest HD, temporal precision may be a useful outcome measure in future clinical trials.

The influence of cognitive reserve on strategy selection in normal aging.

Cognitive reserve (CR) has been proposed as a latent variable that can account for the frequent discrepancy between an individual's underlying level of brain pathology and their observed clinical outcome. A possible behavioral manifestation of CR is best strategy choice. Older adults have been shown to choose sub-optimal strategies for performing various tasks. The present study attempted to investigate whether greater levels of CR could predict greater strategy selection, particularly in older adults. A computational estimation task was administered to 20 healthy young adults (mean age = 24.7 ± 3.6; 20-31 years) and 18 healthy older adults (68.2 ± 4.5; 62-77 years) wherein participants needed to estimate the product of two two-digit numbers by using one of two strategies. The results revealed an effect of age group on strategy choice and supported the hypothesis that CR is associated with increased strategy selection abilities.

Dual-tasking alleviated sleep deprivation disruption in visuomotor tracking: an fMRI study.

Effects of dual-responding on tracking performance after 49-h of sleep deprivation (SD) were evaluated behaviorally and with functional magnetic resonance imaging (fMRI). Continuous visuomotor tracking was performed simultaneously with an intermittent color-matching visual detection task in which a pair of color-matched stimuli constituted a target and non-matches were non-targets. Tracking error means were binned time-locked to stimulus onset of the detection task in order to observe changes associated with dual-responding by comparing the error during targets and non-targets. Similar comparison was made with fMRI data. Our result showed that despite a significant increase in the overall tracking error post SD, from 20 pixels pre SD to 45 pixels post SD, error decreased to a minimum of about 25 pixels 0-6s after dual-response. Despite an overall reduced activation post SD, greater activation difference between targets and non-targets was found post SD in task-related regions, such as the left cerebellum, the left somatosensory cortex, the left extrastriate cortex, bilateral precuneus, the left middle frontal gyrus, and the left motor cortex. Our results suggest that dual-response helps to alleviate performance impairment usually associated with SD. The duration of the alleviation effect was on the order of seconds after dual-responding.

Oxycodone lengthens reproductions of suprasecond time intervals in human research volunteers.

Oxycodone, a popularly used opioid for treating pain, is widely abused. Other drugs of abuse have been shown to affect time perception, which, in turn, may affect sensitivity to future consequences. This may contribute to continued use. This study evaluated the effect of oxycodone on time perception in normal healthy volunteers. For this within-subject, double-blind design study, participants performed a temporal reproduction task before and after receiving placebo or oxycodone (15 mg, orally) over six outpatient sessions. Participants were first trained with feedback to reproduce three standard intervals (1.1, 2.2, and 3.3 s) in separate blocks by matching response latency from a start signal to the duration of that block's standard interval. During testing, participants were instructed to reproduce the three intervals from memory without feedback before and after drug administration. Oxycodone significantly lengthened time estimations for the two longer intervals relative to placebo. These results suggest that opioids alter temporal processing for intervals greater than 1 s, raising questions about the effect of these drugs on the valuation of future consequences.

The variable response-stimulus interval effect and sleep deprivation: an unexplored aspect of psychomotor vigilance task performance.

STUDY OBJECTIVES: The Psychomotor Vigilance Task (PVT) contains variable response-stimulus intervals (RSI). Our goal is to investigate the effect of RSI on performance to determine whether sleep deprivation affects the ability to attend to events across seconds and whether this effect is independent of impairment in sustaining attention across minutes, as measured by time on task. DESIGN: A control group following their normal sleep routines and 3 groups exposed to 54 hours of total sleep deprivation performed a 10-minute PVT every 6 hours for 9 total test runs. SETTING: Sleep deprivation occurred in a sleep laboratory with continuous behavioral monitoring; the control group took the PVT at home. SUBJECTS: Eighty-four healthy sleepers (68 sleep deprivation, 16 controls; 22 women; aged 18-35 years). MEASUREMENTS AND RESULTS: Across groups, as the RSI increased from 2 to 10 seconds, mean RT was reduced by 69 milliseconds (main effect of RSI, P < 0.001). There was no interaction between the sleep deprivation and RSI effects. As expected, there was a significant interaction of sleep deprivation and time on task for mean RT (P = 0.002). Time on task and RSI effects were independent. Parallel analyses of percentage of lapses and percentage of false starts produced similar results. CONCLUSIONS: We demonstrate that the cognitive mechanism of attention responsible for response preparation across seconds is distinct from that for maintaining attention to task performance across minutes. Of these, only vigilance across minutes is degraded by sleep deprivation. Theories of sleep deprivation should consider how this pattern of spared and impaired aspects of attention may affect real-world performance.

A common neural network for cognitive reserve in verbal and object working memory in young but not old.

Epidemiologic evidence suggests that cognitive reserve (CR) mitigates the effects of aging on cognitive function. The goal of this study was to see whether a common neural mechanism for CR could be demonstrated in brain imaging data acquired during the performance of 2 tasks with differing cognitive processing demands. Young and elder subjects were scanned with functional magnetic resonance imaging (fMRI) while performing a delayed item response task that used either letters (40 young, 18 old) or shapes (24 young, 21 old). Difficulty or load was manipulated by varying the number of stimuli that were presented for encoding. Load-dependent fMRI signal corresponding to each trial component (stimulus presentation, retention delay, and probe) and task (letter or shape) was regressed onto 2 putative CR variables. Canonical variates analysis was applied to the resulting maps of regression coefficients, separately for each trial component, to summarize the imaging data--CR relationships. There was a latent brain pattern noted in the stimulus presentation phase that manifested similar relationships between load-related encoding activation and CR variables across the letter and shape tasks in the young but not the elder age group. This spatial pattern could represent a general neural instantiation of CR that is affected by the aging process.

Effects of feedback on time production errors in aging participants.

In two experiments, healthy participants ages 60 years and older provided peak-interval time production data for two target intervals (6 and 17s) over 2 days (baseline and retest sessions). In Experiment 1, three groups of participants were provided with two types of feedback during the baseline session that assisted either decision criteria setting or memory updating. During the retest session, run after a 24-h delay, each group received either one of the two types of feedback, or no feedback at all. Experiment 2 varied three additional groups' feedback during the baseline session only. Results indicated that the duration-dependent timing errors previously associated with aging did not occur during the retest session with the decision-criteria feedback regimen, or during the baseline session even in the complete absence of feedback. Thus, testing following the delay and without decision-criteria feedback are the necessary and sufficient conditions for the expression the timing errors in aging. The efficacy of memory updating feedback could not be established. The discussion contrasts these results with the conditions that produce abnormal timing in Parkinson's disease patients in a similar procedure.

The response-signal method reveals age-related changes in object working memory.

Sixteen healthy young adults (ages 18-32) and 16 healthy older adults (ages 67-81) completed a delayed response task in which they saw the following visual sequence: memory stimuli (2 abstract shapes; 3,000 ms), a blank delay (5,000 ms), a probe stimulus of variable duration (one abstract shape; 125, 250, 500, 1,000, or 2,000 ms), and a mask (500 ms). Subjects decided whether the probe stimulus matched either of the memory stimuli; they were instructed to respond during the mask, placing greater emphasis on speed than accuracy. The authors used D. L. Hintzman & T. Curran's (1994) 3-parameter compound bounded exponential model of speed-accuracy tradeoff to describe changes in discriminability associated with total processing time. Group-level analysis revealed a higher rate parameter and a higher asymptote parameter for the young adult group, but no difference across groups in x-intercept. Proxy measures of cognitive reserve (Y. Stern et al., 2005) predicted the rate parameter value, particularly in older adults. Results suggest that in working memory, aging impairs both the maximum capacity for discriminability and the rate of information accumulation, but not the temporal threshold for discriminability.

A firing rate model of Parkinsonian deficits in interval timing.

To account for deficits in interval timing observed in Parkinson's Disease (PD) patients, we develop a model based on the accumulating firing rate of a neural population with recurrent excitation. This model naturally produces the curvilinear accumulation of neural activity introduced to timing psychophysics by Miall (Models of Neural Timing, Elsevier Science, 1996), and implicated in Parkinsonian timing by Malapani and Rakitin (Functional and Neural Mechanisms of Interval Timing, CRC Press, 2003). The parameters essential for our model are the strength of the net neural feedback and the mean rate of inputs to the population from external brain areas. Systematic variations in these parameters reproduce the PD migration effect, in which estimates of long and short intervals drift towards each other, as well as uniform slowing of time estimates observed under other experimental conditions. For example, our model suggests that dopamine depletion in PD patients increases the neural feedback parameter and decreases the effective input parameter for populations involved in the production of time estimates. The model also explains why the migration effect will be associated with a violation of the scalar property, the linear increase in the standard deviation of time estimates with the duration of the target interval that is ubiquitous in healthy participants. We also show that the effect of systematically decreasing the input rate parameter in our model is equivalent to increasing thresholds, so that either of these changes may be associated with the Parkinsonian state.

Response-Conflict Moderates the Cognitive Control of Episodic and Contextual Load in Older Adults.

OBJECTIVES: Decline in cognitive control is one of the primary cognitive changes in normal aging. Reaching a consensus regarding the nature of these age-related changes, however, is complicated by the complexity of cognitive control as a construct. METHODS: Healthy older and younger adults participated in a multifactorial test of cognitive control. Within participants, the procedure varied as a function of the amount contextual load, episodic load, and response-conflict load present. RESULTS: We found that older adults showed impaired performance relative to younger adults. We also found, however, that the response selection process underlying the response-conflict manipulation was a major moderator of age-related differences in both the contextual and episodic load conditions-suggesting a hierarchical organization. DISCUSSION: These findings are consistent with previous findings, suggesting that deficits in cognitive control in older adults are directly related to the resolution of response-conflict and that other apparent deficits may be derivative upon the more basic response-conflict related deficit.

An event-related fMRI study of the neural networks underlying the encoding, maintenance, and retrieval phase in a delayed-match-to-sample task.

Memory loads exceeding the limited capacity of working memory (WM) have been shown to expand the prefrontal areas that participate in WM and have revealed substantial individual differences in performance. We used a delayed-match-to-sample (DMS) task in an event-related fMRI study to map the full extent of the expanded regional activations associated with supracapacity loads. A 6-letter study array was compared to arrays of 1 and 3 letters. The task comprised separate encoding, retention, and retrieval fMRI epochs. A brain-wide spatial covariance analysis was applied to the data of all task epochs to identify patterns of correlated regional activations whose expression increased monotonically across 3 memory-load levels on a subject-by-subject basis. Such load-related activation patterns were in all task phases. Of greatest interest is the activation pattern that was obtained during the maintenance phase: increasing activation with memory load was found not only in the lateral PFC (BA 9,44) but also in the parietal lobe (BA 7,40), anterior cingulate (BA 32), and cerebellum. Decreasing activation was found in the occipito-temporal lobe (BA 19,39) as well as the medial prefrontal cortex (BA 9,10). Subject increases in pattern expression from 1 to 6 items were positively correlated with the corresponding reaction time increases (p<0.05) and negatively correlated with NARTIQ (p<0.05), indicating that people who were faster in their responses and had higher NARTIQ had to increase their subject expression of the memory-load-related activation pattern less and were more efficient at the cognitive task. Our method thus not only reproduced findings of other WM studies but also addressed the issue of interactions between lateral PFC and other parts of the brain during the task, for the retention of the to-be-remembered information. The load-related activation patterns from encoding and retrieval phase and their relationship to behavior are also discussed.

Predicting age-related dual-task effects with individual differences on neuropsychological tests.

This study examined the relation of dual-task performance to individual differences on neuropsychological tests. Neuropsychological test scores from 16 young and 16 older participants were simultaneously submitted to a factor analysis that yielded 2 factors (Attention/Executive and Memory) that differed by age and 2 (Motor Speed and Cognitive Status) that did not. Regression analyses revealed that these factors were significant predictors of performance on a delayed visual recognition task, but the relationship varied as a function of task condition. The Memory and Motor Speed factors were the strongest predictors of single-task performance, but the Attention/Executive factor was the most important predictor of dual-task performance. The authors conclude that compromised central executive may underlie age-related decline in dual-task performance.

The effects of spatial stimulus-response compatibility on choice time production accuracy and variability.

Five experiments examined the relations between timing and attention using a choice time production task in which the latency of a spatial choice response is matched to a target interval (3 or 5 s). Experiments 1 and 2 indicated that spatial stimulus-response incompatibility increased nonscalar timing variability without affecting timing accuracy and that choice reaction time practice reduced choice time production variability. These data support a "temporal discounting" model in which response choice and timing occur in series, but the interval timed is shortened to account for nontemporal processing. In Experiment 3, feedback and anticipation task demands improved choice time production accuracy. In Experiments 4 and 5, the delay between the start-timing and choice-decision signals interacted with choice difficulty to affect choice time production accuracy and variability when timing a 3- but not a 5-s interval, suggesting that attention mediates timing before and after an interruption in timing.

An event-related fMRI study of the neurobehavioral impact of sleep deprivation on performance of a delayed-match-to-sample task.

Eighteen subjects (ages 18-35) underwent event-related functional magnetic resonance imaging (efMRI) while performing a delayed-match-to-sample (DMS) task before and immediately after 48 h of sustained wakefulness. The DMS trial events were: a 3-s study period of either a one-, three-, or six-letter visual array; a 7-s retention interval; and a 3-s probe period, where a button press indicated whether the probe letter was in the study array. Ordinal Trend Canonical Variates Analysis (OrT CVA) was applied to the data from the probe period for trials with six-letter study lists prior to and immediately following sleep deprivation to find an activation pattern whose expression decreased with sleep deprivation in as many subjects as possible, while being present in both conditions. The first principal component of the OrT analysis identified a covariance pattern whose expression decreased as a function of sleep deprivation in 17 of 18 subjects (p<0.001). While overall expression of the pattern showed a systematic decrease with sleep deprivation, the brain regions that make up the pattern show covarying increases and decreases in activation. Regions that decreased their activation were noted in the parietal (BA 7 and 40), temporal (BA 37, 38 and 39) and occipital (BA 18 and 19) lobes; regions that increased their activation were noted in the cerebellum, basal ganglia, thalamus and the anterior cingulate gyrus (BA 32). The reduction in pattern expression with sleep deprivation for each subject was related to the change in performance on the DMS task. Subject decreases in pattern expression were correlated with reductions in recognition accuracy (p<0.05), increased intra-individual variability in reaction time (p<0.005) and increased lapsing (p<0.005).

Age differences of multivariate network expressions during task-switching and their associations with behavior.

The effect of aging on functional network activation associated with task-switching was examined in 24 young (age=25.2±2.73 years) and 23 older adults (age=65.2±2.65 years) using functional magnetic resonance imaging (fMRI). The study goals were to (1) identify a network shared by both young and older adults, (2) identify additional networks in each age group, and (3) examine the relationship between the networks identified and behavioral performance in task-switching. Ordinal trend covariance analysis was used to identify the networks, which takes advantage of increasing activation with greater task demand to isolate the network of regions recruited by task-switching. Two task-related networks were found: a shared network that was strongly expressed by both young and older adults and a second network identified in the young data that was residualized from the shared network. Both networks consisted of regions associated with task-switching in previous studies including the middle frontal gyrus, the precentral gyrus, the anterior cingulate, and the superior parietal lobule. Not only was pattern expression of the shared network associated with reaction time in both age groups, the difference in the pattern expression across task conditions (task-switch minus single-task) was also correlated with the difference in RT across task conditions. On the contrary, expression of the young-residual network showed a large age effect such that older adults do not increase expression of the network with greater task demand as young adults do and correlation between expression and accuracy was significant only for young adults. Thus, while a network related to RT is preserved in older adults, a different network related to accuracy is disrupted.

The effects of stimulus degradation after 48 hours of total sleep deprivation.

STUDY OBJECTIVES: To test the hypothesis that total sleep deprivation (TSD) slows stimulus detection and evaluation processes. Towards that end we manipulate degradation of the imperative stimulus, a manipulation well established to affect the processes of interest, in a delayed letter recognition (DLR) task and the psychomotor vigilance task (PVT), and predicted that after TSD the ordinary reaction time (RT) slowing effect of stimulus degradation would be increased. These hypotheses were only partially confirmed (see below). DESIGN: Participants were exposed to 48 h of total sleep loss. The PVT and DLR were administered to the same participants. The PVT was administered 8 times -every 6 h from 12:00 on Day 1. The DLR was administered twice, at 09:00 of Day 1 and 48 h later. SETTING: Participants were continuously monitored in a sleep laboratory. SUBJECTS: 26 healthy young adults enrolled. Due to dropouts and technical failures, the final n's were 20 for the DLR and 21 for the PVT. MEASUREMENTS AND RESULTS: General linear mixed models were employed. In the DLR task there was no interaction between TSD and degradation on any variable. There was, however, a significant interaction between TSD and degradation on mean reaction time in the PVT (P = 0.01). CONCLUSIONS: As in our previous reports, we observe the specificity with which total sleep deprivation affects cognitive processes. One aspect of visual processing, stimulus detection, was affected by total sleep deprivation and made a significant contribution to the performance impairments observed. Another aspect of visual processing, stimulus evaluation, remained unaffected after 2 days and nights of total sleep loss.

Task difficulty modulates young-old differences in network expression.

The extent of task-related fMRI activation can vary as a function of task difficulty. Also the efficiency or capacity of the brain networks underlying task performance can change with aging. We asked whether the expression of a network underlying task performance would differ as a function of task demand in old and young individuals. 26 younger and 23 older healthy adults performed a delayed item recognition task that used the response signal method to parametrically manipulate the extrinsic difficulty of the task by imposing five different deadlines for recognition response. Both age groups showed a speed-accuracy trade-off, but the younger group achieved greater discriminability at the longer deadlines. We identified a spatial pattern of fMRI activation during the probe phase whose expression increased as the response deadline shortened and the task became more difficult. This pattern was expressed to a greater degree by the old group at the long deadlines, when the task was easiest. By contrast, this pattern was expressed to a greater degree by the younger group at the short deadlines, when the task was hardest. This suggests reduced efficiency and capacity of this network in older subjects. These findings suggest that neuroimaging studies comparing task-related activation across groups with different cognitive abilities must be interpreted in light of the relative difficulty of the task for each group.

Supporting performance in the face of age-related neural changes: testing mechanistic roles of cognitive reserve.

Age impacts multiple neural measures and these changes do not always directly translate into alterations in clinical and cognitive measures. This partial protection from the deleterious effects of age in some individuals is referred to as cognitive reserve (CR) and although linked to variations in intelligence and life experiences, its mechanism is still unclear. Within the framework of a theoretical model we tested two potential mechanistic roles of CR to maintain task performance, neural reserve and neural compensation, in young and older adults using functional and structural MRI. Neural reserve refers to increased efficiency and/or capacity of existing functional neural resources. Neural compensation refers to the increased ability to recruit new, additional functional resources. Using structural and functional measures and task performance, the roles of CR were tested using path analysis. Results supported both mechanistic theories of CR and the use of our general theoretical model.

The prefrontal model revisited: double dissociations between young sleep deprived and elderly subjects on cognitive components of performance.

STUDY OBJECTIVES: The prefrontal model suggests that total sleep deprivation (TSD) and healthy aging produce parallel cognitive deficits. Here we decompose global performance on two common tasks into component measures of specific cognitive processes to pinpoint the source of impairments in elderly and young TSD participants relative to young controls and to each other. SETTING: The delayed letter recognition task (DLR) was performed in 3 studies. The psychomotor vigilance task (PVT) was performed in 1 of the DLR studies and 2 additional studies. SUBJECTS: For DLR, young TSD (n=20, age=24.60 ± 0.62 years) and young control (n=17, age=24.00 ± 2.42); elderly (n=26, age=69.92 ± 1.06). For the PVT, young TSD (n=18, age=26.65 ± 4.57) and young control (n=16, age=25.19 ± 2.90); elderly (n=21, age=71.1 ± 4.92). MEASUREMENTS AND RESULTS: Both elderly and young TSD subjects displayed impaired reaction time (RT), our measure of global performance, on both tasks relative to young controls. After decomposing global performance on the DLR, however, a double dissociation was observed as working memory scanning speed was impaired only in elderly subjects while other components of performance were impaired only by TSD. Similarly, for the PVT a second double dissociation was observed as vigilance impairments were present only in TSD while short-term response preparation effects were altered only in the elderly. CONCLUSIONS: The similarity between TSD and the elderly in impaired performance was evident only when examining global RT. In contrast, when specific cognitive components were examined double dissociations were observed between TSD and elderly subjects. This demonstrates the heterogeneity in those cognitive processes impaired in TSD versus the elderly.

fMRI activation during failures to respond key to understanding performance changes with sleep deprivation.

STUDY OBJECTIVES: During sleep deprivation (SD), failures to respond (FR) increase across a variety of tasks. This is the first systematic investigation of neural correlates of FR during SD. We use multivariate analysis to model neural activation separately for FR and responses (R) at each trial phase. SETTING: In two experiments a delayed letter recognition task was performed in a 1.5T scanner at 9:30 am after two nights of total SD. Participants were continuously monitored in the laboratory. PARTICIPANTS: Healthy young adults from two SD experiments (combined n=37; aged 25.55 ± 3.86 years). MATERIALS AND METHODS: Multivariate linear modeling (MLM) was used to find networks of activation that differed between FR and R. At each of three trial phases-encoding, retention, and test-two networks were expressed. In the encoding phase, the second network was seen during FR and was not seen during R. This network constituted widespread deactivations (∼26,000 voxels) of fronto-parietal and thalamic areas concomitant with activation of extrastriate cortex and hippocampus. In a multiple regression including activation during FR and R from all networks and all trial phases, expression of this encoding-phase network during FR was the key predictor of SD-related performance impairment, operationalized as greater %FR (η(p)(2)=0.33), lower d' and larger median RT (η(p)(2)=0.17). CONCLUSIONS: FR were most associated with neural disruptions occurring at the encoding phase when subjects must attend to and encode items. Further, expression of this FR-related encoding-phase network made the largest independent contribution to predicting vulnerability to overall SD-related impairment.