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.

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.

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.

Can the default-mode network be described with one spatial-covariance network?

The default-mode network (DMN) has become a well accepted concept in cognitive and clinical neuroscience over the last decade, and perusal of the recent literature attests to a stimulating research field of cognitive and diagnostic applications (for example, (Andrews-Hanna et al., 2010; Koch et al., 2010; Sheline et al., 2009a; Sheline et al., 2009b; Uddin et al., 2008; Uddin et al., 2009; Weng et al., 2009; Yan et al., 2009)). However, a formal definition of what exactly constitutes a functional brain network is difficult to come by. In recent contributions, some researchers argue that the DMN is best understood as multiple interacting subsystems (Buckner et al., 2008) and have explored modular components of the DMN that have different functional specialization and could to some extent be identified separately (Fox et al., 2005; Uddin et al., 2009). Such conception of modularity seems to imply an opposite construct of a 'unified whole', but it is difficult to locate proponents of the idea of a DMN who are supplying constraints that can be brought to bear on data in rigorous tests. Our aim in this paper is to present a principled way of deriving a single covariance pattern as the neural substrate of the DMN, test to what extent its behavior tracks the coupling strength between critical seed regions, and investigate to what extent our stricter concept of a network is consistent with the already established findings about the DMN in the literature. We show that our approach leads to a functional covariance pattern whose pattern scores are a good proxy for the integrity of the connections between a medioprefrontal, posterior cingulate and parietal seed regions. Our derived DMN network thus has potential for diagnostic applications that are simpler to perform than computation of pairwise correlational strengths or seed maps.

Contrasting visual working memory for verbal and non-verbal material with multivariate analysis of fMRI.

We performed a Delayed-Item-Recognition task to investigate the neural substrates of non-verbal visual working memory with event-related fMRI ('Shape task'). 25 young subjects (mean age: 24.0 years; STD=3.8 years) were instructed to study a list of either 1, 2 or 3 unnamable nonsense line drawings for 3s ('stimulus phase' or STIM). Subsequently, the screen went blank for 7s ('retention phase' or RET), and then displayed a probe stimulus for 3s in which subjects indicated with a differential button press whether the probe was contained in the studied shape-array or not ('probe phase' or PROBE). Ordinal Trend Canonical Variates Analysis (Habeck et al., 2005a) was performed to identify spatial covariance patterns that showed a monotonic increase in expression with memory load during all task phases. Reliable load-related patterns were identified in the stimulus and retention phase (p<0.01), while no significant pattern could be discerned during the probe phase. Spatial covariance patterns that were obtained from an earlier version of this task (Habeck et al., 2005b) using 1, 3, or 6 letters ('Letter task') were also prospectively applied to their corresponding task phases in the current non-verbal task version. Interestingly, subject expression of covariance patterns from both verbal and non-verbal retention phases correlated positively in the non-verbal task for all memory loads (p<0.0001). Both patterns also involved similar frontoparietal brain regions that were increasing in activity with memory load, and mediofrontal and temporal regions that were decreasing. Mean subject expression of both patterns across memory load during retention also correlated positively with recognition accuracy (d(L)) in the Shape task (p<0.005). These findings point to similarities in the neural substrates of verbal and non-verbal rehearsal processes. Encoding processes, on the other hand, are critically dependent on the to-be-remembered material, and seem to necessitate material-specific neural substrates.

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.

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.

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.

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.

Neural networks associated with the speed-accuracy tradeoff: evidence from the response signal method.

This functional neuroimaging (fMRI) study examined the neural networks (spatial patterns of covarying neural activity) associated with the speed-accuracy tradeoff (SAT) in younger adults. The response signal method was used to systematically increase probe duration (125, 250, 500, 1000 and 2000 ms) in a nonverbal delayed-item recognition task. A covariance-based multivariate approach identified three networks that varied with probe duration--indicating that the SAT is driven by three distributed neural networks.

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.

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.

Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study.

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

Performance degradation and altered cerebral activation during dual performance: evidence for a bottom-up attentional system.

Subjects performed a continuous tracking concurrently with an intermittent visual detection task to investigate the existence of competition for a capacity-limited stage (a bottleneck stage). Both perceptual and response-related processes between the two tasks were examined behaviorally and the changes in brain activity during dual-tasking relative to single-task were also assessed. Tracking error and joystick speed were analyzed for changes that were time-locked to visual detection stimuli. The associated brain activations were examined with functional magnetic resonance imaging (fMRI). These were analyzed using mixed block and event-related models to tease apart sustained neural activity and activations associated with individual events. Increased tracking error and decreased joystick speed were observed relative to the target stimuli in the dual-task condition only, which supports the existence of a bottleneck stage in response-related processes. Neuroimaging data show decreased activation to target relative to non-target stimuli in the dual-task condition in the left primary motor and somatosensory cortices controlling right-hand tracking, consistent with the tracking interference observed in behavioral data. Furthermore, the ventral attention system, rather than the dorsal attention system, was found to mediate task coordination between tracking and visual detection.

Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease.

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

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.

The impact of age-related changes on working memory functional activity.

This work investigated associations of age-related brain atrophy and functional neural networks identified using multivariate analyses of BOLD fMRI data in young and elder participants (young, N=37; mean age=25; elders, N=15; mean age=74). Two networks were involved in retaining increasing loads of verbal information in working memory. Network utilizations were used to test associations between function and indices of grey matter volume changes using voxel based morphometry. Global changes in brain volume were not associated with the secondary network. Lower regional grey matter volume in the left pre-central gyrus within the primary network was associated with increased secondary network utilization independent of age group. Decreased regional grey matter volume was associated with increased age only in the elders. Increased secondary network expression was associated with increased slope of reaction times across memory load, in the elders. These results support the theory of neural compensation, that elder participants recruit additional neural resources to maintain task performance in the face of age-related decreases in regional grey matter volume.

Evidence for age-related changes to temporal attention and memory from the choice time production task.

The effect of aging on interval timing was examined using a choice time production task, which required participants to choose a key response based on the location of the stimulus, but to delay responding until after a learned time interval. Experiment 1 varied attentional demands of the response choice portion of the task by varying difficulty of stimulus-response mapping. Choice difficulty affected temporal accuracy equally in both age groups, but older participants' response latencies were more variable under more difficult response choice conditions. Experiment 2 tested the contribution of long-term memory to differences in choice time production between age groups over 3 days of testing. Direction of errors in time production between the two age groups diverged over the 3 sessions, but variability did not differ. Results from each experiment separately show age-related changes to attention and memory in temporal processing using different measures and manipulations in the same task.