Effects of proactive interference on non-verbal working memory.

Working memory (WM) is a cognitive system responsible for actively maintaining and processing relevant information and is central to successful cognition. A process critical to WM is the resolution of proactive interference (PI), which involves suppressing memory intrusions from prior memories that are no longer relevant. Most studies that have examined resistance to PI in a process-pure fashion used verbal material. By contrast, studies using non-verbal material are scarce, and it remains unclear whether the effect of PI is domain-general or whether it applies solely to the verbal domain. The aim of the present study was to examine the effect of PI in visual WM using both objects with high and low nameability. Using a Directed-Forgetting paradigm, we varied discriminability between WM items on two dimensions, one verbal (high-nameability vs. low-nameability objects) and one perceptual (colored vs. gray objects). As in previous studies using verbal material, effects of PI were found with object stimuli, even after controlling for verbal labels being used (i.e., low-nameability condition). We also found that the addition of distinctive features (color, verbal label) increased performance in rejecting intrusion probes, most likely through an increase in discriminability between content-context bindings in WM.

Neural correlates of impaired cognitive control over working memory in schizophrenia.

BACKGROUND: One of the most common deficits in patients with schizophrenia (SZ) is in working memory (WM), which has wide-reaching impacts across cognition. However, previous approaches to studying WM in SZ have used tasks that require multiple cognitive-control processes, making it difficult to determine which specific cognitive and neural processes underlie the WM impairment. METHODS: We used functional magnetic resonance imaging to investigate component processes of WM in SZ. Eighteen healthy controls (HCs) and 18 patients with SZ performed an item-recognition task that permitted separate neural assessments of 1) WM maintenance, 2) inhibition, and 3) interference control in response to recognition probes. RESULTS: Before inhibitory demands, posterior ventrolateral prefrontal cortex (VLPFC), an area involved in WM maintenance, was activated to a similar degree in both HCs and patients, indicating preserved maintenance operations in SZ. When cued to inhibit items from WM, HCs showed reduced activation in posterior VLPFC, commensurate with appropriately inhibiting items from WM. However, these inhibition-related reductions were absent in patients. When later probed with items that should have been inhibited, patients showed reduced behavioral performance and increased activation in mid-VLPFC, an area implicated in interference control. A mediation analysis indicated that impaired inhibition led to increased reliance on interference control and reduced behavioral performance. CONCLUSIONS: In SZ, impaired control over memory, manifested through proactive inhibitory deficits, leads to increased reliance on reactive interference-control processes. The strain on interference-control processes results in reduced behavioral performance. Thus, inhibitory deficits in SZ may underlie widespread impairments in WM and cognition.

Expectancy in humans in multisecond peak-interval timing with gaps.

In two experiments, the peak-interval procedure was used with humans to test effects related to gaps in multisecond timing. In Experiment 1, peak times of response distributions were shorter when the gap occurred later during the encoding of the criterion time to be reproduced, suggesting that gap expectancy shortened perceived durations. Peak times were also positively related to objective target durations. Spreads of response distributions were generally related to estimated durations. In Experiment 2, peak times were shortest when gaps were expected but did not occur, confirming that the shortening effect of gap expectancy is independent of the gap occurrence. High positive start-stop correlations and moderate positive peak-time-spread correlations showed strong memory variability, whereas low and negative start-spread correlations suggest small response-threshold variability. Correlations seemed not to be influenced by expectancy. Overall, the peak-interval procedure with gaps provided relevant information on similarities and differences in timing in humans and other animals.

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.

Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing.

The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D2 overexpression is reversed in the adult. Here we report that overexpression of striatal D2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D2 signaling in the adult regulates motivational process. Moreover, overexpression of D2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.

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.

Neuroimaging of interval timing.

Exactly how the brain is able to measure the durations of events lasting from seconds to minutes while maintaining time-scale invariance remains largely a mystery. Neuroimaging studies are only now beginning to unravel the nature of interval timing and reveal whether different timing mechanisms are required for the perception and production of sub- and supra-second intervals that can be defined by different stimulus modalities. We here review the impact that neuroimaging studies have had on the field of timing and time perception and outline the major challenges that remain to be addressed before a physiologically realistic theory of interval timing can be established involving cortico-striatal circuits.

Effects of dopamine antagonists on the timing of two intervals.

Rats were trained on a two-interval (12 and 36 s) temporal production task (the peak procedure). Test sessions were conducted in which either the D(1) antagonist SCH-23390 (SCH; 0.02, 0.04, 0.06 mg/kg) or the D(2) antagonist haloperidol (HAL; 0.05, 0.1, 0.2 mg/kg) were injected prior to testing. Both drugs affected the amount of responding, but only HAL affected timing. Under HAL, both intervals were overestimated, consistent with a HAL-induced decrease in clock speed. Drug-induced decreases in response output were more profound for the long interval than the short. In addition, there was evidence of HAL- and SCH-induced delays in response initiation that were more severe for the long interval, perhaps owing to its status as a weaker conditioned stimulus.

Separating storage from retrieval dysfunction of temporal memory in Parkinson's disease.

Dysfunction of the basal ganglia and the brain nuclei interconnected with them leads to disturbances of movement and cognition exemplified in Parkinson's disease (PD) and Huntington's disease, including disordered timing of movements and impaired time estimation. Previous research has shown that whereas striatal damage in animals can result in the loss of temporal control over behavior, dopaminergic deregulation in the human striatum associated with PD distorts the memory for time. Here we show a dissociation between deficits in storage (writing to) and retrieval (reading from) temporal memory processes. Both are dysfunctional in PD and sensitive to treatment with dopaminergic agents, but produce dissimilar distortions. When time intervals are stored in memory while the subjects are dopamine depleted, the process is slowed, leading to overestimation of two different time intervals. Conversely, when retrieval occurs in a dopamine-depleted state, interference or coupling occurs between two remembered time intervals, producing overestimation of the shorter and underestimation of the longer one. Whether those two separable patterns of dysfunction in storing and retrieving temporal memories rely on distinct neural networks within the basal ganglia and/or their cortical targets remains to be answered by future research.