Delayed Response Task Research Articles

Dorsolateral Prefrontal Cortex, Working Memory, and Prospective Coding for Action

The role of the dorsolateral prefrontal cortex (DLPFC) in the control of behavior remains a topic of ongoing controversy. The discovery of sustained neural discharge in monkey DLPFC neurons during the retention interval of delayed-response (DR) tasks suggested that this region is involved in on-line

Antipsychotic Drugs Exacerbate Impairment on a Working Memory Task in First-Episode Schizophrenia

This study sought to replicate previous findings of worsened performance on a translational spatial working memory task among antipsychotic-naïve first-episode schizophrenia patients after antipsychotic treatment and to extend these findings by examining whether changes in the allocation of covert attention contribute to this effect. Fourteen antipsychotic-naïve schizophrenia patients performed an oculomotor delayed response task before and 6 weeks after antipsychotic treatment (risperidone n = 11; olanzapine n = 3). Fifteen matched healthy individuals were studied in parallel. Patients' pretreatment deficit in accurately remembering spatial locations was exacerbated by antipsychotic treatment, consistent with previous findings; however, this occurred only when covert attention was directed away from remembered locations during delay periods. Disruption in the allocation of covert attention might contribute to patients' decline in spatial working memory after antipsychotic treatment. Alterations in prefrontal dopaminergic systems or reduced thalamocortical drive might account for this apparent adverse cognitive effect of antipsychotic treatment.

Tyrosine depletion alters cortical and limbic blood flow but does not modulate spatial working memory performance or task‐related blood flow in humans

Dopamine appears critical in regulating spatial working memory (SWM) within the PFC of non-human primates; however findings in humans are less clear. Recent studies of the effects of global depletion of dopamine via acute tyrosine/phenylalanine depletion (TPD) on SWM task performance have yielded inconsistent results, which may be partly related to task differences. These previous studies do not address whether TPD can directly impair PFC functioning. The current study investigated the effects of TPD on (1) regional cerebral blood flow (rCBF) during a SWM n-back task using H(2) (15)O Positron Emission Tomography (PET), and (2) behavioural performance on three different SWM tasks. Ten healthy males were scanned twice: once following a placebo (balanced) amino acid mixture and once following an equivalent mixture deficient in tyrosine/phenylalanine (TPD condition). Participants completed two additional delayed-response tasks to examine whether differences in response demands influenced TPD effects on performance. TPD resulted in widespread increases in rCBF, with maximum increases in the region of the parahippocampal gyrus bilaterally, left inferior frontal gyrus, and the putamen. TPD related rCBF reductions were observed in the medial frontal gyrus bilaterally, right inferior temporal gyrus and the pons. Despite widespread changes in blood flow following TPD, no specific effects on SWM neural networks or task performance were observed. The use of three different SWM tasks suggests that task differences are unlikely to account for the lack of effects observed. These findings question the capacity of TPD to consistently modulate dopamine function and SWM neural networks in humans.

Neuronal firing rates account for distractor effects on mnemonic accuracy in a visuo-spatial working memory task

Persistent neural activity constitutes one neuronal correlate of working memory, the ability to hold and manipulate information across time, a prerequisite for cognition. Yet, the underlying neuronal mechanisms are still elusive. Here, we design a visuo- spatial delayed-response task to identify the relationship between the cue-distractor spatial distance and mnemonic accuracy. Using a shared experimental and computational test protocol, we probe human subjects in computer experiments, and subsequently we evaluate different neural mechanisms underlying persistent activity using an in silico prefrontal network model. Five modes of action of the network were tested: weak or strong synaptic interactions, wide synaptic arborization, cellular bistability and reduced synaptic NMDA component. The five neural mechanisms and the human behavioral data, all exhibited a significant deterioration of the mnemonic accuracy with decreased spatial distance between the distractor and the cue. A subsequent computational analysis revealed that the firing rate and not the neural mechanism per se, accounted for the positive correlation between mnemonic accuracy and spatial distance. Moreover, the computational modeling predicts an inverse correlation between accuracy and distractibility. In conclusion, any pharmacological modulation, pathological condition or memory training paradigm targeting the underlying neural circuitry and altering the net population firing rate during the delay is predicted to determine the amount of influence of a visual distraction.

Age-Related Differences in Activation-Performance Relations in Delayed-Response Tasks: a Multiple Component Analysis

We used event-related functional magnetic resonance imaging (fMRI) to measure prefrontal cortex (PFC) activity while younger and older adults performed an item-recognition task in which the memory-set size varied between 1 and 8 letters. Each trial was composed of a 4-sec encoding period in which subjects viewed random letter strings, a 12-sec retention period and a 2-sec retrieval period in which subjects decided whether a single probe letter was or was not part of the memory set. For both groups, reaction-time (RT) increased and accuracy decreased with increasing memory set-size. Analyses of individual subjects' performance and cortical activity indicated that speed and accuracy accounted for variance in different task periods in dorsal and ventral PFC. Age-related differences in accuracy-activation relations were observed in dorsal PFC during encoding and ventral PFC during maintenance. Age-related differences in RT-activation relations were observed in dorsal PFC during retrieval. These results and additional fMRI data we have collected during performance of a speeded processing task, directly support a model of cognitive slowing in which processing rate is related to neural efficiency.

Irregular persistent activity induced by synaptic excitatory feedback

Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV) of interspike intervals (ISI) of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i) the post-spike reset is close enough to threshold , (ii) synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between pre-synaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD). First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

Circuitry underlying temporally extended spatial working memory

Extended maintenance delays decrease the accuracy of information stored in spatial working memory. In order to elucidate the network underlying sustained spatial working memory, 16 subjects were scanned using fast event-related fMRI as they performed an oculomotor delayed response task containing trials with “short” (2.5 s) or “long” (10 s) delay periods. Multiple cortical and subcortical regions were common to both delay trial types indicating core task regions. Three patterns of activity were found in a subset of core regions that reflect underlying processes: maintenance-related (e.g., left FEF, right supramarginal gyrus (SMG)), response planning-related (e.g., right FEF, SEF), and motor response-related (e.g., lateral cerebellum (declive)) activation. Several regions were more active during long than short delay trials, including multiple sites in DLPFC (BA 9, 46), indicating a circuitry dynamically recruited to support sustained working memory. Our results suggest that specialized brain processes support extended periods of working memory.

Premorbid exercising in specific cognitive tasks prevents impairment of performance in parkinsonian monkeys

Adult Cebus apella monkeys were exposed to either one, two or four series of cognitive tasks that place a demand on working memory and inhibitory control (Spatial Delayed Response and Object Retrieval Detour), before administration of the neurotoxin 1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following MPTP treatment, monkeys receiving more than one series successfully reached criteria at delays similar to those attained during the pre-MPTP stage for the Spatial Delayed Response task and avoided increased perseveration in the Object Retrieval Detour task. Results provide evidence that protection towards a neurotoxin in specific cognitive performances can be increased by repeated exposure to task-specific cognitive demands and that motor and cognitive impairment following MPTP treatment can be effectively dissociated in primates.

Load response functions in the human spatial working memory circuit during location memory updating

Previous studies have emphasized that the dorsolateral prefrontal cortex is important for manipulating information in working memory, although activations in other frontal and parietal areas are commonly observed under the same conditions. We conducted an fMRI experiment to examine brain responses as a parametric function of memory updating, which is considered as an elemental process in working memory. In a variant spatial delayed-response task, human subjects performed updating operations over a 9-second delay period, during which they mentally transform the location of a memorized target in a 4 by 4 grid according to 3 to 12 instruction cues. Activity increased monotonically with increasing updating load in numerous cortical and subcortical regions including the rostrodorsal premotor (rdPM), lateral precentral sulcus, lateral prefrontal, posterior associative, striatal and cerebellar areas. The rdPM and superior parietal were particularly sensitive to the updating manipulation. There were several main findings. First, updating spatial working memory involved mostly the same cortical and subcortical regions that were activated during maintenance of spatial information. Second, the updating load response functions of regions in the spatial working memory circuit showed a strong linear component. However, none shows significant increases in activity from 9 to 12 updating operations. Third, activity in the right rdPM and anterior inferior frontal gyrus correlated positively with working memory performance in the high updating load condition. Our findings suggest that updating and maintenance of spatial information may share similar processes and that the rostrodorsal premotor cortex and anterior inferior frontal gyrus may be important for the success of tracking spatial information in working memory.

Top-Down Control of Motor Cortex Ensembles by Dorsomedial Prefrontal Cortex

Dorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding.

Adverse Effects of Risperidone on Spatial Working Memory in First-Episode Schizophrenia

Working memory impairments are a central neurocognitive feature of schizophrenia. The nature of these impairments early in the course of illness and the impact of antipsychotic drug treatment on these deficits are not well understood. The oculomotor delayed response task is a translational spatial working memory paradigm used to characterize the neurophysiologic and neurochemical aspects of working memory in the primate brain. To examine oculomotor delayed response task performance in patients with first-episode schizophrenia before and after antipsychotic drug treatment. Twenty-five antipsychotic drug-naive, acutely ill patients with first-episode schizophrenia performed an oculomotor delayed response task at baseline before any drug treatment and again after 6 weeks of risperidone treatment. Twenty-five matched healthy controls were studied in parallel. Accuracy for remembered spatial locations on an oculomotor delayed response task. Before treatment, patients demonstrated baseline impairment in the ability to maintain spatial location information in working memory at longer delay-period durations (8 seconds), when maintenance demands on working memory were greatest. After 6 weeks of risperidone treatment and significant clinical improvement, this pretreatment impairment worsened such that patients were uniformly impaired across all delay period durations (1-8 seconds). This occurred in the absence of any generalized adverse effect on oculomotor systems or significant extrapyramidal adverse effects. Deficits in the maintenance of spatial information in working memory are present early in the course of illness. Risperidone treatment exacerbated these deficits, perhaps by impairing the encoding of information into working memory. Studies with nonhuman primates performing oculomotor delayed response tasks suggest that the apparent adverse effect of risperidone might result from treatment-related changes in modulatory functions of prefrontal D1 receptor systems.

Evidence for multiple manipulation processes in prefrontal cortex

The prefrontal cortex (PFC) is known to subserve working memory (WM) processes. Brain imaging studies of WM using delayed response tasks (DRTs) have shown memory-load-dependent activation increases in dorsal prefrontal cortex (PFC) regions. These activation increases are believed to reflect manipulation of to-be-remembered information in the service of memory-consolidation. This speculation has been based on observations of similar activation increases in tasks that overtly require manipulation by instructing participants to reorder to-be-remembered list items. In this study, we tested the assumption of functional equivalence between these two types of WM tasks. Participants performed a DRT under two conditions with memory loads ranging from 3 to 6 letters. In an “item-order” condition, participants were required to remember letters in the order in which they were presented. In a “reordering” condition, participants were required to remember the letters in alphabetical order. Load-related activation increases were observed during the encoding and maintenance periods of the order maintenance condition, whereas load-related activation decreases were observed in the same periods of the reordering condition. These results suggest that (1) the neural substrates associated with long-list retention and those associated with reordering are not equivalent, (2) cognitive processes associated with long-list retention may be more closely approximated by item-order maintenance than by reordering, and (3) multiple forms of WM manipulation are dissociable on the basis of fMRI data.

Contributions of prefrontal cue-, delay-, and response-period activity to the decision process of saccade direction in a free-choice ODR task

To examine how the dorsolateral prefrontal cortex (DLPFC) contributes to the decision process of the saccade direction, we recorded single-neuron activity while two monkeys performed two oculomotor delayed-response (ODR) tasks. In an ordinary ODR task, monkeys were required to make a memory-guided saccade to the cue location after a 3-s delay. In a self-selection version of the ODR task (S-ODR), four identical visual cues were presented simultaneously at the cue period, and monkeys were required to make a saccade toward any one of four directions after a 3-s delay. By comparing the same neuron's activity between two tasks, we found (1) neurons having directional cue-period activity in the ODR task did not show directionally selective activity in the S-ODR task, (2) neurons having directional pre-saccadic activity showed highly similar directional preferences in two tasks and exhibited temporal coupling between the onset of pre-saccadic activity and the initiation of saccadic eye movements, (3) neurons with directional delay-period activity in the ODR task exhibited similar directional preferences and showed gradual increase in the strength of the directional selectivity toward the end of the delay period in the S-ODR task. These results suggest that directional delay-period activity contributes to the decision process of the saccade direction in the S-ODR task, while directional cue-period and pre-saccadic activities do not. The gradual increase of the directional selectivity in delay-period activity might correspond to neural correlates of the decision process of the saccade direction in the S-ODR task.

Separate Modulations of Human V1 Associated with Spatial Attention and Task Structure

Functional magnetic resonance imaging (fMRI) was used while normal human volunteers engaged in simple detection and discrimination tasks, revealing separable modulations of early visual cortex associated with spatial attention and task structure. Both modulations occur even when there is no change in sensory stimulation. The modulation due to spatial attention is present throughout the early visual areas V1, V2, V3, and VP, and varies with the attended location. The task structure activations are strongest in V1 and are greater in regions that represent more peripheral parts of the visual field. Control experiments demonstrate that the task structure activations cannot be attributed to visual, auditory, or somatosensory processing, the motor response for the detection/discrimination judgment, or oculomotor responses such as blinks or saccades. These findings demonstrate that early visual areas are modulated by at least two types of endogenous signals, each with distinct cortical distributions.

Brain Basis of Developmental Change in Visuospatial Working Memory

Although brain changes associated with the acquisition of cognitive abilities in early childhood involve increasing localized specialization, little is known about the brain changes associated with the refinement of existing cognitive abilities that reach maturity in adolescence. The goal of this study was to investigate developmental changes in functional brain circuitry that support improvements in visuospatial working memory from childhood to adulthood. We tested thirty 8- to 47-year-olds in an oculomotor delayed response task. Developmental transitions in brain circuitry included both quantitative changes in the recruitment of necessary working memory regions and qualitative changes in the specific regions recruited into the functional working memory circuitry. Children recruited limited activation from core working memory regions (dorsal lateral prefrontal cortex [DLPFC] and parietal regions) and relied primarily on ventromedial regions (caudate nucleus and anterior insula). With adolescence emerged a more diffuse network (DLPFC, anterior cingulate, posterior parietal, anterior insula) that included the functional integration of premotor response preparation and execution circuitry. Finally, adults recruited the most specialized network of localized regions together with additional performance-enhancing regions, including left-lateralized DLPFC, ventrolateral prefrontal cortex, and supramarginal gyrus. These results suggest that the maturation of adult-level cognition involves a combination of increasing localization within necessary regions and their integration with performance-enhancing regions.

Mesocortical dopamine modulation of executive functions: beyond working memory

Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D1 receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D2 and D4) is unclear. This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making. Whereas PFC D1 receptor activity is of primary importance in working memory, D1 and D2 receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the "inverted U-shaped" function of D1 receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D1, D2, and D4 receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.

Maturation of Executive Function in Autism

Executive dysfunction has been reported at different ages in autism. It is not clear however, when this impairment emerges or how its expression is affected by development. 61 non-mentally retarded autism participants (AUT) and 61 age, gender, and IQ matched typically developing participants (CON) were assessed with two oculomotor executive function tasks, the oculomotor delayed response task (ODR) and the antisaccade task (AS), as well as a visually-guided saccade sensorimotor task (VGS). The AUT group demonstrated impairments in response inhibition and spatial working memory at all ages tested. Developmental improvements in speed of sensorimotor processing and voluntary response inhibition were similar in both groups indicating sparing of some attentional control of behavior. Developmental progression in the speed of initiating a cognitive plan and maintaining information on line over time, however, was impaired in the AUT group indicating abnormal development of working memory. These results indicate that while executive dysfunction is present throughout development, there is evidence for both typical and atypical developmental progression of executive functions in autism. The plasticity suggested by the developmental improvements may have implications regarding appropriate developmental epochs and types of interventions aimed at enhancing cognitive capacities in individuals with autism.

Functional magnetic resonance imaging studies of eye movements in first episode schizophrenia: Smooth pursuit, visually guided saccades and the oculomotor delayed response task

Schizophrenia patients show eye movement abnormalities that suggest dysfunction in neocortical control of the oculomotor system. Fifteen never-medicated, first episode schizophrenia patients and 24 matched healthy individuals performed eye movement tasks during functional magnetic resonance imaging studies. For both visually guided saccade and smooth pursuit paradigms, schizophrenia patients demonstrated reduced activation in sensorimotor areas supporting eye movement control, including the frontal eye fields, supplementary eye fields, and parietal and cingulate cortex. The same findings were observed for an oculomotor delayed response paradigm used to assess spatial working memory, during which schizophrenia patients also had reduced activity in dorsolateral prefrontal cortex. In contrast, only minimal group differences in activation were found during a manual motor task. These results suggest a system-level dysfunction of cortical sensorimotor regions supporting oculomotor function, as well as in areas of dorsolateral prefrontal cortex that support spatial working memory. These findings indicate that a generalized rather than localized pattern of neocortical dysfunction is present early in the course of schizophrenia and is related to deficits in the sensorimotor and cognitive control of eye movement activity.

Differential working memory impairment in bipolar disorder and schizophrenia: effects of lifetime history of psychosis

Although bipolar disorder and schizophrenia have long been viewed as distinct illnesses, there is growing evidence that these two complex diseases share some common genes, which may manifest as overlapping neuropsychological impairments. Although working memory dysfunction has been proposed to be central to the pathophysiology of schizophrenia, it has received less attention in studies of bipolar disorder. We applied measures of working memory to patients with schizophrenia (n = 15), patients with schizoaffective disorder (n = 15), patients with psychotic (n = 11) and non-psychotic (n = 15) bipolar disorder, and demographically matched healthy subjects (n = 32), in order to determine the extent to which these groups show common or unique impairments. While patients with bipolar disorder (with and without psychotic features) and those with schizophrenia/schizoaffective disorder were impaired on backward digit span, only patients with a lifetime history of psychotic features, regardless of diagnosis, were impaired on spatial delayed response task. Backward digit span performance is comparable in bipolar disorder and schizophrenia, and may be an appropriate endophenotypic marker that cuts across diagnostic categories. In contrast, spatial working memory performance clearly distinguishes non-psychotic bipolar disorder patients from patients with functional psychosis.

Selection and Maintenance of Saccade Goals in the Human Frontal Eye Fields

In a delayed-response task, response selection marks an important transition from sensory to motor processing. Using event-related functional magnetic resonance imaging, we imaged the human brain during performance of a novel delayed-saccade task that isolated response selection from visual encoding and motor execution. The frontal eye fields (FEFs) and intraparietal sulcus (IPS) both showed robust contra-lateralized activity time-locked to response selection. Moreover, response selection affected delay-period activity differently in these regions; it persisted throughout the memory delay period following response selection in the FEF but not IPS. Our results indicate that the FEF and IPS both make important but distinct contributions to spatial working memory. The mechanism that the FEF uses to support spatial working memory is tied to the selection and prospective coding of saccade goals, whereas the role of the IPS may be more tied to retrospective coding of sensory representations.