Oculomotor Delayed-response Task Research Articles

Effect of short-term plasticity on working memory

The way in which persistent firing activity and synaptic plasticity are orchestrated to underlie working memory in recurrent neural networks is not fully understood. Here, we build a continuous attractor network of pyramidal cells and interneurons to simulate an oculomotor delayed response task. Both short-term facilitation (STF) and short-term depression (STD) manifest at synapses between pyramidal cells. The efficacy of individual synapses depends on the time constants of STF and STD as well as the presynaptic firing rate. Self-sustained firing activity (i.e., a bump attractor) during the delay period encodes the cue position. The bump attractor becomes more robust against random drifts and distractions with enhancing STF or reducing STD. Keeping STF and STD at appropriate levels is crucial for optimizing network performance. Our results suggest that, besides slow recurrent excitation and strong global inhibition, short-term plasticity plays a prominent role in facilitating mnemonic behavior.

Rate-distortion theory of neural coding and its implications for working memory.

Rate-distortion theory provides a powerful framework for understanding the nature of human memory by formalizing the relationship between information rate (the average number of bits per stimulus transmitted across the memory channel) and distortion (the cost of memory errors). Here we show how this abstract computational-level framework can be realized by a model of neural population coding. The model reproduces key regularities of visual working memory, including some that were not previously explained by population coding models. We verify a novel prediction of the model by reanalyzing recordings of monkey prefrontal neurons during an oculomotor delayed response task.

Strong Gamma Frequency Oscillations in the Adolescent Prefrontal Cortex.

Working memory ability continues to mature into adulthood in humans and nonhuman primates. At the single-neuron level, adolescent development is characterized by increased prefrontal firing rate in the delay period, but less is known about how coordinated activity between neurons is altered. Local field potentials (LFPs) provide a window into the computations conducted by the local network. To address the effects of adolescent development on LFP activity, three male rhesus monkeys were trained to perform an oculomotor delayed response task and tested at both the adolescent and adult stages. Simultaneous single-unit and LFP signals were recorded from areas 8a and 46 of the dorsolateral prefrontal cortex. In both the cue and delay period, power relative to baseline in the gamma frequency range (32-128 Hz) was higher in the adolescent than the adult stage. The changes between developmental stages could not be accounted for by differences in performance and were observed in more posterior as well as more anterior recording sites. In the adult stage, high-firing neurons were also more likely to reside at sites with strong gamma power increase from baseline. For both stages, the gamma power increase in the delay was selective for sites with neuron-encoding stimulus information in their spiking. Our results establish gamma power decrease to be a feature of prefrontal cortical maturation.SIGNIFICANCE STATEMENT Gamma-frequency oscillations in extracellular field recordings (e.g., local field potential or EEG) are a marker of normal interactions between excitatory and inhibitory neurons in neural circuits. Abnormally low gamma power during working memory is seen in conditions such as schizophrenia. We sought to examine whether the immature prefrontal cortex similarly exhibits lower power in the gamma-frequency range during working memory, in a nonhuman primate model of adolescence. Contrary to this expectation, the adolescent PFC exhibited stronger gamma power during the maintenance of working memory. Our findings reveal an unknown developmental maturation trajectory of gamma-band oscillations, propose a refinement of information encoding during PFC maturation, and raise the possibility that schizophrenia represents an excessive state of prefrontal maturation.

Chemogenetic inactivation reveals the inhibitory control function of the prefronto-striatal pathway in the macaque brain

The lateral prefrontal cortex (LPFC) has a strong monosynaptic connection with the caudate nucleus (CdN) of the striatum. Previous human MRI studies have suggested that this LPFC-CdN pathway plays an important role in inhibitory control and working memory. We aimed to validate the function of this pathway at a causal level by pathway-selective manipulation of neural activity in non-human primates. To this end, we trained macaque monkeys on a delayed oculomotor response task with reward asymmetry and expressed an inhibitory type of chemogenetic receptors selectively to LPFC neurons that project to the CdN. Ligand administration reduced the inhibitory control of impulsive behavior, as well as the task-related neuronal responses observed in the local field potentials from the LPFC and CdN. These results show that we successfully suppressed pathway-selective neural activity in the macaque brain, and the resulting behavioral changes suggest that the LPFC-CdN pathway is involved in inhibitory control.

Background synaptic input modulates the visuospatial working memory.

It is generally thought that persistent firing of neurons in the prefrontal cortex underlies working memory. Previous studies have focused on the influence of recurrent synaptic connectivity in local circuits on memory storage. Given neurons in the neocortex are extensively connected, individual neural circuits should receive synaptic inputs from other areas. Here we explore how background synaptic inputs (BSIs) modulate the visuospatial working memory in an oculomotor delayed response task. In a local recurrent network composed of pyramidal cells and interneurons, a bump attractor persists across the delay period, encoding the cue location. Under independent BSIs, the spontaneous network state before the cue presentation can be classified as inactive, active, or overactive, occurring successively with increasing the BSI strength, and the active state facilitates the memory storage. Under spatially correlated BSIs, optimal scenarios, in terms of accuracy of representation and resistance to distraction, involve the BSIs with intermediate strength and low correlation or high strength and moderate correlation. Our results demonstrate how the memory storage is regulated via tuning the balance between local excitation and global inhibition in the network. The current work reveals the functional importance of background input and suggests that robust memory storage could be accomplished over a variety of network states.

Age-related alterations in inhibitory control investigated using the minimally delayed oculomotor response task.

Healthy, older adults are widely reported to experience cognitive decline, including impairments in inhibitory control. However, this general proposition has recently come under scrutiny because ageing effects are highly variable between individuals, are task dependent, and are sometimes not distinguished from general age-related slowing. We recently developed the minimally delayed oculomotor response (MDOR) task in which participants are presented with a simple visual target step, and instructed to saccade not to the target when it appears (a prosaccade response), but when it disappears (i.e. on target offset). Varying the target display duration (TDD) prevents offset timing being predictable from the time of target onset, and saccades prior to the offset are counted as errors. A comparison of MDOR task performance in a group of 22 older adults (mean age 62 years, range 50–72 years) with that in a group of 39 younger adults (22 years, range 19–27 years) demonstrated that MDOR latency was significantly increased in the older group by 34–68 ms depending on TDD. However, when MDOR latencies were corrected by subtracting the latency observed in a standard prosaccade task, the latency difference between groups was abolished. There was a larger latency modulation with TDD in the older group which was observed even when their generally longer latencies were taken into account. Error rates were significantly increased in the older group. An analysis of the timing distribution of errors demonstrated that most errors were failures to inhibit responses to target onsets. When error distributions were used to isolate clear inhibition failures from other types of error, the older group still exhibited significantly higher error rates as well as a higher residual error rate. Although MDOR latency in older participants may largely reflect a general slowing in the oculomotor system with age, both the latency modulation and error rate results are consistent with an age-related inhibitory control deficit. How this relates to performance on other inhibitory control tasks remains to be investigated.

Probing oculomotor inhibition with the minimally delayed oculomotor response task

The ability to not execute (i.e. to inhibit) actions is important for behavioural flexibility and frees us from being slaves to our immediate sensory environment. The antisaccade task is one of several used to investigate behavioural inhibitory control. However, antisaccades involve a number of important processes besides inhibition such as attention and working memory. In the minimally delayed oculomotor response (MDOR) task, participants are presented with a simple target step, but instructed to saccade not to the target when it appears (a prosaccade response), but when it disappears (i.e. on target offset). Varying the target display duration prevents offset timing being predictable from the time of target onset, and saccades prior to the offset are counted as errors. Antisaccade error rate and latency are modified by alterations in fixation conditions produced by inserting a gap between fixation target offset and stimulus onset (the gap paradigm; error rate increases, latency decreases) or by leaving the fixation target on when the target appears (overlap paradigm; error rate decreases, latency increases). We investigated the effect of gaps and overlaps on performance in the MDOR task. In Experiment 1 we confirmed that, compared to a control condition in which participants responded to target onsets, in the MDOR task saccade latency was considerably increased (increases of 122–272 ms depending on target display duration and experimental condition). However, there was no difference in error rate or saccade latency between gap and synchronous (fixation target offset followed immediately by saccade target onset) conditions. In Experiment 2, in a different group of participants, we compared overlap and synchronous conditions and again found no statistically significant differences in error rate and saccade latency. The timing distribution of errors suggested that most were responses to target onsets, which we take to be evidence of inhibition failure. We conclude that the MDOR task evokes behaviour that is consistent across different groups of participants. Because it is free of the non-inhibitory processes operative in the antisaccade task, it provides a useful means of investigating behavioural inhibition.

Change of information represented by thalamic mediodorsal neurons during the delay period.

The thalamic mediodorsal (MD) nucleus plays an important role in transforming visual information into motor information during spatial working-memory performances. To understand the neural mechanism of this transformation process, we examined whether or not the information represented in individual MD neuron's activity changes during a trial of the task. Two monkeys performed two oculomotor delayed-response tasks (an ordinary and a rotatory oculomotor delayed-response task). As MD neurons show directional delay-period activity, we compared the directional selectivity of the same MD neuron between these two tasks and determined whether the activity represented the cue direction or the saccade direction. Among the 26 MD neurons that showed directional delay-period activity, representing information of 27% of neurons gradually altered from the visual domain to the oculomotor domain, while the remaining neurons kept holding either the visual or the oculomotor information throughout the delay period. These results indicate that gradual alteration of information representing in individual MD neurons during the delay period plays an important role in spatial working-memory performance. This alteration could be performed by interactions among MD neurons representing different information during the delay period.

A Quadrantic Bias in Prefrontal Representation of Visual-Mnemonic Space.

Single neurons in primate dorsolateral prefrontal cortex (dLPFC) are known to encode working memory (WM) representations of visual space. Psychophysical studies have shown that the horizontal and vertical meridians of the visual field can bias spatial information maintained in WM. However, most studies and models have tacitly assumed that dLPFC neurons represent mnemonic space homogenously. The anatomical organization of these representations has also eluded clear parametric description. We investigated these issues by recording from neuronal ensembles in macaque dLPFC with microelectrode arrays while subjects performed an oculomotor delayed-response task. We found that spatial WM representations in macaque dLPFC are biased by the vertical and horizontal meridians of the visual field, dividing mnemonic space into quadrants. This bias is reflected in single neuron firing rates, neuronal ensemble representations, the spike count correlation structure, and eye movement patterns. We also found that dLPFC representations of mnemonic space cluster anatomically in a nonretinotopic manner that partially reflects the organization of visual space. These results provide an explanation for known WM biases, and reveal novel principles of WM representation in prefrontal neuronal ensembles and across the cortical surface, as well as the need to reconceptualize models of WM to accommodate the observed representational biases.

Ghosts in the machine: memory interference from the previous trial.

Previous memoranda can interfere with the memorization or storage of new information, a concept known as proactive interference. Studies of proactive interference typically use categorical memoranda and match-to-sample tasks with categorical measures such as the proportion of correct to incorrect responses. In this study we instead train five macaques in a spatial memory task with continuous memoranda and responses, allowing us to more finely probe working memory circuits. We first ask whether the memoranda from the previous trial result in proactive interference in an oculomotor delayed response task. We then characterize the spatial and temporal profile of this interference and ask whether this profile can be predicted by an attractor network model of working memory. We find that memory in the current trial shows a bias toward the location of the memorandum of the previous trial. The magnitude of this bias increases with the duration of the memory period within which it is measured. Our simulations using standard attractor network models of working memory show that these models easily replicate the spatial profile of the bias. However, unlike the behavioral findings, these attractor models show an increase in bias with the duration of the previous rather than the current memory period. To model a bias that increases with current trial duration we posit two separate memory stores, a rapidly decaying visual store that resists proactive interference effects and a sustained memory store that is susceptible to proactive interference.

Working memory performance and neural activity in prefrontal cortex of peripubertal monkeys.

The dorsolateral prefrontal cortex matures late into adolescence or early adulthood. This pattern of maturation mirrors working memory abilities, which continue to improve into adulthood. However, the nature of the changes that prefrontal neuronal activity undergoes during this process is poorly understood. We investigated behavioral performance and neural activity in working memory tasks around the time of puberty, a developmental event associated with the release of sex hormones and significant neurological change. The developmental stages of male rhesus monkeys were evaluated with a series of morphometric, hormonal, and radiographic measures. Peripubertal monkeys were trained to perform an oculomotor delayed response task and a variation of this task involving a distractor stimulus. We found that the peripubertal monkeys tended to abort a relatively large fraction of trials, and these were associated with low levels of task-related neuronal activity. However, for completed trials, accuracy in the delayed saccade task was high and the appearance of a distractor stimulus did not impact performance significantly. In correct trials delay period activity was robust and was not eliminated by the presentation of a distracting stimulus, whereas in trials that resulted in errors the sustained cue-related activity was significantly weaker. Our results show that in peripubertal monkeys the prefrontal cortex is capable of generating robust persistent activity in the delay periods of working memory tasks, although in general it may be more prone to stochastic failure than in adults.

P.2.013 Modelling serotonergic neuromodulation of behavioural performance in spatial working memory

The executive functions of prefrontal cortex (PFC) are regulated by ascending monoaminergic systems. In particular, the dorsal PFC is associated with spatial working memory (SWM), linked to persistent neuronal activity, and it receives anatomical projections from the brainstem monoamine centres. Catecholamine regulation of SWM has been studied at mechanistic and computational levels. However, the role of serotonin (5-HT) in SWM is unclear. Thus, while 5-HT is clearly associated with orbitofrontal cortex functions, its association with SWM is controversial, with positive and negative reports. An indirect association between PFC 5-HT and SWM is suggested by the pro-cognitive effects of antipsychotic drugs targeting 5-HT receptors. Several neurocognitive problems are core deficits of schizophrenia and SWM deficits mark a genetic predisposition for the disease. These weak associations between 5-HT and SWM are in contrast with neurobiological observations predicting a stronger link. Indeed, 5-HT receptors are densely expressed in various PFC subfields, and serotonergic projections from the raphe nuclei target specifically PFC and modulate neuronal activity. Moreover, 5-HT2A receptor activation/blockade in dorsal PFC reduces persistent neuronal activity during SWM tasks. Here, we sought to develop a computational model of serotonergic modulation of the PFC network in order to address the possible reasons for this discrepancy. We used a computational network model of spiking neurons [1] which is consistent with PFC neurophysiological data from behaving monkeys in SWM. This model falls within the general class of attractor models proposed to account for behavioural deficits of schizophrenia, and provides a rich set of behavioural output predictions that can be experimentally tested. We incorporated 5-HT receptor mechanisms in the model following electrophysiological evidence, and we tested the effects of 5-HT receptor ligands on network simulation performance during SWM. We found that 5-HT modulated network’s SWM performance non-monotonously via 5-HT2A and especially via 5-HT1A receptors, following an inverted-U shape. This may partly explain the weak behavioural effects of serotonergic agents in previous SWM studies. Our simulations showed that errors committed at low and high 5-HT concentrations are due to different network dynamics instabilities, suggesting that these two conditions can be distinguished experimentally based on their dependency with delay length, on the response confidence declared in error trials and on PFC activation contrasts in neuroimaging studies. We derived specific predictions regarding the expected behavioural effects of serotonin agents in two classic working-memory tasks: an oculomotor delayed-response task and a delayed matchto-sample task. In brief, the probability of memory storage in the oculomotor task and the rate of misses in the match-to-sample task will be most sensitive to serotonin modulation, depending on delay duration for increases but not for decreases in baseline 5-HT. Our study underscores the relevance of identifying different error types in SWM tasks in order to reveal the association between neuromodulatory systems and SWM. Testing these model-derived predictions in electrophysiological and psychophysical studies of SWM will help advance our understanding of the neural basis of SWM and its neuromodulation by 5-HT receptors.

Memory‐guided saccades in youth‐onset psychosis and attention deficit hyperactivity disorder (ADHD)

Working memory deficits have been shown to be present in children and adolescents with schizophrenia and attention deficit hyperactivity disorder. Considering the differences in clinical characteristics between these disorders, it was the goal of this study to assess differences in the specific components of working memory in children and adolescents with psychosis and attention deficit hyperactivity disorder. Children and adolescents (age range 8-20 years) with either a non-affective psychotic disorder (n = 25), attention deficit hyperactivity disorder (n = 33) and controls (n = 58) were administered an oculomotor delayed-response task using both a recall and a control condition. Memory-guided saccades were measured during delay periods of 2, 8 and 20 s. Although both clinical groups were less accurate than controls, there was no evidence of a disproportionate impairment in recall. In addition, there was no evidence of a delay-dependent impairment in psychosis; however, there was a delay-dependent impairment in attention deficit hyperactivity disorder when corrective saccades were included. Speed of information processing was correlated with distance errors in psychosis, suggesting that speed of encoding the stimulus location may have constrained the accuracy of the saccades. Our findings support impairments during encoding in the psychosis group and a delay-dependent deficit in the attention deficit hyperactivity disorder group.

Short-Term Plasticity Explains Irregular Persistent Activity in Working Memory Tasks

Persistent activity in cortex is the neural correlate of working memory (WM). In persistent activity, spike trains are highly irregular, even more than in baseline. This seemingly innocuous feature challenges our current understanding of the synaptic mechanisms underlying WM. Here we argue that in WM the prefrontal cortex (PFC) operates in a regime of balanced excitation and inhibition and that the observed temporal irregularity reflects this regime. We show that this requires that nonlinearities underlying the persistent activity are primarily in the neuronal interactions between PFC neurons. We also show that short-term synaptic facilitation can be the physiological substrate of these nonlinearities and that the resulting mechanism of balanced persistent activity is robust, in particular with respect to changes in the connectivity. As an example, we put forward a computational model of the PFC circuit involved in oculomotor delayed response task. The novelty of this model is that recurrent excitatory synapses are facilitating. We demonstrate that this model displays direction-selective persistent activity. We find that, even though the memory eventually degrades because of the heterogeneities, it can be stored for several seconds for plausible network size and connectivity. This model accounts for a large number of experimental findings, such as the findings that have shown that firing is more irregular during the persistent state than during baseline, that the neuronal responses are very diverse, and that the preferred directions during cue and delay periods are strongly correlated but tuning widths are not.

Dissociative Effects of Methylphenidate in Nonhuman Primates: Trade-offs between Cognitive and Behavioral Performance

Low doses of methylphenidate reduce hyperactivity and improve attention in individuals with attention deficit hyperactivity disorder (ADHD) as well as in healthy humans and animals. Despite its extensive use, relatively little is known about its mechanisms of action. This study investigated the effects of methylphenidate on working memory performance, impulsivity, response accuracy and precision, and the ability to stay on task in rhesus monkeys using an oculomotor delayed response task. Methylphenidate affected task performance in an inverted-U manner in all three subjects tested. The improvements resulted from a reduction in premature responses and, importantly, not from improvement in the memory of target location. The length of time subjects participated in each session was also affected dose dependently. However, the dose at which the length of participation was maximally increased significantly impaired performance on the working memory task. This dissociation of effects has implications for the treatment of ADHD, for the nonprescription use of methylphenidate for cognitive enhancement, and for furthering the basic understanding of the neural substrate underlying these processes.

The Prefrontal Cortex and Oculomotor Delayed Response: A Reconsideration of the “Mnemonic Scotoma”

The concept of the "mnemonic scotoma," a spatially circumscribed region of working memory impairment produced by unilateral lesions of the PFC, is central to the view that PFC is critical for the short-term retention of information. Presented here, however, are previously unpublished data that offer an alternative, nonmnemonic interpretation of this pattern of deficit. In their study, Wajima and Sawaguchi [Wajima, K., & Sawaguchi, T. The role of GABAergic inhibiton in suppressing perseverative responses in the monkey prefrontal cortex. Neuroscience Research, 50(Suppl. 1), P3-P317, 2004] applied the GABA(A) antagonist bicuculline methiodide unilaterally to the PFC of two monkeys while they performed an oculomotor delayed-response task. Consistent with previous studies, errors for the initial memory-guided saccade were markedly higher when the cued location fell into the region of the visual field affected by the infusion. These erroneous saccades tended to select an alternative target location (out of a possible 16) that had not been cued on that trial. By extending the analysis window, however, it was observed that the second, "corrective" saccade often acquired the location that had been cued on that trial. Further analysis of the erroneous initial saccades indicated that they tended to be directed to a location that had been relevant on the previous trial. Thus, the deficit was not one of "forgetting" the cued location. Rather, it was one of selecting between currently and previously relevant locations. These findings suggest a need for a reconsideration of the concept of the mnemonic scotoma, which in turn invites a reconsideration of functional interpretations of sustained neuronal activity in PFC.

Neural correlates of explicit memory in monkeys performing an oculomotor delayed-response task

Neural correlates of explicit memory in monkeys performing an oculomotor delayed-response task

Does response variability predict distractibility among adults with attention-deficit/hyperactivity disorder?

Increased intraindividual variability in response time (RTSD) has been observed reliably in attention-deficit/hyperactivity disorder (ADHD) and has often been used as a measure of inattention. RTSD is assumed to reflect attentional lapses and distractibility, though evidence for the validity of this connection is lacking. We assessed whether RTSD is an indicator of inattention by comparing RTSD on the stop-signal task (SST) with performance on the delayed oculomotor response (DOR) task, a measure of distractibility. Participants included 30 adults with ADHD and 28 controls. Participants completed the SST and the DOR task, which measured subjects' ability to maintain attention and avoid distraction by inhibiting reflexive saccades toward distractors. On the SST, the ADHD group was slower to inhibit than were controls, indicating poorer inhibitory control in ADHD. The ADHD group also displayed slower reaction times (RTs), greater RTSD, and more omission errors. On the DOR task, the ADHD group displayed more premature saccades (i.e., greater distractibility) than did controls. Greater variability in RT was associated with increased distraction on the DOR task, but only in ADHD participants. Results suggest that RTSD is linked to distractibility among adults with ADHD and support the use of RTSD as a valid measure of inattention in ADHD.

Behavioural analysis of decision process in the self-selection oculomotor delayed response task

Behavioural analysis of decision process in the self-selection oculomotor delayed response task

Characterization of trial-to-trial fluctuations in local field potentials recorded in cerebral cortex of awake behaving macaque

In analyzing neurophysiologic data, individual experimental trials are usually assumed to be statistically independent. However, many studies employing functional imaging and electrophysiology have shown that brain activity during behavioral tasks includes temporally correlated trial-to-trial fluctuations. This could lead to spurious results in statistical significance tests used to compare data from different interleaved behavioral conditions presented throughout an experiment. We characterize trial-to-trial fluctuations in local field potentials recorded from the frontal cortex of a macaque monkey performing an oculomotor delayed response task. Our analysis identifies slow fluctuations (<0.1 Hz) of spectral power in 22/27 recording sessions. These trial-to-trial fluctuations are non-Gaussian, and call into question the statistical utility of standard trial shuffling. We compare our results with evidence for slow fluctuations in human functional imaging studies and other electrophysiologic studies in nonhuman primates.