Spatial Delayed Response Task Research Articles

Effects of nicotinic antagonists on working memory performance in young rhesus monkeys

Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-β-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.

Neural Code of Motor Planning and Execution during Goal-Directed Movements in Crows.

The planning and execution of head-beak movements are vital components of bird behavior. They require integration of sensory input and internal processes with goal-directed motor output. Despite its relevance, the neurophysiological mechanisms underlying action planning and execution outside of the song system are largely unknown. We recorded single-neuron activity from the associative endbrain area nidopallium caudolaterale (NCL) of two male carrion crows (Corvus corone) trained to plan and execute head-beak movements in a spatial delayed response task. The crows were instructed to plan an impending movement toward one of eight possible targets on the left or right side of a touchscreen. In a fraction of trials, the crows were prompted to plan a movement toward a self-chosen target. NCL neurons signaled the impending motion direction in instructed trials. Tuned neuronal activity during motor planning categorically represented the target side, but also specific target locations. As a marker of intentional movement preparation, neuronal activity reliably predicted both target side and specific target location when the crows were free to select a target. In addition, NCL neurons were tuned to specific target locations during movement execution. A subset of neurons was tuned during both planning and execution period; these neurons experienced a sharpening of spatial tuning with the transition from planning to execution. These results show that the avian NCL not only represents high-level sensory and cognitive task components, but also transforms behaviorally-relevant information into dynamic action plans and motor execution during the volitional perception-action cycle of birds.SIGNIFICANCE STATEMENT Corvid songbirds have become exciting new models for understanding complex cognitive behavior. As a key neural underpinning, the endbrain area nidopallium caudolaterale (NCL) represents sensory and memory-related task components. How such representations are converted into goal-directed motor output remained unknown. In crows, we report that NCL neurons are involved in the planning and execution of goal-directed movements. NCL neurons prospectively signaled motion directions in instructed trials, but also when the crows were free to choose a target. NCL neurons showed a target-specific sharpening of tuning with the transition from the planning to the execution period. Thus, the avian NCL not only represents high-level sensory and cognitive task components, but also transforms relevant information into action plans and motor execution.

Relationship Between Enhanced Cognitive Function And Autonomic Nervous Activity After A Subjectively Selected Intensity Exercise

PURPOSE: The purpose of this study was to identify a practical method for engaging in exercise that could improve cognitive function. We tested whether cognitive function improves after exercise at subjectively selected intensity by using ratings of perceived exertion (RPE). In addition, we examined the relationship between the improvement in cognitive function and cardiac autonomic nervous system. METHODS: Twelve participants performed cognitive tasks in a running or resting condition with a randomized crossover design. In the running condition, the participants ran on a treadmill for 10 min at the running speed correspond to the RPE10-12 for each participant. Cognitive tasks including the Spatial Delayed Response task and Go/No-Go task were performed before and after running or resting. Cardiac autonomic nervous activity was obtained by calculating from heart rate variability during cognitive tasks. RESULTS: In the running condition, the RPE was 11.1 ± 0.8 immediately after running. Running at the RPE10-12 significantly improved reaction time in the Go trials (688 ± 191 [Pre] vs 568 ± 159 ms [Post], P < 0.05). In the resting condition, cognitive performance was unchanged throughout the experiment (628.5 ± 163.1 ms [Pre] vs 666.9 ± 139.7 ms [Post], P > 0.05). Parasympathetic nervous activity remained lower after running at RPE10-12 (586 ± 424 ms2 [Pre] vs 373 ± 322 ms2), but sympathetic nervous activity was not changed. Moreover, the Δ reaction time (Post-Pre) tended to be positively correlated with Δ parasympathetic nervous activity (r = 0.514, P = 0.088). In contrast, Δ reaction time was not associated with Δ sympathetic nervous activity (r = 0.177, P = 0.581). CONCLUSIONS: The present study demonstrated that subjectively selected intensity of exercise can improve cognitive function. The improvement in cognitive function after exercise may be associated with cardiac autonomic nervous activity.

Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates.

The most common chemogenetic neuromodulatory system, designer receptors exclusively activated by designer drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is insensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug, particularly in experiments using nonhuman primates. We investigated working memory performance after injections of three DREADD actuators, clozapine, olanzapine, and deschloroclozapine, in four male rhesus monkeys tested in a spatial delayed response task before any DREADD transduction took place. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from vehicle in any of the four subjects. 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after 0.1 mg/kg olanzapine and two were impaired after 0.3 mg/kg deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs in the specific tasks under study to confirm that effects following DREADD receptor transduction are not owing to the actuator drug itself. They also suggest that off-target effects of DREADD actuators may limit translational applications of chemogenetic neuromodulation.

Neuronal Correlates of Spatial Working Memory in the Endbrain of Crows

Birds are renowned for their excellent spatial cognition. Corvid songbirds, in particular, rely on explicit representation of spatial cues in memory when caching food and retrieving caches for later consumption. However, the neuronal correlates of flexible spatial memory abilities are largely unknown in birds. We therefore trained carrion crows (Corvus corone) on a spatial delayed-response task in which they had to maintain the variable location of a visual item for a few seconds in working memory. After the crows performed this task with high precision, we recorded single-cell activity from the associative endbrain area Nidopallium caudolaterale (NCL) in the behaving crows. A large fraction of NCL neurons were tuned to individual preferred locations and selectively maintained the spatial location of items in working memory. A comparison of firing rates with reaction times suggested that the majority of delay-selective neurons represented stored location information rather than motor preparation. Almost 30% of all recorded neurons were tuned during both visual presentation and memory delay, and their spatial tuning was significantly correlated. The population of recorded neurons stably maintained spatial information over the course of the working memory period. Importantly, the neural responses of spatially tuned neurons were relevant for the crows' choices and allowed a statistical classifier to predict the subsequently chosen target location in free-choice trials. Our findings demonstrate the pivotal role of the avian NCL in spatial working memory that is reminiscent of the function of the convergently evolved primate prefrontal cortex in spatial working memory.

Chronic phencyclidine treatment impairs spatial working memory in rhesus monkeys.

Phencyclidine (PCP) could induce schizophrenia (Sz) like behavior in both humans and animals, therefore, has been widely utilized to establish Sz animal models. It induced cognitive deficits, the core symptom of Sz, mainly through influencing frontal dopaminergic function. Nonhuman primate (NHP) studies demonstrated impaired object retrieval detour (ORD) and spatial delayed response (SDR) task performance by acute or chronic PCP treatment. However, NHP investigations, continually monitoring SDR performance before, during and after PCP treatment, are lacking. Present study investigated the long-term influence of chronic PCP treatment on SDR performance and the possible increase of SDR deficit severity and duration by the incremental dosing procedure in rhesus monkeys. SDR task was performed repeatedly up to eight weeks after constant dosing procedure (i.m., 0.3 mg/kg, day 12-25), during which drug effects on locomotor activity and blood cortisol concentration were assessed. Incremental dosing procedure (starting dose 0.3 mg/kg, day 6-19) began five months later. Constant dosing procedure induced differential level of hyperactivity across testing days, without significant influence on blood cortisol concentration. It reduced SDR performance, until occurrence of the first and worst impairment on day 15 and 23 respectively. The impaired performance recovered to pretreatment level over one week after drug cessation. In contrast, incremental dosing procedure impaired SDR performance on the first treatment day, which recovered within treatment period. Results suggested increase of SDR deficit severity by repeated PCP administrations, whereas the incremental dosing procedure did not increase SDR deficit severity and duration.

Behavioral Effect of Chemogenetic Inhibition Is Directly Related to Receptor Transduction Levels in Rhesus Monkeys.

We used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male rhesus monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hSyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD-transduced cells using stereological analysis of mCherry-immunolabeled neurons. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared with monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.SIGNIFICANCE STATEMENT Cognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (designer receptor exclusively activated by designer drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine-N-oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.

Functional Dissociation of Confident and Not-Confident Errors in the Spatial Delayed Response Task Demonstrates Impairments in Working Memory Encoding and Maintenance in Schizophrenia

Even though extensively investigated, the nature of working memory (WM) deficits in patients with schizophrenia (PSZ) is not yet fully understood. In particular, the contribution of different WM sub-processes to the severe WM deficit observed in PSZ is a matter of debate. So far, most research has focused on impaired WM maintenance. By analyzing different types of errors in a spatial delayed response task (DRT), we have recently demonstrated that incorrect yet confident responses (which we labeled as false memory errors) rather than incorrect/not-confident responses reflect failures of WM encoding, which was also impaired in PSZ. In the present study, we provide further evidence for a functional dissociation between confident and not-confident errors by manipulating the demands on WM maintenance, i.e., the length over which information has to be maintained in WM. Furthermore, we investigate whether these functionally distinguishable WM processes are impaired in PSZ. Twenty-four PSZ and 24 demographically matched healthy controls (HC) performed a spatial DRT in which the length of the delay period was varied between 1, 2, 4, and 6 s. In each trial, participants also rated their level of response confidence. Across both groups, longer delays led to increased rates of incorrect/not-confident responses, while incorrect/confident responses were not affected by delay length. This functional dissociation provides additional support for our proposal that false memory errors (i.e., confident errors) reflect problems at the level of WM encoding, while not-confident errors reflect failures of WM maintenance. Schizophrenic patients showed increased numbers of both confident and not-confident errors, suggesting that both sub-processes of WM—encoding and maintenance—are impaired in schizophrenia. Combined with the delay length-dependent functional dissociation, we propose that these impairments in schizophrenic patients are functionally distinguishable.

Performance In Square Stepping Exercise Is Associated With Working Memory

Square-Stepping Exercise (SSE) program improves cognitive function as well as lower-extremity functional fitness in the elderly. However, it is unclear which aspects of cognitive function are closely associated with performance in SSE. Given that SSE comprises stepping exercise while remembering step pattern, we hypothesized that working memory plays a key role in performance in SSE. PURPOSE: The purpose of the present study was to test the hypothesis that performance in SSE is associated with working memory. METHODS: Sixteen elderly people (10 males and 6 females, age: 72.9 ± 6.3 years, body mass index: 22.1 ± 3.2 kg/m2) participated in the study. The participants performed a combination of spatial delayed response (SDR) and Go/No-Go (GNG) tasks and SSE. SDR task requires working memory. GNG task requires response inhibition and interference control. The SDR task was graded into three levels of difficulty. Cognitive performance was assessed by reaction time (RT) and accuracy. In SSE, the participants performed multiple directional step patterns on a thin mat partitioned into squares. SSE was graded into five levels of difficulty depending on step pattern. Time to complete SSE was used to assess performance. One-way repeated measures analysis of variance was used for each variable. Pearson correlation analysis was performed to determine the correlation. Data were expressed as mean ± standard deviation. The significance level was set at p < 0.05. RESULTS: RT in the SDR task increased with task difficulty (main effect: p < 0.001, level 1: 1.4 ± 0.2 sec, level 2: 1.8 ± 0.3 sec, level 3: 2.2 ± 0.4 sec), while accuracy was not altered. Time to complete SSE also increased with task difficulty (main effect: P < 0.001, level 1: 5.4 ± 0.7 sec, level 2: 8.6 ± 1.4 sec, level 3: 16.7 ± 1.7 sec, level 4: 18.0 ± 3.4 sec). Only eight participants completed SSE at level 5 (26.6 ± 3.4 sec). RT in the SDR task at level 2 was associated with time to complete SSE at level 2 (r = 0.54, p = 0.03). Performance in the GNG task was not associated with time to complete SSE. CONCLUSION: The moderate correlation suggests that performance in SSE is associated with working memory. Exercise intervention with square stepping may be particularly effective to improve working memory.

Neural encoding of choice during a delayed response task in primate striatum and orbitofrontal cortex.

Reward outcomes are available in many diverse situations and all involve choice. If there are multiple outcomes each rewarding, then decisions regarding relative value lead to choosing one over another. Important factors related to choice context should be encoded and utilized for this form of adaptive choosing. These factors can include the number of alternatives, the pacing of choice behavior and the possibility to reverse one's choice. An essential step in understanding if the context of choice is encoded is to directly compare choice with a context in which choice is absent. Neural activity in orbitofrontal cortex and striatum encodes potential value parameters related to reward quality and quantity as well as relative preference. We examined how neural activations in these brain regions are sensitive to choice situations and potentially involved in a prediction for the upcoming outcome selection. Neural activity was recorded and compared between a two-choice spatial delayed response task and an imperative 'one-option' task. Neural activity was obtained that extended from the instruction cue to the movement similar to previous work utilizing the identical imperative task. Orbitofrontal and striatal neural responses depended upon the decision about the choice of which reward to collect. Moreover, signals to predictive instruction cues that precede choice were selective for the choice situation. These neural responses could reflect chosen value with greater information on relative value of individual options as well as encode choice context itself embedded in the task as a part of the post-decision variable.

Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control.

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease.

Serial dependence is absent at the time of perception but increases in visual working memory

Recent experiments have shown that visual cognition blends current input with that from the recent past to guide ongoing decision making. This serial dependence appears to exploit the temporal autocorrelation normally present in visual scenes to promote perceptual stability. While this benefit has been assumed, evidence that serial dependence directly alters stimulus perception has been limited. In the present study, we parametrically vary the delay between stimulus and response in a spatial delayed response task to explore the trajectory of serial dependence from the moment of perception into post-perceptual visual working memory. We find that behavioral responses made immediately after viewing a stimulus show evidence of adaptation, but not attractive serial dependence. Only as the memory period lengthens is a blending of past and present information apparent in behavior, reaching its maximum with a delay of six seconds. These results dovetail with other recent findings to bolster the interpretation that serial dependence is a phenomenon of mnemonic rather than perceptual processes. However, even while this pattern of effects in group-averaged data has now been found consistently, we show that the relative strengths of adaptation and serial dependence vary widely across individuals. Finally, we demonstrate that when leading mathematical models of working memory are adjusted to account for these trial-history effects, their fit to behavioral data is substantially improved.

Executive function after exhaustive exercise.

Findings concerning the effects of exhaustive exercise on cognitive function are somewhat equivocal. The purpose of this study was to identify physiological factors that determine executive function after exhaustive exercise. Thirty-two participants completed the cognitive tasks before and after an incremental exercise until exhaustion (exercise group: N=18) or resting period (control group N=14). The cognitive task was a combination of a Spatial Delayed-Response (Spatial DR) task and a Go/No-Go task, which requires executive function. Cerebral oxygenation and skin blood flow were monitored during the cognitive task over the prefrontal cortex. Venous blood samples were collected before and after the exercise or resting period, and blood catecholamines, serum brain-derived neurotrophic factor, insulin-like growth hormone factor 1, and blood lactate concentrations were analyzed. In the exercise group, exhaustive exercise did not alter reaction time (RT) in the Go/No-Go task (pre: 861±299ms vs. post: 775±168ms) and the number of error trials in the Go/No-Go task (pre: 0.9±0.7 vs. post: 1.8±1.8) and the Spatial DR task (pre: 0.3±0.5 vs. post: 0.8±1.2). However, ΔRT was negatively correlated with Δcerebral oxygenation (r=-0.64, P=0.004). Other physiological parameters were not correlated with cognitive performance. Venous blood samples were not directly associated with cognitive function after exhaustive exercise. The present results suggest that recovery of regional cerebral oxygenation affects executive function after exhaustive exercise.

A theory of working memory without consciousness or sustained activity.

Working memory and conscious perception are thought to share similar brain mechanisms, yet recent reports of non-conscious working memory challenge this view. Combining visual masking with magnetoencephalography, we investigate the reality of non-conscious working memory and dissect its neural mechanisms. In a spatial delayed-response task, participants reported the location of a subjectively unseen target above chance-level after several seconds. Conscious perception and conscious working memory were characterized by similar signatures: a sustained desynchronization in the alpha/beta band over frontal cortex, and a decodable representation of target location in posterior sensors. During non-conscious working memory, such activity vanished. Our findings contradict models that identify working memory with sustained neural firing, but are compatible with recent proposals of 'activity-silent' working memory. We present a theoretical framework and simulations showing how slowly decaying synaptic changes allow cell assemblies to go dormant during the delay, yet be retrieved above chance-level after several seconds.

On memories, neural ensembles and mental flexibility

Memories are assumed to be represented by groups of co-activated neurons, called neural ensembles. Describing ensembles is a challenge: complexity of the underlying micro-circuitry is immense. Current approaches use a piecemeal fashion, focusing on single neurons and employing local measures like pairwise correlations. We introduce an alternative approach that identifies ensembles and describes the effective connectivity between them in a holistic fashion. It also links the oscillatory frequencies observed in ensembles with the spatial scales at which activity is expressed. Using unsupervised learning, biophysical modeling and graph theory, we analyze multi-electrode LFPs from frontal cortex during a spatial delayed response task. We find distinct ensembles for different cues and more parsimonious connectivity for cues on the horizontal axis, which may explain the oblique effect in psychophysics. Our approach paves the way for biophysical models with learned parameters that can guide future Brain Computer Interface development.

Reduction In Oxygen Delivery Under Severe Hypoxia Affects Cognitive Function During Moderate Exercise

Reduction in oxygen delivery during hypoxia might impair cognitive function at rest. In contrast, acute moderate exercise can improve cognitive function. A recent study suggested that cognitive function improves during moderate exercise even under moderate hypoxia. However, it is unclear how moderate exercise affects cognitive function under severe hypoxia. PURPOSE:To clarify the effects of moderate exercise on cognitive function under severe hypoxia. METHODS:Thirteen subjects completed cognitive tasks under either normoxia or severe normobaric hypoxia (FIO2; 0.12~0.13) in a randomized crossover design. For each condition, participants underwent preliminary testing to assess peak oxygen uptake (peak VO2) while pedaling an ergometer. After a 5-min warm-up (30% peak VO2), they cycled at moderate intensity (50% peak VO2) for 15 min. Cognitive tasks were performed at rest and 5 min after the start of exercise at moderate intensity. Cognitive tasks were a spatial delayed-response task and a Go/NoGo task, which required working memory and executive function. Pulse oximetric saturation (SpO2) and cerebral oxygenation were monitored throughout the experiment. Cerebral oxygenation was recorded by near infrared spectroscopy and was expressed as changes from baseline. RESULTS:Severe hypoxia significantly decreased SpO2 and cerebral oxygenation at rest relative to normoxia (SpO2: 97.9 ± 0.7 vs. 87.8 ± 1.5 %, p < 0.01; cerebral oxygenation: 0.2 ± 1.3 vs -8.9 ± 1.7 %, p < 0.01). Moreover, relative to rest, exercise significantly decreased SpO2 and cerebral oxygenation under hypoxia (SpO2: 87.8 ± 1.5 vs. 77.5 ± 3.0 %, p < 0.01, cerebral oxygenation: -8.9 ± 1.7 vs. -17.0 ± 2.4 %, p < 0.01). Compared with rest, reaction time (RT) on the Go/NoGo task improved during exercise in both conditions (Normoxia: 1015 ± 315 vs. 862 ± 208 ms, p < 0.01, Hypoxia: 1023 ± 228 vs. 896 ± 236 ms, p < 0.01). Neither exercise nor hypoxia altered the accuracy on the cognitive tasks. In the hypoxic condition, ΔRT was negatively correlated with changes in SpO2 (r = -0.56; p < 0.05). CONCLUSIONS:Acute moderate exercise improves cognitive function even under severe hypoxia. However, the improvements under hypoxia appear to lessen as SpO2 decreases during exercise.

Psychotic Experiences and Neuropsychological Functioning in a Population-based Sample.

Psychotic experiences in early life are associated with neuropsychological impairment and the risk for later psychiatric disorders. Psychotic experiences are also prevalent in adults, but neuropsychological investigations spanning adulthood are limited, and confounding factors have not been examined rigorously. To characterize neuropsychological functioning in adults with psychotic experiences while adjusting for important sociodemographic characteristics and familial factors and investigating the effect of age. The South East London Community Health (SELCoH) study is a population-based household survey of physical and mental health in individuals 16 years or older conducted from June 1, 2008, to December 31, 2010, in 2 London boroughs. The study included 1698 participants from 1075 households. Data were analyzed from May 6, 2014, to April 22, 2015. Psychotic experiences measured using the Psychosis Screening Questionnaire. Neuropsychological functioning measured using tests assessing verbal knowledge (Wechsler Test of Adult Reading), working memory (Spatial Delayed Response Task), memory (Visual Object Learning Task), and processing speed (digit symbol coding task). A composite IQ score of general cognitive ability was calculated. A total of 1677 participants with a mean (SD) age of 40 (17) years were included in the analysis. Compared with the group without psychotic experiences, the 171 (9.7%) adults with psychotic experiences did not show a statistically significant impairment on mean (SD) measures of IQ (95.25 [16.58] vs 100.45 [14.77]; Cohen d, -0.22; P = .06) or processing speed (40.63 [13.06] vs 42.17 [13.79]; Cohen d, -0.03; P = .73) but were impaired on measures of verbal knowledge (31.36 [15.78] vs 38.83 [12.64]; Cohen d, -0.37; P = .003), working memory (20.97 [4.12] vs 22.51 [3.26]; Cohen d, -0.34; P = .005), and memory (43.80 [8.45] vs 46.53 [7.06]; Cohen d, -0.28; P = .01). Only participants 50 years and older with psychotic experiences showed medium to large impairments in neuropsychological functioning (mean [SD]) on measures of IQ (81.22 [15.97] vs 91.28 [14.31]; Cohen d, -0.70), verbal knowledge (28.31 [13.83] vs 38.51 [11.50]; Cohen d, -0.88), working memory (19.11 [4.77] vs 21.99 [3.42]; Cohen d, -0.82), and memory (39.17 [8.23] vs 44.09 [6.51]; Cohen d, -0.45) after adjusting for socioeconomic status, cannabis use, and common mental disorders. Medium impairments (mean [SD]) on measures of working memory (21.27 [3.64] vs 22.62 [2.97]; Cohen d, -0.45) and memory (44.32 [5.84] vs 46.91 [5.74]; Cohen d, -0.45) were seen in those aged 35 to 49 years and on a measure of verbal knowledge (30.81 [14.17] vs 37.60 [10.48]; Cohen d, -0.62) in those aged 16 to 24 years. First-degree relatives of adults with psychotic experiences showed a small impairment on a measure of verbal knowledge (34.71 [12.10] vs 38.63 [10.97]; Cohen d, -0.36; P = .02), and unrelated cohabitants showed no neuropsychological impairment. The profile of cognitive impairment in adults with psychotic experiences differed from that seen in adults with psychotic disorders, suggesting important differences between subclinical and clinical psychosis.

Failure to benefit from target novelty during encoding contributes to working memory deficits in schizophrenia

IntroductionAlthough working memory (WM) impairments are well documented in schizophrenic patients (PSZ), the underlying mechanisms are poorly understood. The aim of this study was to investigate the role of target salience during encoding to determine whether impaired visual attention in PSZ leads to poor WM.MethodsThirty-one PSZ and 28 demographically matched healthy controls (HC) performed a spatial delayed-response task. Attentional demands were manipulated during WM encoding by presenting high salient (novel) or low salient (familiar) targets. Participants also rated their level of response confidence at the end of each trial, allowing us to analyse different response types.ResultsWM was impaired in PSZ. Increasing target salience by increasing novelty improved WM performance in HC but not in PSZ. Poor WM performance in PSZ was largely due to an increase in the proportion of incorrect but high confident responses most likely reflecting a failure to encode the correct target.ConclusionsOur findings suggest that dysfunctions of non-mnemonic attentional processes during encoding contribute to WM impairments in schizophrenia and may represent an important target for cognitive remediation strategies.

Exceptional visuospatial imagery in schizophrenia; implications for madness and creativity.

Biographical and historical accounts suggest a link between scientific creativity and schizophrenia. Longitudinal studies of gifted children indicate that visuospatial imagery plays a pivotal role in exceptional achievements in science and mathematics. We asked whether visuospatial imagery is enhanced in individuals with schizophrenia (SZ). We compared SZ and matched healthy controls (HC) on five visuospatial tasks tapping parietal and frontoparietal functions. Two aspects of visuospatial transformation, spatial location and mental imagery manipulation were examined with Paper Folding Test (PFT) and jigsaw puzzle task (JPT), respectively. Visuospatial intelligence was assessed with Ravens Progressive Matrices, which is associated with frontoparietal network activity. Hemispatial inattention implicating parietal function was assessed with line bisection (LB) task. Mediated by prefrontal cortex, spatial delayed response task (DRT) was used to index working memory maintenance, which was impaired in SZ compared to HC. In contrast, SZ showed intact visuospatial intelligence and transformation of location. Further, SZ performed significantly better than HC on JPT indicating enhanced mental imagery manipulation. Spatial working memory (SWM) maintenance and mental imagery manipulation were strongly associated in HC but dissociated in SZ. Thus, we observed enhanced mental imagery manipulation in SZ but the dissociation of mental imagery from working memory suggests a disrupted frontoparietal network. Finally, while HC showed the expected leftward pseudoneglect, SZ showed increased rightward LB bias implicating left hemispatial inattention and impaired right parietal control of spatial attention. The current results chart a unique profile of impaired, spared and enhanced parietal-mediated visuospatial functions implicating parietal abnormalities as a biobehavioral marker for SZ. We discuss these results in relation to creative cognition.

Working memory encoding and false memory in schizophrenia and bipolar disorder in a spatial delayed response task.

Working memory (WM) impairment is a core feature of schizophrenia, but the contributions of different WM components are not yet specified. Here, we investigated the potential role of inefficient encoding in reduced WM performance in patients with schizophrenia (PSZ). Twenty-eight PSZ, 16 patients with bipolar disorder (PBP), 16 unaffected and unmedicated relatives of PSZ (REL), and 29 demographically matched healthy controls (HC) performed a spatial delayed response task with either low or high WM demands. The demands on attentional selection were also manipulated by presenting distractor stimuli during encoding in some of the trials. After each trial, participants rated their level of response confidence. This allowed us to analyze different types of WM responses. WM was severely impaired in PSZ compared to HC; this reduction was mainly due to an increase in the amount of false memory responses (incorrect responses that were given with high confidence) rather than an increase in the amount of incorrect and not-confident responses. Although PBP showed WM impairments, they did not have increased false memory errors. In contrast, reduced WM in REL was also accompanied by an increase in false memory errors. The presentation of distractors led to a decline in WM performance, which was comparable across groups indicating that attentional selection was intact in PSZ. These findings suggest that inefficient WM encoding is responsible for impaired WM in schizophrenia and point to differential mechanisms underlying WM impairments in PSZ and PBP.