Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory

Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters. Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance. The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters. Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.

Functional topography of a distributed neural system for spatial and nonspatial information maintenance in working memory

To assess the effects of NMDA receptor blockade on memory tasks that require the hippocam-pal system, rats were injected with either MK-801, a noncompetitive NMDA antagonist known to block induction of long-term potentiation in vitro, or normal saline before daily behavioral testing in both working-memory (WM) and reference-memory (RM) procedures on an eight-arm radial maze. Even after 64 days of testing, rats given MK-801 performed poorly on both RM and WM tasks relative to rats given saline. The same dose of MK-801 that impaired memory acquisition affected neither WM nor RM performance in trained rats that had been given saline. In these rats, combined MK-801 and naloxone affected neither WM nor RM, larger doses of MK-801 produced slight ataxia and both WM and RM deficits, but none of the doses produced a selective WM impairment. Interposing a 2-h delay between the first two and the last two correct WM choices produced a small increase in both WM and RM errors, which demonstrates that MK-801 does not selectively impair long-term WM. Finally, rats given MK-801 chronically and then withdrawn from the drug learned both the WM and the RM tasks, and were subsequently affected only mildly by low doses of MK-801. The results show that functioning NMDA receptors are necessary for learning spatial WM and RM tasks, but not for performing WM or RM tasks after training, and imply that two mechanisms may be required for storing relational (e.g., spatial) memory: an NMDA-dependent mechanism for long-term storage of spatial representations, and a second, non-NMDA mechanism for operating upon those representations.

The relationship between adolescent cannabis use and susceptibility to persistent cognitive impairments is poorly understood. We examined the effects of repeated exposure to Δ-9-tetrahydrocannabinol (THC) on reinforcement-related learning and performance of spatial working memory (WM) tasks of varying difficulty in adolescent monkeys. Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 12 months. Performance on 4-item spatial WM trials was assessed throughout the 12-month study period. At the 6-month time point, more difficult novel and distractor 8-item spatial WM trials were added. Residual effects on performance were determined 23 or 71 h after THC or vehicle administration throughout the study. Relative to vehicle-exposed animals, repeated THC exposure was initially associated with significantly slower improvement in performance accuracy on 4-item spatial WM trials; however, this performance difference gradually diminished such that by month 12, accuracy did not significantly differ between vehicle and THC groups. Similarly, for the novel and distractor 8-item trials introduced at month 6, performance accuracy improved more slowly in the THC than in the vehicle group, despite comparable performance between groups on the 4-item task during this same period. These findings suggest that compared to vehicle exposure, THC exposure during adolescence impairs the reinforcement-related learning process required for improved performance on spatial WM tasks, but this impairment might be overcome with continued training, even in the face of ongoing THC exposure.

The present study investigated verbal and spatial working memory (WM) functioning in individuals with the neuro-developmental disorder Williams syndrome (WS) using WM component tasks. While there is strong evidence of WM impairments in WS, previous research has focused on short-term memory and has neglected assessment of executive components of WM. There is a particular lack of consensus concerning the profile of verbal WM functioning in WS. Here, WS participants were compared to typically developing participants matched for (1) verbal ability and (2) spatial ability ( N = 14 in each of the 3 groups). Individuals with WS were impaired on verbal WM tasks, both those involving short-term maintenance of information and executive manipulation, in comparison to verbal-matched controls. Surprisingly, individuals with WS were not impaired on a spatial task assessing short-term maintenance of information in memory (remembering spatial locations) compared to spatial-matched controls. They were, however, impaired on a spatial executive WM task requiring the manipulation of spatial information in memory. The present study suggests that individuals with WS show WM impairments that extend to both verbal and spatial domains, although spatial deficits are selective to executive aspects of WM function.

The role of prefrontal cortex in working memory (WM) is well established. However, questions remain regarding the topography and “domain-specific differentiation” of different types of information processing in the cortex. While it has been theorized that dorsolateral (DPFC) and ventrolateral (VPFC) prefrontal cortex preferentially process spatial and object WM, respectively, both electrophysiological evidence in the monkey and neuroimaging in the human have largely failed to demonstrate such regional differentiation. In this study we use near-infrared spectroscopy (NIRS) to detect functional changes, across relatively large cortical cell populations, simultaneously from prefrontal and posterior parietal cortices. Imaging data were recorded from a Rhesus macaque performing two types of WM tasks: a spatial task in which the animal had to retain the spatial position of a visual stimulus, and a non-spatial task where he had to retain its color (red or green) during a 20s delay. During performance of the spatial WM task, cerebral activation trends were found in which DPFC exhibited stronger activation than did the VPFC, and posterior parietal cortex maintained higher delay activation than did frontal regions. These differences were less pronounced during performance of the non-spatial task. Additionally, incorrect trials generally elicited lower activations during the delay period than did trials ending with a correct response. Furthermore, NIRS data collected during the performance of a haptic WM task also appear to exhibit inter-regional differences in delay activation. The data thus suggest the presence of preferential cognitive processing between and within posterior and frontal cortical regions.

Existing literature outlines the quality and location of activation in the prefrontal cortex (PFC) during working memory (WM) tasks. However, the effects of individual differences on the underlying neural process of WM tasks are still unclear. In this functional near infrared spectroscopy study, we administered a visual and auditory n-back task to examine activation in the PFC while considering the influences of task performance, and preferred learning strategy (VARK score). While controlling for age, results indicated that high performance (HP) subjects (accuracy > 90%) showed task dependent lower activation compared to normal performance subjects in PFC region Specifically HP groups showed lower activation in left dorsolateral PFC (DLPFC) region during performance of auditory task whereas during visual task they showed lower activation in the right DLPFC. After accounting for learning style, we found a correlation between visual and aural VARK score and level of activation in the PFC. Subjects with higher visual VARK scores displayed lower activation during auditory task in left DLPFC, while those with higher visual scores exhibited higher activation during visual task in bilateral DLPFC. During performance of auditory task, HP subjects had higher visual VARK scores compared to NP subjects indicating an effect of learning style on the task performance and activation. The results of this study show that learning style and task performance can influence PFC activation, with applications toward neurological implications of learning style and populations with deficits in auditory or visual processing.

Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to schizophrenia.

It appears that functionally segregated visual pathways exist in the primate brain for the processing of visuospatial versus nonspatial information. Functional segregation has been demonstrated for the early associative processing of sensory information but may also exist at higher levels of cognitive analysis. Namely, connections between the dorsal visual system and dorsolateral prefrontal cortex (PFC) appear to mediate spatial working memory, which is modulated by dopamine receptor fields in the principal sulcal region of the PFC. It is speculated that nonspatial working memory may be modulated within connections between ventral visual processing regions and the inferior convexity of the PFC. Whether dopamine facilitates nonspatial memory through connections between the ventral visual system and ventral PFC has not been examined. In this study, normal humans completed spatial and nonspatial working memory tasks under pharmacological challenges with a dopamine receptor agonist (bromocriptine) and antagonist (haloperidol) in a double-blind placebcxontrolled repeated measures design. Findings indicated facilitation of spatial delayed working memory functions by bromocriptine and impairment of spatial working memory functions by haloperidol. Neither drug was effective in manipulating nonspatial memory performance. Control tasks were included to measure drug effects on basic sensorimotor and attentional processes. Findings suggest that separate processing mechanisms for remembering "What" versus "Where" an object is may exist at structural, but also neurochemical, levels in the human brain.

Differential Neural Activation for Updating Rule versus Stimulus Information in Working Memory

Spatial working memory among middle-aged and older patients with schizophrenia and volunteers using fMRI

Dysfunction of executive neuropsychological performance, mediated by the prefrontal cortex, has been the central focus of recent attention deficit/ hyperkinetic disorder (AD-HKD) research. The role of other potential neuropsychological "risk factors", such as recognition memory, remains understudied. Further, the impact of methylphenidate (MPH) on key neuropsychological processes in AD-HKD remains poorly understood. To compare the performance of boys with AD-HKD on a spatial working memory (SWM) task and on two non-working memory tasks [a simultaneous and delayed matching-to-sample task (DMtS) and a pattern-recognition task] with that of healthy boys, and to investigate the impact of acute and chronic MPH on performance of these tasks. Baseline performance of 75 stimulant-naive boys with AD-HKD was compared with that of 70 healthy boys. The AD-HKD boys were then re-tested following the administration of acute and chronic challenges with MPH (0.3 mg/kg and 0.6 mg/kg) under randomised double-blind placebo controlled conditions. Compared with healthy boys, the AD-HKD boys demonstrated performance deficits on all neuropsychological tasks. A single dose of MPH restored performance on the DMtS task but had no impact on the SWM or pattern-recognition tasks. Chronic MPH administration did not alter performance on the SWM task but did improve performance on both the pattern-recognition and DMtS tasks. However, the acute restorative effect of MPH on DMtS diminished with repeated administration. Our results suggest that current conceptualisations of the neuropsychological basis of AD-HKD and the proposed therapeutic mechanisms of MPH require broadening.

Recent research emphasizes how working memory (WM) supports action in dynamic environments. But action almost always involves fast, “saccadic” eye movements that challenge WM representations, requiring spatial remapping and distorting spatial perception, especially along the saccade direction. To capture the impact of these distortions, we used a spatial WM task where participants, after a saccade or fixation, indicated remembered locations of memory items with a mouse. From the responses we extracted multiple measures of spatial error: response variability, shifts relative to the fixation point, rotations, compression and nonlinear distortions of space. These measures submitted to a principal component analysis (PCA) yielded two components: systematic and unsystematic spatial error both of which were correlated with established WM tasks, showing their relevance for WM fidelity. Systematic error revealed a centripetal bias, pulling towards spatial anchors like the fixation point and the memory array’s centre of mass. This suggests that systematic error reflects a spatial scaffold that encodes relational information but is inherently imprecise. Saccades increased both error components and amplified WM load effects. Notably, we found that distortions of systematic error were especially pronounced along saccade direction for items that were remapped across visual fields, implying that WM fidelity is more vulnerable when information needs to pass through the corpus callosum. Together, our findings are consistent with the idea of WM actively reconstructing spatial information. They offer new insights into how saccades and spatial remapping shape WM in a dynamic world.

Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive-Compulsive Drinking Scale-OCDS), alcohol use of the last 90 days, and general intelligence. Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts.

Reorganization of Frontal Systems Used by Alcoholics for Spatial Working Memory: An fMRI Study