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The role of the mid-dorsolateral prefrontal cortex in working memory.

Recent studies with nonhuman primates have shown that lesions of the mid-dorsolateral prefrontal cortex, which extends from the lip of the dorsal bank of the sulcus principalis to the midline (i.e., dorsal area 46 and 9/46 and area 9), give rise to severe and long-lasting impairments on self-ordered and externally ordered tasks designed to tax executive processing within working memory, rather than short-term memory per se. Lesions limited to area 9 give rise to a mild impairment on these tasks. Thus, the mid-dorsolateral prefrontal region has been shown to be critical for the monitoring of multiple events in working memory. The mid-dorsolateral prefrontal region receives visuospatial input from the posterior dorsolateral region (areas 8 and 6) and from the cortex within the middle part (sulcal area 46) and the caudal part (area 8) of the sulcus principalis. Nonspatial visual input originates from the ventrolateral prefrontal cortex. Thus, lesions focused on the middle to caudal part of the sulcus principalis would affect visuospatial input, but would not affect the flow of nonspatial visual object information that reaches the mid-dorsolateral prefrontal region from the ventrolateral prefrontal cortex. Lesions of the sulcus principalis produce a spatially selective impairment, whereas lesions of the mid-dorsolateral prefrontal region produce a more general impairment of the monitoring and manipulation of information in working memory. The results of recent functional neuroimaging studies with human subjects are consistent with the above findings from work with the monkey.

Animals↗

Working memory deficiencies in adults associated with low-level lead exposure: implications of neuropsychological test results.

BACKGROUND: Although lead exposure has steadily decreased in the last few years, some lead is still used in the metal processing industry, mostly for wall paints and plumbing. Recent studies on children showed neurobehavioral effects of low-level exposure, but little is known about the neurocognitive effects of lead concentrations in the upper reference range on adults. METHODS: The neuropsychological effects of lead exposure were examined in 39 adult outpatients at the Unit of Environmental Medicine (UEM), University Hospital, Aachen, Germany. All patients underwent a comprehensive medical examination, including psychiatric. Venous blood and urine samples were collected and tested for heavy metals and selenium. Since the neuropsychological examination was not expected to reveal any severe abnormalities, only specific attentiveness functions were analyzed (alertness, working memory, flexibility, intermodal comparison) since these areas were the likeliest to show objectifiable effects. The tests were conducted using a standardized computerized battery. RESULTS: Lead blood levels ranged from 1 to 65.6 microg/l (mean 27.4 +/- 16.2 microg/l). Although the neuropsychological test results of all patients were within the normal range, there were significant correlations between blood lead levels and the speed of information processing for working memory. CONCLUSIONS: The results indicate working memory dysfunctions in adults, the severity of which correlates directly with blood lead levels, supporting the hypothesis that increased blood lead levels can also be associated with measurable neurocognitive abnormalities.

Adult↗

Functional MR imaging of the prefrontal cortex: specific activation in a working memory task.

Functional magnetic resonance imaging was used to identify cortical regions activated by a working memory task involving letter detection. Twenty four normal subjects were scanned with a conventional 1.5-T magnet while performing one of two tasks: In the activation task, subjects responded by pressing a button whenever any presented letter was the same as the second last in the sequence. In the control condition, subjects had to respond to a single predefined letter without memory update requirements. The activation task and the control condition were identical with regard to perceptual input and motor output. They were different only regarding the task demand. Movement artifacts were minimized in a two way strategy and eight subjects were excluded from further analysis. Functional MR data from the remaining 16 subjects were analyzed on the basis of anatomical regions-of-interest which were manually defined in each subject. The engagement of working memory produced significant activation in the dorsolateral prefrontal cortex (Brodmann's areas 9, 10, 46, and 47) in both hemispheres. Results demonstrate the applicability of the paradigm within a clinical MRI setup and corroborate previous findings of non-lateralized dorsolateral prefrontal activation during continuous context updating and active maintenance.

Adult↗

Executive function and verbal working memory in adolescents with closed head injury (CHI).

The relationship between executive function (EF) and working memory (WM) was studied in eight adolescents with closed head injury (CHI) and eight controls, matched for age, gender and socioeconomic status (SES). A cognitive-linguistic test (Scales of Cognitive Ability for Traumatic Brain Injury, SCATBI) was used to group CHI participants by seventy. EF was tested with a measure of daily functioning (Pro-Ex) and WM was tested with a recognition memory task (RMT). When all subject test data were grouped, a positive linear correlation was found for the Pro-Ex and the RMT. A strong-to-moderate positive correlation was found for components of the EF measure and the RMT. Severity of injury influenced test performance for both the EF and WM measures, with a significance between group effects found on the RMT task. Results indicate a relationship between executive function and working memory, severity of injury and test performance and the need to assess EF of CHI adolescents with a measure of daily functioning.

Activities of Daily Living↗

Decreased brain activation during a working memory task at rested baseline is associated with vulnerability to sleep deprivation.

STUDY OBJECTIVE: To examine whether differences in patterns of brain activation under baseline conditions relate to the differences in sleep-deprivation vulnerability. DESIGN: Using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging, we scanned 33 healthy young men while they performed the Sternberg working memory task following a normal night of sleep and again following 30 hours of sleep deprivation. From this initial group, based on their Sternberg working memory task performance, we found 10 subjects resilient to sleep deprivation (sleep deprivation-resilient group) and then selected 10 age- and education-matched subjects vulnerable to sleep deprivation (sleep deprivation-vulnerable group). SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: Data from 10 young men (mean age 27.8 +/- 1.7 years) in the sleep deprivation-resilient group and 10 young men (mean age 28.2 +/- 1.9 years) in the sleep deprivation-vulnerable group were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We compared functional magnetic resonance imaging BOLD signal at rested baseline and sleep deprivation states in the 2 groups. As hypothesized, following sleep deprivation, both groups showed significant decreases in global brain activation compared to their rested group baseline. At rested baseline and in the sleep-deprivation state, the sleep deprivation-resilient group had significantly more brain activation than did the sleep deprivation-vulnerable group. There were also differences in functional circuits within and between groups in response to sleep deprivation. CONCLUSIONS: These preliminary data suggest that patterns of brain activation during the Sternberg working memory task at the rested baseline and the sleep-deprivation state, differ across individuals as a function of their sleep-deprivation vulnerability.

Adolescent↗

The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys.

BACKGROUND: Previous studies have indicated that beta adrenergic receptor stimulation has no effect on the cognitive functioning of the prefrontal cortex (PFC). Blockade of beta-1 and beta-2 receptors in the PFC with the mixed beta-1/beta-2 antagonist, propanolol, had no effect on spatial working memory performance. However, more selective blockade of beta-1 or beta-2 receptors might show efficacy if the two receptors have opposite effects on PFC function. The current study examined the effects of the selective beta-1 antagonist, betaxolol, on working memory in rats and monkeys. METHODS: In rats, betaxolol (.0011-1.11 microg/.5 microL) was infused into the PFC 5 min before delayed alternation testing. Monkeys were systemically injected with betaxolol (.0000011-.11 mg/kg) 2 hours before delayed response testing. RESULTS: Betaxolol produced a dose-related improvement in working memory performance following either direct PFC infusion in rats, or systemic administration in monkeys. However, some aged monkeys developed serious pancreatic problems over the course of this study. CONCLUSIONS: These findings suggest that endogenous activation of the beta-1 adrenergic receptor impairs PFC cognitive function. These results may have therapeutic relevance to post-traumatic stress disorder or other disorders with excessive noradrenergic activity and PFC dysfunction. Pancreatic side effects in aged subjects taking betaxolol warrants further investigation.

Adrenergic beta-1 Receptor Antagonists↗

Working memory deficits in adult rats after prenatal disruption of neurogenesis.

We investigated the cognitive consequences of a prenatal injection of the mitotic inhibitor methylazoxymethanol (MAM) into pregnant rats at embryonic day 15 (E15) or 17 (E17). The male offspring were tested when adult on a version of the radial-arm maze task that assesses spatial working memory with an extended delay, where performance is dependent, in part, on the hippocampal-prefrontal circuit. A major impairment of spatial learning was observed in E15 MAM rats. However, the E17 MAM rats did learn the rule but were impaired selectively in the 30-min delay-interposed task. Morphologically, the E15 MAM rats exhibited dramatic gross brain abnormalities, whereas the E17 MAM animals displayed aberrant cell migration in the hippocampus and a disrupted laminar pattern in the neocortex. These results suggest that late gestational MAM injection (E17) causes a cognitive impairment in a prefrontal cortex-hippocampus-dependent working memory task. This approach could provide a new developmental model of disorders associated with working memory deficits, such as schizophrenia.

Abnormalities, Drug-Induced↗

The effects of working memory resource availability on prospective memory: a formal modeling approach.

The PAM theory of event-based prospective memory (Smith, 2003; Smith & Bayen, 2004a) proposes that successful prospective memory performance demands upon the interaction of preparatory attentional processes and retrospective memory processes. The two experiments in the current study represent the first application of a formal model to investigate the sensitivity of these underlying processes to variations in working memory resource availability. Multinomial modeling of data from prospective-memory tasks showed that working memory span influenced preparatory attentional processes and retrospective-memory processes.

Attention↗

Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats.

Cannabinoids which impair rat working memory appear to inhibit hippocampal extracellular acetylcholine (Ach) release and reduce choline uptake through an interaction with CB1 cannabinoid receptors. Here we report that CP 55,940, a potent bicyclic synthetic cannabinoid analog, dose-dependently impaired rat performance, when given i.p. 20 min before an eight-arm radial maze test. The selective CB1 cannabinoid receptor antagonist SR 141716A, given i.p. 20 min earlier, significantly reduced the memory deficit Pretreatment with eptastigmine, a second generation cholinesterase inhibitor, given orally 100 min before the cannabinoid agonist, relieved the memory impairment without affecting CP 55,940-induced behavioural alterations such as reduced spontaneous motor activity, analgesia and hind limb splaying. These data suggest that cannabinoid-induced working memory impairment is mediated through a central cholinergic blockade.

Animals↗

Persistent impairment of gait performances and working memory after bilateral common carotid artery occlusion in the adult Wistar rat.

BACKGROUND: The clinical and pathophysiological effects of a chronic reduction of cerebral blood flow in humans are not completely known. We investigated whether rats subjected to bilateral common carotid artery occlusion (bCCA-o) developed focal neurological deficits, gait dysfunction, and working memory alterations. METHODS: Eighteen male Wistar rats were subjected to bCCA-o, 13 were sham-operated. We assessed sensorimotor functions, gait on a 60 cm-long elevated bridge, and working memory (object recognition and Y maze tests) before and 30, 60, and 90 days after surgery. Histological analysis was performed in a subgroup of 10 rats. RESULTS: No rat showed sensorimotor alterations after surgery. Although gait performances of both bCCA-o and sham-operated rats declined over time, the differences reached statistical significance only for the bCCA-o group (mean+/-SE: 26.8+/-5.0; 22.4+/-4.9; 24.5+/-5.5 cm at 30, 60, and 90 days, respectively) in comparison with baseline (52.9+/-5.2 cm; P<0.05). At 60 and 90 days, bCCA-o rats in comparison with sham-operated rats showed decreased performances on object recognition (discrimination index: 0.15+/-0.03 vs. 0.29+/-0.05 at 60 days and 0.10+/-0.04 vs. 0.41+/-0.07 at 90 days; P<0.05) and on Y maze test (alternating rats: 9.9 vs. 85.7% at 60 days and 16.6 vs. 100% at 90 days; P<0.01). In none of the animals were cerebral infarcts detected. Selective neuronal necrosis was observed in the cortex and hippocampus of both bCCA-o and sham-operated rats without any obvious difference. CONCLUSIONS: bCCA-o in the Wistar rat induces persistent and progressive gait and working memory impairment without producing sensorimotor deficit or cerebral infarcts. This model may help to elucidate some physiopathological aspects of neurological impairment associated with states of cerebral chronic ischemia.

Animals↗

Impact of combined estradiol and norethindrone therapy on visuospatial working memory assessed by functional magnetic resonance imaging.

CONTEXT: Hormones regulate neuronal function in brain regions critical to cognition; however, the cognitive effects of postmenopausal hormone therapy are controversial. OBJECTIVE: The goal was to evaluate the effect of postmenopausal hormone therapy on neural circuitry involved in spatial working memory. DESIGN: A randomized, double-blind, placebo-controlled crossover study was performed. SETTING: The study was performed in a tertiary care university medical center. PARTICIPANTS: Ten healthy postmenopausal women of average age 56.9 yr were recruited. INTERVENTIONS: Volunteers were randomized to the order they received hormone therapy (5 microg ethinyl estradiol and 1 mg norethindrone acetate). Subjects received hormone therapy or placebo for 4 wk, followed by a 1-month washout period with no medications, and then received the other treatment for 4 wk. At the end of each 4-wk treatment period, a functional magnetic resonance imaging study was performed using a nonverbal (spatial) working memory task, the Visual Delayed Matching to Sample task. MAIN OUTCOME MEASURE: The effects of hormone therapy on brain activation patterns were compared with placebo. RESULTS: Compared with the placebo condition, hormone therapy was associated with a more pronounced activation in the prefrontal cortex (BA 44 and 45), bilaterally (P < 0.001). CONCLUSIONS: Hormone therapy was associated with more effective activation of a brain region critical in primary visual working memory tasks. The data suggest a functional plasticity of memory systems in older women that can be altered by hormones.

Brain↗

Presentation format and its effect on working memory.

In three experiments, we examined the separate cognitive demands of processing and storage in working memory and looked at how effective the coordination was when items for storage varied in format/modality. A sentence verification task involving arithmetic facts was combined with a span task involving two to six items presented in picture, printed word, or spoken word format. The first two experiments were the same, except for the added requirement of articulation of the math sentence in Experiment 2. Experiment 3 varied the length of the span item and compared recall with recognition performance. The results showed that both spoken words and picture produced superior recall and recognition, as compared with printed words, and are consistent with Baddeley and Logie's (1999) and Mayer's (2001) models of working memory. Also, the differences in processing performance across spans varied with the difficulty of the task but showed the strongest support for the resource allocation model (Foos 1995).

Cognition↗

Hippocampal function required for nonspatial working memory.

The hippocampus has been implicated as a brain structure necessary for normal memory functions and normal spatial behavior. Both these explanations are consistent with the results of previous experiments demonstrating an impairment of choice accuracy following fimbria-fornix lesions on an elevated radial arm maze because the test procedure required working memory and permitted cognitive mapping. In the present experiment, rats were tested in an enclosed radial arm maze in which each arm had a distinctive set of discriminative stimuli and the test procedure required working memory but prevented cognitive mapping. Rats were tested preoperatively, given fimbria-fornix lesions, and then tested postoperatively. The rats with lesions performed at chance levels and showed no evidence of recovery of function. These results are consistent with the hypothesis that the poor choice accuracy in the elevated radial arm maze task arose because of the working memory requirements of that task, rather than its cognitive mapping characteristics, and support interpretations of hippocampal function that emphasize memory processing.

Animals↗

Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats.

There is a unidirectional, ipsilateral and monosynaptic projection from the hippocampus to the prefrontal cortex. The cognitive function of hippocampal-prefrontal cortical circuit is not well established. In this paper, we use muscimol treated rats to investigate the roles of the hippocampal-prefrontal cortical circuits in spatial working memory, as assessed with a delayed spatial alternation task. First of all, the effect of muscimol on EEG power of infusion area was observed for confirmation of the dosage of muscimol to inhibit the function of infusion area. The results show that the EEG power of the ventral hippocampus and the prelimbic area of the prefrontal cortex were inhibited by local infusion of muscimol (0.5 microg in 0.25 microl PBS) into the above areas, respectively. Delayed alternation performance was significantly impaired when muscimol at this dosage was infused (1) bilaterally into the ventral hippocampus, (2) bilaterally into the prelimbic area, (3) unilaterally into the ventral hippocampus and simultaneously contralaterally into the prelimbic area. Infusion of muscimol either unilaterally into the ventral hippocampus or unilaterally into the prelimbic area did not impair delayed alternation performance. The present results suggest that any structures in this circuit is damaged or inhibited bilaterally, the spatial working memory will be disrupted. It means the hippocampal-prefrontal cortical circuit plays an important role in spatial working memory.

Animals↗

Early processing deficits in object working memory in first-episode schizophreniform psychosis and established schizophrenia.

BACKGROUND: While there are many studies showing working-memory deficits in schizophrenia there are only a few that disentangle impairments for working-memory subprocesses such as perceptual, attentional, mnemonic and executive function. METHOD: In this study of delay-dependent memory, 55 patients with schizophreniform psychosis, 50 with established schizophrenia and 56 healthy controls were investigated. Using the delayed matching-to-sample task from the Cambridge Neuropsychological Test Automated Battery (CANTAB), performance deficits were found in both patient groups after controlling for age and pre-morbid IQ. RESULTS: Even after controlling for simultaneous matching-to-sample ability (i.e. perceptual matching), impaired performance in both patient groups was found as soon as the stimuli were no longer present. Impaired performance was not due to different types of errors in patients versus controls. Performance in both patient groups was comparable, except for a slight decrease of overall task performance. This suggests that the deficit is relatively stable during the course of the illness. CONCLUSIONS: Our results suggest a deficit in patients with psychotic illness in the initial processes necessary to actively maintain information, such as the ability to form an internal representation of complex objects.

Adolescent↗

Decision making with the "adaptive toolbox": influence of environmental structure, intelligence, and working memory load.

In 2 experiments with a total of 220 participants, the tendency to use simple heuristics such as the take the best heuristic in an adaptive manner was investigated. In a simulated stock market paradigm, the payoff structure of environments was varied, favoring either compensatory or noncompensatory decision strategies in terms of expected long-term payoff. In both experiments, the majority of participants were classified as using strategies that were adequate for the environment, supporting the notion of adaptive strategy selection. These strategy shifts were moderated by intelligence, as measured with common tests. Neither an additional learning phase (Experiment 1) nor working memory load or working memory capacity (Experiment 2) had additional effects on strategy selection.

Adult↗

The asymmetry of working memory training transfer: A systematic review and meta-analysis.

Working memory (WM) training is widely used to enhance cognitive performance; however, its transfer to untrained tasks remains controversial. Traditional theories emphasize task similarity as the primary determinant of training transfer, but they cannot fully explain emerging evidence of asymmetric transfer across tasks. Two directional transfer hypotheses are proposed here to explain this asymmetry: the resource-based transfer advantage hypothesis predicts stronger transfer from more to less cognitively demanding tasks, whereas the ability-based transfer advantage hypothesis predicts stronger transfer from tasks engaging broader task-general abilities to tasks engaging task-specific narrower abilities. The contrast between span and updating paradigms provides an informative framework for distinguishing these accounts, because updating tasks are generally more cognitively demanding, whereas span tasks involve broader abilities. Accordingly, we conducted a three-level meta-analysis of 55 studies (208 effect sizes; N = 3,492). The results showed that updating training transferred reliably to span tasks (g = 0.176, p < .001), whereas span training did not reliably transfer to updating tasks (g = 0.048, p = .453), supporting the resource-based account. This advantage of updating training also extended to non-WM outcomes and was more pronounced at lower training doses, in non-adult samples, and with verbal stimuli. Together, these findings extend WM transfer theory beyond task similarity by highlighting the importance of cognitive demand and offer guidance for WM training design.

Humans↗

Auditory and visual working memory performance in patients with frontal lobe damage and in schizophrenic patients with low scores on the Wisconsin Card Sorting Test.

Impaired performance in the Wisconsin Card Sorting Test (WCST) has frequently been postulated to be one typical feature indicating frontal dysfunction in patients with schizophrenia. From a functional point of view, impairments were attributed to a dysfunction of working memory. The present study compares the performance of groups of schizophrenic patients, groups of patients with acquired brain damage as well as normal controls on tasks involving visual and auditory working memory. Modified versions of Sternberg tasks were used varying the physical attributes of the material to be rehearsed in order to force a different involvement of both the 'visuo-spatial sketch-pad' and the 'phonological loop'. Within a group of frontal-lobe-damaged patients (n=6), processing was markedly prolonged for both kinds of material, an observation attributed to a dysfunction of the central executive component of the working memory model. On the other hand, results for schizophrenic patients with poor WCST performance (n=6) suggest a more discrete dysfunction of the phonological loop, but not the visuo-spatial sketch-pad. There were no significant differences between normal controls (n=6) and clinical control groups [patients with non-frontal lesions (n=6) and schizophrenic patients with normal scores on the WCST (n=6)]. Comparisons of the various group data rule out an unspecified frontal dysfunction of schizophrenic patients with low scores on the WCST.

Adult↗