Nonspatial Working Memory Research Articles

Working Memory for Letters, Shapes, and Locations: fMRI Evidence against Stimulus-Based Regional Organization in Human Prefrontal Cortex

Investigations of working memory (WM) systems in the frontal cortex have revealed two stimulus dimensions along which frontal cortical representations may be functionally organized. One hypothesized dimension dissociates verbal from nonverbal WM processes, dividing left from right frontal regions. The second hypothesized dimension dissociates spatial from nonspatial WM, dividing dorsal from ventral frontal regions. Here we used functional magnetic resonance imaging to probe WM processes associated with three different types of stimuli: letters (verbal and nonspatial), abstract shapes (nonverbal and nonspatial), and locations (nonverbal and spatial). In a series of three experiments using the “n-back” WM paradigm, direct statistical comparisons were made between activation patterns in each pairwise combination of the three stimulus types. Across the experiments, no regions that demonstrated responses to WM manipulations were discovered to be unique to any of the three stimulus types. Therefore, no evidence was found to support either a left/right verbal/nonverbal dissociation or a dorsal/ventral spatial/nonspatial dissociation. While this could reflect a limitation of the present behavioral and imaging techniques, other factors that could account for the data are considered, including subjects' strategy selection, encoding of information into WM, and the nature of representational schemes in prefrontal cortex.

An fMRI Investigation of Cortical Contributions to Spatial and Nonspatial Visual Working Memory

The experiments presented in this report were designed to test the hypothesis that visual working memory for spatial stimuli and for object stimuli recruits separate neuronal networks in prefrontal cortex. We acquired BOLD fMRI data from subjects while they compared each serially presented stimulus to the one that had appeared two or three stimuli previously. Three experiments failed to reject the null hypothesis that prefrontal cortical activity associated with spatial working memory performance cannot be dissociated from prefrontal cortical activity associated with nonspatial working memory performance. Polymodal regions of parietal cortex (inferior and superior parietal lobules), as well as cortex surrounding the superior frontal sulcus (and encompassing the frontal eye fields), also demonstrated equivalent levels of activation in the spatial and object conditions. Posterior cortical regions associated with the ventral visual processing stream (portions of lingual, fusiform, and inferior temporal gyri), however, demonstrated greater object than spatial working memory-related activity, particularly when stimuli varied only along spatial or featural dimensions. These experiments, representing fMRI studies of spatial and object working memory in which the testing procedure and the stimuli were identical in the two conditions, suggest that domain-specific visual working memory processing may be mediated by posterior regions associated with domain-specific sensory processing.

Non-spatial water radial-arm maze learning in mice

Recently, we published a method for examining working and reference memory in mice using a spatial version of the water radial-arm maze. Here we describe a non-spatial version of the same maze. BXSB mice were able to learn the maze as shown by the decrease in the number of working and reference memory errors over sessions. This maze was used to examine learning differences between males and females and between mice with misplaced clusters of neurons in layer I of cortex (ectopias) and those without. In a prior study using the spatial version of the water radial-arm maze, male BXSB mice had poorer working memory than females during the acquisition phase. Similarly, in this study male BXSB mice demonstrated impaired working memory during the asymptotic phase of non-spatial radial-arm maze learning. Two prior studies showed that mice with neocortical ectopias demonstrated working memory impairments compared to non-ectopic littermates in the spatial version of the water radial-arm maze. Contrary to this, in the non-spatial radial-arm maze used here, ectopic mice were not impaired in working memory and showed better memory when the working memory ‘load’ was the highest. Overall, both versions of the maze can be useful tools to assess spatial and non-spatial working and reference memory in mice.

Using event-related fMRI to assess delay-period activity during performance of spatial and nonspatial working memory tasks

Event-related experimental design and analysis techniques for functional magnetic resonance imaging (fMRI) take advantage of the intrinsic temporal resolution of fMRI to permit investigation of complex human behaviors on the time scale over which they can occur. The protocol described in this report permits the effective isolation and assessment of variance in the fMRI signal that is attributable solely to the delay portion of delayed-response tasks. It permits, therefore, evaluation of the purely mnemonic portions of working memory tasks without requiring the “cognitive subtraction” of nonmnemonic components of such tasks, such as visual processing and motor output. Features of this event-related fMRI technique include the empirical derivation of an impulse response function (IRF) from each subject participating in the experiment, single-subject and random effects group analyses, use of t-values of dependent measures, and the use of regions of interest (ROI) to improve the sensitivity of a priori contrasts. This report provides a detailed exposition of the research methodology of our event-related fMRI technique, the rationale behind many of its critical features, and examples of its application to two empirical datasets. Theme: Neural Basis of Behavior Topic: Cognition

Single, brief exposure to a 50 Hz magnetic field does not affect the performance of an object recognition task in adult mice

A number of studies have shown that power frequency magnetic fields may affect spatial memory functions in rodents. An experiment was performed using a spontaneous object recognition task to investigate if nonspatial working memory was similarly affected. Memory changes in adult, male C57BL/6J mice were assessed by measuring the relative time within which the animals explored familiar or novel stimulus objects. Between initial testing and retesting, the animals were exposed for 45 min to a 50 Hz magnetic field at either 7.5 microT, 75 microT or 0.75 mT. Other animals were sham-exposed with ambient fields of less than 50 nT. No significant field-dependent effects on the performance of the task were observed at any flux density (for all measures, P > 0.05). These data provide no evidence to suggest that nonspatial working memory was affected in mice by acute exposure to an intense 50 Hz magnetic field.

Prenatal exposure to low concentrations of carbon monoxide alters habituation and non-spatial working memory in rat offspring

Inhalation of low concentrations (75 and 150 ppm) of carbon monoxide (CO) by pregnant rats from days 0 to 20 of gestation leads to alterations in habituation and working memory in young adult male offspring subjected to the novel exploration object test. In particular, lack of habituation upon the second presentation of the objects and failure in the ability to discriminate between the novel and the familiar object were found in CO (75 and 150 ppm)-exposed offspring. These alterations were not accompanied by changes in spontaneous motor activity (open field test). The subtle behavioral deficits observed in the present study have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin (HbCO) concentrations equivalent to those observed in human cigarette smokers.

A Developmental Functional MRI Study of Spatial Working Memory

Functional magnetic resonance imaging (fMRI) was used to examine patterns of cortical activity in children during performance of a spatial working memory task. Six children (8–10 years) and six adults (19–26 years) searched a linear array of four boxes for the appearance of a dot. In the visual blocks, participants made no response. In the motor blocks, participants were instructed to indicate the location of the dot on each trial using a button-press response. In the working memory blocks, participants were instructed to indicate at which location the dot had appeared 1 or 2 trials previously. Both children and adults showed activity in the left precentral and postcentral gyri, as well as the right cerebellum for the motor condition as compared to the visual condition. Comparison of the memory and motor conditions revealed reliable activity in the right superior frontal gyrus (BA 8), right dorsolateral prefrontal cortex (BA 10/46), right superior parietal cortex, and bilateral inferior parietal cortex for both adults and children. These results suggest that spatial working memory tasks activate very similar cortical regions for school-age children and adults. The findings differ from previous imaging studies of nonspatial working memory tasks in that the prefrontal activations observed in the current work tend to be more dorsal. Results are discussed in light of the significant behavioral performance differences observed between child and adult participants.

Dissociation of human caudate nucleus activity in spatial and nonspatial working memory: an event-related fMRI study

We employed a novel event-related fMRI design and analysis technique to explore caudate nucleus contributions to spatial and nonspatial working memory. The spatial condition of a delayed-response task revealed greater mnemonic activation in four of six subjects when the delay period preceded immediately a probe stimulus requiring an overt motor response, as contrasted with a probe requiring no response. This effect was not seen in frontal or parietal cortical areas, and was seen in the caudate nucleus in a formally identical object condition in just one of six subjects. We hypothesized that this pattern of activity represented spatially dependent motor preparation. A second experiment confirmed this hypothesis: delay-period activity of the caudate nucleus showed greater time dependence in a task that featured spatial and motoric memory demands than in a comparable nonspatial task that featured the same response contingencies. These results suggest an important subcortical locus of the dissociation between spatial and nonspatial working memory, and a role for the human caudate nucleus in the integration of spatially coded mnemonic information with motor preparation to guide behavior.

Association of Storage and Processing Functions in the Dorsolateral Prefrontal Cortex of the Nonhuman Primate

The prominent role of the prefrontal cortex (PFC) in working memory (WM) is widely acknowledged both in nonhuman primates and in humans. However, less agreement exists on the issue of functional segregation within different subregions of the PFC with regard to the domains of spatial and nonspatial processing or involvement in simpler versus more complex aspects of WM, e.g., maintenance versus processing function. To address these issues, six monkeys were trained to perform four WM tasks that differed with respect to domain (spatial vs nonspatial) and level of WM demand (recall of one vs three items). The delayed response format was used to assess simple one-item memory, whereas self-ordering tasks were used to require the monkey to maintain and organize three items of information within WM. After training, the monkeys received bilateral PFC lesions in one of two different areas, Walker's areas 9 and 8B (dorsomedial convexity; n = 3) or areas 46 and 8A (dorsolateral cortex, n = 3) and then tested postoperatively on all tasks. Monkeys with lesions of the dorsomedial convexity were not impaired either on spatial or nonspatial WM tasks, whether the task required simple storage or sequential processing. By contrast, lesions of the dorsolateral cortex produced a significant and persistent impairment in both simple and complex spatial WM but no impairment in the two nonspatial WM tasks. These results support a functional segregation within the dorsolateral prefrontal cortex for WM: the dorsolateral prefrontal cortex (area 46/8A) is selectively involved in spatial WM, whereas the dorsomedial convexity (area 9/8B) is not critically engaged in either spatial or nonspatial working memory. Furthermore, the specific involvement of area 46/8A in spatial sequencing as well as in single-item storage WM tasks supports, in the nonhuman primate, an areal dissociation based on domain rather than on processing demand.

Redefining the functional organization of working memory processes within human lateral prefrontal cortex.

It is widely held that the frontal cortex plays a critical part in certain aspects of spatial and non-spatial working memory. One unresolved issue is whether there are functionally distinct subdivisions of the lateral frontal cortex that subserve different aspects of working memory. The present study used positron emission tomography (PET) to demonstrate that working memory processes within the human mid-dorsolateral and mid-ventrolateral frontal regions are organized according to the type of processing required rather than according to the nature (i.e. spatial or non-spatial), of the information being processed, as has been widely assumed. Two spatial working memory tasks were used which varied in the extent to which they required different executive processes. During a 'spatial span' task that required the subject to hold a sequence of five previously remembered locations in working memory a significant change in blood-flow was observed in the right mid-ventrolateral frontal cortex, but not in the anatomically and cytoarchitectonically distinct mid-dorsolateral frontal-lobe region. By contrast, during a '2-back' task that required the subject to continually update and manipulate an ongoing sequence of locations within working memory, significant blood flow increases were observed in both mid-ventrolateral and mid-dorsolateral frontal regions. When the two working memory tasks were compared directly, the one that emphasized manipulation of information within working memory yielded significantly greater activity in the right mid-dorsolateral frontal cortex only. This dissociation provides unambiguous evidence that the mid-dorsolateral and mid-ventrolateral frontal cortical areas make distinct functional contributions to spatial working memory and corresponds with a fractionation of working memory processes in psychological terms.

A comparison between the effects of medial septal lesions and entorhinal cortex lesions on performance of nonspatial working memory tasks and reversal learning

Rats with either electrolytic medial septal lesions or cytotoxic entorhinal lesions were compared to unoperated controls on a series of delayed matching-to-sample (DMS) tasks. A DMS trial consisted of two runs. In the first (information) run, the subject was familiarized with a sample discriminandum. In the second (choice) run, the subject was required to discriminate the sample discriminandum from a novel one. When a set of 20 discrete complex objects were used as discriminanda and each discriminandum was used once per day, neither lesions impaired choice accuracy. However, when a single pair of simple discriminanda was employed and re-used between trials within a day, rats with medial septal lesions were severely impaired whereas rats with entorhinal lesions performed at a level comparable to unoperated controls. Next, proactive interference was demonstrated by the introduction of an extra run prior to the information run. When this extra ( pre-information) run required the subjects to visit the (eventual) negative discriminandum such that correct choice had to be guided by relative familiarity judgement, choice performance was reduced. Neither lesion group was selectively affected by this manipulation. But when the relative reinforcement history of the pre-information run and the information run was manipulated, such that a correct response required the subject to approach a discriminandum that had recently been non-rewarded, rats with entorhinal lesions were selectively impaired. The effect of delay was demonstrated when a 20-s interval was imposed between information run and choice run. This reduced overall choice accuracy, and this effect appeared to be more pronounced in both lesion groups, although not significantly so. Finally, neither lesion affected the acquisition of a simple discrimination task, but reversal learning was selectively enhanced in the entorhinal lesion group.

Working memory in dorsolateral frontal cortex

It is widely held that the frontal cortex plays a critical role in certain aspects of both spatial and non-spatial working memory. The prevailing view in recent years has been that there are domain-specific subdivisions within dorsal and ventral regions of the prefrontal cortex, which subserve working memory for spatial and non-spatial information, respectively. However, Owen et al. have now used functional magnetic resonance imaging to demonstrate that performance of such tasks involves identical regions of the lateral prefrontal cortex when all factors unrelated to the type of stimulus material are appropriately controlled[1xFunctional organization of spatial and nonspatial memory processing within the human lateral frontal cortex. Owen, A.M. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7721–7726Crossref | PubMed | Scopus (263)See all References[1]. Two similar tasks, one involving the short-term retention and manipulation of spatial information and the other involving non-spatial visual patterns both activated the mid-dorsolateral frontal cortex in six subjects. These data provide evidence that spatial and non-spatial working memory might not be mediated by dorsal and ventral regions, respectively, of the frontal lobe, as widely assumed, and support the alternative notion that specific regions of the lateral frontal cortex make identical executive functional contributions to working memory.

Functional MRI studies of spatial and nonspatial working memory

Single-unit recordings in monkeys have revealed neurons in the lateral prefrontal cortex that increase their firing during a delay between the presentation of information and its later use in behavior. Based on monkey lesion and neurophysiology studies, it has been proposed that a dorsal region of lateral prefrontal cortex is necessary for temporary storage of spatial information whereas a more ventral region is necessary for the maintenance of nonspatial information. Functional neuroimaging studies, however, have not clearly demonstrated such a division in humans. We present here an analysis of all reported human functional neuroimaging studies plotted onto a standardized brain. This analysis did not find evidence for a dorsal/ventral subdivision of prefrontal cortex depending on the type of material held in working memory, but a hemispheric organization was suggested (i.e., left—nonspatial; right—spatial). We also performed functional MRI studies in 16 normal subjects during two tasks designed to probe either nonspatial or spatial working memory, respectively. A group and subgroup analysis revealed similarly located activation in right middle frontal gyrus (Brodmann's area 46) in both spatial and nonspatial [working memory-control] subtractions. Based on another model of prefrontal organization [M. Petrides, Frontal lobes and behavior, Cur. Opin. Neurobiol., 4 (1994) 207–211], a reconsideration of the previous imaging literature data suggested that a dorsal/ventral subdivision of prefrontal cortex may depend upon the type of processing performed upon the information held in working memory.

Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex.

The present study used functional magnetic resonance imaging to demonstrate that performance of visual spatial and visual nonspatial working memory tasks involve the same regions of the lateral prefrontal cortex when all factors unrelated to the type of stimulus material are appropriately controlled. These results provide evidence that spatial and nonspatial working memory may not be mediated, respectively, by mid-dorsolateral and mid-ventrolateral regions of the frontal lobe, as widely assumed, and support the alternative notion that specific regions of the lateral prefrontal cortex make identical executive functional contributions to both spatial and nonspatial working memory.

Acetylcholine release from the frontal cortex during exploratory activity

The activation of the cortical cholinergic system was investigated in 3- and 25-month-old male Wistar rats, by measuring by transversal microdialysis the changes in cortical extracellular acetylcholine (ACh) levels during the performance of simple spontaneous tasks involving exploratory activity and working memory. Two days after implantation of the microdialysis probe in the frontal cortex, object recognition was investigated by either moving the rats from the home cage to the arena containing the objects or keeping the rats in the arena and introducing the objects. Spontaneous alternation was investigated in a Y runway. Young rats discriminated between familiar and novel objects and alternated in the Y runway, while aged rats were unable to discriminate. Whenever rats were moved from the home cage to the arena, ACh release increased (+70–80%) during the exploratory activity. Handling per se had no effect on extracellular ACh levels. When young rats were left in the arena, introduction of the objects caused some exploratory activity and object recognition but no increase in ACh release. ACh release increased by about 300% during spontaneous alternation. In aging rats basal extracellular ACh levels and their increase after placement in the arena were less than half that in young rats. Our work demonstrates that a novel environment activates the cortical cholinergic system, which presumably is associated with arousal mechanisms and selective attentional functions. It also demonstrates that in aging rats the cortical cholinergic hypofunction is associated with a loss of non-spatial working memory.

Dissociation of mnemonic and perceptual processes during spatial and nonspatial working memory using fMRI

Neuroimaging studies in humans have consistently found robust activation of frontal, parietal, and temporal regions during working memory tasks. Whether these activations represent functional networks segregated by perceptual domain is still at issue. Two functional magnetic resonance imaging experiments were conducted, both of which used multiple-cycle, alternating task designs. Experiment 1 compared spatial and object working memory tasks to identify cortical regions differentially activated by these perceptual domains. Experiment 2 compared working memory and perceptual control tasks within each of the spatial and object domains to determine whether the regions identified in experiment 1 were driven primarily by the perceptual or mnemonic demands of the tasks, and to identify common brain regions activated by working memory in both perceptual domains. Domain-specific activation occurred in the inferior parietal cortex for spatial tasks, and in the inferior occipitotemporal cortex for object tasks, particularly in the left hemisphere. However, neither area was strongly influenced by task demands, being nearly equally activated by the working memory and perceptual control tasks. In contrast, activation of the dorsolateral prefrontal cortex and the intraparietal sulcus (IPS) was strongly task-related. Spatial working memory primarily activated the right middle frontal gyrus (MFG) and the IPS. Object working memory activated the MFG bilaterally, the left inferior frontal gyrus, and the IPS, particularly in the left hemisphere. Finally, activation of midline posterior regions, including the cingulate gyrus, occurred at the offset of the working memory tasks, particularly the shape task. These results support a prominent role of the prefrontal and parietal cortices in working memory, and indicate that spatial and object working memory tasks recruit differential hemispheric networks. The results also affirm the distinction between spatial and object perceptual processing in dorsal and ventral visual pathways. Hum. Brain Mapping 6:14–32, 1998. © 1998 Wiley-Liss, Inc.

Dissociation of mnemonic and perceptual processes during spatial and nonspatial working memory using fMRI

Neuroimaging studies in humans have consistently found robust activation of frontal, parietal, and temporal regions during working memory tasks. Whether these activations represent functional networks segregated by perceptual domain is still at issue. Two functional magnetic resonance imaging experiments were conducted, both of which used multiple-cycle, alternating task designs. Experiment 1 compared spatial and object working memory tasks to identify cortical regions differentially activated by these perceptual domains. Experiment 2 compared working memory and perceptual control tasks within each of the spatial and object domains to determine whether the regions identified in experiment 1 were driven primarily by the perceptual or mnemonic demands of the tasks, and to identify common brain regions activated by working memory in both perceptual domains. Domain-specific activation occurred in the inferior parietal cortex for spatial tasks, and in the inferior occipitotemporal cortex for object tasks, particularly in the left hemisphere. However, neither area was strongly influenced by task demands, being nearly equally activated by the working memory and perceptual control tasks. In contrast, activation of the dorsolateral prefrontal cortex and the intraparietal sulcus (IPS) was strongly task-related. Spatial working memory primarily activated the right middle frontal gyrus (MFG) and the IPS. Object working memory activated the MFG bilaterally, the left inferior frontal gyrus, and the IPS, particularly in the left hemisphere. Finally, activation of midline posterior regions, including the cingulate gyrus, occurred at the offset of the working memory tasks, particularly the shape task. These results support a prominent role of the prefrontal and parietal cortices in working memory, and indicate that spatial and object working memory tasks recruit differential hemispheric networks. The results also affirm the distinction between spatial and object perceptual processing in dorsal and ventral visual pathways.

An FMRI study of the dorsolateral prefrontal cortex activation during non-spatial verbal working memory tasks

An FMRI study of the dorsolateral prefrontal cortex activation during non-spatial verbal working memory tasks

The effects of neurotoxic lesions of the perirhinal cortex combined to fornix transection on object recognition memory in the rat

The effects of lesions centred in the perirhinal cortex region (Prh) or in both the perirhinal cortex region and the fornix (Prh+Fx) were assessed in two different working memory tasks, one spatial the other nonspatial. For the spatial task the rats were tested in an eight arm radial maze, using a standard procedure in which they were rewarded for avoiding previously visited arms. The Prh+Fx, but not the Prh, rats produced significantly more errors (re-entries) and these started significantly earlier in each session when compared with a surgical control group. The nonspatial task was a test of spontaneous object recognition in which rats were tested on their ability to discriminate between a familiar and a novel object. For the initial tests the Prh group failed to discriminate between the objects, but the Prh+Fx group showed a clear preference for the novel object. Observation of the test showed, however, that the Prh+Fx group were spending a greater length of time initially exploring the sample (familiar) object. When the amount of exposure to the sample object was limited to either 20 or 40 s (i.e. was the same for all three groups), the Prh+Fx group now failed to discriminate between the two objects. This change was especially evident for shorter sample duration (20 s). The Prh group did, however, show an amelioration of their deficit with this further testing. The present results support previous dissociation between spatial and nonspatial working memory, and indicate that there may be some recovery of function following perirhinal cortical damage.

Nonhippocampal Muscarinic Receptors Are Required for Nonspatial Working Memory

The effects of scopolamine on nonspatial working memory were examined in rats with hippocampal lesions and sham operations. Performance was examined using a continuous conditional discrimination task in an operant box. Choice accuracy measured nonspatial working memory. Response bias, delay interval responses, and response probability measured response preference, stimulus control, motivation, and sensorimotor ability. Scopolamine (0.05, 0.075, 0.1, and 0.15 mg/kg) or methylscopolamine (0.1 mg/kg) was injected (IP) 15 min prior to behavioral testing. In both control and hippocampal lesioned groups, choice accuracy declined as the delay interval increased. Scopolamine, but not methylscopolamine, produced a dose-dependent impairment of choice accuracy (interaction of Dose × Delay) in both groups. The scopolamine-induced impairment was not different between the control and hippocampally lesioned rats. Response bias, delay interval responses, and response probability were not affected by scopolamine except at the highest dose, which increased delay interval responses. The results suggest that central muscarinic receptors outside the hippocampus are important for working memory of nonspatial stimuli.