Differential anterior prefrontal activation during the recognition stage of a spatial working memory task

Neuroimaging studies commonly show widespread activations in the prefrontal cortex during various forms of working memory and long-term memory tasks. However, the anterior prefrontal cortex (aPFC, Brodmann area 10) has been mainly associated with retrieval in episodic memory, and its role in working memory is less clear. We conducted an event-related functional magnetic resonance imaging study to examine brain activations in relation to recognition in a spatial delayed-recognition task. Similar to the results from previous findings, several frontal areas were strongly activated during the recognition phase of the task, including the aPFC, the lateral PFC and the anterior cingulate cortex. Although the aPFC was more active during the recognition phase, it was also active during the delay phase of the spatial working memory task. In addition, the aPFC showed greater activity in response to negative probes (non-targets) than to positive probes (targets). While our analyses focused on examining signal changes in the aPFC, other prefrontal regions showed similar effects and none of the areas were more active in response to the positive probes than to the negative probes. Our findings support the conclusion that the aPFC is involved in working memory and particularly in processes that distinguish target and non-target stimuli during recognition.     

Dynamic cortical networks of verbal and spatial working memory: effects of memory load and task practice

Working memory (WM), the ability to briefly retain and manipulate information in mind, is central to intelligent behavior. Here we take advantage of the high temporal resolution of electrophysiological measures to obtain a millisecond timescale view of the activity induced in distributed cortical networks by tasks that impose significant WM demands. We examined how these networks are affected by the type and amount of information to be remembered, and by the amount of task practice. Evoked potentials (EPs) were obtained from eight subjects performing spatial and verbal versions of a visual n-back WM task (n = 1, 2, 3) on each of three testing days. In well-trained subjects, WM tasks elicited transient responses reflecting different subcomponents of task processing, including transient (lasting 0.02-0.3 s) task- sensitive and load-sensitive EPs, as well as sustained responses (lasting 1-1.5 s), including the prestimulus Contingent Negative Variation (CNV), and post-stimulus frontal and parietal Slow Waves. The transient responses, with the exception of the P300, differed between the verbal and spatial task versions, and between trials with different response requirements. The P300 and the Slow Waves were not affected by task version but were affected by increased WM load. These results suggest that WM emerges from the formation of a dynamic cortical network linking task-specific processes with non-specific, capacity- limited, higher-order attentional processes. Practice effects on the EPs suggested that practice led to the development of a more effective cognitive strategy for dealing with lower-order aspects of task processing, but did not diminish demands made on higher order processes. Thus a simple WM task is shown to be composed of numerous elementary subsecond neural processes whose characteristics vary with type and amount of information being remembered, and amount of practice.      

Effects of domain-specific interference on brain activation associated with verbal working memory task performance

Previous neuroimaging studies have identified brain regions that underlie verbal working memory in humans. According to these studies a phonological store is located in the left inferior parietal cortex, and a complementary subvocal rehearsal mechanism is implemented by mostly left-hemispheric speech areas. In the present functional magnetic resonance imaging study, classical interfering and non-interfering dual-task situations were used to investigate further the neural correlates of verbal working memory. Verbal working memory performance under non-interfering conditions activated Broca's area, the left premotor cortex, the cortex along the left intraparietal sulcus and the right cerebellum, thus replicating the results from previous studies. By contrast, no significant memory- related activation was found in these areas when silent articulatory suppression prevented the subjects from rehearsal. Instead, this non-articulatory maintenance of phonological information was associated with enhanced activity in several other, particularly anterior prefrontal and inferior parietal, brain areas. These results suggest that phonological storage may be a function of a complex prefronto-parietal network, and not localized in only one, parietal brain region. Further possible implications for the functional organization of human working memory are discussed.     

Wavelength-dependent modulation of brain responses to a working memory task by daytime light exposure

In addition to classical visual effects, light elicits nonvisual brain responses, which profoundly influence physiology and behavior. These effects are mediated in part by melanopsin-expressing light-sensitive ganglion cells that, in contrast to the classical photopic system that is maximally sensitive to green light (550 nm), is very sensitive to blue light (470-480 nm). At present, there is no evidence that blue light exposure is effective in modulating nonvisual brain activity related to complex cognitive tasks. Using functional magnetic resonance imaging, we show that, while participants perform an auditory working memory task, a short (18 min) daytime exposure to blue (470 nm) or green (550 nm) monochromatic light (3 x 10(13) photons/cm2/s) differentially modulates regional brain responses. Blue light typically enhanced brain responses or at least prevented the decline otherwise observed following green light exposure in frontal and parietal cortices implicated in working memory, and in the thalamus involved in the modulation of cognition by arousal. Our results imply that monochromatic light can affect cognitive functions almost instantaneously and suggest that these effects are mediated by a melanopsin-based photoreceptor system.     

Neural correlates of change detection and change blindness in a working memory task

Detecting changes in an ever-changing environment is highly advantageous, and this ability may be critical for survival. In the present study, we investigated the neural substrates of change detection in the context of a visual working memory task. Subjects maintained a sample visual stimulus in short-term memory for 6 s, and were asked to indicate whether a subsequent, test stimulus matched or did not match the original sample. To study change detection largely uncontaminated by attentional state, we compared correct change and correct no-change trials at test. Our results revealed that correctly detecting a change was associated with activation of a network comprising parietal and frontal brain regions, as well as activation of the pulvinar, cerebellum, and inferior temporal gyrus. Moreover, incorrectly reporting a change when none occurred led to a very similar pattern of activations. Finally, few regions were differentially activated by trials in which a change occurred but subjects failed to detect it (change blindness). Thus, brain activation was correlated with a subject's report of a change, instead of correlated with the physical change per se. We propose that frontal and parietal regions, possibly assisted by the cerebellum and the pulvinar, might be involved in controlling the deployment of attention to the location of a change, thereby allowing further processing of the visual stimulus. Visual processing areas, such as the inferior temporal gyrus, may be the recipients of top-down feedback from fronto-parietal regions that control the reactive deployment of attention, and thus exhibit increased activation when a change is reported (irrespective of whether it occurred or not). Whereas reporting that a change occurred, be it correctly or incorrectly, was associated with strong activation in fronto-parietal sites, change blindness appears to involve very limited territories.     

Dissociation of verbal working memory system components using a delayed serial recall task

Functional magnetic resonance imaging (fMRI) was used to investigate the neural substrates of component processes in verbal working memory. Based on behavioral research using manipulations of verbal stimulus type to dissociate storage, rehearsal, and executive components of verbal working memory, we designed a delayed serial recall task requiring subjects to encode, maintain, and overtly recall sets of verbal items for which phonological similarity, articulatory length, and lexical status were manipulated. By using a task with temporally extended trials, we were able to exploit the temporal resolution afforded by fMRI to partially isolate neural contributions to encoding, maintenance, and retrieval stages of task performance. Several regions commonly associated with maintenance, including supplementary motor, premotor, and inferior frontal areas, were found to be active across all three trial stages. Additionally, we found that left inferior frontal and supplementary motor regions showed patterns of stimulus and temporal sensitivity implicating them in distinct aspects of articulatory rehearsal, while no regions showed a pattern of sensitivity consistent with a role in phonological storage. Regional modulation by task difficulty was further investigated as a measure of executive processing. We interpret our findings as they relate to notions about the cognitive architecture underlying verbal working memory performance.     

Changes in prefrontal neuronal activity after learning to perform a spatial working memory task

The prefrontal cortex is considered essential for learning to perform cognitive tasks though little is known about how the representation of stimulus properties is altered by learning. To address this issue, we recorded neuronal activity in monkeys before and after training on a task that required visual working memory. After the subjects learned to perform the task, we observed activation of more prefrontal neurons and increased activity during working memory maintenance. The working memory-related increase in firing rate was due mostly to regular-spiking putative pyramidal neurons. Unexpectedly, the selectivity of neurons for stimulus properties and the ability of neurons to discriminate between stimuli decreased as the information about stimulus properties was apparently present in neural firing prior to training and neuronal selectivity degraded after training in the task. The effect was robust and could not be accounted for by differences in sampling sites, selection of neurons, level of performance, or merely the elapse of time. The results indicate that, in contrast to the effects of perceptual learning, mastery of a cognitive task degrades the apparent stimulus selectivity as neurons represent more abstract information related to the task. This effect is countered by the recruitment of more neurons after training.     

Increased neural efficiency with repeated performance of a working memory task is information-type dependent

Unlike tasks in which practice leads to an automatic stimulus-response association, it is thought working memory (WM) tasks continue to require cognitive control processes after repeated performance. Previous studies investigating WM task repetition are in accord with this. However, it is unclear whether changes in neural activity after repetition imply alterations in general control processes common to all WM tasks or are specific to the selection, encoding and maintenance of the relevant information. In the present study, functional magnetic resonance imaging (fMRI) was used to examine changes during sample, delay and test periods during repetition of both object and spatial delayed recognition tasks. We found decreases in fMRI activation in both spatial and object-selective areas after spatial WM task repetition, independent of behavioral performance. Few areas showed changed activity after object WM task repetition. These results indicate that spatial task repetition leads to increased efficiency of maintaining task-relevant information and improved ability to filter out task-irrelevant information. The specificity of this repetition effect to the spatial task suggests a difference exists in the nature of the representation of object and spatial information and that their maintenance in WM is likely subserved by different neural systems.     

Roles of attention, memory, and motor preparation in modulating human brain activity in a spatial working memory task

Neuronal activity of the human brain was studied with magnetoencephalography (MEG) in a spatial working memory task similar to those commonly used with nonhuman primates. The subject was required to remember target positions for 3 s and make a same-different judgement with a finger lift comparing the position of the probed target with the probe or to execute a memory-guided saccade to the probed target. In this type of task single-unit studies have shown attention- and memory-related activities independent of movement type during the retention interval in a large number of cortical areas of the primates, including the parietal and prefrontal areas. Consistent with these results, there were strong stimulus-driven transient and sustained responses and modulations of oscillatory activity during the retention period. Although we did not determine the source locations, coarse estimates of the currents responsible for the MEG signals showed activity over a wide area of the cortex, most prominently over the Rolandic, parietal and occipital areas, but also over the frontal area. Some of the activities in these cortical areas reflect processes that may be identified with attention and memory, while others were related to preparation of the overt movements.      

Bilateral generic working memory circuit requires left-lateralized addition for verbal processing

According to the Baddeley-Hitch model, phonological and visuospatial representations are separable components of working memory (WM) linked by a central executive. The traditional view that the separation reflects the relative contribution of the 2 hemispheres (verbal WM--left; spatial WM--right) has been challenged by the position that a common bilateral frontoparietal network subserves both domains. Here, we test the hypothesis that there is a generic WM circuit that recruits additional specialized regions for verbal and spatial processing. We designed a functional magnetic resonance imaging paradigm to elicit activation in the WM circuit for verbal and spatial information using identical stimuli and applied this in 33 healthy controls. We detected left-lateralized quantitative differences in the left frontal and temporal lobe for verbal > spatial WM but no areas of activation for spatial > verbal WM. We speculate that spatial WM is analogous to a "generic" bilateral frontoparietal WM circuit we inherited from our great ape ancestors that evolved, by recruitment of additional left-lateralized frontal and temporal regions, to accommodate language.     

Impaired performance in a conditioned reaction time task after thermocoagulatory lesions of the fronto-parietal cortex in rats

The present study examined whether cortical damage in rats may disrupt the integrative processes and motor control involved in the performance of a reaction time (RT) task. To investigate the nature of the deficits in the conditioned task, rats were subjected, after learning, to a coagulation of pia brain surface of varying extent, including the frontal and parietal cortical areas. They were then tested daily for over one month. The behavioural task required the rats to hold a lever down during a variable and random delay and react quickly to the onset of a visual cue by releasing the lever within a RT limit for food reinforcement. Extensive bilateral cortical lesions had no effect on spontaneous motor activity, but severely impaired RT performance. Latencies to release the lever after the cue were dramatically increased during the first postoperative sessions and gradually returned to baseline levels within 3 weeks, whereas less dramatic but long-lasting increase in premature responding (anticipatory response before the visual cue) was observed throughout the testing sessions. More restricted lesions to the frontoparietal cortex produced a similar pattern of incorrect responding with a faster recovery of delayed responses and a strong deficit in premature responding. The major effects of lesions confined to the rostral pole of the frontal cortex were observed on premature responding, however. The present results demonstrate that the impairment in movement initiation is rapidly recovered within 2-3 weeks even after extensive thermocoagulatory lesions of the frontal and parietal areas. This recovery suggests the involvement of adaptive processes developing progressively and probably reflecting the remarkable synaptic plasticity of the extrapyramidal motor output. In contrast, the long-lasting increase in premature responding, supposed to reflect some attentional deficits, may produce anatomofunctional long-term disorganization of subcortical structures such as the basal ganglia. Interestingly enough, these results show that the rat neocortex supports functions very similar to those of primates and provide a good model for studying these higher functions in operant motor procedures that require prior associative learning and appropriate motor coordination.      

High-resolution EEG mapping of cortical activation related to working memory: effects of task difficulty, type of processing, and practice

Changes in cortical activity during working memory tasks were examined with electroencephalograms (EEGs) sampled from 115 channels and spatially sharpened with magnetic resonance imaging (MRI)-based finite element deblurring. Eight subjects performed tasks requiring comparison of each stimulus to a preceding one on verbal or spatial attributes. A frontal midline theta rhythm increased in magnitude with increased memory load. Dipole models localized this signal to the region of the anterior cingulate cortex. A slow (low-frequency), parietocentral, alpha signal decreased with increased working memory load. These signals were insensitive to the type of stimulus attribute being processed. A faster (higher-frequency), occipitoparietal, alpha signal was relatively attenuated in the spatial version of the task, especially over the posterior right hemisphere. Theta and alpha signals increased, and overt performance improved, after practice on the tasks. Increases in theta with both increased task difficulty and with practice suggests that focusing attention required more effort after an extended test session. Decreased alpha in the difficult tasks indicates that this signal is inversely related to the amount of cortical resources allocated to task performance. Practice-related increases in alpha suggest that fewer cortical resources are required after skill development. These results serve: (i) to dissociate the effects of task difficulty and practice; (ii) to differentiate the involvement of posterior cortex in spatial versus verbal tasks; (iii) to localize frontal midline theta to the anteromedial cortex; and (iv) to demonstrate the feasibility of using anatomical MRIs to remove the blurring effect of the skull and scalp from the ongoing EEG. The results are discussed with respect to those obtained in a prior study of transient evoked potentials during working memory.      

Prefrontal cortex lesions augment the location-related firing properties of area TE/perirhinal cortex neurons in a working memory task

It has previously been proposed that prefrontal cortex may have some role in keeping temporal cortex-based representations "on-line" during a working memory task. To test this hypothesis, the effects of electrolytic prefrontal cortex lesions on the firing of area TE and perirhinal cortex (PRC) neurons were examined while rats performed a delayed non-match to position task in the T-maze. The behavioural performance of control (n = 4) and lesioned (n = 4) animals were similar during this task, and many neurons displayed a statistically significant location-related variation in firing rate during the sample (44/56 neurons) and test (39/56 neurons) phases. Units from prefrontal-lesioned animals (82%) were more likely to display a significant variation in firing across the maze compared to controls (50%; P < 0.01), and to have more discrete location-related properties (50% of neurons) compared to the control (5%) group (P < 0.0005). This finding suggests that prefrontal cortex normally modulates the transmission and/or processing of spatial information in area TE/PRC during a working memory task. Modulation could be mediated through direct connections between the structures or via prefrontal control of subcortical structures. This finding has implications for our understanding of prefrontal-temporal involvement in memory and cognitive disorders.     

Brain activation during working memory is altered in patients with type 1 diabetes during hypoglycemia

OBJECTIVE

To investigate the effects of acute hypoglycemia on working memory and brain function in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging during euglycemic (5.0 mmol/L) and hypoglycemic (2.8 mmol/L) hyperinsulinemic clamps, we compared brain activation response to a working-memory task (WMT) in type 1 diabetic subjects (n = 16) with that in age-matched nondiabetic control subjects (n = 16). Behavioral performance was assessed by percent correct responses.

RESULTS

During euglycemia, the WMT activated the bilateral frontal and parietal cortices, insula, thalamus, and cerebellum in both groups. During hypoglycemia, activation decreased in both groups but remained 80% larger in type 1 diabetic versus control subjects (P < 0.05). In type 1 diabetic subjects, higher HbA_1c was associated with lower activation in the right parahippocampal gyrus and amygdala (R² = 0.45, P < 0.002). Deactivation of the default-mode network (DMN) also was seen in both groups during euglycemia. However, during hypoglycemia, type 1 diabetic patients deactivated the DMN 70% less than control subjects (P < 0.05). Behavioral performance did not differ between glycemic conditions or groups.

CONCLUSIONS

BOLD activation was increased and deactivation was decreased in type 1 diabetic versus control subjects during hypoglycemia. This higher level of brain activation required by type 1 diabetic subjects to attain the same level of cognitive performance as control subjects suggests reduced cerebral efficiency in type 1 diabetes.Acute episodes of hypoglycemia are a rate-limiting adverse effect in the treatment of type 1 diabetes. When severe, they can lead to seizures and coma (1). Even mild to moderate hypoglycemia is known to impair cognitive functions, such as working memory (2,3). Working memory is used to actively maintain and manipulate information over a brief period of time and to allocate attentional resources among competing subtasks (4,5). Traditionally, working-memory performance is thought to depend primarily on a network of brain regions, including portions of the frontal and parietal lobes, thalamus, precuneus, cerebellum, and insula (6,7).Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (fMRI), we evaluated how diabetes impacts these neural processes under euglycemic and hypoglycemic conditions when subjects were presented with a working-memory task (WMT). Diabetes is known to negatively affect working memory (8). This task evaluates functional effects that might reflect changes in brain structure and/or presage decreases in cognitive performance. A better understanding of the brain’s metabolic and physiological mechanisms underlying the cognitive functions implicated in working memory could lead to improved treatment strategies to help maintain cortical function in patients with diabetes during hypoglycemia (9).BOLD fMRI is a well-established method for examining regional brain activation in response to physiological, pharmacological, sensory, or cognitive tasks (10). Studies that have examined brain activation in response to sensory stimulation or cognitive challenges using BOLD fMRI during hypoglycemic conditions in nondiabetic subjects (11–13) have shown that hypoglycemia reduces regional brain BOLD activation. This reduction in BOLD response during hypoglycemia has been attributed to low glucose levels causing decreases in neuronal activity, glucose oxidative metabolism, cerebral blood flow, neurovascular coupling, and/or neuronal recruitment (12).Whether cognitive function in patients with type 1 diabetes is affected by hypoglycemia in the same manner as in nondiabetic individuals remains unclear because few studies using functional neural imaging have directly compared diabetic and nondiabetic subjects during the performance of cognitive tasks (14,15). If brain glucose transport or metabolism are altered in type 1 diabetes, as has been suggested in recent studies by our group (16) and others (17), then one would expect that the BOLD activation response during hypoglycemia may differ between diabetic patients compared with nondiabetic control subjects. On the basis of these findings, we hypothesized that 1) patients with type 1 diabetes would have greater BOLD activation during the performance of a WMT during hypoglycemia when compared with nondiabetic control subjects, 2) cognitive performance would deteriorate during hypoglycemia in both groups, and 3) among type 1 diabetic patients, better glycemic control (lower HbA_1c) would correlate with BOLD activation responses to the WMT during hypoglycemia. We also conducted exploratory analyses to examine deactivation patterns in the default-mode network (DMN), the regions of the brain that are more active during rest (18), because of other research by our group examining the effects of diabetes on deactivation patterns during cognitive tasks and previous research suggesting that DMN function may be altered in diseases that affect cognition, such as Alzheimer’s disease (19).     

Neural processes underlying memory attribution on a reality-monitoring task

A relatively common form of memory distortion arises when individuals must discriminate items they have seen from those they have imagined (reality monitoring). The present fMRI investigation (at 1.5 T) focused on the processes that relate to memory assignment regardless of accuracy (e.g. that correspond with the belief that an item was presented as a picture, regardless of whether that belief is correct). Prior to the scan, participants (n = 16) viewed concrete nouns and formed mental images of the object named. Half of the names were followed by the object's photo. During the scan, participants saw the object names and indicated whether the corresponding photo had been studied. Activity in visual-processing regions (including the precuneus and fusiform gyrus) corresponded with the attribution of an item to a pictorial presentation. In contrast, activity in regions thought to be important for self-referential processing (including the ventromedial prefrontal cortex and posterior cingulate gyrus) was associated with attribution to a nonpresented source. These neural findings converge with behavioral evidence indicating that individuals use the amount of different types of information retrieved (e.g. perceptual detail, information about cognitive operations) to determine whether an item was imagined or perceived.     

Interaction of working memory and long-term memory in the medial temporal lobe

Recent findings indicate that regions in the medial temporal lobe (MTL) do not only play a crucial role in long-term memory (LTM) encoding, but contribute to working memory (WM) as well. However, very few studies investigated the interaction between these processes so far. In a new functional magnetic resonance imaging paradigm comprising both a complex WM task and an LTM recognition task, we found not only that some items were successfully processed in WM but later forgotten, but also that a significant number of items which were not successfully processed in the WM task were subsequently recognized. Activation in the parahippocampal cortex (PHC) during successful WM was predictive of subsequent LTM, but was correlated with subsequent forgetting if the WM task was not successfully solved. The contribution of the PHC to LTM encoding thus crucially depends on whether an item was successfully processed in the WM task. Functional connectivity analysis revealed that across-trial fluctuations in PHC activity were correlated with activation in extensive regions if WM and LTM tasks were correctly solved, whereas connectivity broke down during unsuccessful attempts to do the task, suggesting that activity in the PHC during WM has to be well controlled to support LTM formation.     

Attentional modulation of object representations in working memory

We investigated the role of object-based attention in modulating the maintenance of faces and scenes held online in working memory (WM). Participants had to remember a face and a scene, while cues presented during the delay instructed them to orient their attention to one or the other item. Event-related functional magnetic resonance imaging revealed that orienting attention in WM modulated the activity in fusiform and parahippocampal gyri, involved in maintaining representations of faces and scenes respectively. Measures from complementary behavioral studies indicated that this increase in activity corresponded to improved WM performance. The results show that directed attention can modulate maintenance of specific representations in WM, and help define the interplay between the domains of attention and WM.     

Specific cerebral networks for maintenance and response organization within working memory as evidenced by the 'double delay/double response' paradigm

Most of the working memory (WM) tasks used in functional imaging studies are based on the principle of the delayed response in which both the storage and the response organization are present during the delay period. It is therefore difficult to isolate activation specific to the storage function from that specific to the organization of the response. To determine the specific neural networks associated with these two WM operations, we performed a functional MRI study in healthy subjects using a new paradigm, 'the double delay/double response' tasks. This paradigm isolates maintenance from response organization by dividing the delay into two separate parts, the first being dedicated to memory, while the second includes response organization. Activation within the dorsolateral prefrontal cortex (DLPFC) followed a relative hemispheric dissociation: activation related to maintenance was predominant in the right DLPFC but was only detected when the load exceeded three items. Activation related to response organization was predominant in the left DLPFC, regardless of whether this response was based on information held in WM ('memory guided') or was independent of WM ('visually-guided'). These results suggest that activation of the DLPFC, should be interpreted in terms of executive processing for both maintenance and response organization.