Traveling waves in the prefrontal cortex during working memory

Neural oscillations are evident across cortex but their spatial structure is not well- explored. Are oscillations stationary or do they form “traveling waves”, i.e., spatially organized patterns whose peaks and troughs move sequentially across cortex? Here, we show that oscillations in the prefrontal cortex (PFC) organized as traveling waves in the theta (4-8Hz), alpha (8-12Hz) and beta (12-30Hz) bands. Some traveling waves were planar but most rotated. The waves were modulated during performance of a working memory task. During baseline conditions, waves flowed bidirectionally along a specific axis of orientation. Waves in different frequency bands could travel in different directions. During task performance, there was an increase in waves in one direction over the other, especially in the beta band.     

A comparative review of rodent prefrontal cortex and working memory

The prefrontal cortex is critical to working memory processes. Current theories of prefrontal function are largely based on primate behavioural and electrophysiological data. As molecular genetic techniques advance in mice, so investigations into the rodent prefrontal cortex should expand, such that rodent models of prefrontal function during working memory may be used to study the synaptic and molecular basis of the phenomenon. This review attempts to summarize aspects of published data that pertain to working memory and suggest directions that will allow a coherent comparison of prefrontal function and interaction in monkey, rat and mouse.     

The prefrontal cortex and working memory: physiology and brain imaging

Sustained activity has been recorded in the prefrontal cortex during working memory tasks. First, we compare the anatomical distribution of this activity in humans and monkeys. Then, we show that it reflects many factors, maintenance of the items presented, preparation for the response, transformation of the items during the delay, task rules and task goals. Finally, we point out that sustained activity has also been recorded in other areas, such as the parietal cortex. We suggest that the key to prefrontal cortex lies not in the maintenance of sensory information but in the prospective use of that information for behaviour.     

Dynamics of population code for working memory in the prefrontal cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.     

Right prefrontal activity reflects the ability to overcome sleepiness during working memory tasks: a functional near-infrared spectroscopy study

It has been speculated that humans have an inherent ability to overcome sleepiness that counteracts homeostatic sleep pressure. However, it remains unclear which cortical substrate activities are involved in the ability to overcome sleepiness during the execution of cognitive tasks. Here we sought to confirm that this ability to overcome sleepiness in task execution improves performance on cognitive tasks, showing activation of neural substrates in the frontal cortex, by using a modified n-back (2- and 0-back) working memory task and functional near-infrared spectroscopy. The change in alertness was just correlated with performances on the 2-back task. Activity in the right prefrontal cortex changed depending on alertness changes on the 2- and 0-back tasks independently, which indicates that activity in this region clearly reflects the ability to overcome sleepiness; it may contribute to the function of providing sufficient activity to meet the task load demands. This study reveals characteristics of the ability to overcome sleepiness during the n-back working memory task which goes beyond the attention-control function traditionally proposed.     

Auditory event-related potentials dissociate early and late memory processes

Event-related potentials (ERPs) to environmental sounds were recorded from 15 young control subjects in an auditory recognition memory task. Subjects listened to a continuous string of binaurally presented sounds, 20% of which were presented once and 80% were repeated. Of the repeated sounds, some repeated immediately after the initial presentation (2 sec; short delay repetition) while others repeated after 2–6 intervening sounds (4–12 sec; long delay repetition). Subjects were instructed to indicate whether they had heard the sounds before by pressing a “yes” or “no” button.The initial stimulus presentation and long delay repetition stimuli generated both an N4 component and a prolonged latency P3 component while the short delay repetition stimuli elicited no N4 component and an earlier latency P3 component. Subjects' responses were faster and more accurate for short delay repetition. All stimuli generated a sustained frontal negative component (SFN). These data indicate that auditory recognition memory for environmental sounds may involve two processes. The P3 generated by both short and long delay repetition stimuli may index activation of a neocortical template matching system. The N4 generated by initial stimulus presentations and long delay repetition is proposed to measure additional activation of limbic memory systems at long retention intervals.     

Influence of memory demand and contra lateral activity on muscle activity.

Computer mouse work often includes memory demands and contra lateral activity. This study simulated video display unit (VDU) mouse-work and the focus was on forearm muscle activity as a result of standardised postural loads, memory demands and contra lateral activity. Surface and intramuscular electromyography (EMG) were recorded from the right forearm muscles during finger elevation and rest with and without memory demands and with and without contra lateral activity i.e. activity of the left hand. In most situations, memory demand increased activity in the m. extensor carpi radialis brevis and m. flexor digitalis superficialis. Also contra lateral activity increased activity in situations with and without memory demands. While surface EMG level of the m. extensor digitorum communis did not increase during memory demands, intramuscular EMG level increased when memory demands and contra lateral activity was combined. Influence of memory demands and contra lateral activity were most pronounced, in situations where activity levels were small.We presume that it is not only prolonged time of active computer mouse use that is a risk for development of musculoskeletal disorders, but also the time when people interact with the computer mentally or with the 'non-mouse hand', while resting their 'mouse-hand' on the mouse.     

The role of prefrontal cortex in working memory: examining the contents of consciousness.

Working memory enables us to hold in our ''mind''s eye'' the contents of our conscious awareness, even in the absence of sensory input, by maintaining an active representation of information for a brief period of time. In this review we consider the functional organization of the prefrontal cortex and its role in this cognitive process. First, we present evidence from brain-imaging studies that prefrontal cortex shows sustained activity during the delay period of visual working memory tasks, indicating that this cortex maintains on-line representations of stimuli after they are removed from view. We then present evidence for domain specificity within frontal cortex based on the type of information, with object working memory mediated by more ventral frontal regions and spatial working memory mediated by more dorsal frontal regions. We also propose that a second dimension for domain specificity within prefrontal cortex might exist for object working memory on the basis of the type of representation, with analytic representations maintained preferentially in the left hemisphere and image-based representations maintained preferentially in the right hemisphere. Furthermore, we discuss the possibility that there are prefrontal areas brought into play during the monitoring and manipulation of information in working memory in addition to those engaged during the maintenance of this information. Finally, we consider the relationship of prefrontal areas important for working memory, both to posterior visual processing areas and to prefrontal areas associated with long-term memory.     

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.     

Directing the mind's eye: prefrontal, inferior and medial temporal mechanisms for visual working memory

Human and nonhuman primates have a remarkable ability to recall, maintain and manipulate visual images in the absence of external sensory stimulation. Evidence from lesion, single-unit neurophysiological and neuroimaging studies shows that these visual working memory processes are consistently associated with sustained activity in object-selective inferior temporal neurons. Furthermore, results from these studies suggest that mnemonic activity in the inferior temporal cortex is, in turn, supported by top-down inputs from multimodal regions in prefrontal and medial temporal cortex, and under some circumstances, from the hippocampus.     

Integration in working memory: a magnetic stimulation study on the role of left anterior prefrontal cortex

Integration is a fundamental working memory operation, requiring the insertion of information from one task into the execution of another concurrent task. Previous neuroimaging studies have suggested the involvement of left anterior prefrontal cortex (L-aPFC) in relation to working memory integration demands, increasing during presentation of information to be integrated (loading), throughout its maintenance during a secondary task, up to the integration step, and then decreasing afterward (unloading). Here we used short bursts of 5 Hz repetitive Transcranic Magnetic Stimulation (rTMS) to modulate L-aPFC activity and to assess its causal role in integration. During experimental blocks, rTMS was applied (N = 10) over L-aPFC or vertex (control site) at different time-points of a task involving integration of a preloaded digit into a sequence of arithmetical steps, and contrasted with a closely matched task without integration demand (segregation). When rTMS was applied during the loading phase, reaction times during secondary task were faster, without significant changes in error rates. RTMS instead worsened performance when applied during information unloading. In contrast, no effects were observed when rTMS was applied during the other phases of integration, or during the segregation condition. These results confirm the hypothesis that L-aPFC is causally and selectively involved in the integration of information in working memory. They additionally suggest that pre-integration loading and post-integration unloading of information involving this area may be active and resource-consuming processes.     

Visual working memory load-related changes in neural activity and functional connectivity

Background

Visual working memory (VWM) helps us store visual information to prepare for subsequent behavior. The neuronal mechanisms for sustaining coherent visual information and the mechanisms for limited VWM capacity have remained uncharacterized. Although numerous studies have utilized behavioral accuracy, neural activity, and connectivity to explore the mechanism of VWM retention, little is known about the load-related changes in functional connectivity for hemi-field VWM retention.

Methodology/Principal Findings

In this study, we recorded electroencephalography (EEG) from 14 normal young adults while they performed a bilateral visual field memory task. Subjects had more rapid and accurate responses to the left visual field (LVF) memory condition. The difference in mean amplitude between the ipsilateral and contralateral event-related potential (ERP) at parietal-occipital electrodes in retention interval period was obtained with six different memory loads. Functional connectivity between 128 scalp regions was measured by EEG phase synchronization in the theta- (4–8 Hz), alpha- (8–12 Hz), beta- (12–32 Hz), and gamma- (32–40 Hz) frequency bands. The resulting matrices were converted to graphs, and mean degree, clustering coefficient and shortest path length was computed as a function of memory load. The results showed that brain networks of theta-, alpha-, beta-, and gamma- frequency bands were load-dependent and visual-field dependent. The networks of theta- and alpha- bands phase synchrony were most predominant in retention period for right visual field (RVF) WM than for LVF WM. Furthermore, only for RVF memory condition, brain network density of theta-band during the retention interval were linked to the delay of behavior reaction time, and the topological property of alpha-band network was negative correlation with behavior accuracy.

Conclusions/Significance

We suggest that the differences in theta- and alpha- bands between LVF and RVF conditions in functional connectivity and topological properties during retention period may result in the decline of behavioral performance in RVF task.     

Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice

Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.     

The relationships between working memory and long-term memory

Recent studies have led to the proposal that working memory operates not as a gateway between sensory input and long-term memory but as a workspace. The core of argument is that access to acquired knowledge and prior learning occurs before information becomes available to working memory. This proposition is a way to accomodate Baddeley's multiple component working memory model and the view that considers that working memory is nothing other than temporary activations of representations and procedures in long-term memory. However, this ‘workspace’ conception of working memory raises the question of the relationships between the central executive system and long-term memory.     

Encoding memory of winter by noncoding RNAs

In some plant species, prolonged exposure to low temperature during the winter season is necessary to acquire the competence to flower in the following spring. This process, known as vernalization, is an epigenetic change in that a mitotically stable change of the developmental potential of the meristem (competence to flower) is maintained even in the absence of the inducing signal (prolonged cold exposure). In Arabidopsis, vernalization results in stable epigenetic repression of a potent floral repressor, FLOWERING LOCUS C (FLC). Increased enrichment of Polycomb Repressive Complex 2 (PRC2) and trimethylated Histone H3 Lys 27 (H3K27me3) at FLC chromatin is necessary for the stable maintenance of FLC repression by vernalization. Recent recognition of long noncoding RNAs (ncRNAs) in vernalization response indicates that long ncRNAs are evolutionarily conserved components for PRC2-mediated repression in eukaryotes.