Prefrontal cortex function, quasi-physiological stimuli, and synaptic plasticity

The prelimbic area of rat medial frontal cortex may be functionally analogous to human/primate dorsolateral prefrontal cortex. This area may be involved in selective attention to the external stimuli and the coupling of the attention to a repertory of actions. It was suggested that this function may rely on a form of long-term memory [Biol. Rev. 77 (2002) 563]. Indeed, during learning of this type of behavior, a portion of prelimbic neurons persistently change their firing characteristics [Prog. Brain Res. 126 (2000) 287]. It is therefore important to study long-term potentiation (LTP) and depression (LTD) in rat prelimbic neurons. In this article, the author first briefly reviews recent findings on the prefrontal cortex function and discusses that the prefrontal cortex may be involved in long-term memory. Second, the author will show some new results which indicate that quasi-physiological patterns of stimuli mimicking prelimbic neuronal activity during behavior can induce LTP in prelimbic pyramidal neuron synapses. These results suggest that prelimbic neuronal activity during behavior may lastingly modify prelimbic synaptic efficacy.     

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.     

Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex

Dorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding.     

The role of the prefrontal and parietal cortex in learning and memory in monkeys

Removal of the 7th field of parietal cortex and sulcus principalis of prefrontal cortex did not affect learning processes for images with such properties as spatial frequency, orientation, geometrical form, but worsen learning characteristics in visual differentiation of spatial information making the learning processes unstable, longer and below the 85% level. Removal of sulcus principalis also affects learning of differentiation among various colour stimuli. The short-term memory in these monkeys are also much worse than in intact animals. A scheme of learning involving interacting sensory and cognitive processes controlled by motivation system, is proposed.     

Neuronal responses related to long-term recognition memory processes in prefrontal cortex

Much evidence indicates that prefrontal cortex plays an important role in long-term recognition memory processes. Here, we report primate prefrontal neuronal responses carrying information necessary for long-term visual recognition memory. The responses of many neurons signaled stimulus familiarity even when the period over which stimuli had to be remembered extended to 24 hr. Such responses occurred frequently in ventromedial, orbitofrontal, and anterior cingulate but not dorsolateral prefrontal cortex. Prefrontal information processing, as indicated by the response latencies, started after that in inferior temporal cortex and might be related to retrieval processes, as responses were typically larger for familiar than for novel stimuli.     

Time Course of Functional Connectivity in Primate Dorsolateral Prefrontal and Posterior Parietal Cortex during Working Memory

The dorsolateral prefrontal and posterior parietal cortex play critical roles in mediating attention, working memory, and executive function. Despite proposed dynamic modulation of connectivity strength within each area according to task demands, scant empirical data exist about the time course of the strength of effective connectivity, particularly in tasks requiring information to be sustained in working memory. We investigated this question by performing time-resolved cross-correlation analysis for pairs of neurons recorded simultaneously at distances of 0.2–1.5 mm apart of each other while monkeys were engaged in working memory tasks. The strength of effective connectivity determined in this manner was higher throughout the trial in the posterior parietal cortex than the dorsolateral prefrontal cortex. Significantly higher levels of parietal effective connectivity were observed specifically during the delay period of the task. These differences could not be accounted for by differences in firing rate, or electrode distance in the samples recorded in the posterior parietal and prefrontal cortex. Differences were present when we restricted our analysis to only neurons with significant delay period activity and overlapping receptive fields. Our results indicate that dynamic changes in connectivity strength are present but area-specific intrinsic organization is the predominant factor that determines the strength of connections between neurons in each of the two areas.     

Short-term memory trace in rapidly adapting synapses of inferior temporal cortex

Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory.     

Top-down anticipatory control in prefrontal cortex

Summary The prefrontal cortex has been implicated in a wide variety of executive functions, many involving some form of anticipatory attention. Anticipatory attention involves the pre-selection of specific sensory circuits to allow fast and efficient stimulus processing and a subsequently fast and accurate response. It is generally agreed that the prefrontal cortex plays a critical role in anticipatory attention by exerting a facilitatory “top-down” bias on sensory pathways. In this paper we review recent results indicating that synchronized activity in prefrontal cortex, during anticipation of visual stimulus, can predict features of early visual stimulus processing and behavioral response. Although the mechanisms involved in anticipatory attention are still largely unknown, we argue that the synchronized oscillation in prefrontal cortex is a plausible candidate during sustained visual anticipation. We further propose a learning hypothesis that explains how this top-down anticipatory control in prefrontal cortex is learned based on accumulated prior experience by adopting a Temporal Difference learning algorithm.     

Anterior cingulate and posterior parietal cortices are sensitive to dissociable forms of conflict in a task-switching paradigm

The conflict-monitoring hypothesis posits that anterior cingulate cortex (ACC) monitors conflict in information processing and recruits dorsolateral prefrontal cortex (DLPFC) to resolve competition as needed. We used fMRI to test this prediction directly in the context of a task-switching paradigm, in which subjects responded to the color or the motion of a visual stimulus. Conflict was indexed in terms of the product of activities in areas specialized for color or motion processing on a trial-by-trial basis. Here, we report that ACC and posterior parietal cortex (PPC) were sensitive to distinct forms of conflict, at the level of the response and the stimulus representation, respectively. Activity in PPC preceded increased activity in DLPFC and predicted enhanced behavioral performance on subsequent trials. These findings suggest that ACC and PPC may act in concert to detect dissociable forms of conflict and signal to DLPFC the need for increased control.     

Neuronal activity of the medial wall of the frontal cortex of the rat during performance of delayed reactions

Unit activity of the medial wall of the rat prefrontal cortex was studied during delayed response in the U-shaped maze. Prefrontal units were shown to be polysensory. Rhythmical stimulation induced habituation of unit responses. Spatio-selective neurones were found which means that medial part of the prefrontal area is involved in short-term memory. The role of the area is discussed in relation to the goal-directed behaviour.     

Neural activity in the human brain relating to uncertainty and arousal during anticipation

We used functional magnetic resonance neuroimaging to measure brain activity during delay between reward-related decisions and their outcomes, and the modulation of this delay activity by uncertainty and arousal. Feedback, indicating financial gain or loss, was given following a fixed delay. Anticipatory arousal was indexed by galvanic skin conductance. Delay-period activity was associated with bilateral activation in orbital and medial prefrontal, temporal, and right parietal cortices. During delay, activity in anterior cingulate and orbitofrontal cortices was modulated by outcome uncertainty, whereas anterior cingulate, dorsolateral prefrontal, and parietal cortices activity was modulated by degree of anticipatory arousal. A distinct region of anterior cingulate was commonly activated by both uncertainty and arousal. Our findings highlight distinct contributions of cognitive uncertainty and autonomic arousal to anticipatory neural activity in prefrontal cortex.     

Memory trace in prefrontal cortex: theory for the cognitive switch

The dorsolateral prefrontal cortex in human and non-human primates functions as the highest-order executor for the perception-action cycle. According to this view, when perceptual stimuli from the environment are novel or complex, the dorsolateral prefrontal cortex serves to set consciously a goal-directed scheme which broadly determines an action repertory to meet the particular demand from the environment. In this respect, the dorsolateral prefrontal cortex is a short-term activation device with the properties of a cognitive switch', because it couples a particular set of perceptual stimuli to a particular set of actions. Here, I suggest that, in order for the organism to react systematically to the environment, neural traces for the switch function must be stored in the brain. Thus, the highest-order, perception-action interface function of the dorsolateral prefrontal cortex per se depends on permanently stored neural traces in the dorsolateral prefrontal cortex and related structures. Such a memory system may be located functionally between two of the well-documented memory systems in the brain: the declarative memory system and the procedural memory system. Finally, based on available neurophysiological data, the possible mechanisms underlying the formation of cognitive switch traces are proposed.     

Set-Related Activity in the Premotor Cortex of Rhesus Monkeys: Effect of Triggering Cues and Relatively Long Delay Intervals

“Set-related activity” has been defined as a significant alteration in neuronal discharge rate during an “instructed delay period,” a period when a previously instructed movement is being withheld. It has been argued that set-related activity in the primate premotor cortex, or at least a significant proportion of it, reflects motor preparation. In most previous investigations, however, in which visual stimuli have triggered the movement and simultaneously indicated its target, set-related activity might reflect either the anticipation of or attention to the trigger stimulus. The present report shows that set-related activity is robust and can be directionally selective when trigger stimuli do not indicate the target and when a trigger stimulus is absent. Another feature of previous studies has been the relatively brief intervals between the instruction and trigger stimuli (typically 3 sec or less). In the present study, we were able to observe the activity of a small number of cells during longer delay periods. Set-related activity persists, although it becomes less consistent, for as much as 7.5 sec after an instruction stimulus. These results support the hypothesis that set-related activity reflects the preparation for specific limb movements.     

Set-related activity in the premotor cortex of rhesus monkeys: effect of triggering cues and relatively long delay intervals

"Set-related activity" has been defined as a significant alteration in neuronal discharge rate during an "instructed delay period," a period when a previously instructed movement is being withheld. It has been argued that set-related activity in the primate premotor cortex, or at least a significant proportion of it, reflects motor preparation. In most previous investigations, however, in which visual stimuli have triggered the movement and simultaneously indicated its target, set-related activity might reflect either the anticipation of or attention to the trigger stimulus. The present report shows that set-related activity is robust and can be directionally selective when trigger stimuli do not indicate the target and when a trigger stimulus is absent. Another feature of previous studies has been the relatively brief intervals between the instruction and trigger stimuli (typically 3 sec or less). In the present study, we were able to observe the activity of a small number of cells during longer delay periods. Set-related activity persists, although it becomes less consistent, for as much as 7.5 sec after an instruction stimulus. These results support the hypothesis that set-related activity reflects the preparation for specific limb movements.     

Human dorsal and ventral auditory streams subserve rehearsal-based and echoic processes during verbal working memory

To hear a sequence of words and repeat them requires sensory-motor processing and something more-temporary storage. We investigated neural mechanisms of verbal memory by using fMRI and a task designed to tease apart perceptually based ("echoic") memory from phonological-articulatory memory. Sets of two- or three-word pairs were presented bimodally, followed by a cue indicating from which modality (auditory or visual) items were to be retrieved and rehearsed over a delay. Although delay-period activation in the planum temporale (PT) was insensible to the source modality and showed sustained delay-period activity, the superior temporal gyrus (STG) activated more vigorously when the retrieved items had arrived to the auditory modality and showed transient delay-period activity. Functional connectivity analysis revealed two topographically distinct fronto-temporal circuits, with STG co-activating more strongly with ventrolateral prefrontal cortex and PT co-activating more strongly with dorsolateral prefrontal cortex. These argue for separate contributions of ventral and dorsal auditory streams in verbal working memory.     

A frontal variant of Alzheimer's disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex

A frontal variant of Alzheimer's disease (AD) has recently been identified on neuropathological and neuropsychological grounds (Johnson, J.K., Head, E., Kim, R., Starr, A., Cotman, C.W., 1999. Clinical and pathological evidence for a frontal variant of Alzheimer Disease. Arch. Neurol. 56, 1233-1239). Frontal AD differs strikingly from typical AD by the occurrence of neurofibrillary tangle densities in the frontal cortex as high or higher than in the entorhinal cortex. Since cerebrocortical membranes are commonly abnormal in Alzheimer's disease (AD), we assayed frontal AD cases for enzymes regulating membrane phospholipid composition. We specifically measured activity of phospholipase A2s (PLA2s) in dorsolateral prefrontal and lateral temporal cortices of frontal AD cases (n=12), which have respectively high and low densities of neurofibrillary tangles. In neither cortical area was Ca(2+)-dependent PLA2 activity abnormal compared to controls (n=12). In contrast, a significant 42% decrease in Ca(2+)-independent PLA2 activity was found in the dorsolateral prefrontal, but not the lateral temporal, cortex of the frontal AD cases. Similarly, the dorsolateral prefrontal cortex, but not the lateral temporal cortex of the frontal AD cases suffered a 42% decrease in total free fatty acid content, though neither that decrease nor those in any one species of free fatty acid was significant. The observed biochemical changes probably occurred in neurons given (a) our finding that PLA2 activity of cultured human NT2 neurons is virtually all Ca(2+)-independent and (b) the finding of others that nearly all Ca(2+)-independent PLA2 in brain gray matter is neuronal. The decrease in Ca(2+)-independent PLA2 activity is not readily attributable to Group VI or VIII iPLA2s since neither NT2N neurons nor our brain homogenates were greatly inhibited by drugs potently suppressing those iPLA2s. Decreased Ca(2+)-independent PLA2 activity in frontal AD may reflect a compensatory response to pathologically accelerated phospholipid metabolism early in the disorder. That could cause an early elevation of prefrontal free fatty acids, which can stimulate polymerization of tau and thus promote the prefrontal neurofibrillary tangle formation characteristic of frontal AD.     

Specific contributions of ventromedial, anterior cingulate, and lateral prefrontal cortex for attentional selection and stimulus valuation

Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. These valuation signals were topographically largely separated from neurons predicting the stimulus location to which attention covertly shifted, and which were evident across the complete medial-to-lateral extent of the PFC, encompassing anterior cingulate cortex (ACC), and lateral PFC (LPFC). LPFC responses showed particularly early-onset selectivity and primarily facilitated attention shifts to contralateral targets. Spatial selectivity within ACC was delayed and heterogeneous, with similar proportions of facilitated and suppressed responses during contralateral attention shifts. The integration of spatial and valuation signals about attentional target stimuli was observed in a confined cluster of neurons at the intersection of vmPFC, ACC, and LPFC. These results suggest that valuation processes reflecting stimulus-specific outcome predictions are recruited during covert attentional control. Value predictions and the spatial identification of attentional targets were conveyed by largely separate neuronal populations, but were integrated locally at the intersection of three major prefrontal areas, which may constitute a functional hub within the larger attentional control network.     

The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

Representation of attended versus remembered locations in prefrontal cortex

A great deal of research on the prefrontal cortex (PF), especially in nonhuman primates, has focused on the theory that it functions predominantly in the maintenance of short-term memories, and neurophysiologists have often interpreted PF's delay-period activity in the context of this theory. Neuroimaging results, however, suggest that PF's function extends beyond the maintenance of memories to include aspects of attention, such as the monitoring and selection of information. To explore alternative interpretations of PF's delay-period activity, we investigated the discharge rates of single PF neurons as monkeys attended to a stimulus marking one location while remembering a different, unmarked location. Both locations served as potential targets of a saccadic eye movement. Although the task made intensive demands on short-term memory, the largest proportion of PF neurons represented attended locations, not remembered ones. The present findings show that short-term memory functions cannot account for all, or even most, delay-period activity in the part of PF explored. Instead, PF's delay-period activity probably contributes more to the process of attentional selection.     

Competing neural responses for auditory and visual decisions

Why is it hard to divide attention between dissimilar activities, such as reading and listening to a conversation? We used functional magnetic resonance imaging (fMRI) to study interference between simple auditory and visual decisions, independently of motor competition. Overlapping activity for auditory and visual tasks performed in isolation was found in lateral prefrontal regions, middle temporal cortex and parietal cortex. When the visual stimulus occurred during the processing of the tone, its activation in prefrontal and middle temporal cortex was suppressed. Additionally, reduced activity was seen in modality-specific visual cortex. These results paralleled impaired awareness of the visual event. Even without competing motor responses, a simple auditory decision interferes with visual processing on different neural levels, including prefrontal cortex, middle temporal cortex and visual regions.