Christos Constantinidis

A role for inhibition in shaping the temporal flow of information in prefrontal cortex

The prefrontal cortex is important in guiding or inhibiting future responses, which requires the temporal integration of events and which provides continuity to the thought process. No cellular mechanism has been proposed to explain how the mental representation of a response or idea is linked to the next. Using simultaneous recordings in monkeys, we revealed inhibitory interactions between neurons active at different time points relative to the cue presentation, delay interval and response period of a working memory task. These findings suggest an important role of inhibition in the cerebral cortex—controlling the timing of neuronal activities during cognitive operations and thereby shaping the temporal flow of information.

The sensory nature of mnemonic representation in the primate prefrontal cortex.

A long-standing issue concerning the function of the primate dorsolateral prefrontal cortex is whether the activity of prefrontal neurons reflects the perceived sensory attributes of a remembered stimulus, or the decision to execute a motor response. To distinguish between these possibilities, we recorded neuronal activity from monkeys trained to make a saccade toward the brighter of two memoranda, under conditions of varied luminance. Our results indicated that during the delay period when sensory information was no longer available, neuronal discharge was modulated by the luminance of the stimulus appearing in the receptive field, and was directly correlated with psychophysical performance in the task. The findings suggest that although prefrontal cortex codes for a diversity of representations, including the decision for an impending response, a population of neurons maintains the dimensional attributes of remembered stimuli throughout the delay period, which allows for flexibility in the outcome of a mnemonic process.

Coding Specificity in Cortical Microcircuits: A Multiple-Electrode Analysis of Primate Prefrontal Cortex

Neurons with directional specificities are active in the prefrontal cortex (PFC) during tasks that require spatial working memory. Although the coordination of neuronal activity in PFC is thought to be maintained by a network of recurrent connections, direct physiological evidence regarding such networks is sparse. To gain insight into the functional organization of the working memory system in vivo, we recorded simultaneously from multiple neurons spaced 0.2–1 mm apart in monkeys performing an oculomotor delayed response task. We used cross-correlation analysis and characterized the effective connectivity between neurons in relation to their spatial and temporal response properties. The majority of narrow (<5 msec) cross-correlation peaks indicated common input and were most often observed between pairs of neurons within 0.3 mm of each other. Neurons recorded at these distances represented the full range of spatial locations, suggesting that the entire visual hemifield is represented in modules of corresponding dimensions. Nearby neurons could be activated in any epoch of the behavioral task (stimulus presentation, delay, response). The incidence and strength of cross-correlation, however, was highest among cells sharing similar spatial tuning and similar temporal profiles of activation across task epochs. The dependence of correlated discharge on the functional properties of neurons was observed both when we analyzed firing from the task period as well as from baseline fixation. Our results suggest that the coding specificity of individual neurons extends to the local circuits of which they are part.

A Neural Circuit Basis for Spatial Working Memory

The maintenance of a mental image in memory over a time scale of seconds is mediated by the persistent discharges of neurons in a distributed brain network. The representation of the spatial location of a remembered visual stimulus has been studied most extensively and provides the best-understood model of how mnemonic information is encoded in the brain. Neural correlates of spatial working memory are manifested in multiple brain areas, including the prefrontal and parietal association cortices. Spatial working memory ability is severely compromised in schizophrenia, a condition that has been linked to prefrontal cortical malfunction. Recent computational modeling work, in interplay with physiological studies of behaving monkeys, has begun to identify microcircuit properties and neural dynamics that are sufficient to generate memory-related persistent activity in a recurrent network of excitatory and inhibitory neurons during spatial working memory. This review summarizes recent results and discusses issues of current debate. It is argued that understanding collective neural dynamics in a recurrent microcircuit provides a key step in bridging the gap between network memory function and its underlying cellular mechanisms. Progress in this direction will shed fundamental insights into the neural basis of spatial working memory impairment associated with mental disorders.

The primate working memory networks

Working memory has long been associated with the prefrontal cortex, since damage to this brain area can critically impair the ability to maintain and update mnemonic information. Anatomical and physiological evidence suggests, however, that the prefrontal cortex is part of a broader network of interconnected brain areas involved in working memory. These include the parietal and temporal association areas of the cerebral cortex, cingulate and limbic areas, and subcortical structures such as the mediodorsal thalamus and the basal ganglia. Neurophysiological studies in primates confirm the involvement of areas beyond the frontal lobe and illustrate that working memory involves parallel, distributed neuronal networks. In this article, we review the current understanding of the anatomical organization of networks mediating working memory and the neural correlates of memory manifested in each of their nodes. The neural mechanisms of memory maintenance and the integrative role of the prefrontal cortex are also discussed.

Posterior parietal cortex automatically encodes the location of salient stimuli.

We examined the responses of neurons in posterior parietal area 7a to salient stimuli appearing alone or within multiple-stimulus displays in monkeys trained only to maintain fixation. Discharges in a population of parietal neurons encoded the location of the salient stimulus, although the latter had no task significance for the monkey. Neuronal selectivity for the location of the salient stimulus depended solely on its intrinsic difference from the background elements in the array and not on the color of the stimulus per se. These results were similar to those reported in monkeys trained to actively locate a salient stimulus in a multiple-stimulus display. A lower percentage of neurons with significant selectivity for the salient stimulus was observed in the fixation-only animals. These neurons took longer for the selective responses to emerge and showed a lower power of discrimination. The findings suggest that the posterior parietal cortex automatically detects and encodes the location of salient stimuli even when they are unrelated to the behavioral task.

The neuroscience of working memory capacity and training

Working memory — the ability to maintain and manipulate information over a period of seconds — is a core component of higher cognitive functions. The storage capacity of working memory is limited but can be expanded by training, and evidence of the neural mechanisms underlying this effect is accumulating. Human imaging studies and neurophysiological recordings in non-human primates, together with computational modelling studies, reveal that training increases the activity of prefrontal neurons and the strength of connectivity in the prefrontal cortex and between the prefrontal and parietal cortex. Dopaminergic transmission could have a facilitatory role. These changes more generally inform us of the plasticity of higher cognitive functions.

Early involvement of prefrontal cortex in visual bottom-up attention

Visual attention is guided to stimuli either on the basis of their intrinsic saliency against their background (bottom-up factors) or through willful search of known targets (top-down factors). Posterior parietal cortex (PPC) is thought to be important for the guidance of visual bottom-up attention, whereas dorsolateral prefrontal cortex is thought to represent top-down factors. Contrary to this established view, we found that, when monkeys were tested in a task requiring detection of a salient stimulus defined purely by bottom-up factors and whose identity was unknown before the presentation of a visual display, prefrontal neurons represented the salient stimulus no later than those in the PPC. This was true even though visual response latency was shorter in parietal than in prefrontal cortex. These results suggest an early involvement of the prefrontal cortex in the bottom-up guidance of visual attention.

Stimulus Selectivity in Dorsal and Ventral Prefrontal Cortex after Training in Working Memory Tasks

The prefrontal cortex is known to represent different types of information in working memory. Contrasting theories propose that the dorsal and ventral regions of the lateral prefrontal cortex are innately specialized for the representation of spatial and nonspatial information, respectively (Goldman-Rakic, 1996), or that the two regions are shaped by the demands of cognitive tasks imposed on them (Miller, 2000). To resolve this issue, we recorded from neurons in the two regions, before and at multiple stages of training monkeys on visual working memory tasks. Before training, substantial functional differences were present between the two regions. Dorsal prefrontal cortex exhibited higher overall responsiveness to visual stimuli and higher selectivity for spatial information. After training, stimulus selectivity generally decreased, although dorsal prefrontal cortex retained higher spatial selectivity regardless of task performed. Ventral prefrontal cortex appeared to be affected to a greater extent by the nature of the task. Our results indicate that regional specialization for stimulus selectivity is present in the primate prefrontal cortex regardless of training. Dorsal areas of the prefrontal cortex are inherently organized to represent spatial information, and training has little influence on this spatial bias. Ventral areas are biased toward nonspatial information, although they are more influenced by training both in terms of activation and changes in stimulus selectivity.

Semantic confusion regarding the development of multisensory integration: a practical solution

There is now a good deal of data from neurophysiological studies in animals and behavioral studies in human infants regarding the development of multisensory processing capabilities. Although the conclusions drawn from these different datasets sometimes appear to conflict, many of the differences are due to the use of different terms to mean the same thing and, more problematic, the use of similar terms to mean different things. Semantic issues are pervasive in the field and complicate communication among groups using different methods to study similar issues. Achieving clarity of communication among different investigative groups is essential for each to make full use of the findings of others, and an important step in this direction is to identify areas of semantic confusion. In this way investigators can be encouraged to use terms whose meaning and underlying assumptions are unambiguous because they are commonly accepted. Although this issue is of obvious importance to the large and very rapidly growing number of researchers working on multisensory processes, it is perhaps even more important to the non‐cognoscenti. Those who wish to benefit from the scholarship in this field but are unfamiliar with the issues identified here are most likely to be confused by semantic inconsistencies. The current discussion attempts to document some of the more problematic of these, begin a discussion about the nature of the confusion and suggest some possible solutions.