Prefrontal representation of stimulus attributes during delay tasks. II. The role of behavioral significance

Rhesus monkeys were trained to perform two visual discrimination tasks with delayed response. In both tasks, the response depended on the color of the cue, a lighted circle in the center of a panel. Red and green guided one task, yellow and blue the other. In the course of performance, a fifth color (violet), non-relevant and inconsequential, was presented at random in the same location as the cues. All 5 stimuli were of equal brightness. Many cells in the dorsolateral prefrontal cortex (sulcus principalis and superior convexity) treated the relevant cues differently than the irrelevant stimulus. In general, cellular reactions to that stimulus were of lesser magnitude than the reactions to the cues. Cell reaction differences as a function of stimulus significance outnumbered and overshadowed differences as a function of cue-color or any other task variable. The results indicate that, during visual delay tasks, units in the dorsolateral prefrontal cortex differentiate stimuli by their behavioral significance, as well as by other stimulus attributes, including color. Because the motivational evaluation of sensory stimuli is an integral part of the cognitive processes in delay tasks (together with short-term memory and motor set), these results support the notion that the prefrontal cortex integrates motivational inputs into the structure of behavioral action.     

Prefrontal unit activity during delayed conditional discriminations in the monkey

Single unit activity was recorded from the prefrontal cortex (principalis, arcuate and inferior convexity areas) of the monkey while the animal was performing a delayed conditional discrimination task. Sequential events of the task were as follows: instructional cue presentation, 1st delay, presentation of two pattern stimuli on left and right windows respectively as a discriminative cue, 2nd delay and choice response to the left or right window. The positive pattern was dependent on the instructional cue.In total, 424 units obtained from two monkeys showed a correlation with some aspects of the task. Of these 424 task-related units, 169 differentiated between the instructional cues and/or the discriminative cues. The majority of these differential units (n = 123) were found to be related to spatial information processing (related to the side of the response) while 19 differential units were related to non-spatial information processing (related to the color or pattern configuration of the cue). The activity of the remaining 27 differential units was considered to be related to both spatial and non-spatial information processing (related to both the instructional cue and the side of the response) and this type of unit was shown to be involved in conditional information processing. The results indicate that prefrontal units may be related to the meaning of the stimulus independent of its physical properties.     

Effects of cooling parietal cortex on prefrontal units in delay tasks

The effects of cooling posterior parietal cortex (areas 5 and 7) on behavior and on the activity of prefrontal neurons were assessed in monkeys performing two visual discrimination tasks with delayed choice. In both tasks, the visual cue for each trial was displayed for 0.5 s by rear projection through colored filters on a central 2.5-cm translucid button. After a variable delay, the choice stimuli were presented on two lower stimulus-response buttons; to obtain a reward, the animal had to press the correct button in accord with the cue. In one task, a red or a green cue called for the choice of that color when the two colors appeared after the delay; in the other task, a yellow or blue cue called for the choice of, respectively, the right or the left of the two white-illuminated choice buttons. Prefrontal single-unit activity (sulcus principalis area) and eye movements were recorded during task performance while parietal areas were at normal or subnormal (6-20 degrees C) temperature. Two-thirds of the units investigated showed significant spontaneous firing changes, most commonly a decrease, as a result of bilateral parietal cooling. A similar proportion of units showed cooling-related changes, excitatory or inhibitory, of their firing activity during the task; such firing changes could occur in any trial-epoch. Parietal cooling also induced misreaching, slow and inaccurate ocular movements, and longer choice reaction time, but did not alter performance in terms of correct responses. Our results suggest the involvement of posterior parietal cortex in spatial aspects of task performance (reaching speed and accuracy, eye movements, reaction time). They also suggest the existence of functional influences from parietal upon prefrontal cortex. Those influences, however, seem not essential for the basic role of the prefrontal cortex in the temporal integration of behavior.     

Comparative characteristics of unit activity in the prefrontal and parietal areas during delayed performance in monkeys

Neuronal mechanisms of prefrontal and parietal areas were compared in 3 monkeys during delayed performance. Spatioselective neurons were found in both areas in question. In the prefrontal cortex, they constitute 28% of all units sampled and in the parietal cortex they account for 21%. For the prefrontal area, spatial selectivity was particularly great during the delay (8%), and in the parietal area during the cue display (9%). During the delay, however, spatioselective parietal neurons accounted for 4% of all units sampled, i.e. their number was half that in the prefrontal area. The prefrontal cortex appears to play a major role in short-term memory proper, whereas the parietal area is more involved in assessing spatial relationships of emerging sensory stimuli. Spatioselective neurons of both areas were heterogeneous in their functions. Activity of some (11% in the prefrontal and 10% in the parietal area) was related only to the cue location. Activity of others (13% in the prefrontal cortex and 8% in the parietal cortex) was moreover coupled with the forthcoming movement. With lengthening of the delay, units related to the established temporal stereotype and some labile units which quickly rearranged to a new temporal task were recorded. Thus association area neurons reflect two concurrent processes linked with spatial and temporal memories. During cue displays, it is not only their spatial location that is described, but also a future motor act with its temporal and spatial properties programmed.     

Functional analysis of spatially discriminative neurons in prefrontal cortex of rhesus monkey

The present study addresses the question of whether prefrontal neurons that exhibit spatially selective patterns of discharge during the delay period in spatial delayed-response tasks code a mnemonic event. To examine this question, rhesus monkeys were trained to perform two variants of the classical spatial delayed-response task in both of which a delay intervened between cue presentation and response and the discriminative stimulus had to be recalled at the moment of response. They were also trained to perform two control tasks in which memory was not required since cues present throughout the delay informed the monkey of the correct response. Extracellular recordings were obtained from 192 neurons located in and around the principal sulcus of the frontal lobe during performance of both control and delay tasks. Comparison of the same neuron's activity across the 4 task conditions revealed a class of neuron that displayed spatially discriminative activity in the delay period only during delayed-response tasks and not during the same period of the control tasks. These neurons are candidates for units engaged in a central mnemonic process. Other neurons either exhibited similar activity in the delay period of control and delayed-response tasks or stronger discriminative behavior during this period in control tasks than in delayed response tasks. We conclude that delay-related spatially discriminative neurons found in the prefrontal association cortex are diversified and that certain of them play a specific role in mnemonic coding.     

Prefrontal unit activity and delayed response: relation to cue location versus direction of response.

Two monkeys were trained to perform 3 kinds of spatial tasks (right-left DR, up-down DR, and conditional position discrimination with delay). In the conditional position task, the animal was required to respond to the right (left) choice key when the cue had been presented on the upper (lower) position. Single unit activity was recorded from the principalis area of the dorsolateral prefrontal cortex while the animal was performing the tasks. Once a differential delay unit (i.e., unit showing specificity during the delay period for two kinds of trials) was found in right-left DR (or up-down DR), the same unit was tested in the other tasks. A total of 32 differential delay units were investigated sufficiently to allow comparison of all 3 conditions. The results indicate that there are two types of differential delay units. The first type showed a clear dependence on the cue location, while the second type was related to the direction of the impending response. Activity of the second type of differential delay unit during the delay period served to predict the occurrence of errors, whereas this relation between unit discharge and correct or incorrect responses was not seen for the first type of differential delay unit.     

The effects of dorsolateral-frontal and ventrolateral-orbitofrontal lesions on nonspatial test performance.

Performance of four Rhesus monkeys with lesions of the dorsolateral-prefrontal cortex was compared with that of five monkeys with ventrolateral-orbitofrontal lesions and four normal controls on tasks of spatial and nonspatial discrimination and delayed response. All of the tasks were presented in auditory and in visual modalities. Results suggest that removal of the spatial cue improves normal auditory discrimination performance, but retards normal visual discrimination performance. Lesions of either of the two areas of prefrontal cortex resulted in a large decrement in nonspatial visual discrimination performance, but did not change the nonspatial auditory discrimination scores. Removal of the spatial cue also had a deleterious effect upon normal delayed-response performance, more so with auditory than with visual cues. Removal of ventrolateral-orbitofrontal cortex produced effects similar to those observed with normal monkeys, but lesions of dorsolateral cortex had no effect on delayed-response performance in either modality.     

Cellular discharge in the dorsolateral prefrontal cortex of the monkey in cognitive tasks

Single-unit activity was recorded in the prefrontal cortex of monkeys performing two visual short-term memory tasks: delayed matching-to-sample and delayed response. The animal had to retain a color (sample) in the first task and a positional cue in the second. Cells reacting to the sample or the cue were found throughout the dorsolateral prefrontal cortex, some cells differentiating colors (red and green) and others positions (right and left). About one-half of all cells showed altered discharge during the retention period (delay). In some of them that discharge differed depending on the sample or cue. One cell type showed descending firing frequency in the course of the delay. Another showed the opposite, that is, increasing firing as the delay progressed. Cells with altered delay-period discharge were more common in the cortex of the sulcus principalis and the inferior convexity than in other prefrontal areas. The findings are viewed as reflecting the participation of prefrontal neurons in the temporal structuring of behavior.     

Principal sulcus and posterior parieto-occipital cortex lesions in the monkey.

In order to assess the roles of the posterior parieto-occipital and principal sulcus cortices in processing spatial information, both with and without delays, monkeys were given lesions of one or the other area or no lesion and tested on a series of conditional discrimination tasks. There were six basic tasks, and the cue locations differed from the response locations within each task. The first two had mixed dimensions in that the location of the cue indicated the color of the correct response alternative or the color of the cue indicated the correct response location. The animals were trained preoperatively on these tasks and then tested for postoperative retention. For the next two tasks color was the only relevant dimension, but different colors were used for the cues and response alternatives. For the final two tasks location was the only relevant dimension. When an animal learned a given task it was subsequently tested on it with a 5-sec. delay. The deficits observed suggest that the roles of these areas can not be expressed simply in terms of spatial or delay functions. No group appeared to be impaired on any delay task on which it was tested. The animals with the posterior cortex removed had a great deal of difficulty in using information from one dimension to identify the correct response alternative by the other dimension, but not when the relevant cue and response dimensions were the same. These results suggest that the posterior parieto-occipital area is involved in making associations across dimensions with in the visual modality. The animals with the principal sulcus removed appeared to have difficulty only when they were required to respond with reference to the colors of the response alternatives. On such tasks the relevant dimension (color) was not available until the presentation of the response array. On the other tasks the correct response location could be determined from the cue presentation alone, that is, before the presentation of the response array. This suggests that these animals had a tendency to respond without reference to the color dimension, but rather just to the presentation of the response array, and therefore a principal sulcus function of inhibiting a response until the appropriate information has been processed.     

Anterior limbic unit activity during delayed response in cats

The extracellular activity of 328 units was recorded from the anterior limbic cortex of cats performing a spatial delayed response task (DR). The DR task required the cat to make a lever-press response after a delay period of a few seconds to a previously cued location. Of the cells recorded, 139 (42%) showed some relation to DR performance. Task-related units were assigned to one of eight class and type categories consistent with the cell's active phase during the trial periods. Class B units, 23% of the total number of cells recorded, responded during the cue and choice lights. Class C units, 9% of the total recorded, were responsive to the cue and throughout the delay until the lever-press response. Class D units, 4% of the total, were related to the delay phase of DR only. Class E units, 6% of the cells, were active during the cue and displayed activity opposite in sign during the delay. Differential reactivity of units for left and right trials were observed for some units in the B,C, and E response categories, including some cells displaying differential activity during the delay period. It is concluded that visually driven sensory units typically responded to the cue and choice lights, whereas delay related units appeared to represent an intrinsic process, without postural or other external concomitants.     

Neural correlates to both emotion and cognitive functions in the monkey amygdala

Recent lesion and non-invasive studies identify the medial temporal lobe, including the amygdala, not only with emotion but also with working memory in relation to the prefrontal cortex. In the present study, amygdalar neuronal activity was recorded from monkeys during performance of discrimination tasks that led to presentation of emotion-related (rewarding or aversive) stimuli. The task had three phases: (1) discrimination (visual, auditory), (2) operant response (bar pressing) and (3) ingestion (reward) or avoidance (aversion). These neurons were further analyzed by a short-term memory task, delayed pair comparison (DPC) using colored lamps. Of 585 amygdalar neurons, 107 responded primarily to single sensory stimulation (40 vision related, 26 audition related, 41 ingestion related), 117 to multimodal stimulation (multimodal) and 14 responded selectively to only one item (selective). Of 417 neurons tested by the DPC, 122 responded in one or more phases. Of these 122 neurons, 10.7% responded in the delay period. These delay-responsive neurons also responded to various objects with positive and negative affective significance. These results suggest that amygdalar neurons are not specifically related to working memory, as are those in the inferotemporal and prefrontal cortices, but are related to more general non-specific functions or processes such as arousal or attention during the cognitive tasks. A functional role of the amygdala in working memory is discussed in terms of recent non-invasive studies suggesting a functional coupling between the amygdala and prefrontal cortex.     

Neuronal Activity during a Cued Strategy Task: Comparison of Dorsolateral, Orbital, and Polar Prefrontal Cortex

We compared neuronal activity in the dorsolateral (PFdl), orbital (PFo), and polar (PFp) prefrontal cortex as monkeys performed three tasks. In two tasks, a cue instructed one of two strategies: stay with the previous response or shift to the alternative. Visual stimuli served as cues in one of these tasks; in the other, fluid rewards did so. In the third task, visuospatial cues instructed each response. A delay period followed each cue. As reported previously, PFdl encoded strategies (stay or shift) and responses (left or right) during the cue and delay periods, while PFo encoded strategies and PFp encoded neither strategies nor responses; during the feedback period, all three areas encoded responses, but not strategies. Four novel findings emerged from the present analysis. (1) The strategy encoded by PFdl and PFo cells during the cue and delay periods was modality specific. (2) The response encoded by PFdl cells was task and modality specific during the cue period, but during the delay and feedback periods it became task and modality general. (3) Although some PFdl and PFo cells responded to or anticipated rewards, we could rule out reward effects for most strategy- and response-related activity. (4) Immediately before feedback, only PFp signaled responses that were correct according to the cued strategy; after feedback, only PFo signaled the response that had been made, whether correct or incorrect. These signals support a role in generating responses by PFdl, assigning outcomes to choices by PFo, and assigning outcomes to cognitive processes by PFp.     

The prefrontal cortex is required for incidental encoding but not recollection of source information in rodents

Lesion studies have suggested that the prefrontal cortex is involved in memory for contextual details surrounding the prior observation of objects or events, but it is unknown whether it is crucial for encoding details about the location at which cues are experienced, or for recall of that information. We used intracranial infusions of the GABA(A) receptor agonist muscimol in rodents to directly assess the role of the medial prefrontal cortex (mPFC) during incidental encoding and retrieval of information about the location of a cue during a spatial sensory preconditioning procedure. Rats experienced a single, discrete, sensory cue as they explored an open platform, and then were tested after a 24 h delay on recollection of the prior location of the cue. Activity in the mPFC was suppressed with muscimol during either encoding or retrieval of the information, with a control group receiving saline infusions before both phases. We found that mPFC suppression during the encoding phase blocked the formation of incidental memory about the cues but mPFC suppression during retrieval had no effect. Moreover, animals with suppressed frontal cortical activity in the encoding phase expressed smaller cue-directed orienting responses, indicating they attended less to the cue. These results suggest that the frontal cortex may be required to sustain attention to incidental cues in order to later recollect the location in which they have been previously experienced, but that once the location information is encoded the frontal cortex is not required for retrieval of that information.     

Single cell activity in ventral prefrontal cortex of behaving monkeys

Single unit activity was recorded extracellularly from ventral prefrontal cortex (VPC) of monkeys during performance of two short-term memory tasks: spatial delayed response and delayed matching to sample. The tasks required perception, retention and recognition of visual cues differing in either color or spatial location. Two separate areas of VPC were explored: a lateral area in the lower prefrontal convexity and a medial area around the medial orbital sulcus.Two categories of unit activity were distinguished on the basis of frequency changes to the cue. One was characterized by non-specific discharge independent upon which cue was presented, the other by discriminative discharge related not only to visual qualities of the cue but to the animal's subsequent use of it. Nearly one-half of all units showed altered firing during the retention (delay) period as compared with intertrial control firing. Eighteen per cent displayed delay activity related to the quality of the preceding cue. The lateral and medial segments of VPC were not distinguished by differences of unit activity in cue or delay periods.Post-trial activity was related to presence or absence of reward. Type I cells showed firing changes following choice reinforcement as well as gratuitous reward; some showed changes in opposite direction following unreinforced choices. They may encode the availability of reward. Type II cells showed changes of activity after unreinforced trials and, in some cases, opposite changes after unexpected reward; they were not affected by the reward of normal correct-choice trials. These cells appear to react to deviations from expectancy of reward. Type III cells exhibited comparable firing changes following reinforced and unreinforced choices. They may encode termination of a trial sequence. Type I was more common in lateral than medial VPC, whereas the opposite was true for type II; type III did not clearly predominate in either area.Ablation studies have shown that the two areas of VPC differe in behavioral functions. This study of their cellular properties revealed topographic differences only during the post-trial period. It is therefore possible that the combination of cue and delay activity (related to exteroceptive input) with post-trial activity (related to interoceptive input) constitutes the neuronal basis for the two areas' differences in behavioral function.     

Contributions of prefrontal cue-, delay-, and response-period activity to the decision process of saccade direction in a free-choice ODR task.

To examine how the dorsolateral prefrontal cortex (DLPFC) contributes to the decision process of the saccade direction, we recorded single-neuron activity while two monkeys performed two oculomotor delayed-response (ODR) tasks. In an ordinary ODR task, monkeys were required to make a memory-guided saccade to the cue location after a 3-s delay. In a self-selection version of the ODR task (S-ODR), four identical visual cues were presented simultaneously at the cue period, and monkeys were required to make a saccade toward any one of four directions after a 3-s delay. By comparing the same neuron's activity between two tasks, we found (1) neurons having directional cue-period activity in the ODR task did not show directionally selective activity in the S-ODR task, (2) neurons having directional pre-saccadic activity showed highly similar directional preferences in two tasks and exhibited temporal coupling between the onset of pre-saccadic activity and the initiation of saccadic eye movements, (3) neurons with directional delay-period activity in the ODR task exhibited similar directional preferences and showed gradual increase in the strength of the directional selectivity toward the end of the delay period in the S-ODR task. These results suggest that directional delay-period activity contributes to the decision process of the saccade direction in the S-ODR task, while directional cue-period and pre-saccadic activities do not. The gradual increase of the directional selectivity in delay-period activity might correspond to neural correlates of the decision process of the saccade direction in the S-ODR task.     

Insights into the nature of fronto-temporal interactions from a biconditional discrimination task in the monkey

Previous work in monkeys has shown that both frontal and inferior temporal cortices are required to solve visual learning tasks. When communication between these cortical areas is prevented within the same hemisphere by crossed lesions of the frontal cortex in one hemisphere and the inferior temporal cortex in the opposite hemisphere, most learning tasks are impaired, but learning of object-reward associations is unimpaired. The current experiment aims to understand further the role of the interaction between the frontal and inferior temporal cortices in learning tasks. We trained monkeys on a biconditional discrimination task, in which different visual cues guided behaviour towards choice objects. One visual cue predicted immediate delivery of reward to a correct response, the other visual cue predicted a delayed delivery of reward to a correct response. Pre-operative behavioural data clearly shows that the monkeys form expectations of the reward outcome for the individual cues and choice objects. Crossed lesions of frontal and inferior temporal cortices, however, produce no impairment on this task. The result suggests (in combination with previous experiments) that task difficulty does not determine the reliance of a task on interactions between the frontal cortex and the inferior temporal cortex within the same hemisphere. Instead, we propose that tasks that can be solved by using expectation of the reward outcome do not require interaction of frontal and inferior temporal cortices within the same hemisphere. The results are discussed in the context of other data on frontal interactions with inferior temporal cortex in learning tasks.     

Activity of prefrontal neurons during location and color delayed matching tasks.

Many cells in prefrontal cortex show enhanced activity prior to movement onset in delayed or memory-guided saccade tasks. This activity is a possible neural correlate of spatial attention and working memory. The goal of this study was to determine whether delay activity is evoked when non-spatial cues such as color are used to guide saccades. Monkeys were trained on a saccade target selection task in which they were cued for either the location or color of the rewarded target. When the location of the target was specified explicitly, many cells showed visual responses and delay activity that were spatially selective. Color selective visual responses or delay activity were both rare and weak. However, for many cells, spatially selective delay activity could be evoked when color was used to specify the location of the target. These results indicate that color is capable of eliciting spatially selective activity from cells that have no overt color selectivity.     

Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI.

OBJECTIVE: Functional magnetic resonance imaging (MRI) was used to investigate the hypothesis that attention deficit hyperactivity disorder (ADHD) is associated with a dysfunction of prefrontal brain regions during motor response inhibition and motor timing. METHOD: Generic brain activation of seven adolescent boys with ADHD was compared to that of nine comparison subjects equivalent in sex, age, and IQ while they were performing a stop task, requiring inhibition of a planned motor response, and a motor timing task, requiring timing of a motor response to a sensory cue. RESULTS: The hyperactive adolescents showed lower power of response in the right mesial prefrontal cortex during both tasks and in the right inferior prefrontal cortex and left caudate during the stop task. CONCLUSIONS: ADHD is associated with subnormal activation of the prefrontal systems responsible for higher-order motor control. Functional MRI is a feasible technique for investigation of neural correlates of ADHD.     

Microstimulation of the dorsolateral prefrontal cortex biases saccade target selection

A long-standing issue concerning the executive function of the primate dorsolateral prefrontal cortex is how the activity of prefrontal neurons is linked to behavioral response selection. To establish a functional relationship between prefrontal memory fields and saccade target selection, we trained three macaque monkeys to make saccades to the remembered location of a visual cue in a delayed spatial match-to-sample saccade task. We electrically stimulated sites in the prefrontal cortex with subthreshold currents during the delay epoch while monkeys performed this task. Our results show that the artificially injected signal interacts with the neural activity responsible for target selection, biasing saccade choices either towards the receptive/movement field (RF/MF) or away from the RF/MF, depending on the stimulation site. These findings might reflect a functional link between prefrontal signals responsible for the selection bias by modulating the balance between excitation and inhibition in the competitive interactions underlying behavioral selection.     

Dissociation of egocentric and allocentric spatial processing in prefrontal cortex

Monkeys with lesions of areas 9 and 46 performed three variants of the spatial delayed response (SDR) task. There were no impairments in allocentric spatial memory in which geometrical relationships between environmental cues were used to identify spatial location; thus, memory of a 3D environmental map is intact. In contrast, there were severe impairments in egocentric spatial memory guided by visual or tactile cues that monkeys can relate to their viewing perspective during testing. These results strongly suggest that dorsolateral prefrontal cortex selectively mediates spatial memory tasks that are solved by referencing the location of targets to the body's orientation.