Spatial and temporal distribution of visual information coding in lateral prefrontal cortex.

Prefrontal neurons code many kinds of behaviourally relevant visual information. In behaving monkeys, we used a cued target detection task to address coding of objects, behavioural categories and spatial locations, examining the temporal evolution of neural activity across dorsal and ventral regions of the lateral prefrontal cortex (encompassing parts of areas 9, 46, 45A and 8A), and across the two cerebral hemispheres. Within each hemisphere there was little evidence for regional specialisation, with neurons in dorsal and ventral regions showing closely similar patterns of selectivity for objects, categories and locations. For a stimulus in either visual field, however, there was a strong and temporally specific difference in response in the two cerebral hemispheres. In the first part of the visual response (50-250 ms from stimulus onset), processing in each hemisphere was largely restricted to contralateral stimuli, with strong responses to such stimuli, and selectivity for both object and category. Later (300-500 ms), responses to ipsilateral stimuli also appeared, many cells now responding more strongly to ipsilateral than to contralateral stimuli, and many showing selectivity for category. Activity on error trials showed that late activity in both hemispheres reflected the animal's final decision. As information is processed towards a behavioural decision, its encoding spreads to encompass large, bilateral regions of prefrontal cortex.

Prefrontal-temporal disconnection impairs recognition memory but not familiarity discrimination.

Neural mechanisms in the temporal lobe are essential for recognition memory. Evidence from human functional imaging and neuropsychology, and monkey neurophysiology and neuropsychology also suggests a role for prefrontal cortex in recognition memory. To examine the interaction of these cortical regions in support of recognition memory we tested rhesus monkeys with prefrontal-inferotemporal (PFC-IT) cortical disconnection on two recognition memory tasks, a "constant negative" task, and delayed nonmatching-to-sample (DNMS). In the constant negative task monkeys were presented with sets of 100 discrimination problems. In each problem one unrewarded object was presented once every day, and became familiar over the course of several days testing. The other, rewarded object was always novel. In this task monkeys learned to avoid the familiar constant negatives and choose the novel objects, so performance on this task is guided by a sense of familiarity for the constant negatives. Following PFC-IT disconnection monkeys were severely impaired at reacquiring the rule (to avoid familiar items) but were subsequently unimpaired at acquiring new constant negative problems, thus displaying intact familiarity recognition. The same monkeys were impaired in the acquisition of the DNMS task, as well as memory for lists of objects. This dissociation between two tests of recognition memory is best explained in terms of our general hypothesis that PFC-IT interactions support the representation of temporally complex events, which is necessary in DNMS but not in constant negative. These findings, furthermore, indicate that stimulus familiarity can be represented in temporal cortex without input from prefrontal cortex.

Acetylcholine facilitates recovery of episodic memory after brain damage.

Episodic memory depends on a network of interconnected brain structures including the inferior temporal cortex, hippocampus, fornix, and mammillary bodies. We have previously shown that a moderate episodic memory impairment in monkeys with transection of the fornix is exacerbated by prior depletion of acetylcholine from inferotemporal cortex, despite the fact that depletion of acetylcholine from inferotemporal cortex on its own has no effect on episodic memory. Here we show that this effect occurs because inferotemporal acetylcholine facilitates recovery of function following structural damage within the neural circuit for episodic memory. Episodic memory impairment caused by lesions of the mammillary bodies, like fornix transection, was exacerbated by prior removal of temporal cortical acetylcholine. However, removing temporal cortical acetylcholine after the lesion of the fornix or mammillary bodies did not increase the severity of the impairment. This lesion order effect suggests that acetylcholine within the inferior temporal cortex ordinarily facilitates functional recovery after structural lesions that impair episodic memory. In the absence of acetylcholine innervation to inferotemporal cortex, this recovery is impaired and the amnesia caused by the structural lesion is more severe. These results suggest that humans with loss of cortical acetylcholine function, for example in Alzheimer's disease, may be less able to adapt to memory impairments caused by structural neuronal damage to areas in the network important for episodic memory.

Severe scene learning impairment, but intact recognition memory, after cholinergic depletion of inferotemporal cortex followed by fornix transection.

To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex.

Hierarchical coding for sequential task events in the monkey prefrontal cortex.

The frontal lobes play a key role in sequential organization of behavior. Little is known, however, of the way frontal neurons code successive phases of a structured task plan. Using correlational analysis, we asked how a population of frontal cells represents the multiple events of a complex sequential task. Monkeys performed a conventional cue-target association task, with distinct cue, delay, and target phases. Across the population of recorded cells, we examined patterns of activity for different task phases, and in the same phase, for different stimulus objects. The results show hierarchical representation of task events. For different task phases, there were different, approximately orthogonal patterns of activity across the population of neurons. Modulations of each basic pattern encoded stimulus information within each phase. By orthogonal coding, the frontal lobe may control transitions between the discrete steps of a mental program; by correlated coding within each step, similar operations may be applied to different stimulus content.

Target detection by opponent coding in monkey prefrontal cortex.

The pFC plays a key role in flexible, context-specific decision making. One proposal [Machens, C. K., Romo, R., & Brody, C. D. Flexible control of mutual inhibition: A neural model of two-interval discrimination. Science, 307, 1121-1124, 2005] is that prefrontal cells may be dynamically organized into opponent coding circuits, with competitive groups of cells coding opposite behavioral decisions. Here, we show evidence for extensive, temporally evolving opponent organization in the monkey pFC during a cued target detection task. More than a half of all randomly selected cells discriminated stimulus category in this task. The largest set showed target-positive activity, with the strongest responses to the current target, intermediate activity for a nontarget that was a target on other trials, and lowest activity for nontargets never associated with the target category. Second most frequent was a reverse, antitarget pattern. In the ventrolateral frontal cortex, opponent organization was strongly established in phasic responses at stimulus onset; later, such activity was widely spread across dorsolateral and ventrolateral sites. Task-specific organization into opponent cell groups may be a general feature of prefrontal decision making.

Detection of fixed and variable targets in the monkey prefrontal cortex.

Behavioral significance is commonly coded by prefrontal neurons. The significance of a stimulus can be fixed through experience; in complex behavior, however, significance commonly changes with short-term context. To compare these cases, we trained monkeys in 2 versions of visual target detection. In both tasks, animals monitored a series of pictures, making a go response (saccade) at the offset of a specified target picture. In one version, based on "consistent mapping" in human visual search, target and nontarget pictures were fixed throughout training. In the other, based on "varied mapping," a cue at trial onset defined a new target. Building up over the first 1 s following this cue, many cells coded short-term context (cue/target identity) for the current trial. Thereafter, the cell population showed similar coding of behavioral significance in the 2 tasks, with selective early response to targets, and later, sustained activity coding target or nontarget until response. This population similarity was seen despite quite different activity in the 2 tasks for many single cells. At the population level, the results suggest similar prefrontal coding of fixed and short-term behavioral significance.

The magnocellular mediodorsal thalamus is necessary for memory acquisition, but not retrieval.

Damage to the magnocellular mediodorsal thalamic nucleus (MDmc) in the human brain is associated with both retrograde and anterograde amnesia. In the present study we made selective neurotoxic MDmc lesions in rhesus monkeys and compared the effects of these lesions on memory acquisition and retrieval. Monkeys learned 300 unique scene discriminations preoperatively and retention was assessed in a one-trial preoperative retrieval test. Bilateral neurotoxic lesions of the MDmc, produced by 10 x 1 microl injections of a mixture of ibotenate and NMDA did not affect performance in the postoperative one-trial retrieval test. In contrast, new postoperative learning of a further 100 novel scene discriminations was substantially impaired. Thus, MDmc is required for new learning of scene discriminations but not for their retention and retrieval. This finding is the first evidence that MDmc plays a specific role in memory acquisition.

Prefrontal cortex function in the representation of temporally complex events.

The frontal cortex and inferior temporal cortex are strongly functionally interconnected. Previous experiments on prefrontal function in monkeys have shown that a disconnection of prefrontal cortex from inferior temporal cortex impairs a variety of complex visual learning tasks but leaves simple concurrent object-reward association learning intact. We investigated the possibility that temporal components of visual learning tasks determine the sensitivity of those tasks to prefrontal-temporal disconnection by adding specific temporal components to the concurrent object-reward association learning task. Monkeys with crossed unilateral lesions of prefrontal cortex and inferior temporal cortex were impaired compared with unoperated controls at associating two-item sequences of visual objects with reward. The impairment was specific to the learning of visual sequences, because disconnection was without effect on object-reward association learning for an equivalent delayed reward. This result was replicated in monkeys with transection of the uncinate fascicle, thus determining the anatomical specificity of the dissociation. Previous behavioral results suggest that monkeys represent the two-item serial compound stimuli in a configural manner, similar to the way monkeys represent simultaneously presented compound stimuli. The representation of simultaneously presented configural stimuli depends on the perirhinal cortex. The present experiments show that the representation of serially presented compound stimuli depends on the interaction of prefrontal cortex and inferior temporal cortex. We suggest that prefrontal-temporal disconnection impairs a wide variety of learning tasks because in those tasks monkeys lay down similar temporally complex representations.

Prefrontal-inferotemporal interaction is not always necessary for reversal learning.

Prefrontal cortex (PFC) is thought to have a wide-ranging role in cognition, often described as executive function or behavioral inhibition. A specific example of such a role is the inhibition of representations in more posterior regions of cortex in a "top-down" manner, a function thought to be tested by reversal learning tasks. The direct action of PFC on posterior regions can be directly tested by disconnecting PFC from the region in question. We tested whether PFC directly inhibits visual object representations in inferotemporal cortex (IT) during reversal learning by studying the effect, in macaque monkeys, of disconnecting PFC from IT by crossed unilateral ablations. We tested two visual object reversal learning tasks, namely serial and concurrent reversal learning. We found that the disconnection severely impairs serial reversal learning but leaves concurrent reversal learning completely intact. Thus, PFC cannot be said to always have direct inhibitory control over visual object representations in reversal learning. Furthermore, our results cannot be explained by generalized theories of PFC function such as executive function and behavioral inhibition, because those theories do not make predictions that differentiate different forms of reversal learning. The results do, however, support our proposal, based on other experimental evidence from macaque monkeys, that PFC has a highly specific role in the representation of temporally complex events.

Dissociable roles for cortical and subcortical structures in memory retrieval and acquisition.

The relationship between anterograde and retrograde amnesia remains unclear. Previous data from both clinical neuropsychology and monkey lesion studies suggest that damage to discrete subcortical structures leads to a relatively greater degree of anterograde than retrograde amnesia, whereas damage to discrete regions of cortex leads to the opposite pattern of impairments. Nevertheless, damage to the medial diencephalon in humans is associated with both retrograde and anterograde amnesia. In the present study, we sought to reconcile this by assessing retention as well as subsequent relearning and new postoperative learning. Rhesus monkeys learned 300 unique scene discriminations preoperatively, and retention was assessed in a preoperative and postoperative one-trial retrieval test. Combined bilateral subcortical lesions to the magnocellular mediodorsal thalamus and fornix impaired postoperative retention of the preoperatively acquired information. In addition, subsequent relearning and new postoperative learning were also impaired. This contrasts with the effects of a discrete lesion to just one of these structures, after which retention is intact in both cases. Discrete bilateral ablations to the entorhinal cortex impaired retention but had no effect on new learning. Combined with previous work from our laboratory, these results support the hypothesis that subcortical damage has a relatively greater effect on new learning, and cortical damage has a relatively greater effect on retention. Furthermore, the results demonstrate that retrograde amnesia occurs as a result of subcortical damage only if it is widespread, leading to an extensive disruption of cortical functioning. Damage of this nature may account for dense amnesia.

Ventrolateral prefrontal cortex is required for performance of a strategy implementation task but not reinforcer devaluation effects in rhesus monkeys.

The ability to apply behavioral strategies to obtain rewards efficiently and make choices based on changes in the value of rewards is fundamental to the adaptive control of behavior. The extent to which different regions of the prefrontal cortex are required for specific kinds of decisions is not well understood. We tested rhesus monkeys with bilateral ablations of the ventrolateral prefrontal cortex on tasks that required the use of behavioral strategies to optimize the rate with which rewards were accumulated, or to modify choice behavior in response to changes in the value of particular rewards. Monkeys with ventrolateral prefrontal lesions were impaired in performing the strategy-based task, but not on value-based decision-making. In contrast, orbital prefrontal ablations produced the opposite impairments in the same tasks. These findings support the conclusion that independent neural systems within the prefrontal cortex are necessary for control of choice behavior based on strategies or on stimulus value.

Dissociable performance on scene learning and strategy implementation after lesions to magnocellular mediodorsal thalamic nucleus.

Monkeys with aspiration lesions of the magnocellular division of the mediodorsal thalamus (MDmc) are impaired in object-in-place scene learning, object recognition, and stimulus-reward association. These data have been interpreted to mean that projections from MDmc to prefrontal cortex are required to sustain normal prefrontal function in a variety of task settings. In the present study, we investigated the extent to which bilateral neurotoxic lesions of the MDmc impair a preoperatively learnt strategy implementation task that is impaired by a crossed lesion technique that disconnects the frontal cortex in one hemisphere from the contralateral inferotemporal cortex. Postoperative memory impairments were also examined using the object-in-place scene memory task. Monkeys learnt both strategy implementation and scene memory tasks separately to a stable level preoperatively. Bilateral neurotoxic lesions of the MDmc, produced by 10 x 1 microl injections of a mixture of ibotenate and NMDA did not affect performance in the strategy implementation task. However, new learning of object-in-place scene memory was substantially impaired. These results provide new evidence about the role of the magnocellular mediodorsal thalamic nucleus in memory processing, indicating that interconnections with the prefrontal cortex are essential during new learning, but are not required when implementing a preoperatively acquired strategy task. Thus, not all functions of the prefrontal cortex require MDmc input. Instead, the involvement of MDmc in prefrontal function may be limited to situations in which new learning must occur.

Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task.

The orbital prefrontal cortex is thought to be involved in behavioral flexibility in primates, and human neuroimaging studies have identified orbital prefrontal activation during episodic memory encoding. The goal of the present study was to ascertain whether deficits in strategy implementation and episodic memory that occur after ablation of the entire prefrontal cortex can be ascribed to damage to the orbital prefrontal cortex. Rhesus monkeys were preoperatively trained on two behavioral tasks, the performance of both of which is severely impaired by the disconnection of frontal cortex from inferotemporal cortex. In the strategy implementation task, monkeys were required to learn about two categories of objects, each associated with a different strategy that had to be performed to obtain food reward. The different strategies had to be applied flexibly to optimize the rate of reward delivery. In the scene memory task, monkeys learned 20 new object-in-place discrimination problems in each session. Monkeys were tested on both tasks before and after bilateral ablation of orbital prefrontal cortex. These lesions impaired new scene learning but had no effect on strategy implementation. This finding supports a role for the orbital prefrontal cortex in memory but places limits on the involvement of orbital prefrontal cortex in the representation and implementation of behavioral goals and strategies.

Fornix transection impairs learning of randomly changing object discriminations.

The hippocampus has a well established role in spatial memory, but increasing evidence points to a role in nonspatial aspects of memory. To investigate such a role, six macaque monkeys received a bilateral transection of the fornix to disconnect subcortical inputs and outputs of the hippocampus. An additional six macaque monkeys constituted an unoperated control group. To test the involvement of the hippocampus in nonspatial aspects of memory, both groups were trained postoperatively on four concurrent visual object discrimination problems, each problem having one rewarded object and one unrewarded. After acquisition to criterion of these discriminations, the monkeys learned five subsequent stages of discriminations using the same objects. In each of these stages, both the pairings of objects one with another, and the reward assignments for the objects, were randomly reassigned. In the initial acquisition stage, control and fornix animals were equally proficient in learning the discriminations. In the five reassigned stages, however, monkeys with fornix transection made on average three times as many errors as the controls in learning the discriminations. This impairment was noted even in trials where the reward assignments from the previous stage were maintained in the new stage. These findings are consistent with other recent evidence for a role beyond the spatial domain for the fornix in monkeys.

Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal-temporal interaction.

Theories of dorsolateral prefrontal cortex (DLPFC) involvement in cognitive function variously emphasize its involvement in rule implementation, cognitive control, or working and/or spatial memory. These theories predict broad effects of DLPFC lesions on tests of visual learning and memory. We evaluated the effects of DLPFC lesions (including both banks of the principal sulcus) in rhesus monkeys on tests of scene learning and strategy implementation that are severely impaired following crossed unilateral lesions of frontal cortex and inferotemporal cortex. Dorsolateral lesions had no effect on learning of new scene problems postoperatively, or on the implementation of preoperatively acquired strategies. They were also without effect on the ability to adjust choice behaviour in response to a change in reinforcer value, a capacity that requires interaction between the amygdala and frontal lobe. These intact abilities following DLPFC damage support specialization of function within the prefrontal cortex, and suggest that many aspects of memory and strategic and goal-directed behaviour can survive ablation of this structure.

Global retrograde amnesia but selective anterograde amnesia after frontal-temporal disconnection in monkeys.

Prefrontal cortex and inferior temporal cortex interact in support of a wide variety of learning and memory functions. In macaque monkeys, a disconnection of prefrontal and temporal cortex produces severe new learning impairments in a range of complex learning tasks such as visuo-motor conditional learning and object-in-place scene learning. The retrograde effects of this disconnection, however, have never been fully examined. We therefore assessed the postoperative retention of 128 preoperatively learned object discrimination problems in monkeys with prefrontal-temporal disconnection using 1 trial postoperative retention tests. Because previous experiments have suggested that both spatial and temporal factors may be important in engaging frontal-temporal interaction we used object discrimination problems with a variety of spatial and temporal properties. Postoperatively, although monkeys with prefrontal-temporal disconnection displayed a retrograde amnesia for all problem types, subsequent assessments of new learning revealed selective anterograde amnesia, which was limited to problems in which objects were presented as serial compound stimuli. The pattern of broad retrograde amnesia with selective anterograde amnesia contrasts with recent data from monkeys with lesions which disrupt subcortical-cortical connectivity and which show the opposite pattern, namely no retrograde amnesia but severe anterograde amnesia. These results support the hypothesis that visual memory acquisition is supported by subcortical-cortical interactions while the retrieval of visual memories normally depends on the interaction between prefrontal cortex and inferior temporal cortex.

Impairment in object-in-place scene learning after uncinate fascicle section in macaque monkeys.

Three previous experiments have shown that a disconnection of frontal cortex from inferior temporal cortex in monkeys impairs a variety of visual learning tasks but leaves concurrent object discrimination learning intact. In the present experiment, three monkeys were trained on an object-in-place task where concurrent object discrimination learning took place within unique background scenes. After surgery to transect the uncinate fascicle, the monosynaptic route between prefrontal cortex and inferior temporal cortex, all three monkeys showed an impairment relative to their preoperative performance. Combined with previously reported impairments after uncinate fascicle transection, the interaction between frontal cortex and inferotemporal cortex is likely to be important in discrimination learning in background scenes because learning depends on associating the visual elements of a scene together with the appropriate choice object. This result adds to recent evidence showing that tasks such as object-in-place learning and conditional learning are impaired after disconnection of frontal cortex from inferior temporal cortex because those tasks require the representation of temporally extended events.

Fornix transection impairs visuospatial memory acquisition more than retrieval.

It has been hypothesized that some fornical fibres may instantiate a neuromodulatory reinforcement signal supporting memory acquisition in medial temporal cortical regions. This suggests that fornix transection should impair postoperative new learning more severely than the recall of preoperatively acquired information. Here, postoperative recall of 288 concurrent visuo-spatial discrimination problems acquired preoperatively was unaffected after fornix transection in the macaque, whereas new postoperative learning of 72 problems was impaired. This and other recent evidence supports the idea that the main function of the fornix in macaque monkeys is to support new learning about spatio-temporal context.

Medial temporal and prefrontal function: recent behavioural disconnection studies in the macaque monkey.

In the macaque monkey, disconnection syndromes can be produced experimentally either by selective section of axonal pathways or by crossed unilateral asymmetrical ablations. Behavioural investigation of the effects of these disconnections gives information that cannot be derived either from clinical studies or from the effects of bilateral symmetrical ablations in the monkey. Disconnection experiments are particularly suited to the study of the interactions between the components of widespread cortical networks. We propose that memory acquisition is dependent on plastic cortical changes that are widespread, rather than limited to the medial temporal lobe. Further, memory acquisition depends on cortical-subcortical interactions to a greater extent than memory retrieval does. Prefrontal cortex, we suggest, is specifically important in the representation of temporally complex events.