Addition of fornix transection to frontal-temporal disconnection increases the impairment in object-in-place memory in macaque monkeys.

Both frontal-inferotemporal disconnection and fornix transection (Fx) in the monkey impair object-in-place scene learning, a model of human episodic memory. If the contribution of the fornix to scene learning is via interaction with or modulation of frontal-temporal interaction--that is, if they form a unitary system--then Fx should have no further effect when added to frontal-temporal disconnection. However, if the contribution of the fornix is to some extent distinct, then fornix lesions may produce an additional deficit in scene learning beyond that caused by frontal-temporal disconnection. To distinguish between these possibilities, we trained three male rhesus monkeys on the object-in-place scene-learning task. We tested their learning on the task following frontal-temporal disconnection, achieved by crossed unilateral aspiration of the frontal cortex in one hemisphere and the inferotemporal cortex in the other, and again following the addition of Fx. The monkeys were significantly impaired in scene learning following frontal-temporal disconnection, and furthermore showed a significant increase in this impairment following the addition of Fx, from 32.8% error to 40.5% error (chance = 50%). The increased impairment following the addition of Fx provides evidence that the fornix and frontal-inferotemporal interaction make distinct contributions to episodic memory.

Selective perceptual impairments after perirhinal cortex ablation.

It has been suggested that the primate perirhinal cortex contributes exclusively to memory. However, recent studies in macaque monkeys have implied that the perirhinal cortex may also contribute to object perception. To investigate whether the perirhinal cortex does contribute to perception, we devised several perceptual oddity tasks in which monkeys had to choose which stimulus of several presented concurrently on a touch screen was different. Macaques with bilateral perirhinal cortex ablations were selectively impaired relative to controls at perceptually discriminating the odd stimulus when the odd stimulus was a different object and when the discrimination could not be done on the basis of simple differences in features between the stimuli. They remained unimpaired relative to controls on discriminating the odd stimulus when the odd stimulus was a different color, a different shape, or a different size even when these discriminations were extremely difficult. They were also impaired on human and monkey face oddity tasks and oddity tasks with scenes containing objects. Therefore, we reject the notion that the macaque perirhinal cortex has a role exclusive to memory and conclude that the macaque perirhinal cortex does contribute to perception. We argue that the perirhinal cortex is neither specialized for perception nor memory processes alone, but rather, is specialized for processing stimuli that require processing at a more abstract level such as at the level of an object and that the perirhinal cortex contributes to both memory and perception of such stimuli.

Amnesia for Complex Naturalistic Scenes and for Objects Following Fornix Transection in the Rhesus Monkey.

Rhesus monkeys (Macaca mulatta) were trained to discriminate among many complex naturalistic scenes. The scenes were still frames from a cinema film. They were presented as the discriminative stimuli in a concurrent discrimination learning task in which each discriminative stimulus was presented on one trial each day. Learning of this task was severely impaired by fornix transection. The same animals were also deficient in a similar concurrent discrimination learning task, with each discriminative stimulus presented on one trial each day, but with objects, not complex scenes, as the stimulus material. The impairment in object discrimination learning in the present experiment is attributable to an interaction of object discrimination learning with scene discrimination learning, and can be understood as an effect of interference in long-term memory. In contrast to these impairments in long-term memory, a test of within-session learning of complex scenes, in which the average interval between successive presentations of the same stimulus was < 3 min, was performed without significant impairment by the fornix-transected animals. These results show that long-term memory for complex naturalistic scenes reveals analogues in the monkey of human episodic memory and its impairment in amnesia.

Mediodorsal Thalamic Lesions Impair Long-Term Visual Associative Memory in Macaques.

Six cynomolgus monkeys (Macaca fascicularis) were trained to associate visual stimuli with the delivery of various amounts of food reward. The animals had to choose correctly between pairs of stimuli drawn from a population of 16. Four of these stimuli were associated with 0 reward pellets, four with 1 pellet, four with 2 pellets and four with 4 pellets. Mediodorsal thalamic lesions including the medial part of the mediodorsal nucleus, similar to those which are frequently seen in Korsakoff amnesia, produced a severe impairment in this task. The impairment was seen both in memory for the quantity of reward, as expressed in choices between 1-pellet and 2-pellet stimuli or choices between 2-pellet and 4-pellet stimuli, and also in memory for the qualitative absence or presence of reward, as expressed in choices between 0-pellet and 1-pellet stimuli. The deficit in this task establishes that mediodorsal thalamic lesions in monkeys can impair long-term memory tasks, in addition to their known effects on several short-term memory tasks. The contrast between the present results and those of previous experiments on visual long-term memory in the monkey following mediodorsal thalamic lesions can be related to similar contrasts in studies of lesions in the amygdala, suggesting that the functions of these two structures are related.

Additive effects of forgetting and fornix transfection in the temporal gradient of retrograde amnesia.

Nine Rhesus monkeys (Macaca mulatta) learned to discriminate among 320 complex naturalistic scenes (Set A) for food reward. Six months later they learned to discriminate among a further 192 scenes (Set B). Immediately after learning Set B the animals were given a preoperative retention test of both sets, consisting of a single trial with every scene they had learned. Three monkeys were then operated upon to transect the fornix, the other six forming an unoperated control group. Two weeks after operation the scenes were presented once each in a postoperative retention test. The animals with fornix transection showed significantly poorer memory than the control animals at the postoperative retention test. Furthermore, within the fornix-transected animals' performance, postoperative amnesia for Set B was more marked than amnesia for Set A, by comparison with the animals' own preoperative retention of the two sets. However, a similar pattern of performance was also seen within the control animals' results, in that they forgot more of Set B than of Set A in the interval between the preoperative and postoperative retention tests. There was no significant difference between the groups in the gradient of forgetting, defined as the difference between forgetting of Set B and forgetting of Set A in the interval between the preoperative and postoperative retention tests. These results give no support to the idea that the severity of retrograde amnesia is graded as a function of the remoteness of the memory at the onset of amnesia, and they give some indication of possible reasons why the impression of such a gradient is frequently reported clinically.

Normal forgetting, impaired acquisition in memory for complex naturalistic scenes by fornix-transected monkeys.

As part of an earlier experiment three rhesus monkeys (Macaca mulatta) with fornix transection and three normal control monkeys had learned to discriminate among 320 naturalistic complex scenes. The fornix-transected animals had been much slower than the controls to reach criterion in learning this task, but eventually did so. The present experiment measured long-term forgetting of these scenes. Seven weeks after reaching criterion each animal was retested. All animals showed some forgetting of the scene discriminations they had learned. The amount forgotten was equal in the two groups. These results show that the slower learning of the scenes following fornix transection was not caused by accelerated forgetting. The present findings in fornix-transected monkeys are similar to previous findings in human amnesic patients.

Crossed unilateral lesions of the medial forebrain bundle and either inferior temporal or frontal cortex impair object-reward association learning in Rhesus monkeys.

In an accompanying paper we showed that combined transection of the fornix, amygdala and temporal stem in monkeys produced dense amnesia, including an impairment in visual object-reward association learning. We proposed that this combined surgical section had its effect by isolating temporal cortex from the ascending projections of the basal forebrain and midbrain structures. To test this hypothesis, in the present experiment we disconnected the inferior temporal cortex from these basal forebrain and midbrain structures, while sparing cortical white matter, by crossed unilateral lesions of the medial forebrain bundle in one hemisphere and inferior temporal cortex in the opposite hemisphere. The aim of the medial forebrain bundle lesion was to section axons of cells, both those that project to the cortex via the medial forebrain bundle, and those which control the activity of these same structures. A single unilateral lesion alone had no effect on the ability to learn and remember visual object-reward associations, but the crossed unilateral lesions produced an impairment in this task which was equal in severity to the impairment seen earlier after bilateral section of the fornix, amygdala and temporal stem. The impairment was not an effect of interrupting fibres to the cortex from the ventromedial hypothalamus, or of unilateral sensory neglect. This supports the hypothesis that these midbrain and basal forebrain afferents to the inferior temporal cortex are important for new visual learning. Furthermore, an impairment of equal severity was demonstrated in a separate group of animals that received crossed unilateral lesions of the medial forebrain bundle in one hemisphere and of the frontal cortex in the opposite hemisphere. We propose that the frontal cortex acts to modulate basal forebrain activity which in turn reinforces object representations in the inferior temporal cortex during learning.

The effect of anterior thalamic and cingulate cortex lesions on object-in-place memory in monkeys.

Six Macaque monkeys (Macaca mulatta) were trained in an object-in-place memory task, designed to capture the 'whole scene' nature of episodic memory. In this task the correct, rewarded, response in each scene was to a particular object of a pair, which always occupied a particular position in a unique background which had been generated using randomly chosen colours and shapes. In each session, the monkey learned a new list of these unique scenes. The animals then underwent surgical ablation of either the anterior thalamic nuclei or the cingulate cortex. It was found that the animals with anterior thalamic lesions showed a substantial impairment, whereas the monkeys with cingulate cortex ablations were not significantly impaired at the task. These results confirm the importance of the anterior thalamic nuclei in episodic memory, and suggest that the cingulate gyrus is not a region which is crucial in the type of episodic memory task used in the present experiment.

Memory after frontal/temporal disconnection in monkeys: conditional and non-conditional tasks, unilateral and bilateral frontal lesions.

Seven Cynomolgus monkeys (Macaca fascicularis) learned a series of reward-visual conditional discrimination problems, in which the arrival or non-arrival of a food pellet at the beginning of each trial acted as an instruction cue, signalling which of two visually distinct stimulus objects the animal should choose on that trial in order to obtain a further food pellet reward. Following surgical removal of the ventrolateral prefrontal cortex in one hemisphere and the inferior temporal cortex in the contralateral hemisphere, combined with forebrain commissurotomy, the four operated animals were severely impaired at relearning this task. They were not impaired, however, in non-conditional visual discrimination learning. Extending the unilateral frontal lesion to include the ventromedial prefrontal cortex had no detrimental effect, nor did complete unilateral removal of the frontal cortex. In a third experiment, the operated animals underwent a further surgery to remove either ventrolateral, ventral or complete frontal cortex similar to that in the opposite hemisphere. Compared to their previous level of performance, the animals with bilateral ventrolateral prefrontal lesions were now mildly impaired and the animals with the bilateral lesion extended to the ventromedial cortex more severely impaired on the non-conditional visual discrimination task. The bilaterally lobectomized animals were unable to relearn the task. We suggest that behaviour in visual learning tasks is controlled by cortical convergence upon subcortical structures, possibly by striatal efferents from both the visual cortex and frontal cortex, and that intrahemispheric convergence of these two efferents within the corpus striatum of one hemisphere could allow detailed control of visual choices by non-visual information, while subcortical interhemispheric transfer allows only less detailed, more general control.

Dense amnesia in the monkey after transection of fornix, amygdala and anterior temporal stem.

The traditional explanation of dense amnesia after medial temporal lesions is that the amnesia is caused by damage to the hippocampus and related structures. An alternative view is that dense amnesia after medial temporal lesions is caused by the interruption of afferents to the temporal cortex from the basal forebrain. These afferents travel to the temporal cortex through three pathways, namely the anterior temporal stem, the amygdala and the fornix-fimbria, and all these three pathways are damaged in dense medial temporal amnesia. In four experiments using different memory tasks, we tested the effects on memory of sectioning some or all of these three pathways in macaque monkeys. In a test of scene-specific memory for objects, which is analogous in some ways to human episodic memory, section of fornix alone, or section of amygdala and anterior temporal stem sparing the fornix, each produced a significant but mild impairment. When fornix section was added to the section of anterior temporal stem and amygdala in this task, however, a very severe impairment resulted. In an object recognition memory task (delayed matching-to-sample) a severe impairment was seen after section of anterior temporal stem and amygdala alone, with or without the addition of fornix section; this impairment was significantly more severe than that which was seen in the same task after amygdalectomy leaving the temporal stem intact, with or without fornix section. Animals with combined section of anterior temporal stem, amygdala and fornix were also impaired in object-reward association learning. However, the retention of pre-operatively acquired object-reward associations was at a high level. These results show that the pattern of impairments after section of anterior temporal stem, amygdala and fornix in the monkey, leaving hippocampus intact, resembles human dense amnesia and is different from the effects of hippocampal lesions in the monkey.

The role of the vertical meridian in visual memory for objects.

It is widely believed that, in human and nonhuman primates, visual memories of objects are stored in the temporal lobe. Electrophysiological results in monkeys, however, indicate that when a visual scene contains two or more objects, with at least one object in each visual hemifield, neurons in the temporal lobe of each hemisphere respond only to the objects that are in the contralateral visual hemifield, and their activity is unaffected by the objects in the ipsilateral hemifield. Putting these two premises together predicts that object memory should fail, or at least suffer a substantial decrement, when an object is presented for learning and retention as part of such a scene, but crosses the vertical meridian between the learning trial and the retention test. The effect of this change should be much greater than the effect of an equal retinal translation that crosses the horizontal rather than the vertical meridian. An experiment with normal human subjects verified this prediction under conventional conditions of tachistoscopic viewing, with a single constant fixation spot. A further condition in the same experiment, however, tested the same retinal translations in a more naturalistic condition, where the retinal changes were produced by varying the position on the display screen of the fixation spot rather than of the objects. Here, there was no significant special effect of crossing the vertical meridian. We conclude that visual memories are not stored exclusively in the temporal lobe.

Perirhinal cortex ablation impairs configural learning and paired-associate learning equally.

Combined damage to the perirhinal and entorhinal cortex has been implicated in the formation of stimulus-stimulus associative memories. We show in this article that relative to three normal controls three cynomolgus monkeys with ablations restricted to the perirhinal cortex were impaired on a visual paired associate learning task in which subjects had to learn which of two visual stimuli were associated with a cue stimulus. The subjects with perirhinal cortex ablations also showed an impairment of a similar magnitude on a visual configural learning task in which they had to learn which of two configurations of visual stimuli were associated with food-reward. The stimuli in both tasks were comprised of alphanumeric characters presented upon a touch-screen. Both groups made fewer errors on the configural learning task than on the paired associate learning task. We suggest that performance on both tasks relies critically on the perirhinal cortex due to the specialization of the perirhinal cortex in processing knowledge about objects. We argue that the specializations of this system and of other memory systems such as the hippocampal-fornix spatial/episodic memory system, are conferred by the specialization of their anatomical connections to other structures. We reject the notion that there are specific memory processes such as the hippocampal based configural associative system that was proposed to be critical for configural associative learning.

Hemifield-specific visual recognition memory impairments in patients with unilateral temporal lobe removals.

Recent evidence on visual neglect suggests that each hemisphere maintains a retinotopically organized representation of the visual world contralateral to the current fixation point and that this representation is based not only on analysis of the current retinal input but, equally importantly, on information retrieved from memory. This idea predicts that unilateral damage to memory systems should produce a lateralized impairment of memory for the retinotopically contralateral visual world. To test this prediction we examined visual recognition memory performance in the left and right visual hemifields of patients who had undergone partial unilateral temporal lobe removals for the relief of epilepsy, either in the left hemisphere (n = 5) or the right (n = 5). The patients were given complex artificial scenes to remember, constructed of independent left and right halves, and were then tested for recognition of the left and the right halves separately. Stimuli were exposed tachistoscopically throughout and fixation was maintained on a central position. Patients made significantly more errors with half-scenes in the hemifield contralateral to their removal than in the ipsilateral hemifield, an increase of 50% in the error rate on average. The effect was seen equally in patients with left and right removals. This finding supports the idea that visual memory retrieval is retinotopically organized.

The effect of cingulate lesions on social behaviour and emotion.

Functional and structural neuroimaging of the human cingulate cortex has identified this region with emotion and social cognition and suggested that cingulate pathology may be associated with emotional and social behavioural disturbances. The importance of the cingulate cortex for emotion and social behaviour, however, has not been clear from lesion studies. Bilateral lesions in the cingulate cortex were made in three macaques and their social interactions were compared with those of controls. Subsequently, cingulate lesions were made in the three controls and their behaviour was compared before and after surgery. Cingulate lesions were associated with decreases in social interactions, time spent in proximity with other individuals, and vocalisations but an increase in manipulation of an inanimate object. The results are consistent with a cingulate role in social behaviour and emotion.

Comparison of perirhinal cortex ablation and crossed unilateral lesions of the medial forebrain bundle from the inferior temporal cortex in the rhesus monkey: effects on learning and retrieval.

Seven monkeys learned new object-reward associations and scene problems and were overtrained on 100 problems of each type. Four monkeys received crossed lesions of the medial forebrain bundle (MFB) and inferior temporal cortex, with the later addition of a fornix section ipsilateral to the MFB lesion. The remaining 3 monkeys received bilateral perirhinal cortex ablation. Disconnection of the MFB from the inferior temporal cortex impaired postoperative new learning, but the retrieval of problems overtrained preoperatively was relatively preserved. Subjects with perirhinal cortex ablation were severely impaired in new learning and at the retrieval of scene problems, but retention of object-reward associations was relatively well preserved. The results support the hypothesis that isolation of the inferior temporal cortex from basal forebrain and midbrain afferents results in dense anterograde amnesia, whereas the role of the perirhinal cortex in learning is dependent on the perceptual difficulty of the task.

Olfactory-visual associative learning in monkeys depends on intrahemispheric olfactory-visual interaction.

Three Cynomolgus monkeys (Macaca fasicularis) learned a series of food-visual conditional discrimination problems. In each problem, 1 of 2 possible food items was presented at the beginning of each trial and acted as an instruction cue as to which of 2 visually distinct stimulus objects the monkey must displace on that trial to obtain a further food reward. Following surgical disconnection of olfactory-visual intrahemispheric interaction, the monkeys were unable to use olfactory properties of the food items to guide visual choices. These results show both that olfactory differences between foodstuffs are a powerful olfactory stimulus, which can enter into cross-modal association with visual stimuli, and that this association depends on an intrahemispheric pathway of olfactory-visual interaction.

Removal of the amygdala plus subjacent cortex disrupts the retention of both intramodal and crossmodal associative memories in monkeys.

Naive rhesus monkeys (Macaca mulatta) were trained preoperatively in an automated test apparatus on an auditory-visual (crossmodal) conditional task or on a visual-visual (intramodal) conditional task that involved learning a fixed set of stimulus-stimulus associations or paired associates. After having learned their respective tasks, each monkey received bilateral removal of the amygdala plus subjacent cortex. The 2 experimental groups showed equally poor retention of the stimulus-stimulus associations and subsequently relearned their respective crossmodal and intramodal associations at the same rate. These data argue against the idea that the amygdala is specialized for crossmodal associations. Instead, the data indicate that the amygdala or its underlying cortex, or both, play a more generalized role in stimulus-stimulus associative memory.

Monkeys (Macaca fascicularis) with rhinal cortex ablations succeed in object discrimination learning despite 24-hr intertrial intervals and fail at matching to sample despite double sample presentations.

Six cynomolgus monkeys (Macaca fascicularis) learned preoperatively a set of 10 concurrent object discriminations with 24-hr intertrial intervals. Three then had the rhinal cortex removed bilaterally, whereas the other 3 remained as unoperated controls. The animals with ablations were impaired in reacquiring the preoperatively acquired set but subsequently learned without any impairment a new set of 10 discriminations that was presented in the same way. The monkeys with rhinal cortex ablations then failed to learn delayed matching to sample, with double sample presentations, in 510 trials, whereas the control animals learned this task in 270 trials on average. The results add to existing evidence that rhinal cortex ablation produces a severe impairment in visual short-term recognition memory and show for the first time that this impairment is accompanied by normal long-term discrimination learning ability.

Impairment of visual object-discrimination learning after perirhinal cortex ablation.

Eight cynomolgus monkeys learned preoperatively 20 concurrent visual discriminations between pairs of colored shapes presented on a touch screen with 24-hr intertrial intervals. Three then received bilateral perirhinal cortex ablation, and 5 remained controls. The ablated monkeys were severely impaired in reacquiring the preoperatively acquired set, whereas postoperative learning of 20 new discriminations was not significantly affected. The task was then made more difficult. First, the number of foils from which the stimulus had to be selected was increased to 2, 4, 7, and then 14. Second, larger sets of 40, 80, and 160 problems were presented. Both manipulations revealed some significant but relatively mild impairments in the monkeys with ablations. It is suggested that perirhinal cortex ablation impairs the monkey's capacity to identify individual objects, which leads to deficits in both visual-object recognition memory and discrimination learning.

Learning and transfer of object-reward associations and the role of the perirhinal cortex.

Perirhinal cortex ablation has previously been shown only to impair new postoperative object discrimination learning with large stimulus set sizes (> or = 40 problems). In this study, 3 cynomolgus monkeys (Macaca fascicularis) with bilateral perirhinal cortex ablations were impaired relative to 3 normal controls on concurrent discrimination learning tasks with only 10 problems with the objects presented in different orientations in each trial to increase the demands placed on object identification. This supports the hypothesis that perirhinal cortex damage impairs the ability to identify multiple individual objects. Fewer errors were made to digitized images of objects than toward real objects. Both groups subsequently transferred specific object-reward associations from real objects to digitized images of the respective objects and vice versa, providing evidence that cynomolgus monkeys can recognize photographic representations of objects with experience.