Biomedical subjects
Publications and source records attributed to M Mishkin.
Chronic 'blindness' was produced in monkeys by a lesion that combined right optic tract section, forebrain commissurotomy, and a large cortical ablation in the left hemisphere that spared most of the modality specific visual cortex. The finding suggests that, contrary to implications from earlier studies, central visual processes can influence behavior only with the participation of nonvisual cortex.
Visual recognition in monkeys appears to involve the participation of two limbothalamic pathways, one including the amygdala and the magnocellular portion of the medial dorsal nucleus (MDmc) and the other, the hippocampus and the anterior nuclei of the thalamus (Ant N). Both MDmc and Ant N project, in turn, to the prefrontal cortex, mainly to its ventral and medial portions. To test whether the prefrontal projection targets of the two limbothalamic pathways also participate in memory functions, performance on a variety of learning and memory tasks was assessed in monkeys with lesions of the ventromedial prefrontal cortex (Group VM). Normal monkeys and monkeys with lesions of dorsolateral prefrontal cortex (Group DL) served as controls. Group VM was severely impaired on a test of object recognition, whereas Group DL did not differ appreciably from normal animals. Conversely, the animals in Group VM were able to learn a spatial delayed response task, whereas 2 of the 3 animals in Group DL could not. Neither group was impaired in the acquisition of visual discrimination habits, even though the successive trials on a given discrimination were separated by 24-h intervals. The patterns of deficit suggest that ventromedial prefrontal cortex constitutes another station in the limbothalamic system underlying cognitive memory processes, whereas the dorsolateral prefrontal cortex lies outside this system. The results support the view that the classical delayed-response deficit observed after dorsolateral prefrontal lesions represents a perceptuo-mnemonic impairment in spatial functions selectively rather than a memory loss of a more general nature.
The visual recognition of rhesus monkeys was evaluated by means of a delayed nonmatching-to-sample task with trial-unique objects. Each daily session consisted of two lists of 20 objects each, which untreated animals were able to recognize at approximately 75% accuracy. When they were performing at this level reliably, doses of physostigmine (0.32, 1.0, 3.2, 10.0, 32.0, 56.0 micrograms/kg), scopolamine (1.0, 3.2, 5.6, 10.0, 17.8, 32.0 micrograms/kg), or saline were administered 20 min prior to the session. Physostigmine and scopolamine produced dose-related increases and decreases, respectively, in the number of objects correctly remembered. The systematic changes in performance support the view that cholinergic mechanisms contribute to recognition memory and suggest that tasks with trial-unique objects may be particularly useful for studying the mnemonic effects of cholinergic drugs.
The acquisition of discrimination of five pairs of pattern cues in a Wisconsin General Testing Apparatus by 223 naive macaque monkeys was compared. The pairs of discriminanda were identical in configuration but varied slightly in either the size of the cue or the size of the background plaque; thus, the degree of separation of the cue from the fringe of the plaque, the response site, was slightly different for each pair of discriminanda. These small differences in cue-response separation had marked effects on the rate of acquisition of the discriminations. Even an increment of separation as small as 0.5 cm resulted in a remarkable retardation of the acquisition. This retardation was due entirely to prolonged performance at the chance level, and not to a slow rate of improvement from the chance to a criterion level. The finding indicates that the difficulty in the acquisition learning on pattern tasks depends largely on the difficulty of attending to the pattern cues at small cue-response separations.
Performance on a visual recognition task was assessed in cynomolgus monkeys with ablations of rhinal (i.e., ento-, pro-, and perirhinal) cortex in combination with either amygdalectomy or hippocampectomy, as well as in unoperated controls. Removal of the hippocampal formation plus rhinal cortex resulted in a mild recognition deficit, whereas removal of the amygdaloid complex plus rhinal cortex resulted in a severe deficit. Comparison of the results with those of an earlier study (Mishkin, 1978) indicates that adding a rhinal cortical removal to hippocampectomy yields little, if any, additional impairment in recognition. By contrast, adding a rhinal cortical removal to an amygdalectomy has a profound effect; indeed, the recognition impairment in monkeys with amygdaloid plus rhinal removals was at least as severe as that seen in monkeys with combined amygdaloid and hippocampal removals. Taken together, these results support the conclusion that combined damage to the amygdaloid and hippocampal systems is necessary to produce a severe recognition deficit. In addition, they suggest that the effect of ablating the rhinal cortex is equivalent to that of removing the entire hippocampal formation, presumably because the rhinal cortical ablation disconnects the hippocampus from its neocortical input.
Monkeys trained on both visual and tactual versions of an object memory task (delayed nonmatching-to-sample) received bilateral ablations of either the amygdaloid complex or the hippocampal formation of the brain. Although both groups performed well on the two intramodal versions (visual-to-visual and tactual-to-tactual), the amygdalectomized monkeys were severely impaired relative to the hippocampectomized monkeys on a crossmodal version (tactual-to-visual). The findings suggest that the amygdala is critical for certain forms of crossmodal association and that the loss of such associations underlies many of the bizarre behaviors that make up the Klüver-Bucy syndrome.
An earlier finding from this laboratory of only a mild recognition impairment after hippocampal removal in mature monkeys (Mishkin 1978) contrasts with the severe deficit originally reported by Gaffan (1974) following transection of the fornix in immature monkeys. Investigation of some of the methodological differences between the two studies (lesion site, age of monkeys, and behavioral paradigm) failed to resolve the discrepancy in results, only a small impairment resulting under all conditions examined. While some still unexplored differences must underlie the divergent findings, it appears that only a comparatively mild impairment in recognition memory results from damage to the hippocampal system under a wide variety of conditions.
Performance on an object recognition test was assessed in monkeys with transections of either the fornix, the amygdalofugal pathways, or both. Whereas separate transection of the two pathways produced only small and unreliable effects, their combined transection produced a severe deficit. Comparison with the results of a previous study (Mishkin 1978) indicates that combined disconnection of the amygdala and hippocampus from the diencephalon yields a memory impairment similar to that following combined damage to the two limbic structures themselves. The findings suggest that recognition memory in monkeys depends on two parallel limbo-diencephalic pathways.
Cynomolgus monkeys with complete bilateral destruction of the medial mamillary nucleus exhibited little, if any, deficit in object recognition, although they did show evidence of impairment in spatial memory. The pattern of effects thus resembled that found previously after either hippocampal ablations or transections of the fornix and suggests that, like such damage, mamillary-body damage alone is insufficient to produce the global amnesia attributed to it in clinical cases.
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Area MT is a visuotopically organized area in extrastriate cortex of primates that appears to be specialized for the analysis of visual motion. To examine the full extent and topographic organization of the subcortical projections of MT in the macaque, we injected tritiated amino acids in five cynomolgus monkeys and processed the brains for autoradiography. The injection sites, which we identified electrophysiologically, ranged from the representation of central through peripheral vision in both the upper and lower visual fields and included, collectively, most of MT. Projections from MT to the superior colliculus are topographically organized and in register with projections from striate cortex to the colliculus. Unlike projections from striate cortex, those from MT are not limited to the upper layer of the stratum griseum superficiale but rather extend ventrally from the upper through the lower layer of the stratum griseum superficiale and even include the stratum opticum. Projections from MT to the pulvinar are organized into three separate fields. One field (P1) is located primarily in the inferior pulvinar but extends into a portion of the adjacent lateral pulvinar. The second field (P2) partially surrounds the first and is located entirely in the lateral pulvinar. The third and heaviest projection field (P3) is located posteromedially in the inferior pulvinar but also includes small portions of the lateral and medial pulvinar that lie dorsal to the brachium of the superior colliculus. While projections from MT to P1 and P2 are topographically organized, there appears to be a convergence of MT inputs to P3. Projections from MT to the reticular nucleus of the thalamus are located in the ventral portion of the nucleus, approximately at the level of the caudal pulvinar. There was some evidence that MT sites representing central vision project more caudally than do those representing peripheral vision. Projections from MT to the caudate, putamen, and claustrum are localized to small, limited zones in each structure. Those to the caudate terminate within the most caudal portion of the body and the tail. Similarly, projections to the putamen are always to its most caudal portion, where the structure appears as nuclear islands. Projections to the claustrum are located ventrally, approximately at the level of the anterior part of the dorsal lateral geniculate nucleus. Projections from MT to the pons terminate rostrally in the dorsolateral nucleus, the lateral nucleus, and the dorsolateral portion of the peduncular nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
The projections of the amygdala to the thalamus in cynomolgus monkeys (Macaca fascicularis) were studied with both anterograde and retrograde axonal tracing techniques. Horseradish peroxidase (HRP) was injected into medial and midline thalamic sites in five animals, and tritiated amino acids were injected into selected amygdaloid regions in a total of 13 hemispheres in ten animals. The findings from the two types of tracer experiments demonstrated the origins, course, and terminal pattern of amygdaloid projections to two thalamic nuclei--medialis dorsalis (MD) and reuniens. Almost all of the amygdaloid nuclei contribute projections to MD, though the greatest proportion arise from the basal group and terminate in discrete, interlocking patches within the medial, magnocellular portion of MD. In addition to this major projection, the central and medial amygdaloid nuclei send a lighter projection to the lateral portion of nucleus reuniens. The amygdalothalamic projections took a variety of routes out of the amygdala before the large majority joined the inferior thalamic peduncle and entered the rostral head of the thalamus where they turned caudally toward their targets. A small number of amygdalothalamic fibers may also run in the stria terminalis.
Parkinson's disease most consistently involves pathologic changes in the substantia nigra, which is the major source of dopamine to the striatum. It has been shown that either fetal substantia nigra or adrenal medulla tissue implanted into the rat brain survives, produces dopamine, and improves behavioral abnormalities induced by deprivation of the caudate nucleus of its dopaminergic innervation. Thus, catecholamine-containing grafts could be potential replacements for destroyed or damaged dopaminergic neurons in patients with Parkinson's disease. To explore the potential of this therapeutic approach, fetal substantia nigra or host adrenal medulla were grafted to the denervated caudate nucleus of the rhesus monkey. Under the specific conditions of our experiment, fetal substantia nigra did not survive in either of two animals tested. On the other hand, some tissue from adrenal medulla grafts survived in all four animals tested. These grafted cells contained catecholamines, as indicated by the presence of specific glyoxylic acid-induced catecholamine fluorescence. In two of the four animals, however, the grafts contained fewer than 10 surviving cells, and in the other two animals, about 190 and 300 cells were found, respectively. Despite the small numbers of cells, this is the first demonstration that peripheral tissue autografts can survive implantation into the nonhuman primate central nervous system.
The medial temporal neuropathology found in an amnesic neurosurgical patient [17] was simulated in monkeys in an attempt to determine whether the patient's mnemonic disorder, which had been ascribed to bilateral hippocampal destruction, may have also been due in part to unilateral amygdaloid removal. For this purpose, monkeys were prepared with bilateral hippocampectomy combined with unilateral amygdalectomy, and (as a control) bilateral amygdalectomy combined with unilateral hippocampectomy. The animals were trained both before and after surgery on a one-trial visual recognition task requiring memory of single objects for 10 sec each and then given a postoperative performance test in which their one-trial recognition ability was taxed with longer delays (up to 2 min) and longer lists (up to 10 objects). The two groups, which did not differ reliably at any stage, obtained average scores on the performance test 75 and 80%, respectively. Comparison with the results of an earlier experiment [8] indicates that this performance level lies approximately midway between that of monkeys with amygdaloid or hippocampal removals alone (91%) and that of monkeys with combined amygdalo-hippocampal removals (60%). The results point to a direct quantitative relationship between degree of recognition impairment and amount of conjoint damage to the amygdala and hippocampus irrespective of the specific structure involved. Evidence from neurosurgical cases tested in visual recognition [21] indicates that the same conclusion may apply to man.
Rhesus monkeys with ablations of either the second somatosensory cortex (SII) or of the superior parietal lobule (area 5) were tested on a battery of tactile discrimination tasks in order to help determine which of these areas might constitute part of a postulated cortico-limbic tactile processing pathway. Monkeys with ablations of SII were severely impaired on both texture and shape discrimination learning and had markedly elevated size and roughness discrimination thresholds relative to control animals. By contrast, monkeys with area 5 lesions were impaired only on roughness thresholds, and these were elevated only moderately. Although more severe tactile deficits following lesions of area 5 have been reported previously, they were found in the present study only when the area 5 removals were extended slightly rostrally, in a third operated group, to include the posteromedial part of the hand representation of area 2. These results are consistent with the suggestion that SII, but not area 5, is a critical station in a tactile processing pathway that proceeds from the primary somatosensory cortex (SI) to the limbic structures of the temporal lobe through links in SII and the insular cortex.
Monkeys with combined amygdalo-hippocampal removal show severe impairments on visual memory tasks after delays of only a minute or two, yet they learn visual discrimination habits about as quickly as normal animals with intertrial intervals of the same duration. In an attempt to resolve this discrepancy between abnormally rapid forgetting and successful retention, tests were conducted to determine whether discrimination learning would be prevented in animals with limbic lesions if intertrial intervals lasted 24 hr. The results showed that as long as the lesion did not encroach on inferior temporal cortex, the operated animals could acquire concurrent sets of 20 object discrimination habits at the same rate as normal animals, in an average of about 10 trials per set. The findings suggest that learning and retention processes are divisible into a mechanism for memory formation that is dependent on the limbic system and a mechanism for habit formation that is not.
On the evidence that memory formation and habit formation represent two qualitatively different learning processes based on separate neural mechanisms, the functional development of these two processes was followed ontogenetically. Separate groups of rhesus monkeys of different ages were tested in delayed nonmatching-to-sample and 24-hr concurrent discrimination learning, considered to be measures of recognition memory and discrimination habit formation, respectively. The youngest group of infant monkeys failed to learn the nonmatching task until they were approximately 4 months old. With further maturation, learning ability on this task gradually improved, yet it did not reach adult levels of proficiency even at 1 year of age. Postlearning evaluation with long delays and lists confirmed this slow ontogenetic development of recognition memory to adult levels of function. By contrast, infant monkeys 3-4 months old learned to discriminate long lists of object-pairs about as quickly as adult monkeys despite the use of 24-hr intertrial intervals. This striking dissociation in the ability of infants on the two tasks closely resembles the dissociation first found in adult monkeys rendered amnesic by limbic lesions. The results suggest that whereas the nonlimbic habit system matures early in infancy, the limbic-dependent memory system develops only slowly.
To determine whether medial temporal limbic structures are essential for memory in more than one modality, we trained monkeys preoperatively on both visual and tactual versions of a sensory memory task and then retested them after they had been given bilateral ablations of either the amygdaloid complex, the hippocampal formation, or both. Monkeys with the combined ablations were severely impaired in both modalities. By contrast, the amygdalectomized monkeys were only moderately impaired in the two modalities, while the hippocampectomized monkeys were impaired in neither. Further examination revealed that the source of the impairment in the monkeys with amygdalectomy alone, unlike that in the animals with combined lesions, was the small size of the pool from which the test objects were drawn. The latter result suggests that, whereas the sensory memory impairment following the combined lesions is basically a recognition loss, the more selective impairment following amygdalectomy alone reflects special difficulty in determining whether a recognized object was presented recently. By demonstrating that the profound sensory memory impairment that follows combined ablation of the amygdala and hippocampus extends beyond a single modality, the present results strengthen the proposals that these two structures are important for sensory memory in all modalities and the multimodal or global amnesia observed in patients with medial temporal lobe damage is likewise due to combined amygdaloid and hippocampal lesions.