Localization of brain function: the legacy of Franz Joseph Gall (1758-1828).
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Europe↗
Biomedical subjects
S Zola-Morgan
Publications and source records attributed to S Zola-Morgan.
Transient memory impairment in monkeys with bilateral lesions of the entorhinal cortex.
Performance on five behavioral tasks was assessed post-operatively in Macaca fascicularis monkeys prepared with bilateral lesions of the entorhinal cortex (E group). Three of the tasks were also readministered 9-14 months after surgery. Initial learning of the delayed nonmatching-to-sample (DNMS) task was impaired in the E animals relative to unoperated control monkeys. On the delay portion of DNMS, the performance of E animals was nearly at control levels at short delays (up to 60 sec) but was impaired at 10 min and 40 min retention intervals. On the retest of DNMS, the E animals performed normally at all retention intervals. The E animals were unimpaired on the four other memory tasks. Neuroanatomical studies revealed a significant transverse expansion of the terminal field of the perirhinal cortical projection in the CA1 region of the hippocampus. Compared to unlesioned, anatomical control monkeys, the transverse length of the perirhinal terminal field in CA1 increased approximately 70% in the E monkeys. Although this was a striking morphological alteration, it is not known whether the sprouting of this projection influenced the behavioral recovery. The results of these studies suggest that the entorhinal cortex may normally participate in the learning and performance of tasks that are dependent on the medial temporal lobe memory system. However, recovery of normal DNMS performance demonstrates that the entorhinal cortex is not, by itself, essential for learning and performance of such tasks.
Animals↗
Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys.
Research in humans and monkeys has demonstrated a system of anatomically related structures in the medial temporal lobe that is important for memory function. This system is comprised of the hippocampal region (i.e., the dentate gyrus, hippocampus proper and subicular complex) and the entorhinal, perirhinal, and parahippocampal cortices. While the hippocampal region has long been thought to be important in memory, there are few systematic studies in primates of the effects on memory of damage limited to the hippocampal region. We have used magnetic resonance imaging techniques, together with a stereotaxic approach, to produce bilateral lesions limited to the hippocampal region (the H lesion). Damage to the adjacent perirhinal, entorhinal, and parahippocampal cortex was minimal. Monkeys with the H lesion exhibited significant and long-lasting impairment on the delayed non-matching to sample task. At the same time, on this and other amnesia-sensitive tasks, monkeys with the H lesion performed better overall than monkeys with lesions of the hippocampal region that also included damage to the adjacent entorhinal and parahippocampal cortices (the H+ lesion). These findings show that, first, the hippocampal region itself is essential for normal memory function; and second, the adjacent entorhinal and parahippocampal cortices, either alone or in combination, are also an essential component of the medial temporal lobe memory system.
Animals↗
Severity of memory impairment in monkeys as a function of locus and extent of damage within the medial temporal lobe memory system.
During the past decade, work with monkeys has helped identify the structures in the medial temporal lobe that are important for memory: the hippocampal region (including the hippocampus proper, the dentate gyrus, and the subicular complex) and adjacent cortical areas that are anatomically linked to the hippocampus, i.e., the entorhinal, perirhinal, and parahippocampal cortices. One idea that has emerged from this work is that the severity of memory impairment might increase as more components of the medial temporal lobe are damaged. We have evaluated this idea directly by examining behavioral data from 30 monkeys (ten normal monkeys and 20 monkeys with bilateral lesions involving structures within the medial temporal lobe) that have completed testing on our standard memory battery during the last 10 years. The main finding was that the severity of memory impairment depended on the locus and extent of damage to the medial temporal lobe. Specifically, damage limited to the hippocampal region produced a mild memory impairment. More severe memory impairment was produced when the damage was increased to include the adjacent entorhinal and parahippocampal cortices (the H+ lesion). Finally, memory impairment was even more severe when the H+ lesion was extended forward to include the anterior entorhinal cortex and the perirhinal cortex (H++ lesion). Taken together, these findings suggest that, whereas damage to the hippocampal region produces measurable memory impairment, a substantial part of the severe memory impairment produced by large medial temporal lobe lesions in humans and monkeys can be attributed to damage to entorhinal, perirhinal, and parahippocampal cortices adjacent to the hippocampal region.
Animals↗
Impairment of long-term memory and sparing of short-term memory in monkeys with medial temporal lobe lesions: a response to Ringo.
During the last decade, an animal model of human amnesia was developed in the monkey. Studies using this model have identified structures in the medial temporal lobe that are essential for forming long-term memory (i.e. the hippocampus and the entorhinal, perirhinal and parahippocampal cortices). Recently, an important aspect of these studies was questioned by Ringo (Behav. Brain Res., 42 (1991) 123-134). He suggested that the data from the delayed non-matching-to-sample task, which has been extensively used in these studies, have been analyzed in a potentially misleading way. He reanalyzed the data from several laboratories by transforming percent correct data to a discriminability (d') measure based on signal detection theory. In monkeys with lesions, performance appeared to be equivalently impaired at short and long retention delays. He concluded that the data do not support the idea that medial temporal lobe damage produces an impairment in long-term memory, but not short-term memory. However, most of the studies he analyzed were not designed to address the distinction between short-term and long-term memory. We show here that, in studies designed to compare short-term and long-term memory directly, medial temporal lobe lesions impair long-term memory while leaving short-term memory intact. This result is obtained whether the data are analyzed using a percent correct measure, the d' measure, or an arcsine transform.
Animals↗
Enduring memory impairment in monkeys after ischemic damage to the hippocampus.
Patient RB became amnesic following an episode of global ischemia that resulted in a bilateral lesion of the CA1 field of the hippocampus. This finding suggested that damage restricted to the hippocampus is sufficient to produce clinically significant memory impairment. To evaluate further the effect of ischemic brain damage on memory, we have developed an animal model of cerebral ischemia in the monkey. Monkeys were subjected to 15 min of reversible ischemia, using a noninvasive technique involving carotid occlusion and pharmacologically induced hypotension. These monkeys sustained significant loss of pyramidal cells in the CA1 and CA2 fields of the hippocampus, as well as loss of somatostatin-immunoreactive cells in the hilar region of the dentate gyrus. Cell loss occurred bilaterally throughout the rostrocaudal extent of the hippocampus but was greater in the caudal portion. Except for patchy loss of cerebellar Purkinje cells, significant damage was not detected in areas outside the hippocampus, including adjacent cortical regions, that is, entorhinal, perirhinal, and parahippocampal cortex, and other regions that have been implicated in memory function. On behavioral tests, the ischemic monkeys exhibited significant and enduring memory impairment. On the delayed nonmatching to sample task, the ischemic monkeys were as impaired as monkeys with lesions of the hippocampal formation and adjacent parahippocampal cortex (the H+ lesion). On two other memory tasks, the ischemic monkeys were less impaired than monkeys with the H+ lesion. In neuropathological evaluations, it has always been difficult to rule out the possibility that significant areas of neuronal dysfunction have gone undetected. The finding that ischemic lesions produced overall less memory impairment than H+ lesions indicates that the ischemic monkeys (and by extension, patient RB) are unlikely to have widespread neuronal dysfunction affecting memory that was undetected by histological examination. These results provide additional evidence that the hippocampus is a focal site of pathological change in cerebral ischemia, and that damage limited to the hippocampus is sufficient to impair memory.
Amnesia↗
The medial temporal lobe memory system.
Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.
Amnesia↗
Independence of memory functions and emotional behavior: separate contributions of the hippocampal formation and the amygdala.
Structures and connections in the medial temporal lobe of humans and nonhuman primates have long been recognized as important for normal memory and emotional behavior. The present study investigated memory and emotional behavior in normal monkeys and six groups of monkeys with lesions of the medial temporal lobe. Two groups had damage to the hippocampal formation (or adjacent perirhinal and parahippocampal cortex) but not the amygdaloid complex; two groups had either partial or complete damage to the amygdaloid complex but not the hippocampal formation; and two groups had damage to both the hippocampal formation and the amygdaloid complex. Memory was evaluated with three tasks sensitive to human amnesia: (1) delayed nonmatching to sample; (2) retention of object discriminations; and (3) concurrent discrimination learning. Emotional behavior was assessed by measuring the responsiveness of monkeys to 12 different stimulus situations. Damage to the hippocampal formation or anatomically related cortex impaired memory but did not affect emotional behavior. Partial or complete damage to the amygdaloid complex affected emotional behavior but not memory. These findings show that memory impairment and abnormal emotional behavior are anatomically dissociable and independent effects of damage to the medial temporal lobe.
Amygdala↗
Stereotaxic lesions of the hippocampus in monkeys: determination of surgical coordinates and analysis of lesions using magnetic resonance imaging.
A technique is described for producing accurate stereotaxic lesions of the hippocampus in monkeys. This technique overcomes the problem that the size and shape of the brain can vary considerably from monkey to monkey. Magnetic resonance imaging (MRI) is used to create an individual brain atlas for each monkey. The atlas is then used to derive coordinates for making stereotaxic radio frequency lesions of the hippocampus. There are two key features of this procedure. First, a specially-designed, acrylic, stereotaxic headholder was constructed that could be used safely with the MR magnet. Second, small glass beads, anchored to the skull of the monkey, served as common landmarks from which lesion coordinates were determined in the MR images and then again in neurosurgery. MRI techniques are also described for determining the extent of tissue damage postoperatively. This technique could also prove useful in other areas of neuroscience research that depend on accurate stereotaxic placement of electrodes (e.g., electrophysiological studies and neuroanatomic tracing studies).
Animals↗
Inhibition of glucocorticoid secretion by the hippocampal formation in the primate.
Inhibition of the adrenocortical axis by glucocorticoids (GCs) occurs at both hypothalamic and suprahypothalamic sites. In the rat, the hippocampus has been shown to be an essential suprahypothalamic site. The present study shows that the hippocampal system serves a similar role in the nonhuman primate. Bilateral lesions that included the hippocampal formation and the parahippocampal cortex; the hippocampal formation, parahippocampal cortex, and the amygdala; or the fornix all produced GC hypersecretion in cynomolgus monkeys. The hypersecretion occurred throughout the day. Moreover, these lesions were also associated with dexamethasone resistance (i.e., GC hypersecretion following administration of the synthetic GC dexamethasone). The hypersecretion could not be attributed to acute surgical trauma, because neither circumscribed lesions of the amygdala nor conjoint lesions of the perirhinal and parahippocampal cortex produced adrenocortical abnormalities. Finally, in agreement with data derived from the rat, the GC hypersecretion following hippocampal lesions was transient. Secretory activity returned to normal levels by 6-15 months in all operated groups. Thus, the primate hippocampal system appears to share some neuroendocrine functions with the rodent.
Animals↗
Memory: organization of brain systems and cognition.
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Amnesia↗
The neuropsychology of memory. Parallel findings in humans and nonhuman primates.
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Amnesia↗
Description of brain injury in the amnesic patient N.A. based on magnetic resonance imaging.
N.A. has been amnesic since 1960 when at the age of 22 years he sustained a penetrating brain injury with a miniature fencing foil. The amnesia primarily affects verbal material and occurs in the absence of other detectable cognitive deficits. Previous CT scans demonstrated a lucency in the region of the left mediodorsal thalamic nucleus, but no additional damage was revealed. Beginning in 1986 when he was 48 years old, N.A. was evaluated with a series of magnetic resonance imaging (MR) studies. Three major areas of damage were identified. In the left thalamus there is a prominent 3- to 4-mm-wide linear lesion that approximates the position and orientation of the internal medullary lamina. The defect extends for approximately 20 mm anteroposteriorly and likely involves the rostral group of intralaminar nuclei (central medial, paracentral, central lateral, rhomboid, and reuniens nuclei), the caudal group of intralaminar nuclei (centrum medianum and parafascicular nuclei), the ventral aspect of the mediodorsal nucleus, and the ventral lateral and ventral anterior nuclei. It also likely interrupts the trajectories of the mammillothalamic tract and postcommissural fornix. The posterior hypothalamus is markedly disrupted and the mammillary nuclei appear to be missing bilaterally. Finally, the right anterior temporal lobe is damaged for a distance of about 3.5 cm from the pole to midway through the amygdaloid complex. This damage probably occurred during exploratory neurosurgery done at the time of N.A.'s injury. The hippocampal formation appears intact on both sides. A comparison of these findings with those from other patients with diencephalic amnesia suggests that amnesia can result when several diencephalic structures are damaged conjointly, including the internal medullary lamina, the intralaminar nuclei, the mediodorsal nucleus, and the mammillothalamic tract. Whether amnesia as severe as N.A.'s would result from selective damage to any one of these structures remains to be determined.
Adult↗
Successful performance by monkeys with lesions of the hippocampal formation on AB and object retrieval, two tasks that mark developmental changes in human infants.
In this study, (a) what determines success or failure on the AB and object retrieval tasks and (b) the relation between brain maturation and cognitive development as indexed by these tasks were examined. Specifically, does improved performance on these tasks with age reflect maturation of memory functions dependent on the medial temporal lobe? In AB, the S watches a reward being hidden in 1 of 2 wells; after a brief delay S reaches for that reward. The AB error consists of the S continuing to reach to the first location (A) when side of hiding is shifted to the second location (B). In object retrieval, a reward is placed in a transparent box open on 1 side. Although the reward is visible through all sides of the box, it can only be retrieved through the 1 open side. Intact cynomolgus monkeys and those with bilateral lesions of the hippocampal formation (H+) were tested. Although H+ monkeys exhibited impaired memory by performing poorly on the delayed nonmatching to sample taks, they performed well on AB at delays of 2-15 s. Performance declined as delays increased to 30 s, but H+ monkeys never showed the AB error pattern. On object retrieval, H+ monkeys succeeded quickly and efficiently, even when required to detour to the box opening. This reseach demonstrates that memory impairment alone cannot account for deficits on AB or on object retrieval and strengthens the conclusion (Diamond, 1988a, 1988b, in press) that improved performance on AB and object retrieval during infancy reflects maturation of dorsolateral prefrontal cortex.
Aging↗
Lesions of the hippocampal formation but not lesions of the fornix or the mammillary nuclei produce long-lasting memory impairment in monkeys.
A group of tasks sensitive to human amnesia were used to characterize the severity and duration of memory impairment in monkeys following bilateral damage to the hippocampal formation, fornix, or mammillary nuclei. Monkeys with hippocampal formation lesions (which included the hippocampus proper, dentate gyrus, subiculum, posterior entorhinal cortex, and much of the parahippocampal gyrus) exhibited a substantial and lasting memory impairment. Monkeys with fornix transection or bilateral damage to the mammillary nuclei were impaired on the first task administered after surgery (delayed nonmatching to sample). However, they performed all the other tasks normally and were unimpaired when the delayed nonmatching to sample task was re-administered 18 months after surgery. The findings are consistent with reports that damage limited to the human hippocampus can produce a clinically significant and permanent amnesia. Because fornix transection or mammillary lesions produced only transient memory impairment, it seems unlikely that similar damage in humans can cause a severe or permanent amnesia.
Animals↗
Lesions of perirhinal and parahippocampal cortex that spare the amygdala and hippocampal formation produce severe memory impairment.
In monkeys, bilateral damage to the medial temporal region produces severe memory impairment. This lesion, which includes the hippocampal formation, amygdala, and adjacent cortex, including the parahippocampal gyrus (the H+A+ lesion), appears to constitute an animal model of human medial temporal lobe amnesia. Reexamination of histological material from previously studied monkeys with H+A+ lesions indicated that the perirhinal cortex had also sustained significant damage. Furthermore, recent neuroanatomical studies show that the perirhinal cortex and the closely associated parahippocampal cortex provide the major source of cortical input to the hippocampal formation. Based on these 2 findings, we evaluated the severity of memory impairment in a group of monkeys that received bilateral lesions limited to the perirhinal cortex and parahippocampal gyrus (the PRPH lesion). The performance of the PRPH group was compared with that of monkeys with H+A+ lesions, who had been studied previously, and with a group of normal monkeys. Monkeys with PRPH lesions were severely impaired on 3 amnesia-sensitive tasks: delayed nonmatching to sample, object retention, and 8-pair concurrent discrimination. On pattern discrimination, a task analogous to ones that amnesic patients perform well, monkeys in the PRPH group performed normally. Overall, monkeys with PRPH lesions were as impaired or more impaired than the comparison group of monkeys with H+A+ lesions. These and other recent findings (Zola-Morgan et al., 1989b) suggest that the severe memory impairment in monkeys and humans associated with bilateral medial temporal lesions results from damage to the hippocampal formation and adjacent, anatomically related cortex, not from conjoint hippocampus-amygdala damage.
Amygdala↗
Lesions of the amygdala that spare adjacent cortical regions do not impair memory or exacerbate the impairment following lesions of the hippocampal formation.
Monkeys with stereotaxic lesions of the amygdaloid complex that spared the surrounding cortex (i.e., the periamygdaloid, entorhinal, and perirhinal cortices) performed normally on the delayed nonmatching to sample task, as well as on 3 other memory tasks (object retention, concurrent discrimination, and delayed response) administered during the 1 1/2 years after surgery. These animals also performed normally on pattern discrimination and motor-skill learning, 2 tasks analogous to ones amnesic patients perform well. A second group of monkeys with conjoint lesions that included both the amygdaloid complex, as just described, and the hippocampal formation were impaired on the same 4 memory tasks. However, the severity of impairment in this group was no greater than in monkeys with lesions of the hippocampal formation alone. Thus, circumscribed bilateral lesions of the amygdala did not impair performance on 4 different memory tasks, nor did they exacerbate the memory impairment that followed hippocampal formation lesions alone. These findings suggest that one must look to structures other than the amygdala to account for the severe memory impairment that follows large lesions of the medial temporal region. One possibility is that damage to the cortical regions that surround the amygdala contributes to memory impairment.
Amygdala↗
Memory: brain systems and behavior.
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Amnesia↗