Human Amnesia Research Articles

Macaque monkey retrosplenial cortex: III. Cortical efferents

We have investigated the cortical efferent projections of the macaque monkey retrosplenial and posterior cingulate cortices by using (3)H-amino acids as anterograde tracers. All the injections produced extensive local connections to other portions of this region. There were also a number of extrinsic efferent cortical connections, many of which have not hitherto been reported. Major projections from the retrosplenial cortex were directed to the frontal lobe, with heaviest terminations in areas 46, 9, 10, and 11. There were also very substantial projections to the entorhinal cortex, presubiculum, and parasubiculum of the hippocampal formation, as well as to areas TH and TF of the parahippocampal cortex. Some injections led to labeling of area V4, the dorsal bank of the superior temporal sulcus, and area 7a of the parietal cortex. Projections from the posterior cingulate cortex innervated all these same regions, although the density of termination was different from the retrosplenial projections. The posterior cingulate cortex gave rise to additional projections to parietal area DP and to the cortex along the convexity of the superior temporal gyrus. The ventral portion of the posterior cingulate cortex (area 23v) gave rise to much denser efferent projections to the hippocampal formation than the dorsal portions (areas 23e and i). These connections are discussed in relation to the clinical syndromes of retrosplenial amnesia and topographic disorientation in humans commonly caused by lesions in the caudoventral portions of the retrosplenial and posterior cingulate cortices.

Spatial relational learning persists following neonatal hippocampal lesions in macaque monkeys

The hippocampus is important for the acquisition of spatial representations of the environment and consequently in contextual memory. This suggests that the neural substrates underlying spatial cognition might be essential for remembering specific life episodes. Indeed, hippocampal lesions prevent spatial relational learning in adult rodents and monkeys, and result in profound amnesia in adult humans. In contrast, we show here that monkeys with neonatal hippocampal lesions learned new spatial relational information. Our experiments suggest that early hippocampal damage leads to functional brain reorganization that enables spatial information to be acquired through the use of brain regions that normally do not subserve this function.

Transverse Patterning and Human Amnesia

The transverse patterning (TP) task (A+ B-, B+ C-, C+ A-) has played a central role in testing the hypothesis that medial-temporal (and, in particular, hippocampal) brain damage selectively impairs learning on at least some classes of configural (i.e., nonlinear) learning tasks. Results in the animal and human literature generally support that hypothesis. Reed and Squire [Impaired transverse patterning in human amnesia is a special case of impaired memory for two-choice discrimination tasks. Behavioral Neuroscience, 113, 3-9, 1999], however, advanced an alternative account in which impaired TP performance in amnesia reflects a generic scaling artifact arising from the greater difficulty of the TP task compared to the elemental (i.e., linear) control task that is typically used. We begin with a critique of Reed and Squire, countering their conceptual arguments and showing that their results, when analyzed appropriately, support the configural deficit hypothesis. We then report results from eight new amnesic patients and controls on an improved version of the TP task. Despite substantial practice, accuracy of patients with bilateral hippocampal damage due to anoxia reached and maintained an asymptote of only 54% correct, well below the maximum accuracy obtainable (67%) in the absence of configural learning. A patient with selective bilateral damage to the anterior thalamic nuclei exhibited a TP accuracy asymptote that was near 67%, a pattern of two out of three correct consecutive trials, and a pattern of nearly always answering correctly for two of the three TP item pairs. These results are consistent with a set of unique and parameter-free predictions of the configural deficit hypothesis.

Essential Role of the Hippocampal Formation in Rapid Learning of Higher-Order Sequential Associations

Evidence from studies of amnesia and functional imaging in humans suggest that the medial temporal lobe is involved in the learning of higher-order sequences during acquisition of serial reaction time (SRT) tasks. However, these studies have not clarified whether the hippocampal formation specifically is essential to this type of learning. Here, we developed a rodent model of the SRT task to examine the specific roles of the hippocampal formation in learning first- and second-order conditional sequences. Selective hippocampal formation lesions speeded performance and impaired accuracy on both first- and second-order sequences. Additionally, whereas controls distinguished the sequences based on their complexity alone, animals with hippocampal lesions initially differentiated sequences only by their length. Over multiple sessions, hippocampal rats gradually differentiated sequences by their complexity and not length, similar to control subjects. These findings indicate that the hippocampal formation itself plays an essential role in rapid acquisition of higher-order sequence representations. Extrahippocampal systems can also acquire complex sequential representations, albeit via a gradual learning mechanism.

The Contribution of the Human Medial Temporal Lobe to Perception: Bridging the Gap between Animal and Human Studies

The medial temporal lobe (MTL) has been considered traditionally to subserve declarative memory processes only. Recent studies in nonhuman primates suggest, however, that the MTL may also be critical to higher order perceptual processes, with the hippocampus and perirhinal cortex being involved in scene and object perception, respectively. The current article reviews the human neuropsychological literature to determine whether there is any evidence to suggest that these same views may apply to the human MTL. Although the majority of existing studies report intact perception following MTL damage in human amnesics, there have been recent studies that suggest that when scene and object perception are assessed systematically, significant impairments in perception become apparent. These findings have important implications for current mnemonic theories of human MTL function and our understanding of human amnesia as a result of MTL lesions.

Conditional discrimination and reversal in amnesia subsequent to hypoxic brain injury or anterior communicating artery aneurysm rupture

Human anterograde amnesia can develop following bilateral damage to the hippocampus and medial temporal lobes, as in hypoxic brain injury, or following damage to the basal forebrain, as following anterior communicating artery (ACoA) aneurysm rupture. In both cases, the mnestic deficit may be similar when assessed by standard neuropsychological measures. However, animal and computational models suggest that there are qualitative differences in the pattern of impaired and spared memory abilities following damage to hippocampus versus basal forebrain. Here, we show such a dissociation in human amnesia using a single two-stage task, involving conditional discrimination and reversal. Consistent with a prior study, 10 individuals with anterograde amnesia subsequent to hypoxic brain injury were spared on acquisition but impaired at reversal. However, 10 individuals with amnesia subsequent to ACoA aneurysm showed the opposite pattern of impaired acquisition but spared reversal. The differences between groups cannot be easily ascribed to severity of mnestic or cognitive deficit, since the two amnesic groups performed similarly on neuropsychological tests of memory, intelligence and attention. The results illustrate qualitative differences in memory impairments in hypoxic and ACoA amnesics and highlight the importance of considering etiology in evaluating mnemonic deficits in amnesic populations.

An emotion-induced retrograde amnesia in humans is amygdala- and beta-adrenergic-dependent.

The influence of emotion on human memory is associated with two contradictory effects in the form of either emotion-induced enhancements or decrements in memory. In a series of experiments involving single word presentation, we show that enhanced memory for emotional words is strongly coupled to decrements in memory for items preceding the emotional stimulus, an effect that is more pronounced in women. These memory effects would appear to depend on a common neurobiological substrate, in that enhancements and decrements are reversed by propranolol, a beta-adrenergic antagonist, and abolished by selective bilateral amygdala damage. Thus, our findings suggest that amygdala-dependent beta-adrenergic modulation of episodic encoding has costs as well as benefits.

Isoflurane Antagonizes the Capacity of Flurothyl or 1,2-Dichlorohexafluorocyclobutane to Impair Fear Conditioning to Context and Tone

In animals, the conventional inhaled anesthetic, isoflurane, impairs learning fear to context and fear to tone, doing so at concentrations that produce amnesia in humans. Nonimmobilizers are inhaled compounds that do not produce immobility in response to noxious stimulation, nor do they decrease the requirement for conventional inhaled anesthetics. Like isoflurane, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) impairs learning at concentrations less than those predicted from its lipophilicity to produce anesthesia. The capacity of the nonimmobilizer di-(2,2,2,-trifluoroethyl) ether (flurothyl) to affect learning and memory has not been studied. Both nonimmobilizers can cause convulsions. We hypothesized that if isoflurane, 2N, and flurothyl act by the same mechanism to impair learning and memory, their effects should be additive. We found that isoflurane, 2N, and flurothyl (each, alone) impaired learning fear to context and fear to tone in rats, with the nonimmobilizers doing so at concentrations less than those that cause convulsions. (Fear was defined by freezing [volitional immobility] in the presence of the conditioned stimulus [context or tone].) However, the combination of isoflurane and 2N or flurothyl produced an antagonistic rather than an additive effect on learning, a finding in conflict with our hypothesis. And flurothyl was no less potent than 2N (at least no less potent relative to the concentration of each that produced convulsions) in its capacity to impair learning. We conclude that conventional inhaled anesthetics and nonimmobilizers impair learning and memory by different mechanisms. The basis for this impairment remains unknown. Conventional inhaled anesthetics and nonimmobilizers are antagonistic in their effects on learning and memory, and this finding suggests that they impair learning and memory, at least in part, by different mechanisms.

A Cholinergic Explanation of Dense Amnesia

Traditionally, dense amnesia in humans has been thought to be caused by damage to memory structures within the medial temporal lobe, either the hippocampus, the perirhinal cortex or a combination of the two. Recent work in animals has indicated that damage to the hippocampus results in memory impairments that are specific to memories for events. In contrast, damage to the perirhinal cortex impairs object memories in primates, which are likely to be analogous to human semantic memory. Discrete damage to either of these structures does not appear to result in severe and global memory impairments. We propose an alternative to this medial temporal lobe explanation of dense amnesia, based on our recent work. We have shown that the cholinergic cells of the basal forebrain are essential for new learning of both object and event-like memories in the monkey. Our model of learning in the primate brain rests on the proposal that there is a route of communication between the frontal cortex and inferior temporal cortex and hippocampus via the basal forebrain, which is critical for memory encoding. Interruption to this circuit at any stage will result in a severe and global anterograde amnesia.

Consolidation theory and retrograde amnesia in humans.

Recent research on the cognitive dysfunctions experienced by human anmesic patients indicates that very long term (multidecade) changes may occur in memory. Flat retrograde amnesia (RA), consisting of a uniform memory deficit for information from all preamnesia time periods, indicates a simple, monolithic retrieval problem, whereas graded RA, with greater memory deficits for information from recent as opposed to remote time periods, suggests the presence of a gradual long-term encoding, or consolidation, process. An evaluation of 247 outcomes from 61 articles provides strong evidence of graded RA across different cerebral injuries, materials, and test procedures, as well as in measures of both absolute and relative (patient vs. control) performance. Future conceptualizations of human memory should address the possibility that memories increase in resistance to forgetting, or reduction in trace fragility, across many decades.

In vivo genetics of anaesthetic action

In vivo genetics of anaesthetic action

Temporal order memory in patients with Korsakoff’s syndrome and medial temporal amnesia

Two groups of patients with global amnesia resulting either from Korsakoff’s syndrome (KS) or from medial temporal lobe (MTL) damage were compared with groups of matched healthy control subjects on a list discrimination paradigm. Item recognition memory was matched across the amnesic and control groups in order to determine whether KS, but not MTL amnesics are disproportionately impaired on list discrimination as predicted by Parkin’s [Functional significance of etiological factors in human amnesia. In: Squire LR, Butters N, editors. Neuropsychology of memory, 2nd ed. New York: The Guilford Press, 1992] hypothesis. However, both patient groups were impaired disproportionately on the temporal order memory task, which is inconsistent with Parkin’s hypothesis. It remains possible that the KS patients are more disproportionately impaired than those with MTL damage because both patient groups performed at floor on the list discrimination task. The results are consistent with theories that postulate a critical role for the hippocampus in the kind of associative memory which underlies memory for temporal order, but not in recognition of single items or arbitrary associations between items of similar kinds.

Hippocampal Role in Cognitive Functions and Memory, and Effects of a Novel Cognitive Enhancer on Learning Deficits Due to Hippocampal Lesions

Abstract: In the 21st century, advances in basic research on higher brain functions in both system and molecular levels will proceed therapeutics to alleviate senile dementia, including Alzheimer's disease. In this review, we present our recent experimental results in the hippocampal formation (HF) in reference to human amnesia and a role of the HF in episodic memory and learning. First, we analyzed the activity of the HF neurons in both monkeys and rats. Neural activity in the monkey HF was analyzed during a spatial moving task in which the monkey could control a motorized, movable device (cab) and its route to a target location by pressing the bars. Some HF neurons responded to the occurrence of significant events (or episodes) in the place field where neuronal activity increased. This indicates that HF gating of incoming information may depend on where the monkey is located. These responses suggest representation related to episodic memory, and linkage among diverse information including both spatial and non‐spatial cues. Rats were also trained to explore a circular open‐field to obtain rewards [intracranial self‐stimulation (ICSS)]. When ICSS delivery place was changed, about 20% of the place neurons shifted place fields to locations newly associated with ICSS rewards. These neurophysiological results suggest that the HF is crucial to represent associative relations among multiple cues or factors and to learn such relations. Second, we investigated effects of the newly developed compound (T‐588), on learning and memory in rats. Treatment with the compound ameliorated deficits in learning the spatial tasks due to selective lesions of the CA1 subfield.

Neural systems underlying episodic memory: insights from animal research.

Two strategies used to uncover neural systems for episodic-like memory in animals are discussed: (i) an attribute of episodic memory (what? when? where?) is examined in order to reveal the neuronal interactions supporting that component of memory; and (ii) the connections of a structure thought to be central to episodic memory in humans are studied at a level of detail not feasible in humans. By focusing on spatial memory (where?) and the hippocampus, it has proved possible to bring the strategies together. A review of lesion, disconnection and immediate early-gene studies in animals reveals the importance of interactions between the hippocampus and specific nuclei in the diencephalon (most notably the anterior thalamic nuclei) for spatial memory. Other parts of this extended hippocampal system include the mammillary bodies and the posterior cingulate (retrosplenial) cortex. Furthermore, by combining lesion and immediate early-gene studies it is possible to show how the loss of one component structure or tract can influence the remaining regions in this group of structures. The validity of this convergent approach is supported by new findings showing that the same set of regions is implicated in anterograde amnesia in humans.

Contextual memory in a virtual world

Decades of human and animal research suggest that the medial temporal lobes (MTL) play an important role in memory. We know from work in human amnesia that MTL structures are crucial in forming memories of everyday events. We also know from animal work that MTL structures are critical to forming spatial memories of an organism's physical environment. Paradoxically, however, only a small proportion of functional imaging studies have shown MTL activation during memory performance for healthy humans. This has led researchers to speculate that conventional memory tasks fail to capture the complexities of memory as it operates in real-world contexts, and thus fail to activate MTL structures that are uniquely critical to real-world memory function.Burgess et al. overcome this limitation by examining memory processing in a virtual reality (VR) environment using event-related functional magnetic resonance imaging (efMRI) 1xA temporoparietal and prefrontal network for retrieving the spatial context of lifelike events. Burgess, N. et al. NeuroImage. 2001; 14: 439–453Crossref | PubMed | Scopus (312)See all

Are Some Memory Deficits Unique to Lesions of the Mammillary Bodies?

The role of the mammillary bodies in human memory is still in debate. A recent model of human amnesia proposes similar functions for the mammillary bodies and the hippocampus. But the main evidence for this model comes from animal studies using the delayed non-matching to sample paradigm. We describe a patient who developed a severe memory impairment after surgical removal of a germinoma. Postsurgical high resolution MRI revealed bilaterally shrunken mammillary bodies and an infarct of the left mammillary body. There were no other relevant lesions. Neuropsychological testing showed mildly impaired frontal lobe functions (executive functions, working memory and word fluency), almost intact learning and recognition, but severely impaired free and delayed recall. Experimental investigations revealed a reduced but preserved release of proactive interference and a pronounced impairment of recency and source judgments. We conclude that the mammillary bodies do play a prominent role in human memory, although the role differs slightly from that of the hippocampus.

Long‐term spatial memory in rats with hippocampal lesions

In animal models of human amnesia, using lesion methods, it has been difficult to establish the role played by the hippocampus in the formation of long-term spatial knowledge. For example, lesions sustained after acquisition have generally produced a flat retrograde amnesia for spatial information. These results have not made it possible to dissociate the participation of the hippocampus in retrieval/performance processes from its participation in consolidation/retention. The present study was designed to investigate if electrolytic hippocampal lesions made before training lead to a deficit in the long-term retention of spatial knowledge when the rats show equal performance levels during the acquisition. Results show that lesioned rats learn a place response just as well as the control rats when, during the training, an intramaze cue orients the animal in its navigation towards the goal arm. One day after reaching criterion, lesioned and control rats remember the task perfectly during a transfer test in which the intramaze signal used previously is not present. However, 24 days later, the hippocampal animals manifest a profound deficit in the retention of the spatial information. When the spatial task learned during the acquisition phase requires only the use of a guidance strategy, control and lesioned animals show the same level of performance during the training phase and the same degree of retention during the retraining phase 24 days after criterion. Taken together, these results suggest that the hippocampus plays a crucial role in long-term retention of allocentric spatial information.

Recovery of function processes in human amnesia: evidence from transient global amnesia

Recovery of function processes in human amnesia: evidence from transient global amnesia

Prefrontal cortical involvement in visual working memory

Studies of human amnesia provide evidence for a short-term memory store with information transfer to long term memory occurring within 60 s of sensory encoding. Human and nonhuman primate research has shown that maintenance of this short-term or working memory store is dependent upon frontal cortical activation, although the critical temporal parameters of frontal involvement throughout this 60-s window are undetermined. We examined prefrontal contributions to rapid (under 2 s) and sustained (over 4 s) visual working memory by recording behavioral performance and event-related potentials (ERPs) in patients with lesions in dorsolateral frontal cortex and age-matched control subjects. Prefrontal lesioned patients generated a reduced sustained frontal positivity at all delays. At short delays, patients generated reduced performance to stimuli presented in the contralesional field. Patients generated a negative potential (N400), greatest to contralesionally presented stimuli, that was observed in the control subjects only at long delays. The results indicate that prefrontal lesions impair the frontal component of an anterior–posterior working memory network activated during rapid and sustained visual memory processing. Frontal patients may require activation of limbic cortex, indexed by N400, for maintenance of both rapid and sustained working memory.

Impaired transverse patterning in human amnesia is a special case of impaired memory for two-choice discrimination tasks.

Three amnesic patients with damage limited to the hippocampal formation, a severely amnesic patient with extensive medial temporal lobe damage, and 9 controls were tested on the transverse patterning problem (A + B-, B + C-, and C + A-) and also on 2 control problems. One of the control problems was matched to the transverse patterning problem with respect to the number of pairwise decisions that were required. The 2nd control problem was matched to the transverse patterning problem with respect to the number of trials needed by controls to learn the task. The amnesic patients were impaired at solving both the transverse patterning problem and the control problems. The findings suggest that impaired learning of the transverse patterning problem by amnesic patients derives from their general impairment in declarative memory, which affects performance on most 2-choice discrimination tasks.