Medial Temporal Lobe Memory System Research Articles

Interictal Slow-Wave Focus in Left Medial Temporal Lobe during Bilateral Electroconvulsive Therapy

The interictal state between two electroconvulsive therapy (ECT) sessions is clinically characterised by possible cognitive adverse effects like mild amnestic syndrome. ECT-induced mnestic deficits can persist for several weeks after ECT. Electrophysiologically, slowing of brain electrical activity in the interictal state has often been reported. Especially, for bilateral ECT a correlation between enhanced left frontotemporal theta activity and retrograde amnesia has been demonstrated. This study focuses on the topographic distribution of cortical slow-wave oscillations during the interictal state of a bilateral ECT cycle. Twelve patients with major depression have been investigated with 32-channel resting EEG 24 h after the 6th ECT session. As controls, 8 major depressive patients were investigated prior to antidepressive treatment. The generating sources of slow-wave activity are estimated within the theta frequency band with low-resolution brain electromagnetic tomography. Source analysis revealed a distinct pattern of theta activity in the depth of the left temporal lobe (fusiform and parahippocampal gyri, Brodmann areas 37 and 36, respectively; p< 0.05) during the interictal state. This finding suggests a dysfunction of the left medial temporal lobe memory system during the interictal state of a bilateral ECT cycle. It will further be discussed whether it is possible to obtain information about activity of deep brain structures like the hippocampal formation from scalp-recorded signals.

Towards an explicit account of implicit learning

The human brain supports acquisition mechanisms that can extract structural regularities implicitly from experience without the induction of an explicit model. Reber defined the process by which an individual comes to respond appropriately to the statistical structure of the input ensemble as implicit learning. He argued that the capacity to generalize to new input is based on the acquisition of abstract representations that reflect underlying structural regularities in the acquisition input. We focus this review of the implicit learning literature on studies published during 2004 and 2005. We will not review studies of repetition priming ('implicit memory'). Instead we focus on two commonly used experimental paradigms: the serial reaction time task and artificial grammar learning. Previous comprehensive reviews can be found in Seger's 1994 article and the Handbook of Implicit Learning. Emerging themes include the interaction between implicit and explicit processes, the role of the medial temporal lobe, developmental aspects of implicit learning, age-dependence, the role of sleep and consolidation. The attempts to characterize the interaction between implicit and explicit learning are promising although not well understood. The same can be said about the role of sleep and consolidation. Despite the fact that lesion studies have relatively consistently suggested that the medial temporal lobe memory system is not necessary for implicit learning, a number of functional magnetic resonance studies have reported medial temporal lobe activation in implicit learning. This issue merits further research. Finally, the clinical relevance of implicit learning remains to be determined.

The Role of the Perirhinal Cortex and Hippocampus in Learning, Memory, and Perception

One traditional and long-held view of medial temporal lobe (MTL) function is that it contains a system of structures that are exclusively involved in memory, and that the extent of memory loss following MTL damage is simply related to the amount of MTL damage sustained. Indeed, human patients with extensive MTL damage are typically profoundly amnesic whereas patients with less extensive brain lesions centred upon the hippocampus typically exhibit only moderately severe anterograde amnesia. Accordingly, the latter observations have elevated the hippocampus to a particularly prominent position within the purported MTL memory system. This article reviews recent lesion studies in macaque monkeys in which the behavioural effects of more highly circumscribed lesions (than those observed to occur in human patients with MTL lesions) to different subregions of the MTL have been examined. These studies have reported new findings that contradict this concept of a MTL memory system. First, the MTL is not exclusively involved in mnemonic processes; some MTL structures, most notably the perirhinal cortex, also contribute to perception. Second, there are some forms of memory, including recognition memory, that are not always affected by selective hippocampal lesions. Third, the data support the idea that regional functional specializations exist within the MTL. For example, the macaque perirhinal cortex appears to be specialized for processing object identity whereas the hippocampus may be specialized for processing spatial and temporal relationships.

The Perceptual-Mnemonic/Feature Conjunction Model of Perirhinal Cortex Function

The perirhinal cortex was once thought to be "silent cortex", virtually ignored by researchers interested in the neurobiology of learning and memory. Following studies of brain damage associated with cases of amnesia, perirhinal cortex is now widely regarded as part of a "medial temporal lobe (MTL) memory system". This system is thought to be more or less functionally homogeneous, having a special role in declarative memory, and making little or no contribution to other functions such as perception. In the present article, we summarize an alternative view. First, we propose that components of the putative MTL system such as the hippocampus and perirhinal cortex have distinct and dissociable functions. Second, we provide evidence that the perirhinal cortex has a role in visual discrimination. In addition, we propose a specific role for perirhinal cortex in visual discrimination: the contribution of complex conjunctive representations to the solution of visual discrimination problems with a high degree of "feature ambiguity". These proposals constitute a new view of perirhinal cortex function, one that does not assume strict modularity of function in the occipito-temporal visual stream, but replaces this idea with the notion of a hierarchical representational continuum.

Functional Magnetic Resonance Imaging Activity during the Gradual Acquisition and Expression of Paired-Associate Memory

Recent neurophysiological findings from the monkey hippocampus showed dramatic changes in the firing rate of individual hippocampal cells as a function of learning new associations. To extend these findings to humans, we used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine the patterns of brain activity during learning of an analogous associative task. We observed bilateral, monotonic increases in activity during learning not only in the hippocampus but also in the parahippocampal and right perirhinal cortices. In addition, activity related to simple novelty signals was observed throughout the medial temporal lobe (MTL) memory system and in several frontal regions. A contrasting pattern was observed in a frontoparietal network in which a high level of activity was sustained until the association was well learned, at which point the activity decreased to baseline. Thus, we found that associative learning in humans is accompanied by striking increases in BOLD fMRI activity throughout the MTL as well as in the cingulate cortex and frontal lobe, consistent with neurophysiological findings in the monkey hippocampus. The finding that both the hippocampus and surrounding MTL cortex exhibited similar associative learning and novelty signals argues strongly against the view that there is a clear division of labor in the MTL in which the hippocampus is essential for forming associations and the cortex is involved in novelty detection. A second experiment addressed a striking aspect of the data from the first experiment by demonstrating a substantial effect of baseline task difficulty on MTL activity capable of rendering mnemonic activity as either "positive" or "negative."

Remembering one year later: role of the amygdala and the medial temporal lobe memory system in retrieving emotional memories.

The memory-enhancing effect of emotion can be powerful and long-lasting. Most studies investigating the neural bases of this phenomenon have focused on encoding and early consolidation processes, and hence little is known regarding the contribution of retrieval processes, particularly after lengthy retention intervals. To address this issue, we used event-related functional MRI to measure neural activity during the retrieval of emotional and neutral pictures after a retention interval of 1 yr. Retrieval activity for emotional and neutral pictures was separately analyzed for successfully (hits) vs. unsuccessfully (misses) retrieved items and for responses based on recollection vs. familiarity. Recognition performance was better for emotional than for neutral pictures, and this effect was found only for recollection-based responses. Successful retrieval of emotional pictures elicited greater activity than successful retrieval of neutral pictures in the amygdala, entorhinal cortex, and hippocampus. Moreover, in the amygdala and hippocampus, the emotion effect was greater for recollection than for familiarity, whereas in the entorhinal cortex, it was similar for both forms of retrieval. These findings clarify the role of the amygdala and the medial temporal lobe memory regions in recollection and familiarity of emotional memory after lengthy retention intervals.

Dissociating intentional learning from relative novelty responses in the medial temporal lobe

The establishment of a role for medial temporal lobe (MTL) structures in episodic memory has led to an investigative focus on the specific contributions and interactions between constituent MTL regions, including the hippocampus and surrounding medial temporal cortices. By dissociating an intentional stimulus-category learning condition from a passive viewing condition, we demonstrate, using fMRI, that novelty- and familiarity-driven responses in human anterior and posterior hippocampus, respectively, only occur during intentional learning. With increasing familiarity of stimulus-category associations, there is a shift in neuronal responses from anterior to posterior hippocampal regions. This anterior/posterior response gradient may reflect a weighting of functional hippocampal architecture related to encoding of novel and retrieval of familiar information. By contrast, perirhinal cortex is engaged by novel stimuli irrespective of task, highlighting this region as a component of a generic familiarity discrimination system. By introducing distinct stimulus types, we further demonstrate that these MTL responses are independent of stimulus complexity. Different patterns of activity for intentional learning vs. passive viewing indicate that intentional encoding/retrieval of stimulus-category associations and automatic novelty/familiarity assessment of stimuli are processed in anatomically dissociable neuronal ensembles within the MTL memory system.

Hippocampal lesions that abolish spatial maze performance spare object recognition memory at delays of up to 48 hours

The hippocampus is widely considered to be a critical component of a medial temporal lobe memory system, necessary for normal performance on tests of declarative memory. Object recognition memory is thought to be a classic test of declarative memory function. However, previous tests of the effects of hippocampal lesions on object recognition memory have not always supported this view. One possible reason for this inconsistency is that previously reported effects of hippocampal lesions on object recognition memory tasks may have stemmed not from a deficit in object recognition memory per se, but as a result of spatial and contextual confounds in the task. Thus, in the present study, we used a spontaneous object recognition test in a modified apparatus designed to minimize spatial and contextual factors. A group of rats with complete excitotoxic lesions of the hippocampus and a group of control rats were tested on this modified spontaneous object recognition task with retention delays of up to 48 h. These rats were also tested on a spatial nonmatching-to-place task. Spatial memory performance was abolished following hippocampal lesions, whereas performance on the recognition memory task was intact at all delays tested.

New Semantic Learning and Generalization in a Patient With Amnesia.

New learning of semantic information is impaired in amnesia. Several reports have demonstrated that "errorless" learning techniques have allowed patients with amnesia to acquire at least some form of new semantic information, although this information appears to be relatively inflexible. Using insights and principles from connectionist modeling of cortical and medial temporal lobe memory systems, the authors describe why errorless learning procedures act as a poor proxy for the medial temporal lobe, suggesting that they artificially eliminate the variability that defines semantic information. The authors trained a patient with severe amnesia on new semantic sentences both with and without variance and then tested him on both repeated and related novel sentences to assess generalization. He successfully learned new semantic information in both conditions but demonstrated better generalization of semantic concepts following training with variance.

Perirhinal and Postrhinal Contributions to Remote Memory for Context

The perirhinal (PER) and postrhinal (POR) cortices, two components of the medial temporal lobe memory system, are reciprocally connected with the hippocampus both directly and via the entorhinal cortex. Damage to PER or POR before or shortly after training on a contextual fear conditioning task causes deficits in the subsequent expression of contextual fear, implicating these regions in the acquisition or expression of contextual memory. Here, we examined the contribution of PER and POR to the processing of remotely learned contextual information. Male Long-Evans rats were trained in an unsignaled contextual fear conditioning paradigm. After training, rats received bilateral neurotoxic lesions to PER or POR or sham control surgeries at three different training-to-lesion intervals: 1, 28, or 100 d after training. Two weeks after surgery, lesioned and control rats were returned to the training context to assess contextual fear as measured by freezing. Rats with PER or POR damage froze significantly less in the training context than control rats but were not different from each other. The severity of the deficit did not differ across training-to-lesion intervals for any group. This pattern of deficits differs from that of posttraining hippocampal lesions, for which longer training-to-lesion intervals produce significantly more fear-conditioned contextual freezing than shorter training-to-lesion intervals. In the absence of such a retrograde gradient in the present study, our interpretation is that PER and POR have an ongoing role in the storage or retrieval of representations for context. Alternatively, these regions may be involved in a more extended consolidation process that becomes apparent beyond 100 d after learning.

Evidence for a dysfunctional retrosplenial cortex in patients with schizophrenia: a functional magnetic resonance imaging study with a semantic—perceptual contrast

We investigated whether the retrosplenial and the posterior cingulate cortex (RS-PCC) is functionally impaired in schizophrenia patients. Therefore, we measured functional magnetic resonance imaging (fMRI) signal changes associated with a synonym-judgment task known to activate, among other areas, the RS-PCC. Compared to 12 matched control subjects, 12 schizophrenia patients exhibited reliably weaker activations in the RS-PCC, the dorsolateral prefrontal cortex and the left orbitofrontal cortex ( P < 0.05, corrected). Differences in frontal activations are in line with previous studies showing a structurally and functionally affected prefrontal cortex in schizophrenia. The impaired RS-PCC functionality in a semantic task may relate to verbal memory deficits frequently observed in schizophrenia patients, because this region is pivotal for gating information into the medial temporal lobe memory system.

Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate.

Memory decline in aging results from multiple factors that influence both executive function and the medial temporal lobe memory system. In advanced aging, frontal-striatal systems are preferentially vulnerable to white matter change, atrophy, and certain forms of neurotransmitter depletion. Frontal-striatal change may underlie mild memory difficulties in aging that are most apparent on tasks demanding high levels of attention and controlled processing. Through separate mechanisms, Alzheimer's disease preferentially affects the medial temporal lobe and cortical networks, including posterior cingulate and retrosplenial cortex early in its progression, often before clinical symptoms are recognized. Disruption of the medial temporal lobe memory system leads directly to memory impairment. Recent findings further suggest that age-associated change is not received passively. Reliance on reserve is emerging as an important factor that determines who ages gracefully and who declines rapidly. Functional imaging studies, in particular, suggest increased recruitment of brain areas in older adults that may reflect a form of compensation.

How do memory systems interact? Evidence from human classification learning

Studies of human classification learning using functional neuroimaging have suggested that basal ganglia and medial temporal lobe memory systems may interact during learning. We review these results and outline a set of possible mechanisms for such interactions. Effective connectivity analyses suggest that interaction between basal ganglia and medial temporal lobe are mediated by prefrontal cortex rather than by direct connectivity between regions. A review of possible neurobiological mechanisms suggests that interactions may be driven by neuromodulatory systems in addition to mediation by interaction of inputs to prefrontal cortical neurons. These results suggest that memory system interactions may reflect multiple mechanisms that combine to optimize behavior based on experience.

Detecting location-specific neuronal firing rate increases in the hippocampus of freely-moving monkeys

The spatial properties of the firing of hippocampal neurons have mainly been studied in (a) freely moving rodents, (b) non-human primates seated in a moveable primate chair with head fixed, and (c) epileptic patients subjected to virtual navigation. Although these studies have all revealed the ability of hippocampal neurons to generate spatially selective discharges, the detected firing patterns have been found to be considerably different, even conflicting, in many respects. The present cellular electrophysiological study employed squirrel monkeys ( Saimiri sciureus), which moved freely on the walls and floor of a large test chamber. This permitted the examination of the spatial firing of hippocampal neurons in nearly ideal conditions, similar to those used in rodents, yet in a species that belongs to the primate Suborder Anthropoidea. The major findings were that: (1) a group of slow-firing complex-spike cells increased their basal, awake firing rate more than 20-fold, often above 30 spikes/s, when the monkey was in a particular location in the chamber, (2) these location-specific discharges occurred consistently, forming 4–25 s action potential volleys, and (3) fast-firing cells displayed no such electrical activity. Thus, during free movement in three dimensions, primate hippocampal complex-spike cells do generate high-frequency, location-specific action potential volleys. Since these cells are components of the medial temporal lobe memory system, their uncovered firing pattern may well be involved in the formation of declarative memories on places.

Interaction between the Amygdala and the Medial Temporal Lobe Memory System Predicts Better Memory for Emotional Events

Emotional events are remembered better than neutral events possibly because the amygdala enhances the function of medial temporal lobe (MTL) memory system (modulation hypothesis). Although this hypothesis has been supported by much animal research, evidence from humans has been scarce and indirect. We investigated this issue using event-related fMRI during encoding of emotional and neutral pictures. Memory performance after scanning showed a retention advantage for emotional pictures. Successful encoding activity in the amygdala and MTL memory structures was greater and more strongly correlated for emotional than for neutral pictures. Moreover, a double dissociation was found along the longitudinal axis of the MTL memory system: activity in anterior regions predicted memory for emotional items, whereas activity in posterior regions predicted memory for neutral items. These results provide direct evidence for the modulation hypothesis in humans and reveal a functional specialization within the MTL regarding the effects of emotion on memory formation.

Corticohippocampal contributions to spatial and contextual learning.

Spatial and contextual learning are considered to be dependent on the hippocampus, but the extent to which other structures in the medial temporal lobe memory system support these functions is not well understood. This study examined the effects of individual and combined lesions of the perirhinal, postrhinal, and entorhinal cortices on spatial and contextual learning. Lesioned subjects were consistently impaired on measures of contextual fear learning and consistently unimpaired on spatial learning in the Morris water maze. Neurotoxic lesions of perirhinal or postrhinal cortex that were previously shown to impair contextual fear conditioning (Bucci et al., 2000) or contextual discrimination (Bucci et al., 2002) caused little or no impairment in place learning and incidental learning in the water maze. Combined lesions of perirhinal plus lateral entorhinal or postrhinal plus medial entorhinal cortices resulted in deficits in acquisition of contextual discrimination but had no effect on place learning in the water maze. Finally, a parahippocampal lesion comprising combined neurotoxic damage to perirhinal, postrhinal, and entorhinal cortices resulted in profound impairment in acquisition of a standard passive avoidance task but failed to impair place learning. In the same experiment, rats with hippocampal lesions were impaired in spatial navigation. These results indicate that tasks requiring the association between context and an aversive stimulus depend on corticohippocampal circuitry, whereas place learning in the water maze can be accomplished without the full complement of highly processed information from the cortical regions surrounding the hippocampus. The evidence that different brain systems underlie spatial navigation and contextual learning has implications for research on memory when parahippocampal regions are involved.

Functional Neuroanatomy of the Medial Temporal Lobe Memory System

Functional Neuroanatomy of the Medial Temporal Lobe Memory System

Ca2+-independent muscarinic excitation of rat medial entorhinal cortex layer V neurons.

Cholinergic activation of entorhinal cortex (EC) layer V neurons plays a crucial role in the medial temporal lobe memory system and in the pathophysiology of temporal lobe epilepsy. Here, we demonstrate that muscarinic activation by focal application of carbachol depolarizes EC layer V neurons and induces epileptiform activity in rat brain slices. These seizure-like bursts are associated with a somatic [Ca2+]i increase of 293 +/- 82 nm and are blocked by the glutamate receptor antagonists CNQX and APV. Muscarinic activation did not directly evoke a [Ca2+]i increase, but subthreshold and suprathreshold depolarization did. Functional axon mapping revealed local axon branching as well as axon collaterals ascending to layers II and III. During blockade of ionotropic glutamatergic AMPA and NMDA receptors, carbachol depolarized layer V neurons by +7.5 +/- 3.4 mV. This direct muscarinic depolarization was associated with a conductance increase of 35 +/- 10.3% (+4.3 +/- 1.25 nS). Intracellular buffering of [Ca2+]i changes did not block this depolarization, but prolonged action potential duration and reduced adaptation of action potential firing. The muscarinic depolarization was neither blocked by combining intracellular Ca2+-buffering (EGTA or BAPTA) with non-specific Ca2+-channel inhibition by Ni+ (1 mm), nor by Ba2+ (1 mm) nor during inhibition of the h-current by 2 mm Cs+. In whole-cell patch-clamp recording, reversal of the muscarinic current occurred at about -45 mV and -5 mV with complete substitution of intrapipette K+ with Cs+. Thus, muscarinic depolarization of EC layer V neurons appears to be primarily mediated by Ca2+-independent activation of non-specific cation channels that conduct K+ about three times as well as Na+.

Cyclic Estrogen Replacement Improves Cognitive Function in Aged Ovariectomized Rhesus Monkeys

Among the identified risks and benefits of hormone-replacement therapy, the effects of treatment on cognitive function in postmenopausal women have proved difficult to define. Here we conducted a controlled, prospective analysis in a nonhuman primate model to test whether surgical menopause and estrogen replacement influence the cognitive outcome of normal aging. Sixteen aged rhesus monkeys were ovariectomized, and throughout the course of subsequent neuropsychological assessment, half received a regimen of low-dose, cyclic estradiol replacement. Hormone treatment substantially reversed the marked age-related impairment vehicle-injected monkeys exhibited on a delayed response test of spatial working memory. Modest improvement was also observed on a delayed nonmatching-to-sample recognition memory task. In contrast, ovariectomy exacerbated age-related deficits in object discrimination learning; the magnitude of this effect was equivalent among vehicle- and estrogen-treated monkeys. Together, these results demonstrate that ovarian hormone status can broadly influence normal cognitive aging in monkeys, affecting capacities mediated by multiple brain regions, including the prefrontal cortex and the medial temporal lobe memory system. The animal model established here should enable progress toward defining the neurobiological mechanisms that mediate the beneficial effects of estrogen on age-related cognitive decline in primates.

Deep processing activates the medial temporal lobe in young but not in old adults

Age-related impairments in episodic memory have been related to a deficiency in semantic processing, based on the finding that elderly adults typically benefit less than young adults from deep, semantic as opposed to shallow, nonsemantic processing of study items. In the present study, we tested the hypothesis that elderly adults are not able to perform certain cognitive operations under deep processing conditions. We further hypothesised that this inability does not involve regions commonly associated with lexical/semantic retrieval processes, but rather involves a dysfunction of the medial temporal lobe (MTL) memory system. To this end, we used functional MRI on rather extensive groups of young and elderly adults to compare brain activity patterns obtained during a deep (living/nonliving) and a shallow (uppercase/lowercase) classification task. Common activity in relation to semantic classification was observed in regions that have been previously related to semantic retrieval, including mainly left-lateralised activity in the inferior prefrontal, middle temporal, and middle frontal/anterior cingulate gyrus. Although the young adults showed more activity in some of these areas, the finding of mainly overlapping activation patterns during semantic classification supports the idea that lexical/semantic retrieval processes are still intact in elderly adults. This received further support by the finding that both groups showed similar behavioural performances as well on the deep and shallow classification tasks. Importantly, though, the young revealed significantly more activity than the elderly adults in the left anterior hippocampus during deep relative to shallow classification. This finding is in line with the idea that age-related impairments in episodic encoding are, at least partly, due to an under-recruitment of the medial temporal lobe memory system.