A Study of the Participation of NMDA Glutamate Receptors in the Mechanisms of Specific Anterograde Amnesia Reversion.

We studied the involvement of NMDA glutamate receptors in the mechanisms of anterograde amnesia. It was found that repeated training of amnestic animals treated with D-cycloserine, a potent agonist of the glycine site of NMDA receptors, did not lead to consolidation of long-term memory, while expression of short-term memory was more pronounced in comparison with control animals that received saline before repeated training. It was shown that D-cycloserine in amnestic snails did not affect the food reactions caused by the presentation of a conditioned stimulus during the reminder (without combination with the unconditioned stimulus). It is assumed that NMDA glutamate receptors in amnestic animals are involved in the neural plasticity mechanisms that underlie short-term memory, but their activation does not influence the anterograde amnesia processes and does not lead to the formation or recovery of long-term memory.

Isolated, relative aproverbia without focal lesion.

We have seen a patient with a profound, isolated, and quite selective deficit in proverb interpretation-aproverbia. The patient presented to us after an anoxic brain injury with aproverbia. Interestingly, the aproverbia appeared to be premorbid to the presenting event. Furthermore, the patient had no brain lesion that has been associated or even proposed as a cause of deficit in proverb or metaphor interpretation. The patient did have acute bilateral hippocampi lesions and associated severe anterograde amnesia, but he retained good retrograde memory with which he is able to give good, logical but concrete explanations for proverbs. This case highlights the need, importance, and interest in further neuropsychologic, imaging and functional studies of proverb and interpretation in patients and normal subjects populations.

Impaired picture recognition in transient epileptic amnesia.

Transient epileptic amnesia (TEA) is an epileptic syndrome characterized by recurrent, brief episodes of amnesia. Transient epileptic amnesia is often associated with the rapid decline in recall of new information over hours to days (accelerated long-term forgetting - 'ALF'). It remains unknown how recognition memory is affected in TEA over time. Here, we report a systematic study of picture recognition in patients with TEA over the course of one week. Sixteen patients with TEA and 16 matched controls were presented with 300 photos of everyday life scenes. Yes/no picture recognition was tested 5min, 2.5h, 7.5h, 24h, and 1week after picture presentation using a subset of target pictures as well as similar and different foils. Picture recognition was impaired in the patient group at all test times, including the 5-minute test, but it declined normally over the course of 1week. This impairment was associated predominantly with an increased false alarm rate, especially for similar foils. High performance on a control test indicates that this impairment was not associated with perceptual or discrimination deficits. Our findings suggest that, at least in some TEA patients with ALF in verbal recall, picture recognition does not decline more rapidly than in controls over 1week. However, our findings of an early picture recognition deficit suggest that new visual memories are impoverished after minutes in TEA. This could be the result of deficient encoding or impaired early consolidation. The early picture recognition deficit observed could reflect either the early stages of the process that leads to ALF or a separable deficit of anterograde memory in TEA. Lastly, our study suggests that at least some patients with TEA are prone to falsely recognizing new everyday visual information that they have not in fact seen previously. This deficit, alongside their ALF in free recall, likely affects everyday memory performance.

Clinical, neuropsychological, and metabolic characteristics of transient epileptic amnesia syndrome.

OBJECTIVE: Transient epileptic amnesia (TEA) is a recently individualized syndrome occurring in adult patients that includes epileptic seizures with amnestic features and interictal memory disturbances. METHODS: We investigated the clinical, neuropsychological, and 18F-FDG positron emission tomography (18F-FDG-PET) features of 30 consecutive cases of TEA in our center. RESULTS: The mean age of onset of amnestic seizures was 59 years. Pure acute amnesia was the only epileptic manifestation in 17% of cases. Interictal electroencephalography (EEG) abnormalities were present in 57% on awake recording and in most patients in whom sleep EEG was performed (96%). Nine of 30 patients showed anterograde memory deficit and six of 30 exhibited mild executive functioning impairment. On the autobiographical memory interview (AMI), patients showed a significant deficit for the recent period of the episodic subscale. Outcome under treatment was favorable in the majority of cases. A significant improvement was noted on recollection of autobiographical memory. 18F-FDG-PET (22 cases) showed positive correlations between left mesial temporal metabolism levels and anterograde and retrograde memory scores. SIGNIFICANCE: TEA is an emerging epileptic syndrome that likely remains misidentified and misdiagnosed. Neurometabolic data support a dysfunction of a hippocampal-neocortical network sustaining episodic memory.

Temporal lobectomy with delayed amnesia following a new lesion on the other side.

PURPOSE: To describe a delayed severe complication of temporal lobectomy for intractable epilepsy. METHOD: A case of amnesia occurring 24 years after surgery is described and five similar cases from the literature reviewed. RESULTS: Mean age at surgery (5 right) was 40 years (19-62 years), 3 female. Four of five tested had impaired visual and verbal memory preoperatively but not sufficient to contraindicate surgery. Pathology was mesial temporal sclerosis in 3, 1 cavernoma, 1 dysembryoplastic neuroepithelial tumor (DNET) and 1 normal. Postoperatively, four were seizure free 3-12 years off medication and two continued with seizures. There was no unexpected postoperative memory change until incapacitating anterograde amnesia developed 1-24 years after surgery. In five patients, including ours, this followed definite or possible status epilepticus with new mesial temporal sclerosis on the opposite side in the four that were investigated by MRI. One patient developed a glioblastoma in the opposite temporal lobe. CONCLUSION: Continuing or late recurrence of seizures from the remaining temporal lobe after temporal lobectomy can result in incapacitating amnesia if status epilepticus occurs. Other new lesions on the opposite side to surgery can have the same effect.

Retrosplenial amnesia without topographic disorientation caused by a lesion in the nondominant hemisphere.

We report the case of a 68-year-old right-handed man who was admitted to our hospital because of sudden onset of headache. On admission, he presented with left homonymous hemianopsia, disorientation, and recent memory disturbance; however, he had normal remote memory and digit span. He was able to recall the room layout of his house and describe the route from the nearest station to his home on a map. However, at the hospital, he sometimes lost his way because of amnesia. Computed tomography (CT) and magnetic resonance imaging revealed a subcortical hematoma in the right occipital forceps and the parietal lobe, involving the cingulate isthmus. Single-photon emission CT imaging showed reduced perfusion not only in the retrosplenial region but also in the right thalamus. These findings suggested that the retrosplenial amnesia might have been caused by the interruption of hippocampal input into the anterior thalamus.

Pure amnestic seizure: A clinico-intracranial EEG study.

OBJECTIVE: Enduring anterograde amnesia is caused by lesions in bilateral mesial temporal lobes. However, whether transient dysfunction of bilateral mesial temporal regions induces reversible amnesia has not been proven. We investigated this association in patients with epilepsy and analyzed the electroclinical correlation during pure amnestic seizures (PAS). PAS are defined as seizures with anterograde amnesia as the only ictal manifestation, accompanied by preserved responsiveness and other cognitive functions. METHODS: We retrospectively searched our intracranial EEG database to find PAS. Pure ictal amnesia was confirmed by immediate and comprehensive ictal examinations. RESULTS: Among 401 patients who underwent intracranial EEG recording, three patients with temporal lobe epilepsy (TLE) manifesting PAS were identified. The patients talked and behaved normally during seizure but did not remember the episodes afterwards. Ictal discharges were confined to bilateral mesial temporal regions, with no or mild involvement of surrounding structures. Spread of low-voltage fast activities to bilateral mesial temporal regions corresponded to onset of ictal anterograde amnesia. Two patients underwent unilateral mesial temporal resection and became seizure-free with improvement in cognitive functions. SIGNIFICANCE: PAS is a rare ictal semiology in TLE. Bilateral mesial temporal regions that play a critical role in memory encoding are presumably the symptomatogenic zones for PAS.

Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1.

After hypoxia, a critical adverse outcome is the inability to create new memories. How anterograde amnesia develops or resolves remains elusive, but a link to brain-based IL-1 is suggested due to the vital role of IL-1 in both learning and brain injury. We examined memory formation in mice exposed to acute hypoxia. After reoxygenation, memory recall recovered faster than memory formation, impacting novel object recognition and cued fear conditioning but not spatially cued Y-maze performance. The ability of mice to form new memories after hypoxia/reoxygenation was accelerated in IL-1 receptor 1 knockout (IL-1R1 KO) mice, in mice receiving IL-1 receptor antagonist (IL-1RA), and in mice given the caspase 1 inhibitor Ac-YVAD-CMK. Mechanistically, hypoxia/reoxygenation more than doubled caspase 1 activity in the brain, which was localized to the amygdala compared to the hippocampus. This reoxygenation-dependent activation of caspase 1 was prevented by broad-spectrum adenosine receptor (AR) antagonism with caffeine and by targeted A1/A2A AR antagonism with 8-cyclopentyl-1,3-dipropylxanthine plus 3,7-dimethyl-1-propargylxanthine. Additionally, perfusion of adenosine activated caspase 1 in the brain, while caffeine blocked this action by adenosine. Finally, resolution of anterograde amnesia was improved by both caffeine and by targeted A1/A2A AR antagonism. These findings indicate that amygdala-based anterograde amnesia after hypoxia/reoxygenation is sustained by IL-1ß generated through adenosine-dependent activation of caspase 1 after reoxygenation.

Amnesiacs might get the gist: reduced false recognition in amnesia may be the result of impaired item-specific memory.

It is a common finding in tests of false recognition that amnesic patients recognize fewer related lures than healthy controls, and this has led to assumptions that gist memory is damaged in these patients (Schacter, Verfaellie, & Anes, 1997, Neuropsychology, 11; Schacter, Verfaellie, Anes, & Racine, 1998, Journal of Cognitive Neuroscience, 10; Schacter, Verfaellie, & Pradere, 1996, Journal of Memory and Language, 35). However, clinical observations find that amnesic patients typically hold meaningful conversations and make relevant remarks, and there is some experimental evidence highlighting preserved immediate recall of prose (Baddeley & Wilson, 2002, Neuropsychologia, 40; Gooding, Isaac, & Mayes, 2005, Neuropsychologia, 43; Rosenbaum, Gilboa, Levine, Winocur, & Moscovitch, 2009, Neuropsychologia, 47), which suggests that amnesiacs can get the gist. The present experiment used false recognition paradigms to assess whether the reduced rate of false recognition found in amnesic patients may be a consequence of their impaired item-specific memory. It examined the effect of increasing the item-specific memory of amnesic patient DA by bringing her to criterion on relevant study-lists and compared her performance on a false recognition paradigm with a group of 32 healthy young adults. Results indicated that when DA's item-specific memory was increased she was more able to gist and her performance was no different to the healthy young adults. Previous assumptions that gist memory is necessarily damaged in amnesia might therefore be revisited, since the reduced rate of false recognition could be caused by impaired item-specific memory. The experiment also highlights a positive relationship between item-specific and gist memory which has not previously been accounted for in false-recognition experiments.

Prevalence and clinical characteristics of unremembered nocturnal eating in diabetic subjects: Kurume sleep trouble in obesity and metabolic disorders (KUSTOMED) study.

Nighttime food intake is associated with weight gain and higher HbA1c levels. We experienced night eaters who have no memory of their nocturnal eating in the morning. In this study, the curious night eating behavior was designated as "unremembered nocturnal eating syndrome (UNES)". We screened 1,169 patients with diabetes for sleep quality and abnormal eating behavior at night using the Pittsburgh Sleep Quality Index questionnaire with an additional question regarding UNES. When abnormal nocturnal eating behavior was noted, detailed clinical information was extracted from interviews with the patients. We identified 9 patients who experienced UNES. They had a higher BMI compared with subjects who reported no such episodes. Among them, 6 patients who consumed food at night without memory 2-5 times per month or more had significantly higher HbA1c levels. Continuous glucose monitoring in a patient with type 1 diabetes revealed an abrupt elevation of glucose levels from midnight when some foods were consumed. Eight of the 9 patients were taking benzodiazepine and/or non-benzodiazepine hypnotic agents when they experienced the episodes. The prevalence of UNES was 0.8% in all subjects and 4% in those taking hypnotic drugs. The ratio of hypnotic drug use in subjects with UNES was significantly higher than for individuals without UNES (89% vs. 17%, p<0.0001). Although UNES seems to be etiologically heterogeneous, hypnotics-induced parasomnia and/or anterograde amnesia may be associated with the behavior. UNES is not rare in diabetic patients on hypnotic medicine and may be a hidden cause of unexpected morning hyperglycemia.

Temporal factors control hippocampal contributions to fear renewal after extinction.

Fear can be extinguished by repeated exposure to a cue that signals threat. However, extinction does not erase fear, as an extinguished cue presented in a context distinct from that of extinction results in renewed fear of that cue. The hippocampus, which is involved in the formation of contextual representations, is a natural candidate structure for investigations into the neural circuitry underlying fear renewal. Thus far, studies examining the necessity of the hippocampus for fear renewal have produced mixed results. We isolated the conditions under which the hippocampus may be required for renewal. Rats received lesions of the dorsal hippocampus either prior to tone fear conditioning or following extinction. Fear renewal was measured using discrete tone presentations or a long, continuous tone. The topography of fear responding at test was assessed by comparing "early" and "sustained" renewal, where early fear was determined by freezing to the first discrete tone or the equivalent initial segment of a continuous tone and sustained fear was determined by freezing averaged across all discrete tones or the entire continuous tone. We found that following pretraining damage of the hippocampus, early renewal remained intact regardless of lesion condition. However, sustained renewal only persisted in discrete, but not continuous, tone-tested animals. A more extensive analysis of the topography of fear responding revealed that the disruption of renewal was generated when the tone duration at test began to violate that used during extinction, suggesting that the hippocampus is sensitive to mismatches in CS-duration. Postextinction lesions resulted in an overall reduction of fear renewal. This pattern of results is consistent with those observed for contextual fear conditioning, wherein animals display a resistance to anterograde amnesia despite the presence of a strong retrograde amnesia for the same contextual information. Furthermore, the data support a role for the hippocampus in sustaining renewal when the CS duration at test does not match that used during extinction.

Dissociable anterograde amnesic effects of retrosplenial cortex and hippocampal lesions on spontaneous object recognition memory in rats.

The amnesic effects of excitotoxic lesions of the rat retrosplenial cortex (RS) and hippocampus (HPC) in the spontaneous object recognition (SOR) performance were investigated. The SOR test consisted of the sample-exposure session(s) and a test session. First, to test retrograde amnesia, rats received four sample-exposure sessions within a day at 4 weeks and 1 day before the surgery, respectively. In the test sessions conducted 1 week after the surgery, both lesion groups showed a temporally ungraded retrograde amnesia. Second, to test anterograde amnesia, 1- and 4-week retention intervals were inserted between the four sample-exposure sessions and the test session. The RS-lesioned rats showed a retention interval-dependent impairment in the test sessions, while the HPC-lesioned rats showed an impairment regardless of the retention interval. Finally, to test short-term recognition memory, 5- or 30-min delay was interposed between the single sample-exposure session and the test session. Both lesion groups performed normally irrespective of the delay length. These results suggest that both the RS and HPC are important for long-term object recognition memory, but these areas have different roles in it.

Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: implications for fornix function.

It is now clear that the integrity of the fornix is important for normal mnemonic function. The fornix, however, is a major white matter tract, carrying numerous hippocampal formation afferents and efferents, and it is not known which specific components support memory processes. Established theories of extended hippocampal function emphasize the sequential pathway from the hippocampal formation (i.e., subicular complex) to the mammillary bodies and, thence, to the anterior thalamus, as pathology in each of these structures is implicated in anterograde amnesia in humans and spatial memory deficits in rats. The specific importance of the hippocampal formation projections that just innervate the mammillary bodies has, however, never been tested. This study isolated these specific projections in the rat by selectively cutting the descending component of the postcommissural fornix. Two successive, cohorts of rats with these tract lesions were tested on working memory tasks in the water-maze, T-maze, and radial-arm maze. Disconnecting the descending postcommissural fornix had only a mild effect or sometimes no apparent effect on the performance of these spatial memory tasks, even though tracing experiments confirmed the loss of hippocampal formation-mammillary projections. One implication is that the spatial deficits found in rats following standard fornix lesions are only partly attributable to the loss of projections from the hippocampal formation to the mammillary bodies. Perhaps more surprising, the behavioral impact of cutting the descending postcommissural fornix in rats appeared appreciably less than the effect of either mammillary body or mammillothalamic tract lesions. The present experiments show that the mammillary bodies can still effectively support spatial memory in the absence of their dense subicular complex inputs, so revealing the importance of the other afferents for sustaining mammillary body function. This new evidence for independent functions shows that the mammillary bodies are more than just a hippocampal relay.

The postictal state: effects of age and underlying brain dysfunction.

There is relatively little information on the underlying parameters that affect clinical features of the postictal period. Age-related physiological changes, including alterations in cerebral blood flow and metabolism, neurotransmitter function, and responses of the brain to seizure activity may affect postictal clinical phenomena. Some conclusions can be drawn. Elderly adults and children, particularly in the presence of diffuse cerebral dysfunction, may have more prolonged postictal confusion. Postictal dysphasia strongly suggests a dominant hemisphere focus, more often temporal, and Todd's paralysis is always contralateral to the epileptogenic zone. Much additional information could be derived from the vast amount of video/EEG monitoring data available.

[Anterograde declarative memory and its models]. / La mémoire déclarative antérograde et ses modèles.

INTRODUCTION: Patient H.M.'s recent death provides the opportunity to highlight the importance of his contribution to a better understanding of the anterograde amnesic syndrome. The thorough study of this patient over five decades largely contributed to shape the unitary model of declarative memory. This model holds that declarative memory is a single system that cannot be fractionated into subcomponents. As a system, it depends mainly on medial temporal lobes structures. The objective of this review is to present the main characteristics of different modular models that have been proposed as alternatives to the unitary model. It is also an opportunity to present different patients, who, although less famous than H.M., helped make signification contribution to the field of memory. STATE OF THE ART: The characteristics of the five main modular models are presented, including the most recent one (the perceptual-mnemonic model). The differences as well as how these models converge are highlighted. PERSPECTIVES: Different possibilities that could help reconcile unitary and modular approaches are considered. CONCLUSION: Although modular models differ significantly in many aspects, all converge to the notion that memory for single items and semantic memory could be dissociated from memory for complex material and context-rich episodes. In addition, these models converge concerning the involvement of critical brain structures for these stages: Item and semantic memory, as well as familiarity, are thought to largely depend on anterior subhippocampal areas, while relational, context-rich memory and recollective experiences are thought to largely depend on the hippocampal formation.

Synaptic Correlates of Anterograde Amnesia and Intact Retrograde Memory in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Clinical evidence indicates that patients affected by Alzheimer's Disease (AD) fail to form new memories although their memories for old events are intact. This amnesic pattern depends on the selective vulnerability to AD-neurodegeneration of the hippocampus, the brain region that sustains the formation of new memories, while cortical regions that store remote memories are spared. OBJECTIVE: To identify the cellular mechanisms underlying impaired recent memories and intact remote memories in a mouse model of AD. METHODS: Glutamatergic synaptic currents were recorded by patch-clamp in acute hippocampal and anterior Cingulate Cortical (aCC) slices of AD-like Tg2576 mice and Wild-type (Wt) littermates subjected to the Contextual Fear Conditioning (CFC) task or in naïve conditions. RESULTS: We identified a deficit in the formation of recent memories, but not in the recall of remote ones, in Tg2576 mice. With electrophysiological recordings, we detected CFC-induced modifications of the AMPA/NMDA ratio in CA1 pyramidal cells of Wt, but not Tg2576, mice one day after training. CFC-induced changes in the AMPA/NMDA ratio were also detected in the aCC of both Wt and Tg2576 mice 8 days after training. CONCLUSION: Our data suggest that in the early AD stages synaptic plasticity of CA1 synapses, crucial to form new memories, is lost, while plasticity of aCC synapses is intact and contributes to the persistence of long-term memories.

Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies.

OBJECTIVE: To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs). METHODS: We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration. RESULTS: Median age was 30 years (range 2-63), 32/35 (91%) patients were female, and median follow-up was 68 months (range 7-232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia (n = 10) and behavioral disturbances (n = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment (n = 25), and apparition of behavioral disturbances (n = 4) or mood disorders (n = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient's daily life activities, and 28/35 (80%) still had active seizures. CONCLUSION: Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.

Dissociable roles for cortical and subcortical structures in memory retrieval and acquisition.

The relationship between anterograde and retrograde amnesia remains unclear. Previous data from both clinical neuropsychology and monkey lesion studies suggest that damage to discrete subcortical structures leads to a relatively greater degree of anterograde than retrograde amnesia, whereas damage to discrete regions of cortex leads to the opposite pattern of impairments. Nevertheless, damage to the medial diencephalon in humans is associated with both retrograde and anterograde amnesia. In the present study, we sought to reconcile this by assessing retention as well as subsequent relearning and new postoperative learning. Rhesus monkeys learned 300 unique scene discriminations preoperatively, and retention was assessed in a preoperative and postoperative one-trial retrieval test. Combined bilateral subcortical lesions to the magnocellular mediodorsal thalamus and fornix impaired postoperative retention of the preoperatively acquired information. In addition, subsequent relearning and new postoperative learning were also impaired. This contrasts with the effects of a discrete lesion to just one of these structures, after which retention is intact in both cases. Discrete bilateral ablations to the entorhinal cortex impaired retention but had no effect on new learning. Combined with previous work from our laboratory, these results support the hypothesis that subcortical damage has a relatively greater effect on new learning, and cortical damage has a relatively greater effect on retention. Furthermore, the results demonstrate that retrograde amnesia occurs as a result of subcortical damage only if it is widespread, leading to an extensive disruption of cortical functioning. Damage of this nature may account for dense amnesia.

Recall of remote episodic memories can appear deficient because of a gist-based retrieval orientation.

Determining whether patients with amnesia can succeed in remembering their distant past has pivotal implications for theories of memory storage. However, various factors influence recall. We speculated that some patients with anterograde amnesia adopt a gist-based retrieval orientation for memories from all time periods, thereby exaggerating remote recall deficits. We tested whether an experimentally induced gist-based retrieval orientation could indeed hinder remote recall. Healthy individuals described photographs of complex scenes (e.g., of a cluttered desk) either with many words or few words (detail- or gist-based manipulation, respectively). They subsequently recalled autobiographical events and produced less episodic information after engaging the gist-based compared to the detail-based orientation. These results demonstrate the ease with which a gist-based orientation can produce apparent recall impairments. Deficits in remote episodic recall, and in future-event imagining, must thus be interpreted in light of habitual tendencies toward gist-based retrieval that some amnesic patients may exhibit.