Neuropsychological and neuropathological observations of a long-studied case of memory impairment.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairment in the formation of long-term, declarative memory (anterograde amnesia), together with temporally graded retrograde amnesia covering ∼5 y prior to the cardiac arrest. More remote memory for both facts and autobiographical events was intact. His neuropathology was extensive and involved the medial temporal lobe, the diencephalon, cerebral cortex, basal ganglia, and cerebellum. In the hippocampal formation, there was substantial cell loss in the CA1 and CA3 fields, the hilus of the dentate gyrus (with sparing of granule cells), and the entorhinal cortex. There was also cell loss in the CA2 field, but some remnants remained. The amygdala demonstrated substantial neuronal loss, particularly in its deep nuclei. In the thalamus, there was damage and atrophy of the anterior nuclear complex, the mediodorsal nucleus, and the pulvinar. There was also loss of cells in the medial and lateral mammillary nuclei in the hypothalamus. We suggest that the neuropathology resulted from two separate factors: the initial cardiac arrest (and respiratory distress) and the recurrent seizures that followed, which led to additional damage characteristic of temporal lobe epilepsy.

Has multiple trace theory been refuted?

Multiple trace theory (Nadel & Moscovitch, Current Opinion in Neurobiology, 1997, 7, 217-227) has proven to be one of the most novel and influential recent memory theories, and played an essential role in shifting perspective on systems-level memory consolidation. Here, we briefly review its impact and testable predictions and focus our discussion primarily on nonhuman animal experiments. Perhaps, the most often supported claim is that episodic memory tasks should exhibit comparable severity of retrograde amnesia (RA) for recent and remote memories after extensive damage to the hippocampus (HPC). By contrast, there appears to be little or no experimental support for other core predictions, such as temporally limited RA after extensive HPC damage in semantic memory tasks, temporally limited RA for episodic memories after partial HPC damage, or the existence of storage of multiple HPC traces with repeated reactivations. Despite these shortcomings, it continues to be a highly cited HPC memory theory.

Retrograde amnesia with transposition in the past: A neuropsychological and PET study of a case.

OBJECTIVE: Retrograde amnesia (RA) with a "transposition in the past" phenomenon has been rarely reported. Patients presenting disproportionate RA for all events over a defined period of time offer an opportunity to investigate the unclear relationship between autobiographical memory and the self, through the well-known self-memory system (SMS). METHOD: We report the case of a 31-year-old right-handed woman who presented to the emergency department of our tertiary care center with an ongoing episode of RA. After resolution of the episode, she had a second transient episode of RA. An extensive neuropsychological battery was performed to assess her autobiographical and nonautobiographical memory during and after the 2 episodes of RA. She also had an 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG PET) scan during the second RA episode. RESULTS: During the 2 RA episodes, results showed lacunar amnesia for autobiographical as well as nonautobiographical memories of the time period between the present and the past 15 years, with preserved anterograde memory. Moreover, her memories before this lost period were more accurate than those after the 2 RA episodes. During the 2 RA episodes, our patient experienced a "transposition in the past" phenomenon. Statistical analysis of the PET scan demonstrated a significant hypometabolism within the right hippocampus. CONCLUSION: The "transposition in the past" phenomenon illustrates the relationship between both episodic and autobiographical memories and the functioning of self, according to the SMS model. Moreover, this case suggests the involvement of the hippocampus in this phenomenon. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Hippocampal Damage Causes Retrograde Amnesia and Slower Acquisition of a Cue-Place Discrimination in a Concurrent Cue-Place Water Task in Rats.

Explanations of memory-guided navigation in rodents typically suggest that cue- and place-based navigations are independent aspects of behavior and neurobiology. The results of many experiments show that hippocampal damage causes both anterograde and retrograde amnesia (AA; RA) for place memory, but only RA for cue memory. In the present experiments, we used a concurrent cue-place water task (CWT) to study the effects of hippocampal damage before or after training on cue- and place-guided navigation, and how cue and place memory interact in damaged and control rats. We found that damaging the hippocampus before training caused a delay in the expression of cue-place navigation strategies relative to intact control animals; surprisingly, place navigation strategies emerged following pre-training hippocampal damage. With additional training, both control and damaged rats used local cues to navigate in the CWT. Damaged animals also show minor impairments in latency to navigate to the correct cue following a cue contingency reversal. By contrast to these anterograde effects, damage made after training causes RA for cue choice accuracy and latency to navigate to the correct cue. In addition, the extent of hippocampal damage predicted impairments in choice accuracy when lesions were made after training. These data extend previous work on the role of the hippocampus in cue and place memory-guided navigation, and show that the hippocampus plays an important role in both aspects of memory and navigation when present during the learning experience.

Parallel pathways of seizure generalization.

Generalized convulsive status epilepticus is a life-threatening emergency, because recurrent convulsions can cause death or injury. A common form of generalized convulsive status epilepticus is of focal onset. The neuronal circuits activated during seizure spread from the hippocampus, a frequent site of seizure origin, to the bilateral motor cortex, which mediates convulsive seizures, have not been delineated. Status epilepticus was initiated by electrical stimulation of the hippocampus. Neurons transiently activated during seizures were labelled with tdTomato and then imaged following brain slice clearing. Hippocampus was active throughout the episode of status epilepticus. Neuronal activation was observed in hippocampus parahippocampal structures: subiculum, entorhinal cortex and perirhinal cortex, septum, and olfactory system in the initial phase status epilepticus. The tdTomato-labelled neurons occupied larger volumes of the brain as seizures progressed and at the peak of status epilepticus, motor and somatosensory cortex, retrosplenial cortex, and insular cortex also contained tdTomato-labelled neurons. In addition, motor thalamic nuclei such as anterior and ventromedial, midline, reticular, and posterior thalamic nuclei were also activated. Furthermore, circuits proposed to be crucial for systems consolidation of memory: entorhinal cortex, retrosplenial cortex, cingulate gyrus, midline thalamic nuclei and prefrontal cortex were intensely active during periods of generalized tonic-clonic seizures. As the episode of status epilepticus waned, smaller volume of brain was activated. These studies suggested that seizure spread could have occurred via canonical thalamocortical pathway and many cortical structures involved in memory consolidation. These studies may help explain retrograde amnesia following seizures.

Retrosplenial cortex damage produces retrograde and anterograde context amnesia using strong fear conditioning procedures.

Contextual fear conditioning relies upon a network of cortical and subcortical structures, including the hippocampus and the retrosplenial cortex (RSC). However, the contribution of the hippocampus is parameter-dependent. For example, with "weak" training procedures, lesions of the hippocampus produce both retrograde and anterograde context amnesia. However, with "strong" training procedures (e.g., more trials and/or higher levels of footshock), lesions of the hippocampus produce retrograde context amnesia but not anterograde amnesia (Wiltgen et al., 2006). Likewise, prior studies have shown that with weak training, RSC lesions produce both retrograde and anterograde context amnesia (Keene & Bucci, 2008). The purpose of the current study was to examine the effects of RSC damage on contextual fear conditioning following strong training. In Experiment 1, lesions of the RSC resulted in both retrograde and anterograde context amnesia following strong training using the same unsignaled fear conditioning procedures described by Wiltgen et al. (2006). In Experiment 2, using a signaled fear conditioning procedure, we replicated these effects on context memory observing both retrograde and anterograde context amnesia. In contrast, there were no lesion effects on tone-fear memory. Thus, unlike lesions of the hippocampus, lesions of RSC produce both retrograde and anterograde context amnesia even when rats undergo strong fear conditioning. These findings suggest that the RSC has an essential role in contextual fear conditioning and that other systems or pathways are unable to compensate for the loss of RSC function.

Retrograde Autobiographical Memory From PTA Emergence to Six-Month Follow-Up in Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: The overwhelming focus of research on memory following traumatic brain injury (TBI) has been on anterograde amnesia, and very little attention has been paid to retrograde amnesia. There is evidence to suggest that retrograde autobiographical memory deficits exist after severe TBI, although there have been no prospective studies of autobiographical memory in a representative sample of moderate to severe cases recruited from hospital admissions. METHODS: The purpose of the present study was to report changes in autobiographical memory performance among a group of patients soon after emergence from posttraumatic amnesia (PTA) and at the 6-month follow-up compared with a healthy control (HC) group. The authors also examined associations with anterograde memory function and community integration to assist in understanding the functional impact of autobiographical memory deficits and potential underlying mechanisms. The Autobiographical Memory Interview and the Rey Auditory Verbal Learning Test were used as measures of retrograde and anterograde memory, respectively, and the Community Integration Questionnaire was used as a measure of functional outcome in the TBI group. RESULTS: The results demonstrated that both personal semantic and episodic autobiographical memory scores were impaired following emergence from PTA and at the 6-month follow-up. Only subtle differences emerged in change over time in different injury severity groups. Recent retrograde memory function was associated with anterograde memory performance, which supports some degree of overlap in underlying mechanisms. CONCLUSIONS: The findings suggest that autobiographical memory deficits are prevalent following moderate to severe TBI and warrant consideration in rehabilitation.

The Rhesus Monkey Hippocampus Critically Contributes to Scene Memory Retrieval, But Not New Learning.

Humans can recall a large number of memories years after the initial events. Patients with amnesia often have lesions to the hippocampus, but human lesions are imprecise, making it difficult to identify the anatomy underlying memory impairments. Rodent studies enable great precision in hippocampal manipulations, but not investigation of many interleaved memories. Thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. Furthermore, disagreement exists as to whether hippocampal inactivations lead to temporally graded or ungraded amnesia, which could be a consequence of differences between rodent and human studies. In the current study, rhesus monkeys of both sexes received either bilateral neurotoxic hippocampal lesions or remained unoperated controls and were tested on recognition and new learning of visual object-in-place scenes. Monkeys with hippocampal lesions were significantly impaired at remembering scenes that were encoded before the lesion. We did not observe any temporal gradient effect of the lesion on memory recognition, with recent and remote memories being equally affected by the lesion. Monkeys with hippocampal lesions showed no deficits in learning new scenes. Thus, the hippocampus, like other cortical regions, may be engaged in the acquisition and storage of new memories, but the role of the damaged hippocampus can be taken over by spared hippocampal tissue or extra-hippocampal regions following a lesion. These findings illustrate the utility of experimental paradigms for studying retrograde and anterograde amnesia that make use of the capacity of nonhuman primates to rapidly acquire many distinct visual memories.SIGNIFICANCE STATEMENT Recalling old memories, creating new memories, and the process by which memories transition from temporary to permanent storage all may rely on the hippocampus. Whether the hippocampus is necessary for encoding and retrieval of multiple related visual memories in primates is not known. Monkeys that learned many visual memory problems before precise lesions of the hippocampus were impaired at recalling those memories after hippocampal damage regardless of when the memories were formed, but could learn new memory problems at a normal rate. This suggests the hippocampus is normally vital for retrieval of complex visual memories regardless of their age, and also points to the importance of investigating mechanisms by which memories may be acquired in the presence of hippocampal damage.

Synapse-specific representation of the identity of overlapping memory engrams.

Memories are integrated into interconnected networks; nevertheless, each memory has its own identity. How the brain defines specific memory identity out of intermingled memories stored in a shared cell ensemble has remained elusive. We found that after complete retrograde amnesia of auditory fear conditioning in mice, optogenetic stimulation of the auditory inputs to the lateral amygdala failed to induce memory recall, implying that the memory engram no longer existed in that circuit. Complete amnesia of a given fear memory did not affect another linked fear memory encoded in the shared ensemble. Optogenetic potentiation or depotentiation of the plasticity at synapses specific to one memory affected the recall of only that memory. Thus, the sharing of engram cells underlies the linkage between memories, whereas synapse-specific plasticity guarantees the identity and storage of individual memories.

Cognitive, neurohistological and mortality outcomes following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion: The impact of diabetes and aging.

Chronic cerebral hypoperfusion (CCH) may be involved in the etiology of aging-related dementias, and several risk factors contribute to their development and/or aggravation. We previously reported on the development of the 4-VO/ICA model of CCH, and the impact of hypertension on the cognitive and histological outcomes of CCH. Here, we advanced those studies by investigating how 4-VO/ICA alone or in combination with diabetes affects survival, body weight and cognitive performance in both young and middle-aged rats. Subsequently, middle-aged rats were examined for the impact of diabetes on CCH-induced neurodegeneration, white matter damage, and glial cells response. Diabetes alone reduced body weight and increased mortality rate slightly in young rats; these effects were striking, however, in the older animals. After CCH alone, neither body weight nor mortality rate changed significantly in both age groups. However, when CCH was combined with diabetes, mortality rate increased significantly in both aged groups. Young rats were cognitively asymptomatic to CCH, but they became 'mildly' impaired after CCH combined with diabetes. In middle-aged rats, CCH severely impaired memory, which was significantly worsened by diabetes. Moreover, diabetes aggravated neurodegeneration in the hippocampus and white matter injury in the corpus callosum and it promoted glial activation in the hippocampus and white matter of CCH middle-aged rats. These data suggest that diabetes interacts synergistically with age and reduces the capacity of the brain to adequately respond to CCH and highlight the importance of associating risk factors in the preclinical investigation of age-related cerebrovascular diseases physiopathology and potential therapies.

Silent memory engrams as the basis for retrograde amnesia.

Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams "silent engrams" and the cells bearing them "silent engram cells." The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the full-fledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21-activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells.

Dissociative amnesia: Disproportionate retrograde amnesia, stressful experiences and neurological circumstances.

Dissociative amnesias have been reported in neurological episodes mild enough to not cause any visible lesions on morphological examination. Disproportionate retrograde amnesia with or without identity loss happens in the context of psychological trauma (known or not). In metabolic imaging studies, some authors have reported functional alterations, particularly in the bilateral hippocampus, right temporal regions and inferolateral prefrontal cortex, despite normal morphological imaging. To avoid the presumption of an organic, psychogenic or mixed origin for such changes, De Renzi et al. suggested the term 'functional amnesia' to describe the condition. Patients have sometimes recovered during events similar to those preceding the amnesia in either a spectacular fashion or never. Also, in some cases, distraction or sedation may trigger the start of recovery. During psychotherapy, one patient remembered seeing a car on fire when he was a boy, and his amnesia started when his house was on fire. This suggests control by the frontal cortex, with repression blocking amnesic traces in the new emotional and biological context.

Retrograde amnesia of contextual fear conditioning: Evidence for retrosplenial cortex involvement in configural processing.

It has been suggested that contextual fear conditioning can be supported by either an elemental system, where individual features of the environment are associated with shock, or a configural system, where environmental features are bound together and associated with shock. Although the retrosplenial cortex (RSC) is known to be involved in contextual fear conditioning, it is not clear whether it contributes to the elemental or configural system. To isolate the role of the RSC in contextual fear conditioning, the current experiments examined the influence of RSC lesions on the context preexposure facilitation effect, a procedure known to produce conditioning to a configural representation of context. In Experiment 1, rats that were preexposed to the conditioning context froze more compared to rats that were not, replicating the context preexposure facilitation effect. Although pretraining lesions of the RSC had no impact on the context preexposure facilitation effect (Experiment 2a), posttraining lesions attenuated the effect (Experiment 2b), suggesting that the RSC normally contributes to a configural context representation. Retrohippocampal contributions to contextual fear conditioning are discussed. (PsycINFO Database Record

Spatial memory impairment in Morris water maze after electroconvulsive seizures.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most efficient treatments for severe major depression, but some patients suffer from retrograde memory loss after treatment. Electroconvulsive seizures (ECS), an animal model of ECT, have repeatedly been shown to increase hippocampal neurogenesis, and multiple ECS treatments cause retrograde amnesia in hippocampus-dependent memory tasks. Since recent studies propose that addition of newborn hippocampal neurons might degrade existing memories, we investigated whether the memory impairment after multiple ECS treatments is a cumulative effect of repeated treatments, or if it is the result of a delayed effect after a single ECS. METHODS: We used the hippocampus-dependent memory task Morris water maze (MWM) to evaluate spatial memory. Rats were exposed to an 8-day training paradigm before receiving either a single ECS or sham treatment and tested in the MWM 24 h, 72 h, or 7 days after this treatment, or multiple (four) ECS or sham treatments and tested 7 days after the first treatment. RESULTS: A single ECS treatment was not sufficient to cause retrograde amnesia whereas multiple ECS treatments strongly disrupted spatial memory in the MWM. CONCLUSION: The retrograde amnesia after multiple ECS is a cumulative effect of repeated treatments rather than a delayed effect after a single ECS.

Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation.

BACKGROUND: Neuroplastin cell recognition molecules have been implicated in synaptic plasticity. Polymorphisms in the regulatory region of the human neuroplastin gene (NPTN) are correlated with cortical thickness and intellectual abilities in adolescents and in individuals with schizophrenia. METHODS: We characterized behavioral and functional changes in inducible conditional neuroplastin-deficient mice. RESULTS: We demonstrate that neuroplastins are required for associative learning in conditioning paradigms, e.g., two-way active avoidance and fear conditioning. Retrograde amnesia of learned associative memories is elicited by inducible neuron-specific ablation of Nptn gene expression in adult mice, which shows that neuroplastins are indispensable for the availability of previously acquired associative memories. Using single-photon emission computed tomography imaging in awake mice, we identified brain structures activated during memory recall. Constitutive neuroplastin deficiency or Nptn gene ablation in adult mice causes substantial electrophysiologic deficits such as reduced long-term potentiation. In addition, neuroplastin-deficient mice reveal profound physiologic and behavioral deficits, some of which are related to depression and schizophrenia, which illustrate neuroplastin's essential functions. CONCLUSIONS: Neuroplastins are essential for learning and memory. Retrograde amnesia after an associative learning task can be induced by ablation of the neuroplastin gene. The inducible neuroplastin-deficient mouse model provides a new and unique means to analyze the molecular and cellular mechanisms underlying retrograde amnesia and memory.

Reversible hippocampal lesions detected on magnetic resonance imaging in two cases of transient selective amnesia for simple machine operation.

We report two extremely rare cases involving the development of transient selective retrograde amnesia for simple machine operation lasting for several hours. A 61-year-old male taxi driver suddenly became unable to operate a taximeter, and a 66-year-old female janitor suddenly became unable to use a fax machine. They could precisely recount their episodes to others both during and after the attacks, and their memories during their attacks corresponded to the memory of the witness and the medical records of the doctor, respectively. Therefore, it appears that these individuals remained alert and did not develop anterograde amnesia during their attacks. On day 4, they underwent high-resolution magnetic resonance imaging (MRI), and diffusion-weighted MRI with 2-mm section thickness revealed small high-intensity signal lesions in the left hippocampal cornu ammonis area 1 (CA1) region. However, these lesions disappeared during the chronic phase. This is the first report describing lesions detected by MRI in patients with transient selective amnesia without anterograde amnesia. Reversible damage to the hippocampal CA1 region may cause transient selective amnesia by impairing the retrieval of relevant memories.

Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats.

Chronic cerebral hypoperfusion (CCH) is a common condition associated with the development and/or worsening of age-related dementia.We previously reported persistent memory loss and neurodegeneration after CCH in middle-aged rats. Statin-mediated neuroprotection has been reported after acute cerebral ischemia. Unknown, however, is whether statins can alleviate the outcome of CCH. The present study investigated whether atorvastatin attenuates the cognitive and neurohistological outcome of CCH. Rats (12­15 months old) were trained in a non-food-rewarded radial maze, and then subjected to CCH. Atorvastatin (10 mg/kg, p.o.) was administered for 42 days or 15 days, beginning 5 h after the first occlusion stage. Retrograde memory performance was assessed at 7, 14, 21, 28, and 35 days of CCH, and expressed by "latency," "number of reference memory errors" and "number of working memory errors." Neurodegeneration was then examined at the hippocampus and cerebral cortex. Compared to sham, CCH caused profound and persistent memory loss in the vehicle-treated groups, as indicated by increased latency (91.2% to 107.3%) and number of errors (123.5% to 2508.2%), effects from which the animals did not spontaneously recover across time. This CCH-induced retrograde amnesia was completely prevented by atorvastatin (latency: −4.3% to 3.3%; reference/working errors: −2.5% to 45.7%), regardless of the treatment duration. This effect was sustained during the entire behavioral testing period (5 weeks), even after discontinuing treatment. This robust and sustained memory-protective effect of atorvastatin occurred in the absence of neuronal rescue (39.58% to 56.45% cell loss). We suggest that atorvastatin may be promising for the treatment of cognitive sequelae associated with CCH.

Cholinergic deafferentation of the hippocampus causes non-temporally graded retrograde amnesia in an odor discrimination task.

Dementia of the Alzheimer's type (DAT) is a neurodegenerative disorder marked by loss of hippocampal cholinergic tone and significant memory impairments, specifically for memories acquired prior to disease onset. The nature of this relationship, however, remains debated. The current study used the string pulling task to evaluate the temporal effects of odor discrimination learning in animals with selective cholinergic lesions to determine the role of the septohippocampal cholinergic system in mnemonic function. Rats with 192-IgG-Saporin lesions to the medial septum had a higher number of correct responses in the reversal training when compared to sham rats, suggesting an inability to retrieve the previously learned discrimination; however, no temporal gradient was observed. Furthermore, there were no group differences when learning a novel odor discrimination, demonstrating the ability for all rats to form new memories. These results establish a role for the cholinergic medial septum projections in long-term memory retrieval. The current study provides a behavioral assessment technique to investigate factors that influence mnemonic deficits associated with rodent models of DAT.