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.

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.

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.

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.

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.

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.

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.

Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?

Active (new and reactivated) memories are considered to be labile and sensitive to treatments disrupting the time-dependent consolidation/reconsolidation processes required for their stabilization. Active memories also allow the integration of new information for updating memories. Here, we investigate the possibility that, when active, the internal state provided by amnesic treatments is represented and integrated within the initial memory and that amnesia results from the absence of this state at testing. We showed in rats that the amnesia resulting from systemic, intracerebroventricular and intrahippocampal injections of the protein synthesis inhibitor cycloheximide, administered after inhibitory avoidance training or reactivation, can be reversed by a reminder, including re-administration of the same drug. Similar results were obtained with lithium chloride (LiCl), which does not affect protein synthesis, when delivered systemically after training or reactivation. However, LiCl can induce memory given that a conditioned taste aversion was obtained for a novel taste, presented just before conditioning or reactivation. These results indicate that memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation. The findings more likely support the integration hypothesis: posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval. This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory. SIGNIFICANCE STATEMENT: This study provides evidence challenging the traditional consolidation/reconsolidation hypotheses that have dominated the literature over the past 50 years. Based on amnesia studies, that hypothesis states that active (i.e., new and reactivated) memories are similarly labile and (re)established in a time-dependent manner within the brain through processes that require de novo protein synthesis. Our data show that new/reactivated memories can be formed without protein synthesis and that amnesia can be induced by drugs that do not affect protein synthesis. We propose that amnesia results from memory integration of the internal state produced by the drug that is subsequently necessary for retrieval of the memory. This interpretation gives a dynamic view of memory, rapidly stored and easily updated when active.

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.

Prefrontal microcircuit underlies contextual learning after hippocampal loss.

Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders.

Human amnesia and the medial temporal lobe illuminated by neuropsychological and neurohistological findings for patient E.P.

We present neurohistological information for a case of bilateral, symmetrical damage to the medial temporal lobe and well-documented memory impairment. E.P. developed profound memory impairment at age 70 y and then was studied for 14 y He had no capacity for learning facts and events and had retrograde amnesia covering several decades. He also had a modest impairment of semantic knowledge. Neurohistological analysis revealed bilaterally symmetrical lesions of the medial temporal lobe that eliminated the temporal pole, the amygdala, the entorhinal cortex, the hippocampus, the perirhinal cortex, and rostral parahippocampal cortex. The lesion also extended laterally to involve the fusiform gyrus substantially. Last, the superior, inferior, and middle temporal gyri were atrophic, and subjacent white matter was gliotic. Several considerations indicate that E.P.'s severe memory impairment was caused by his medial temporal lesions, whereas his impaired semantic knowledge was caused by lateral temporal damage. His lateral temporal damage also may have contributed to his extensive retrograde amnesia. The findings illuminate the anatomical relationship between memory, perception, and semantic knowledge.

Retrograde and anterograde memory following selective damage to the dorsolateral entorhinal cortex.

Anatomical and electrophysiological evidence suggest the dorsolateral entorhinal cortex (DLEC) is involved in processing spatial information, but there is currently no consensus on whether its functions are necessary for normal spatial learning and memory. The present study examined the effects of excitotoxic lesions of the DLEC on retrograde and anterograde memory on two tests of allocentric spatial learning: a hidden fixed-platform watermaze task, and a novelty-preference-based dry-maze test. Deficits were observed on both tests when training occurred prior to but not following n-methyl d-aspartate (NMDA) lesions of DLEC, suggesting retrograde memory impairment in the absence of anterograde impairments for the same information. The retrograde memory impairments were temporally-graded; rats that received DLEC lesions 1-3 days following training displayed deficits, while those that received lesions 7-10 days following training performed like a control group that received sham surgery. The deficits were not attenuated by co-infusion of tetrodotoxin, suggesting they are not due to disruption of neural processing in structures efferent to the DLEC, such as the hippocampus. The present findings provide evidence that the DLEC is involved in the consolidation of allocentric spatial information.

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.

Neither time nor number of context-shock pairings affect long-term dependence of memory on hippocampus.

There are still basic uncertainties concerning the role of the hippocampus (HPC) in maintaining long-term context memories. All experiments examining the effects of extensive HPC damage on context memory for a single learning episode find that damage soon after learning results in robust retrograde amnesia. Some experiments find that if the learning-to-damage interval is extended, remote context memories are spared. In contrast, other experiments fail to find spared remote context memory. One possible explanation for inconsistency might be the potency of the context memory conditioning procedure, as the experiments showing spared remote memory used a greater number of context-shock pairings, likely creating a stronger context fear memory. We designed an experiment to directly test the question: does increasing the number of context-shock pairings result in sparing of remote context memory after HPC damage? Six independent groups of rats received either 3 or 12 context-shock pairings during a single conditioning session and then either received extensive HPC damage or Control surgery at 1-week, 2-months, or 4-months after conditioning. 10 days after surgery rats were tested for memory of the shock context. Consistent with all relevant studies, HPC damage at the shortest training-surgery interval produced robust retrograde amnesia for both 3- and 12-shock groups whereas the Control rats expressed significantly high levels of memory. At the longer training-surgery interval, HPC damage produced similarly robust retrograde amnesia in the rats in both the 3- and 12-shock groups. These results clearly demonstrate that increasing the number of context-shock pairings within a single learning session does not change the dependence of the memory on the HPC. Current evidence from our group on retrograde amnesia has now shown that partial damage, dorsal vs. ventral damage, discrete cue+context conditioning, time after training, and number of context-shock pairings do not affect HPC dependence of context fear memories. When taken together, the evidence strongly supports a permanent role of the HPC in context memory.

Transient improvement in sensorimotor conversion during post-anoxic encephalopathy with bilateral medial temporal ischemia.

We report the case of a patient with sensorimotor conversion that improved transiently during post-anoxic medial temporal ischemia inducing anterograde and retrograde amnesia. Symptoms reappeared in parallel with mnesic recovery. This case raises a hypothesis concerning the role of hippocampi and amygdalae, which are involved in emotionally-associated memory. The amnesia may have modified the patient's "self," giving her a "distant" point of view. Another hypothesis is that cerebral anoxic stress may have "reset" the cerebral network that controls behavior. These findings give clues about the mechanisms of somatoform disorder and highlight the possibility of specific therapeutic strategies to induce cognitive reappraisal of emotionally-associated experiences.

Transient global amnesia associated with accidental high-frequency stimulation of the right hippocampus in deep brain stimulation for segmental dystonia.

We report on a 66-year-old woman with segmental dystonia treated with chronic bilateral deep brain stimulation of the globus pallidus internus, in whom accidental high-voltage, high-frequency stimulation induced an episode of transient global amnesia (TGA) via an electrode contact which was misplaced in the right hippocampus. A possible mechanism underlying this TGA episode may have been the inhibition of local neuronal activity or fiber activation by high current density via direct electrical stimulation of hippocampal structures. While a unifying etiology of TGA has not been proven so far, our case demonstrates a possible link between focal electrical stimulation of hippocampal structures and the full clinical picture of the syndrome.

Sensitivity of the RBANS to acute traumatic brain injury and length of post-traumatic amnesia.

OBJECTIVE: Although the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been shown to be a useful tool in evaluating the cognitive status of patients with dementia, stroke, schizophrenia and post-acute traumatic brain injury (TBI), no studies have examined its utility in an acute TBI setting. The current study investigates the RBANS' sensitivity to acute TBI, hypothesizing that the presence and severity of injury is predictive of worse RBANS performance. METHOD: Neuropsychological testing was conducted an average of 6.1 days after emergence from post-traumatic amnesia (PTA). RBANS results were evaluated based on a normative basis, pre-injury estimates, and brain injury severity. RESULTS: In this sample of acute TBI patients (n = 51), the mean index scores on the RBANS ranged from 1.59-2.36 SD below the mean of the standardization sample. Each WRAT-4 Reading sub-test score was above the corresponding RBANS Total Scale Index score (t(31) = 10.32, p < 0.001). Regression analyses revealed that Delayed Memory (ß = - 0.365, p < 0.007) and Total Score (ß = -0.297, p < 0.023) indices were significantly predicted by PTA length after controlling for age and education. CONCLUSIONS: The RBANS appears to be a useful tool in assessing the presence and severity of acute TBI.

Speech pathologists' current practice with cognitive-communication assessment during post-traumatic amnesia: a survey.

PRIMARY OBJECTIVE: To investigate speech pathologists' current practice with adults who are in post-traumatic amnesia (PTA). METHOD: Speech pathologists with experience of adults in PTA were invited to take part in an online survey through Australian professional email/internet-based interest groups. RESULTS: Forty-five speech pathologists responded to the online survey. The majority of respondents (78%) reported using informal, observational assessment methods commencing at initial contact with people in PTA or when patients' level of alertness allowed and initiating formal assessment on emergence from PTA. Seven respondents (19%) reported undertaking no assessment during PTA. Clinicians described using a range of techniques to monitor cognitive-communication during PTA, including static, dynamic, functional and impairment-based methods. CONCLUSIONS: The study confirmed that speech pathologists have a key role in the multidisciplinary team caring for the person in PTA, especially with family education and facilitating interactions with the rehabilitation team and family. Decision-making around timing and means of assessment of cognitive-communication during PTA appeared primarily reliant on speech pathologists' professional experience and the culture of their workplace. The findings support the need for further research into the nature of cognitive-communication disorder and resolution over this period.