The essential circuit for both item and associative stimulus recognition in any given sensory modality consists of the relevant cortical sensory processing stream(s), the medial temporal periallocortex (i.e. parahippocampal, rhinal cortices), the ventromedial prefrontal cortex, and the medial dorsal nucleus of the thalamus. Associative recall, on the other hand, appears to be organized hierarchically;whereas context-free recall, familiaritybased recognition, or fact memory, seems to depend primarily on the above basic memory circuit, context-rich recall, recollection-based recognition, or event memory, seems to depend in addition on a higher-order circuit superimposed on the basic one and consisting of the hippocampus, mammillary body, and anterior thalamic nuclei. Several years ago we discovered that hypoxic ischemic events sustained within the first year of life may result in a form of amnesia. This 'developmental amnesia'(DA), characterized by markedly impaired episodic (or event) memory combined with relative preservation of both semantic (or fact) memory and familiarity-based recognition memory, and is associated with pathology that seems to be restricted to the hippocampus. Hypoxia/ischaemia is associated with a variety of congenital or perinatal cardiorespiratory disorders. Depending on the aetiology and severity of the hypoxic/ischaemic insult, a selective or a more widespread pattern of brain damage may occur. To investigate this proposal with a large population of children known to have been exposed to neonatal hypoxia/ischaemia, we examined patients from three cohorts and compared them with healthy controls using voxel-based morphometry. The three patient groups were diagnosed as neonates with (i) cardiorespiratory disease, (ii) cyanosis resulting from the Transposition of the Great Arteries, or (iii) extreme prematurity. None of the children had a history of known neurodevelopmental disorders or neurological impairments, and all attended mainstream schools. Neuropsychological assessment included measures of delayed memory. Compared to the controls, patients showed reduced gray matter density mainly in the hippocampus and the anterior thalamus. In a second analysis, we compared each of the three clinical groups separately to the control group and found that the cardiorespiratory group had tissue loss restricted to the regions reported above, but was more extensive in the other groups, especially in the children born prematurely. Analyses exploring the relation of areas of reduced density to the measures of delayed memory revealed a significant correlation with the bilateral hippocampal pathology only. The delayed memory deficit in DA patients appears to be a problem in the recollection of the source, i.e., the context in which the stimulus had been previously encountered. Although such observations raise the possibility that selective hippocampal injury impairs recollection, evidence for a correlative relationship between the severity of hippocampal injury and the severity of impairment in recollection has been missing. To address this we compared adolescent DA patients with varying degrees of memory impairment, and age-matched controls on a memory paradigm that was designed to assess both item recognition and source memory. Subjects were required to memorize word-scene pairs. At Test, old words (seen in the Study phase) and new words (experimentally novel) were presented. Participants were required to state whether the presented word was old or new (item recognition). If an old response was given, three scenes were presented on screen and the participant was required to choose the scene that was originally paired with the word in the Study phase (source memory). A correct response on this source memory task was assumed to require recollection of the scene-context. Although the patients achieved item recognition performance equivalent to that of their age-matched controls, they showed a marked deficit in source memory. Importantly, we observed a significant positive correlation between hippocampal volumes and source memory performance across DA patients. In contrast, there was no correlation between hippocampal volume and item recognition performance. These data show for the first time that the extent of hippocampal volume reduction in patients with early hypoxic injury correlates with source memory performance and provide further evidence that the hippocampus is critical for the ability to recollect episodic information. Previous studies have shown that increased theta amplitude associated with the hippocampus before stimulus presentation is associated with enhanced encoding. It has been speculated that this increase in theta amplitude could reflect the pre-activation of contextual information, facilitating encoding by enabling individual items to be associatively linked with specific contextual information. We tested this possibility by manipulating the context before the presentation of individual words during encoding using magnetoencephalography (MEG). The contexts were represented by line drawings of either a cat, a dog, or a mouse. At test, subjects were presented with a mixture of repeated (old) and novel (new) words. They first had to indicate via button press whether a word was old or new. If a word was considered old, they had to indicate which context the word had been associated with during encoding. We found that theta amplitude before word onset during encoding was enhanced when subjects correctly remembered the context, but not when subjects correctly recognized the word in the absence of context memory. Thus, the present results suggest that pre-stimulus theta oscillations support memory formation by linking a pre-established context with item information. There is a growing body of evidence in humans that supports the notion that recollection judgments are probabilistic in nature and items are only recognized if a threshold is exceeded, whereas familiarity judgments are based on a signal detection process, in that memory strength reflects a continuous scale with new and old items forming overlapping gaussian distributions. While a large body of evidence in humans supports the idea that recognition memory can be supported by both recollection and familiarity. It has so far been unknown whether monkeys rely on similar mnemonic processes to perform recognition memory tasks. Recently we completed a behavioral study of receiver operating characteristics (ROCs), which in recognition memory relate the proportion of correctly recognized repeated, or old, items to the proportion of incorrectly recognized novel distracters as a function of response bias. We trained monkeys on a visual running-recognition task with trial unique stimuli. We manipulated the monkeys bias to respond old or new by manipulating the relative amount of reward (juice) that was obtainable for correct old and new responses. ROCs were curvilinear, suggesting that a threshold process alone is not able to account for the data. Furthermore, the zROCs were significantly U-shaped, suggesting that a signal detection process alone cannot account for the data. Instead, a combination of a signal detection process and a threshold process can reliably characterize the empirical data. Thus, our results suggest that recognition memory in monkeys, as in humans, is supported by two processes. We are now in the process of assessing the relative contribution of the medial temporal lobe structures (e.g. hippocampus vs rhinal cortex) to the two processes important for recognition memory.

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Geva, Sharon; Cooper, Janine M; Gadian, David G et al. (2016) Impairment on a self-ordered working memory task in patients with early-acquired hippocampal atrophy. Dev Cogn Neurosci 20:12-22
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