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 rhinal cortex, the ventromedial prefrontal cortex, and the medial dorsal nucleus of the thalamus. Context-free recall, familiarity based recognition, or fact memory, seems to depend primarily on the above basic memory circuit. Associative 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) is 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 medial temporal pathology that seems to be restricted to the hippocampus. Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of DA patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our DA patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition. One of the features of both adult-onset and developmental forms of amnesia is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocampus and in macaque monkeys with neonatal hippocampal lesions. These studies suggest that successful performance on working memory tasks with high memory load require the contribution of the hippocampus. Here we compared performance on a working memory task (the Self-ordered Pointing Task), between patients with early onset hippocampal damage and a group of healthy controls. Consistent with the findings in the monkeys with neonatal lesions, we found that the patients were impaired on the task, but only on blocks of trials with intermediate memory load. Importantly, only intermediate to high memory load blocks yielded significant correlations between task performance and hippocampal volume. Additionally, we found no evidence of proactive interference in either group, and no evidence of an effect of time since injury on performance. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans or primates is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with moderate hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes. We also investigated the effect of hippocampal lesions on allocentric spatial navigational memory in monkeys using a similar virtual environment. The task, a variant of the Morris Water Maze, which has been used extensively to test navigational spatial memory in rodents, required monkeys to use a joystick to navigate to a rewarded location within a circular arena. This circular arena resided in a larger hexagonal room, with six unique images at the walls of the room providing cues for orientation. The orientation cues, as well as the rewarded location within the arena, were different on each testing day, thus providing a different allocentric spatial memory problem in each session. In each trial, monkeys started navigating from a random location within the circular arena. Performance was assessed as the ratio between the distance traveled and the optimal distance, given each trial's starting location (perfect performance thus being 1) Pre-operatively, monkeys were able to reach a performance asymptote of around 1.5 and reliably learned to locate the reward within 20-30 trials. To our surprise, neither learning rate nor ceiling performance was significantly reduced after bilateral lesions of the hippocampus. The results thus suggest that the integrity of the hippocampus in rhesus monkeys may not be critical for memory-based allocentric spatial navigation in this virtual reality environment.
| 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 |
| Patai, Eva Zita; Gadian, David G; Cooper, Janine M et al. (2015) Extent of hippocampal atrophy predicts degree of deficit in recall. Proc Natl Acad Sci U S A 112:12830-3 |
| Aggleton, John P; Wright, Nicholas F; Rosene, Douglas L et al. (2015) Complementary Patterns of Direct Amygdala and Hippocampal Projections to the Macaque Prefrontal Cortex. Cereb Cortex : |
| Guderian, Sebastian; Dzieciol, Anna M; Gadian, David G et al. (2015) Hippocampal Volume Reduction in Humans Predicts Impaired Allocentric Spatial Memory in Virtual-Reality Navigation. J Neurosci 35:14123-31 |
| Aggleton, John P; Saunders, Richard C; Wright, Nicholas F et al. (2014) The origin of projections from the posterior cingulate and retrosplenial cortices to the anterior, medial dorsal and laterodorsal thalamic nuclei of macaque monkeys. Eur J Neurosci 39:107-23 |
| Cooper, Janine M; Gadian, David G; Jentschke, Sebastian et al. (2013) Neonatal Hypoxia, Hippocampal Atrophy, and Memory Impairment: Evidence of a Causal Sequence. Cereb Cortex : |
| Kravitz, Dwight J; Saleem, Kadharbatcha S; Baker, Chris I et al. (2013) The ventral visual pathway: an expanded neural framework for the processing of object quality. Trends Cogn Sci 17:26-49 |
| Guderian, Sebastian; Brigham, Danielle; Mishkin, Mortimer (2011) Two processes support visual recognition memory in rhesus monkeys. Proc Natl Acad Sci U S A 108:19425-30 |
| Munoz, M; Chadwick, M; Perez-Hernandez, E et al. (2011) Novelty preference in patients with developmental amnesia. Hippocampus 21:1268-76 |
| Kravitz, Dwight J; Saleem, Kadharbatcha S; Baker, Chris I et al. (2011) A new neural framework for visuospatial processing. Nat Rev Neurosci 12:217-30 |
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