Neural Mechanisms Of Stimulus Memory And Habit Formation

National Institute Of Mental Health

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Abstract

(1) The essential circuit for both item and associative stimulus recognition in any given sensory modality (or across modalities) consists of the relevant cortical sensory processing stream(s), the medial temporal periallocortex (i.e. parahippocampal, perirhinal, and entorhinal cortices), the ventromedial prefrontal cortex, and the magnocellular division of the medial dorsal nucleus of the thalamus. Associative recall, on the other hand, appears now to be organized hierarchically; thus, whereas context-free recall, or fact memory, also seems to depend primarily on the above basic memory circuit, context-rich recall, or event memory, seems to depend in addition on a higher-order circuit superimposed on the basic one and consisting of the hippocampus, mamillary body, anterior thalamic nuclei, and, possibly, cingulate cortex. That item recognition at least does not depend on the higher-order memory circuit is supported by evidence obtained in previous studies of children conducted at the Developmental Cognitive Neuroscience Unit (DCNU) in the Institute of Child Health/University College London. In these experiments we discovered that hypoxic ischemic events sustained within the first year of life can result in a form of amnesia that appears to differ from the global anterograde amnesia commonly reported in adult-onset cases. The early-onset form, which we labeled '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. In a follow-up study, we found the same selective disorder in children who had sustained hypoxia-induced pathology between the ages of 6 and 14, indicating that the effective age-at-injury for DA to result from hypoxic-ischemic episodes extends from birth to puberty. We have now examined two new cohorts of children, those who as neonates were treated with extra corporeal membrane oxygenation to treat cardiorespiratory disease or who underwent corrective surgery to repair a common form of congential heart disease. In both series of patients we found a graded memory impairment that was correlated to a volume reduction of the hippocampus. These children could be potential cases of DA. (2) We have also found that early hippocampal pathology leads to DA only when the volume of this structure is reduced below normal by 20 to 30% on each side, although milder memory deficits may be associated with smaller volume reductions. (3) More recently we tested the hypothesis that DA is associated with a disproportionate impairment in recall vis-a-vis recognition. DA patients tested on the Doors and People test, a task which affords a quantitative comparison between measures of the two memory processes. The DA patients showed a sharp, though not complete, recall-recognition dissociation, exhibiting impairment on both measures but with a far greater loss in recall than in recognition. Whether their relatively spared recognition ability is due to restriction of their medial temporal lobe damage to the hippocampus or whether it is due to their early age at injury is not certain. (4) In DA patients we have found that there is some success in learning novel facts, but compared with a control group intertrial retention was impaired during acquisition and, except for the most frequently repeated facts, DA patients are less accurate in correctly sourcing these facts to the experiment. These new results support our hypothesis that despite a severely compromised episodic memory and hippocampal system there is nevertheless the capacity to accrue semantic knowledge available to recall.[unreadable] (5) Associative recognition in monkeys also does not depend on the higher-order memory circuit (but does require the basic circuit) is supported by our evidence on spatial memory. Our results indicate that the ability to form object-place associations is unaffected by selective, excitotoxic damage to the hippocampus, and yet is severely impaired by ablation of the underlying parahippocampal tissue, revealing the first known mnemonic role for this area. (6) In a follow-up experiment, parahippocampal lesions made with ibotenic acid, which spared the underlying fibers of passage, still yielded a significant impairment in postoperative performance (71% correct compared with 82% correct preoperatively), but this impairment was significantly less than that following the original parahippocampal ablations (60% correct), despite the comparable extent of damage to the parahippocampal cortex in both studies. This result suggests that although the parahippocampal cortex contributes significantly to object-place associations, other areas of the medial temporal lobe, such as the perirhinal and entorhinal cortex, possibly deafferented by undercutting the white matter in parahippocampal-ablation group, might also contribute to that groups more severe impairment. (7) Ibotenic acid lesions of perirhinal cortex resulted in a significant impairment in post-operative performance (71% correct compared with 80% preoperatively) on the object-place task. This impairment was of the same magnitude as that following the ibotenic acid lesions of the parahippocampal cortex. In contrast, ibotenic acid lesions of the entorhinal cortex resulted in only a mild impairment which reached significance only in the first block of post-operative testing. Thus, multiple cortical areas of the parahippocampal gyrus appear to contribute to the object-place associations, presumably each of them to a different component of this complex task. [unreadable] (8) Studies performed earlier at the DCNU and Oxford University demonstrated that half the 30 members of the 3-generational KE family suffer from a speech and language disorder characterized by misarticulation associated with orofacial dyspraxia, which is due in turn to structural brain abnormalities caused by a mutation in the FOXP2 gene. To locate the functional brain abnormalities associated with this mutation, we used both overt and covert verb generation and word repetition during fMRI. The results indicated that whereas the unaffected family members showed the typical left-dominant pattern of activation involving Brocas area and the neostriatum, among other brain regions, the affected members showed an abnormal distribution of activation located more posteriorly and bilaterally, suggesting that the FOXP2 gene plays a critical role in the development of the frontostriatal system that normally mediates speech.