(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. (2) In a second follow-up study we found that early hippocampal pathology leads to DA only when the volume of this structure is reduced below normal by 20?30% on each side. (3) To measure incidental nonverbal recall in DA, we also studied deferred imitation of action sequences with objects. Like cases of adult-onset amnesia, DA patients performed normally in the spontaneous production of such sequences prior to watching them being modeled but, after seeing them modeled, recalled fewer target actions and action pairs than their matched controls after a 24-hour delay. However, the degree of impairment was less than that reported for the adult-onset cases. (4) We studied the ability of subjects with DA to acquire new information by reading texts, accompanied by listening to audiotapes of the same texts, with the aim of determining how much repetition they would require to learn the material and how well it would be retained over time. Whereas the control subjects recalled approximately 50, 70 and 80% of the information on learning trials 1-3, respectively, the subjects with DA recalled only 22, 28, and 32% on these three trials and reached a plateau of about 35% on the next three trials. Tested again both 30 min and one week later, all the subjects retained the level they had achieved initially. Despite their pronounced impairment due presumably to the absence of episodic recollection resulting from their extensive bilateral hippocampal damage, the patients with DA were able to acquire and retain in long-term memory a significant amount of new factual information. We also investigated factors that might boost episodic recall in subjects with DA. Recall was improved following a semantic study task compared with a non-semantic study task, as well as following four, repeated study trials as compared with only one. Recall in subjects with DA could also be improved after ?acting-out? compared with reading action phrases at study, but only if the phrases were well integrated semantically. Taken together the results provide suggests that episodic recall in DA subjects may depend on the extent to which these subjects are able to retrieve events using semantic memory.? (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. (6) 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 group?s 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. (8) Perirhinal cortex appears to be the critical cortical limbic substrate for visual recognition. More recently we found that monkeys with bilateral removals of the perirhinal cortex failed to relearn one-trial object-reward associations even after 1500 trials, suggesting that this type of memory may also be subserved by the rhinal cortex. ? (9) 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 [8]. The results indicated that whereas the unaffected family members showed the typical left-dominant pattern of activation involving Broca?s 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.
| de Haan, Michelle; Mishkin, Mortimer; Baldeweg, Torsten et al. (2006) Human memory development and its dysfunction after early hippocampal injury. Trends Neurosci 29:374-81 |
| Brandt, Karen R; Gardiner, John M; Vargha-Khadem, Faraneh et al. (2006) Using semantic memory to boost 'episodic' recall in a case of developmental amnesia. Neuroreport 17:1057-60 |
| Belcher, Annabelle M; Harrington, Rebecca A; Malkova, Ludise et al. (2006) Effects of hippocampal lesions on the monkey's ability to learn large sets of object-place associations. Hippocampus 16:361-7 |
| de Haan, Michelle; Wyatt, John S; Roth, Simon et al. (2006) Brain and cognitive-behavioural development after asphyxia at term birth. Dev Sci 9:350-8 |
| Saunders, Richard C; Mishkin, Mortimer; Aggleton, John P (2005) Projections from the entorhinal cortex, perirhinal cortex, presubiculum, and parasubiculum to the medial thalamus in macaque monkeys: identifying different pathways using disconnection techniques. Exp Brain Res 167:1-16 |
