Elsevier

Neuropsychologia

Volume 39, Issue 2, February 2001, Pages 151-172
Neuropsychologia

Long-term retrograde amnesia… the crucial role of the hippocampus

https://doi.org/10.1016/S0028-3932(00)00103-2Get rights and content

Abstract

For patients with hippocampal pathology, disagreement exists in the literature over whether retrograde amnesia is temporally limited or very extensive depending on whether the anatomical damage is restricted to this structure or also involves additional temporal cortex. We report a comprehensive assessment of retrograde and anterograde memory functions of a severely global amnesic patient (VC). We found that he presented with a remarkably extensive and basically ungraded retrograde amnesia. This impairment profoundly affected four decades preceding the onset of his amnesia and encompassed both non personal and personal facts and events. VC also presented with a severe anterograde amnesia and a deficit in the acquisition of new semantic knowledge in the post-morbid period. Detailed MRI volumetric measurements revealed gross abnormalities in both hippocampi which were markedly shrunken. Of relevance to the debate on retrograde amnesia were the observations that the volumes of both entorhinal cortices and the remainder of both temporal lobes were normal. These data suggest that the hippocampus is critical not only for the efficient encoding and hence normal recall of new information but also for the recall of episodic information acquired before the onset of amnesia. Our results are compatible with the view that retrograde amnesia is both extensive and ungraded when the damage is limited to the hippocampus.

Introduction

Organic amnesia caused by non-progressive brain damage is a selective impairment of memory that usually occurs in the absence of clear intellectual dysfunction and/or loss of general knowledge [43]. The memory impairment in amnesia is usually global, being both anterograde and retrograde [55]. Occasionally patients may present with severe anterograde amnesia (AA) but minimal retrograde amnesia (RA) [90], [91]. Even less commonly, patients may present with what Kapur [26] named ‘focal retrograde amnesia’, namely severe RA in the context of very mild or completely absent AA [16], [34], [73]. Both the anterograde and the retrograde memory impairments cover complex sets of phenomena whose extent, nature and anatomical bases are still relatively poorly understood. Thus, the precise relationship between RA, AA and additional ‘executive’ cognitive deficits remains unclear (see for discussion [58]). Also different, often contrasting, cognitive theories have been put forward to account for the pattern of retrograde and anterograde memory loss [8], [10], [11], [30], [57].

The present paper focuses on the controversial issue of the structures involved in RA. It is generally accepted that severe amnesic states are only observed in patients with bilateral damage [42]. However, there is considerable debate over the role played in amnesia by several critical structures within the medial temporal lobe (hippocampus, entorhinal, perirhinal and parahippocampal cortices) and the related diencephalic midline structures (mammillary bodies, anterior thalamic nuclei, medial dorsal thalamic nuclei, thalamic nucleus and mammillothalamic tract). We will be primarily concerned with the role of the hippocampus. The role of the hippocampus in memory has been a topic of much debate and speculation. Different theories have been put forward regarding its function and its interaction with the neocortex. Those theories suggesting that only a particular kind of memory is dependent on the hippocampus will not be considered here [19], [49], [50].

Central to most of the theories focusing on the role of the hippocampus in RA is the notion expressed by Ribot [54] more than 100 years ago that the loss of memories from the past could be temporally graded. This phenomenon has influenced a number of accounts which have accorded to the hippocampus a relatively extended but nevertheless time limited role in memory tasks. Marr [36] was among the first to propose that the hippocampus acts as a temporary memory store for the storage of new information whilst the neocortex acts as a permanent memory store. On this type of theory, the hippocampus is viewed as a ‘simple memory’ temporarily storing traces and playing them back to be consolidated in the neocortex for permanent storage possibly during dream sleep. The view that the hippocampus plays a role in memory consolidation and in providing extra learning opportunities for the neocortical permanent memory store is also present in the work of Squire and colleagues [65], [69], [70], [71], [72]. The authors proposed that over a somewhat vaguely specified period of time, contents are assumed to become gradually independent of the hippocampus and dependent on neocortical storage sites. This is due to the action of the memory consolidation process.

Recently, a number of neuronal network models have also been based on this view ([39], [40], [45], [76], [77]; see for a review [67]). For example, on the Treves and Rolls [76], [77] model there is detailed discussion of how the hippocampus might store information rapidly and have a crucial role in directing memory consolidation. In particular, in this model, when a partial cue is presented the hippocampus can reconstruct memory in the neocortex by activating neocortical sites. Across time and as a result of repeated reactivation, memories are fully established in the neocortex. Similar ideas are present in the model described by Murre [44], [45] and Alvarez and Squire [2]. Murre's TraceLink model stressed the importance of hippocampus as a temporary ‘scaffold’ for new memories, serving as an intermediate ‘link system’ of connections, before they are well established at a neocortical level, the ‘trace system’. In the Alvarez and Squire's neuronal network model of consolidation, information is first stored in a fast learning ‘medial temporal lobe area’ which then gradually strengthens slower-changing connections in a distributed ‘neocortical’ network. In the computational model proposed by McClelland and colleagues [40] it has also been suggested that recently experienced events are first stored through fast-changing synapses in the hippocampus in a ‘condensed’ form. This computational model offered a principled justification of why the consolidation process would require complementary learning systems in the hippocampus and neocortex. According to this view, rapid learning of new association would provoke fast changes in the cortical representations that would lead to so-called catastrophic interference. Thus, it is crucial to have a system that can learn rapidly independently of neocortex, but able to gradually modify it. So, on this model, repeated reinstatement of the hippocampal memory results in the accumulation of gradual and slow neocortical changes. This process allows the new memory to be integrated into existing neocortical networks. Remote memory is based on these accumulated neocortical changes.

All these theories would predict that if the pathology is restricted to the hippocampus, the RA should be temporally graded such that recent memory is more impaired than remote memory. The existence of an extensive and ungraded RA would only occur if the pathology also involves the neocortex and is not restricted to the hippocampus. Furthermore, if the damage is limited to the neocortex and the hippocampus is spared then the RA should primarily affect remote memories with recent memories being preserved. In support of this, several empirical studies have documented extensive and ungraded RA in patients whose pathology was NOT confined to the hippocampus but also extends to the neocortex [9], [14], [37], [78]. Furthermore, relative preservation of more recent memories has been found in patients with semantic dementia, a pathology that is thought to mainly involve the temporal neocortex and much less so the hippocampus [21].

Even more compelling evidence for the view that the hippocampus has an important but temporally limited role in memory comes from studies reporting that hippocampal amnesics show selective memory deficits only for material acquired shortly before their lesion. Retrieval of more remote memories appears to be relatively preserved (see for review [66], [67]). Among the best known examples, are four patients (RB, [92] and GD, WH and LM, [53]) who presented with RA limited to 1 or 2 years (RB and GD) or ∼15 years (WH and LM). Neurohistological data indicated that RB and GD had a bilateral lesion limited to the CA1 region of the hippocampus. WH and LM presented with a bilateral lesion involving all the cell fields of the hippocampus and the dentate gyrus. However, LM also had cell loss in layers II and III of the midportion of the entorhinal cortex. WH had more substantial cell loss in the entorhinal cortex.

Recently four new patients (LJ, AB, EP and GT) have been reported whose RA has been investigated extensively [52]. In two patients (LJ and AB), the RA was limited to the decade preceding the onset of amnesia whilst in the other two (EP and GT) the RA was severe and extensive. MRI examinations revealed that LJ presented with a roughly 36% bilateral volumetric reduction of the hippocampus. In contrast EP and GT presented with severe bilateral temporal damage involving the hippocampus. For AB the authors presumed a circumscribed hippocampal lesion on the basis of the aetiology of his amnesia, a cardiac arrest. Thus, according to the authors, this study provides further compelling support for the position that damage to the hippocampus produces only limited RA and that additional temporal cortical damage is needed to produce severe and extensive RA. Moreover, the authors refer specifically in their discussion to the two patients (WH and LH; see [53]) who presented with an extensive RA of 15 and 25 years, respectively, in whom the additional temporal damage was located in the entorhinal cortex.

However, there are also on record a few patients in whom it is unclear what role any impairment in temporal cortical areas is playing in their extensive and ungraded RA. One example is patient NT. This patient was first reported in 1964 as presenting a severe memory impairment following a right temporal lobectomy for the treatment of epilepsy [15]. Formal investigation of her remote memories indicated an extensive and ungraded RA [56]. The neuropathological investigation revealed an old sclerotic lesion of the left hippocampus. Examination of the previously removed right temporal lobe revealed no clear abnormalities [84]. Thus, it is tempting to conclude that the RA in this patient was a consequence of the bilateral damage to the hippocampus, given that the left temporal lobe was pathologically intact. Patient HJ with a Korsakoff's psychosis presented with a severe amnesia in the absence of any other focal cognitive impairment [33]. His retrograde amnesia was of very long duration and not temporally graded on formal testing. The only abnormalities present at the neuropathological investigation involved the mammillary bodies and the medial dorsal nucleus of the thalamus. All other regions, including the neocortex, were normal.

In the context of these findings it is useful to consider the patient described by Kartsounis et al. [29]. The MRI findings on this patient showed a circumscribed abnormal signal in the CA1 and CA2 fields. An initial neuropsychological investigation suggested a severe amnesic syndrome. In particular, the patient was described as having an extensive retrograde memory loss, although no formal documentation of the extent of the RA was reported This study, therefore provided some preliminary clinical evidence of severe RA due to damage limited to the hippocampus.

Thus, attempts to identify the role of the hippocampus on RA have produced conflicting and controversial results, which have led to extensive debate in the literature. For example, suggestions have been made that the patients reported above with extensive and ungraded RA without clear cortical involvement must have had cortical ‘hidden pathology’ (see for further discussion [1], [28], [52], [67]). One possible problem which is often mentioned is that the neuronal dysfunction caused by ischaemia may be more extensive than the region of gross pathology [3], [20]. In line with this position, a recent PET study [35] has been held to highlight the limitation of relying on MRI to uncover functional damage, especially in cases of anoxia (for example see [1]). It should, however, be noted that the patient described by Markowitsch and colleagues to demonstrate this point performed poorly on non-verbal tests of general intelligence and had an MRI scan indicating subcortical and cortical atrophy with widening of the ventricles.

The problems of hidden cortical pathology, for example, apply to Kartsounis et al.'s [29] patient. However, they apply equally to the hippocampal patient LJ described by Reed and Squire [52]. Reed and Squire [52] also described patient AB as an hippocampal patient. However, this was based on an highly speculative inference based on the aetiology. No neuroradiological or post-mortem evidence was available. It should also be noted that the argument for hypothetical but undetected cortical pathology is one which allows theorists to select findings as they please. For instance, Reed and Squire [52] in the same paper quote the Kartsounis et al.'s patient as supporting their position that the hippocampus is central for learning new factual knowledge but reject the evidence from him on the role of the hippocampus in retrograde amnesia. On the basis of an inadequate argument from his neurological history, they conclude ‘…it seems unlikely that his damage could be limited to the CA fields of the hippocampus…’.

In addition, concerns have been expressed about the patients presenting with temporally limited RA where remote memories are spared. Often in these cases the severity of the amnesia [89] and the methodology employed for testing remote memories [60] have been criticised. For instance, consider the two hippocampal patients (AB and LJ) with temporally limited RA recently reported by Reed and Squire [52]. For the only patient (LJ) who we can be relatively sure had circumscribed hippocampus damage, there is a serious question over the severity of the amnesia. This patient's WMS-R verbal score was only one standard deviation below her IQ, although her WMS-R visual score was two standard deviations below her IQ. More critically, her performance on recall tests of public events and famous faces was within the control range for all three time periods considered (1–10 years before amnesia; 11–20 years before amnesia; and 21–30 years before amnesia). Given these indications of only limited amnesia, the significance of her apparent temporal gradient in autobiographical memory is questionable.

Even more critically, the methodology used to test retrograde memory was inadequate. Tests were used in which the level of performance was equated across different retention intervals. However, it was shown mathematically by Shallice [60] that if one differentiates semantic from episodic memory processes, for which now there is strong neurological evidence, then this is methodologically inappropriate (see also [86]). One is comparing the retention of predominantly semantic, or personal semantic [9] information for longer time intervals with retention of predominantly episodic information over shorter time periods. No justification is provided by Reed and Squire [52] for the methodology used. It should be noted that a similar problem also applies to the investigation of the retrograde amnesia of patient RB reported by Zola-Morgan et al. [91].

An alternative methodology is not subject to this criticism. This involves matching information retained over different time intervals by how well it was initially laid down, rather than by how well it is remembered. This was the procedure adopted in the initial investigation of retrograde memory by Warrington and Sanders [87]. The authors carried out an internal test of their assumption. They confirmed that the material used in their tests was not part of the general knowledge (semantic memory) of anyone in the culture by showing that intelligent teenagers could only retrieve the most recent events.

In this Introduction we have concentrated on the controversial issue related to the role of the hippocampus in retrograde memory. It seems likely that for this issue, detailed investigations of a large number of individual case studies are needed in order to determine the critical anatomical structures. Without such studies we will be unable to identify the roles not only of the hippocampus but also of a number of structures in the medial temporal lobe and diencephalic midline which may be of potential relevance for the processes involved in retrograde memory. For this purpose two types of patients are important: (1) those who show surprising sparing in memory skills given the relevant anatomical structures damaged; (2) those who despite restricted lesions show severe deficits in retrograde memory tasks.

In this study we report a further examination of a patient of the second type, namely the profoundly amnesic patient (VC) previously described by Kartsounis et al. [29]. Detailed MRI volumetric examinations were undertaken and revealed the presence of very restricted and quantifiable areas of neuronal damage. Comprehensive assessment of his amnesia revealed a remarkably extensive and ungraded RA affecting both personal and non-personal memories. These results assist in the understanding of the anatomical structures which are necessary for effective storing and retrieval of the mnestic traces.

Section snippets

Case report

The patient (VC) is a 73-year-old (born 1926) retired chief engineer in large ships such as liners who was reported by his wife as having an excellent memory. In May 1992 he developed an apparent severe migraine attack which was followed by a seizure. He was found to have a tachyrhythmia when admitted to hospital and recovered. In September 1993 he had two further seizures four days apart with a tachyrhythmia requiring cardioversion. Following these episodes, at the age of 67, he was profoundly

MRI

T2-weighted images of the whole brain were obtained in the axial, coronal and sagittal planes (Signa 1.5 T MRI system, GE Milwaukee). Increased signal return was found throughout the length of both hippocampi (see Fig. 1). Formal measurement of the T2 relaxation time was in excess of 90 ms (greater than three standard deviations above normal) at all levels of both hippocampi. The hippocampi were atrophied and there was also abnormal signal return from the left amygdala. There was no evidence of

Results

Summary of the results are reported in Table 1.

Experimental investigation

In the following experimental investigation we investigated VC's memory functions further. We assessed systematically the severity and the temporal extent of VC's retrograde memory using four different tests: the dead or alive test, the famous public events questionnaire test, the famous faces test, and the famous people names familiarity test. The status of VC's autobiographical memory and semantic knowledge in both the anterograde and the retrograde domains was also explored.

For the novel

Discussion

The neuroanatomy of the different aspects of the amnesic syndrome is the subject of intense and extensive debate. In the Introduction we have argued that detailed analysis of neurological patients presenting with restricted lesions and severe memory impairments are of great theoretical interest. In this series of experiments we have reported our investigation of the profoundly globally amnesic patient VC, whose intellectual and cognitive skills were otherwise entirely satisfactory. In

Acknowledgements

We thank Dr Sally Barrington of the Clinical PET Unit of St. Thomas's Hospital for the PET images and helpful discussion. We are also grateful to Professor M.N. Rossor for his advice and support.

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